Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:13][C:10]1[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 57.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (260 mg, 1.2 mmol), 2-nitrobenzene-1-sulfonyl chloride (597 mg, 2.69 mmol), DMAP (cat) and pyridine (0.3 ml, 3.67 mmol) in DCM (5 ml) gave the title compound (275 mg, 56%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].[CH2:8](N(CC)CC)[CH3:9].C(=O)C.[BH4-].[Na+]>CO>[ClH:1].[CH2:8]([NH:5][CH2:4][C:3]([F:7])([F:6])[F:2])[CH3:9]
Reactant: CCN(CC)CC
Reactant: NCC(F)(F)F
Agent: CC=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CCNCC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 743.5 %

Procedure:
To a solution of 2,2,2-trifluoroethylamine hydrochloride (0.5 g, 3.7 mmol) in MeOH (5 mL) was added triethylamine (0.51 mL, 0.37 mmol) followed by acetaldehyde (1.0 mL, excess). The reaction mixture was then stirred at 0° C. for 3 h. Sodium borohydride (1 g, 5.9 mmol) was then added and the reaction mixture was stirred at 0° C. for 20 min. The reaction was quenched with 1M NaOH (10 mL) and the aqueous layer was extracted with DCM (25 mL). The organic layer was separated and to it was added 2M HCl in Et2O (10 mL). The resultant precipitate was filtered to give 0.45 g of N-ethyl-2,2,2-trifluoroethanamine hydrochloride, (yield: 75%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@@H:4]([C:17]([OH:19])=[O:18])[CH2:3]1.N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.CCOC(C)=O.CCCCCC>[Si:29]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@@H:4]([C:17]([OH:19])=[O:18])[CH2:3]1)([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a mixture of cis4-hydroxy-N-benzyloxycarbonyl-D-proline (18.74 g) and imidazole (11.56 g) in DMF (100 mL) was added TBDMSCl (23.36 g) at 5° C. After stirring at room temperature for 16 hours, the reaction mixture was diluted with EtOAc-hexane (1:1, 600 mL), washed with 1N HCl, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was dissolved in MeOH-THF (3:1, 400 mL). To the solution was added an aqueous solution (100 mL) of K2CO3 (9.77 g) at 5° C., and the mixture was stirred at the same temperature for 1 hour. The organic solvent was evaporated, and the residue was adjusted to pH 2 by the addition of 3N HCl, and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography to give cis-4-(tert-butyldimethylsilyloxy)-N-benzyloxycarbonyl-D-proline (23.99 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](=[O:33])(=[O:32])[NH:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](=[O:33])(=[O:32])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Yield: 53.9 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 2-(4-bromo-2-trifluoromethyl-phenylsulfamoyl)-5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester (0.108 g), 4-pyridineboronic acid (0.036 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (0.4 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.023 g) to obtain the desired compound (0.058 g) as a brownish foam. MS (ISN): 548.3 (M−H)−
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([NH2:18])=O)[CH:10]=[CH:9]2)=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:1]([N:3]([CH2:4][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH2:16][NH2:18])[CH:10]=[CH:9]2)[CH2:19][CH3:20])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc2cc(C(N)=O)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc2cc(CN)ccc2c1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 6-(diethylaminocarbonyl)-2-naphthalenecarboxamide (11.6 g, 42 mmol) in THF (100 ml) was slowly added to a refluxing suspension of lithium aluminium hydride (4.9 g, 128 mmol) in THF (100 ml). The mixture was refluxed for 2 hours, then cooled at room temperature and treated with a mixture of THF (16 ml) and water (2.2 ml), with 20% sodium hydroxide (5.5 ml) and finally with water (22 ml). The white solid was filtered off and the solvent was removed under reduced pressure. Crude was purified by chromatography on silica gel (eluent chloroform-methanol-ammonium hydroxide 15:1:0.1) yielding 8.1 g (Yield 80%) of pure 6-(diethylaminomethyl)-2-naphthylmethylamine as waxy solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(O)=O.[Na+]>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>[C:10]1([C:2]2[CH:6]=[CH:5][O:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1occc1Br
Reactant: OB(O)c1ccccc1
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: [Na+]
Product: O=C(O)c1occc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To 3-bromo-2-furancarboxylic acid (540 mg, 2.8 mmol dissolved in DME (105 ml)) was added of (Ph3P)4Pd (936 mg, 0.81 mmol), and the resulting solution was stirred at room temperature for 15 min. The mixture was treated with 500 mg (3.0 mmol) of benzene boronic acid, an aqueous solution of 2M NaHCO3 (4 mmol) and heated to reflux for 10 hours. After cooling to room temperature, the solvent was partially removed under reduced pressure, and the resulting mixture was extracted twice with diethyl ether. The water layer was acidified with 10% HCl and extracted with ethyl acetate (5 times). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated under reduced pressure. The residue was crystallized from a mixture of n-hexane/ethyl acetate (about 8:2) to give the title compound. Yield: 70%.
