Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.C([Li])CCC.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([NH:33][C:34]([C:10]2[N:11]([CH3:21])[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Reactant: O=C=NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole (50 mg, 0.15 mmol) from Example 32, Step C in THF (3 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.11 mL, 0.18 mmol). The reaction was stirred for 1 hr and then cyclohexyl isocyanate (0.040 mL, 30 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (1 mm, silica) (100% methylene chloride) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[S:14][C:13]([NH2:16])=[N:12][C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[S:14][C:13]([NH:16][C:20]([CH:17]4[CH2:19][CH2:18]4)=[O:21])=[N:12][C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc2[nH]nc(-c3ccc(O)cc3)c2s1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2[nH]nc(-c3ccc(O)cc3)c2s1)C1CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
To a vial charged with 3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine (60 mg, 0.259 mmol), PS-DMAP (Argonaut resin, 1.05 g, 6 equiv.), and a stirring bar were added THF (2.5 mL) and cyclopropane-carbonyl chloride (118 μL, 1.29 mmol). The reaction mixture was stirred at 70° C. for 15 hours, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 1.26 g, 20 equiv.) at 50° C. for 48 hours. The resin was filtered, washed with DMF and the solvent was evaporated. Purification on silica gel with 0-8% MeOH in CH2Cl2 as eluent provided 32 mg (41% yield) of cyclopropanecarboxylic acid [3-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-yl]-amide as a white solid. 1H-NMR (d6-DMSO) δ: 13.3 (broad s, 1H), 12.6 (broad s, 1H), 9.80 (broad s, 1H), 7.52 (d, 2H), 6.88 (d, 1H), 1.98 (m, 1H), 0.93 (m, 4H); HPLC/MS m/z: 301.0 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1C(=O)Cl
Reaction time: 3 h

Procedure:
4-Chloro-2-methylbenzoic acid (1.365 g, 8 mmol, commercially available from e.g. Maybridge, Fluorochem or Sigma-Aldrich) in dichloromethane (DCM) (40 mL) was cooled to 0° C., before oxalyl chloride (0.770 mL, 8.80 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours. The solvent was then evaporated in vacuo and the remaining residue was azeotroped with toluene (2×20 mL) to yield the product in 1.464 g.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:32]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][CH:39]=2)[N:34]([C:41]2[CH:42]=[C:43]3[C:47](=[CH:48][CH:49]=2)[CH:46]([C:50](O)=[O:51])[CH2:45][C:44]3=[O:53])[CH:33]=1.[C:54]([C:58]1[CH:59]=[C:60]([NH2:69])[N:61]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[N:62]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C=O)C>[C:54]([C:58]1[CH:59]=[C:60]([NH:69][C:50]([CH:46]2[C:47]3[C:43](=[CH:42][C:41]([N:34]4[C:35]5=[N:36][CH:37]=[CH:38][CH:39]=[C:40]5[N:32]=[CH:33]4)=[CH:49][CH:48]=3)[C:44](=[O:53])[CH2:45]2)=[O:51])[N:61]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[N:62]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C1CC(C(=O)O)c2ccc(-n3cnc4cccnc43)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)C2CC(=O)c3cc(-n4cnc5cccnc54)ccc32)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
HATU (46.7 mg, 0.12 mmol) and triethylamine (29.5 μL, 0.21 mmol) are added to a solution of (R/S)-5-imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid (30 mg, 0.1 mmol) in DMF (2.5 mL). The reaction is stirred at rt for 2 min then 5-tert-butyl-2-phenyl-2H-pyrazol-3-ylamine (21.5 mg, 0.1 mmol) is added. After stirring at rt for 8 h, DMF is removed in vacuo. The residue is purified by reversed phase MPLC using ACN/Water as eluant and 5-imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid (5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-amide is obtained as a white solid. Title compound: ES-MS: 491.00 [M+H]+, tR=1.6 min (System 2).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C@H:3]1[OH:17].