Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])=[N:17][N:18]([CH3:21])[C:19]=1[CH3:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: Cc1c(N)c(CC(C)C)nn1C
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Solvent: c1ccncc1
Product: Cc1c(NS(=O)(=O)c2c(Cl)cc(Br)cc2Cl)c(CC(C)C)nn1C
Yield: 12.4 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.68 g, 2.1 mmol) and 4-amino-1,5-dimethyl-3-isobutyl-1H-pyrazole (0.35 g, 2.1 mmol) in pyridine (5 ml) according to the method of intermediate 1, to give the title compound as a white solid (120 mg, 0.26 mmol, 12%). δH (D-6 DMSO, 300K) 7.65 (2H, s), 6.54 (1H, s), 3.70 (3H, s), 2.17 (3H, s), 1.96 (2H, d J 7.9 Hz), 1.74 (1H, m), 0.78 (6H, d J 6.6 Hz). m/z (ES+, 70V) 456.0 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29](=O)[CH:28]=[C:27]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:30])[CH2:28][C:27](=[O:26])[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccs2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1NC(=O)CC(=O)c1cccs1
Yield: 25.8 %

Procedure:
Prepared from (2-amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester (Example G24) (259 mg, 0.5 mmol) and 2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) (135 mg, 0.55 mmol) according to the general procedure K. Obtained as a light yellow solid (60 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(#N)C>[N:14]1([C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:6][CH:7]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: C1CNCCN1
Reactant: Clc1ccc(-c2ccccn2)nn1
Solvent: CC#N
Product: c1ccc(-c2ccc(N3CCNCC3)nn2)nc1
Yield: 77 %

Procedure:
To a solution of 3-chloro-6-pyridin-2-ylpyridazine (0.250 g, 1.300 mmol) in acetonitrile (15 mL) was added piperazine (0.335 g, 3.900 mmol) and the mixture was stirred at reflux for 4 hours. The solvent was removed in vacuo. The residue was purified by column chromatography to afford the title compound in 77% yield (0.240 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:38])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:30]3[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)c1cc(O)cc(C(F)(F)F)c1
Product: CC(C)c1cc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc(C(F)(F)F)c1
Yield: 81.5 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-isopropyl-5-trifluoromethyl-phenol (54 mg, 0.26 mmol) to give the title compound (58 mg, 81%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[H-].[Na+].[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36]Br)[CH3:33]>CN(C)C=O>[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C:2]1=[O:1])[CH3:33]
Reactant: O=C(NC1CN(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN1C(=O)C(NC(=O)OCc2ccccc2)CN(c2ccccc2)c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
Under argon atmosphere, 2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (930 mg) in anhydrous N,N-dimethylformamide (20 ml) was added to a suspension of 60% sodium hydride (192 mg) in anhydrous N,N-dimethylformamide (20 ml), then stirred at room temperature for one hour. After bromoacetaldehyde diethylacetal (946 mg) in anhydrous N,N-dimethylformamide (10 ml) was added to the mixture, the resultant mixture was stirred overnight internal temperature at 70-75° C. Ice-water was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby obtain 468 mg of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CC(C)=O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:2]=1)([O-:13])=[O:12]
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1-c1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
2-Bromo-2′-nitroacetophenone (7.65 g, 31.3 mmol) and 2-aminopyridine (2.95 g, 31.3 mmol) were dissolved in acetone (50 ml) and brought to reflux. After 10 minutes a light yellow/white precipitate forms in addition to strong boiling. Refluxing was continued for 3 hours and cooled to room temperature. The volume was reduced ½ by evaporation and the intermediate solids were collected by filtration and washed with acetone (20 ml) and air dried (7.26 g of intermediate). The intermediate (7.20 g) was dissolved in MeOH (100 ml) with HBr (4 drops, catalytic) and brought to reflux. The reaction was monitored by TLC (10% MeOH in CH2Cl2). After 70 minutes, the reaction mixture was cooled to room temperature, adjusted to pH=12 with 1 M NaOH, and concentrated to remove the methanol. The yellow product was collected by filtration, washed with water and air dried. 5.54 g (74%) of 2-(2-Nitro-phenyl)-imidazo[1,2-a]pyridine was obtained as a yellow crystalline solid (MS, M++H=240.1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:17])[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:3])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:17][C:18](=[O:20])[CH3:19])[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
The product from Example 96a (0.98 g, 3.97 mmol) in pyridine (10 mL) was treated with acetic anhydride (0.38 g, 3.74 mmol) and heated at 80° C. 2 hr. the solvent was concentrated under vacuum leaving the title compound as a red oil which was used without further purification (0.96 g, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])=[O:5])[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)=[O:15])=[O:10])=[O:5])[CH3:2]
Reactant: OCc1cccnc1
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1cccnc1

