Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([NH:10][C:11](=O)[CH3:12])[CH2:8][CH3:9].N1C(C)=CC=CC=1C.[CH:22]1([C@H:25]([NH:33][C:34]([CH2:36][C:37]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=2[C:39]([OH:41])=O)=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH2:24][CH2:23]1.Cl>ClCCCl.[Cl-].[Na+].O>[CH:22]1([C@H:25]([NH:33][C:34]([C:36]2[C:37]3[C:38](=[C:42]([F:46])[CH:43]=[CH:44][CH:45]=3)[C:39](=[O:41])[N:10]([CH2:7][CH2:8][CH3:9])[C:11]=2[CH3:12])=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH2:23][CH2:24]1
Reactant: O=C(Cc1cccc(F)c1C(=O)O)N[C@H](c1cccc(F)c1)C1CC1
Reactant: CCCNC(C)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCCl
Product: CCCn1c(C)c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(F)c2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Oxalyl chloride (0.7 mL, 8 mmol) was added to N-propyl-acetamide (1.11 mL, 10 mmol) and 2,6-lutidine (1.39 mL, 12 mmol) in 50 mL 1,2-dichloroethane at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. 2-({[(S)-Cyclopropyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-6-fluoro-benzoic acid was added and the reaction mixture was refluxed for 20 hours. The reaction mixture was poured into 35 mL 1N HCl (aq.) and 50 mL brine. The mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was flash chromatographed on silica gel (gradient heptane-ethyl acetate) to give 344 mg of the title compound, yield 42%. LC-MS (m/z) 411.3 (MH+); tR=1.34.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:16][CH:15]=1.CNN>ClCCl>[NH2:3][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CON3C(=O)c4ccccc4C3=O)cc2)cs1
Agent: CNN
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CON)cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
N-{4-[2-(4-{[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (200 mg), methylhydrazine (0.038 ml) and dichloromethane (4 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 hours, and filtered in vacuo. The filtrate was washed with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with acetonitrile to give N-[4-(2-{4-[(aminooxy)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (81.8 mg) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[C:27]([CH2:31][C:32](OC)=O)[CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[CH2:31][C:32]1[NH:19][C:17](=[O:18])[C:3]2[C:4]([CH3:16])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=2[N:1]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cccc(CC(=O)OC)c1
Reactant: CCCCCCC(CC)n1nc(C)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(C)c2c(=O)[nH]c(Cc3cccc(C(=O)OCC)c3)nc21
Yield: 36.9 %

Procedure:
11 mg (0.042 mmol) of 5-amino-3-methyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 37 mg (0.167 mmol) of methyl 3-ethoxycarbonylphenylacetate are refluxed for 6 hours in 0.5 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 6.8 mg (37%) of a solid, Rf=0.47 (dichloromethane/methanol=15:1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH2:7][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: O=Cc1occc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1ccoc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.5 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and morpholine (0.5 mL, 5.71 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (670 mg, 89%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH2:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[C:14](Cl)(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][NH:6][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar was added 2-azidoethanamine (0.102 g, 1.18 mmol), DCM (5 mL) and then triethylamine (0.239 g, 2.37 mmol). To this reaction mixture, tetradecanoyl chloride (0.292 g, 1.18 mmol) was added dropwise and allowed to stir at room temperature for 24 hr. Then, the reaction mixture was concentrated de vacuo and then purified via silica gel column chromatography (100% dichloromethane to 1:40 methanol:dichloromethane) to give N-(2-azidoethyl)tetradecanamide (0.245 g, 79% yield). 1H NMR (300 MHz, CDCl3) δ 5.86 (s, 1H), δ 3.42 (s, 4H), δ 2.18 (t, 2H), δ 1.62 (m, 2H), δ 1.24 (m, 20H), δ 0.87 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.7, 51.2, 39.1, 36.9, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 25.9, 22.9, 14.4 ppm; HRMS (ESI) calcd for C16H32N4O (M+) 296.2576. Found 296.2566.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20](=[O:35])[NH:21][C@H:22]([C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)[C@@H:23]([OH:25])[CH3:24])([CH3:18])([CH3:17])[CH3:16].[N+:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([NH:21][C@H:22]([C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)[C@H:23]([O:25][C:43](=[O:44])[C:42]1[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:47][CH:46]=1)[CH3:24])=[O:35])([CH3:16])([CH3:17])[CH3:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
In nitrogen atmosphere, diisopropylazodicarboxylate (6 mL) was dropwise added under ice-cooling to a THF solution (100 mL) of [(1R,2S)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamic acid tert-butyl ester (5.88 g), 4-nitrobenzoic acid (4.84 g), and triphenylphosphine (7.59 g). The resulting reaction solution was stirred at room temperature for 2 hr and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=97:3), and then the obtained powder was triturated with toluene-hexane to give 6.69 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: O1CCCC1.[C:6]([C:8]1([OH:23])[C:19]([CH3:21])([CH3:20])[CH2:18][C:11]2([O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]2)[CH:10]=[C:9]1[CH3:22])#[CH:7].[CH2:24]([SnH:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>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.O>[CH3:16][CH:14]1[CH:13]([CH3:17])[O:12][C:11]2([CH2:18][C:19]([CH3:21])([CH3:20])[C:8](/[CH:6]=[CH:7]/[Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])([OH:23])[C:9]([CH3:22])=[CH:10]2)[O:15]1
Reactant: C#CC1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2
Reactant: CCCC[SnH](CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.4 %

