Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[O:32])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClCCl.CO>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[O:32])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(C(=O)Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)Cn2nc(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c3cc(OC(F)F)ccc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66559.5 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (41.7 mg, 62.2 μmol) in dichloromethane (3 mL) under Ar trifluoroacetic acid (208 mg, 0.140 mL, 1.83 mmol) was added at 25° C. After 18 h, the reaction was concentrated in vacuo to give a yellow residue. The residue was dissolved in a mix of dichloromethane/methanol/NH3OH (3:2:0.25, 5.25 mL) and stirred at 25° C. After 2.5 h, the material was concentrated and dried in vacuo (200 mTorr, 40° C.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22.4 mg, 41.4 mmol, 67%) as a yellow solid. MS (M)'=541; 1H NMR (DMSO-d6) δ: 12.84 (d, J=2.8 Hz, 1H), 9.02 (s, 1H), 8.41 (d, J=3.0 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J=9.3 Hz, 1H), 7.41 (dd, J=2.3, 9.0 Hz, 1H), 7.21 (t, J=74.5 Hz, 1H), 5.71 (br. s, 2H), 3.82 (br. s, 2H), 3.50 (br. s, 2H), 2.74 (br. s, 2H), 2.67 (br. s, 2H), 2.33 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2)(=[O:26])=[O:25]>>[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]1)(=[O:26])=[O:25]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCC(O)CC1)CCCC2
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCC(O)CC1)CCCC3)C(=O)N2

Procedure:
3-[3-(4-Hydroxy-piperidin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (58 mg, 0.2 mmol) was condensed with 5-methylaminosulfonyloxindole (45 mg, 0.2 mmol) following the procedure used in Example 1 to provide (66 mg, 67%yield) of the desired compound.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C@H:8]1[O:13][C@H:12]([CH2:14]I)[CH2:11][C@H:9]1[OH:10])([CH3:4])[CH3:3].[N-:28]=[N+:29]=[N-:30].[Li+]>CN(C)C=O.O>[N:28]([CH2:14][C@H:12]1[O:13][C@H:8]([CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:9]([OH:10])[CH2:11]1)=[N+:29]=[N-:30]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CI)C[C@H]1O)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution, under argon, of 5.0 g of product from Example 275 in 10 ml of dry N,N-dimethylformamide is treated with 0.986 g of lithium azide. The mixture is stirred at 80° C. for 1 hour followed by room temperature for 18 hours. The reaction is diluted with water, extracted with diethyl ether, concentrated in vacuo, purified by chromatography (silica gel: 5-50% ethyl acetate/hexane) to give 4.0 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][C@H:45]([CH2:50][C:51]#[CH:52])[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])[CH3:39].C(NC(C)C)(C)C>C(N(CC)CC)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([CH3:17])[C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([C:52]#[C:51][CH2:50][C@@H:45]([NH:44][C:42]([O:41][C:38]([CH3:40])([CH3:39])[CH3:37])=[O:43])[C:46]([O:48][CH3:49])=[O:47])=[N:20][CH:19]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)[C@@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Yield: 168.5 %

