Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S-])#N.[K+:4].[CH3:5][C:6]1([S:9]([O:12]CC2C=CC=CC=2)(=[O:11])=[O:10])[CH2:8][CH2:7]1>COCCOC.O>[CH3:5][C:6]1([S:9]([O-:12])(=[O:11])=[O:10])[CH2:8][CH2:7]1.[K+:4]
Reactant: CC1(S(=O)(=O)OCc2ccccc2)CC1
Agent: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1(S(=O)(=O)[O-])CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
KSCN (2.48 g, 25.5 mmol) was added to a solution of Benzyl 1-methylcyclopropane-1-sulfonate (4.9 g, 25.5 mmol) in DME/H2O (1:1, 120 mL) and continued stirring at 100° C. for 16 h. Reaction mixture was concentrated under reduced pressure and the residue was washed with n-Pentane and dried to afford Potassium 1-methylcyclopropane-1-sulfonate (Int-26) which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:22]([O:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(O)(c2ccc(F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(c2ccc(F)cc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 82 %

Procedure:
To a solution of 4-hydroxy-4-(4-fluorophenyl)cyclohexanone (520 mg, 2.5 mmol), pyridine (2 ml) and 4-dimethylaminopyridine (46 mg) in CH2Cl2 (25 ml) at 0° C. was added dropwise a solution of acetic anhydride (1 ml) in CH2Cl2 (5 ml). The mixture was warmed to room temperature and stirred for 28 h before being quenched with water (30 ml). The organic phase was washed with 1 M HCl (2×30 ml) and brine (30 ml), dried over MgSO3, and concentrated in vacuo. The residue was purified by flash chromatography (25% ether in petroleum ether) to afford the desired ketone (510 mg, 82%) as a colorless solid. mp 113-115° C. 1H NMR (500 MHz, CDCl3) δ2.11 (s, 3H), 2.20 (m, 2H), 2.43 (m, 2H), 2.68 (m, 2H), 2.86 (m, 2H), 7.05 (t, J=8.3, 2H), 7.35-7.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1Cl
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCCC2=O)cc1Cl

Procedure:
A mixture of 500 mg of 2-chloro-4-florobenzonitrile, 821 mg of 2-pyrrolidinone and 3 g of cesium carbonate in 5 mL of DMF was heated to 100° C. in a sealed microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-80% ethyl acetate/hexane) to afford 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile. 890 mg of 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid. 80 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopyrrolidin-1-yl)benzamide. MS (Q1) 426.2 (M)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([CH3:12])=[N:6][C:5]=2[S:4][C:3]=1[CH3:13].O.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH:26]=[CH:27][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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.C(OCC)(=O)C>[NH2:11][C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]2[S:4][C:3]([CH3:13])=[C:2]([C:23]3[CH:24]=[C:25]([N:29]4[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]4)[CH:26]=[CH:27][CH:28]=3)[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: Cc1cc(N)c2c(Br)c(C)sc2n1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(N)c2c(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)c(C)sc2n1
Temperature: 120 °C
Yield: 88.8 %

