Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:28][C:29]1[CH:30]=[C:31]([C:35](=[O:40])[CH2:36][C:37](=O)[CH3:38])[CH:32]=[CH:33][CH:34]=1>>[CH3:38]/[C:37](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:36]/[C:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=1)=[O:40]
Reactant: CC(=O)CC(=O)c1cccc(C)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1cccc(C)c1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 48 mg (0.27 mmol) of Intermediate 21 to yield 104 mg of Example 46. 1H NMR (DMSO-d6, 400 MHz) δ11.47 (d, 1H, J=9.06), 7.95 (m. 2H), 7.65 (m, 2H), 7.54 (m, 3H), 7.31 (m, 2H), 7.19 (d, 2H, J=8.51), 6.88 (d, 2H, J=8.51), 5.64 (s, 1H), 4.23 (m, 1H), 4.23 (m, 3H), 3.21 (m, 1H), 2.96 (m, 2H), 2.86 (m, 1H), 2.60 (s, 3H), 1.80 (s, 3H); low resolution MS (ES) m/e 525.2 (MH+); RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 50-100% CH3CN in H2O) with 0.1% HCO2H buffer 30 minutes; 1 mL/min: tf15.57 min (to=1.43).
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]#[CH:23])[CH:15]=1.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N+:33]([O-])=[O:34])[CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:23]=[C:22]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[O:34][N:33]=1)[CH3:25]
Reactant: CCOC(=O)CCCCC[N+](=O)[O-]
Reactant: C#Cc1cc(Cl)ccc1OC
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCc1cc(-c2cc(Cl)ccc2OC)on1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
Add 1,4-phenylenediisocyanate (8.41 g, 52.5 mmol) to a stirred solution of 4-chloro-2-ethynyl-1-methoxy-benzene (4.0 g, 30.3 mmol) and 6-nitro-hexanoic acid ethyl ester (8.6 g, 45.4 mmol) in toluene (300 mL, anhydrous) and stir at room temperature under N2. Add triethylamine (7.3 mL, 52.5 mmol) and heat to reflux under N2 overnight. Filter mixture through a pad of Celite® and rinse with toluene. Concentrate to get 6.6 g of a orange oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-40% EtOAc/hexanes to afford the title compound (4.51 g, 76%). MS (IS) 338 (M+1)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([C:42]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:43])=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:50].O1CCOCC1>CO>[ClH:50].[ClH:50].[ClH:50].[N:44]1([C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:19]3[N:20]=[C:21]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]5[N:32]=[CH:33][CH:34]=[CH:35][C:23]=5[N:22]4[C:18]=3[C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)=[CH:37][CH:38]=2)=[O:43])[CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(C(=O)N5CCCC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccc(C(=O)N5CCCC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reaction time: 12 h