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO2005/002577, 1.05 g, 1.97 mmol), methyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 11, 1.343 g, 5.91 mmol), Pd(PPh3)2Cl2 (69 mg, 0.098 mmol), copper(I) iodide (19 mg, 0.100 mmol) and triphenylphoshine (52 mg, 0.198 mmol) in triethylamine (2 ml)/diisopropylamine (8 ml) was heated at 100° C. under microwave irradiation for 30 min. This reaction was carried out three times always using the amounts of reagents reported above. The reaction mixtures were combined and evaporated to dryness. The final reaction crude was taken-up in water (50 ml) and extracted with DCM (3×50 ml). The organic phases were collected, dried over sodium sulphate and concentrated. Purification on Si (SP1, 65M column) with Cyclohexane/EtOAc [from Cyclohexane 100 to Cyclohexane/EtOAc 70/30 in 4CV and then Cyclohexane/EtOAc 70/30] elution afforded the title compound (2.4 g, 3.32 mmol, 56.1% yield) as a yellow-brown solid. UPLC: Rt 1.02 min, m/z 724 [M+H+]. Chiral analysis, chromatographic conditions: [Column Chiralpak AD-H (25×0.46 cm); mobile phase: n-hexane/Ethanol 70/30% v/v; Flow rate 0.8 ml/min; DAD 210-340 nm, CD 250] Rt 13.43 min, 99.2% e.e.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:8]1[CH:3]([N:2]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:5][CH:6]([OH:9])[CH2:7]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
trans-4-Aminocyclohexanol hydrochloride (25 g, 217 mmol) was suspended in acetonitrile (500 mL). Benzyl bromide (54.2 mL, 456 mmol) and potassium carbonate (120 g, 868 mmol) were added to the suspension and the resulting mixture was stirred vigorously overnight at room temperature. The reaction mixture was filtered through a plug of celite and the plug was washed thoroughly with acetonitrile. The filtrate was condensed to give a white solid. The crude solids were purified by silica gel chromatography (0-60% ethyl acetate in hexanes). Pure product containing fractions were combined and concentrated to afford (1r,4r)-4-(dibenzylamino)cyclohexanol (25 g, 85 mmol, 39.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.26-7.36 (m, 8H), 7.16-7.22 (m, 2H), 4.43 (d, J=4.69 Hz, 1H), 3.55 (s, 4H), 3.27-3.33 (m, 1H), 2.28-2.40 (m, 1H), 1.69-1.88 (m, 4H), 1.40 (qd, J=12.56, 2.93 Hz, 2H), 0.89-1.05 (m, 2H); MS (ESI) m/z 296.3 [M+1]+.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10]CC)=[NH:5])#[N:2].C(N[CH2:16][CH3:17])C.[SH2:18]>CO>[CH3:16][CH2:17][CH:7]([NH:6][C:4]([NH:3][C:1]([NH2:2])=[S:18])=[NH:5])[CH2:8][CH2:9][CH3:10]
Reactant: S
Reactant: CCNCC
Reactant: CCCCCCNC(=N)NC#N
Solvent: CO
Product: CCCC(CC)NC(=N)NC(N)=S
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Gaseous hydrogen sulfide was bubbled through a mixture of 4.5 g. (0.027 mole) of 1-cyano-3-n-hexylguanidine, 75 ml. of methanol and 0.5 ml. of diethylamine for 6 hours, with stirring. Stirring was continued for 16 hours and then the mixture was heated to reflux temperature and hydrogen sulfide was again bubbled through the mixture. The resulting mixture was heated under reflux for an additional 16 hours, and then it was cooled to room temperature and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with 1:9 methanol-chloroform to give 4.4 g. of the title compound as a solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[N:22]1[CH:27]=[CH:26][C:25]([S:28]([C:31]2[S:35][C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:33][CH:32]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:39]2[CH2:38][CH2:37][N:36]([C:34]3[S:35][C:31]([S:28]([C:25]4[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=4)(=[O:29])=[O:30])=[CH:32][N:33]=3)[CH2:41][CH2:40]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: O=S(=O)(c1ccncc1)c1cnc(N2CCNCC2)s1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccncc3)s2)CC1)C(F)(F)F
Yield: 32 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 52(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light yellow crystalline solid (yield 32%). MS (m/e): 551.2 (M+H+, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:15][CH3:16])=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:15]([C:7]1[C:6]([CH2:4][OH:3])=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1)[CH3:16]
Reactant: CCOC(=O)c1c(CC)nn2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn2ccccc2c1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
A solution of 2-ethyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (15 g, 68.7 mmol) in tetrahydrofuran (300 mL) was cooled in an ice bath and lithium aluminum hydride (2.6 g, 68.7 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Water was added until bubbling stopped. Silica gel was added and the solvent was evaporated in vacuo. The resulting residue was purified via silica chromatography (20-100% ethyl acetate/heptane) to yield the title compound as a yellow/brown oil (9.67 g, 80% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1)[CH3:2].C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.[Br:29]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[Br:29][C:13]1[C:14]([OH:16])=[N:15][C:10]([S:9][CH2:8][C:7]2[S:6][CH:5]=[N:4][C:3]=2[CH2:1][CH3:2])=[N:11][C:12]=1[C:17]([F:20])([F:19])[F:18]
Reactant: BrBr
Reactant: CCc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCc1ncsc1CSc1nc(O)c(Br)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
To a solution of 2-{[(4-ethyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (500 mg, 1.56 mmol) in a mixture of 2:1 CCl4-DCM (40 mL) was dropwise added bromine (80 μL, 1.56 mmol) at 0° C. After 1 hour of stirring at room temperature, water and a solution of sodium thiosulfate were added. The mixture was extracted with DCM (3 times). The combined organic phases were washed with brine, dried over magnesium sulfate, and evaporated to afford a crude oil. The residue was dissolved in DCM and purified on silica gel using DCM/MeOH (0 to 15%) to provide 5-bromo-2-{[(4-ethyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol as a white solid (72 mg, 12% yield). 1H NMR (500 MHz, DMSO-d6): δ 1.17 (t, J=7.4 Hz, 3H), 2.75 (q, J=7.4 Hz, 2H), 4.64 (s, 2H), 8.87 (s, 1H). LRMS (ES′) m/z 402 (50%, M+2), 400 (50%, M).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.CCN(CC)CC.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH3:37][C:38]1([CH3:66])[CH2:43][CH2:42][C:41]([C:44]2[N:49]=[C:48]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH:47]=[CH:46][C:45]=2[NH:56][C:57]([C:59]2[NH:60][CH:61]=[C:62]([C:64]#[N:65])[N:63]=2)=[O:58])=[CH:40][CH2:39]1>C(Cl)Cl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([N:53]1[CH2:54][CH2:55][CH:50]([C:48]2[CH:47]=[CH:46][C:45]([NH:56][C:57]([C:59]3[NH:60][CH:61]=[C:62]([C:64]#[N:65])[N:63]=3)=[O:58])=[C:44]([C:41]3[CH2:42][CH2:43][C:38]([CH3:66])([CH3:37])[CH2:39][CH:40]=3)[N:49]=2)[CH2:51][CH2:52]1)=[O:5]
Reactant: CC1(C)CC=C(c2nc(C3CCNCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CN(C)CC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)n2)CC1
Yield: 42.8 %