Procedure:
Under nitrogen, 3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-amine (130 mg, 0.506 mmol) (Description 8) was dissolved in 1,4-dioxane (3 mL) and water (1 mL) and 1,1-dimethylethyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperazinecarboxylate (294 mg, 0.758 mmol), tetrakis(triphenylphosphine)palladium(0) (58.4 mg, 0.051 mmol) and potassium carbonate (210 mg, 1.517 mmol) were added. The mixture was then heated in a microwave at 120° C. for 30 min. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-70% ethyl acetate in cyclohexane, afforded the title compound (197 mg). LCMS (A) m/z: 439 [M+1]+, Rt 0.99 min (acidic).
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:5]=[C:6]([CH:11]([CH:16]2[CH2:19][N:18]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)C(OC)=O)[CH:7]=[C:8]([F:10])[CH:9]=1.CO.CC[O:37][CH2:38][CH3:39]>C1COCC1>[F:10][C:8]1[CH:7]=[C:6]([C@H:11]([CH:16]2[CH2:19][N:18]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17]2)[C:38]([CH3:39])([OH:37])[CH3:1])[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: [Li]C
Reactant: CCOCC
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 67.03 g (272 mmole) of CeCl3 in 500 mL dry THF was stirred in a 2 L three-necked flask under N, at rt. After 30 minutes, the mixture was cooled to −78° C. in a dry ice-acetone bath and 155 mL of a 1.6M solution of methyllithium in ether was added dropwise with vigorous stirring. The yellow-green mixture was stirred at −78° C. for an additional 30 minutes and then a solution of 28.75 g (70.6 mmole) of methyl (3,5-difluorophenyl)[1-(diphenylmethyl)azetidin-3-yl]acetate in 100 mL of dry THF was added over 30 minutes, at such a rate as to keep the temperature below −60° C. The mixture was left stirring at −78° C. for 1 h, then excess carbanion was decomposed by the dropwise addition of 20 mL of methanol and 1000 mL of ether while the solution warmed to −40° C. The reaction was quenched by addition of saturated aqueous NH4Cl until the most of the solids had precipitated to the bottom surface of the flash. The liquid layer was decanted into a 2 L separatory funnel and the solids were triturated with three 200 mL portions of dichloromethane. The combined organic layers were washed with two 400 mL portions of aqueous NH4Cl solution and brine, then dried over Na2SO4 and concentrated to a white solid. The residue was purified on ChiralPak AD resin using 5% isopropanol-heptane. Fractions containing the faster enantiomer were pooled and concentrated to afford the title compound, which is the (+) enantiomer; 1H NMR(CDCl3) δ 1.07 (s, 3H), 1.14 (S, 3H), 2.28 (t, 1H, J=7.5 Hz), 2.74 (d, 1H, J=10.7 Hz), 2.82 (t, 1H, J=7.5 Hz), 3.10-3.16 (m, 2M), 3.62 (m, 1H), 4.20 (s, 1H), 6.67-6.73 (m, 3H), 7.21-7.45 (m, 10); Mass Spectrum: m/e=408.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[C:14]([CH3:16])[NH:15][C:11]=2[CH:10]=1)#[N:2].[H-].[Na+].Br[CH:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[CH:17][C:12]2[N:13]([CH:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]([CH3:16])=[N:15][C:11]=2[CH:10]=1)#[N:2]
Reactant: Cc1nc2ccc(-c3ccccc3C#N)cc2[nH]1
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCC(C(=O)OCC)n1c(C)nc2cc(-c3ccccc3C#N)ccc21
Reaction time: 0.5 h

Procedure:
5-(2-Cyanophenyl)-2-methylbenzimidazole (3.43 mmoles, 0.8 g) was dissolved in DMF. Sodium hydride (3.75 mmoles, 0.15 g.) was added. The solution was stirred for 30 minutes. Ethyl 2-bromooctanoate was added. The solution was stirred for 1 hour. Water and ethyl acetate were added; and the layers separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The intermediate was chromatographed on silica gel eluted with 50% ethyl acetate in hexane to yield 1.0 g of ethyl 2-[5-[2-cyanophenyl]-2-methyl-1H-benzimidazol-1-yl]octanoate. The nitrile was dissolved in 10 ml of tributyltinazide and heated at 70° C. for 3 days. The solution was stirred in a mixture of acetonitrile, water, and acetic acid (100 ml of 8:1:1) for 3 hours, washed with hexane (4×250 ml), and concentrated. The residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated in vacuo. The intermediate was triturated with hexane, filtered and chromatographed over silica gel eluted with 10% ethanol in ethyl acetate with 1% acetic acid. The isomers were separated by reverse phase HPLC eluted with a gradient of 30-50% acetonitrile in water with 1% ammonium acetate. The intermediate was dissolved in ethanol (20 ml) and 5N NaOH (5 ml) and heated on a steam bath for 1 hour. The solution was concentrated to 75 ml. The pH was adjusted to 3.0 using 5N HCl. The precipitate was collected and dried. The reaction yielded 110 mg of 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-2-methyl-1H-benzimidazol-1-yl]octanoic acid. (MS)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[SH:19][C:20]1[N:24]([CH3:25])[CH:23]=[N:22][N:21]=1>>[CH3:25][N:24]1[CH:23]=[N:22][N:21]=[C:20]1[S:19][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1
Reactant: Cn1cnnc1S
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1nccs1
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3nccs3)c2c1

Procedure:
The compound of Example 2 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, 2-amino-thiazole and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([F:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]=1[F:12].Cl.Cl[CH2:16][C:17]1[N:18]=[CH:19][S:20][CH:21]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:10][C:9]1[CH:8]=[C:7]([O:11][CH2:16][C:17]2[N:18]=[CH:19][S:20][CH:21]=2)[CH:6]=[C:5]([F:12])[C:4]=1[C:3]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:13]
Reactant: COC(=O)c1c(F)cc(O)cc1F
Reactant: ClCc1cscn1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: Cl
Product: O=C(c1c(F)cc(OCc2cscn2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2,6-difluoro-4-hydroxy-benzoic acid methyl ester [CAS 194938-88-0], 4-(chloromethyl)thiazole hydrochloride [CAS 7709-58-2], and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 408.3
Reaction SMILES: [H-].[Na+].O[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:14][C:15]([Cl:19])([Cl:18])[C:16]#[N:17].C([OH:22])C>CCOCC>[Cl:14][C:15]([Cl:19])([Cl:18])[C:16]([NH:17][CH:6]([CH:5]=[CH2:4])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:22]
Reactant: CCO
Reactant: CCOC(=O)CCC=CCO
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CC(CCC(=O)OCC)NC(=O)C(Cl)(Cl)Cl
Yield: 727.1 %