Reaction SMILES: [Br:1]C1C=NNC=1.[H-].[Na+].[CH2:9]([O:16][CH2:17][CH2:18]O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[Br:1][CH2:18][CH2:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cn[nH]c1
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
4-Bromopyrazole (2.205 g) was dissolved in tetrahydrofuran (20 ml). Under ice cooling, 60% sodium hydride (625 mg) was added thereto followed by stirring. After 30 min, benzyl 2-bromoethyl ether (3.872 g) obtained from 2-benzyloxyethanol in the same manner as the one of Production Example 1 was added thereto and the resultant mixture was stirred at room temperature overnight. Then the reaction solution was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (2.287 g) as a colorless oil (yield: 53%).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:31])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])=[N:14][C:13]=1[CH3:30].CI>>[CH3:9][O:10][C:11](=[O:31])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])=[N:14][C:13]=1[CH2:30][CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(C)n1
Agent: [Li+]
Solvent: CI
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(CC)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
LDA (19 mg, 89 μL of 2 M solution in THF, 0.18 mmol) at −78° C. is added to a solution of 6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-nicotinic acid methyl ester (27 mg, 0.086 mmol). The mixture is stirred for 30 minutes at −78° C. Methyl iodide (15 μL, 0.24 mmol) is added and the resulting yellow mixture is stirred for 10 minutes at −78° C. After quenching with saturated NH4Cl the mixture is extracted with EtOAc. The combined extracts are dried, concentrated, and purified by flash-chromatography to give 6-(2,6-diethyl-phenyl)-2-ethyl-4-methoxy-nicotinic acid methyl ester.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([CH:7]1[CH2:10][N:9]([C:11](=[O:26])[C@H:12]([CH2:24][OH:25])[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8]1)=[O:6].Cl.C(OCC)(=O)C>O.CO>[C:14]([NH:13][C@H:12]([C:11]([N:9]1[CH2:10][CH:7]([C:5]([OH:6])=[O:4])[CH2:8]1)=[O:26])[CH2:24][OH:25])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: COC(=O)C1CN(C(=O)[C@H](CO)NC(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(N[C@@H](CO)C(=O)N1CC(C(=O)O)C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
20 ml of a ca. 1M solution of lithium hydroxide in water was added to a stirred solution of 3.36 g of 1C in 100 ml of methanol at 0° C., and the mixture was stirred for 1.5 hours at 0° C. The mixture was neutralized (to pH 6-7) with 6N hydrochloric acid, the filtrate was stripped of solvent under reduced pressure and a temperature up to 55° C., and the residue was subjected to very low pressure (<1 Torr.). The residue was dissolved in 75 ml of methanol, 100 ml of ethyl acetate was added, the mixture was filtered, and the solvents were evaporated under reduced pressure. The residue was purified by flash chromatography, using a 2:1 v:v mixture of ethyl acetate and methanol as eluent. The solvents were evaporated and the residue was recrystallized from ethanol/ether, to give N-(N-carbobenzyloxy-L-seryl)-3-azetidinecarboxylic acid (1D) as a colorless hygroscopic solid, m.p.: 138°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S(=O)(O)[O-].[Na+]>CCOCC.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1ccc(F)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a stirred solution of 326 (1.134 g, 3.914 mmol) and DCM (8 mL) under nitrogen cooled to 0° C. was added NaHCO3 (0.9864 g, 11.74 mmol) followed by Dess-Martin periodinane (2.490 g, 5.871 mmol) both as solids. After 3 h, the reaction was about 50% complete by TLC. The reaction was warmed to RT for 1 h, then the reaction was diluted with Et2O (10 mL) and poured into ice cold satd. aq. NaHCO3 (50 mL) containing sodium bisulfite (15 gm). After stirring for 15 min, the layers were separated and the aqueous phase was extracted with Et2O (2×30 mL). The combined organic extracts were washed sequentially with satd. aq. NaHCO3 (2×50 mL) and brine (1×50 mL), dried (MgSO4), filtered and concentrated to afford 0.814 g (72%) of (S)-tert-butyl 1-(3-chloro-4-fluorophenyl)-2-oxoethylcarbamate (328) as a yellow foam.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[C:10]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:11]([C:23]2[O:27][C:26]([CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][CH:24]=2)[C:12]([O:19][CH2:20][O:21][CH3:22])=[CH:13][C:14]=1[O:15][CH2:16][O:17][CH3:18]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1(C)C=CC=CC=1>[Br:8][C:9]1[C:10]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:11]([C:23]2[O:27][C:26]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][CH:24]=2)[C:12]([O:19][CH2:20][O:21][CH3:22])=[CH:13][C:14]=1[O:15][CH2:16][O:17][CH3:18]