Procedure:
Under argon, tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.20 mmol) was initially charged in a round-bottom flask that had been dried by heating, and abs. tetrahydrofuran (25 ml) and 8-ethynyl-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-ol (1.0 g, 3.99 mmol) were added. Stirring at room temperature for 5 minutes was followed by the addition of tributyltin hydride (1.29 ml, 4.79 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and then water was added. The aqueous phase was repeatedly extracted thoroughly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), it was possible to obtain 2,3,7,9,9-pentamethyl-8-[(E)-2-(tributylstannyl)vinyl]-1,4-dioxaspiro[4.5]dec-6-en-8-ol (1.50 g, 66% of theory) in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.13 (d, 1H), 5.93 (d, 1H), 5.42 (s, 1H), 4.22/3.63 (m, 2H), 1.61 (s, 3H), 1.59 (d, 1H), 1.52 (d, 1H), 1.49 (m, 6H), 1.32-1.24 (m, 12H), 1.09 (s, 3H), 0.89 (m, 18H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18](=[O:33])([O:26]C1C=CC=CC=1)[O:19]C1C=CC=CC=1.C(OC1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH3:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH3:9].[C:18]([OH:33])([OH:26])=[O:19]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C(Oc1ccccc1)c1ccccc1
Product: O=C(O)O
Temperature: 150 °C

