Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH2:13]2)[CH2:19]3)=[O:9])[C:5]([Cl:22])=[CH:4][N:3]=1.C(OC([N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=O)(C)(C)C.Cl>CS(C)=O.CO.O1CCOCC1>[ClH:1].[Cl:22][C:5]1[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]4)[CH2:19]2)[CH2:21]3)=[O:9])=[CH:7][C:2]([N:30]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:3][CH:4]=1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CS(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCCNCC2)ncc1Cl
Yield: 78.8 %

Procedure:
A solution of 2,5-dichloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-pyridine-4-carboxamide (0.50 g, Example 1a) and 1-t-butoxycarbonylhomopiperazine (0.76 g) in dimethylsulfoxide (5 ml) was heated at 100-120° C. for 24 hours. The solution was cooled and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane and the organic layer dried over magnesium sulphate. Concentration in vacuo and chromatography on silica gave a colourless solid. This was redissolved in methanol (10 ml) and treated with 4M HCl in dioxan (2 ml). Once deprotection was complete (14 hours) the solution was partially concentrated in vacuo then diluted slowly with diethyl ether with rapid stirring. The resulting white precipitate was filtered, washed with diethyl ether and dried to afford the title compound (0.51 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[N:10]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O.NN>CO.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N(Cc1ccc([N+](=O)[O-])cc1)C1CCCCC1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Yield: 101 %

Procedure:
The compound (1.24 g) obtained in Example 87-1 was dissolved in methanol (12 ml) and THF (6.2 ml) and added with activated carbon (124 mg) and iron trichloride hexahydrate (12.4 mg), followed by thermal reflux for 0.5 hour. After standing to cool, the solution was added with hydrazine monohydrate (0.89 ml) and then subjected to thermal reflux for 3 hours. After completion of the reaction, the resultant was filtrated through Celite and the solvent was then distilled off. The residue was dissolved in chloroform and washed with water. The solution was dried with anhydrous magnesium sulfate. The solvent was distilled off, thereby obtaining the subject compound (1.15 g) as a yellow viscous liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([NH2:15])[CH2:13][CH2:14]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(NCc2cccc([N+](=O)[O-])c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(NCc2cccc([N+](=O)[O-])c2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 149.1 %

Procedure:
Tert-butyl N-(4-[(3-nitrobenzyl)amino]cyclohexyl)carbamate (30.0 g, 86.1 mmol, 1.0 eq) was dissolved in 300 mL of TFA:DCM (1:10) and the resulting solution was stirred at 30° C. overnight. The reaction mixture was then concentrated under vacuum to provide crude 1-N-(3-nitrobenzyl)cyclohexane-1,4-diamine (32 g, TFA salt) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][S:8][C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH:12]=[CH:13][C:14]=13)=O)C.[NH3:19]>C(O)C>[S:8]1[C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH:12]=[CH:13][C:14]3=[C:6]([C:4]([NH2:19])=[O:3])[CH2:7]1
Reactant: CCOC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Reactant: N
Solvent: CCO
Product: NC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
In 30 ml of ethanol was dissolved 487 mg of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester and ammonia gas was slowly blown into the solution for 15 minutes under ice-cooling. After allowing the solution to stand for 3 days at room temperature, crystals thus deposited were collected by filtration to provide 410 mg (yield of 89%) of benzo[b]thieno[2,3-c]pyridine-3-carboamide.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]2[CH:6]3[C:13]4([CH2:14][CH2:15][C:4]=2[CH:3]=1)[CH:9]([CH2:10][N:11]([C:16](=[O:18])[CH3:17])[CH2:12]4)[CH2:8][CH2:7]3.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:16]([N:11]1[CH2:12][C:13]23[CH:6]([CH2:7][CH2:8][CH:9]2[CH2:10]1)[C:5]1[CH:19]=[CH:20][C:2]([O:1][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:3][C:4]=1[CH2:15][CH2:14]3)(=[O:18])[CH3:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)N1CC2CCC3c4ccc(O)cc4CCC23C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC2CCC3c4ccc(OC(=O)c5ccccc5)cc4CCC23C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
1-(2-Hydroxy-5,6,6a,7,10,11-hexahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrol-8-yl)-ethanone (Example 5B) (10.0 mg, 0.037 mmol) and triethylamine (15.4 μL, 0.11 mmol) were dissolved in CH2Cl2 (2 mL). Benzoyl chloride (5.1 μL, 0.044 mmol) was added dropwise. The mixture was stirred at rt for 12 hr, quenched with water (2 mL), and extracted with CH2Cl2 (5 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane, providing 11.1 mg (80.4%) of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[CH3:38][C:39]1[S:40][CH:41]=[C:42]([CH2:44][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:43]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:44]\[C:42]4[N:43]=[C:39]([CH3:38])[S:40][CH:41]=4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: Cc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\c2csc(C)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.5 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), [(2-methyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.98 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(Z)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.33 g, yield 35%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][C:4]#[CH:5].C(N(CC)CC)C.S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1>C(O)C>[CH2:2]([NH:6][C:15]1[CH2:19][S:18][C:17](=[O:20])[N:16]=1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCCN
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C#CCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
To a solution of but-3-yn-1-amine hydrochloride (4.88 g) and triethylamine (6.44 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.08 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (1.95 g).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH:13]1([NH:19][C:20]2[C:25]([C:26](N(OC)C)=[O:27])=[CH:24][N:23]=[C:22]3[N:32]([CH2:35][CH3:36])[N:33]=[CH:34][C:21]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[CH:13]1([NH:19][C:20]2[C:25]([CH:26]=[O:27])=[CH:24][N:23]=[C:22]3[N:32]([CH2:35][CH3:36])[N:33]=[CH:34][C:21]=23)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C(=O)N(C)OC)cnc21
Agent: COCCO[AlH2-]OCCOC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCn1ncc2c(NC3CCCCC3)c(C=O)cnc21
Reaction time: 0.17 h