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH3:26][S:27]([O:17][C@H:3]1[C@H:4]([NH:8][C@@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:5][CH2:6][CH2:7][C:2]1([F:18])[F:1])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](N[C@H]1CCCC(F)(F)[C@@H]1O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](N[C@@H]1CCCC(F)(F)[C@H]1OS(C)(=O)=O)c1ccccc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a solution of (23) (1.02 g, 4.01 mmol) in THF (20 mL) was added triethyl amine (0.56 mL, 4.01 mmol), followed by methanesulfonyl chloride (0.34 mL, 4.41 mmol). The reaction was allowed to stir at 35° C. overnight. After cooling to room temperature, the reaction mixture was filtered and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 20-60% ethyl acetate in hexanes) to yield (1S,6R)-2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexyl methanesulfonate (1.01 g, 3.03 mmol, 76% yield). In a microwave vial, the sulfonate intermediate (1.02 g, 3.07 mmol) was dissolved in THF (15.4 mL) and triethylamine (0.58 mL, 4.15 mmol). The vial was sealed and was heated to 100° C. and was stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under pressure. The resultant residue was directly purified by column chromatography (silica gel, 0-70% ether in hexanes, linear gradient) to yield aziridine 73.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33].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>C(Cl)Cl>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:10]1)=[O:29]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 24.6 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 2,2-dimethyl-propylamine (34.2 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propyl)-amide (24.6 mg, 24.6%).
Reaction SMILES: Br[CH:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5]CC)=O.[CH2:11]([NH2:14])[CH2:12][NH2:13].[O-]CC.[Na+]>C(O)C>[CH:8]([CH:2]1[NH:14][CH2:11][CH2:12][NH:13][C:3]1=[O:5])([CH3:9])[CH3:10]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: NCCN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)C1NCCNC1=O

Procedure:
Ethyl 2-bromo-3-methylbutanoate (2.2 g, 10.52 mmol) in ethanol (15 mL) was added dropwise over a period of 2.5 hours to a stirred refluxing solution of ethane-1,2-diamine (13.2 mL, 197 mmol) in ethanol (60 mL). The mixture was heated for another 2.5 hours, and sodium ethoxide in ethanol (21% by wt) (4.0 mL, 10.80 mmol) was added and the mixture was heated for another 90 minutes. The reaction was then cooled and concentrated. After trituration with ether, the title compound was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:29]([S:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH3:30].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:7]([C:5]2[O:6][C:2]([C:34]3[CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=[C:32]([S:31][CH2:29][CH3:30])[CH:33]=3)=[CH:3][CH:4]=2)=[CH:8][C:9]([C:25]([F:28])([F:27])[F:26])=[C:10]([C:23]#[N:24])[C:11]1=[O:22]
Reactant: CCSc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccc(Br)o2)n(Cc2ccc(F)cc2F)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCSc1cc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)o2)cc(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 56.2 %

Procedure:
6-(5-Bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (310 mg, 0.7 mmoles), 2-(3-Ethylsulfanyl-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (287 mg, 0.86 mmoles), tetrakis(triphenylphosphine)palladium (0) (81 mg, 0.07 mmoles), K2CO3 (450 mg, 3.3 mmoles) were combined in 12 ml of DME/H2O (9:1, degassed), and were stirred at 85° C. for 16 hours. After this period the reaction mix was evaporated and purified using flash silica chromatography (0-20% EtOAc/Hexane) to yield 1-(2,4-difluoro-benzyl)-6-[5-(3-ethylsulfanyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (0.23 g, 55%) as a yellow residue.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC([O-])(C)C.[K+].CN1CCCC1=O.[Cl:25][C:26]1[CH:31]=[C:30](F)[CH:29]=[CH:28][N:27]=1>CCOC(C)=O>[Cl:25][C:26]1[CH:31]=[C:30]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccnc(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
