Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1([O:50]C)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[C:17]([C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[C:24](=[O:28])[C:23]([O:31]C)([O:29]C)[C:22]5=[O:33])[CH:16]=[C:15]([C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[C:39](=[O:43])[C:38]([O:46]C)([O:44]C)[C:37]5=[O:48])[CH:14]=3)[CH:9]=2)[C:4]1=[O:49].C(O)(=O)C.Br>O>[OH:31][C:23]1([OH:29])[C:22](=[O:33])[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:17]3[CH:16]=[C:15]([C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[C:39](=[O:43])[C:38]([OH:46])([OH:44])[C:37]5=[O:48])[CH:14]=[C:13]([C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[C:4](=[O:49])[C:3]([OH:50])([OH:2])[C:11]5=[O:12])[CH:18]=3)[CH:20]=2)[C:24]1=[O:28]
Reactant: COC1(OC)C(=O)c2ccc(-c3cc(-c4ccc5c(c4)C(=O)C(OC)(OC)C5=O)cc(-c4ccc5c(c4)C(=O)C(OC)(OC)C5=O)c3)cc2C1=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(-c3cc(-c4ccc5c(c4)C(=O)C(O)(O)C5=O)cc(-c4ccc5c(c4)C(=O)C(O)(O)C5=O)c3)cc2C(=O)C1(O)O
Temperature: 110 °C
Yield: 87.3 %

Procedure:
1,3,5-tris(2,2-dimethoxy-1,3-dioxoindan-5-yl)benzene (26) (101 mg, 0.146 mmol) was suspended in a solvent mixture of 2 ml of acetic acid and 2 ml of water, and the suspension was mixed with 2 ml of 47% hydrobromic acid. The mixture was refluxed at 110° C. for 1.5 hours. After it was cooled to room temperature, the reaction solution was diluted with water, and the resulting solid was filtered and dried, to obtain 77.3 mg (87%) of 1,3,5-tris(2,2-dihydroxy-1,3-dioxoindan-5-yl)benzene (27) in the form of a gray solid. The readings for this compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:15]([O:17][C:18](=[O:25])[C@H:19]([CH2:21][CH2:22][S:23][CH3:24])[NH2:20])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:25])[C@H:19]([CH2:21][CH2:22][S:23][CH3:24])[NH:20][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:16]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)[C@@H](N)CCSC
Agent: Cl
Product: CCOC(=O)[C@H](CCSC)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure G above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride. NMR data was as follows:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][CH3:21].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>O1CCCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:20]([CH3:21])[CH3:19])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(O)Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: CN(C)C(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
(4′-Bromobiphenyl-4-yl)acetic acid (1.0 g, 3.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and methanol (20 mL), and dimethylamine hydrochloride (0.42 g, 5.2 mmol), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.3 g, 4.7 mmol) and N-methylmorpholine (0.95 mL, 8.6 mmol) were added, followed by stirring at room temperature for 18 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: dichloromethane/ethyl acetate), and a fraction corresponding to the Rf value=0.55 (dichloromethane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.82 g, 2.6 mmol) as a white solid (yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH:11][C:25](=[O:27])[CH3:26])[CH:10]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NC(C)=O)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (3.672 mmol, 884.9 mg) and pyridine (36.7 mmol, 3 mL) in 8 mL of dry CH2Cl2 was added acetic anhydride (7.3 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate (150 mL). The organic layer was washed with saturated aqueous CuSO4 solution, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5-acetylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (quant. Yield), which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:34]1[N:39]([CH2:40][CH2:41][NH2:42])[CH2:38][CH2:37][O:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:42][CH2:41][CH2:40][N:39]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(4-morpholino)ethylamine employing methods similar to those described in Example 5. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). This procedure gave the product as an off-white rigid foam: 1H NMR (CDCl3) δ 10.46 (1H, br t, J˜6 Hz), 8.59 (1H, d, J=1.3 Hz), 8.12 (1H, s), 7.24 (2H, dd, J=8.6, 5.4 Hz), 7.00 (2H, t, J=8.6 Hz), 4.32 (2H, br t, J=7 Hz), 4.16 (2H, s), 3.98 (4H, br), 3.91 (2H, q, J=6 Hz), 3.77 (2H, br), 3.50 (4H, m), 3.39 (2H, t, J=6 Hz), 2.92 (2H, br), 2.41 (2H, t, J=8 Hz), 2.05 (2H, m); ES+ MS: 538 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]2[C:11]=1[C:12]([NH:14][NH2:15])=[O:13].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26].O>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([NH:15][NH:14][C:12]([C:11]1[N:5]2[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1])=[O:13])=[O:26]
Reactant: Cc1ccc2nc(C)c(C(=O)NN)n2c1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(C)c(C(=O)NNC(=O)CCl)n2c1
Temperature: 25 °C
Yield: 105.6 %

