Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]([CH3:18])([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C]=O>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:5][C:6](=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])([CH3:18])[CH3:17])[CH:11]=1
Reactant: CC(C)(Cc1cccc(Br)c1)NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CC(C)(C)NC(=O)OC(C)(C)C)c1
Yield: 116.5 %

Procedure:
A solution of [2-(3-bromophenyl)-1,1-dimethylethyl]carbamic acid tert-butyl ester (Preparation 32) (7.0 g, 21 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.74 g, 2.1 mmol) and triethylamine (5.94 ml, 43 mmol) in methanol (250 ml) was heated to 100° C. under 100 psi carbon monoxide for 12 hours. The reaction mixture was filtered through arbocel and the filtrate concentrated in vacuo and purified by flash column chromatography on silica gel eluting with dichloromethane:pentane (50:50 by volume) to afford the title compound as a yellow solid (3.76 g). 1H NMR (400 MHz, CDCl3) δ=7.92-7.90 (1H, m), 7.82 (1H, s), 7.35-7.34 (2H, m), 4.24 (1H, bs), 3.90 (3H, s), 3.05 (2H, s), 1.48 (9H, s), 1.26 (6H, s). LRMS (electrospray) m/z 208 [M+H−BOC]+
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24]1>>[NH2:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:3]=2)[CH2:24]1
Reactant: N[C@H]1CCNC1
Reactant: O=C(CCC1CCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: N[C@H]1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)C1
Yield: 69.7 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclopentanepropanamide (Example 62(a)) (500 mg) and (3S)-3-pyrrolidinamine (390 mg). Purification (SiO2, methanol:dichloromethane:ammonium hydroxide solution 7:93:1 as eluant) gave the title compound as a solid (400 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Cl[C:16]1[S:17][C:18]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=2[N:20]=1.Cl.O1CCOCC1>C(O)(C)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=3)[S:17][C:18]=2[CH:24]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(O)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
To a suspension of tert-butyl 4-aminobenzoate (6.36 g, 32.9 mmol) and 2,6-dichlorobenzothiazole (5 g, 24.5 mmol) in isopropanol (150 mL) was added 4 N HCl in 1,4-dioxane (4 mL, 16 mmol). The mixture was refluxed at 100° C. for 7 h, and then allowed to cool to room temperature. White precipitates formed during cooling were isolated by filtration to yield the first crop of the title compound as a white solid (3.13 g). The filtrate was concentrated in vacuo and then stirred in a mixed solvent of TEA (20 mL) and CH2Cl2 (20 mL) overnight. The solvent was removed in vacuo, and the residue was triturated with isopropanol/ethyl acetate. The isolated white solid was stirred in a mixed solvent of isopropanol (12 mL) and ethyl acetate (8 mL) for 0.5 h and collected by filtration to yield the second crop of the title compound (3.5 g) (total 6.63 g, 85% yield). HPLC/MS (Method C): retention time=2.51 min, [M+H]+=305.3. 1H NMR (500 MHz, DMSO-d6) δ 11.08 (bs, 1H), 7.98 (d, J=2.20 Hz, 1H), 7.94 (m, 2H), 7.88 (m, 2H), 7.64 (d, J=8.25 Hz, 1H), 7.36 (dd, J=8.80, 2.20 Hz, 1H).
Reaction SMILES: [C@@H:1]1([NH2:7])[CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:6].[C:8]([O:12][C:13](ON=C(C1C=CC=CC=1)C#N)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>C(Cl)Cl.C(N(CC)CC)C>[NH2:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@H:1]1[NH:7][C:13](=[O:14])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: N[C@@H]1CCC[C@H]1N
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
(±)-trans-1,2-Cyclopentanediamine (WO98/30574) (692 mg) was dissolved in methylene chloride (10 ml), to which triethylamine (1.1 ml) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) were added, and the mixture was stirred at 0° C. for 1 hour. Thereafter, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) were additionally added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (methylene chloride:methanol=9:1) to obtain the title compound (395 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[NH:19]C(=O)OC(C)(C)C)O1.Br[C:29]1[C:30]([C:35]#[N:36])=[N:31][CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[F:16][C:15]([F:17])([F:18])[C:12]1[CH:13]=[CH:14][C:9]2=[C:29]3[C:30](=[C:35]([NH2:36])[N:19]=[C:10]2[CH:11]=1)[N:31]=[CH:32][CH:33]=[CH:34]3
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Nc1nc2cc(C(F)(F)F)ccc2c2cccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenylcarbamate (from step 2) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.24 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (4.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give a solid which was then triturated in 10% ethyl acetate in hexane to give 8-(trifluoromethyl)benzo[f][1,7]naphthyridin-5-amine. 1H NMR (acetone d-6): δ 9.13 (d, 1H), 9.00 (d, 1H), 8.67 (d, 1H), 7.91-7.94 (dd, 1H), 7.86 (s, 1H), 7.58 (d, 1H), 6.9 (br, 2H). LRMS [M+H]=264.1
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH3:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])=[O:12])[CH2:6][CH2:5]1)=[S:3].Cl[CH:22]([C:30]#[N:31])[C:23]([O:25][C:26](C)(C)C)=O>CO>[Cl:18][C:17]1[C:16]([Cl:19])=[C:15]([CH3:20])[NH:14][C:13]=1[C:11]([NH:10][CH:7]1[CH2:8][CH2:9][N:4]([C:2]2[S:3][C:22]([C:30]#[N:31])=[C:23]([O:25][CH3:26])[N:1]=2)[CH2:5][CH2:6]1)=[O:12]
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(N)=S)CC2)c(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)C(Cl)C#N
Solvent: CO
Product: COc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C#N
Temperature: 80 °C

