Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][CH2:29]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:29][CH2:28][O:27][CH3:26])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 2-chloroethyl methyl ether (0.067 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 8 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (20 mg, yield 12%).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)(=[O:4])[CH:2]=[CH2:3]>Cl.CO>[NH:11]1[CH2:12][CH2:13][CH:8]([CH2:7][CH2:6][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9][CH2:10]1
Reactant: C=CC(=O)NCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: C=CC(=O)NCCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 141.7 %

Procedure:
A mixture of tert-butyl 4-(2-acrylamidoethyl)piperidine-1-carboxylate (600 mg, 2.13 mmol) in HCl/MeOH (60 mL, 2.86 M) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to yield the crude product (550 mg) as a solid which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCNC1CCCc2c(ccc(N)c2OC)C1
Product: COCCNC1CCCc2c(ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c2OC)C1

Procedure:
The title compound was prepared from 1-methoxy-N(6)-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2,6-diamine (70 mg, 0.3 mmol) and N-[(1R,2R)-2-(2,5-dichloropyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (90 mg, 0.26 mmol) in an analogous manner to Example 946 to afford a peach foam (47 mg, 31%). Mp: 81-3° C. LCMS (m/e) 567 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.96 (m, 2H), 7.33 (d, J=6 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 5.47 (d, J=8 Hz, 1H), 3.92 (m, 1H), 3.73 (s, 3H), 3.51 (m, 2H), 3.37 (s, 3H), 3.29 (m, 1H), 3.11 (m, 1H), 2.87 (m, 4H), 2.82 (s, 3H), 2.61 (m, 2H), 2.21 (m, 2H), 2.10 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H), 1.67 (m, 3H), 1.51-1.31 (m, 5H).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1.ClC[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26].CCC(O)CC>>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[C:13]([CH:18]=1)[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[N:7]1
Reactant: CCC(CC)CCl
Reactant: COC(=O)CCc1cc(C)n(Cc2cc(Cl)ccc2O)n1
Solvent: CCC(O)CC
Product: CCC(CC)Oc1ccc(Cl)cc1Cn1nc(CCC(=O)O)cc1C

Procedure:
The title compound was prepared following the methods described in example 1 and example 2 starting from (example 2 step 5) 3-[1-(5-Chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid methyl ester replacing the method in example 2 step 6 with Mitsunobu method and 3-chloromethylpentane with 3-pentanol.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([O:14]C)[CH:10]=[CH:9][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C(Cl)Cl>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([OH:14])[CH:10]=[CH:9][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCNc1ccc(OC)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: CCCCNc1ccc(O)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
To a stirred solution of 2,3-dichloro-4-methoxy-N-n-butylaniline (8.5 g) in 1,1,2,2-tetrachloroethane (80 ml) is added anhydrous aluminium chloride (8.5 g), and the mixture is refluxed for about 40 hours. The resulting mixture is poured into ice/water (about 500 ml), and the precipitated material is extracted twice with methylene chloride. The combined extracts are dried and evaporated in vacuo to give the title compound as a heavy oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of ethyl 4-nitro-1H-pyrrole-2-carboxylate (10 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.4 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Benzylbromide (8.0 mL) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-4-nitro-1H-pyrrole-2-carboxylate (14.3 g, yield 97%) as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 73° C.
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:22][CH3:23].[Li]CCCC.CCCCCC.Cl>C(OCC)(=O)C>[CH2:22]([S:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[B:1]([OH:6])[OH:2])[CH3:23]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCSc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCSc1ccccc1B(O)O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
9.5 g (50 mmol) of triisopropyl borate are added to a solution of 10.9 g (50.0 mmol) of 1-bromo-2-ethylsulfanylbenzene kept at −70° C. 33.3 ml of a 15% solution of BuLi in hexane (55 mmol) are then added. The mixture is stirred at −70° C. for a further 30 minutes, then 1 N hydrochloric acid and ethyl acetate are added. The organic phase is separated off, dried and evaporated. The residue is taken up in diethyl ether and filtered. A colourless solid is obtained; FAB 182
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH3:30][O:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][S:34]([CH2:33][CH2:32][O:31][CH3:30])(=[O:36])=[O:35])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: COCCS(=O)(=O)Cl
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COCCS(=O)(=O)Nc1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 123 mg (0.77 mmol) 2-methoxyethanesulfonyl chloride and 0.11 ml (0.77 mmol) triethylamine. The mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 ml), and to the solution were added 0.175 ml (2.27 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 32 mg (30% of th.) of the title compound.
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, 0.29 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.58 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/EtOAc 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).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].CO[C:8](=[O:42])[CH2:9][CH2:10][C:11]1[S:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:26][CH:25]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][CH:12]=1.Cl>CO>[OH:3][NH:2][C:8](=[O:42])[CH2:9][CH2:10][C:11]1[S:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:28][CH:29]=2)[CH2:17][CH:18]([CH3:19])[CH3:20])=[N:13][CH:12]=1
Reactant: NO
Reactant: COC(=O)CCc1cnc(C(CC(C)C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)NO)s2)cc1
Temperature: 90 °C
Yield: 21.8 %