Procedure:
0.15 mol bisphenol A, 0.16 mol diphenyl carbonate 2×10-6 mol tetrabutyl ammonium bis-4-nitrophenolate, 3×10-3 mol phenyl benzoate were placed in a reactor which was blanketted with nitrogen. Temperature was raised from ambient to 150° C. during one hour while the reactor contents were maintained at atmospheric pressure. Then changing the temperature to 240° C. and pressure to 90 mm Hg in 11/2 hours, phenol removed from the reactor was nearly 75%. On subsequent increase in temperature to 260° C. and decrease in pressure to 20 mm Hg, phenol collected in 2 hours was 99%. In the end the reaction mixture was heated to 280° C. at 1 mm Hg for 1 hour. The colorfree polymer, bisphenol A polycarbonate in 99% yield obtained had a relative viscosity 1.24.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]([OH:22])[C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([NH:2][C:34](=[O:36])[CH3:35])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[CH:17][CH:16]=2)=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and acetic anhydride by using the same techniques as in Example 41.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](N)[CH:10]=2)[CH2:5][CH2:4][NH:3]1.[N+]([O-])([O-])=O.[Na+].[NH2:18][C:19](N)=O.[OH-].[Na+].[C-]#N.[K+]>O.S([O-])([O-])(=O)=O.[Ni+2].C1C=CC=CC=1>[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:19]#[N:18])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: NC(N)=O
Reactant: Nc1ccc2c(c1)CNCC2
Agent: [Ni+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccccc1
Solvent: O
Product: N#Cc1ccc2c(c1)CNCC2
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
Hydrochloric acid (30.6 ml; 2 equiv.) was added at 0° C. to a solution of 1,2,3,4,-tetrahydroisoquinoline-7-amine (15.3 g; 1 equiv.) in 40 ml of water, and the reaction mixture was stirred for 10 minutes at −5° C. Sodium nitrate solution (7.13 g of sodium nitrate in 35 ml of water) was added dropwise at 0° C. in the course of 30 minutes, and the resulting reaction mixture was stirred for 30 minutes at 0° C. Finally, urea (1.86 g; 0.3 equiv.) was added. A mixture of sodium hydroxide solution (10.3 g of NaOH in 70 ml of H2O), potassium cyanide solution (33.5 g (5 equiv.) of KCN in 50 ml of H2O) and 76.5 ml of benzene was cooled to 0° C.; a nickel sulfate solution (32.6 g (1.2 equiv.) of NiSO4*6H2O in 50 ml of H2O) was added slowly, and stirring was carried out for 30 min. at 0° C. The diazonium solution was slowly added dropwise at 0° C., and the resulting reaction mixture was stirred first for 2 h at room temperature and then for 1 h at 50° C. When the conversion was complete, the mixture was cooled to 0° C., adjusted to a pH value of 8-9 with sodium hydroxide solution and filtered over Celite, and the filter cake was then washed with dichloromethane. The aqueous solution was extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 10% methanol/chloroform). 1,2,3,4-Tetrahydroisoquinoline-7-carbonitrile (4 g; 24.5%) was obtained in the form of a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]([NH:21]S(C(C)(C)C)=O)([CH3:20])[CH2:10][S:11]([C:14]2([C:18]#[N:19])[CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])[C:5]([F:8])=[N:6][CH:7]=1.Cl.C(OCC)C>CO>[NH2:21][C@@:9]([C:4]1[C:5]([F:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:20])[CH2:10][S:11]([C:14]1([C:18]#[N:19])[CH2:17][CH2:16][CH2:15]1)(=[O:13])=[O:12]
Reactant: CC(C)(C)S(=O)N[C@@](C)(CS(=O)(=O)C1(C#N)CCC1)c1cc(Br)cnc1F
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@](N)(CS(=O)(=O)C1(C#N)CCC1)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N—((R)-2-(5-bromo-2-fluoropyridin-3-yl)-1-((1-cyanocyclobutyl)sulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide (7.0 g, 14.57 mmol) in MeOH (10 mL) was added hydrogen chloride, 1 m in diethyl ether (58.3 ml, 58.3 mmol) and stirred at room temperature for 30 min until starting material was consumed. The mixture was concentrated, diluted with DCM and neutralized with 10% Na2CO3 and 1 N NaOH. The organic phase was dried over Na2SO4, filtered and concentrated to afford a pale yellow oil as (R)-1-((2-amino-2-(5-bromo-2-fluoropyridin-3-yl)propyl)sulfonyl)cyclobutanecarbonitrile. This product was dissolved in DCE (40 mL), placed in a water bath at room temperature and trimethylaluminum solution, 2.0M in toluene (11.66 ml, 23.31 mmol) was added dropwise. After the addition was completed, the water bath was removed and the resulting mixture was stirred at room temperature for 17 h. The mixture was cooled to 0° C. and 1N aqueous hydrochloric acid (43.7 ml, 43.7 mmol) was added dropwise via an addition funnel (slowly at first until vigorous reaction subsided) and stirred at room temperature. The aqueous solution was extracted with DCM. The pH of the aq. phase was adjusted to pH>10 with 10 N NaOH and extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-100% EtOAc/hexanes to afford a light yellow solid as (R)-9-amino-7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5-thia-8-azaspiro[3.5]non-8-ene 5,5-dioxide (3.9 g, 10.37 mmol, 71.1% yield). LC/MS (ESI+) m/z=375.6 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:14][NH:15][S:16](Cl)(=[O:18])=[O:17].[BH4-].[Na+]>N1C=CC=CC=1>[CH3:14][N:15]1[S:16](=[O:18])(=[O:17])[NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[CH:5]=[CH:4][C:3]=2[CH2:12]1
Reactant: Nc1c(C=O)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1Cc2ccc3cccnc3c2NS1(=O)=O
Yield: 13.8 %

