Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1(C(O)=O)[C:9](=[O:10])[CH2:8][CH2:7][S:6][CH2:5]1)[CH2:2][CH3:3].N1CCOCC1>O1CCCC1.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>[CH2:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][S:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1(C(=O)O)CSCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCC1CSCCC1=O

Procedure:
To a stirred solution of 3-propyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.272 g, 1.1 mmol) in 5.0 mL dry tetrahydrofuran at room temperature was successively added morpholine (0.979 g, 1.12 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.055 mmol). Stirring was continued until the thin layer chromatography indicated the completion of reaction at which point the reaction mixture was evaporated and the crude product was purified by flash column chromatography on silica gel eluted eluted with hexane:ether (19:1) to give 0.163 g of 3-propyl-tetrahydrothiopyran-4-one.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([NH:24][C:3]([C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: NN1CCOCC1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NN2CCOCC2)on1
Yield: 71.6 %

Procedure:
As described for example 18, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.33 mmol) was converted, using 4-aminomorpholine (136 mg, 1.3 mmol) instead of N,N-dimethylhydrazine, to the title compound (91 mg, 71%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=9:1 to 7:3). MS: m/e=386.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]([CH3:12])[CH2:14][CH2:15][OH:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCO)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 111.8 %

Procedure:
5-bromo-2-fluoronitrobenzene (5.0 g, 22.7 mmol), 2-(methylamino)ethanol (4.26 g, 56.8 mmol) and K2CO3 (9.4 g, 68.1 mmol) in DMF (20 mL) was heated to 60° C. for 1.5 hours, cooled to rt, diluted with water and extracted with EtOAc. The organic phases were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6.98 g (100%) of the desired product 2-((4-bromo-2-nitrophenyl)(methyl)amino)ethanol (25B): 1H NMR (300 MHz, CDCl3) δ 7.87 (1H, d), 7.51 (1H, dd), 7.10 (1H, d), 3.77 (2H, t), 3.39 (2H, t), 2.83 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[C:24]=1[C:25]([OH:27])=[O:26].C(N(C(C)C)C(C)C)C>CC(O)C>[Br:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[C:24]=1[C:25]([OH:27])=[O:26]
Reactant: Nc1cccc(Br)c1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(Br)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 90 °C
Yield: 49.2 %

Procedure:
A suspension of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2 g, 5.84 mmols), 2-amino-6-bromobenzoic acid (2.53 g, 11.69 mmols), and N-ethyl-N-(1-methylethyl)-2-propanamine (7.55 g, 58.4 mmols) in 2-propanol (150 ml) was heated at 90° C. for 5 days. The solvent was removed, residue redissolved in DCM (150 ml), washed with 1M HCl(100 ml), organic layer separated, adsorbed onto silica gel, and purified by silica gel chromatography (DCM to 10% MeOH/DCM). The crude product was then recrystallized from ethyl acetate/hexanes to obtain 2-bromo-6-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid (1.5 g, 49%). ESIMS (M+H)+=521.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Br:17].[I:18]I>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([I:18])[C:11]=1[Br:17]
Reactant: II
Reactant: Fc1ccc(Br)c(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(Br)c(Br)c1I
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of freshly-prepared LDA (33.9 mmol) in anhyd THF (100 mL) at −78° C. was added a solution of 1,2-dibromo-4-fluorobenzene (4 mL, 32.3 mmol) in THF (8 mL), dropwise at such a rate that the internal temperature remained <−70° C. The mixture was stirred 30 min and iodine (9.02 g, 35.5 mmol) was added in one portion. The mixture was stirred 30 min, quenched by addition of 10% Na2S2O3, and removed from the cooling bath. Upon warming the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was eluted from a pad of silica (hexanes→2% EtOAc/hexanes) and recrystallized from MeOH-water affording 1,2-dibromo-4-fluoro-3-iodobenzene (8.59 g, 70% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J=8.8, 5.5 Hz, 1H), 6.93 (dd, J=8.8, 7.0 Hz, 1H); MS (GCMS EI) m/z 378 ([M]+, Br isotopes, 56%), 380 ([M]+, Br isotopes, 100%), 382 ([M]+, Br isotopes, 51%).
Reaction SMILES: C([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:6]([CH3:31])[CH2:5]1)C=C.C(O)(=O)C1C(=CC=CC=1)S.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:31][C@H:6]1[CH2:5][NH:4][C@H:9]([CH3:10])[CH2:8][N:7]1[C@H:11]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])=[CH:29][CH:30]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2ccccc2)c2ccc(C(=O)N(CC)CC)cc2)C[C@H]1C
Agent: O=C(O)c1ccccc1S
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Yield: 45.6 %