Procedure:
To a mixture of 14.8 g of 2,6-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide and 7.36 g of triethylamine in 300 ml of chloroform with stirring under cooling is added dropwise a solution of 8 g of chloroacetyl chloride in 50 ml of chloroform at 5°-10° C. After the mixture is stirred for 30 minutes, the reaction temperature is raised to room temperature and the resultant mixture is further stirred for 30 minutes. To the reaction mixture is added water and the precipitated crystals are collected by filtration to give 21 g of N'-chloroacetyl-2,6-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide, melting at 290°-291° C. with decomposition.
Reaction SMILES: [CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)[CH2:2][CH:3]=[CH2:4].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[N:17][OH:18])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1C(=O)CCc2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCCC1C(=NO)CCc2ccccc21

Procedure:
A mixture of 5.43 g of 1-(but-3-ene-yl)-2-tetralone, 54 ml of methanol, 2.06 g of hydroxylamine hydrochloride, and 2.41 g of sodium acetate was stirred and heated at reflux for 20 minutes. The reaction mixture was concentrated in vacuo to a small volume and the residue partitioned between ether and water. The ether layer was washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated to an oil, 5.78 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1>C(#N)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)Cc1ccc(O)c(CNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(CNC(=O)OC(C)(C)C)c1
Temperature: 82 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-hydroxyphenyl)acetate (200 mg, 0.677 mmol) was diluted with ACN (2 mL) followed by the addition of K2CO3 (206 mg, 1.49 mmol) and 1-fluoro-4-nitrobenzene (0.103 mL, 0.948 mmol). The reaction mixture was heated to reflux (at about 82° C.) and stirred for 5 hours. The reaction mixture was then diluted with ethyl acetate and water. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40S eluting with hexanes/ethyl acetate (3:1) to yield 242 mg of methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-nitrophenoxy)phenyl)acetate as a clear oil.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[CH:14]=[CH:15][C:16](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[N:17][C:18]=2[O:19][CH3:20])[CH:12]=[CH:11][N:10]=[CH:9]1>ClCCl>[N:8]1([C:13]2[CH:14]=[CH:15][C:16](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[N:17][C:18]=2[O:19][CH3:20])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: COc1nc(/C=C/C(=O)OC(C)(C)C)ccc1-n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(/C=C/C(=O)O)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A solution of trifluoroacetic acid (3 mL) in dichloromethane (1.5 mL) was added to tert-butyl (E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylate (490 mg) under ice-cooling, and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, diluted with chloroform and then concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration. The solid was washed with diethyl ether to obtain the title compound as a solid (345 mg). The property values of the compound are as follows.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1([N:11]2[C:15]([NH2:16])=[C:14]([C:17]#[N:18])[C:13]([CH2:19][CH3:20])=[N:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1>[OH-].[NH4+]>[CH:6]1([N:11]2[C:15]([NH2:16])=[C:14]([C:17]([NH2:18])=[O:2])[C:13]([CH2:19][CH3:20])=[N:12]2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C#N
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To concentrated sulfuric acid (50 ml) cooled in an ice/sodium chloride bath was added in small portions 1-cyclopentyl-3-ethyl-4-cyano-5-amino-1H-pyrazole. The reaction mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was slowly added to a solution of concentrated ammonium hydroxide (150 ml) in ice-water (500 ml). A yellow precipitate formed which was collected by filtration, washed with water and dried at 90° C. for 60 hours in high vacuum to afford 3.47 g (85%) of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide, m.p. 167°-168° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][CH3:11])[CH:4]=1.[C-:12]#[N:13].[Na+]>C(O)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:12]#[N:13])=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1cc(CBr)ccc1Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CC#N)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60° C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])([C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].I[CH2:38][C:39]([F:42])([F:41])[F:40].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[O:26])([C:16]2[CH:21]=[C:20]([O:22][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:34])[F:35]
Reactant: FC(F)(F)CI
Reactant: O=C(NCC(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(O)cc(F)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(NCC(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(F)cc(OCC(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 58 %