Procedure:
The solution of 2.37 g of N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid, 0.61 g of 3-pyridylcarbinol and 1.15 g of dicyclohexylcarbodiimide in 25 ml of methylene chloride is stirred at room temperature for two days. The solid is removed, and the filtrate is diluted with 150 ml of ether and extracted with 0.5N hydrochloric acid. The acidic aqueous layer is separated, basified and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, filtered, concentrated and flash chromatographed on silica gel eluting with ethyl acetate:ethanol (9:1) to yield 3-pyridylmethyl N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl)-3-aminopropionate as an oil; NMR (CDCl3) δ8.70 (m, 2H), 7.77 (m, 1H), 7.28 (m, 11H), 5.56 (t, 1H, J=7 Hz), 5.12 (s, 2H), 4.03 (q, 2H, J=8 Hz), 1.08 (t, 3H, J=8 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[CH:20]=[C:21]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=[C:23]([Cl:26])[C:24]=1[OH:25].O>CC(C)=O>[C:28]([NH:27][C:21]1[CH:22]=[C:23]([Cl:26])[C:24]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:19]([Cl:18])[CH:20]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CCCCCOc1c(Cl)cc(NC(C)=O)cc1Cl

Procedure:
13.3 ml (74.9mmol) of ethyl 6-bromohexanoate and 52.1 g (160 mmol) of cesium carbonate were added to a solution of 15.0 g (68.1 mmol) of N-(3,5-dichloro-4-hydroxyphenyl)acetamide in 300 ml of acetone. The suspension was boiled under reflux for 8 hours, and then 600 ml of water were added. The mixture was extracted twice with 400 ml of dichloromethane and with 400 ml of MTB ether each time. The combined organic phases were washed with water and concentrated in a rotary evaporator. The product was employed in the next step without purification. Crude yield was 30 g.
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>CO.ClCCl>[CH2:23]([NH:27][C:3](=[O:22])[C@H:4]([CH:19]([CH3:20])[CH3:21])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CN
Reactant: COC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)CNC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C

Procedure:
Following General Procedure H above and using N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-L-valine methyl ester (from Example 1 above) and isobutylamine (Aldrich), the title compound was prepared as a oil. The reaction was monitored by tlc (Rf=0.3 in 10% methanol/dichloromethane).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[H-].[Na+].[CH3:14][SH:15].O>CN(C)C(=O)C>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([CH3:11])([S:15][CH3:14])[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSC(C)(C)C1(O)CC=C(C)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 15.2 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 100 ml of N,N-dimethylacetamide was added 4.4 g of 60% sodium hydride. The mixture was cooled to 5°-10° C. and saturated with methyl mercaptan. Stirring was continued while heating the reaction mixture to 100° C. over a two and one-half hour period. After an additional hour at 100° C., the reaction mixture was poured into water and extracted twice with n-pentane. The combined extracts was washed with water, dried and Claisen-distilled to give 15.8 g of the desired product, b.p. 83°-85° C. (0.2 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:10]=2)=[CH:14][CH:15]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1nc(-c2ccc(CO)cc2)[nH]c1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(-c2nc(C(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
tert-Butyl 5-(4-chlorophenyl)-2-(4-hydroxymethylphenyl)-imidazole-4-carboxylate is dissolved in pyridine and reacted with acetic anhydride to give the objective tert-butyl 2-(4-acetoxymethylphenyl)-5-(4-chlorophenyl)imidazole-4-carboxylate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])=[O:6].[CH:13](I)([CH3:15])[CH3:14].Cl>CN(C)C=O>[CH:13]([C:7]1([C:5]([O:4][CH3:3])=[O:6])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: COC(=O)C1CCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(C)C)CCCC1=O
Reaction time: 3.5 h