Procedure:
tert-Butyl[1-(4-{2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (12 mg, 0.018 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at r.t for 12 hours. The mixture was concentrated to afford the desired product (12 mg, quant) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.62 (s, 1H), 8.60 (br s, 2H), 8.11 (dd, J=4.6 Hz and 1.7 Hz, 1H), 7.97 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.53 (t, J=8.0 Hz, 4H), 7.45 (d, J=8.6 Hz, 2H), 7.39-7.34 (m, 3H), 7.30 (d, J=7.4 Hz, 1H), 7.13 (td, J=8.6 Hz and 1.1 Hz, 1H), 6.90 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.74 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.73-3.65 (m, 1H), 2.61-2.53 (m, 6H), 2.23-2.14 (m, 1H), 1.89-1.78 (m, 6H). LCMS: 553 [M+H].
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[CH3:11][C:12]1([CH3:29])[O:17][C:16](=[O:18])[C:15](=[C:19](SC)[NH:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:14](=[O:28])[O:13]1>ClCCl.CO>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][C:19]([NH:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[C:15]1[C:14](=[O:28])[O:13][C:12]([CH3:29])([CH3:11])[O:17][C:16]1=[O:18])[CH3:2]
Reactant: CSC(Nc1ccsc1)=C1C(=O)OC(C)(C)OC1=O
Reactant: CCOC(CCN)OCC
Solvent: ClCCl
Solvent: CO
Product: CCOC(CCNC(Nc1ccsc1)=C1C(=O)OC(C)(C)OC1=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3,3-Diethoxypropylamine (210.7 g, 1.43 mol) was added in portions to the solution of 2,2-dimethyl-5-(methylsulfanyl-thiophene-3-ylamino-methylene)-[1,3]dioxane-4,6-dione (407.3 g, 1.36 mol) in dichloromethane (1.7 L) and methanol (0.36 L) over 60 min, while the reaction temperature was kept under 25° C. with a water bath. After stirring for 1.5 h at room temperature, the reaction mixture was diluted with dichloromethane (0.8 L). The organic layer was separated and washed with aqueous ammonium chloride solution (400 mL, made of 200 mL of sat. NH4Cl and 200 mL of water), brine (300 mL) and dried over magnesium sulfate. Concentration of the reaction mixture under reduced pressure afforded a dark oil. Xylenes (500 ml) were added and the mixture concentrated under reduced pressure to give the intermediate 5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. The resultant dark oil was used directly in next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.65 (m, 6H), 1.73 (s, 6H), 1.78 (m, 2H), 2.98 (q, 2H, J=6.4 Hz), 3.45 (m, 2H), 3.60 (m, 2H), 4.50 (t, 1H, J=5.2 Hz), 6.98 (dd, 1H, J=1.6, 5.2 Hz), 7.05 (dd, 1H, J=1.2, 3.2 Hz), 7.33 (dd, 1H, J=3.2, 5.2 Hz), 10.2 (s, 1H), 11.3 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:32]=C[C:30](C#N)=[C:29](N)[CH:28]=2)[CH:21]([C:36]([O:38][CH3:39])=[O:37])[CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:40]1[CH:45]=[N:44][CH:43]=[N:42][CH:41]=1.CC(O)=O>CCO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:32]=[C:41]3[C:30]([C:45]([NH2:40])=[N:44][CH:43]=[N:42]3)=[CH:29][CH:28]=2)[CH:21]([C:36]([O:38][CH3:39])=[O:37])[CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(C#N)c(N)c1
Reactant: c1ncncn1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Yield: 24.9 %

Procedure:
A solution containing (±)-2-[4-(3-amino-4-cyano-benzyl)-3-methoxycarbonyl-5-oxo-piperazin-1-ylmethyl]-5-chloro-indole-1-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol), 1,3,5-triazine (146 mg, 1.81 mmol), and glacial HOAc (99 mg, 1.81 mmol) in absolute EtOH (10 mL) is maintained at reflux for 16 hours. A second portion of 1,3,5-triazine (146 mg, 1.81 mmol) and glacial HOAc (99 mg, 1.81 mmol) is added and the reaction mixture is maintained at reflux for an additional 16 hours. The reaction mixture is concentrated in vacuo and the crude product is diluted with water/CH3CN and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 26 mg (20%) of the title compound as a white solid which is used directly in the next reaction without further characterization.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.O=S(Cl)Cl.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)#[N:11]>C(Cl)Cl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:16][CH:17]=1)#[N:11]
Reactant: N#Cc1ccc(C(=O)CCc2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=CCc2ccc(F)cc2)n2ccnc2)cc1
Reaction time: 0.17 h

