Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].Br[C:20]1[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=1.O>COCCOC.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>[CH3:8][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:12][CH:11]=1)[CH3:9]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)c1ccc(-c2cccnc2N)cc1
Yield: 92.4 %

Procedure:
A mixture of 2M aqueous sodium carbonate solution (8.67 ml), tetrakis(triphenylphosphine)palladium(0) (668 mg), 4-isopropylphenylboronic acid (2844 mg) and 3-bromopyridin-2-amine (2.0 g) in 1,2-dimethoxyethane (30 mL) was heated under reflux overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2267 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([NH:15][CH3:16])[S:13][CH:14]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CI.[CH2:25]([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].Cl>C1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([N:15]([CH3:25])[CH3:16])[S:13][CH:14]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CI
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (415 mg, 1.33 mmol) in benzene (6 ml) was added methyl iodide (370 mg, 2.61 mmol), tetra-n-butyl ammonium hydrogene sulfate (435 mg, 1.33 mmol) and 50% NaOH aq. (3 ml), then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, then acidified with 2N-HCl to pH 6 and the aqueous solution was extracted with benzene. The extracts were washed with water, dried and then evaporated under reduced pressure to a residue, which chromatographed to afford 4-(1-(2-fluoro-4-biphenylyl)ethyl-2-dimethylaminothiazole (369 mg, 85% yield): NMR(CDCl3)δ 1.62(d, 3H), 3.06(s, 6H), 4.09(q, 1H), 6.06(s, 1H), 7.02-7.63(m, 8H) ppm; IR(neat) 2950, 1620, 1550, 1420, 1340 cm-1.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.CO.[OH-].[Na+]>O1CCCC1>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2.5 g of methyl 6-[([1,1'-Biphenyl]-2-carbonyl)amino]-pyridine-3-carboxylate in 50 ml of 1:1 tetrahydrofuran:methanol is added 10 ml of 5N sodium hydroxide and the mixture stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo to a residue which is dissolved in water and neutralized with acetic acid. The separated colorless solid is filtered and air dried to give 2.0 g of the desired product:M+ =318.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([OH:35])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[C:46]([O:45][C:44](=[O:50])[NH:43][C@H:40]1[CH2:39][CH2:38][C@H:37]([NH:36][C:33]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]=2[CH3:32])=[O:35])[CH2:42][CH2:41]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[O:23]1[CH:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1.[ClH:34]>C(#N)C>[OH2:23].[ClH:34].[ClH:34].[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:24][CH:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[OH:23])[CH2:12][CH2:11]2)=[CH:21][CH:20]=1.[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:9]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:24][CH:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[OH:23])[CH2:12][CH2:11]2)[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1.[ClH:34].[ClH:34]
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: Cl
Solvent: CC#N
Product: O
Product: OC(COc1ccccc1)CN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 53 %

Procedure:
A mixture of 3.41 g (11.3 mmol) of the N,α-bis(4-fluorophenyl)-4-piperidinemethanamine and 2.20 g (14.7 mmol) of 1,2-epoxy-3-phenoxypropane in 400 mL of acetonitrile was heated at reflux for 46 h. The solvent was removed in vacuo, and the residue was subjected to flash chromatography (silica gel, eluted with 3% CH3OH in CH2Cl2) to give an oil. This was converted to the HCl salt, and the salt was recrystallized from CH3OH-ether to give give 3.20 g (53%) of a crystalline white solid, mp 229°-232° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1>C(O)(=O)C>[Cl:4][CH2:21][C:20](=[O:22])[C:14](=[N:13][O:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:24][CH:23]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C(=O)CCl
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Sulfuryl chloride (39.26 g.) was added to a solution of ethyl 2-(4-chlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 75.03 g.), in acetic acid (75 ml.), and then stirred at 37° to 40° C. for 8 hours. After air was bubbled into the reaction mixture, the mixture was added to ice water. The mixture was extracted with methylene chloride, and the extract was washed with sodium bicarbonate saturated aqueous solution and sodium chloride saturated aqueous solution in turn. The solution was dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-chloro-2-(4-chlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 77.23 g.).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:29][C:11]2[N:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33]>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[S:29][C:11]2[N:12]=[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:32]([O:34][C:35]4[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=4)=[O:33])[CH:17]=3)[C:10]=2[C:9]=1[NH2:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(N)c3)c2c1N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c2c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 5-amino-2-phenyl-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 31(g), 2.0 g) was dissolved in dry CH2Cl2 (20 ml). Subsequently, a solution of p-nitro-phenyl chloroformate (520 mg) in dry CH2Cl2 (10 ml) was added dropwise and the reaction mixture was stirred at room temperature. After 3 h, the reaction mixture was washed with H2O. The organic layer was dried (MgSO4) and concentrated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:21][CH2:22][OH:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCO)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCOS(C)(=O)=O)c2c1

