Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:11]2[N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]3=[N:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:18]1[CH2:19][CH2:20][C:14]2=[N:13][N:12]=[C:11]([C:6]3([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:7][CH2:8][CH2:9][CH2:10]3)[N:15]2[CH2:16][CH2:17]1)(=[O:29])[CH3:28]
Reactant: c1csc(C2(c3nnc4n3CCNCC4)CCCC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCc2nnc(C3(c4cccs4)CCCC3)n2CC1
Reaction time: 15 h

Procedure:
3-[1-(2-Thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine (190 mg) was dissolved in dichloromethane (15 ml) and then pyridine (106 μl) and acetic anhydride (62 μl) were added at room temperature, followed by stirring at the same temperature for 15 hours. The residue obtained by removing the solvent by evaporation was diluted with ethyl acetate and washed with 0.3M hydrochloric acid, water, and brine, successively. The solution was dried over anhydrous magnesium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 95:5) to obtain 110 mg of 7-acetyl-3-[1-(2-thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine (white solid).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)[CH3:3].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1.C(N=[N+]=[N-])(=O)C1C=CC=NC=1>C1(C)C=CC=CC=1>[CH3:3][N:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:20](=[O:21])[NH:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:7]2)[CH3:1]
Reactant: CN(C)c1ccc2c(c1)CCN2
Reactant: O=C=Nc1cccnc1
Agent: [N-]=[N+]=NC(=O)c1cccnc1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc2c(c1)CCN2C(=O)Nc1cccnc1
Reaction time: 8 h
Yield: 99 %

Procedure:
5-(N,N-dimethylamino)indoline (D13) (0.29 g, 1.79 mmol) was added to solution of 3-pyridylisocyanate derived from nicotinoyl azide (0.52 g, 1.2 eq) heated at reflux in dry toluene for 1.5 h. The solution was allowed to stand overnight evaporated under reduced pressure and purified by column chromatography (SiO2, CHCl3 /MeOH 2-5%) to afford a pale blue oil which on trituration with Et2O afforded a pale blue solid (550 mg, 99%).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]1[C:11]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:12]2)[CH2:10]1.CI>C1COCC1>[CH3:2][C:13]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12][C:11]2([CH2:10][CH2:9]2)[CH2:14]1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(OCc1ccccc1)C1CC2(CC2)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)OCc2ccccc2)CC2(CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of LDA (3.47 mL, 6.94 mmol 2M in THF) in THF (5 mL) cooled to −78° C., was added dropwise a solution of benzyl spiro[2.3]hexane-5-carboxylate (0.5 g, 2.312 mmol) in THF (2 mL). The resulting solution was stirred for 30 min. prior to the dropwise addition of MeI (0.723 mL, 11.56 mmol) at −78° C. The resulting reaction mixture was allowed to warm to RT and stir for 12 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (20 mL) and extracted with EtOAc (3×10 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 5% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford the Intermediate 317A as a colorless liquid (200 mg, 38% yield). MS(ES): m/z=231.2 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.50-7.28 (m, 5H), 5.36-4.94 (s, 2H), 2.87-2.47 (m, 2H), 2.01-1.77 (m, 2H), 1.62-1.39 (s, 3H), 0.60-0.22 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19]>CC(C)=O>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21]([NH:20][C:18]([O:17][CH3:16])=[O:19])=[S:22])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCSc1ccc(N)c([N+](=O)[O-])c1
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: CCCCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
2.5 G. of 1-amino-4-n-butylthio-2-nitrobenzene (alternatively prepared according to Example II) is dissolved in 25 ml. acetone and treated at room temperature with 3 g. methoxy carbonyl isothiocyanate. The mixture is left overnight, stripped under vacuum and the residue triturated with methanol and recrystallized from methanol to yield pure 4-n-butylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH2:3][CH2:4][CH3:5].C1CCC(NC2CCCCC2)CC1.[NH2:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:32][S:33][CH3:34].Cl.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)OC
Reaction time: 8 h
Yield: 71 %