Procedure:
Hydroxylamine hydrochloride (6.96 g) was suspended in methanol (35 mL) and heated to 90° C. This solution was added to potassium hydroxide (8.34 g) dissolved in methanol (21mL) After 15 minutes of stirring, the solution was filtered and 3-[2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid methyl ester (0.80 g, 1.53 mmol) was added. The reaction was stirred at room temperature for 15 minutes, 1N HCl (50 mL) was added, and the methanol was removed in vacuo. The residue was partitioned between ethyl acetate and hydrochloric acid (1N). The organic portion was dried over sodium sulfate and the solvent removed in vacuo. The title compound (0.175 g, 17%) was isolated by crystallization from a mixture of ethyl acetate and methanol. MS [M+1]524.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:13][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([O-:3])=[O:2]
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 79.2 %

Procedure:
A mixture of 3,4-dinitrophenol (250 mg), 4-(2-chloroethyl)morpholine hydrochloride (252 mg) and potassium carbonate (375 mg) in dimethylformamide (3 ml) was heated at 120° C. for 20 minutes in a Personal Chemistry Smith Creator microwave. The reaction mixture was partitioned between ethyl acetate and water and the organic layer dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 4-[2-(3,4-dinitro-phenoxy)-ethyl]-morpholine (319 mg) as a yellow oil. LC-MS (METHOD B): RT=2.13 minutes, 298 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)=[C:10]([CH2:29][CH2:30][CH3:31])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:38]1([N:44]=[C:45]=[O:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC(C)=O>[CH:38]1([NH:44][C:45]([NH:26][S:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:11]3[CH:27]=[CH:28][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][C:10]=3[CH2:29][CH2:30][CH3:31])[CH:18]=2)(=[O:24])=[O:25])=[O:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C=NC1CCCCC1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(S(N)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(S(=O)(=O)NC(=O)NC2CCCCC2)c1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
To a solution of 3-[3-(4-phenoxy-2-propyl phenoxy)propoxy]benzenesulfonamide (0.04 g, 0.0906 mmol) and acetone (3 mL) was added potassium carbonate (0.025 g, 0.181 mmol). To the resulting suspension was added cyclohexyl isocyanate (0.023 mL, 0.181 mmol) dropwise. The reaction suspension was then stirred in a 65° C. oil bath for 5 h. After cooling to room temperature, the reaction was concentrated to a residue. The residue was partitioned between ethyl acetate and water. The ethyl acetate phase was dried over sodium sulfate, filtered, and concentrated to an oil. The oil was chromatographed over silica gel with hexanes/ethyl acetate (4:1) and hexanes/ethyl acetate (3:1) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].C(N1CCOCC1)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: C[C@H](N)C(=O)O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCC(=O)N[C@@H](C)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.1 %

