Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(F)c1F
Product: Fc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1F

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3-Difluorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 505.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:39](=[O:40])[CH2:38][Cl:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CN(Cc1ccccc1)C(=O)CCl)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (1RS,2SR)-3-(benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(3,4-dichlorophenyl)propan-1-ol (10.9 g) and triethylamine (4.00 mL) in THF (100 mL) was added chloroacetyl chloride (1.91 mL) under ice-cooling, and the mixture was stirred at 0° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (12.5 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C=O.[C:39]([BH3-])#N.[Na+]>CO.CC(O)=O>[CH3:39][N:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[C:20]1[N:19]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)[CH:21]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc([C@H]4CCCN4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC[C@@H]1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into an 8 mL vial was weighed 20.7 mg (40 μmol) of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-4-((R)-pyrrolidin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole. The material was dissolved in MeOH (400 μL) and HOAc (100 μL). The solution was treated with 20 μL (240 μmol) of 37% aqueous formaldehyde solution, and then 8 mg (125 μmol) of sodium cyanoborohydride was added at ambient temperature. After stirring for 15 minutes at ambient temperature LC/MS analysis of the reaction showed complete conversion to product. The reaction solution was directly injected into the reverse phase preparative HPLC and eluted with acetonitrile/water. (Phenomenex Axia Gemini C18 30×100 mm 5 μm, A=H2O with 0.1% trifluoroacetic acid, B=acetonitrile with 0.1% trifluoroacetic acid, 17 minute gradient from 10% B to 100% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3×), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting 4-((R)-1-methylpyrrolidin-2-yl)-1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole was isolated as a white foam, yield: 16.9 mg (79%); 1H NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.93-7.90 (m, 1H), 7.83-7.79 (m, 1H), 7.72-7.68 (m, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.54-7.48 (m, 4H), 7.43-7.38 (m, 1H), 7.27-7.18 (m, 4H), 3.41-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.08 (s, 3H), 2.44 (s, 3H), 2.41-2.26 (m, 2H), 2.13-1.94 (m, 2H), 1.90-1.79 (m, 1H); MS (ES): 526.5 [M+H]+.
Reaction SMILES: P(=O)(O)(O)O.Cl[C:7]1[CH:12]=[CH:11][C:10](NC(=O)COCC(O)=O)=[C:9]([C:22]([O:24]C)=[O:23])[CH:8]=1>>[C:22]([OH:24])(=[O:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Agent: O=P(O)(O)O
Product: O=C(O)c1ccccc1

Procedure:
Using the same method as in Example 1-(ii), phosphoric acid.[4-(3-aminophenyl)-1H-pyrazol-1-yl]methyl.di-tert-butyl was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([2-([3-(1-([(di-tert-butoxyphosphoryl)oxy]methyl)-1H-pyrazol-4-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 45%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>C(Cl)Cl>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Solvent: ClCCl
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) was added to 100 mL of methylene dichloride and stirred for 30 minutes. (S)-epichlorohydrin (21 g, 0.23 mol) was then added. The mixture was stirred at room temperature (25° C.) for 20 hours. Filtered, and the solvent was evaporated to provide 55 g of colorless oil in 93% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4].[BH4-].[Na+].[OH-].[NH4+:22]>>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][C:10]=1[NH2:22])=[O:4]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: [NH4+]
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1=C(N)CCN(Cc2ccccc2)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
rac-1-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (25 g) was suspended in 100 ml ammonium hydroxide 25% and heated at 50° C. during 18 h. The mixture was cooled with ice and then, NaBH4 (1 g) was added in several portions. Stirring was continued for 18 h at ambient temperature and the mixture was diluted with water/ice, with cooling, and extracted with AcOEt. The organic extract was washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, heptane/AcOEt, 1/1) and precipitated (AcOEt/heptane) to give 12.1 g (56%) of the title compound as white solid and 6 g (25%) of the title compound as its borane salt.
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:21]([N:23]1[CH2:34][CH2:33][CH2:32][C@H:24]1[C:25]([NH:27][CH2:28][C:29]([NH2:31])=[O:30])=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=O)C1C=CC=CC=1>CO>[ClH:1].[NH2:12][C@H:13]([C:21]([N:23]1[CH2:34][CH2:33][CH2:32][C@H:24]1[C:25]([NH:27][CH2:28][C:29]([NH2:31])=[O:30])=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: Cl
Solvent: CO
Product: N=C(N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reaction time: 0.67 h

