Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:19]([N:21]([CH2:25][CH:26]=[CH2:27])[CH2:22][CH:23]=[CH2:24])=[O:20].[SH2:28]>CO>[CH:19]([N:21]1[CH2:25][CH:26]([CH3:27])[S:28][CH:23]([CH3:24])[CH2:22]1)=[O:20]
Reactant: S
Reactant: C=CCN(C=O)CC=C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCNCC1
Product: CC1CN(C=O)CC(C)S1
Reaction time: 48 h

Procedure:
Piperidine (10 ml) and 10 ml of a 40% solution of benzyltrimethylammoniumhydroxide in methanol were added to a solution of N-formyl-diallylamine (55 g) in methanol (200 ml). Hydrogen sulfide (50 g) was introduced into the resulting solution, and unreacted hydrogen sulfide was kept at reflux for 7 hours by means of "cold finger". The mixture was left at room temperature for 48 hours, flushed with nitrogen, diluted with ether, and washed with water. The organic phase was dried, and the solvent evaporated in vacuo. Distillation of the residue gave the title compound with boiling point 145° C./15 mmHg.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1.[NH2:13][C:14]1[CH:19]=[C:18]([O:20]C)[CH:17]=[C:16]([Br:22])[C:15]=1O>>[Br:22][C:16]1[C:15]2[O:9][C:7]([C:6]3[CH:10]=[CH:11][C:3]([OH:2])=[CH:4][C:5]=3[CH3:12])=[N:13][C:14]=2[CH:19]=[C:18]([OH:20])[CH:17]=1
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: COc1cc(N)c(O)c(Br)c1
Product: Cc1cc(O)ccc1-c1nc2cc(O)cc(Br)c2o1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 21, from 4-methoxy-2-methylbenzoic acid, and 2-amino-6-bromo-4-methoxyphenol, and was obtained as a light purple solid, m.p. 120–135° C.; MS m/e 320 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.Cl.[CH3:38][O:39][CH:40]1[CH2:43][NH:42][CH2:41]1>>[CH3:38][O:39][CH:40]1[CH2:43][N:42]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=3)=[CH:7][CH:8]=2)[CH2:41]1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COC1CNC1
Agent: Cl
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CN3CC(OC)C3)cc2)cc1
Yield: 68.1 %

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.50 g) as obtained in Example 16-(1) and 3-methoxyazetidine hydrochloride (0.16 g), there was obtained (2S)-2-{[4-({4-[(3-methoxyazetidin-1-yl)methyl]phenyl}ethynyl)benzoyl](methyl)amino}-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) (0.39 g, 68%) in the same manner as in Example 16-1-(3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH:7](I)[CH:8]1[O:27][C@H:11]2[CH2:12][C@@H:13]([OH:26])[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:25])[CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23])[C@H:10]2[CH2:9]1.Cl.P([O-])([O-])([O-])=O>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1/[CH2:9][C@@H:10]2[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:25])[CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23])[C@H:13]([OH:26])[CH2:12][C@@H:11]2[O:27]/1
Reactant: COC(=O)CCCC(I)C1C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CCCCCl)[C@H](O)C[C@@H]2O1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: COC(=O)CCC/C=C1/C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CCCCCl)[C@H](O)C[C@@H]2O1
Temperature: 0 °C
Yield: 58.6 %