Procedure:
A suspension of N-[1-(aminocarbonothioyl)piperidin-4-yl]-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide (Intermediate 95, 0.22 g, 0.7 mmol) and tert-butyl chloro(cyano)acetate (0.12 g, 0.7 mmol) in MeOH was heated to 80° C. in the microwave reactor for 40 minutes. The product precipitated and was filtered off.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:33])[CH2:15][C:16](=[N:31]O)[CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:3]>[Ni].CO.N>[NH2:31][CH:16]([CH2:17][CH:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:15][C:14]([NH:13][C:5]1[C:4]([CH:2]([CH3:1])[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[O:33]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CC(CC(c1ccccc1)c1ccccc1)=NO
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(N)CC(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by treating N-[2,6-bis(1-methylethyl)phenyl]-β-(hydroxyimino)-δ-phenylbenzenepentanamide (0.23 g, 0.53 mmol) with Raney nickel (0.2 g) in 50 mL methanol/ammonia at 25° C. for 18 hours (ΔP=13.7 psi). The reaction mixture was concentrated in vacuo to give a white solid, the title compound.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>>[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:47][C:36]([C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([C:23]4[CH:22]=[C:21]([N:15]5[C:14](=[O:39])[C:13]6[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:8])=[O:10])[CH:12]=6)[C:16]5=[O:20])[CH:26]=[CH:25][CH:24]=4)[O:28][C:29]=3[CH:35]=2)=[O:37])=[CH:44][CH:43]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Product: COc1ccc(CNC(=O)c2ccc3nc(-c4cccc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)c4)oc3c2)cc1

Procedure:
Prepared by the method of Example 76 g), from 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) and 4-methoxybenzylamine (19 mg, 0.14 mmol) the title compound was obtained (22 mg, 45%). 1H NMR (DMSO) δ 9.20(t, 1H), 8.43(dd, 1H), 8.36(m, 2H), 8.30(m, 2H), 8.09(d, 1H), 7.99(dd, 1H), 7.91(d, 1H), 7.82–7.89(m, 2H), 7.28(d, 2H), 6.89(d, 2H), 4.45(d, 2H), 3.73(s, 3H). MS 545.9 m/z (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a stirred solution of (3SR,4RS)-1-benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine (15.0 g, 0.0427 mol) in EtOAc (200 ml) was added portionwise SnCl2.2H2O (43.36 g, 0.192 mol). The reaction mixture was then heated at reflux for 4 hours, cooled down to RT and a saturated aqueous solution of NaHCO3 (500 ml) was added. The salts were filtered off and the product extracted with EtOAc. The organic phases were then dried over Na2SO4, and concentration under vacuum gave 9.30 g (75%) of the title compound as a light yellow oil. The product was then used in the next step without further purification. ES-MS m/e: 321.1 (M+H+).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1B(O)O>>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][C:26]=5[CH3:25])[N:10]4[N:9]=3)=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: Cc1ccncc1B(O)O
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Product: Cc1ccncc1-c1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12