Add 4-methyl-3-nitrophenol (6.95 g, 45.46 mmol) and t-BuOK (5.94 g, 53.03 mmol) to N-methylpyrrolidin-2-one (100 mL), stir for 30 min, then add 2-chloro-4-fluoro-pyridine (5 g, 37.88 mmol) and stir the reaction at 70° C. overnight. TLC (PE:EtOAc=3:1) shows the reaction is complete. Add water (250 mL) to the reaction mixture, extract with EtOAc (100 mL×4), combine the organic layers, wash with water, brine respectively and dry over Na2SO4. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (5.8 g, 58%). MS: (M+1): 265.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22](O)=[O:23])[CH2:17]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:23]=[C:22]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:21][CH:18]1[CH2:19][CH2:20][N:16]([CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:17]1
Reactant: O=C(O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Reactant: C1CCNC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CCN(CCc2ccccc2N2CCCCC2=O)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetic acid a14-1 (115 mg, 0.348 mmol, 1 eq) and pyrrolidine (32 μl, 0.382 mmol 1.1 eq) in dichloromethane (5 ml) are added dicyclohexylcarbodiimide (79 mg, 0.82 mmol, 1.1 eq), hydroxybenzotriazole (52 mg, 0.382 mmol, 1.1 eq) and diisopropylethylamine (131 μl, 0.731 mmol, 2.1 eq). The reaction mixture is stirred overnight at room temperature, then filtered and concentrated under reduced pressure. The residue is purified by reverse phase chromatography (gradient: CH3CN/H2O/NH4OH from 30/70/0.1 to 60/40/0.1) to afford 9 mg of 1-[2-(2-{3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]pyrrolidin-1-yl}ethyl)phenyl]piperidin-2-one 86 as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13].O>CS(C)=O>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:13]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(Cn1ccc2ccccc21)OCC
Reaction time: 1 h

Procedure:
To a solution of 12 g of indole in 100 ml of dimethyl sulfoxide was added 6.5 g of sodium hydride at room temperature. The mixture was stirred at the same temperature for 1 hour, and 20 ml of bromoacetaldehyde diethyl acetal was added thereto, followed by further stirring at 50° C. for 1 hour. After cooling, the reaction mixture was poured into water, and the product was extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 23 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+:22]>[Pd]>[Na+:22].[F:12][C:9]1[CH:10]=[CH:11][C:6]([C@H:2]([NH:1][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](C(=O)O)c1ccc(F)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])[C@@H](NCc1ccccc1)c1ccc(F)cc1
Temperature: 15 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A solution of (S)-α-amino-4-fluorobenzeneacetic acid (1.00 kg, 5.91 moles) in aqueous sodium hydroxide (1M, 5.91 L) was filtered and added to 10% palladium-on-carbon (25 g). A solution of benzaldehyde (941 g, 8.87 moles) was added and the batch was stirred under hydrogen (50 psi) for 4 hours. The batch was filtered and the filtrate was evaporated to residue under vacuum, then flushed with ethanol (2×3 L). The residue was slurried in boiling ethanol (1.5 L), then cooled to 15° C. The slurry was filtered and the filter cake was washed with cold ethanol (2×500 mL), then dried under vacuum at 55° C. to give 1.83 kg (92% yield) of (S)-4-fluoro-α-[(phenylmethyl)-amino]benzeneacetate sodium salt.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]#[N:25])=[CH:22][C:21]([CH3:26])=[N:20]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:25][CH2:24][C:23]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[N:20]=[C:21]([CH3:26])[CH:22]=1)=[S:11]
Reactant: Cc1cc(C#N)n(-c2ccc(Cl)cc2)n1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Product: Cc1cc(CNC(=S)Nc2cccc(Cl)c2Cl)n(-c2ccc(Cl)cc2)n1
Yield: 56 %

Procedure:
Prepared in 56% yield from 2,3-dichlorophenylisothiocyanate and the product of Example 205A according to the procedure described for Example 153B.