Procedure:
In a similar fashion using route 27 general procedure 70, 8-amino-quinoline-7-carbaldehyde (100 mg, 0.58 mmol), N-methylsulfamoyl chloride (226 mg, 1.74 mmol), NaBH4 (22 mg, 0.58 mmol) and pyridine (1 ml) gave the title compound (20 mg, 14%) after purification by column chromatography with heptane/EtOAc (90:10) as the eluent.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[CH2:27][S:26][C@H:9]1[S:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=O)C.O1CCCC1>CO.C(O)C.O>[S:10]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)[C@@H:9]1[S:26][CH2:27][C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:8]1[OH:7]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(S(=O)(=O)c3ccccc3)cc2)SC[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(S[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
A solution of 0.35 cm3 of sodium methylate in methanol (3.5 molar) is added to a suspension of 6.5 g of 4-(phenylsulfonyl)phenyl 2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside in 150 ml of methanol. The mixture obtained is stirred at room temperature for 1.5 h under nitrogen and 250 cm3 of tetrahydrofuran are then added. A clear solution is obtained, after which Amberlite® IR 120 H+ resin is added to pH 6. The mixture is filtered and the solvents are evaporated off under reduced pressure. After recrystallization from a methanol/water mixture (50/50 v/v), followed by dissolution in an ethanol/water mixture (50/50 v/v) and lyophilization, 3.3 g of the expected product (yield: 67%) are obtained.
Reaction SMILES: Br[CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH:3](Br)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH3:23][O-:24].[Na+].[K+].[Br-]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([CH:3]([O:24][CH3:23])[CH2:2][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cc1)C(Br)C(Br)C(=O)c1ccc(Br)cc1
Reactant: C[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COC(CC(=O)c1ccc(Br)cc1)C(=O)c1ccc(Br)cc1

Procedure:
To a solution of 1,2-dibromo-1,2-di(4-bromobenzoyl) ethane (11.1 g, 0.02 mole) in 150 ml dry methanol was added a solution of sodium methoxide in methanol (0.92 g sodium in 50 ml methanol). The yellow brown mixture was refluxed for 1-1.5 hr. The solvent was removed by distillation, the residue was suspended in water and the mixture was extracted with 100 ml chloroform. The chloroform extract was washed with water, dried (Na2SO4) and concentrated. The residue obtained was titrated with dry methanol-ether (3:1) to yield off-white crystalline solid, 6.6 g (78%), mp 153°-154° C. IR (KBr): 3106, 3062, 2932, 1689, 1649, 1583, 1556, 1403, 1223, 1202, 1182, 1086, 1010, 1000, 857, 814, 738, 618, 472 cm-1. 1H (DMSO-d6 /40° C.): 7.95 (d, 2H, J=7.8), 7.77 (4H, J=8.8), 7.72 (d, 2H, J=7.8), 6.89 (s, 1H), 4.03 (s, 3H). 13C (DMSO-d6 /40° C.): 189.9, 187.2, 168.8, 139.9, 135.9, 133.1, 132.2, 131.8, 130.3, 128.1, 127.4, 98.6, 58.5. MS m/e 424 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH:3]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[OH:31])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(O)c2ccccc2Cl)cc1OC
Reaction time: 18 h
Yield: 43.9 %

Procedure:
To 0.152 g of the compound obtained in Example 5.1 dissolved in 5 ml of ethanol is added 0.036 g of sodium borohydride and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is taken up in a minimum amount of ethyl acetate and the precipitate formed is filtered off and dried to give 0.067 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][N:23]3[C@H:28]4[CH2:29][CH2:30][C@@H:24]3[CH2:25][CH:26]([N:31]3[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=[C:32]3[CH3:40])[CH2:27]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH2:20])[CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:41][CH2:42][C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>>[Cl:41][CH2:42][C:43]([NH:20][C@H:16]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:21][CH2:22][N:23]2[C@H:24]3[CH2:30][CH2:29][C@@H:28]2[CH2:27][CH:26]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[CH2:25]3)[CH2:9][CH2:10]1)=[O:15])[CH:17]([CH3:18])[CH3:19])=[O:44]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](N)C(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)CCl)C(C)C)CC1
Yield: 66.1 %

Procedure:
2-chloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}carbamate (0.614 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.512 g, 99%). {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.050 g, 0.09 mmol), Chloro-acetyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-N{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide (0.037 g, 66%) as an oil. ES-LCMS m/z 622 (M+1).