Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[CH2:11](O)[CH2:12]O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:10][CH2:12][CH2:11][O:9]1
Reactant: Nc1ccccc1B(O)O
Reactant: OCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccccc1B1OCCO1
Reaction time: 0.33 h

Procedure:
To a solution of o-aminophenylboronic acid (13.7 g, 100 mmoles) in dichloromethane (200 ml) is added ethylene glycol (6.30 g, 102 mmoles). The solution is shaken for 20 minutes, and then stirred over solid sodium sulfate. Removal of the volatiles affords ethylene o-aminophenylboronate. To a flame dried three neck round bottom flask equipped with septum, stopper and gas inlet, is added ethylene o-aminophenylboronate (0.36 g, 2.20 mmoles) in dry dimethylformamide (10 ml). To this solution is added Z-Gly-Ala (0.62 g, 2.21 mmoles), triethylamine (0.62 ml, 4.45 mmoles), and finally diethyl cyanophosphonate (0.37 ml, 2.44 mmoles). After stirring the reaction at room temperature for 17 hours, the DMF is removed under reduced pressure. The remaining residue is dissolved in ethyl acetate, and washed sequentially with 10% HCl, saturated sodium bicarbonate, and brine. After drying the organic phase over magnesium sulfate, the salts are removed by filtration and filtrate concentrated in vacuum to leave (0.63 g) of Z-Gly-Ala-o- aminophenylboronic acid. This compound can be used "as is" in the present invention, or the benzyloxycarbonyl (Z) group can be removed by hydrogenolysis (see first step of Example 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][O:17]2)[C:12](O)=[O:13])[C:8](=[O:21])[CH:7]=1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[OH:35][C:33]([CH3:36])([CH3:34])[CH2:32][N:29]1[CH:30]=[CH:31][C:27]([NH:26][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]([O:5][C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[O:2][CH3:1])=[CH:7][C:8]2=[O:21])[CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][O:17]2)=[N:28]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCO2)C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCO2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
A solution of (S)-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-furan-2-yl)-propionic acid (90 mg, 0.26 mmol) in dichloromethane (10 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 45 mg, 0.29 mmol), Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (140 mg, 0.31 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford (S)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-furan-2-yl)-propionamide (45 mg, 36%) as a yellow solid: LR-ES-MS m/z calculated for C25H32N4O6 [M]+ 484, observed [M+H]+ 485; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H) 1.06 (br. s., 3H) 1.35-2.11 (m, 6H) 3.54-3.79 (m, 3H) 3.81 (s, 3H) 3.89 (s, 2H) 4.18, 4.22 (2×d, J=18.0, 1H) 4.45 (d, J=18.0 Hz, 1H) 4.68 (s, 1H) 4.70 (s, 1H) 4.77-4.91 (m, 1H) 6.40-6.48 (m, 1H) 6.95-7.06 (m, 1H) 7.18-7.25 (m, 1H) 7.25-7.36 (m, 2H) 7.51-7.56 (m, 1H) 10.70, 10.73 (2×s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:13]1[C:12]2[CH:17]=[C:8]([CH2:7][C:6]3[CH:18]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[Cl:19])[CH:9]=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc2c(c1)NCCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(Br)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 50 °C
Yield: 69 %

Procedure:
To a stirred solution of 6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (8.0 g, 23.66 mmol) in DMF (35 mL) was added potassium carbonate (6.53 g, 36.0 mmol), benzyl bromide (4.33 mL, 35.50 mmol) and heated to 50° C. for 8 h. Reaction mixture was cooled to room temperature, quenched by the addition of water (50 mL), extracted with ethyl acetate (3×20 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (7.0 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[Sn](CCCC)(CCCC)CCCC.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][C:14]1[C:13]([O:12][CH2:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:26]2[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=2)[N:7]=3)=[CH:21][CH:20]=[C:19]([F:22])[C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cccc1-c1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.10 g, 0.24 mmol) in 5 ml of anhydrous DMF was added 1-methyl-2-tributylstannanyl-1H-pyrrole (0.120 g, 0.32 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.004 g, 0.0037 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. The reaction mixture was then cooled to room temperature, added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/Hexane (40:60) as the eluent to provide the title compound as yellow solid (0.032 g, 32%). 1H NMR (DMSO-d6, 400 MHz): δ 3.73 (s, 3H), 5.72 (s, 2H), 6.13 (br s, 1H), 6.40 (br s, 1H), 6.97 (s, 1H), 7.12 (m, 1H), 7.42 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H), 8.48 (s, 1H) and 8.75 (s, 1H). MS ES+ (401.26), HPLC (method I) Rt=15.61 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6]C(=O)[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].C(O)(=O)C>O>[NH2:6][C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=1[SH:8]
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)cc1S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.7 %

