Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH:11]3[CH2:14][CH:13]([CH:15]=O)[CH2:12]3)[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[CH:25]=1.[CH3:30][C:31]1([CH3:54])[O:35][C@@H:34]2[C@@H:36]([CH2:49][NH:50][CH:51]([CH3:53])[CH3:52])[CH2:37][C@@H:38]([N:39]3[C:43]4[N:44]=[CH:45][N:46]=[C:47]([NH2:48])[C:42]=4[CH:41]=[CH:40]3)[C@@H:33]2[O:32]1.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>ClCCCl.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([C:26]([F:29])([F:27])[F:28])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH:11]3[CH2:12][CH:13]([CH2:15][N:50]([CH2:49][C@@H:36]4[C@H:34]5[O:35][C:31]([CH3:54])([CH3:30])[O:32][C@H:33]5[C@H:38]([N:39]5[C:43]6[N:44]=[CH:45][N:46]=[C:47]([NH2:48])[C:42]=6[CH:41]=[CH:40]5)[CH2:37]4)[CH:51]([CH3:52])[CH3:53])[CH2:14]3)[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])[C:6]=2[CH:25]=1
Reactant: CC(C)NC[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reactant: C[Si](C)(C)CCOCn1c(CC2CC(C=O)C2)nc2cc(C(F)(F)F)c(Cl)cc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CC(C)N(CC1CC(Cc2nc3cc(C(F)(F)F)c(Cl)cc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
A solution of 3-{[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutane-1-carbaldehyde (223 mg, 0.50 mmol), 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-[(propan-2-ylamino)methyl]-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (172 mg, 0.50 mmol) and MgSO4 (600 mg, 5.00 mmol) in DCE (10 ml) was stirred for 15 min. STAB (148 mg, 0.70 mmol) was then added to the reaction mixture and stirred for 1 h at RT. The reaction was monitored by LCMS, no amine was seen after 2.5 h. Sat. NaHCO3 (20 ml) was added to the reaction mixture and stirred for 5 mins. Brine (20 ml) was then added to the reaction mixture. The product was extracted with DCM (2×30 ml), dried over Na2SO4, filtered and evaporated. Purification by prep. HPLC gave the desired product (174 mg, 45%) as a white solid; MS (ESI+) for C38H53ClF3N7O3Si m/z 776.30 [M+H]+; HPLC purity 100% (ret. time, 1.68 min); 1H NMR (500 MHz, MeOD) δH ppm −0.25-0.11 (9H, m), 0.90 (2H, td, J=7.88, 3.47 Hz), 1.30 (3H, s), 1.37 (6H, t, J=7.49 Hz), 1.55 (3H, s), 1.63-1.84 (1H, m), 1.99-2.37 (2H, m), 2.37-3.03 (6H, m), 3.04-3.28 (3H, m), 3.34-3.50 (1H, m), 3.61 (2H, td, J=7.92, 2.29 Hz), 3.79 (1H, br. s.), 4.68 (1H, t, J=6.70 Hz), 4.95-5.27 (2H, m), 5.55-5.81 (1H, m), 6.88 (1H, d, J=3.63 Hz), 7.06-7.62 (2H, m), 7.61-7.94 (1H, m), 7.94-8.16 (1H, m), 8.22 (1H, s)
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[CH:10]=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[C:30](=[O:32])[CH3:31]>>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[C:10]([C:30](=[O:32])[CH3:31])=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2c(ccc3[nH]ccc23)C1
Reactant: CC(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1CCc2c(ccc3[nH]cc(C(C)=O)c23)C1
Temperature: 80 °C
Yield: 89 %

Procedure:
A mixture of dipropyl-(6,7,8,9-tetrahydro-3H-benzo[e]indol-7-yl)amine (55 mg, 0.20 mmol) and phosphorous oxychloride (130 μL, 213 mg, 1.39 mmol) in N,N-dimethylacetamide (200 μL) was heated at 80° C. for 4 hours. After cooling 5M sodium hydroxide was added and the mixture was heated again for 0.5 hours. After cooling the mixture was extracted 3 times with ethyl acetate, dried (magnesium sulfate), filtered and evaporated to yield a residue to which 99% ethanol was added. This was then evaporated to dryness. A few repetitions of the last procedure yielded a residue of 56 mg (89%) of the product, which was further purified on silica using methanol as eluant to give the pure material as a solid.:
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[Cl:27].[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][Br:28])=[CH:22][C:21]=1[Cl:27]
Reactant: Cc1ccc(Br)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)ccc1Br
Yield: 94.1 %