Procedure:
The compound of Example 1 was de-allylated by the method of Genet [J. P. Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270 (1995)] as follows. A solution of 4-((alpha-S)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (Example 1, 8.392 g, 20 mmol) and thiosalicylic acid (3.70 g, 24 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred under nitrogen for 3 h at room temperature with a catalyst solution prepared by dissolution of bis(dibenzylidineacetone)palladium (575 mg, 1.0 mmol) and 1,4-bis(diphenylphosphino)butane (426 mg, 1.0 mmol) in tetrahydrofuran (10 mL). The reaction mixture was evaporated to dryness, the residue dissolved in a mixture of ethyl acetate/ether (1:3, 300 mL) and extracted with 5% sodium carbonate solution (2×300 mL). The organic layer was diluted with two volumes of pentane and extracted with 3M-hydrochloric acid (6×50 mL). The aqueous solution was filtered to remove suspended solid and the pH adjusted to 12 with 5-M NaOH. The resulting oily suspension was extracted with methylene chloride (2×125 mL) and the combined organic extracts dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ethyl acetate to yield fine white needles of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (3.46 g). The product showed a single spot on thin layer chromatography (silica gel, EM60F264, 4% NH4OH/10% EtOH in ethyl acetate, Rf=0.47). 1H NMR (CDCl3, 600 MHz); δ 0.93 (d, J=6.3 Hz, 3H); 1.12 (br m, 3H); 1.20 (d, J=6.1 Hz, 3H); 1.24 (br m, 3H); 1.55 (dd, J=9.7, 11.3 Hz, 1H, partially obscured by br m, 2H); 2.33 (m, 1H); 2.68 (m, 2H); 2.89 (m, 1H); 2.92 (dd, J=12.1, 3.1 Hz, 1H); 3.29 (br m, 2H); 3.54 (br m, 2H); 5.38 (s, 1H); 7.14 (m, 2H); 7.30 (m, 3H); 7.35 (m, 2H); 7.46 (d, J=7.8 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1)=O)(C)(C)C>ClCCl>[NH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C)c1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
Trifluoroacetic acid (6 mL) was added to a solution of ethyl 2-(4-((tert-butoxycarbonylamino)methyl)phenyl)propanoate (6.0 g, 19.54 mmol) in dichloromethane (30 mL) at 0° C. and stirred for 4 h at room temperature. The volatiles were evaporated under reduced pressure, basified with saturated NaHCO3 and extracted with ethyl acetate (3×50 mL). Combined organic layers washed with water (100 mL), brine solution (50 mL), dried over sodium sulfate and concentrated to give ethyl 2-(4-(aminomethyl)phenyl)propanoate (3.5 g, 86%) as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([CH2:22][N:11]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18](=[O:19])[NH2:20])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:24][CH:25]=1
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN([C@@H]2CCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.6 %

