Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:7][CH2:6][C:5]([N+:32]([O-:34])=[O:33])([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5C=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.C(OC1C=CC(O)=CC=1)CCCC>>[CH3:35][C:2]1([CH3:1])[O:3][CH2:4][C:5]([N+:32]([O-:34])=[O:33])([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:24]=4)[CH:14]=3)[CH:9]=2)[CH2:6][O:7]1
Reactant: CC1(C)OCC(c2ccc3cc(Oc4ccc(Oc5ccccc5)cc4)ccc3c2)([N+](=O)[O-])CO1
Agent: CCCCCOc1ccc(O)cc1
Product: CCCCCOc1ccc(Oc2ccc3cc(C4([N+](=O)[O-])COC(C)(C)OC4)ccc3c2)cc1
Yield: 58 %

Procedure:
2,2-dimethyl-5-nitro-5-(6-(4-(pentyloxy)phenoxy)naphthalen-2-yl)-1,3-dioxane was synthesized as per 2,2-dimethyl-5-nitro-5-(6-(4-phenoxyphenoxy)naphthalen-2-yl)-1,3-dioxane (Example 243) in 58% yield using 4-pentyloxy-phenol as the reagent.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12>ClCCl.FC(F)(F)C(O)=O>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
A mixture of (R)-tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (700 mg, 1.44 mmol, 1.00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:19][N:20]=[C:21]([CH3:23])[CH:22]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[C:8]([C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:17]=[C:18]3[NH:19][N:20]=[C:21]([CH3:23])[C:22]=23)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)nc1
Reactant: Cc1cc(N)[nH]n1
Product: Cc1n[nH]c2nc(-c3ccc(Cl)nc3)c(-c3ccncc3)c(-c3ccc(Cl)nc3)c12
Yield: 9 %

Procedure:
Following a similar procedure to that described in example 1 method A, but using 1-(6-chloropyridin-3-yl)-2-(4-pyridyl)ethanone (obtained in example reference 9) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone and 3-amino-5-methyl-2H-pyrazole instead of 3-amino-2H-pyrazole, the title compound was obtained (yield: 9%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][O:12][CH3:13].O>CN(C)C=O>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: COCCCBr
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCn1cccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 363.9 %

Procedure:
To a solution of 1H-pyrrole (5.0 g) in N,N-dimethylformamide (40 mL) was added drop by drop sodium hydride (3.58 g) under ice-cooling, and then the mixture was stirred at room temperature for 20 minutes. Then, thereto was added dropwise a solution of 1-bromo-3-methoxypropane (2.74 g) in N,N-dimethylformamide (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=100/1→20/1) to give 1-(3-methoxypropyl)-1H-pyrrole [REx(105-1)] (9.07 g) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:18]([OH:20])=[O:19])[CH2:6][S:7][S:8][CH2:9][C@H:10]([NH:14][C:15](=[O:17])[CH3:16])[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O>[NH2+:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[C:15]([NH:14][C@H:10]([C:11]([O-:13])=[O:12])[CH2:9][S:8][S:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([O-:20])=[O:19])(=[O:17])[CH3:16]
Reactant: CC(=O)N[C@@H](CSSC[C@H](NC(C)=O)C(=O)O)C(=O)O
Reactant: C1CNCCN1
Solvent: O
Product: C1C[NH2+]CCN1
Product: CC(=O)N[C@@H](CSSC[C@H](NC(C)=O)C(=O)[O-])C(=O)[O-]