Procedure:
To a solution of (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 254, 15 mg, 0.03 mmol) in DMSO (0.15 mL) was added ICH2CF3 (0.02 mL) and K2CO3 (20 mg, 0.2 mmol). The reaction mixture was heated at 70° C. overnight. The reaction was cooled to rt and diluted with CH3CN, filtered and purified by prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to give (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 255) as white solid (10 mg, yield 58%). LCMS: RT=2.18 min [M+H] 601.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.43 (2H, m), 7.21 (1H, d, J=6.60 Hz), 7.12-7.19 (2H, m), 6.68 (2H, d, J=7.70 Hz), 6.54-6.63 (3H, m), 4.19-4.30 (2H, m), 3.73-3.84 (4H, m).
Reaction SMILES: CN(C)[CH:3]=[O:4].[NH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH2:17])=[C:12]([Cl:18])[CH:11]=1)[OH:9].Br[CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][O:28][C:29](=[O:39])[CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:23][CH2:22]1>C(N(CC)CC)C>[NH2:17][C:13]1[C:12]([Cl:18])=[CH:11][C:10]([CH:8]([OH:9])[CH2:7][NH:6][CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][O:28][C:29](=[O:39])[CH2:30][CH2:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:23][CH2:22]2)=[CH:15][C:14]=1[Cl:16].[C:3]([O-:4])(=[O:9])/[CH:31]=[CH:30]\[C:29]([O-:28])=[O:39]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CN(C)C=O
Reactant: O=C(CCCc1ccccc1)OC[C@H]1CC[C@H](CBr)CC1
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C(O)CNC[C@H]2CC[C@H](COC(=O)CCCc3ccccc3)CC2)cc1Cl
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
According to method I (dimethylformamide, 2 hours at 90° C.) from 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol and {4-(bromomethyl)[trans]cyclohexylmethyl}(4-phenyl)butanoate. Working up by means of chromatography (ethyl acetate/petroleum ether 60-80/triethylamine 4:2:1). Recrystallized as the maleate from ethyl acetate. Melting point: 155°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([N:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1.C1COCC1>[Pd].C(O)(C)C>[CH3:1][O:2][C:3](=[O:42])[CH:4]([N:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1)n1c2ccccc2c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)C(CCCCNC(=O)c1ccc(N)cc1)n1c2ccccc2c2ccccc21
Reaction time: 4 h
Yield: 97.6 %