Procedure:
A suspension of 20.9 mg (0.203 mmol) N,N-dimethylglycine in 4 mL CH2Cl2 was treated with 49.8 mg (0.197 mmol) bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) and 75 μL (0.54 mmol) Et3N at room temperature for 1 h. The mixture was then treated with 70.0 mg (0.135 mmol) 4-cyano-1H-imidazole-2-carboxylic acid [6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide trifluoroacetate (as prepared in Example 54, step(f)) at room temperature for 18 h. The mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min to afford 34.9 mg (53%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.38 (d, 1H, J=8.4 Hz), 8.05 (s, 1H), 7.33 (d, 1H, J=8.4 Hz), 6.05-5.98 (m, 1H), 4.68 (d, 1H, J=15.2 Hz), 3.82 (d, 1H, J=15.2 Hz), 3.16-3.05 (m, 1H), 3.01-2.94 (m, 6H), 2.52-2.40 (m, 2H), 2.39 (s, 6H), 2.17-2.10 (m, 2H), 2.09-1.87 (m, 2H), 1.67-1.59 (m, 2H), 1.12 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H35N7O2, 490.3 (M+H). found 490.4.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.O.O.Cl[Sn]Cl>Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Cc1ccc2cc(N)ccc2n1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2-methyl-6-nitroquinoline (12 g, 63.84 mmol) in HCl (1N, 450 mL) was added a solution of SnCl2.2H2O (72 g, 0.32 mol) in HCl (1N, 150 mL) slowly. The reaction mixture was heated to reflux for 15 min, then cooled to room temperature. The precipitate was filtered. The filtrate was basified by aqueous KOH and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to give 6.9 g of 2-methylquinolin-6-amine (68.3%). MS[M++1]=159, LC-MS: tR=0.255 min.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH:24]([C:27]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:31]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[C:30]([CH2:45][OH:46])=[C:29]([CH:47]([CH3:49])[CH3:48])[N:28]=1)([CH3:26])[CH3:25]>ClCCl>[CH:24]([C:27]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:31]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[C:30]([CH2:45][O:46][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[C:29]([CH:47]([CH3:48])[CH3:49])[N:28]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COC2CCCCO2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
1.88 g (22.4 mmol) of dihydropyran and 0.525 g (1.49 mmol) of pyridinium p-toluene-sulphonate are added to a solution of 5.36 g (14.9 mmol) of the compound from Example 4 in 100 ml of dry dichloromethane and the mixture is heated to reflux for 48 hours. After cooling to room temperature, the mixture is diluted using dichloromethane and extracted several times using water. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using dichloromethane).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([F:28])[C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9])=C>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([F:28])[C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9]
Reactant: C=COCCONC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Solvent: CO
Product: O=C(NOCCO)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Yield: 47.6 %

