Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](#[N:11])[CH:9]=[CH2:10].C1(N)CCCCC1.[C:19]1(C=CC(O)=CC=1)[OH:20]>C(O)(=O)C>[CH2:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[C:19]([CH2:10][CH2:9][C:8]#[N:11])=[O:20]
Reactant: C=CC#N
Reactant: O=C1CCCCC1
Reactant: Oc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: NC1CCCCC1
Product: N#CCCC(=O)C1CCCCC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A reactor is loaded with 980 g of cyclohexanone, 22 g of acrylonitrile, 18 g of glacial acetic acid, 40 g of cyclohexylamine and 11 g of hydroquinone. The reaction mixture is slowly raised to 130° C. and then kept at this temperature for 2 hours. The reaction product is cooled to 25° C., the catalyst is filtered out and distillation is performed, collecting 552 g of 3-(2-cyclohexanoly)propionitrile (b.p. 113-116° C./4 mm Hg).
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[C:9]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:10][CH:11]=[CH:12][CH:13]=2)[O:5][N:4]=1.C(N(CC)CC)C.COCCOC.P(Br)(Br)[Br:43]>O>[C:18]([O:17][C:15]([N:14]([C:9]1[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][Br:43])[CH:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:16])([CH3:20])([CH3:19])[CH3:21]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(CO)no1
Solvent: COCCOC
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(CBr)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.4 %

Procedure:
To a mixture of di-tert-butyl {3-[3-(hydroxymethyl)isoxazol-5-yl]pyridin-2-yl}imidodicarbonate (0.78 g, 2 mmol), triethylamine (1.95 mL, 14 mmol) and 1,2-dimethoxyethane (10 mL) was added phosphorus tribromide (0.37 mL, 4 mmol) dropwise at 0° C., which was stirred at room temperature for two hours, and then stirred at 50° C. for 30 minutes. The reaction mixture was cooled to 0° C., then water was added thereto and extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride water. After drying over anhydrous magnesium sulfate and filtering, the solvent was evaporated under a reduced pressure, the residue was purified by silica gel column chromatography, so as to obtain the title compound (0.14 g).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[CH:16]=[C:3]2[C:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)=[N:29][N:28]=1
Reactant: NN
Reactant: COc1ccccc1C(=O)CP(=O)(OC)OC
Reactant: O=C1C(=O)C2CCC1C2
Solvent: O
Product: COc1ccccc1-c1cc2c(nn1)C1CCC2C1

Procedure:
light yellow gum. MS (ESI): 253.3 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(2-Methoxy-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.S(=O)(=O)(O)[OH:19]>O>[OH:19][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(C2CCOCC2)cc1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C2CCOCC2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.2 g of sodium nitrite in 10 ml of water was added to a mixture of 13 g of 4-(p-aminophenyl)-tetrahydropyran and 100 ml of concentrated sulfuric acid cooled to 5° C and the mixture was stirred at 5° C for 30 minutes. The mixture was poured into a solution of 100 ml of water and 10 ml of concentrated sulfuric acid heated to 75°-80° C and the mixture was held at 75°-80° C for 15 minutes and was then cooled to 4° C. The mixture was filtered and the recovered crystals were washed with water and dried to obtain 12.7 g of 4-(p-hydroxyphenyl)-tetrahydropyran melting at 164° C.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[S:21]([CH3:24])(=[O:23])=[O:22])[O:11][CH3:12])=[O:9])[C:4](=[O:25])O1.[CH2:27]=O.[N:29]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8]([C:7]2[CH2:27][N:37]([CH2:36][CH2:35][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4](=[O:25])[C:5]=2[OH:6])=[O:9])=[C:15]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=1
Reactant: CON(Cc1ccc(F)cc1S(C)(=O)=O)C(=O)C=C1OC(C)(C)OC1=O
Reactant: C=O
Reactant: NCCN1CCOCC1
Product: CON(Cc1ccc(F)cc1S(C)(=O)=O)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 45 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methoxy-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine using the method described for the preparation of compound 767 to give the title compound as a white solid (0.021 g, 45% yield). 1HNMR (300 MHz, MeOD) δ: 7.75 (1H, dd, J=8.78, 2.93 Hz), 7.63–7.54 (2H, m), 5.34 (2H, s), 4.29 (2H, s), 4.01–3.99 (2H, m), 3.84–3.81 (2H, m), 3.77 (3H, s), 3.63–3.45 (6H, m), 3.39 (3H, s), 3.16–3.08 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]3[CH2:22][CH2:21][CH2:20]3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH2:26]([N:28](CC)CC)C>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:28][CH3:26])[N:15]=[C:14]([N:19]3[CH2:22][CH2:21][CH2:20]3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N3CCC3)n2)cc1
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N2CCC2)n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
0.20 g (0.00059 mol) of 4-amino-N-(2-azetidin-1-yl-6-chloro-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol, treated with 0.4 g (0.00588 mol) of methylamine hydrochloride and 2.28 ml (0.0176 mol) of triethylamine and stirred in an autoclave at 130° C. for 8 hours. The reaction mixture was freed from solvent and the residue was chromatographed on silica gel with methanol/dichloromethane 1:19. There was obtained 0.053 g (27%) of 4-amino-N-(2-azetidin-1-yl-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide as light beige crystals; m.p.: >260° C. (dec.)
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:31])=[O:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C(=O)=O.CO>C(Cl)(Cl)Cl>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S@@:29]([CH3:31])=[O:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)=O)cc4)nc3)CC2)n1
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc([S@@](C)=O)cc4)nc3)CC2)n1
Yield: 8.6 %