Reactant: COCOc1cc(OCOC)c(-c2ccc(C=CC(=O)OC)o2)c(CC(=O)OC)c1Br
Agent: [Rh]
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COCOc1cc(OCOC)c(-c2ccc(CCC(=O)OC)o2)c(CC(=O)OC)c1Br
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In an argon atmosphere, triethylsilane (0.15 mL, 0.94 mmol) and tris(triphenylphosphine)rhodium(I) chloride (30 mg, 0.032 mmol) were added to toluene (2.0 mL) solution of methyl 3-{5-[3-bromo-2-(methoxycarbonylmethyl)-4,6-bis(methoxymethoxy)phenyl]furan-2-yl}acrylate (89 mg, 0.18 mmol) obtained in the above, and stirred at 50° C. for 3 hours. The reaction solution was concentrated, and the residue was purified through silica chromatography (n-hexane to ethyl acetate/n-hexane=1/2) to obtain methyl 3-{5-[3-bromo-2-(methoxycarbonylmethyl)-4,6-bis(methoxymethoxy)phenyl]furan-2-yl}propanoate. Then, the resulting compound was dissolved in methanol solution (5.0 mL) of 10% hydrochloric acid, stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (methanol/chloroform=1/9) to obtain Compound 267 (35 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)c1
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of crude (4′-aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl ester (8.2 g 27 mmol) and Et3N (4.2 g, 40 mmol) in dichloromethane (250 mL) was added dropwise MsCl (3.2 g, 27 mmol) at 0° C. The reaction mixture was stirred at this temperature for 30 min and was then washed with water and saturated aqueous NaCl solution, dried over Na2SO4, and concentrated to dryness. The residue was recrystallized with DCM/pet ether (1:3) to give [4′-(methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic acid tert-butyl ester (7.5 g, yield 73%). 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.23-7.41 (m, 5H), 6.57 (s, 1H), 4.65-4.77 (m, 1H), 4.35 (d, J=6 Hz, 2H), 2.90 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.[C:15]([N:22]([CH3:31])[C@H:23]([C:28]([OH:30])=O)[CH2:24][CH:25]([CH3:27])[CH3:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[NH2:32][C@H:33]([C:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36])[CH3:34]>C(Cl)(Cl)Cl>[C:15]([N:22]([CH3:31])[C@H:23]([C:28]([NH:32][C@H:33]([C:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36])[CH3:34])=[O:30])[CH2:24][CH:25]([CH3:26])[CH3:27])([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: C[C@H](N)C(=O)Cc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
23.3 ml (18.9 g=157 mMol) pivaloyl chloride and 48 ml (28.9 g=286 mMol) triethylamine are added to a solution of 35 g (143 mMol) BOC-MeLeu-OH in 500 ml chloroform and the mixture stirred for 2 hrs. at room temperature under a nitrogen atmosphere. 30.7 g (171 mMol) H-Ala-Bzl dissolved in 300 ml chloroform are then added and the reaction mixture stirred for a further 2 hrs. at room temperature, again under a nitrogen atmosphere. The product is purified in accordance with the technique of example 1a) to yield the title compound:
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:8]1([Li])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CCOCC>[OH:6][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4][CH2:5][C:1]1=[O:7]
Reactant: O=C1CCCC1=O
Reactant: [Li]c1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=C1CCCC1(O)c1ccccc1
Yield: 58.4 %

Procedure:
A solution of 73.5 g (0.75 mole) of 1,2-cyclopentanedione in 400 ml of ether was added to 1.5 moles of phenyl lithium in 1.2 liter of ether, and the mixture was stirred under N2 for one half hour. After careful addition of water, the ethereal layer was separated, dried over magnesium sulfate and the solvent evaporated. The residue was distilled under reduced pressure and gave 77.2 g of 2-hydroxy-2-phenylcyclopentanone, b.p. 122°-126° C. (1.5 mm), nD25 1.5551. The oxime was prepared by known procedures, m.p. 110°-112° C., and was reduced by hydrogenation over Raney nickel in 20% alcoholic ammonia. Removal of catalyst, evaporation of solvent and addition of HCl gave 2-hydroxy-2-phenylcyclopentylamine hydrochloride, m.p. 198°-199° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:12]([OH:14])=O)=[CH:5][N:6]2[CH3:11].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:29]([F:40])[CH:28]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:33][C:32]1[C:27]([NH:26][C:12]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[N:6]([CH3:11])[CH:5]=2)=[O:14])=[CH:28][C:29]([F:40])=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Reactant: Cn1cc(C(=O)O)c2c(F)cccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3cccc(F)c23)cc1F
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a suspension of 4-fluoro-1-methylindole-3-carboxylic acid (700 mg, 3.62 mmol) and DMF (28.0 μl, 0.36 mmol) in methylene chloride (20 ml) was added oxalyl chloride (0.35 ml, 3.99 mmol) in portions under stirring at room temperature. After the reaction mixture was stirred at room temperature for 50 minutes, oxalyl chloride (30 μl) was added, and the mixture was stirred for further 40 minutes. To the reaction mixture, a solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (839 mg, 3.62 mmol) and triethylamine (1.52 ml, 10.9 mmol) in methylene chloride (5 ml) was added and the mixture was heated under reflux at room temperature for 4 hours. After cooling to room temperature, the reaction mixture was added with water, followed by extraction with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography opn a silica gel column, whereby from n-hexane-ethyl acetate (2:1, v/v) eluate fractions, ethyl (5-chloro-2-fluoro-4-((4-fluoro-1-methyl-3-indolylcarbonyl)amino)phenyl)acetate (762 mg, 52%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O1CCOCC1.[OH-].[Na+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.O>[CH2:21]([O:28][C:29]([NH:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc2ccccc2[nH]c1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cc2ccccc2[nH]c1=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution containing 0.5 g (3.10 mmol) of 3-amino-quinoline-2-(1H)-one described by Anderson, et. al. (J. Heterocyclic Chem., 30:1533 (1993)) in 40 mL, of dioxane under a nitrogen atmosphere was added 0.14 g (3.4 mmol) of sodium hydroxide in 14 ml, of water. The reaction mixture was cooled to 0° C., followed by the addition of 0.50 mL (3.4 mmol) of benzylchloroformate. The pH of the reaction was maintained above 8.0 with additional 1 N sodium hydroxide. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was diluted with methylene chloride and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent under reduced pressure and column chromatography of the residue on silica gel with 2% methanol/dichloromethane afforded 0.32 g (35%) of product as a white solid. FAB MS [M+H] m/z; Calcd: 295, Found: 295
Reaction SMILES: [Na].[CH:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)=O.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1.ClCCl.C(OCC)(=O)C.C(OCC)C.C(O)(=O)C>[O:15]=[C:14]1[C:13]([C:11]#[N:12])=[CH:2][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[NH:16]1
Reactant: O=CC1CCCCC1=O
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: N#Cc1cc2c([nH]c1=O)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 318.9 %

Procedure:
To a solution of sodium salt of 2-formylcyclohexanone (16.0 g, 10.8 mmol) in toluene (300 mL) was added cyanoacetamide (22.00 g, 0.237 mol), and the reaction was allowed to stir at room temperature for 1 h. After this time, a 2M solution of piperidine acetate in dichloromethane (25 mL) was added, and the reaction was refluxed for 24 h. The reaction mixture was then cooled to 0° C., and acidified with acetic acid. The resulting suspension was filtered and the precipitate was washed with toluene. The filtrate was concentrated to give a sticky residue, which was was treated with diethyl ether followed by ethyl acetate, to provide 2-oxo-1,2,5,6,7,8-hexahydro-quinoline-3-carbonitrile as a fine solid (6.00 g), yield: 31.8%.