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-(2-hydroxyethyl)-1H-indole-6-carboxylate (3.43 g, 9.01 mmol) in chloroform (30 ml) were added triethylamine (1.40 ml, 10.0 mmol) and methanesulfonyl chloride (0.77 ml, 9.90 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 30 min. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was successively washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-bromo-3-cyclohexyl-1-(2-methanesulfonyloxyethyl)-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 4 without purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:31]([NH:33][CH2:34][CH3:35])=[O:32].CCN(C(C)C)C(C)C>C(#N)CC.CS(C)=O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[N:39]1[CH2:40][CH2:41][N:42]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][S:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:43][CH2:44]1)[C:31]([NH:33][CH2:34][CH3:35])=[O:32]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 26 %

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (154 mg, 0.613 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (179 mg, 0.735 mmol) and 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (186 mg, 0.613 mmol) and DIEA (321 μl, 1.838 mmol). The vial was heated to 90° C. for 16 hours. The crude rxn was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (80 mg, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H), 8.43 (t, J=5.6 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.6, 2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.27 (dd, J=10.7, 3.2 Hz, 1H), 3.40 (s, 2H), 3.18-3.30 (m, 2H), 2.90-3.16 (m, 5H), 2.67-2.85 (m, 3H), 2.52 (br. s., 4H), 2.45 (dd, J=13.5, 1.6 Hz, 1H), 1.10 (t, J=7.2 Hz, 3H). [M+H] calc'd for C24H29ClN6O2S, 501; found, 501.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([CH3:19])=[C:15]([CH:18]=1)[CH:16]=[O:17]>>[CH3:19][C:14]1[CH:13]=[CH:12][C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc(Br)cc1C=O
Product: Cc1ccc(-c2ccncc2)cc1C=O

Procedure:
Pyridine-4-boronic acid (14 mg, 96 μmol) is coupled to aryl bromide 230 (19 mg, 96 μmol) using Method A to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-:8])=[O:7].[CH3:14][N:15]([CH3:19])[C:16](=[S:18])[S-:17].C[NH2+]C.C(=S)=S>CO>[CH3:14][N:15]([CH3:19])[C:16](=[S:17])[S:18][CH:4]([CH2:5][N+:6]([O-:8])=[O:7])[C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1Cl
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Solvent: CO
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
2,4-Dichloro-β-nitrostyrene (6.6 grams, 0.030 mole) was added to a stirred solution of dimethylammonium dimethyldithiocarbamate (5.1 grams, 0.030 mole) and carbon disulfide (1.8 ml., 0.030 mole) in methanol (30 ml.). The temperature of the resulting reaction was 16° - 32° C. After 2 hours at room temperature, the precipitated product was filtered off, washed with cold methanol, and dried in air. Recrystallization without heating was accomplished by dissolving the sample in acetone and then adding absolute ethanol to give 2,4-dichloro-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 127° - 128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1.C(Cl)Cl.ClC(OCC)=O.[NH2:25][CH2:26][C@@H:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C@H:28]1[OH:40]>C(N(CC)CC)C>[OH2:7].[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:25][CH2:26][C@@H:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][C@H:28]2[OH:40])=[O:15])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)[C@H](O)C1
Reactant: O=C(O)c1cc(Cl)cc2c1OCCCO2
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)c2cc(Cl)cc3c2OCCCO3)[C@H](O)C1
Product: O
Reaction time: 0.5 h
Yield: 191.7 %