Procedure:
6-Bromo-2-benzothiazolinone (4.65 g, 20.0 mmole) and sodium hydroxide (15.4 g, 0.385 mole) were mixed in 40 ml water. The mixture was stirred at room temperature for 30 minutes to form a slurry, was then heated at 100° C. and became a clear solution. The mixture continued to stir at 100° C. overnight after which it was cooled to room temperature. While cooling in an ice bath, the pH of the solution was adjusted to 6 with acetic acid (22 ml). The resulting solid was collected by filtration, washed three times (3×) with water and dried under vacuum to give 4.60 g of title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.23 (s, 1H), 6.98 (d, J=7.80 Hz, 1H), 6.59 (d, J=8.82 Hz, 1H), 5.41 (br, 2H). MS: (M+H)+=203/205, (M+H)+=406.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: NCCC=C1c2ccccc2C=Cc2ccccc21
Solvent: O
Product: CC(=O)NCCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
5-(3-Aminopropylidene)-5-H-dibenzo[a,d]cycloheptene is dissolved in acetic anhydride and the solution is heated to refluxing for 20 minutes. The solution is then cooled and poured into a large volume of water. The mixture is stirred until the excess acetic anhydride is hydrolyzed. The product is extracted into ether, the extract washed with sodium bicarbonate solution, followed by washing with water and dried over sodium sulfate. The product is isolated by evaporating the ether.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4](OCC)=O.BrC[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:20][CH:19]=1.Cl>C(O)C.C(O)(=O)C>[C:2]([CH2:3][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][CH2:15][CH2:4][CH2:3][C:2]([OH:10])=[O:9])=[CH:23][CH:22]=1)([OH:10])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCCCc1ccc(CCCCBr)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)CCCCCc1ccc(CCCCCC(=O)O)cc1
Temperature: 0 °C
Yield: 68.9 %

Procedure:
First, 483 mg of metallic sodium was dissolved in 21 ml of absolute ethanol, and after adding dropwise 6.72 g of diethyl malonate under ice-cooling, the mixture was refluxed for 5 minutes. After cooling, a mixture of 3.48 g of 1,4-bis(4-bromobutyl)benzene and 1.12 g of diethyl malonate was added dropwise at a room temperature, and the mixture was refluxed for 50 minutes. To the resulting white suspension, after cooling, 21 ml of ice water was added. The mixture was adjusted to pH 7.0 with 1N hydrochloric acid, and evaporated under a reduced pressure to remove the ethanol. The aqueous layer was twice extracted with 50 ml of benzene, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to remove the solvent, and then the remaining diethyl malonate at 140° C. To the colorless oil thus obtained were added 30 ml of acetic acid and 30 ml of concentrated hydrochloric acid, and the mixture was refluxed for 20 hours, and then cooled. The resulting crystal was filtered, washed with water and dried to obtain 2.11 g of the title compound as a colorless crystal.
Reaction SMILES: NC1C=CC(O[C:7]2[CH:20]=[CH:19][C:10]3N[C:12](NC(=O)OC)=[N:13][C:9]=3[CH:8]=2)=CC=1.C[OH:24]>[Pd]>[C:9]1([N:13]=[C:12]=[O:24])[CH:10]=[CH:19][CH:20]=[CH:7][CH:8]=1
Reactant: CO
Reactant: COC(=O)Nc1nc2cc(Oc3ccc(N)cc3)ccc2[nH]1
Agent: [Pd]
Product: O=C=Nc1ccccc1
Yield: 17 %