Procedure:
The racemic sulfoxide 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfinyl)phenyl]pyridine (prepared as in Example 171, 290 mg) was subjected to Chiral HPLC [column: Chiralcel OJ-H, column mobile phase: 80% CO2: 20% (80% MeOH: 20% CHCl3) (2 mL/min), pressure 140 bar, temperature 30° C., 254 nm] analysis and then separation to give two (R and S) enantiomers. The title compound (25 mg) was isolated a tan solid with Tr of 11.15 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][CH:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)[CH2:4][CH2:3]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>CCOCC>[CH3:22][N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:6]([CH:5]2[CH2:23][CH2:24][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: CN1CCC(C(=O)Nc2ccccc2N(C)c2ccccc2)CC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CN1CCC(C2=Nc3ccccc3N(C)c3ccccc32)CC1
Temperature: 0 °C

Procedure:
A mixture of 9 g of crude 1-methyl-2'-(N-methylanilino)isonipecotanilide base, 10 g of phosphorus pentoxide and 30 ml of phosphorus oxychloride is heated under reflux for 4 hours, and the reaction mixture is diluted with ether and slowly added to an ice-cold solution of ammonium hydroxide. The mixture is filtered, and the ether layer is separated, dried over anhydrous potassium carbonate and evaporated to yellow solid residue (8.0 g). This crude cyclized base is dissolved in 100 ml of dilute acetic acid, the solution is clarified with activated charcoal and the filtrate is made basic with ammonium hydroxide. The precipitated base is collected, dissolved in 30 ml of ether, and the ether layer is dried over anhydrous potassium carbonate. This solution is filtered into 100 ml of petroleum ether. The product crystallizes as a yellow solid and is collected and dried in vacuo; 5-methyl-11-(1-methyl-4-piperidyl)-5H-dibenzo[b,e][1,4]-diazepine, m.p. 119°-121° C., is thereby obtained; IR (KBr) 6.15μ (anil C=N).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N+:23]=[N-:24]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCN=[N+]=[N-]

Procedure:
3-(2-azidoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole was prepared according to method D Step IV with 3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole (0.548 g; 1.35 mmol) and sodium azide (0.262 g; 4.04 mmol) in DMF (8 mL); the yield was quantitative as a brown oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:6]1OS(C(F)(F)F)(=O)=O)(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.C(Cl)Cl>[N:32]([C@@H:6]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:26][C@H:5]1[O:4][C:1](=[O:3])[CH3:2])=[N+:33]=[N-:34]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 40 °C
Yield: 80.6 %

Procedure:
To a solution of mannose triflate 56 (1.28 g, 2.66 mmol) in 14 mL of DMF is added sodium azide (0.69 g, 10.5 mmol). The reaction mixture is heated at 40° C. for 1.75 h, cooled to room temperature, diluted with 100 mL of CH2Cl2, washed with H2O (100 mL), saturated NaCl (100 mL), dried over MgSO4, filtered, and concentrated to afford a yellow oil. The product is purified by flash chromatography (33% EtOAc/hexane) to afford 0.80 g (81%) of 2-azido-2-deoxy-1,3,4,6-tetra-O-acetyl-β-D-glucopyranose 57: Rf 0.31 (33% EtOAc/hexane) δ 5.55 (d, J=8.6 Hz, 1H, H-1), 5.015.15 (m, 2H, H-3, H-4), 4.31 (dd, J=12.7, 4.5 Hz, 1H, H-6), 4.08 (d, J=12.5 Hz, 1H, H-6), 3.77-3.84 (m, 1H, H-5), 3.69 (app t, J=9.1 Hz, 1H, H-2), 2.10 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: S([Cl:11])(C1C=CC(C)=CC=1)(=O)=O.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N+:14]=1[O-].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(CCl)c(C)c1
Yield: 66.2 %