Procedure:
Sodium hydride (0.03 g of a 50% dispersion in oil, 0.5 mmol, was added to a solution of ethyl 6-hydroxy-4-hexenoate (0.7 g, 5 mmol) and trichloroacetonitrile (0.6 g, 5 mmol) in anhydrous ether (50 mL) under N2 at 0° C. After 1 H, ethanol (0.5 mmol) was added and the solvent was removed in vacuo. The formation of the imidate was controled by NMR (NH,~8.5 ppm). A solution of the crude imidate in xylene (30 mL) was heated at reflux 48 H. Then the solvent was removed in vacuo and the residue was purified by flash chromatography on SiO2. (eluant AcOEt: hexane, 2:8) to give the title product (1.1 g, ~70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25]>>[Cl:1][C:2]1[C:3]2[C:11]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#Cc1ccccn1
Product: COc1c(C)cnc(Cn2cc(C#Cc3ccccn3)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see Example 1) with 2-ethynylpyridine according to the General Procedure A. tR: 4.65 min. 1H-NMR (DMSO-d6) δ 8.59 (s, 1H), 8.07 (s, 1H), 7.82 (td, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.36 (td, 1H), 6.84 (br. s, 2H), 5.36 (s, 2H), 3.74 (s, 3H), 2.28 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][OH:5]
Reactant: NC(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(CCO)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a suspension of 3-amino-3-phenylpropanoic acid (2.0 g, 12.1 mmol) in dry THF (45 mL) cooled to 0° C. under N2 was added portionwise over 20 minutes solid LiAlH4 (920 mg, 24.2 mmol). Stirring was continued at room temperature for 24 h. after which time solid Na2SO4.10H2O was added with stirring until only a heavy white precipitate was present. The organic layer was diluted with ether and filtered through Celite® and the concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and extracted with 1N HCl (3×40 mL). The aqueous layers were combined and basified to pH˜12 with 5M NaOH. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic phases dried (Na2SO4) and concentrated in vacuo to separate the product which was used without further purification (0.9 g, 49%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].ClCCl.Cl[CH2:13]/[CH:14]=[CH:15]\[CH2:16]Cl.CCCCCC>CCCCCC.C(OCC)(=O)C>[N:6]1([C@@H:5]([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:16][CH:15]=[CH:14][CH2:13]1
Reactant: CCOC(=O)[C@H](C)N
Reactant: ClC/C=C\CCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)[C@H](C)N1CC=CC1
Yield: 56.7 %

Procedure:
From L-alanine ethyl ester (383 mg, 3.2 mmol), dichloromethane (0.1 ml) and cis-1,4-dichloro-2-butene (140 mg, 1.0 mmol). Flash chromatography: silica gel, gradient neat hexane to hexane:ethyl acetate (1:2) afforded the product (96 mg, 52%) as yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14]C(C)(C)C)=O)[CH2:4]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:19]([NH:23][C:12](=[O:14])[CH2:11][C@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:8][C:7]([CH3:9])([CH3:10])[O:6]1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 42.5 °C