Procedure:
BOC-Nva-OH, liberated from 4.78 g (12 mmoles) of the DCHA salt as described in Step 1 of Example 4, and 2.6 g (13 mmoles) of H-Met-OMe.HCl are dissolved in 40 ml of chloroform, and 1.82 ml (13 mmoles) of triethylamine are added. The mixture is cooled with ice, and a solution of 2.58 g (12.5 mmoles) of DCC in 20 ml of chloroform is added under stirring. The reaction mixture is allowed to stand at 5° C. overnight, thereafter the separated DCU is filtered off. The filtrate is washed thrice with 20 ml of n hydrochloric acid, each, thrice with 20 ml of n sodium hydrocarbonate solution, each, and then with 20 ml of water, dried over anhydrous sodium sulfate, and evaporated. The oily residue is crystallized from petroleum ether, and the resulting 3.42 g of crude product is recrystallized from a mixture of ethyl acetate and petroleum ether. 3.08 g (71%) of BOC-Nva-Met-OMe are obtained; m.p.: 69°- 70° C., Rf2 =0.81, [α]D25 =-42.7° (c=1%, in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:22]([NH:7][CH2:6][C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc(CN)cc(OC)c1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CNC(=O)c2ccccc2)cc(OC)c1OC
Temperature: -2 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a mixture of 3,4,5-trimethoxybenzylamine (20.0 g, 0.101 mol), THF (88.0 mL) and triethylamine (14.9 g, 0.147 mol) was added dropwise benzoyl chloride (14.3 g, 0.101 mol) at −6-−3° C., and the dropping funnel was washed with THF (10 mL). The reaction mixture was stirred under a nitrogen atmosphere at −6-2° C. for 1 hr. The consumption of the starting material was confirmed by TLC (hexane/ethyl acetate (1:1)). To the reaction mixture was added water (44 mL) at 2-10° C., and the mixture was extracted three times with ethyl acetate (17, 40, 18 mL). The combined organic layers were washed twice with 18% brine (20 mL), and dried over magnesium sulfate (7.4 g). Silica gel (5.1 g) was added thereto, and the mixture was stirred for 11 min, and filtered through silica gel (19 g). The filtrate was concentrated to 35 g under reduced pressure in a bath at 35° C. To the concentrate was added ethyl acetate, and the solid was dissolved with heating. The solvent was evaporated under reduced pressure (content 52 g) in a bath at 40-30° C. until the content ceased to flow. During evaporation, seed crystals were added thereinto. Ethyl acetate in an amount necessary for filtration was added thereto, and the crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure at 50° C. or lower to give N-benzoyl-3,4,5-trimethoxybenzylamine (27.3 g, 89.3%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([NH:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=[O:41])=[CH:38][C:37]=2[O:46][CH3:47])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([C:33]([NH:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([OH:42])=[O:41])=[CH:38][C:37]=2[O:46][CH3:47])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(NC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1NC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A mixture of 243 mg of methyl 4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)-3-methoxybenzoate and 6.0 ml of a THF-methanol (2:1) mixed solvent was mixed with 1.0 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the residue was mixed with 1 M hydrochloric acid, extracted with chloroform and dried with anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 227 mg of 4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)-3-methoxybenzoic acid as a pale brown oily substance.
Reaction SMILES: [C@@H:1]1([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:7][CH2:6][CH2:5]CC=[CH:2]1.[Br:19]N1C(=O)CCC1=O.[CH2:27]([OH:29])[CH3:28]>C(Cl)(Cl)Cl>[Br:19][C@@H:2]1[C@@H:27]([OH:29])[CH2:28][CH2:5][CH2:6][CH2:7][C@H:1]1[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1C=CCCCC1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCO
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCCC[C@H](O)[C@H]1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a solution of (R)-2-(Cyclohept-2-enyl)isoindoline-1,3-dione (4.00 g, 16.58 mmol) in chloroform (40.0 ml) and ethanol (1.400 mL) was added N-bromosuccinimide (3.78 g, 21.22 mmol) as a solid over 5 minutes at room temperature. After addition was complete, the reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. An additional portion of N-bromosuccinimide (1.9 g) and 1.4 mL of ethanol were then added and the mixture was allowed to continue to mix at room temperature overnight under a nitrogen atmosphere. A third portion of N-bromosuccinimide (1.0 g) and 1.4 mL additional ethanol were added to the mixture and it was again mixed at room temperature for a third night under a nitrogen atmosphere. The reaction mixture was then concentrated to dryness. The resulting residue was triturated with 25 mL fresh chloroform. The solids were filtered, rinsed with chloroform, and the filtrate concentrated under reduced pressure to dryness. THF (40 mL) and 1N hydrochloric acid (aq.) (10 mL) were added to the concentrated filtrate and the resulting mixture was stirred at room temperature for 90 minutes. The solution was concentrated under reduced pressure to remove THF. The concentrate was diluted with 125 mL ethyl acetate and 75 mL of a 1:1 mixture of water:saturated aqueous sodium bicarbonate. The layers were separated and the aqueous was back extracted with 75 mL ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford an oil that was purified by silica gel chromatography (0-30% ethyl acetate in hexanes). Fractions containing the desired product were concentrated under reduced pressure to the title compound (3.9 g, 11.53 mmol, 69.6% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (d, J=7.42 Hz, 4H), 5.48 (d, J=5.47 Hz, 1H), 4.73 (dd, J=10.54, 6.25 Hz, 1H), 4.24-4.38 (m, 1H), 3.91-3.99 (m, 1H), 2.32 (br. s., 1H), 1.67-1.96 (m, 5H), 1.40-1.60 (m, 2H). MS (ESI) m/z 320.1 [M−18]+. A COSY NMR experiment and the 1H NMR data reported above were used to verify the bromohydrin regiochemistry. An NOE (via NOESY experiment) was observed between the protons on the amino group carbon and the hydroxyl group carbon. This verifies a cis relationship between these two functional groups (a trans relationship, lacking this spacial proximity, would not show such an effect).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C(N=[N+]=[N-])=O)[CH:5]=[N:6][CH:7]=1.[N-:13]=[C:14]=[O:15].[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[C:27]([F:30])([F:29])[F:28])[NH:23][CH2:22][CH2:21]2>C1(C)C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][CH3:16])=[C:26]([C:27]([F:29])([F:30])[F:28])[CH:25]=3)[CH2:21][CH2:22]2)=[O:15])[CH:5]=[N:6][CH:7]=1
Reactant: [N-]=C=O
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: [N-]=[N+]=NC(=O)c1cncc(Br)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cncc(Br)c1)CC2
Reaction time: 8 h
Yield: 81 %