Procedure:
Tosyl chloride (12.5 g, 65.6 mmol) was added to a solution of 2,3,5-trimethylpyridine 1-oxide (6.0 g, 43.7 mmol), and triethylamine (6.6 g, 65.6 mmol) in DCM (60 ml) at RT under an atmosphere of nitrogen. The reaction mixture was heated to reflux and reflux was maintained 4 h (reaction was monitored by TLC). The reaction was quenched with water and extracted with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexanes and silica gel (230-400 Mesh) to afford 2-(chloromethyl)-3,5-dimethylpyridine (4.5 g, 66.1%,) as a brown thick syrup. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.45 (s, 1H), 4.75 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H). MS: [M+H]+: m/z=156.3.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15])[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cccc(C(=O)CSC#N)c1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of 2-bromo-1-(3-methoxyphenyl)ethanone (7.63 g, 33.3 mmol) and potassium thiocyanate (3.24 g, 33.3 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 6.71 g (97.2%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]([NH2:5])([CH3:4])[CH3:3].[Cl:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][N:9]=1>>[ClH:6].[CH3:1][C:2]([NH:5][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][N:9]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: Cn1nnnc1CCl
Product: Cl
Product: Cn1nnnc1CNC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A mixture of 2-methylpropan-2-amine (75-64-9, 281 mg, 404 μL, 3.85 mmol) and 5-(chloromethyl)-1-methyl-1H-tetrazole (57235-84-4, 100 mg, 754 μmol) was stirred at ambient temperature for 16 h and concentrated in vacuo to give the title compound (112 mg, 72%) as yellow solid; MS (EI): m/e=169 [M+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C.[CH2:8]([O:10][P:11]([CH2:16][CH2:17][CH2:18][Br:19])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9].[C:20](OCC)(=O)C>CN(C=O)C>[Br-:19].[CH2:8]([O:10][P:11]([CH2:16][CH2:17][CH2:18][N+:1]1[CH:2]=[CH:3][C:4]([CH3:20])=[CH:5][CH:6]=1)([O:12][CH2:13][CH3:14])=[O:15])[CH3:9]
Reactant: CCOC(C)=O
Reactant: Cc1ccccn1
Reactant: CCOP(=O)(CCCBr)OCC
Solvent: CN(C)C=O
Product: CCOP(=O)(CCC[n+]1ccc(C)cc1)OCC
Product: [Br-]
Temperature: 130 °C

Procedure:
A mixture of picoline (0.5 g, 5.4 mmol) and diethyl(3-bromopropyl)-phosphonate (1.54 g, 5.9 mmol) was heated in a pressure tube at 130° C. for 4 hours. The mixture was allowed to cool to room temperature, and the resulting mass was dissolved in DMF (4 ml). The combined mixture was then added drop wise to ethyl acetate (40 ml). An oily residue was obtained which was washed with ethyl acetate (2×40 ml) and dried under vacuum to yield 1.7 g of Compound 3 which was then used without any further purification. The structure of Compound 3 is given below:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.C([S:22][C@H:23]1[CH2:28][CH2:27][C@H:26](/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH2:25][CH2:24]1)(=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([S:22][C@H:23]1[CH2:28][CH2:27][C@H:26](/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=2)[CH2:25][CH2:24]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(=O)S[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Product: C[C@@H](S[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Reaction was carried out in the same manner as in Example 1 using (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane and trans-1-(acetylthio)-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]cyclohexane as described in Reference example 43 to obtain the title compound having a melting point of 74 to 76° C. in a yield of 59%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](Cl)=[O:43]>N1C=CC=CC=1>[CH2:15]([NH:14][C:12](=[O:13])[NH:11][C:8]1[S:9][C:10]2[C:2]([NH:1][C:42](=[O:43])[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=3)=[CH:3][C:4]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)[CH3:16]
Reactant: O=C(Cl)c1ccccn1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(N)c2s1
Agent: Cl
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(NC(=O)c3ccccn3)c2s1
Yield: 67.9 %