Procedure:
Toluene was cooled to −30 to −35° C. and vitride (0.12 ml, 0.0006 mole) was added. After about 10 min., 4-(cyclohexylamino)-1-ethyl-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (0.10 gm, 0.0003 mole) (example 6) was added and the reaction mixture was stirred for about 4 h. Citric acid (10%) solution was added dropwise to quench the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate and concentrated in vacuo. The compound was purified over preparative thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1>O=[Mn]=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(O)c1cc2ccc(F)cc2nc1Cl
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2ccc(F)cc2nc1Cl
Yield: 81.5 %

Procedure:
1-(2-Chloro-7-fluoroquinolin-3-yl)ethanol (7.7 g, 34 mmol), MnO2 (30 g, 10 eq) and Toluene (200 mL) were heated to reflux for 2 h. LC-MS showed completion of the reaction. Filtration followed with removal of solvent gave an off-white solid of 1-(2-chloro-7-fluoroquinolin-3-yl)ethanone (6.2 g, 81%). Mass Spectrum (ESI) m/e=224 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][CH:44]([NH2:46])[CH3:45]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:46][CH:44]([CH3:45])[CH3:43])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: CC(C)NC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and propan-2-amine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CCCO)c1
Solvent: CCN(CC)CC
Product: COc1cccc(CCCOS(C)(=O)=O)c1

Procedure:
In a manner analogous to the preparation of Example 83(a), 3-(3-methoxy-phenyl)-propan-1-ol (0.83 g, 5.00 mmol), Et3N (1.40 mL, 10.0 mmol) and MsCl (0.46 mL, 6.00 mmol) gave the desired compound as a light brown oil. 1H NMR (300 MHz, CDCl3) δ2.04-2.09 (m, 2H), 2.69-2.74 (t, 2H) 2.99 (s, 3H), 3.82 (s, 3H), 4.22-4.26 (t, 2H), 6.70-6.80 (m, 3H), 7.16-7.19 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([NH2:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:14][C:15]([NH2:17])=[O:16])=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1ccc(Cl)c2ccccc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A mixture of 4-chloronaphthalen-1-ol (3.57 g, 20.0 mmol), 2-bromoacetamide (2.76 g, 20.0 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (40 mL) was stirred at 70° C. overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (2.32 g, 49%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=[CH:12][C:5]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reaction time: 0.17 h