Procedure:
7.7 g of sodium hydride (free of oil) was added to 80 ml of dimethylformamide. 25 g of 2-methoxycarbonylcylopentanone was slowly added dropwise while cooling with ice. The reaction mixture was allowed to come to room temperature, whereupon 45 g of isopropyl iodide was added, followed by stirring for a further 3.5 hours at 70°-80° C. The reaction mixture thus obtained was poured into 400 ml of 10% hydrochloric acid solution and extracted with 100 ml of ethyl acetate. The organic layer was washed with water, dried, and concentrated to obtain 25.5 g (yield, 78.7%) of the title compound.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH3:16][O:17][NH2:18]>C(O)C>[CH3:16][O:17][N:18]=[C:2]([CH2:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCCC(=O)CC(=O)C(=O)OCC
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CCCCC(=O)CC(=NOC)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.5 %

Procedure:
To an ethanol (100 ml) solution of ethyl 2,4-dioxooctanoate (20 g) (K. Seki et al., Chem. Pharm. Bull., 32, 1568(1984)) was added, under ice-cooling, methoxyamine hydrochloride (8.4 g), and the mixture was stirred for one hour, then it was stirred for further 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ether. The extract solution was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless oil (16.6 g, 72%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.CCN(CC)CC.[H][H]>CO.[Pd]>[NH:8]1[C:7]2=[CH:2][N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: Clc1nccc2cc[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: c1cc2cc[nH]c2cn1
Yield: 96.8 %

Procedure:
A mixture of Example 695H (3.6 g, 23.6 mmol), Pd/C (0.5 g, 5%), and Et3N (2.3 g, 23.6 mmol) in MeOH (100 mL) was stirred under a balloon of hydrogen at room temperature overnight. The reaction mixture was filtered through diatomaceous earth (Celite®), and the solid was washed with additional MeOH. The solvent was removed to near dryness, and the semi-solid was treated with 300 mL of EtOAc. The precipitate was removed right away by filtration, and the filtrate was concentrated. The residue was re-dissolved in CH2Cl2, and loaded onto a silica gel column eluted with 100/5:0/5 (EtOAc/MeOH/NH4OH) to give 2.7 g (100%) of the desired product. MS (DCI) m/e 119 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 11.6 (br s, 1H), 8.76 (dd, J=1.0, 1.0 Hz, 1H), 8.08 (d, J=5.4 Hz, 1H), 7.60 (d, J=3.0 Hz, 1H), 7.53 (dd, J=5.4, 1.0 Hz, 1H), 6.50 (dd, J=3.0, 1.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[C:14]([NH:16][C:17]([NH:19][C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=3[Cl:35])=S)[C:13]([NH:36][CH3:37])=[CH:12][C:11]=2[F:38])=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[C:11]([F:38])=[CH:12][C:13]3[N:36]([CH3:37])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=4[Cl:35])=[N:16][C:14]=3[CH:15]=2)=[O:39])=[CH:4][CH:3]=1
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1NC(=S)Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(F)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of crude N-(4-Bromophenyl)-5-(3-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenyl}-thioureido)-2-fluoro-4-methylamino-benzamide (400 mg), DIC (111 μl, 0.700 mmol) and DMF (5 mL) is stirred at 80° C. for 8 h. The crude mixture is concentrated and purified by flash chromatography (silica gel; DCM→DCM/EtOH 97:3) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.IC.[C:22]([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:12]([CH3:22])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)c1cn(C)cc(-c2ccc(F)cc2)c1=O
Yield: 69.9 %