Procedure:
Under an atmosphere of nitrogen, a solution of 116 mg of (13E)-(5RS,6RS,9α,11α,15S,16RS)-5-iodo-6,9-epoxy-11,15-dihydroxy-16-methyl-20-chloroprost-13-enoic acid methyl ester (prepared as described in Example 1) and 0.4 ml of 1,5-diazabicyclo[5,4,0]undecene-5 (DBU) was stirred at room temperature for 18 hours, and then cooled to 0° C. To the reaction mixture were added 2 ml of 1 N hydrochloric acid and 2 ml of phosphate buffer solution (pH 6.86) with cooling to 0° C. The reaction mixture was extracted quickly with diethyl ether. The extract was dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on Florisil (an activated magnesium silicate: "Florisil" is a registered Trade Mark of Florin Co.) using a mixture of ethyl acetate and n-hexane (1:1) containing 0.1% of triethylamine as eluent to give 52 mg of the title compound having the following physical characteristics:
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:15][C:16]([F:44])([F:43])[C:17]1[CH:41]=[C:40]([NH2:42])[C:20]2[NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)=[N:23][C:19]=2[CH:18]=1.[F:45][C:46]1[CH:47]=[C:48]([CH:51]=[C:52]([F:55])[C:53]=1[F:54])[CH:49]=O>C(Cl)(Cl)Cl>[F:45][C:46]1[CH:47]=[C:48]([CH:51]=[C:52]([F:55])[C:53]=1[F:54])[CH2:49][NH:42][C:40]1[C:20]2[NH:21][C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[C:35]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:28][CH2:29]3)=[N:23][C:19]=2[CH:18]=[C:17]([C:16]([F:15])([F:43])[F:44])[CH:41]=1
Reactant: Nc1cc(C(F)(F)F)cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c12
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(CNc2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c23)cc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaBH(OAc)3 (211 mg, 1 mmol, Aldrich) was added to a mixture of 5-(trifluoromethyl)-2-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-benzimidazol-7-amine (215 mg, 0.5 mmol, Example 58) and 3,4,5-trifluoro-benzaldehyde (88 mg, 0.55 mmol, Aldrich) in chloroform (2 mL) in one portion. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (30 mL), and washed successively with 1 N NaOH (15 mL) and brine (15 mL), dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography, eluting with 25% EtOAc/hexane to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 575 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=O)[C@H:14]([OH:16])[CH3:15])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].B.CO>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C@H:14]([OH:16])[CH3:15])[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H](O)C(=O)N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)CN1CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
[(R)-1-((R)-2-Hydroxy-propyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (244 mg) was prepared from [(R)-1-((R)-2-hydroxy-propionyl)-pyrrolidin-3-yl]carbamic acid tert-butyl ester (500 mg) and 1 M borane in THF (6 mL). The reaction was stirred at room temperature for 30 min and then stirred at 50° C. for 8 h. The reaction was added to methanol (20 mL). The solvent was evaporated and crude compound was purified by flash chromatography using DCM:methanol gradient.
Reaction SMILES: [NH2:1]/[C:2](=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.O.[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32](=[CH2:35])[CH:33]=O)=[CH:29][CH:28]=1>CCCCO>[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32]2[CH:35]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:1][CH:33]=2)=[CH:29][CH:28]=1
Reactant: C=C(C=O)Cc1ccc(F)cc1
Reactant: CCOC(=O)/C=C(\N)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Product: CCOC(=O)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of diethyl 2-aminofumarate (153 g, 0.81 mol) and p-TsOH.H2O (1.5 g, 8.1 mmol) in n-BuOH (325 mL) was added 2-(4-fluorobenzyl)propenal (162 g, 0.98 mol) dropwise at 120° C. The mixture was stirred for 17 h at 120° C. and at rt for ca. 24 h. The mixture was filtered and concentrated under vacuum to yield the crude diethyl 5-(4-fluorobenzyl)-2,3-pyridinedicarboxylate. This material was dissolved in EtOH (400 mL) and an ice-cold solution of NaOH (88 g, 2.2 mol) in water (300 mL) was added. The mixture was stirred for 2 h at rt. After removal of EtOH in vacuo, water (400 mL) and 6N HCl (200 mL) were added and the mixture was extracted with EtOAc. The EtOAc layer was washed with water and the combined aqueous layers adjusted to pH 2 with 6N HCl (175 mL). The mixture was stirred for 1 h at ice-bath temperature and the product was collected by filtration: 1H NMR (d6-DMSO) δ 8.64 (1H, d, J=2 Hz), 8.01 (1H, d, J=2 Hz), 7.32 (2H, dd, J˜9, 6 Hz), 7.12 (2H, t, J˜9 Hz), 4.05 (2H, s); ES+ MS: 276 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:16]([C:18]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:21][N:20]([CH3:30])[N:19]=2)=[O:17])=[N:6][CH:7]=1.[Cu][C:32]#[N:33]>CN1CCCC1=O.O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:18]([C:16]([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[CH2:9][NH:8][C:5]3[N:4]=[CH:3][C:2]([C:32]#[N:33])=[CH:7][N:6]=3)=[O:17])=[N:19][N:20]([CH3:30])[CH:21]=2)=[CH:24][CH:25]=1
Reactant: N#C[Cu]
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCC[C@H]2CNc2ncc(Br)cn2)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCC[C@H]2CNc2ncc(C#N)cn2)n1
Yield: 6.1 %