Procedure:
N-(5-(2-Nitro-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide (Intermediate 7) was hydrogenated under an H2 atmosphere with Pd—C (10%) in MeOH. After the reaction was complete, the solid was filtered off, and the filtrate was evaporated to give intermediate 8 (47 mg, 17%): 1H NMR (DMSO-d6) δ 11.56 (brs, 1H) 7.51 (d, 1H), 7.32 (d, 1H), 7.05 (dd, 1H), 6.97 (d, 1H), 6.74 (dd, 1H), 6.70 (d, 1H), 5.02 (br s, 2H), 3.74 (s, 3H), 7.08 (d, 2H), 6.84 (d, 1H), 6.61 (d, 1H), 3.75 (s, 3H); MS m/e 284 (M+1).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12]>C(O)(=O)C>[CH3:9][N:10]([CH3:14])[C:11]([C:3]1[CH:4]=[C:5]([OH:6])[CH:7]=[CH:8][C:1]=1[OH:2])=[O:12]
Reactant: CN(C)C(=O)Cl
Reactant: Oc1ccc(O)cc1
Solvent: CC(=O)O
Product: CN(C)C(=O)c1cc(O)ccc1O
Temperature: 110 °C

Procedure:
In the solution of 220 g(2 mol) of hydroquinone in 500 ml of acetic acid, 107.5 g(1 mol) of dimethylcarbamyl chloride was drop-added for one hour while agitating the solution at 110° C. The mixture was maintained at 110° C. for two hours, and acetic acid was distilled under vacuum. 1 liter of methylene chloride was added to the reaction mixture, and the unreacted excess hydroquinone was filtered and collected (recoverd amount: 110 g, recycled without any purification process). A desired mono N,N-dimethylcarbamyl hydroquinone was obtained by evaporating the residue under vacuum. (Yield: 178.6 g(98%). mp: 144-146° C., 1H-NMR(200 MHz, CDCl3, ppm) 3.05 (d, 6H), 6.59 (d, 2H), 6.80 (br, 1H) 6.82 (d, 2H).
Reaction SMILES: [C:1]1([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:22]([O-])([OH:24])=[O:23].[OH-].[Na+]>C(OC(=O)C)(=O)C>[N+:22]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:21])=[CH:6][CH:5]=1)([O-:24])=[O:23]
Reactant: O=C1CCCC(c2ccc(Cl)c(Cl)c2)N1c1ccccc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCC(c2ccc(Cl)c(Cl)c2)N1c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
To a solution of 1.0 g of 1-phenyl-6-(3,4-dichlorophenyl)-2-piperidone in 0.5 ml of acetic anhydride was added 1 ml of fuming nitric acid at 0° to 10° C., and the mixture was stirred for 3 hours. The mixture was made alkaline under cooling with an aqueous 10% sodium hydroxide solution and extracted with toluene. After washing with water and drying, the solvent was evaporated. The residue was purified by silica gel column chromatography (solvent; acetone:n-hexane=1:1) to give 0.35 g of 1-(4-nitrophenyl)-6-(3,4-dichlorophenyl)-2-piperidone as colorless foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(=O)COC[C@@H](C)[C@H](N(C(OC(C)(C)C)=O)C)C2OC=CC=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](COCC(=O)N1CCN(C(=O)OCc2ccccc2)CC1)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCNCC1
Reaction time: 1 h
Yield: 160.3 %

Procedure:
To a solution of 4-{2-[(2S,3S)-3-(tert-butoxycarbonyl-methylamino)-3-furan-2-yl-2-methyl-propoxy]-acetyl}-piperazine-1-carboxylic acid benzyl ester (250.0 mg, 0.47 mmol) in DCM (4 mL) at 0° C. was added TFA (4 mL). After stirring for 1 hour, the reaction mixture was diluted with DCM (30 mL) and washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 4-[2-(2S,3S)-3-furan-2-yl-2-methyl-3-methylamino-propoxy)-acetyl]-piperazine-1-carboxylic acid benzyl ester as a solid (166.0 mg) which was used for the next step without further purification. MS m/z (M+1) 430.3
Reaction SMILES: [F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>[Cu](Cl)Cl.C(Cl)Cl>[F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH:3]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=CC(F)c1ccccc1
Reactant: CC(C)(C)[S@](N)=O
Agent: Cl[Cu]Cl
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/C(F)c1ccccc1
Temperature: 23 °C
Reaction time: 0.03 h
Yield: 30.1 %