Procedure:
Benzoic peroxyanhydride (3.73 g, 15.41 mmol) was added to a degassed mixture of 1-bromo-2-chloro-4-methylbenzene (24.35 g, 118.50 mmol) and 1-bromopyrrolidine-2,5-dione (23.20 g, 130.35 mmol) in CCl4 (100 mL) at room temperature under nitrogen. The resulting mixture was stirred at reflux for 18 hrs. The reaction was cooled and washed with water (equal volume); satd sodium thiosulfite (equal volume) and water (equal volume). Mixture dried by passing through a phase seperating cartridge. Solvent removed to give crude 1-bromo-4-(bromomethyl)-2-chlorobenzene (31.7 g, 94%) as pale brown oil which was progressed without further purification.
Reaction SMILES: [CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)C(Br)c1ccccc1
Yield: 99.6 %

Procedure:
196 g (1 mole) of phenyl benzyl ketone were suspended in 1 liter of carbon tetrachloride. A solution of 51 ml (1 mole) of bromine in 50 ml of carbon tetrachloride were added dropwise, under irradiation (UV), at a rate such that a steady consumption of bromine took place. The solvent was then distilled off in a water pump vacuum. 274 g (quantitative yield) of ω-bromo-ω-phenyl-acetophenone of melting point 48°-50° C. were obtained.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=2)[CH2:3][CH2:2]1.[F:13][C:14]1[CH:15]=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=[C:18]([F:21])[C:19]=1F.[H-].[Na+]>C1COCC1>[CH:1]1([C:4]2[N:8]([C:19]3[C:18]([F:21])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=3[F:13])[N:7]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: FC(F)(F)c1cc(C2CC2)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Temperature: 25 °C

Procedure:
Intermediate 5 (1 g, 5.7 mmol) and 3,4,5-trifluoronitrobenzene (1 g 5.7 mmol) were dissolved in THF and added sodium hydride (274 mg, 11.3 mmol). Mixture was refluxed for 2 h and reaction mixture cooled to rt and quenched with water. Work-up (H2O/AcOEt) gave the desired product as a yellow gummy liquid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.05-8.01 (m, 2H), 6.31 (s, 1H), 1.60-1.50 (m, 1H), 1.00-0.91 (m, 2H), 0.80-0.71 (m, 2H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:29][NH:30][C:31](=O)[O:32]C1C=CC=CC=1.O>C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])[CH2:23][C@H:24]3[CH2:28][CH2:27][N:26]([C:31]([NH:30][OH:29])=[O:32])[CH2:25]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: O=C(NO)Oc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCN(C(=O)NO)C1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 5 h
Yield: 54.3 %

Procedure:
The (R)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (39.1 mg, 92.3 μmol) obtained in Step 1 of Example 2 was dissolved in ethanol (2 mL), and phenyl N-hydroxycarbamate (56.0 mg, 366 μmol) was then added to the obtained solution. The obtained mixture was stirred for 5 hours at reflux. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→20%) to obtain the captioned compound (24.2 mg, 54%) in the form of a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[N+:28]([O-:30])=[O:29])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(N2CCN(Cc3ccccc3)CC2CC(=O)O)c1
Temperature: 90 °C

Procedure:
To a solution of Example 12C (0.907 g, 3.65 mmol) in acetonitrile (11.69 mL) was added 2-fluoro-4-methoxy-1-nitrobenzene (0.50 g, 2.92 mmol) and potassium carbonate (2.019 g, 14.61 mmol) in water (2.92 mL) followed by 18-crown-6 (0.039 g, 0.146 mmol), and the mixture was heated with an oil bath at 90° C. (reflux) for 24 hours. The solvent was evaporated and water was added followed by dichloromethane. The water phase was washed three times with dichloromethane to remove starting material and then acidified with 1N HCl until pH=1. The acid product was extracted three times with dichloromethane, dried quickly with sodium sulfate and concentrated to give the title compound. MS (ESI) m/z 386.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:31])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:30])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[Cr](O)(O)(=O)=O.N1C=CC=CC=1.C(Cl)Cl>[O-2].[O-2].[O-2].[Cr+6].O>[CH3:1][CH:2]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:31])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:30])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: O=[Cr](=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Yield: 79.6 %