Procedure:
Nα -Benzyloxycarbonyl-L-arginyl-L-prolyl-glycinamide hydrochloride, (Example 1, part m) 1.2 g., is dissolved in 60 ml. of absolute methanol, treated with 380 mg. of 10% palladium-on-carbon and the flask flushed with nitrogen, then with hydrogen and the reduction carried out for 40 minutes. Completion of the reaction is determined by thin layer chromatography. The mixture is filtered to separate the catalyst and the filtrate is evaporated and dried under reduced pressure to yield L-arginyl-L-prolyl-glycinamide hydrochloride.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.N#N.[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[Si:28]([C:20]1[C:19]([F:23])=[CH:18][N:17]=[C:16]([F:15])[C:21]=1[F:22])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: Fc1cnc(F)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
n-BuLi (41.09 mL of 1.6 M, 65.75 mmol) was added dropwise to a solution of diisopropylamine (6.919 g, 9.583 mL, 68.38 mmol) in THF (130 mL), cooled to −5° C. (under N2). After stirring for 15 min, the reaction mixture was cooled down to −78° C. 2,3,5-Trifluoropyridine (7 g, 52.60 mmol) was added dropwise to the reaction mixture which was stirred for 45 min. A solution of tert-butyl-chloro-dimethyl-silane (10.31 g, 68.38 mmol) in THF (15 mL) was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 2 hours. It was quenched with a saturated ammonium chloride aqueous solution (˜50 ml). The reaction mixture was partitioned between ethyl acetate and a saturated sodium bicarbonate aqueous solution. The aqueous was extracted with ethyl acetate twice. The combined organics were washed with brine. The organic was dried over magnesium sulfate and concentrated in vacuo after filtration. The crude mixture was purified on silica gel, eluting with petrol ether/ethyl acetate 0 to 20% to afford the title compound as a pale yellow solid (11.8 g, 90%). 1H NMR (CDCl3) 0.34 (6H, s), 0.87 (9H, s), 7.71 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:12]=2)=[C:4]([O:29][CH2:30][CH3:31])[CH:3]=1.[C:32](Cl)([Cl:34])=[O:33]>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:32]([Cl:34])=[O:33])[C:11]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[C:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[N:9]=2)=[C:4]([O:29][CH2:30][CH3:31])[CH:3]=1
Reactant: CCOc1cc(Br)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(Br)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(4-bromo-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [CH2:1]([N:6]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:30]([OH:32])=[O:31])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N+](=[CH2:40])=[N-]>CO.C(OCC)C>[CH2:33]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:30]([O:32][CH3:40])=[O:31])[CH2:10]1)=[O:8])[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C=[N+]=[N-]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)[C@H](C(=O)O)C1
Solvent: CO
Solvent: CCOCC
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)[C@H](C(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 368 mg (0.725 mmole) of (S)-4-(dipentylcarbamoyl)-1-(diphenylacetyl)piperazine-2carboxylic acid (from Example 9) in 5 ml of methanol was treated at 0° C. with 20 ml of diazomethane solution in diethyl ether (prepared by the procedure above). The solution was stirred at 0° C. for 30 minutes and at 25° C. for 30 minutes. The excess diazomethane was destroyed by the dropwise addition of acetic acid until the solution became colorless. The resulting solution was concentrated in vacuo and the residue was chromatographed over an 85×2.5 cm LH-20 column and concentrated in vacuo to 225 mg (59%) of pale colored oil which was homogeneous by TLC (1:1 hexane-ethyl acetate, Rf =0.7).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[OH:8].O.S(S([O-])=O)([O-])=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>O.C(O)C>[NH2:9][C:6]1[CH:5]=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=[C:2]([F:1])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(F)c1O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)cc(F)c1O
Reaction time: 0.5 h

Procedure:
The product from (e) (4.1 g) in water (50 ml) was stirred vigorously while sodium dithionite hydrate (10 g) was added in portions. The mixture was stirred for 30 minutes and then ethanol (25 ml) and further sodium dithionite (5 g) were added. The mixture was stirred for another 15 minutes and then diluted to 400 ml, acidified (HCl) and extracted with dichloromethane (4×200 ml). The dichloromethane extract was dried (MgSO4) and evaporated to give a yellow oil which crystallised on cooling. This was identified as 3-amino-5-fluoro-4-hydroxybenzotrifluoride (2.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:30])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1CCNC1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2- one (Example 96) (219 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (157 mg, 64%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:5]1([CH2:4][O:3][C:1](=[O:2])[NH:11][C@@H:12]([CH3:13])[C:14](=[O:16])[NH:17][N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nn1cccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.3 %

