Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:30](COCCOC)[C:29](=[O:37])[O:28][N:27]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:40][C:41]([C:43]1[CH:52]=[CH:51][CH:50]=[CH:49][C:44]=1[C:45]([O:47]C)=[O:46])=[O:42].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:37])[O:28][N:27]=4)=[CH:18][CH:19]=3)[C:8](=[O:12])[N:9]([CH2:40][C:41]([C:43]3[CH:52]=[CH:51][CH:50]=[CH:49][C:44]=3[C:45]([OH:47])=[O:46])=[O:42])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)n4COCCOC)cc3)c2s1
Reactant: COC(=O)c1ccccc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccccc3C(=O)O)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
To a mixture of 6-ethyl-1-[(2′-{4-[(2-methoxyethoxy)methyl]-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl}biphenyl-4-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), methyl 2-(bromoacetyl)benzoate (1.06 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (0.18 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, tetrahydrofuran (15 mL), methanol (15 mL) and 1N aqueous sodium hydroxide solution (10 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), N,N′-carbonyldiimidazole (0.2 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.18 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:27][CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (70.7 mg, 0.419 mmol) and tert-butyl (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-1,4-diazepane-1-carboxylate (87 mg, 0.23 mmol) in DMSO (1.2 mL). Triethylamine (162 μL, 1.17 mmol) was added to the mixture which was then heated to 90° C. After 1 hour, UPLC indicated the reaction was complete. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography (SiO2, 25-100% EtOAc/heptanes gradient) to give the title compound as a foam (81 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35-1.52 (m, 12H), 1.91 (s, 2H), 2.24 (s, 3H), 2.95-3.19 (m, 4H), 3.57 (d, J=5.56 Hz, 4H), 3.80 (br s, 1H), 5.90-6.01 (m, 1H), 6.49 (d, J=3.28 Hz, 1H), 6.95 (br s, 4H), 7.55 (d, J=3.03 Hz, 1H), 7.81 (d, J=6.82 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[NH2:13][NH2:14].O.[ClH:16]>C(O)C>[ClH:16].[OH:6][C:5]1[NH:14][N:13]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (18.4 g (0.1 mol)) was dissolved in 20 mL of ethanol. The resulting solution was cooled to 10° C. or less with stirring, and 6.0 g (0.12 mol) of hydrazine was added dropwise thereto over 0.5 hours. After the dropwise addition, the solution was stirred at room temperature for 1 hour and subsequently at the reflux temperature for 5 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water and 20.6 g (0.2 mol) of 35% hydrochloric acid were added thereto. The produced crystal was collected by filtration, washed twice with 10 mL of water and dried by a hot air drier to obtain 12.8 g (yield: 68.1%) of the title compound as a white crystal.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][C:16]([CH3:23])([CH3:22])/[CH:17]=[CH:18]/[C:19]([Cl:21])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:21].[CH3:15][C:16]([CH3:23])([CH3:22])/[CH:17]=[CH:18]/[C:19]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: CC(C)(C)/C=C/C(=O)Cl
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
To a solution of (E)-4,4-dimethyl-2-pentenoic acid (Gream, G. E.; Serelis, A. K. Aust. J. Chem. 1978, 31, 863) (200 mg, 1.6 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-4,4-dimethyl-2-pentenoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (150 mg, 0.81 mmol) and (E)-4,4-dimethyl-2-pentenoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate yielded the titled compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:13])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C.O>[NH2:1][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:13]
Reactant: Cc1cc(C#N)ccc1CN=[N+]=[N-]
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: Cc1cc(C#N)ccc1CN

Procedure:
The sub-title compound was prepared according to the method described in Example 1(ii) above from 1.4 g (8.1 mmol) of 4-azidomethyl-3-methylbenzonitrile (from step (iv) above) and 2.3 g (9.0 mmol) of triphenylphosphine in 18 mL of ethanol and 2 mL of water. Yield: 0.60 g (contaminated by triphenylphosphine oxide; estimated actual yield: 0.36 g (28%)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:33](O)[CH2:34][CH2:35][OH:36].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:33][CH2:34][CH2:35][OH:36])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of 3-(3-chlorophenylsulfonyloxy)-5-methylphenol (450 mg, 1.5 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl) dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a colorless oil (480 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 6.64 (s, 1H), 6.41 (s, 1H), 6.37 (s, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 1.99 (m, 2H), 1.65 (br s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)[CH3:2].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO>[Br:12][C:8]1[C:7]([CH2:9][CH3:10])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: [Br-]
Reactant: CCc1cc(O)cc(CC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: CCc1cc(O)cc(CC)c1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 13 %