Procedure:
[4-(4-Methyl-piperazin-1-yl)-phenyl]-[7-(4-methyl-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine and 4-methylpyridine-3-boronic acid in an analogous manner to Example 1031b. Product isolated as a yellow foam (28 mg, 25%). LCMS (m/e) 400 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.75-8.69 (m, 2H), 8.58-8.52 (m, 1H), 7.35 (d, 2H, J=7.5 Hz), 7.31-7.25 (m, 1H), 6.88-6.79 (m, 3H), 6.79-6.74 (m, 1H), 6.65 (s, 1H), 3.17-3.10 (m, 4H), 2.61-2.54 (m, 4H), 2.35 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: C(O[C:6]([N:8](C)[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:27]>C(OCC)(=O)C>[ClH:27].[CH2:13]([O:12][C:10]([NH:9][NH:8][CH3:6])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17.7 g of N′-benzyloxycarbonyl-N-methyl-hydrazine carboxylic acid tert-butyl ester was dissolved in 20 mL of ethyl acetate, added with 70 mL 4N hydrogen chloride-ethyl acetate solution, and stirred at room temperature for 4 hours. The solvent was evaporated, and the resulting crystals were washed with diethyl ether and filtered, to afford 11.4 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:23]3[CH2:22][CH2:21][N:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)[CH2:25][CH2:24]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1.3 h
Yield: 77 %

Procedure:
A mixture of 2-(chloromethyl)-6-chloroimidazo[1,2-a]pyridine (Example 4, Step 1; 0.50 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.471 g), triethylamine (0.277 g), and ethylene glycol (2 mL) is stirred at 80° C. for 1.3 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (2/98) and the appropriate fractions are combined and concentrated. The resulting material is crystallized from dichloromethane/hexane to give 0.66 g of the title compound; mp 129.5-131° C.; MS m/z at 344; IR (mineral oil) 1511, 1236, 1330, 1325, 825 cm-1; 1 H NMR (CDCl3) δ2.74, 3.15, 6.86-6.98, 7.13, 7.52, 7.54, 8.14.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.CCN(CC)CC>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1]([N:15]1[CH:14]=[C:13]([I:12])[CH:17]=[N:16]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Ic1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)n1cc(I)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
CbzCl (95% grade, 2.9 mL, 20 mmol) is added to a solution of 4-iodo-1H-pyrazole (2.97 g, 15.3 mmol) and Et3N (3.2 mL, 23 mmol) in toluene (30 mL) at 0° C. The mixture is stirred at 0° C. for 1 h and partitioned between EtOAc and aq. NaHCO3. The organic layer is dried over MgSO4, concentrated and chromatographed to afford the title compound as a white solid: 1H NMR (CDCl3) δ 8.20 (s, 1H), 7.72 (s, 1H), 7.50-7.31 (m, 5H), 5.46 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH:10](O)=[O:11]>[Pt].[O-2].[V+5].[O-2].[O-2].[O-2].[O-2].[V+5]>[CH:10]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:11]
Reactant: O=CO
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Pt]
Agent: [V+5]
Agent: [O-2]
Product: O=CNc1ccccc1
Temperature: 92.5 °C
Yield: 79.9 %

Procedure:
Nitrobenzene (12.31 g, 100 mmol), formic acid (80%; 278 mL, 328.0 g), a sulfided platinum catalyst (5% Pt on charcoal, Engelhard No. 43045, lot No. 08554; dry weight 1.55 g) and vanadium(v) oxide (57 mg) were charged under argon in a double-walled 0.3 L stirring vessel with temperature control. The argon flow was stopped and the slurry was heated to 91-94° C. for 2 h. HPLC analysis of the reaction mixture indicated a 79.9% yield of formanilide, accompanied by 18.3% of aniline.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]#[N:27])=[C:24]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[N:23]=[C:22]2[CH2:33][CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na]>C(O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]#[N:27])=[C:24]([CH:28]([OH:32])[CH2:29][CH2:30][CH3:31])[N:23]=[C:22]2[CH2:33][CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(=O)c1nc(CCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C#N
Agent: [Na]
Solvent: CCO
Product: CCCc1nc(C(O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 94.3 %

Procedure:
Following a procedure similar to that described in Example 45(b), but using 1.13 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-butyryl-2-propylimidazole-5-carbonitrile [prepared as described in step (a) above] and 0.091 g of sodium borophydride in 23 ml of ethanol, 1.07 g of the title compound were obtained as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][CH2:16][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnc2ccccc2c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cnc3ccccc3c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 3-vinylquinoline and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(O)ncc(S(N)(=O)=O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c(Cl)ncc(S(N)(=O)=O)c12
Temperature: 110 °C
Yield: 80 %