Procedure:
10% Pd/C (0.035 g) was added in one portion to a stirred solution of (S)-6-(4-benzyloxycarbonylamino-benzoylamino)-2-carbazol-9-yl-hexanoic acid methyl ester 11 (0.350 g, 0.62 mmol) in a 1:1 mixture of THF (5 mL) and isopropanol (5 mL) and nitrogen atmosphere. The reaction mixture was subsequently stiffed under hydrogen atmosphere for 4 h at room temperature. The reaction mixture was passed through a celite pad, and the filtrate was concentrated in under reduced pressure to give (S) 6-(4-amino-benzoylamino)-2-carbazol-9-yl-hexanoic acid methyl ester (12) (0.260 g, 98%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O.N1C(C)=CC=CC=1C>O1CCCC1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([CH:9]([N+:10]#[C-:11])[C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cc(F)ccc2F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: [C-]#[N+]C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
A 5 L three-necked round-bottomed flask, equipped with a mechanical stirrer, an addition funnel and a thermometer, was charged with N-[(2,5-Difluoro-phenyl)-(toluene-4-sulfonyl)-methyl]-formamide (207.0 g, 0.636 moles) and tetrahydrofuran (J. T. Baker, low water, 1.5 L). Phosphorous oxychloride (118.6 ml, 1.27 moles) was quickly poured into the reaction mixture (less than 5 minutes). The mixture was stirred at room temperature for 10 minutes and then cooled to 4° C. using an ice/water bath. 2,6-Lutidine (445 ml, 3.82 moles) was added via the addition funnel over a period of 30 minutes. The cooling bath was then removed and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into a stirred and ice-water cooled solution of 1.5 kg of ice and 1.1 L of saturated aqueous sodium bicarbonate (NaHCO3). The mixture was then extracted with ethyl acetate (2 L plus 1.5 L). The combined organic extracts were washed with 1N aqueous hydrochloric acid (3 L), saturated aqueous NaHCO3 (3 L) and brine (3 L); and then dried (MgSO4). After removing all solvents, isopropanol (1.8 L) was added to the residual brownish solid. The resulting slurry was stirred at room temperature for 2 hours. Water (0.9 L) was added and the slurry was stirred for additional 30 minutes at room temperature and then filtered. The cake was washed with 2:1 isopropanol-water (2×500 ml) and dried in a vacuum-oven (30° C.) for 48 hours. The product, [α-(p-Toluenesulfonyl)-2,5-difluorobenzyl]isonitrile (133.4 g, yield 68%,), was obtained as a brownish powder.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[CH3:34][S:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1COCC1>[CH3:34][S:35][C:36]1[CH:41]=[CH:40][C:39]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[CH:38][CH:37]=1
Reactant: CSc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
A solution of diethyl azodicarboxylate in toluene (6.76 ml, 14.9 mmol) was added dropwise to a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol), 4-(Methylsulfanyl)phenol (2,8 g, 20 mmol), triphenylphosphine (3.9 g, 15 mmol) and THF (20 ml) over the period of 0.5 h at 0° C. The resulting solution was stirred at room temperature for 3 d. The mixture was diluted in ethyl acetate (20 ml) and the whole was washed with 1N aqueous sodium hydroxide (20 ml), 0.5N hydrochloric acid (20 ml) and saturated sodium chloride solution (20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 25 g, ethyl acetate/hexane=1/20 to 1/10) to give the title compound (1.8 g, 52%) as a colorless powder.
Reaction SMILES: C(OC([N:8]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([Cl:40])[CH:38]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12](C(OC(C)(C)C)=O)[CH:11]2[C:31](C)=[CH2:32])[C:9]1=[O:41])=O)(C)(C)C.[F-:42].[K+].FS([C:48]([F:57])(F)[C:49](O[Si](C)(C)C)=O)(=O)=O>C1(C)C=CC=CC=1>[Cl:40][C:37]1[CH:38]=[C:39]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C@@:31]3([CH3:32])[CH2:49][C:48]3([F:57])[F:42])[C:34]2=[CH:35][CH:36]=1
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Reactant: [F-]
Reactant: C=C(C)C1N(C(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Agent: [K+]
Solvent: Cc1ccccc1
Product: C[C@]1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1(F)F

Procedure:
Racemic (2′R,3R,4′S)-1′-(tert-butoxycarbonyl)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (100 mg, 1.6 mmol) prepared in Example 226a, catalytic amount of KF and a large amount of trimethylsilyl fluorosulfonyldifluoroacetate was dissolved in toluene (1 mL). Then the reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 115° C. for 30 min. The solution was concentrated and the residue was purified by Prep-TLC (CH2Cl2:CH3OH=30:1) to obtain title compound (2.6 mg) of Example 226d and (4.1 mg) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[CH3:19])=[CH:5][C:4]=1[N+:20]([O-])=O.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:5]=[C:4]([NH2:20])[C:3]([NH:2][CH3:1])=[CH:8][CH:7]=2)=[C:11]([CH3:19])[CH:12]=1
Reactant: [H][H]
Reactant: CNc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc(Oc2ccc(N)cc2C)cc1N

Procedure:
To a solution of N-methyl-4-(2-methyl-4-nitrophenoxy)-2-nitrobenzenamine (1.90 g, 6.27 mmol) in ethyl acetate (10 mL) and ethanol (20 mL) was added 10% Pd/C (0.342 g, 0.321 mmol). After shaking under 50 psi of hydrogen for 1 hour, the mixture was filtered and the filtrate was concentrated under reduced pressure to provide the product as clear oil.