Procedure:
To a solution of 3,5-diethylphenol (9.30 g, 61.9 mmol) in methanol (100 mL) was added tetrabutylammonium tribromide (29.8 g, 61.9 mmol), and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75), and the obtained crystals were recrystallized from heptane to give the title compound (1.85 g) as colorless crystals. The mother liquor was concentrated under reduced pressure to give the title compound (8.68 g) as dark-brown crystals (total 10.5 g, total yield 74%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[C:21]([O:22]C=O)=[C:20]([O:25][CH2:26][C@@H:27]3[O:29][CH2:28]3)[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].O>O1CCCC1>[Cl:7][C:8]1[C:9]2[C:21]3[O:22][C@@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:20]=3[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1sc2ccc(OC[C@H]3CO3)c(OC=O)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2ccc3c(c2c1Cl)O[C@@H](CO)CO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
Saturated aqueous potassium carbonate solution (20 ml) was added to a stirred solution of ethyl (R)-3-chloro-5-(2,3-epoxypropoxy)-4-formyloxy-benzo[b]thiophene-2-carboxylate (1.85 g, prepared as described above) in tetrahydrofuran (20 ml) and the mixture stirred for 24 hours at room temperature. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were dried over sodium sulphate and evaporated under reduced pressure to give a yellow solid. Purification by flash chromatography on silica using a 1:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant gave ethyl (S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-f]-1,4-benzodioxin-8-carboxylate (1.44 g) as a pale-yellow solid; m.p. 165-166° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.C(O)C>[Pd].CO>[NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reaction time: 72 h
Yield: 91.8 %

Procedure:
A mixture of 21 gm (89.9 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 10% palladium on carbon pre-wet with 30 mL ethanol in 180 mL methanol were hydrogenated at 65 p.s.i for 3 days. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The residual solid was slurried in 120 mL ethyl acetate, filtered, and washed 3×30 mL ethyl acetate. The remaining solid was dried under reduced pressure to provide 19 gm (92%) the title compound as a light brown solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:13]=[CH:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[CH2:7])CCC.O.[Br:35]N1C(=O)CCC1=O>O1CCCC1>[Br:35][CH2:5][C:6]([C:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:13]=[CH:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[O:7]
Reactant: C=C(OCCCC)c1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2c(c(C(=O)CBr)cn2COCC[Si](C)(C)C)c1=O
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To 8.80 g (17.8 mmol) of 3-(1-butoxyvinyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 57-(a) were added 21.1 ml of water and 341 ml of tetrahydrofuran, and 100 ml of tetrahydrofuran solution containing 4.70 g (26.4 mmol) of N-bromosuccinimide was added dropwise to the mixture under cooling in ice-bath. After the dropwise addition, the mixture was stirred at the same temperature 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 6.64 g of the title compound as a white solid. (Yield: 72%)
Reaction SMILES: [OH:1][C@H:2]([C@@H:8]([OH:35])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH:10]=1)[C:3]([O:5]CC)=O.[NH3:36]>>[OH:1][C@H:2]([C@@H:8]([OH:35])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH:10]=1)[C:3]([NH2:36])=[O:5]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)c1cn(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c2ccccc12
Reactant: N
Product: NC(=O)[C@H](O)[C@@H](O)c1cn(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c2ccccc12

Procedure:
(2R,3S)-2,3-Dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide (5) was prepared as follows: A solution of compound 4 (100 mg) and NH3 (in MeOH ˜7N, 6 mL) was shaken at room temperature for 72 hours. The solvent was evaporated, and the residue was purified by column (EtOAc/MeOH 8/1.5) to afford compound 5 as a white solid (70 mg): 1H-NMR (400 MHz, CD3OD) δ: 8.49 (s, 1H), 8.06 (1H, dd, 2.6 & 8.7 Hz), 7.82 (1H, d, 7.8 Hz), 7.56-7.65 (m, 4H), 7.38-7.41 (m, 2H), 7.15-7.25 (m, 3H), 5.51 (dd, 1H, 0.8 & 2.6 Hz), 4.37 (1H, d, 2.6 Hz); LC/MS: m/z=480.2 [M+Na+] (Calc: 457.4).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]3[CH3:26])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl.[CH3:28][C@@H:29]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[NH:30]1>>[CH3:28][C@@H:29]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[N:30]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]3[CH3:26])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H]1CC[C@@H](C)N1C(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: Cl
Product: C[C@@H]1CC[C@@H](C)N1CCCOc1ccc(-c2ccc(C(=O)N3[C@H](C)CC[C@H]3C)cc2)cc1