Procedure:
Imidazole (0.55 g, 8 mmol) is dissolved in dry tetrahydrofaran. The solution is cooled on icebath and SOCl2 (0.16 ml, 2 mmol) is added dropwise to the cooled solution. The mixture is stirred for 10 min. 1-(4-cyanophenyI)-3-(4-fluorophenyl)-1-propanone (0.34 g, 1.3 mmol) is added and the mixture is stirred in room temperature for 4 days. Methylene chloride is added and the mixture is washed with water. The organic layer is dried and the solvent is evaporated. The residue contains 35% of the product (1H NMR) as a 9:1 mixture of the isomers. The product is purified by flash chromatography (eluent CH2Cl2 -MeOH 99:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#CCCC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of methyl 5-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-4-pentynoate (243) (0.16 g, 0.38 mmol) in a mixture of EtOH (5 mL) and THF (5 mL) was added an aqueous solution of 1 N NaOH (6 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Concentration gave a white residue, which was triturated with hot hexanes containing 1% MeOH to yield the title compound (244) as white solid (0.15 g, 95%), mp 233-234° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.94 (s, 2H), 1.98 (s, 2H), 2.50-2.60 (m, 2H), 2.60-2.70 (m, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H). LCMS (ESI): m/z 417 (M+H)+, 415 (M−H)−.
Reaction SMILES: [C:1]([O:5][CH2:6]C)(=[O:4])[CH:2]=[CH2:3].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:21][CH2:3][CH:2]([C:1]([O:5][CH3:6])=[O:4])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=CC(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl acrylate (86 g, 1.0 mole) in dichloromethane (2 L) was cooled to 0° C. and treated with N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (D8) (300 g, 80% pure by 1H NMR, 1 mole) with stirring over a period of 10 min whilst maintaining the temperature between -5° C. and 0° C. A solution of trifluoroacetic acid in dichloromethane (100 ml, 1 molar) was added at such a rate that the temperature did not rise above 5° C. and the reaction allowed to warm to room temperature overnight. The solution was then washed with saturated aqueous potassium carbonate solution, dried over sodium sulphate and concentrated in vacuo to a gum. The gum was distilled in vacuo to afford the title compound (D16) as a single main fraction. Bpt 150°-160° at 8 mm (232 g, 100%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O-:32].[Na+].O>O1CCCC1>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cn1
Yield: 85 %

Procedure:
To 250 mg of 6-fluoro-4-(4-phenoxy-phenylamino)-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 266 mg (85%) of 6-(2-dimethylamino-ethoxy)-4-(4-phenoxy-phenylamino)-[1.7]naphthyridine-3-carbonitrile as a yellow solid: melting point 159-161° C.; mass spectrum (m/e): M+H 426.0
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][C:14]1[CH:15]=[C:16]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH2:13][C:14]3[CH:15]=[C:16]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CN(c1cccc(CN)c1)S(C)(=O)=O
Product: CN(c1cccc(CNc2cccn3nc(Cl)nc23)c1)S(C)(=O)=O

Procedure:
169 d) N-{3-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (184.0 mg, 0.7915 mmol) and N-(3-aminomethyl-phenyl)-N-methyl-methanesulfonamide (188.0 mg, 0.8773 mmol) in a manner analogous to Example 2d. Product isolated as a yellow resin (0.082 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.89 (d, J=6.7 Hz, 1H), 7.42-7.36 (m, 2H), 7.33-7.29 (m, 2H), 6.85 (t, J=7.4 Hz, 1H), 6.39 (d, J=7.8 Hz, 1H), 5.43-5.38 (m, 1H), 4.49 (d, J=5.7 Hz, 2H), 3.32 (s, 3H), 2.83 (s, 3H). MS=366, 368 (MH)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[NH:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1.CCN(CC)CC.[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>C(Cl)Cl>[CH2:29]([O:36][C:37]([N:14]1[C@H:13]([C:11](=[O:12])[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:20])([F:1])[F:21])[CH:5]=2)[CH2:17][CH2:16][C@@H:15]1[CH2:18][OH:19])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (797 mg, 2.62 mmol) (prepared as described in Scheme B3) in CH2Cl2 (10 mL) was added under nitrogen atmosphere Et3N (440 μl, 3.14 mmol) and benzylchloroformate (406 μl, 2.88 mmol) and the mixture was further stirred at RT overnight. CH2Cl2 and HCl 0.1N were added, the layers were separated and the aqueous one re-extracted with CH2Cl2. The crude organic extracts were washed with brine dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 1:1) to give the title compound. MS (LC-MS): 439 [M+H]+; tR (HPLC conditions b) 4.88 min.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH3:29])=[N:15][C:16]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=C([N+]([O-])=O)C=1Cl)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][N:2]=2)[C:16]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:15][C:14]=1[CH3:29])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1c(C)nc(N2CCCCC2)c([N+](=O)[O-])c1Cl
Reactant: CN1CCNCC1
Product: CCOC(=O)c1c(C)nc(N2CCCCC2)c2nccnc12