Procedure:
A mixture of Example A7 (1.5 g, 5.7 mmol) and iodomethane (0.9 g, 6.3 mmol) in satd. NaHCO3 (25 mL) was heated at 60° C. overnight. The mixture was filtered. The solid was concentrated under vacuum to afford ethyl 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (1.1 g, 69.9% yield) which was used without further purification.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:27])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:27][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (3.85 g, 14.7 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (3.00 g, 13.4 mmol), HATU (6.10 g, 16.1 mmol) in anhydrous DMF (6 mL) is added DIPEA (3.30 mL, 20.1 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is recrystallized from EtOAc to give a pure product (147) as white solid (3.90 g, 62%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35](O)=[O:36])=[CH:4]1)[CH3:2].ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([CH2:35][OH:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCn1cc(CO)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a suspension of 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (20 g, 39.4 mmol) in Tetrahydrofuran (THF) (100 mL) was added TEA (6.04 mL, 43.3 mmol) and isobutyl chloroformate (5.69 mL, 43.3 mmol). The resulting mixture was stirred at r.t. for 1 h. Then the mixture was cooled down to −78° C. and a solution of DIBAL-H (52.5 mL, 79 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 2 h, LCMS indicated completion of the reaction. The reaction was quenched with sat. NH4Cl (aq.), and was warmed up to r.t., concentrated, diluted with sat. NH4Cl and extracted with dichloromethane. The organic mixture was filtered through Celite to remove gummy precipitate. The combined organic solution was then washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford 1-ethyl-5-fluoro-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (11.5 g, 23.30 mmol, 59.1% yield) as a yellow solid, which was used in the next oxidation step without further purification. LCMS: (M+H)+: 494.2
Reaction SMILES: [K].[C:2]([C:4]1[C:5]([N:7]([CH3:12])[C:8](=[O:11])[C:9]=1O)=[O:6])#[N:3].O=P(Cl)(Cl)[Cl:15]>>[C:2]([C:4]1[C:5]([N:7]([CH3:12])[C:8](=[O:11])[C:9]=1[Cl:15])=[O:6])#[N:3]
Reactant: CN1C(=O)C(O)=C(C#N)C1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [K]
Product: CN1C(=O)C(Cl)=C(C#N)C1=O
Yield: 56 %

Procedure:
19 parts of the potassium salt of 2-cyano-3-hydroxy-N-methylmaleimide (prepared by a method similar to that for the salts described in J.Amer.Chem.Soc. 80 (1958), 3924) and 15.3 parts of phosphorus oxytrichloride in 100 parts by volume of heavy naphtha are heated at the boil for half an hour, the hot mixture is then filtered, the filtrate is allowed to cool, and the resulting precipitate is filtered off under suction, washed with gasoline and dried. 9.6 parts (56% of theory) of 2-cyano-3-chloro-N-methylmaleimide of melting point 141°-143° C. are obtained. IR (KBr): 2270, 1720, 1630 cm-1.
Reaction SMILES: [CH3:1][CH:2]([NH:4][S:5](Cl)(=[O:7])=[O:6])[CH3:3].[CH3:9][S:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][S:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][S:5]([NH:4][CH:2]([CH3:3])[CH3:1])(=[O:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CSc1ccc(N)cc1
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(NS(=O)(=O)NC(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(1-Methylethyl)sulfamoyl chloride (6.63 g, 0.034 mol) was added dropwise to a solution of 4-(methylthio) aniline (4.48 g, 0.032 mol) and triethylamine (4.87 ml, 0.035 mol) in dry dichloromethane (100 ml) at 0° C. under a nitrogen atmosphere. After addition, the resultant mixture was allowed to warm to room temperature and was stirred for 6 hr. The reaction mixture was further extracted with dichloromethane and the organic extracts washed with water (2×50 ml), dried (MgSO4) and concentrated in vacuo to yield N-(4-methylthiophenyl)-N′-(1-methylethyl)sulfamide as a white solid. δ (1H NMR, DMSO, ppm): 0.8 (6H, d), 2.3 (3H, s), 3.2 (1H, m), 3.35 (1H, s), 6.9-7.1 (4H, m), 9.5 (1H, s). M.P. 65-68° C.