Procedure:
To N,N'-diacetyl-L-cystine (4.60 mmole, 1.49 g) dissolved in 5 mL of water was added piperazine (4.60 mmole, 0.90 g). To the solution was added enough isopropanole to cause formation of an oil, which slowly solidifies. The salt was isolated and dried.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:31]=[CH:30][C:29]4[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=4[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.O.CC(=O)OCC>C1COCC1>[CH3:32][C:28]1([CH3:33])[CH2:27][CH2:26][C:25]([CH3:34])([CH3:35])[C:24]2[CH:23]=[C:22]([C:20]3[N:21]=[C:17]([N:14]4[CH2:15][CH2:16][CH:11]([NH:10][CH2:9][CH:7]5[CH2:8][CH:6]5[CH2:4][OH:3])[CH2:12][CH2:13]4)[S:18][CH:19]=3)[CH:31]=[CH:30][C:29]1=2
Reactant: CCOC(=O)C1CC1CNC1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCC5CC5CO)CC4)n3)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
49 mg (0.10 mmol) of 2-({1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamino}methyl)cyclopropanecarboxylic acid ethyl ester from step a were dissolved in 2 ml of THF under nitrogen. 475 μl of a 1M diisobutylaluminium hydride solution in THF were added dropwise. The mixture was stirred at 60° C. overnight, water and EA were added, the mixture was filtered through Cellite, evaporated and purified by means of flash chromatography on silica gel.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]([CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:25](=[O:29])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1cc(OCc2ccccc2)ccn1
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCn1ccc(OCc2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (345 mg, 1.20 mmol) and 4-(benzyloxy)pyridin-2-ol (201 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was added cesium carbonate (652 mg, 2.00) at ambient temperature. The resulting mixture was stirred at 50° C. overnight. The mixture was allowed to cool to ambient temperature and filtered through a celite pad. The pad was washed with ethyl acetate; the filtrates were combined and concentrated to a crude residue. The material was purified via filtration through a silica gel pad and eluted with heptanes/ethyl acetate. The desired fractions were isolated and the solvent removed via rotary evaporation affording ethyl 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate as a white solid. 302.2 mg. 1H NMR (CD3OD) 7.47, (1H, d), 7.41-7.29 (5H, m), 6.15-6.13, (1H, dd), 5.96 (1H, d), 5.07 (2H, s), 4.20-4.12 (2H, m), 4.00-3.93 (1H, m), 3.47 (1H, q), 3.21 (3H, s), 2.60-2.53 (1H, m), 2.32-2.25 (1H, M), 3.20 (3H, s), 1.26 (3H, t) ppm.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=2)=[C:10]([Br:24])[CH:9]=1)=[O:6])C.[OH-].[Na+]>CO>[Br:14][C:12]1[CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:25])=[O:3])[CH:9]=[C:10]([Br:24])[C:11]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1
Reactant: CCOC(=O)C(=O)Nc1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)Nc1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Temperature: 25 °C

Procedure:
Ethyl-N-[3,5-dibromo-4-(3-bromobenzyloxy)phenyl]oxamate (18 mg) was dissolved in methanol (1 mL) and treated with sodium hydroxide (IN, 6–8 equivalents). After stirring over night at room temperature, the reaction mixture was acidified to pH 5. The mixture was purified on semi-preperative HPLC using the same conditions as described for Examples 27, 28 and 30. This gave 7.8 mg (46%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)phenyl]oxamic acid. MS: m/z 508.0 (M+−1).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:19]=3)[C:14]([OH:29])=[C:13]([C:30](OC)=[O:31])[C:12]2=[O:34])=[CH:7][CH:6]=1)=[O:4].[NH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41]>CO>[C:40]([NH:39][CH2:38][CH2:37][NH:36][C:30]([C:13]1[C:12](=[O:34])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([N:2]([CH3:35])[CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:20]2[C:15]([C:14]=1[OH:29])=[N:16][CH:17]=[C:18]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH:19]=2)=[O:31])(=[O:42])[CH3:41]
Reactant: CC(=O)NCCN
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(C(=O)N(C)C)cc2)c1=O
Solvent: CO
Product: CC(=O)NCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(C(=O)N(C)C)cc2)c1=O
Yield: 53.5 %