Procedure:
1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone (0.35 g) in N-methylpyrrolidinone (10 ml) containing copper(I)cyanide (0.13 g) was heated to reflux for 5 h. The reaction mixture was diluted with water, filtered (Kieselguhr) and the filtrate extracted with ethyl acetate. The ethyl acetate phase was washed with water and brine, dried (MgSO4), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel; ethyl acetate:pentane 1:1→ethyl acetate eluant), the appropriate fractions combined and solvent removed at reduced pressure to give the title compound (0.019 g).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[S:15][CH3:16])(=[O:8])=[O:7])(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:14][N:11]1[CH:12]=[CH:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[C:10]1[S:15][CH3:16]
Reactant: CSc1c(S(=O)(=O)NC(C)(C)C)ccn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a solution of 4.63 g (17.66 mmol) N-(1,1-dimethylethyl)-1-methyl-2-(methylthio)-1H-pyrrole-3-sulfonamide in 50 mL of methylene chloride was added 50 mL of trifluoroacetic acid (TFA) under a nitrogen atmosphere. The orange reaction mixture was stirred at room temperature overnight ca. 16 hours. The reaction mixture was concentrated to a tan solid. Diethyl ether was added to the tan solid and was removed by evaporation to remove residual TFA. The solid was suspended in diethyl ether and filtered giving 2.9 g of the title compound as a solid, m.p. 135°-137° C.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])[CH:9]=[CH:10][C:11]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:43]1([CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59]O)[CH:54]=2)[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:45][CH2:44]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:43]1([CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][O:12][C:11]3[CH:10]=[CH:9][C:8]([C:13]4[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=4[F:21])=[CH:7][C:6]=3[CH2:5][CH2:4][CH2:3][C:2]([CH3:23])([CH3:22])[CH3:1])[CH:54]=2)[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:45][CH2:44]1
Reactant: COc1ccc(F)c(-c2ccc(O)c(CCCC(C)(C)C)c2)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2CCCC(C)(C)C)c1)C1CC1
Yield: 78.5 %

Procedure:
To a solution of 3-(4,4-dimethylpentyl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (280 mg) in THF (5.0 mL) were added triphenylphosphine (348 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (330 mg) and a 40% solution of diethyl azodicarboxylate in toluene (600 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (380 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]>CO.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
To a solution of methyl 2-(2-methoxy-4-nitrophenyl) acetate (step 3, 1.2 g, 5.5 mmol) in methanol (10 ml) was added 10% Pd/C (130 mg, 0.12 mmol) and stirred under hydrogen atmosphere for 3 h at room temperature. The catalyst was filtered off through a pad of celite and well washed with ethanol and ethyl acetate. The filtrate was concentrated to give 1.1 g of title compound as pink oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.B([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 94.6 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (B-8) (5.1 g, 14 mmol), 4-boronobenzoic acid (3.4 g, 20 mmol), 1 M K2CO3 (54 mL, 54 mmol), Pd-FibreCat 1007 (810 mg, 1.35 mmol), and DMF (135 mL) were combined. The mixture was heated at 80° C. for 3 h. After cooling, the mixture was filtered and DMF was removed in vacuo. The residue was partitioned between dichloromethane (250 mL) and 1N HCl (250 mL). The organics were separated, washed with saturated NaCl solution (250 mL), and dried over Na2SO4. Evaporation of organics yielded 4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]benzoic acid (5.5 g, 98%). ESI-MS m/z calc. 415.1. found 416.5 (M+1)+; Retention time 3.19 minutes. 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.83 (s, 1H), 8.06-8.04 (m, 2H), 7.58-7.56 (m, 1H), 7.50-7.48 (m, 3H), 7.27-7.24 (m, 1H), 7.05-7.04 (m, 1H), 6.98-6.94 (m, 2H), 6.07 (s, 2H), 2.22 (s, 3H), 1.46-1.44 (m, 2H), 1.12-1.09 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[CH:23]=[CH:24][C:25]([F:30])=[C:26]([CH:29]=1)[C:27]#[N:28]>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[CH:23]=[CH:24][C:25]([F:30])=[C:26]([CH:29]=3)[C:27]#[N:28])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)ccc1F
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-2-fluorobenzonitrile generally according to the procedures described in examples 82 and 1. An off-white solid: mp 197-199° C.; 1H NMR (DMSO-d6): δ 10.09 (s, 1H), 8.25 (dd, J=6.35, 2.44 Hz, 1H), 8.02-8.05 (m, 1H), 7.68 (dd, J=8.3, 1.95 Hz, 1H), 7.61 (d, J=1.95 Hz, 1H), 7.7 (dd, JHF=9.28 Hz, JHH=9.28 Hz, 1H), 7.56 (dd, J=5.37, 1.47 Hz, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.0 (dd, J=4.88, 3.42 Hz, 1H), 6.95 (dd, J=3.9, 1.47 Hz, 1H), 4.08 (d, J=15.62 Hz, 1H), 3.94 (d, J=15.13 Hz, 1H), 2.46-2.57 (m, 2H), 0.76 (t, J=6.83 Hz, 3H); MS (ESI) m/z 393 ([M+H]+); MS (ESI) m/z 391 ([M−H]−); Anal. calcd for C22H17FN2O2S: C: 67.33; H: 4.37; N: 7.14. Found: C: 67.26; H: 4.38; N: 6.90.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]([C:41]([F:44])([F:43])[F:42])=[CH:4][C:5]([NH:7][C@:8]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH:38]([CH3:40])[CH3:39])[CH:31]=1)([C:16]1[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1(C2C=C[N+]([O-:59])=CC=2)C=CC=CC=1.[O-]Cl.[Na+]>C(#N)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:8]([NH:7][C:5]([CH:4]2[C:3]([C:41]([F:43])([F:44])[F:42])([C:2]([F:1])([F:45])[F:46])[O:59]2)=[O:6])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:31][C:32]=1[O:37][CH:38]([CH3:40])[CH3:39]
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C=C(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C2OC2(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
At 0° C. to a solution of (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide (Example 291, 130 mg, 0.19 mmol) and 4-phenyl pyridine N-oxide (26 mg, 0.15 mmol) in acetonitrile (5 mL) was added NaOCl solution (206 μL, chlorine wt % 10−3%, 0.58 mmol). The reaction mixture was stirred at 0° C. for 10 min, then at rt for 1 h. The solvents were removed under reduced pressure and the residue was diluted with EtOAc (30 mL), washed with saturated Na2SO3 (30 mL), dried over MgSO4, filtered and concentrated. The resulting residue was right away purified by ISCO chromatography (40 g column, flow rate 25 mL/min) using hexanes/EtOAc (0-10% over 30 min) to give N—((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide as a diastereomer mixture at a retention time of 26 min (97 mg, 74% yield). The diastereomer mixture was separated by Chiral preparative HPLC chiralpak AD 20μ column, 5×50 cm, eluting with 5% IPA/Heptane with flow rate 50 mL/min.
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([CH3:16])[CH:10]=1.[CH3:17][S:18]SC>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([S:18][CH3:17])=[C:11]([CH3:16])[CH:10]=1
Reactant: CSSC
Reactant: Cc1cc(Cl)ccc1N
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1ccc(Cl)cc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 908.2 %