Procedure:
Intermediate (11) (0.1 mol), triethylamine (0.1 mol) and DCM (500 ml) were stirred at a temperature below 10° C. Ethyl chloroformate (0.1 mol) was added dropwise at temperature below 10° C. The mixture was stirred for 30 minutes at a temperature below 10° C. A solution of 1,1-dimethylethyl (3S-trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (0.1 mol) in triethylamine (250 ml) was added at a temperature below 10° C. The reaction mixture was stirred for one hour at room temperature. The mixture was concentrated to half the initial volume. The concentrate was washed with water, with H2O/50% NaOH, and again with water. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 44 g of 1,1-dimethylethyl(3S-trans)-4-[[[(8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6-yl)carbonyl]amino]methyl]-3-hydroxy-1-piperidinecarboxylate monohydrate (intermediate 12) (mp: 88° C.; sticky) [α]D20=−0.97° (c=25.71 mg/5 ml in CH3OH).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][NH:23][C:24]1[C:25]([O:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=2)=[N:26][C:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[N:28][CH:29]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][NH:23][C:24]1[C:25]([O:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][F:7])=[CH:39][CH:38]=2)=[N:26][C:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[N:28][CH:29]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(-c2cccnc2)nc1Oc1ccc(CO)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(-c2cccnc2)nc1Oc1ccc(CF)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To a solution of (diethylamino)sulfur trifluoride (0.036 mL; 0.28 mmol) in CH2Cl2 (2 mL), cooled to −78° C., was added a solution of Compound 18b (100 mg; 0.21 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at −78° C. for 20 min. The resultant mixture was partitioned between EtOAc and H2O. The organic phase was washed with water and dried over Na2SO4. The mixture was filtered and the solvent removed under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 18c (50 mg; 50% yield). MS: m/z 480.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1)=O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:35]=[CH:34][C:32]([NH:33][CH2:1][C:3]3[CH:12]=[C:11]4[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]4)=[CH:5][CH:4]=3)=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: N#Cc1ccc2ccc(C=O)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-Formyl-2-naphthalenecarbonitrile obtained in Reference Example 1 (849 mg) and 1,370 mg of 4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]aniline were dissolved in 10 ml of dichloromethane and 2.7 ml of acetic acid, 1,290 mg of sodium triacetoxyborohydride was added to the solution, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was washed with 2M potassium carbonate, water and 10% citric acid aqueous solution in that order, dried over sodium sulfate, and then evaporated. By recrystallizing the resulting residue from methanol, 1,698 mg of 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile was obtained.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([O:9][C:10]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=CC=1C=O)CO.[O:20]1CCC[CH2:21]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:3]([C:2]1[CH:1]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=1[O:9][CH2:6][O:20][CH3:21])=[CH2:4]
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: COc1ccc(OCCO)c(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=Cc1cc(OC)ccc1OCOC
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a suspension of 104 g (0.291 moles) of methyltriphenylphosphonium bromide in 100 ml dry tetrahydrofuran at 0° was added 115 ml (0.275 moles) of 2.4M n-butyllithium and the dark red solution was stirred at 0° for 30 minutes. Then a solution of 38.2 g (0.195 moles) of 2-(3-oxapropyloxy)-5-methoxybenzaldehyde in 100 ml of dry tetrahydrofuran was added and the solution was stirred at room temperature for 60 minutes. The solution was concentrated and the residue partitioned between ether and water. The ether layer was washed with aqueous Na2CO3, then brine, then dried (Na2SO4) and concentrated. The oily residue was dissolved in 500 ml of 10% ethylacetate-hexane and cooled at 0° overnight, then filtered. The filtrate was concentrated to give 33.8 g (89%) of 2-ethenyl-4-methoxy-1-O-methoxymethylphenol as a pale yellow liquid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>O1CCCC1>[CH2:11]([N:14]([CH2:18][CH3:19])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(CC)C(=O)Cl
Reactant: CCS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
A mixture of 6.45 g. 3-ethylsulphonyl-1,2,4-triazole, 5.9 g. N-allyl-N-ethylcarbamoyl chloride, 6.5 ml. dry triethylamine and 80 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 6 hours. The reaction mixture was worked up as described in Example 1 to produce a solid residue which was recrystallized from benzene/petroleum ether, b.p. 40° - 60° C. to give 1-(N-allyl-N-ethylcarbamoyl)-3-ethylsulphonyl-1,2,4-triazole, m.p. 41° - 43° C.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:5][N:4]([C:6]2[C:7]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:8]C(C#N)=[N:10][CH:11]=2)[CH2:3]1.[OH-:21].[K+].[CH3:23][CH2:24][OH:25]>C(OCC)(=O)C>[F:1][C:2]1([F:20])[CH2:5][N:4]([C:6]2[C:7]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:8][C:23]([C:24]([OH:21])=[O:25])=[N:10][CH:11]=2)[CH2:3]1
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Temperature: 105 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile (example 223a, 680 mg, 2.32 mmol) in EtOH (8 ml) in a schlenk tube was added a 4M aqueous solution of potassium hydroxide (651 mg, 11.6 mmol). The reaction mixture was stirred at 105° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and poured in a separatory funnel. The organic phase was extracted with a 1M aqueous solution of hydrochloric acid. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness to yield the title compound (397 mg, 55%) as a crude solid which was used without any purification. MS (ESI, m/z): 311.2 (M−H+).