Procedure:
A solution of 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (200 mg, 0.39 mmol) in methanol (1 mL) was loaded onto an SCX-2 column. The column was washed with methanol (10 mL) then the product was then eluted with ammonia in methanol (20 mL, 2M), the appropriate fractions were concentrated in vacuo. The resultant residue was subjected to reverse phase preperative HPLC (10-90% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The aqueous fraction was extracted twice with ethyl acetate (2×10 mL) and the combined organics were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid (88 mg, 39%). LCMS (Method A): RT=7.71 min, [M+H]+=475. 1H NMR (DMSO-d6): 8.20 (1 H, s), 7.60 (1 H, s), 7.57 (1 H, dd, J=10.73, 1.96 Hz), 7.26 (1 H, dd, J=8.43, 1.82 Hz), 6.82 (1 H, d, J=11.14 Hz), 6.30 (1 H, t, J=8.71 Hz), 3.65 (2 H, t, J=4.77 Hz), 3.45 (2 H, t, J=4.68 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[C:15]3[C:16](=[O:30])[N:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[N:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:14]=3[NH:13][N:12]=2)=[CH:5][CH:4]=1)#N.S(=O)(=O)(O)[OH:32].[OH2:36]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[C:15]3[C:16](=[O:30])[N:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[N:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:14]=3[NH:13][N:12]=2)=[CH:7][CH:8]=1)([OH:32])=[O:36]
Reactant: N#Cc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Reactant: O=S(=O)(O)O
Reactant: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1

Procedure:
To a solution of 3-[2-(4-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (100 mg, 0.26 mmol, prepared in Example 12) in DMSO (2 ml) was added 50% sulfuric acid (2 ml) and the mixture was heated under reflux for 2 hours. To the resultant reaction mixture was added water, and precipitates were filtered off, and dried to give 3-[2-(4-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (107 mg, quantitative yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]#[N:9].[CH2:10]=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[O:15]1[CH2:16][CH2:17][N:12]([CH2:10][CH:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]#[N:9])[CH2:13][CH2:14]1
Reactant: C=O
Reactant: N#CCc1ncccn1
Reactant: C1COCCN1
Solvent: CO
Product: N#CC(CN1CCOCC1)c1ncccn1

Procedure:
The above prepared 2-(2-pyrimidyl)acetonitrile is reacted with formaldehyde and morpholine in methanol to give 3-morpholino-2-(2-pyrimidyl)propionitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]>>[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]3[NH:30][C:11]([C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=5)[NH:7][N:6]=4)=[N:31][C:26]=3[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(N)c2)ccn1
Reactant: O=Cc1n[nH]c2ccc(F)cc12
Product: CNC(=O)c1cc(Oc2ccc3[nH]c(-c4n[nH]c5ccc(F)cc45)nc3c2)ccn1

Procedure:
The title compound was synthesized from 5-fluoro-1H-indazole-3-carbaldehyde and 4-(3,4-diamino-phenoxy)-pyridine-2-carboxylic acid methylamide using the method described above in Example 4. LC/MS (m/z) 403.1 (MH+), Rt 2.26 minutes.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=O)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:19]([F:30])[CH:18]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH:10]([NH:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([F:30])[CH:18]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1F
Reactant: CC(=O)Nc1cc2c(cc1Br)C(=O)CC2
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CC(=O)Nc1cc2c(cc1Br)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of 5-acetamido-6-bromoindan-1-one (0.370 g, 1.38 mmol) in anhydrous methanol (32 ml) was added tert-butyl 4-amino-2-fluorobenzoate (V. Bavetsias et al, J. Med. Chem. 1996, 39, 73-85; 0.322 g, 1.52 mmol) followed by decaborane (0.030 g). The reaction mixture was stirred at room temperature for 11 hours then more decaborane (0.005 g) was added and stirring was continued for a longer 12 hours under argon. The solvent was removed in vacuo, and the residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexane (30 to 40%). The desired compound was obtained as a white solid: 0.455 g (71%) m.p.>70° C. (softens); 1H-NMR (250 MHz, CDCl3, TMS) 1.57 (s, 9H, C(CH3)3), 2.24 (s, 3H, COCH3), 1.98, 2.56 (2×m, 2H, indanyl 2-H), 2.94 (m, 2H, indanyl 3-H), 4.33(d, J=7.90 Hz, 1H, N—H), 4.99 (q, J=7.06 Hz, 1H, indanyl 1-H), 6.37 (m, 2H, 3,5-H), 7.48, 8.25, 7.60 (3×s, each 1H, indanyl 4-H, 7-H, CONH), 7.72 (t, J=8.75 Hz, 6-H); MS (ESI, mz) 485, 487 {(M+Na)+, bromine isotopic pattern}.