Procedure:
Ethyl 1-(5-(7-amino-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (119 mg, 0.25 mmol) was dissolved in pyridine (2 ml) then picolinoyl chloride hydrochloride (58 mg, 0.33 mmol) was added with stirring and the reaction stirred at rt for 18 h. The pyridine was removed under reduced pressure and the residue triturated with water. The resulting solid was collected by filtration and dried to afford the crude product 100 mg (68%). This material was used directly in the next step without further purification.
Reaction SMILES: C(O)C.C([BH3-])#N.[Na+].[CH2:8]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH:23](C=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29]C)=[O:27])[CH2:19][CH2:18]2)=[C:13]([F:35])[C:12]=1[F:36])[CH3:9].Cl>O>[CH2:8]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH:23]3[CH2:29][O:28][C:26](=[O:27])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[C:13]([F:35])[C:12]=1[F:36])[CH3:9]
Reactant: CCOC(=O)CCC(C=O)C1CCC(COc2ccc(OCC)c(F)c2F)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(OCC2CCC(C3CCC(=O)OC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.3 %

Procedure:
In a reactor under nitrogen atmosphere, 20 mL of ethanol and 0.4 g of sodium cyanoborohydride were added to 5.4 g of ethyl 4-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]5-oxopentanoate obtained in the eleventh step, and pH of the mixture was adjusted to about 3 with hydrochloric acid (2M), followed by stirring at room temperature for 15 hours. 30 mL of water was added to the reaction solution, which was extracted three times with 20 mL of toluene. The mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was placed in a flask equipped with a Dean-Stark apparatus, to which 100 mL of toluene and 0.1 g of p-toluenesulfonic acid monohydrate were added, and the mixture was refluxed for 1 hour while the solvent was distilled off with the Dean-Stark apparatus. The solution was cooled to room temperature, washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to provide 4.5 g of 5-[4-(4-ethoxy2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-one.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH:8]([CH3:19])[C:9]3[S:13][C:12]([C:14]([O:16]CC)=O)=[N:11][C:10]=3[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C@:28]([OH:32])([C:30]#[CH:31])[CH3:29].CC1C2SC(C([O-])=O)=[N:40]C=2C2C=CC=CC=2OC1>>[OH:32][C@:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1)([CH3:29])[C:30]#[C:31][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH:8]([CH3:19])[C:9]3[S:13][C:12]([C:14]([NH2:40])=[O:16])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CC1COc2ccccc2-c2nc(C(=O)[O-])sc21
Reactant: CCOC(=O)c1nc2c(s1)C(C)COc1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1ccccn1
Product: CC1COc2ccc(C#C[C@@](C)(O)c3ccccn3)cc2-c2nc(C(N)=O)sc21

Procedure:
Similar to as described in General Procedure G, ethyl 9-bromo-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (R)-2-(pyridin-2-yl)but-3-yn-2-ol to give a diasteromeric mixture of ethyl 94(R)-3-hydroxy-3-(pyridin-2-yl)but-1-yn-1-yl)-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate. Following aminolysis of the ethyl ester (similar to as described in General Procedure M) a diasteromeric mixture of the titled compounds was obtained and separated by Prep HPLC.
Reaction SMILES: [F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4].[CH2:13](O)[CH3:14].C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:13][CH3:14])=[O:4]
Reactant: CC(C)CC(O)C(F)(F)C(=O)O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 84.9 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 20 g of ethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 20 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried, and concentrated, obtaining 24.5 g (yield 85%) of crude ethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][C:19]#N)=[CH:15][CH:14]=1.Cl.C([O:26]CC)C>II>[Cl:10][C:5]1[CH:4]=[C:3]([C:19](=[O:26])[CH2:18][O:17][C:16]2[CH:21]=[CH:22][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[Cl:9]
Reactant: COc1ccc(OCC#N)cc1
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CCOCC
Agent: Cl
Agent: II
Agent: [Mg]
Product: COc1ccc(OCC(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
To a solution of magnesium (2.23 g) and iodine (5 mg) in diethyl ether (20 mL) was added dropwise a solution of 1-bromo-3,4-dichlorobenzene (20.7 g) in diethyl ether (20 ml), and the mixture was stirred at 35° C. for 1 hr. The reaction mixture was cooled to −10° C., and diethyl ether (100 mL) was added. A solution of (4-methoxyphenoxy)acetonitrile (10 g) in diethyl ether (20 ml) was added dropwise at −10° C., and the mixture was stirred for 1 hr while warming to room temperature. To the reaction mixture was added 1 N aqueous HCl solution (200 ml), and the mixture was stirred at room temperature for 1 hr, and extracted with ethyl acetate. The obtained extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (15.6 g).