Procedure:
To a stirred suspension of sodium hydride (1.12 g; 60% dispersion in mineral oil) in THF (3 ml) kept below 15° C., a suspension of 4-bromo-1H-pyrrolo[2,3-b]pyridine (5 g) (prepared for example, according to the method described in Organic Letters, 2003, 5, 5023) in THF (27 ml) was added over 20 minutes. The reaction was left to stir for 10 minutes. Then a solution of benzenesulfonyl chloride (3.6 ml) in THF (6 ml) was added over 5 minutes. The reaction was left to stir at RT for 1 hour, then 0.5M hydrochloric acid solution (10 ml) was added. The layers were separated and the organic layer washed with brine, dried over magnesium sulphate and the solvent removed in vacuo and left on the vacuum line for 3 days. The solid was triturated using methanol (30 ml) then dried in the oven for 5 hours to give the title compound as a pale pink solid (7.42 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Chloro-4′-hydroxybenzophenone (50 g, 0.215 mol) is dissolved in dichloromethane (400 ml). 3,4-Dihydro-2H-pyran (21.7 g, 0.257 mol) and a catalytic amount of p-toluenesulfonic acid are added to the solution. The solution is stirred for 6 hours at room temperature and then allowed to stand over night. 1 N aqueous sodium hydroxide solution (100 ml) is added to the reaction mixture and stirred for 15 minutes. Organic layer is separated and washed twice with 1 N aqueous sodium hydroxide solution and once with water. Dichloromethane solution is dried and evaporated to dryness. Yield 68.6 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:21]([OH:23])=O)=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:35][CH:36]1[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1C=CN=C1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:32]([O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:20]([NH:19][C:17]([C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:10])=[O:9])=[O:18])[C:21](=[O:23])[NH:35][CH:36]2[CH2:37][C:38]([CH3:45])([CH3:44])[NH:39][C:40]([CH3:43])([CH3:42])[CH2:41]2)=[CH:30][CH:29]=1)([CH3:33])[CH3:34]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cn1ccnc1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)NC2CC(C)(C)NC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
(S)-2-{[(S)-1-(3-Fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-(4-isopropoxy-phenyl)-propionic acid (60 mg, 0.12 mmol), 4-amino-2,2,6,6-tetramethylpiperidine (25 mg, 0.16 mmol), TBTU (51 mg, 1.60 mmol) and N-methyl imidazole (13 mL, 0.16 mmol) were mixed in anhydrous THF (2 mL). The mixture was stirred overnight at room temperature. A saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was chromatographed (dichloromethane/methanol, 95/5) on silica gel to afford 48 mg (63%) of the title compound as a clear glass. MS: m/e 631.3 (M+H). 1H NMR (300 MHz, d6-DMSO): δ0.70-1.60 (m, 28H), 1.90 (d, 1H, J=12 Hz), 2.75 (m, 2H), 3.20 (m, 1H), 3.60 (d, 1H, J=12 Hz), 3.90 (m, 1H), 4.25 (dd, 1H, J1=9 Hz, J2=6 Hz), 4.50 (m, 2H), 6.80 (d, 2H, J=12 Hz), 7.10 (d, 2H, J=12 Hz), 7.45 (m, 4H), 7.65 (d, 1H, J=12 Hz), 7.90 (d, 1H, J=12 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15](F)([F:26])[O:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][NH2:25])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:25][CH2:24][CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH:15]([F:14])[F:26])[CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
0.55 ml of 4-tert-butylbenzaldehyde (9.19 mmol), 1.37 g of 2-(3-trifluoromethoxy-phenyl)-ethylamine hydrochloride (6.13 mmol) and 0.304 g of potassium carbonate (6.13 mmol) were suspended in 18 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 348 mg (9.19 mmol) of sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was refluxed for 22 h. After cooling down to rt, the reaction mixture was treated with 0.4 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo to give 1.82 g off-white oil (89%). MS (ISP) 334.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[N:8]([CH3:13])[C:9](=O)[CH2:10][S:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+]>C1COCC1>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[N:8]([CH3:13])[CH:9]=[CH:10][S:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CN1C(=O)CSc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C=CSc2cc([N+](=O)[O-])ccc21

Procedure:
7 g 7-Nitro-4-methyl-4H-benzo[1,4]thiazin-3-one (from j)) in 10 ml THF were treated dropwise with 67.57 ml 2M borane dimethyl sulfide complex in THF at room temperature. After 16 hrs the mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The solvent was evaporated and the solid residue triturated with ether.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:46])[CH2:44][CH3:45]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:46][CH2:43][CH2:44][CH3:45])=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and propylamine (10.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-propylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (28.7 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O1CCOCC1.C(OCC)(=O)C.O.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]([C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:27]=[C:26]3[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]3[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])=[CH:21][CH:20]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(C#N)cc3)ccc12
Yield: 189.8 %

Procedure:
853 mg of 4-cyanophenylboronic acid, 15 cm3 of water, 1.0 g of sodium carbonate and 314 mg of tetrakis(triphenylphosphine)palladium are added to 500 mg of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared as described in Example 51, in 100 cm3 of dioxane. The reaction medium is then refluxed for 4 hours and diluted with 70 cm3 of ethyl acetate and 75 cm3 of water. The organic phase is separated out after settling of the phases has taken place and washed with 50 cm3 of distilled water and then with 2×50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue obtained, 2.0 g, is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 1.0 g of N-[6-(4-cyanophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is obtained in the form of a yellow solid melting at 136° C.