Procedure:
A mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (10 grams), methanol (80 ml), n-butyl amine (20 ml) and potassium carbonate (10.6 grams) was heated to 40-45° C. and stirred up to completion of the reaction. The reaction mixture was distilled under reduced pressure and methylene chloride (100 ml) was added to the obtained residue at 25-30° C. and stirred for 15 minutes. The unwanted solid was filtered off and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (32 ml) and a mixture of TEMPO (0.015 grams), potassium bromide (0.36 grams) in methylene chloride (48 ml) was added to it and stirred for 15 minutes. Sodium hypochlorite solution (20.8 ml) was added to the reaction mixture at −15 to 15° C. and stirred for an hour. After completion of the reaction, the reaction mixture was quenched with sodium thio sulfate solution at below 10° C. Both organic and aqueous layers were separated and aqueous layer extracted with methylene chloride. The solvent from organic layer was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]([OH:15])[C@H:6]2[N:7]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1.ClCCl>[C:17]([O:13][CH2:12][C@H:10]1[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:16])[CH3:1])[S:4]2)[C@@H:8]([OH:15])[C@@H:9]1[OH:14])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63.8 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5 g, 20 mmol) in pyridine (150 mL) was added a solution of benzoyl chloride (3.4 g, 24 mmol) in dichloromethane (10 mL) at 0° C. within 10 minutes, and then stirred for 5 hours at 0° C. in an ice/salt bath. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (100 mL), and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (2×20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography with 2% 5% methanol in dichloromethane to afford the title compound as an off-white solid (4.5 g, 63%). (ES, m/z): [M+H]+ 353.0; 1H NMR (300 MHz, CD3OD) δ 8.07-8.01 (m, 2H), 7.99-7.40 (m, 3H), 6.43 (d, J=6.6 Hz, 1H), 4.88-4.85 (m, 1H), 4.63-4.45 (m, 1H), 4.19-4.15 (m, 1H), 3.99-3.93 (m, 2H), 3.36-3.32 (m, 1H), 3.06 (s, 6H).
Reaction SMILES: O=O.[CH2:3]([N:10]1[CH2:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[C:12]([C:23]([OH:25])=[O:24])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO>[CH2:3]([N:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C@H:12]([C:23]([OH:25])=[O:24])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)C1=C(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C1
Agent: O=O
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
A 185-ml stainless steel autoclave was charged under argon in a glove box (O2 content≦2 ppm) with 1-benzyl-4-(3,4-dichloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1.00 g, 2.87 mmol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP)] (0.22 mg, 0.29×10−6 mol, S/C 10′000) and methanol (30 ml). The asymmetric hydrogenation was run for 20 h at 80° C. under 40 bar of hydrogen (99.8% conversion). After the pressure was released, the formed white suspension was evaporated to dryness to yield 1.03 g (>99%) of crude (S,S)-Ib with 98.0% purity and 97.6% ee.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24](=[O:26])[CH3:25])[CH2:18][CH2:17]2)[CH2:3]1.[BH4-].[Na+].[Cl-:30].[NH4+]>CO>[ClH:30].[CH3:27][C:2]1([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])[CH2:18][CH2:17]2)[CH2:3]1
Reactant: CC(=O)CCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Reactant: [Cl-]
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(O)CCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Product: Cl
Reaction time: 2 h

Procedure:
To a mixture of 4-[4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl]butan-2-one (138 mg, 0.372 mmol) produced in (Example 110) and methanol (1.5 mL) was gradually added sodium borohydride (14.1 mg, 0.372 mmol) at an external temperature of room temperature, followed by stirring for 2 hours under the same conditions. Aqueous solution of ammonium chloride was added to the reaction mixture, and stirring was continued for 20 minutes. After making the mixture basic with aqueous solution of potassium carbonate, extraction was performed with ethyl acetate. The separated organic layer was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 136 mg of the free form of the title compound as a colorless oil. The free from of the title compound (19 mg, 0.051 mmol) was dissolved in a mixed solvent of ethyl alcohol and ethyl acetate, and then a 4N solution of hydrogen chloride in ethyl acetate (0.014 mL, 0.056 mmol) was added. The mixed solution was concentrated under reduced pressure and the resulting solid residue was washed with a diethyl ether-heptane mixed solvent and then dried under reduced pressure to give 21 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[Cl:16][C:17]1[CH:18]=[C:19]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[N:21][CH:22]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][C:19]2[CH:20]=[N:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH2:27][CH2:28]1)#[N:2]
Reactant: Clc1cncc(OCCN2CCNCC2)c1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cncc(Cl)c2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(5-chloro-3-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:12][CH2:13][Mg+].[Br-].[Cl-].[NH4+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]([OH:6])[CH2:12][CH3:13]
Reactant: COc1cc(C)ccc1C=O
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)c1ccc(C)cc1OC
Reaction time: 2 h

Procedure:
To a stirring solution of 2-methoxy-4-methylbenzaldehyde (1 g, 6.66 mmol) in diethyl ether (35 ml) at 0° C. is added EtMgBr (2.220 ml, 6.66 mmol). The mixture is stirred for 2 hours and then added to sat ammonium chloride solution. The mixture is extracted with ethyl acetate and the combined organic portions are washed with NaHCO3, water and brine dried (MgSO4) and reducing under vacuum to yield the title product as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, 1H), 6.78 (d, 1H), 6.72 (s, 1H), 4.77 (t, 1H), 3.85 (s, 3H), 2.37 (s, 3H), 1.83 (m, 2H), 0.96 (t, 3H).