Procedure:
A mixture of (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (670 mg, 2.12 mmol), methyl 4-(bromomethyl)benzoate (534 mg, 2.33 mmol), cesium carbonate (1.04 g, 3.18 mmol) and acetonitrile (20 mL) was stirred vigorously at room temperature for 18 h. The crude mixture was filtered through celite and concentrated in vacuo. The product was purified by silica gel column chromatography (methanol/chloroform, 0.25%) to afford 213 mg (22% yield) of 4-[[(1R,2S)-(2-carbamoyl-cyclohexyl)-(4-chlorobenzenesulfonyl)-amino]-methyl]-benzoic acid methyl ester. An analytical sample was obtained after recrystallization from ethyl acetate/hexanes: 1H NMR (400 Mz, DMSO) δ 7.85 (d, 2 H, J=8.3), 7.82 (d, 2 H, J=8.5), 7.63 (d, 2 H, J=8.5), 7.42 (d, 2 H, J=8.3), 7.28 (br s, 1 H), 6.60 (br, s, 1 H), 4.64 (ABq, 2 H, Δv=69.4, Jab=17.4), 3.88 (m, 1 H), 3.85 (s, 3 H), 2.79 (m, 1 H), 2.42 (m, 1 H), 1.78 (m, 1 H), 1.64 (m, 2 H), 1.38–1.21 (m, 3 H), 0.90 (m, 1 H); MS m/e 465.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[K+].O1CCCC1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>O>[O:35]1[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:33][CH2:34]1
Reactant: ClCCN1CCOCC1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCOCC1)=N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 34 ml of a 10% aqueous potassium hydroxide and 2.5 ml of tetrahydrofuran is added 4.5 g of 1-chloro-2-morpholinoethane hydrochloride, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-(2-morpholinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from isopropyl alcohol to obtain 7.5 g of 2-(2-morpholinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 191°-193° C.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[N:2]1
Reactant: NCCCNc1nsc2ncccc12
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCCCNc2nsc3ncccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
N1-(Isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine (100 mg, 0.48 mmol) was dissolved in anhydrous methylene chloride with diisopropylethylamine (0.23 mL, 1.34 mmol). The mixture was cooled in an ice-bath under nitrogen and a solution of 4-methoxybenzoyl chloride (98 mg, 0.58 mmol) in methylene chloride (5 mL) was added drop-wise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield N-(3-(isothiazolo[5,4-b]pyridin-3-ylamino)propyl)-4-methoxybenzamide (54 mg). 1H NMR (300 MHz, DMSO-d6): 8.68 (d, 1H), 8.55 (t, 1H), 8.45 (d, 1H), 8.18 (s, 1H), 7.82-7.85 (m, 2H), 7.41 (dd, 1H), 7.26-7.36 (m, 2H), 3.95 (s, 3H), 3.40-3.42 (dd, 2H), 3.39-3.40 (dd, 2H), 1.82-1.95 ppm (m, 2H). MW=342 confirmed by LC-MS, tr=10.82 min (Method Y) MH+=343.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cccc(C2CCCN2)c1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2cccc(Cl)c2)cc1

Procedure:
The title compound, off-white solid, m.p. 107° C. and MS: m/e=335 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1cccc(-c2ccccn2)c1F
Product: Fc1c(-c2ccccn2)cccc1-c1ccnc2nc(C(F)(F)F)ccc12
Yield: 20.9 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-fluoro-3-(pyridin-2-yl)benzeneboronic acid (61 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(2-fluoro-3-pyridin-2-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (17 mg, 21%). δH (360 MHz, CDCl3) 7.30-7.36 (1H, m), 7.42-7.55 (2H, m), 7.66 (1H, d, J 4.2), 7.77-7.83 (3H, m), 8.19 (1H, td, J 7.6 and 2.1), 8.38 (1H, dd, J 2.3 and 8.6), 8.78 (1H, dt, J 4.9 and 1.4), 9.33 (1H, d, J 4.2). m/z (ES+) 370 [MH]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:14]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CCNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3 hydroxy 4-(p-toluenesulfonyloxy)butylamine hydrochloride (8.8 g) in methanol 90 ml), sodium carbonate (3.3 g) was added and the mixture was stirred at room temperature for 8 hours. Then, the mixture was filtered, and the filtrate was evaporated under reduced pressure to obtain crude 3 pyrrolidinol. One tenth of the crude 3-pyrrolidinol was dissolved in methylene chloride. To the solution, triethylamine (432 μl ) was added, and after cooling to 0° C., benzoyl chloride (360 μl ) was added. After stirring for 2 hours, the mixture was evaporated under reduced pressure and purified by silica gel column chromatography (Wako Gel C200, an eluent: ethyl acetate/methanol (volume ratio of 95/5) to obtain pure N-benzoyl-3-pyrrolidinol (438 mg). Yield, 85 %.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.Cl.[NH2:8][C:9]1[CH:10]=[C:11]([C:17](=[O:38])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH2:36][CH3:37])[CH2:22][CH2:21]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].C(N(CC)CC)C>O1CCCC1>[ClH:5].[CH2:36]([O:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][C:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=2)=[O:38])[CH2:21][CH2:22]1)[CH3:37]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(N)c2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(NS(C)(=O)=O)c2)CC1
Reaction time: 12 h