Procedure:
t-Butyl nitrite (1.52 g) was added to a mixture of 4-chloro-2-methylaniline (2.0 g) and dimethyl disulphide (14.49 g) in chloroform The mixture was heated to 70° C. to initiate the reaction. A solution of 4-chloro-2-methylaniline (9.0 g) in chloroform and t-butyl nitrite (7.25 g) were added simultaneously while maintaining the temperature in the range 60°-70° C. Further dimethyl disulphide (11.83 g) was added followed by the simultaneous addition of a solution of 4-chloro-2-methylaniline (9.0 g) in chloroform and t-butyl nitrite (7.25 g) while maintaining the temperature in the range 50°-55° C. The mixture was stirred at room temperature for 2 hours. It was washed thoroughly with water, 2M hydrochloric acid, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 5-chloro-2-(methylsulphenyl)toluene (22.15 g) as a red oil which was not further characterized.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([F:23])[C:17]=2[C:24]#[N:25])=[N:9]S(C(C)(C)C)=O)[CH:5]=[CH:6][CH:7]=1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[C:16]3[C:17](=[C:18]([F:23])[CH:19]=[C:20]([Cl:22])[CH:21]=3)[C:24]([NH2:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cc(Cl)cc(F)c1C#N
Product: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cc(Cl)cc32)ccn1
Yield: 83 %

Procedure:
The title compound was synthesized as described for Example 11i in 83% yield, starting from N-((3-bromophenyl)(5-chloro-2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (2 g, 4.53 mmol) and 4-bromo-2-methylpyridine (0.935 g, 5.43 mmol)
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1>C(Cl)Cl>[N+:19]([C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=1)[CH2:8][N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1)([O-:21])=[O:20]
Reactant: O[C@H]1CCNC1
Reactant: O=[N+]([O-])c1cc(CBr)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CN2CC[C@H](O)C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.7 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine (1.84 g, 21 mmol) in DCM (10 mL) at 0° C. was added a solution of 1-(bromomethyl)-3-nitro-5-(trifluoromethyl)benzene (2.00 g, 7 mmol) in DCM (10 mL) dropwise. After the addition, the reaction mixture was allowed to stir at rt for 2 h and then diluted with DCM and washed with brine. Removal of solvent gave (3S)-1-[3-nitro-5-(trifluoromethyl)benzyl]pyrrolidin-3-ol (2.25 g, 100% yield) as yellow oil. LCMS: (FA) ES+ 291.3.Step 2: 3-[((3S)-3-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-1-yl)methyl]-5-(trifluoromethyl)aniline
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=3)[NH2:12])[O:8][C:4]=2[CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].O>N1C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([NH:12][C:21]([NH:20][CH2:18][CH3:19])=[O:22])[CH:13]=[CH:14][CH:15]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Solvent: c1ccncc1
Solvent: O
Product: CCNC(=O)Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)aniline (Compound of Example 267) (925 mg) in pyridine (15 ml) was added ethyl isocyanate (680 mg) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, successively, and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain N-[3-(6-bromobenzoxazol-2-yl)phenyl]-N′-ethylurea (986 mg, 86%).