Procedure:
A mixture of 1-hydroxy-5-methylisoquinolin-4-sulfonamide (Intermediate-40) (4 mmol) in POCl3 (10 mL) was heated to 110° C. for 30 min. Then, it was poured into ice water to give precipitate that was filtered, washed with water, and dried to yield the desired compound in 80-86% yield.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])[C:10](=[O:25])[N:9]([CH3:26])[C:7]=2[N:8]=1)#[N:2].OC1C2C=NC(S(C)(=O)=O)=NC=2N(C)C(=O)C=1C(NCC(OC(C)(C)C)=O)=O.[C-]#N.[Na+]>>[C:1]([C:3]1[N:4]=[CH:5][C:6]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:25])[N:9]([CH3:26])[C:7]=2[N:8]=1)#[N:2]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cnc(C#N)nc21
Agent: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cnc(S(C)(=O)=O)nc21
Agent: [C-]#N
Agent: [Na+]
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cnc(C#N)nc21

Procedure:
tert-Butyl 2-(2-cyano-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate. The title compound is prepared by reaction of tert-butyl 2-(5-hydroxy-8-methyl-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate with sodium cyanide according to the procedure described in Bioorg. Med. Chem. Lett., 17, 6206 (2007).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][N:7]=[CH:6]2.Br[CH2:17][CH2:18][CH2:19][Cl:20].C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([CH2:17][CH2:18][CH2:19][Cl:20])[N:7]=[CH:6]2
Reactant: ClCCCBr
Reactant: COc1cc2cn[nH]c(=O)c2cc1OC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2cnn(CCCCl)c(=O)c2cc1OC

Procedure:
1-[6,7-Dimethoxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane was prepared analogous to Example 1 (a) by reaction of 6,7-dimethoxy-1(2H)-phthalazinone with 1-bromo-3-chloro-propane in dimethylformamide. Rf -value (chloroform/methanol = 9/1) : 0.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[S:19][C:18]([C:20]([OH:22])=O)=[CH:17][CH:16]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28](=[O:38])[CH2:29][CH:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[C:23]([O:27][C:28](=[O:38])[CH2:29][CH:30]([NH:37][C:20]([C:18]1[S:19][C:15]([C:13](=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:16][CH:17]=1)=[O:22])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)CC(N)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(NC(=O)c1ccc(C(=O)NCCCNC(=O)OC(C)(C)C)s1)c1ccccc1
Yield: 53.4 %

Procedure:
With continued reference to Scheme G, 5-(3-tert-Butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carboxylic acid (200 mg, 0.704 mmol) was reacted with 3-Amino-3-phenyl-propionic acid tert-butyl ester (187 mg, 0.845 mmol) in 4.0 ml of anhydrous DMF using HATU (321 mg, 0.845 mmol) with 2,4,6-collidine (0.25 ml, 2.112 mmol), chromatographied on silica gel using ethyl acetate: hexane (8:2) to give 200 mg (58% yield) of the desired product as a clear semi-solid oil. 1H NMR (400 Mhz, CDCl3) 1.3 (s, 9H), 1.45 (s, 9H), 1.7 (m, 2H), 2.9 (ddd, 2H), 3.25 (m, 2H), 3.5 (q, 2H), 4.85 (bs, 1H), 5.55 (m, 1H), 7.23 (m, 1H), 7.33 (m, 4H), 7.4-7.6 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1/[O:14][C:15]([CH3:26])([CH3:25])[C:16]([C:18]2[CH:19]=[N:20][C:21](F)=[CH:22][CH:23]=2)=[CH:17]/1.[CH3:27][NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32].O>CN(C=O)C>[OH:33][CH:30]([CH2:31][OH:32])[CH2:29][N:28]([CH3:27])[C:21]1[N:20]=[CH:19][C:18]([C:16]2[C:15]([CH3:26])([CH3:25])[O:14]/[C:13](=[C:5]3/[C:6](=[O:12])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)/[CH:17]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(F)nc1
Reactant: CNCC(O)CO
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(O)CO)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)c(F)cc43)OC2(C)C)cn1
Temperature: 100 °C

Procedure:
A mixture of (3E)-5,6-difluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.14 mmol) and 3-methylamino-1,2-propanediol (50 mg, 0.48 mmol) in 5 mL of DMF was heated in 100° C. bath under nitrogen for 16 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-3-[4-{6-[(2,3-dihydroxypropyl)(methyl)amino]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-5,6-difluoro-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 51 mg, 82%.