Procedure:
In a similar manner to that described in example 196, from from methyl 1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (8 mg, 0.0168 mmol), N-(2-aminoethyl)acetamide (10 mg, 0.098 mmol) and methanol (2 mL), was prepared N-[2-(acetylamino)ethyl]-1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (4.9 mg, 54% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.14 (m, 1 H), 8.52 (s, 1 H), 7.65 (d, J=8.4 Hz, 2 H), 7.27 (d, J=8.4 Hz, 2 H), 7.02-6.98 (m, 2 H), 6.95-6.90 (m, 2 H), 6.79 (s, 1 H), 6.03 (br s, 1 H), 3.94 (s, 2 H), 3.57-3.54 (m, 2 H), 3.47-3.42 (m, 2 H), 3.16 (s, 3 H), 3.04 (s, 3 H), 1.95 (s, 3 H); MS m/z 546 (M+1).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:13][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)OC.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[BH4-].[Na+]>CO>[NH3:1].[CH3:7][OH:8].[CH2:31]([NH:39][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][C:12]2[N:13]=[CH:14][C:9]([C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])=[CH:10][CH:11]=2)=[CH:17][CH:18]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1ccc(Oc2ccc(C(=O)N3CCCCC3)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: N
Product: O=C(c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)nc1)N1CCCCC1
Reaction time: 72 h
Yield: 151.1 %

Procedure:
Combine 4-[5-(Piperidine-1-carbonyl)-pyridin-2-yloxy]-benzaldehyde (72.0 mg, 0.23 mmol), MeOH (2.3 mL), Trimethylorthoformate (1.6 mL), and Phenethylamine (26 uL, 0.21 mmol). After the reaction stirs for 72 hours at room temperature under a Nitrogen atmosphere, add NaBH4 (10.5 mg, 0.28 mmol). After 5 hours, concentrate the reaction under reduced pressure and add the mixture to a 2 g SCX column. Wash with MeOH and then 1N NH3 MeOH to afford 72.2 mg (75% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5-1.8 (6H, m), 2.8-3.0 (4H, m), 3.3-3.8 (4H, m), 3.85 (2H, s), 6.8 (1H, d), 7.1-7.4 (9H, m), 8.0 (1H, d), 8.2 (1H, s); MS m/z 416 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-])=O)=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(O)C.O.O1CCCC1.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NCc4ccccc4[N+](=O)[O-])cc3)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCc4ccccc4N)cc3)c2cc1OC
Temperature: 25 °C
Yield: 56.9 %