Procedure:
The product from Example 4A and (2R,5R)-2,5-dimethylpyrrolidine hydrochloride were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:9].[H-].[Na+].IC.[C:43](OCC)(=O)C>C1COCC1>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:17]2[CH2:16][CH2:15][CH2:14][N:13]([CH3:43])[C:12]=2[C:11]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2c(c(=O)n1C)CCCN2
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2c(c(=O)n1C)CCCN2C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In THF (3 ml) was dissolved N-[3,5-bis(trifluoro methyl)benzyl]-8-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-N,6-dimethyl-5-oxo-7-pyrido[4,3-b]pyridinecarboxamide (Example 27)(68 mg). To the solution were added sodium hydride (60% oil) (6 mg) and iodomethane (1.5 ml). The mixture was stirred for 15 hours at room temperature. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and dried, then the solvent was distilled off to give the above-titled compound as colorless crystals (39 mg), m.p.230°-232° C. (recrystallized from ethyl acetate-ethyl ether)
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([O:19]C)=[O:18])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].CO.Cl>O>[CH2:1]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(-c2ccncc2)sc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCNc1cc(-c2ccncc2)sc1C(=O)O
Yield: 84.7 %

Procedure:
A mixture of methyl 3-(butylamino)-5-(pyridin-4-yl)thiophene-2-carboxylate (0.460 g, 1.58 mmol), sodium methoxide (0.257 g, 4.75 mmol), methanol (6.4 mL) and water (1.6 mL) was refluxed overnight. The mixture was cooled in an ice-bath and conc. HCl (0.390 mL, 4.75 mmol) was added. The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (0.370 g, 85%) as a yellow solid:
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[NH2:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1>C(=O)=O.CC(C)=O>[NH2:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:1])=[O:17])=[CH:10][CH:9]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CO
Agent: O=C=O
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccc(N)nc1

Procedure:
To methanol (5 ml) in dry ice-acetone bath was added thionyl chloride (0.41 ml) dropwise over 5 minutes. After (E)-3-(6-Aminopyridin-3-yl)acrylic acid (700 mg) was added to the mixture, the reaction mixture was heated at reflux for 1 hour, and the solvent was removed under reduced pressure. The reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The precipitate was collected by vacuum filtration and washed with isopropyl ether to give methyl (E)-3-(6-aminopyridin-3-yl)acrylate (725 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1.Cl.[Cl:30]CC[CH2:33][N:34](C)[CH3:35]>>[ClH:1].[ClH:30].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][N:34]([CH3:35])[CH3:33])[CH:10]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Sc2ccccc2Cl)c1
Reactant: CN(C)CCCCl
Agent: Cl
Product: Cc1csc(Nc2ncc(SCCCN(C)C)cc2Sc2ccccc2Cl)n1

Procedure:
Prepared according to the method of Example 16 using methyl 3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. 1H NMR (d6-DMSO) δ 10.12 (bs, 1H), 8.41 (s, 1H), 7.61 (d, 1H), 7.33 (m, 2H), 7.07 (m, 1H), 6.52 (s, 1H), 3.09 (m, 2H), 2.90 (m, 2H), 2.70 (d, 6H), 2.18 (s, 3H), 1.84 (m, 2H); Mass spectrum (esi) m/z=451.0 (M+H-2HCl).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].O[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([N+:16]([O-:18])=[O:17])[C:9]=1[O:19][CH3:20].S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[CH3:20][O:19][C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:14]=[CH:15][C:8]=1[O:4][CH3:1])[CH:12]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)c([N+](=O)[O-])c1OC
Yield: 78 %

Procedure:
Anhydrous sodium carbonate (957 g., 9.03 moles), toluene (5 liters), 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (1424 g., 7.22 moles) and dimethyl sulfate (810 ml., 8.67 moles) were refluxed for 4 hours. Toluene was removed in vacuo and the residual solid dissolved in 5 liters of ethyl acetate and 3 liters of water. The organic layer was separated, washed with 2 liters of 1 N NaOH and 6 liters of brine, decolorized with charcoal, dried over magnesium sulfate and filtered. Hexane (7.6 liters) was added slowly. After cooling in an ice bath, 1527 g. product was obtained by filtration. The crude material was recrystallized from ethanol to yield 1187 g. (78%) of the title compound as a pale yellow solid, 60°-62° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[ClH:13].[NH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[NH2:15]>>[ClH:13].[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:15][NH:14][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:18][CH:17]=1
Reactant: Nc1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: Nc1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 5-amino-1H-indole-2,3-dione and 4-hydrazinobenzenesulfonamide hydrochloride according to Procedure G: 1H NMR (DMSO-d6): δ 6.95 (d, J=8 Hz, 1H), 7.2 (d, J=8 Hz, 1H), 7.26 (s, 2H), 7.46 (s, 1H), 7.5 (d, J=8 Hz, 2H), 7.8 (d, J=8 Hz, 2H), 9.7 (br s, 3H), 11.2 (s, 1H), 12.8 (s, 1H); APCI-MS m/z 330.2 (M−H)−.