Procedure:
By substituting piperidine for N-methylpiperazine in Example 1 b and the resulting 4-chloro-2-methyl-6-(1-piperidinyl)-5-nitropyridine-3-carboxylic acid ethyl ester is processed according to the procedure in Example 1 c-e, 7-methyl-5-(1-piperidinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester is obtained, m.p. 73°-74° (petroleum ether).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[N:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[N:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-n3ccc(C(C)C)n3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 25 °C

Procedure:
A solution of the acid (146) (53 mg, 0.084 mmol), and carbonyldiimidazole (29.4 mg, 0.181 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (50.3 mg, 0.415 mmol) and DBU (34.1 mg, 0.224 mmol) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between AcOEt and diluted HCl, the organic layer was washed with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography (EtOAc/CH2Cl2, 2:8) provided the desired product which was subsequently dissolved in a minimum of ethanol and diluted with water. Filtration of the precipitate afforded the title compound (14.8 mg, 24%) as a white powder, m/z=734 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH:9]=[CH:8]2)=[O:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNC(=O)c1ccc2[nH]ccc2c1
Product: CNC(=O)c1ccc2c(ccn2-c2ccc([N+](=O)[O-])cc2)c1

Procedure:
The title compound can be synthesized from 1H-indole-5-carboxylic acid methylamide and 4-fluoronitrobenzene in the same manner as in Step A of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:74]([NH2:78])[CH:75]([CH3:77])[CH3:76]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:78][CH2:74][CH:75]([CH3:77])[CH3:76])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CC(C)CN
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCC(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and isobutylamine (8.28 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.4 mg, 53%). LC-MS m/z 629 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CN1CCCC1=O.O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)nccc12
Temperature: 110 °C
Yield: 75 %

Procedure:
To a solution of 1-chloro-5-nitroisoquinoline (1.0 g, 4.8 mmol) in N-methylpyrrolidinone (2 mL) was added 3-(trifluoromethyl)aniline (917 mg, 5.7 mmol). The reaction mass was heated at 110° C. for 2 h. The reaction mass was diluted with water and was extracted with chloroform. The organic layer was dried, filtered, concentrated and purified by column chromatography to afford 1.2 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, J=7.8 Hz, 1H), 8.33-8.29 (m, 2H), 7.96-7.89 (m, 3H), 7.68 (t, J=8.1 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.26 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:10](/[O-:18])=[CH:11]/P(OC)(OC)=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li+].O=[C:21]1[CH2:24][CH:23]([C:25]#[N:26])[CH2:22]1>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH:11]=[C:21]2[CH2:24][CH:23]([C:25]#[N:26])[CH2:22]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1/C([O-])=C/P(=O)(OC)OC
Reactant: N#CC1CC(=O)C1
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(Br)cc1C(=O)C=C1CC(C#N)C1
Temperature: 120 °C

Procedure:
A mixture of lithium (Z)-1-(5-bromo-2-methoxypyridin-3-yl)-2-(dimethoxyphosphoryl)ethenolate (2.0 g, 5.8 mmol) and 3-oxocyclobutanecarbonitrile (1.1 g, 12 mmol) in p-dioxane (6 ml) was heated at 120° C. by Microwave in 1 h. The mixture was cooled, taken up in H2O, extracted with EtOAc (3×), dried over MgSO4, concentrated to provide the title compound. MS (m+1): 307.0.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.[CH3:27][NH:28]CC1C=CC=CC=1.COC1C=CC(C2NC(C(N)=O)=C(C3C=CC(OC)=CC=3)N=2)=CC=1>CO.[Pd]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:28][CH3:27])=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: CNCc1ccccc1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Agent: [Pd]
Agent: COc1ccc(-c2nc(-c3ccc(OC)cc3)c(C(N)=O)[nH]2)cc1
Solvent: CO
Product: CNCCOc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1

Procedure:
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide with N-methylbenzylamine, according to the procedure described in example S-1, step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 60° C., 0.05M in MeOH). 1H NMR (DMSO) δ 2.35 (3H, s), 2.87 (2H, t), 4.10 (2H, t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.55 min; m/z (ES+) 374.