Procedure:
6,7-Dimethoxy-4-(4-(2-nitrophenylmethylamino)phenyloxy)quinoline (150 mg, 0.35 mmol) was dissolved in ethanol (2.8 ml) and water (0.7 ml), and then iron powder (78 mg, 1.4 mmol) and ammonium chloride (150 mg, 2.8 mmol) were added and the mixture was heated to reflux for 1 hour. After cooling to room temperature, the reaction solution was diluted with tetrahydrofuran and water, and the insoluble portion was filtered off. The filtrate was distilled off under reduced pressure, and then the residue was purified with a silica gel column (ethyl acetate system), the obtained amorphous substance was solidified with hexane and ethyl acetate, and the obtained crystals were washed with hexane-ethyl acetate, filtered out, washed with hexane and dried by aspiration at room temperature to obtain the title compound (80 mg, 0.1993 mmol, 56.93%) as milky white crystals.
Reaction SMILES: C[O:2][PH:3]([CH2:5][CH:6]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[OH-].[Na+]>CO.O>[OH:4][PH:3]([CH2:5][CH:6]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[O:2]
Reactant: CO[PH](=O)CC(CCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)C(CCc1ccccc1)C[PH](=O)O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of benzyl 2-((methoxyphosphinyl)methyl)-4-phenylbutanoate (4.02 g, 11.6 mmol) in methanol (20 mL) was cooled in an ice bath and 2.5N aqueous sodium hydroxide (5.1 mL. 12.8 mmol) was added over 10 min. The resulting solution was stirred at 0° C. for 45 min before being diluted with water (150 mL) and washed with a mixture of ether (75 mL) and hexane (25 mL). The aqueous layer was washed with hexane (75 mL), acidified by the addition of 2N aqueous hydrochloric acid (20 mL), and extracted with ethyl acetate (2×75 mL). The ethyl acetate layers were washed in succession with saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), decanted, and evaporated. The residue was dried overnight under vacuum to give crude (±)-benzyl 2-((hydroxyphosphinyl)methyl)-4-phenylbutanoate as 3.67 g of colorless oil (95% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:5]([NH:17][C:18](=[O:33])[CH2:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:4][CH2:3]1.N[C@H:35]1[CH2:40][C@@H](CCC(O)=O)[C@@H](NC(=O)CNC(=O)C2C=CC=C(C(F)(F)F)C=2)C[CH2:36]1.[C:63](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCCl.C(O)(=O)C.CC(C)=O>[CH:35]([N:1]([CH3:63])[C@H:2]1[CH2:7][C@@H:6]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@@H:5]([NH:17][C:18](=[O:33])[CH2:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:4][CH2:3]1)([CH3:40])[CH3:36]
Reactant: CC(C)(C)OC(=O)CC[C@@H]1C[C@H](N)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: N[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CCC(=O)O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CCC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
The crude mixture of tert-butyl 3-((1R,2S,5R)-5-amino-2-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexyl)propanoate and 3-((1R,2S,5R)-5-amino-2-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexyl)propanoic acid prepared in Example 7a, Step 6 was dissolved in 1,2-dichloroethane (2 mL) and treated sequentially with acetone (32 μL), acetic acid (25 μL) and sodium triacetoxyborohydride (92 mg). The mixture was stirred at rt for 19.5 h, then was treated with aqueous formaldehyde (33 μL). After 1.5 h, additional aqueous formaldehyde (20 μL) and sodium triacetoxyborohydride (50 mg) were added and the mixture was stirred for an additional 2.5 h. The mixture was concentrated under vacuum and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over Na2SO4 and concentrated under vacuum to provide the title product, tert-butyl 3-((1R,2S,5R)-5-(isopropyl(methyl)amino)-2-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexyl)propanoate, as a glassy foam (45 mg). MS found: (M+H)+=528.4.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=O.N>>[Br:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: N
Product: Brc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 3-bromobenzoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.71 (m, 2H), 7.98 (ddd, J=8.1, 2.0, 1.0 Hz, 1H), 8.22 (ddd, J=7.4, 1.6, 1.3 Hz, 1H), 8.35 (t, J=1.8 Hz, 1H), 8.46 (dt, J=7.9, 2.0 Hz, 1H), 8.83 (dd, J=4.8, 1.6 Hz, 1H), 9.27 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 302 (M+H)+, 304 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(OC(N1CCC(C(Cl)=O)CC1)=O)C1C=CC=CC=1.COCCN>C(O)C.[Pd]>[CH3:22][O:21][CH2:20][CH2:19][NH:18][C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:23]
Reactant: COCCNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: COCCN
Agent: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCNC(=O)C1CCNCC1

Procedure:
1-Benzyloxycarbonyl-4-[N-(2-methoxyethyl)carbamoyl]piperidine [5.76 g, m.p. 85°-86°, Analysis %: C, 63.9; H, 7.5; N, 8.4; Calculated: C, 63.7; H, 7.6; N, 8.8; prepared similarly to Preparation C but using toluene in place of chloroform and starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2-methoxyethylamine] in ethanol (75 ml) was hydrogenated over 5% palladium on charcoal at 50 p.s.i./50°. The catalyst was removed by filtration, and the filtrate evaporated to give 4-[N-(2-methoxyethyl)carbamoyl]piperidine as an oil which solidified on standing. I.r. and n.m.r. spectra were consistent with this structure and the product was used in Example 7 without further purification.
Reaction SMILES: B([O-])=O.[Na+].[CH3:5][C:6]1[CH2:10][CH2:9][CH:8]([C:11]([CH3:13])=[CH2:12])[C:7]=1[CH2:14][C:15]([CH3:19])([CH3:18])[CH:16]=[O:17].S(=O)(=O)(O)O>C(O)C>[CH3:5][C:6]1[CH2:10][CH2:9][CH:8]([C:11]([CH3:13])=[CH2:12])[C:7]=1[CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17]
Reactant: C=C(C)C1CCC(C)=C1CC(C)(C)C=O
Agent: O=B[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: C=C(C)C1CCC(C)=C1CC(C)(C)CO
Yield: 82 %