Procedure:
To a mixture of ethyl 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-2-ol-1-carboxylate (217 g) and pyridine (215 ml), chromic acid-pyridine (prepared by adding portionwise chromium trioxide (300 g) to a mixture of pyridine (480 ml) and methylene chloride (3000 ml) while cooling with ice) is added thereto, and the resultant mixture is stirred for 4 hours. The reaction mixture is added to water, and the methylene chloride layer is separated, washed with water, dried and evaporated. The residual material (203 g) is chromatographed on silica gel (1kg) using benzene to give ethyl 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-2-one-1-carboxylate (172 g). IR: 1740, 1225 cm-1 (COO); 1710 cm-1 (C=O).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C[CH2:53][O:54][C:55](C)=[O:56].C1(C)C=CC=CC=1>CO.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:55]([O:54][CH3:53])=[O:56])[CH:11]=[CH:10]2)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)c1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc2cc(C(C)(C)C)ccc2c1
Temperature: 80 °C
Yield: 94 %

Procedure:
A mixture of 2-bromo-6-tert-butylnaphthalene (980 mg, 3.72 mmol), palladium acetate (84 mg, 0.37 mmol), 1,3-bis(diphenylphophino)propane (153 mg, 0.37 mmol) and triethylamine (1.56 ml, 11.2 mmol) in MeOH (6 ml) and DMF (10 ml) was heated at 80° C. under carbon monooxide gas pressure (balloon) for 15 hours. After cooling to ambient temperature, the mixture was diluted with EtOAc-toluene (8:1) (160 ml) and filtered through a pad of celite. The filtrate and washings were washed with water, then brine, dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified through silica gel column chromatography, eluting with hexane/EtOAc (10:1), to furnish the title compound as colorless oil (843 mg, 94%). 1H NMR (CDCl3): δ 1.43 (9H, s), 3.97 (3H, s), 7.61-7.67 (1H, m), 7.79-7.93 (3H, m), 8.01-8.07 (1H, m), 8.57 (1H, br, s).
Reaction SMILES: O[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[Na+]>C(OCC)(=O)C>[Cl:18][C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOCCn1c(O)nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOCCn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine 2-hydroxy-1-(2-ethoxyethyl)-1H-benzimidazole (36.4 g, 177 mmol) and phosphorous oxychloride (72 mL) and reflux. After 30 minutes, cool to ambient temperature and pour the reaction mixture onto crushed ice. Adjust the pH to about 9 using aqueous 50% sodium hydroxide solution. Extract three times with ethyl acetate. Combine the organic layers and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:8]1([C:1]2([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][O:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCCO1
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
To a solution of delta-valerolactone (1.854 mL, 19.98 mmol) in THF (20 mL) was added 1M phenylmagnesium bromide (19.98 mL, 19.98 mmol) dropwise at room temperature (exothermic), and the mixture was stirred at room temperature for 5 hrs. Then the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The extract was washed with brine, and the combined aqueous layers were back extracted with EtOAc once and combined. The extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) eluting with 4:6 followed by 1:1 EtOAc-hexane to give 1.97 g of 2-phenyltetrahydro-2H-pyran-2-ol as oil.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.F[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1>O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(O)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.9 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added to a DMF (20 ml) solution of 4-methoxyphenol (2.4 g). The reaction mixture was stirred at room temperature for 5 minutes, to which was added 4-fluorobenzenecarbonitrile (2.4 g). The reaction mixture was stirred at room temperature for 4 hours, which was further stirred at 50° C. for one hour. The reaction mixture was poured into water, which was extracted with toluene. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1), and then recrystallized from toluene-hexane to obtain 4-[(4-methoxyphenyl)oxy]benzenecarbonitrile (2.0 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[O:40][CH3:41])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=3)[N:8](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+].FC(F)(F)C(O)=O>O1CCOCC1.ClCCl>[F:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[O:40][CH3:41])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCNCC3)cc12
Reaction time: 3 h

Procedure:
A mixture of Example 231D (2.00 g, 3.44 mmol) and 5M sodium hydroxide (2.407 mL, 12.04 mmol) in dioxane (20 mL) was heated at 90° C. for 8 hours. After concentration, the residue was treated with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (6:4 to 4:6) to give the protected intermediate. A solution of the intermediate in dichloromethane (25 mL) was treated with trifluoroacetic acid (2.27 mL, 29.4 mmol) and the mixture was stirred for 3 hours and concentrated. The residue was dissolved in 6 mL methanol and treated slowly with 5 mL 2M hydrogen chloride in ether. The suspension was sonicated, diluted with ether and stirred for 10 minutes. The solid was filtered, washed with ether and vacuum oven-dried to give the title compound as a hydrochloride salt. MS (ESI+) m/z 342.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18]CC)=[O:17])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[OH-].[Na+].O.Cl>CCO>[NH2:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of ethyl 3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate (300 mg, 0.990 mmol) in EtOH (10 ml), 2M NaOH (0.495 ml, 0.990 mmol) was added dropwise over 1 minute. After stirring at RT for 30 minutes the reaction mixture was poured into water (30 ml) and the pH was adjusted to pH 4 by addition of 1M HCl. The mixture was extracted with EtOAc (2×50 ml) and the combined organic extracts were washed with brine (30 ml), dried over MgSO4 (5 g), filtered and concentrated in vacuo to afford the title compound as an off white crystalline solid;
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([CH2:19][CH3:20])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]1=[O:21])[CH:2]=[CH2:3].B.C1C[O:26]CC1.[OH-].[Na+].OO>C1COCC1.CCO>[CH2:19]([C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:7][CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH2:2][CH2:3][OH:26])[C:5]1=[O:21])[CH3:20]
Reactant: C=CCN1CCCCC(CC)(c2cccc(OC)c2)C1=O
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CCC1(c2cccc(OC)c2)CCCCN(CCCO)C1=O
Temperature: 0 °C