Procedure:
5-Bromo-3-pyridylcarbonylazide (3.7 g, 16 mmoles) was heated under reflux in dry toluene (100 ml) for 1 hr. After cooling the resulting solution of isocyanate was treated with a solution of 5-methoxy-6-trifluoromethyl indoline (D11) (3.5 g, 16 mmoles) in dichloromethane (600 ml) and stirred overnight. The mixture was concentrated in vacuo and the residue triturated with diethyl ether. Filtration and washing with more diethyl ether gave the title compound (D26) (5.4 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:12]([CH3:18])[C:13]([CH3:17])=[CH:14][C:15]=1[CH3:16])=[O:10].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCCl>[Cl:23][CH2:24][C:25]([C:14]1[C:15]([CH3:16])=[C:11]([C:9](=[O:10])[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:12]([CH3:18])[C:13]=1[CH3:17])=[O:26]
Reactant: Cc1cc(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1c(C(=O)CCl)c(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 87.7 %

Procedure:
A solution of 48.65 g (0.17 mole) of (2,4-dichlorophenyl)(1,3,5-trimethyl-1H-pyrrol-2-yl)-methanone (5) in 480 mL 1,2-dichloroethane was cooled in an ice bath and 53.5 g (0.425 mole) of AlCl3 was added in four portions. A 33.5 mL portion of (0.425 mole) chloroacetyl chloride was added dropwise. The ice bath was removed and the reaction allowed to stir for 3h under argon. A 10 g sample of AlCl3 was added and the reaction was stirred overnight. The mixture was poured into 1N HCl/ice and the organic layer was separated. The aqueous layer was extracted twice with methylene chloride. The organics were combined and washed with water, NaHCO3, water, brine, and dried (MgSO4). The solvent was evaporated in vacuo and the residue recrystallized from methylcyclohexane to give 53.50 g of product: mp 100-102° C.; mass spectrum (Cl—CH4) m/z=358 (M+1); NMR 300 MHz (CDCl3) d 7.55 (s, 1 H); 7.4 (s, 2 H); 4.4 (s, 2 H); 3.7 (s, 3 H); 2.5 (s, 3 H); 1.9 (s, 3 H). Anal Calcd for C16H14NO2: C, 53.58; H, 3.93; N, 3.91. Found: C, 53.48; H, 3.81; N, 3.93.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]([CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:21][C:20]=3[S:28]([NH:31]C(C)(C)C)(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:10][N:11]=1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:48]>C(Cl)Cl.O>[CH2:50]([O:49][C:47]([NH:31][S:28]([C:20]1[S:21][C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:23][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:14]=1)(=[O:29])=[O:30])=[O:48])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccccn3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-[3-(2-pyridin-2-ylimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (46.7 mg, 0.0918 mmol; see step (b)) in CH2Cl2 (1 mL) was added BCl3 (0.18 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (43.8 mg, 0.413 mmol), water (2 mL) and butyl chloroformate (16.3 μL, 0.0129 mmol) and the reaction mixture was stirred for 23 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the title compound as a white solid in 63% yield, over two steps, (32 mg, 0.058 mmol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13](SC)[S:14][CH3:15])[C:11]#[N:12].O.[NH2:19][NH2:20].O>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:12])=[N:19][NH:20][C:13]=1[S:14][CH3:15]
Reactant: CSC(SC)=C(C#N)c1nc2ccccc2s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1[nH]nc(N)c1-c1nc2ccccc2s1
Yield: 44 %