Procedure:
A solution of 1 l of ethanol and 27 g (0.7 mole) of sodium boranate was added in the course of 2 hours to 412 g (2 moles) of the product from Example 1, at from 25° to 30° C. The ethanol was then stripped off and the residue was acidified with dilute sulfuric acid, washed and then worked up by distillation in the conventional manner. Boiling point: 77° C/0.1 mm Hg; nD25 : 1.4894; yield 82%; the structure was confirmed by the nuclear resonance spectrum.
Reaction SMILES: [C:1]([C:4]1[O:5][CH2:6][CH2:7][N:8]=1)(C)=[CH2:2].[S:9](=[O:12])([OH:11])[O-:10].[Na+]>>[C:4]([NH:8][CH2:7][CH2:6][S:9]([OH:12])(=[O:11])=[O:10])(=[O:5])[CH:1]=[CH2:2]
Reactant: O=S([O-])O
Reactant: C=C(C)C1=NCCO1
Agent: [Na+]
Product: C=CC(=O)NCCS(=O)(=O)O

Procedure:
A process of claim 1 wherein a homopolymer of 2-isopropenyloxazoline is reacted with sodium bisulfite in order to provide a homopolymer of 2-acrylamido-ethane-1-sulfonic acid.
Reaction SMILES: [OH-:1].[Na+].OO.[OH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([S:12][C:13]2[CH:20]=[C:19]([N:21]3[C:25]4=[N:26][CH:27]=[CH:28][C:29]([C:30]5[CH:31]=[N:32][C:33]6[C:38]([CH:39]=5)=[CH:37][CH:36]=[CH:35][CH:34]=6)=[C:24]4[C:23]([CH3:40])=[CH:22]3)[CH:18]=[CH:17][C:14]=2[C:15]#[N:16])[CH2:8][CH2:7]1.O>CS(C)=O.C(O)C>[OH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([S:12][C:13]2[CH:20]=[C:19]([N:21]3[C:25]4=[N:26][CH:27]=[CH:28][C:29]([C:30]5[CH:31]=[N:32][C:33]6[C:38]([CH:39]=5)=[CH:37][CH:36]=[CH:35][CH:34]=6)=[C:24]4[C:23]([CH3:40])=[CH:22]3)[CH:18]=[CH:17][C:14]=2[C:15]([NH2:16])=[O:1])[CH2:8][CH2:7]1
Reactant: [OH-]
Reactant: Cc1cn(-c2ccc(C#N)c(S[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2ccc(C(N)=O)c(S[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reaction time: 0.5 h

Procedure:
Trans-4-mercaptocyclohexanol (0.050 g), tris(dibenzylideneacetone)dipalladium(0) (0.008 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.010 g), and N,N-diisopropylethylamine (0.116 mL) were added to a solution of (40f) (0.150 g) prepared in Example 40(6) in 1,4-dioxane (1.71 mL), followed by stirring under nitrogen flow at 120° C. for 6 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain a crude product of 2-(trans-4-hydroxycyclohexylthio)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile. Subsequently, an aqueous sodium hydroxide solution (4 M, 0.851 mL) and a 30% hydrogen peroxide solution (0.193 mL) were added to a solution of this 2-(trans-4-hydroxycyclohexylthio)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile in DMSO (0.4 mL) and ethanol (1.6 mL) at room temperature, followed by stirring for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration, washed by sprinkling water and ether, and then dried under reduced pressure to obtain (67) (0.023 g, the second stage yield: 13%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[NH2:16])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:2][C:3]1[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[NH:16][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[C:25]([F:24])([F:35])[F:36])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: NC1CCCCC1c1ncc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 34.9 %

Procedure:
0.70 g of 2-[3,5-dichloro-2-pyridinyl]cyclohexanamine hydrochloride (0.00022 mol), 0.07 ml of triethylamine, 49 mg (0.00023 mol) of 2-trifluoromethylbenzoyl chloride are stirred in 3 ml of dichloromethane at room temperature overnight. Dichloromethane is added (5 ml) to the reaction mixture, which is washed twice with water (5 ml). After separation, the organic phase is dried over magnesium sulfate, filtered, concentrated to dryness and purified on silica to yield to 32 mg of N-{2-[3,5-dichloro-2-pyridinyl]-cyclohexyl}-2-(trifluoromethyl)benzamide (31%).