Procedure:
To a solution of 1-allyl-3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one (as described above in Step A) (0.83 g, 2.89 mmol) in THF (20 mL) at 0° C. was added BH3.THF (1M, 2.85 mL, 2.89 mmol) with stirring. After 1 hr at 25° C. the reaction mixture was cooled to 0° C. and EtOH (5 mL), 1M NaOH (5 mL), and 30% H2O2 (10 mL) were added. The reaction mixture was stirred for 1 hr at 25° C. The solvents were removed in vacuo and the residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine and dried (MgSO4), the solvents removed in vacuo and the crude product chromatographed on silica gel with hexane and ethyl acetate 1:1 to obtain the title compound.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:20]1([NH:26][C:27]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: S=C=Nc1ccccc1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Solvent: c1ccccc1
Product: S=C(Nc1ccccc1)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 24 h

Procedure:
4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate (1.31 g, 0.005 mole) was dissolved in benzene (125 ml) and phenyl isothiocyanate (0.74 g, 0.0055 mole) added dropwise with stirring. After 24 hr., the mixture was filtered to give the title compound (free base) as a white amorphous solid (1.76 g). This was dissolved in a minimum of hot ethanol, saturated ethanol-HCl added until acid, and then the solution allowed to crystallise. Filtration afforded the title compound hydrochloride as colourless prisms (1.75 g), m.p. 224.8°.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[C:12]([F:14])[F:13])[CH:6]=1.[CH:15](N1CCCCC1)=[O:16].Cl>O1CCCC1>[F:13][C:12]([F:14])=[CH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH:15]=[O:16]
Reactant: O=CN1CCCCC1
Reactant: FC(F)=Cc1cccc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=Cc1cccc(C=C(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
To a mixture of 0.67 g of magnesium and 10 ml of tetrahydrofuran was added a catalytic amount of iodine, and added dropwise a solution of 6.0 g of 1-bromo-3-(2,2-difluoroethenyl)benzene in 20 ml of tetrahydrofuran at 55° C. After stirred at room temperature for 15 minutes, a solution of 3.98 g of 1-formylpiperidine in 5 ml of tetrahydrofuran was added dropwise. This was heated under reflux for 15 minutes, and ice water and 10% hydrochloric acid were added, followed by extraction with t-butyl methyl ether. The organic layer washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography to obtained 1.13 g of oily 3-(2,2-difluoroethenyl)benzaldehyde [Compound No. (l)].
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]2([CH2:22][NH:21][C:20](=O)[CH2:19][O:18]2)[CH2:15]1)([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>C1COCC1.CCCC(C)C>[CH:1]([N:14]1[CH2:17][C:16]2([CH2:22][NH:21][CH2:20][CH2:19][O:18]2)[CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COC2(CN1)CN(C(c1ccccc1)c1ccccc1)C2
Solvent: CCCC(C)C
Solvent: C1CCOC1
Product: c1ccc(C(c2ccccc2)N2CC3(CNCCO3)C2)cc1
Temperature: 25 °C

Procedure:
Borane-methyl sulfide complex in THF (13.38 mL) was added in one portion to 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one (2.5 g) (WO2009098448, example 33, step e) in THF (50 mL) at room temperature under argon. The resulting solution was stirred at reflux for 90 minutes. The reaction was cooled to room temperature then the reaction mixture was quenched with methanol (50.0 mL). N,N′-Dimethylethylenediamine (5.18 mL) was added and the reaction mixture allowed to stir at room temperature for 1 week. The reaction mixture was evaporated to dryness and re-dissolved in ethyl acetate (250 mL), and washed with water (250 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was dissolved in iso-hexane (10 mL) and was purified by flash silica chromatography, eluting with 10% methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonane. Yield 1.647 g.