Procedure:
To a suspension of 2-benzothiazol-2-yl-3,3-bismethylsulfanylacrylonitrile (50 mg, 0.18 mmol) in ethanol (2 mL) was added hydrazine hydrate (15 μL). The mixture was heated to reflux for 2 hours. The reaction mixture was then cooled and water was added. The resulting precipitate was isolated by filtration to yield 21 mg (44%) of the title compound as a yellow solid. MS (m/z, ES+): 263 (M+1, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[OH:7][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCOC1
Product: Oc1ccc(C(O)CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0° C. solution of 4-hydroxybenzaldehyde (6.1 g) in THF (75 mL) is added a 3.6 M ethereal solution of 3-phenylpropyl-magnesium bromide (30.5 mL). The resulting suspension was stirred at 25° C. for 16 hrs. and then transferred slowly into ice cold 25% aqueous NH4OAc. The product was extracted into EtOAc (3×100 mL) and the combined extracts were washed with brine, dried with MgSO4 and the solvents were removed under reduced pressure. The residue was swished in a 1:5 mixture of EtOAc and hexanes for 2 hrs. and the solid was filtered and dried to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]=[C:30]1[NH:34][CH:33]([C:35](O)=[O:36])[CH2:32][CH2:31]1>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][N:1]4[C:35](=[O:36])[CH2:33][CH2:32][CH:31]4[C:30]([NH2:34])=[O:29])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C1CCC(C(=O)O)N1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN1C(=O)CCC1C(N)=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-N-(5-cyclopropyl-1H-pyrazol -3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.08 g, 0.2 mmol), 5-oxopyrrolidine-2-carboxylic acid loaded TFP resin (1.4 mmol/g loading, 0.2 mmol), and a THF-DCM solution (3 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.013 g, 10%). 1H NMR (400 MHz, CD3OD) δ 7.41-7.32 (m, 2H), 7.21-7.13 (m, 1H), 7.05-6.97 (m, 2H), 6.05 (s, 1H), 5.21-5.02 (m, 1H), 4.34-4.19 (m, 3H), 2.44-2.28 (m, 3H), 2.11-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.51 (d, J=5.2 Hz, 3H), 0.99-0.86 (m, 2H), 0.69-0.61 (m, 2H). MS: Calcd.: 495 Found: [M+H]+ 496.
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1/[C@H:4]2[C@:8]([CH3:12])([CH2:9][CH2:10][CH2:11]/1)/[C:7](=[CH:13]/[CH3:14])/[CH2:6][CH2:5]2.CS(N)(=O)=[O:17].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+].[OH2:84]>C(OCC)(=O)C.C(O)(C)(C)C>[Br:1]/[CH:2]=[C:3]1/[C@H:4]2[C@:8]([CH3:12])([CH2:9][CH2:10][CH2:11]/1)[C@:7]([C@H:13]([OH:17])[CH3:14])([OH:84])[CH2:6][CH2:5]2
Reactant: CS(N)(=O)=O
Reactant: C/C=C1\CC[C@H]2/C(=C/Br)CCC[C@]12C
Reactant: O
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@@]1(O)CC[C@H]2/C(=C/Br)CCC[C@@]21C
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.3 %

Procedure:
To a mixture of (1E,3aR,4E,7aS)-4-(bromomethylene)-1-ethylidene-octahydro-7a-methyl-1H-indene (Compound 21: 19.2 mg, 0.07524 mmol), methanesulfonamide (21.5 mg, 0.2257 mmol) and AD-mix-α (105 mg), t-butanol (0.4 ml) and water (0.4 ml) were added, and the reaction mixture was stirred at room temperature for 48 hours. Sodium sulfite (113 mg) was added thereto and the resulting mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added thereto, and the resulting mixture was extracted 3 times with ethyl acetate. The organic layer was washed with 2 M aqueous potassium hydroxide solution (1 ml) and saturated brine (2.5 ml), and dried over sodium sulfate, followed by evaporation under reduced pressure. The obtained crude product (23.2 mg) was purified by flash column chromatography to obtain (E,1R,3aR,7aS)-4-(bromomethylene)-octahydro-1-{(R)-1-hydroxyethyl}-7a-methyl-1H-indene-1-ol (18.6 mg, 85.3%).