Procedure:
To a stirred solution of carbobenzyloxy-L-alanine (10.0 g) and N-aminopyrrole (3.68 g) in dry DCM (224 ml) was added DCC (9.71 g) at 0° C. under nitrogen. The cooling bath was removed after ten minutes and the reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was filtered and the solid DCU filter cake was washed with hot ethyl acetate. Concentration of the combined filtrate gave the crude product. Recrystallization from ethyl acetate/hexane afforded 10.46 g of the product as a solid, m.p. 169°-171° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][NH:23][C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: NCC1CC1
Product: Cc1c(-c2ccc(C(=O)NCC3CC3)s2)noc1C(F)(F)F
Yield: 67 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and cyclopropylmethylamine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, triturated and filtered with the aid of water, then washed with an aqueous 1 N hydrochloric acid solution followed by water. The crude solid was then triturated with a 25% EtOAc/hexanes solution (3×1 mL) and air dried to afford product as a colorless solid (110 mg, 67%). 1H NMR (CDCl3) 0.27-0.32 (m, 2H), 0.55-0.61 (m, 2H), 1.03-1.12 (m, 1H), 2.37 (d, J=0.9, 3H), 3.31 (d, J=5.7, 1H), 3.33 (d, J=5.7, 1H), 6.23 (br s, 1H), 7.50 (d, J=4.0, 1H), 7.56 (d, J=4.0, 1H). 19F NMR −63.1. LC/MS 6.5 min, [M+1]+ 331.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl[CH:20]([CH3:24])[C:21]([OH:23])=[O:22].[OH-].[Na+]>>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(Cl)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
5.1 g of 4-(4-trifluoromethylphenoxy)phenol and 2.1 g of α-chloropropionic acid were heated at 80° C. with stirring, and 6.2 g of a 30% aqueous solution of sodium hydroxide was added. The reaction was carried out for 0.5 hour at 90° to 95° C. After allowing the reaction mixture to cool, the resulting solid precipitate was withdrawn, and washed with a small amount of methanol. The precipitate was dried overnight at reduced pressure to afford 5.3 g (yield: 81.5%) of the final product having a melting point of 138° to 140° C.
Reaction SMILES: [CH2:1]([C:15]([O:17][CH3:18])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-])=[O:13].O=S(Cl)[Cl:21]>C(Cl)Cl>[CH3:18][O:17][C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:21])=[O:13])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)CCCCCCCCCCCC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold solution of 4.8 gms monomethyl 1,11-undecanedicarboxylate in 10 ml CH2Cl2 was added 5 ml SOCl2 dropwise over 5 minutes; then it was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give 4.8 gms of an oily residue which was used without further purification.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)=[CH:9][CH:8]=1)[CH:2]=[CH2:3].[CH:18]([NH2:21])([CH3:20])[CH3:19]>CO>[CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:14])[CH2:15][NH:21][CH:18]([CH3:20])[CH3:19])=[CH:9][CH:8]=1)[CH:2]=[CH2:3]
Reactant: CC(C)N
Reactant: C=CCOCCc1ccc(OCC2CO2)cc1
Solvent: CO
Product: C=CCOCCc1ccc(OCC(O)CNC(C)C)cc1
Yield: 73.9 %

Procedure:
A solution of the compound of formula (5) (3.70 g, 0.016 mol), isopropyl amine (7.46 ml, 0.127 mol) in methanol (20 ml) was stirred under reflux for 2 hours and then concentrated. The residue was partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was crystallized from pet ether to afford compound of formula (1) as a white solid 3.47 g (75%) mp 52–53° C.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].OS(O)(=O)=O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:2][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)=[O:3])[CH3:19]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc[nH]c2c1
Reaction time: 4 h

Procedure:
Combine 6-carboxy-1H-indole and ethanol (110 ml) and cool to 5° C. Add dropwise concentrated H2SO4 (96%, 11.08 ml) while keeping the temperature below 10° C. Heat to reflux. After 4 hours, cool and pour onto ice/water, adjust the pH to about pH 9 and extract with ethyl acetate. Combine the organic extracts, wash with brine, dry (Na2SO4), then concentrate to residue. Chromatograph the residue on silica gel eluting with chloroform to give, after evaporation, the title compound: mp 72–75° C. MS (ACPI): m/e 189.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(=O)C)[CH2:6][CH2:5]2.C([O-])([O-])=O.[Na+].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Brc1ccc2c(c1)CCN2
Yield: 54.9 %

Procedure:
A mixture of crude 1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanone (100 g, 0.34 mol) in HCl (20%, 1200 mL) was heated at reflux for 6 h. The mixture was basified with Na2CO3 to pH 8.5-10 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-bromo-2,3-dihydro-1H-indole (37 g, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[C:9]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt].C(O)C>[C:1]([O:5][C:6]([CH2:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C1CC(C(=O)O)C1
Agent: [Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1

Procedure:
A mixture of 2 g of 3-tert-butoxycarbonylmethylene-cyclobutanecarboxylic acid, 150 mL of ethanol, 0.5 g of 5% platinum on carbon, and 200 mL of ethanol was stirred under 1 atm of hydrogen for 48 h overnight, filtered, diluted with 20 mL of toluene and concentrated under reduced pressure. Drying under vacuum overnight gave 2 g of product, which was predominantly as a colorless oil: 1H NMR (400 MHz, CDCl3) 10.2 (br s, 1H), 3.0 (m, 1H), 2.3 (m, 1H), 2.38 (m, 4H), 2.0 (dd, 2H), 1.4 (s, 9).
Reaction SMILES: [NH2:1][C@H:2]([C:10](O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)C.[OH-].[K+].[C:18](=[S:20])=[S:19]>>[SH:19][C:18]1[S:20][CH2:10][CH:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: SC1=NC(Cc2ccccc2)CS1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
A total of 75 mmoles of Phe in 225 mmoles of ethanol containing 300 mmoles of carbon disulfide and 75 mmoles of solid potassium hydroxide is added with stirring while maintaining the temperature below 40° C. The temperature is then raised to 40° C. and the reaction mixture held in a closed vessel for 12 hours. At the end of this period, the alcohol and carbon disulfide are removed by rotary evaporation. The residue is suspended in a small amount of cold water, and the product recrystallized from the water-ethanol mixture.