Procedure:
Methanesulfonyl chloride (0.108 ml) was added to a solution of 1-(3-amino-4-methoxyphenyl)-3-{1-[2-(2-ethoxyphenoxy)ethyl]-4-piperidinyl}-1-propanone dihydrochloride (300 mg) obtained in Example 327 and triethylamine (0.195 ml) in tetrahydrofuran (10 ml) at room temperature, the mixture was stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure. Water (30 ml) and ethyl acetate (40 ml) were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate-methanol (9:1)) to give a free base compound of the title compound as a colorless oil (291 mg). The free base compound (290 mg) was treated with a hydrogen chloride-ethanol solution to give the title compound (277 mg) as colorless amorphous powders.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[O:16])[C:13](=[O:24])[N:12]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[C:11]3[CH2:35][CH2:36][C:37](=[O:38])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].OO.S([O-])(O)(=O)=[O:42].[K+].O>C(O)C.C[Re](=O)(=O)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH:18]3[CH2:19][CH2:20][S:21](=[O:42])[CH2:22][CH2:23]3)=[O:16])[C:13](=[O:24])[N:12]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[C:11]3[CH2:35][CH2:36][C:37](=[O:38])[C:10]2=3)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCSCC2)cc1
Reactant: O=S(=O)([O-])O
Agent: C[Re](=O)(=O)=O
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=O)CC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-(4-cyanophenyl)-2,5-dioxo-N-(tetrahydro-2H-thiopyran-4-yl)-1-(3-(tri-fluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxamide (example 42.7, 94 mg, 0.18 mmol) in ethanol (1.0 mL) is cooled at −78° C. with an acetone/dry ice bath. Aqueous hydrogen peroxide (36%, 87 μL, 1.0 mmol) is added, and the mixture is stirred at −78° C. for 30 min Methyltrioxorhenium(VII) (1 mg, 4 μmol) is a) added, and the mixture is stirred at −78° C. for 30 min Another portion of methyltrioxo-rhenium(VII) (1 mg, 4 μmol) is added, and the mixture is stirred at −78° C. for 1 h. Aqueous potassium hydrogen sulfate solution (10%, 0.5 mL) and water is (10 mL) is added, and the mixture is filtered. The precipitate is dissolved in N,N-dimethylformamide, and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 40 mg; ESI mass spectrum [M+H]+=557; Retention time HPLC: 0.96 min (Z018_S04).
Reaction SMILES: [C:1]([Cu])#[N:2].[Na+].[I-].CN[C@@H]1CCCC[C@H]1NC.ClC1C=CC=CC=1.CCCCC[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(OCC)(=O)C>[CH3:34][C:33]1[CH:28]=[CH:29][C:30]([C:1]#[N:2])=[CH:31][CH:32]=1
Reactant: CCCCCCCCCCCC
Reactant: N#C[Cu]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [I-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)cc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
A Schlenk tube was charged with CuCN (108 mg, 1.21 mmol), NaI (150 mg, 1.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (190 μL, 1.21 mmol) and 4-chlorobenzene (0.95 mL, 8.01 mmol) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 20 h. The resulting black suspension was allowed to reach room temperature. Ethyl acetate (3 mL) and dodecane (internal GC standard, 230 μL) were added to the reaction mixture. A 50 μL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 60% yield of 4-methylbenzonitrile.
Reaction SMILES: [F:1][C@H:2]1[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]1([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10].[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C@H:2]1[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]1([C:11]1[CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=1[F:17])[CH3:10]
Reactant: C[C@]1(c2ccccc2F)N=C(N)COC[C@@H]1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)COC[C@@H]1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5R,6R)-6-fluoro-5-(2-fluorophenyl)-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (1.2 mmol) in sulfuric acid (5.0 ml) was added at 0° C. red fuming nitric acid (1.9 mmol) over a period of 20 min and stirring was continued for 30 min. The solution was dropped slowly into ice/water (60 ml), the pH was adjusted to 9 by addition of aqueous 4 N NaOH and extracted with ethyl acetate. The organic layer was dried, evaporated and the residue purified by chromatography on silca-NH2 using n-heptane/ethyl acetate to give (5R,6R)-6-fluoro-5-(2-fluoro-5-nitro-phenyl)-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine as a pale yellow solid. MS (ISP): m/z=286.2 [M+H]+.