Reaction SMILES: [CH3:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[CH2:7]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13](=[NH:16])OC)[CH2:8][CH3:9].[NH3:21]>C(O)C>[CH3:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[CH2:7]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH2:21])=[NH:16])[CH2:8][CH3:9]
Reactant: N
Reactant: CCCOc1ccccc1C(=N)OC
Agent: COS(=O)(=O)O
Solvent: CCO
Product: CCCOc1ccccc1C(=N)N
Reaction time: 17 h
Yield: 60 %

Procedure:
To a warm, stirred solution of 2-n-propoxybenzamide (896 g., 5.0 moles) in 1,2-dichloroethane (5 l) was added dimethyl sulfate (950 ml., 10.0 moles) over a period of about 0.5 hour. The mixture was stirred and heated under reflux for 17 hours. The solvent was removed. The residual oily solid was collected by filtration, washed with ethyl acetate and dried to give methyl 2-n-propoxybenzimidate methyl sulfate (403 g.), m.p. 79°-82°. The combined filtrate and washings were stored at 0° for 18 hours and gave a second crop (503 g.) of benzimidate, m.p. 81°-83°. A slurry of the methyl 2-n-propoxybenzimidate methyl sulfate (906 g.) in ethanol (1 l) was added to ethanol ( 4 l) which had previously been saturated with gaseous ammonia. The mixture was stored at room temperature for 17 hours. The mixture was filtered. The filtrate was evaporated to dryness to give 2-n-propoxybenzamidine methyl sulfate (872 g., 60%), m.p. 86°-88°.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[C:10]([C:13]1[CH:14]=[C:15]([CH:19]2[CH2:28][C:27]([CH3:30])([CH3:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:31](O)=[O:32])[CH:25]=3)[NH:20]2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])[NH2:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH:1]1([S:4]([NH:7][C:31]([C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:10]([NH2:11])=[O:12])[CH2:28][C:27]3([CH3:30])[CH3:29])=[O:32])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.1 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (200 mg, 1.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (66 mg, 1.65 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A34. A solution of 2-(3-carbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.66 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B34. Solution B34 was added to Solution A34 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-cyclopropanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzamide (10 mg, 24%) as a white solid: MS (ESI) M+1=428.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:18](=[O:29])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH2:30]([N:32](CC)CC)[CH3:31].C(=N)(OCC)C>CO>[ClH:2].[C:30]([N:26]1[CH2:25][CH2:24][CH:23]([NH:22][N:19]2[CH2:20][CH2:21][N:16]([S:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=4)[CH:9]=3)(=[O:14])=[O:15])[CH2:17][C:18]2=[O:29])[CH2:28][CH2:27]1)(=[NH:32])[CH3:31]
Reactant: CCN(CC)CC
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCNCC1
Agent: CCOC(C)=N
Agent: Cl
Solvent: CO
Product: CC(=N)N1CCC(NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-[1-(tert-Butoxycarbonyl)-4-piperidinylamino]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (300 mg) was combined with a 4N solution of hydrochloric acid in ethyl acetate (10 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to obtain a crude crystal of 4-(6-chloronaphthalene-2-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone hydrochloride. A solution of the resultant 4-(6-chloronaphthalene-2-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone hydrochloride and triethylamine (1.16 g) in methanol (15 ml) was combined with ethyl acetoimidate (712 mg) and stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with a 1N aqueous solution of sodium hydroxide, dried and concentrated. The resultant residue was dissolved in ethyl acetate, combined with a solution of hydrochloric acid in ethyl acetate to precipitate a hydrochloride, which was collected by filtration and dried to obtain the title compound (243 mg) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([N:11]=[C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[OH:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([N:11]=[C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:27])[CH3:10]
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1O)C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1OC(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.8 g. of [(5-chloro-2-hydroxy-α-phenylbenzyliden)amino] malonic acid diethyl ester in 15 ml. of pyridine is treated at 10°-15° C. with 3.5 ml. of benzoyl chloride. The mixture is stirred at room temperature for 1 hour and then poured on to 150 ml. of ice-water. The separated oil product is extracted with ehter and the organic phase washed with water, then with 2-N sodium carbonate solution and finally with water. After drying over sodium sulfate and evaporation of the solvent, the oily residue is triturated with hexane, crystallization setting in. There is obtained [(2-benzoyloxy-5-chloro-α-phenylbenzyliden)amino] malonic acid diethyl ester in the form of colorless crystals, having a melting point of 108°-110° C. Recrystallization from ethanol increases the melting point to 109°-111° C.