Procedure:
To a solution of p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and L-alanine (45 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added N-ethylmorpholine (128 μl, 1.0 mmol). The mixture was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off and the residue was chromatographed on a Sephadex LH20 column under the same conditions as above. The eluate was evaporated to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-alanine (23 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[C:12]([N+:24]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[NH2:24][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:27]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of the product of Example 37B (116.6 mg, 0.2717 mmol) and iron powder (60.7 mg, 1.087 mmol) in acetic acid (2 mL) and ethanol (2 mL) was heated at reflux under a nitrogen atmosphere for 1 hour. The reaction was then cooled to room temperature. The mixture was diluted with water (20 mL), the pH adjusted to 6 with solid sodium carbonate, and the aqueous extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a beige solid (100 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C@H:10]1[CH2:14][NH:13][C@H:12]([C:15]([NH:17][C:18]2([C:21]#[N:22])[CH2:20][CH2:19]2)=[O:16])[CH2:11]1.[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:37][CH2:36][CH:35]2[C:38]([O-])=[O:39])[CH2:30][CH2:29]1)=[O:27])[CH3:24].[Li+]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C@H:10]1[CH2:14][N:13]([C:38]([CH:35]2[CH2:36][CH2:37][N:34]2[CH:31]2[CH2:30][CH2:29][N:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH2:33][CH2:32]2)=[O:39])[C@H:12]([C:15](=[O:16])[NH:17][C:18]2([C:21]#[N:22])[CH2:20][CH2:19]2)[CH2:11]1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccc(F)cc3Cl)CN2)CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](Sc3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chloro-4-fluorophenylthio)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 12A and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(2-chloro-4-fluorophenylthio)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (82%). MS ISP (m/e): 578.3/580.4 (100/38) [(M+H)]]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([P:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)(=[O:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pt]>[NH2:1][C:4]1[CH:5]=[C:6]([P:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)(=[O:11])[OH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(P(=O)(O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Pt]
Solvent: CO
Product: Nc1cccc(P(=O)(O)c2cccc(N)c2)c1

Procedure:
The compound bis(3-nitrophenyl)phosphinic acid (14.0 g, 45.4 mmol) from Example 1 was suspended in methanol (200 ml). Platinum (5 wt. %, on activated carbon, 1.4 g) was added. The mixture was shaken on a hydrogenation apparatus (50 psi) until no further hydrogen consumption was observed. The mixture was filtered through celite and then evaporated to dryness. The solid obtained (9.87 g, 88%) was used without purification. The structure of bis(3-aminophenyl)phosphinic acid is:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][C:7]1[CH:8]=[C:9]([S:21](Cl)(=[O:23])=[O:22])[CH:10]=[CH:11][C:12]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15]>O1CCCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[S:21]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])=[C:7]([CH3:6])[CH:8]=1)(=[O:23])=[O:22])[CH3:2]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of diethylamine (1 g) and 3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) in tetrahydrofuran (20 ml) was allowed to stand overnight. The resultant mnixture was concentrated and shaken with chloroform and 5% aqueous hydrochloric acid. The chloroform extract was concentrated and recrystallized from a mixture of ethanol and water to give 0.97 g of N,N-diethyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 6). M.P., 128°-128.5° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)C)C1C=CC=CC=1.C([O-])=O.[NH4+]>[C].[Pd].C(O)C>[CH3:1][NH:8][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1
Reactant: CN(CCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CNCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Yield: 100.1 %

Procedure:
A mixture of 1-[1-{4-[3-(N-benzyl-N-methylamino)propoxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (5.3 g), 5% palladium-carbon (0.8 g), ammonium formate (2.6 g) and ethanol (300 ml) is refluxed with heating for 2 hours. The catalyst is filtered off and ethanol is distilled off under reduced pressure. To the residue is added chloroform and the mixture is washed successively with saturated sodium hydrogen carbonate, water and saline solution. Further the mixture is dried with sodium sulfate and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol=20:1→5:1) to give 1-[1-{4-[3-(N-methylamino)propoxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (4.37 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=3)[CH2:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(C)cc1)C2
Reaction time: 20 h

Procedure:
6.0 g (21.1 mmol) of methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate hydrochloride are suspended in 60 ml of chloroform and 5.0 g (25.3 mmol) of p-toluenesulphonyl chloride are added. 5.1 g (50 mmol) of triethylamine are added, with vigorous stirring, a clear solution being formed. After 20 hours at room temperature, the mixture is washed with water, the chloroform solution is evaporated and the residue is recrystallised from methanol.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>C(Cl)(Cl)Cl.CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1I
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccccc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-iodobenzoic acid (5.00 g, 20.1 mmol) in chloroform (50 ml) were added oxalyl chloride (1.9 ml, 21.7 mmol) and N,N-dimethylformamide (5 drops with Pasteur pipette) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and ethyl acetate (5 ml) was added to the residue to give a solution of 2-iodobenzoyl chloride in ethyl acetate.