Procedure:
To a 500 mL RBF containing 2-fluoro-2-phenylacetaldehyde (320.00 mg, 2316.5 μmol) was added DCM (10 mL) and the mixture was allowed to stir at 23° C. for 2 min. At this time, (R)-2-methylpropane-2-sulfinamide (364.99 mg, 3011.5 μmol) was added in one portion to the mixture followed by copper(II) chloride (856.51 mg, 6370.4 μmol) at 5:30 pm. The reaction was allowed to stir overnight and then filtered through a plug of celite over silica gel. The solvent was removed and the crude residue was purified on a silica gel column (15 to 35% EtOAc in hexanes) to give the product (168 mg, 30%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[C:28]1([CH:36]=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:28]1([CH2:36][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: O=CC1=CCCCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CC4=CCCCCCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and cyclooctene-1-carbaldehyde (0.08 g) dissolved in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.12 g) under ice cooling, and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was neutralized with a 1 N aqueous solution of sodium hydroxide, was then concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent. The residue was subjected to purification using a silica gel column (ethyl acetate) to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/diethyl ether/hexane to obtain N-(1-(cycloocten-1-yl)methylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 57) (0.11 g) as colorless prisms.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A solution of 22.2 g of 2-bromopyridine in 100 ml of THF is cooled to −70° C., 87.8 ml of n-butyllithium are added dropwise and the mixture is stirred for 30 minutes. A solution of 25.6 g of 1-benzyl-4-piperidinone in 100 ml of THF is then added dropwise at −60° C., and the mixture is stirred overnight while allowing the temperature to rise to rt. The reaction mixture is poured into water and extracted with ether, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H gel, eluting with DCM and then with a DCM/MeOH mixture gradient of from (99/1; v/v) to (90/10; v/v). 21.5 g of the expected product are obtained.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11]O)[N:10]=1)[CH3:4].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:15].[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][Cl:1])[N:10]=1)[CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CN(C)Cc1nc(CO)cs1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1nc(CCl)cs1

Procedure:
The methanols produced by the process of this example are readily converted to the corresponding thiazolemethyl chlorides according to the following procedure: A suspension was prepared from 1.05 grams of 2-dimethylaminomethyl-4-thiazolemethanol hydrochloride and 15 ml. of chloroform. Thionyl chloride (2.50 g) was added and the resulting mixture was stirred at reflux temperature for about 2.75 hours. Any volatile constituents including excess thionyl chloride were removed by evaporation. The residue was suspended in chloroform and the chloroform removed by evaporation. The residue was then recrystallized from a methanol-ethyl acetate solvent mixture to yield 2-dimethylaminomethyl-4-thiazolylmethylchloride hydrochloride melting at 136-8° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:9]([OH:23])[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH2:45][CH:46]1[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43]>C(Cl)Cl>[C:27]([O:26][C:25]([NH:24][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@H:9]([OH:23])[CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)[C:42]([O:44][CH2:45][CH:46]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:52]=2[C:53]2[C:58]1=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:43])=[O:31])([CH3:28])([CH3:30])[CH3:29]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc(CNC[C@@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)cc(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(CN(C[C@@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)OCC2c3ccccc3-c3ccccc32)cc(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of tert-butyl (2S,3R)-1-cyclohexyl-4-(3,5-dimethoxybenzylamino)-3-hydroxybutan-2-ylcarbamate (66.5 mg, 0.153 mmol) in CH2Cl2 (10 mL) at 0° C. was added DIEA (1.5 mL) followed by 9-fluorenylmethyl chloroformate (39.5 mg, 0.153 mmol) and the resulting mixture was stirred at 0° C. for 2 h and at rt for 2 h. The reaction mixture was concentrated and the residue was diluted with EtOAc and water. The organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel to provide (2R,3S)-3-(t-butoxycarbonylamino)-4-cyclohexyl-1-(N-(3,5-dimethoxybenzyl)-N-((9H-fluoren-9-yl)methoxycarbonyl)amino)butan-2-ol (78.5 mg, 78%). 1H NMR: 0.79 (m, 1H), 0.95 (m, 1H), 1.06-1.38 (m, 6H), 1.42 (s, 9H), 1.56-1.70 (m, 6H), 1.83 (m, 1H), 3.25-3.50 (m, 2H), 3.70 (m, 1H), 3.73 (s, 6H), 3.85 (m, 1H), 4.22 (m, 1H), 4.29-4.70 (m, 5H), 6.35 (m, 3H), 7.20 (m, 1H), 7.32-7.48 (m, 4H), 7.58 (m, 1H), 7.69 (m, 1H), 7.75 (m, 1H). MS (E/Z): 659 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(CCl)ccn1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)ccn1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 4-chloromethyl-2-methyl-pyridine (described in WO 2006023707) gave the title compound. ES-MS m/e (%): 504.2 (M+H+).