Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16].Br[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: BrCC1CCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31 M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid (696 mg, 3.39 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of 2-bromomethyl-tetrahydro-furan (672 mg, 4.07 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. The excess solvent was removed in vacuo. The residue was diluted with water (50 mL) and was treated with a 1N aqueous hydrochloric acid solution until the solution was acidic. The resulting solution was extracted into ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate with glacial acetic acid) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid (692.3 mg, 70.8%) as a white solid: mp 100–102° C.; FAB-HRMS m/e calcd for C13H14Cl2O3 (M+H)+ 289.0399, found 289.0404.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)[CH2:16][CH2:15]1.[C:28]([Cl:34])(=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31].N.[NH4+].[Cl-]>CO.C(Cl)Cl>[ClH:34].[CH3:31][CH:30]([CH3:32])[CH2:29][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][CH:17]2[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]2)[CH:22]=1)=[O:33]
Reactant: CC(C)CC(=O)Cl
Reactant: CN1CCC(Nc2cccc(N)c2)CC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CC(=O)Nc1cccc(NC2CCN(C)CC2)c1
Product: Cl
Temperature: 0 °C

Procedure:
Combine 1-methyl-4-(3-aminophenylamino)piperidine triacetate (Preparation 18, 460 mg, 1.17 mmol) and CH2Cl2 (13 mL); stir and cool to 0° C. Add isovaleryl chloride (135 μL, 1.05 mmol), and stir at room temperature for 18 hr. Load onto a 5 g SCX cartridge (mega bond elut, Varian). Wash resin with methanol, then elute product with 2 M ammonia in methanol. Concentrate in vacuo, and chromatograph on silica gel, eluting with a gradient of 1–15% (2M ammonia in methanol) in CH2Cl2. Concentrate in vacuo. Dissolve the purified oil (115 mg, 38% isolated yield) in methanol, add solid NH4Cl (21.2 mg, 1 eq) and sonicate the solution at room temperature for 15 min. Concentrate in vacuo to provide the title compound: mass spectrum (ion spray): m/z=290.2 (M+1); Anal calc'd for C17H28ClN3O.0.1H2O: Theory: C, 62.31; H, 8.67; N, 12.82. Found: C, 62.32; H, 8.78; N, 12.56.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:10][C@@H:9]1[C:36]([OH:38])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1CCOCC1.CN>C1COCC1.C(Cl)Cl>[Cl:34][C:30]1[C:29]([F:35])=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][C@@H:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([C:36]([NH:40][CH3:39])=[O:38])[CH2:10]4)[CH:16]=3)[N:21]=[CH:20][N:19]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CN1CCOCC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 108.2 %

Procedure:
A stirred solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (5.35 g, 9.80 mmol) in THF (50 ml) was cooled to −15° C. (acetone/ice). NMM (1.49 ml, 14.9 mmol) was added to the solution followed by IBCF (2.0 ml, 12.75 mmol). The reaction mixture was held at −15° C. (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with a 2.0M solution of methylamine in THF (10 ml) at −15° C. and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2×20 ml) and concentrated to give tert-butyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (5.94 g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 560.1.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:34]([NH:24][CH2:23][C:22]([N:20]([C:15]1[C:14]([Cl:26])=[C:13]([C:18]([Cl:19])=[CH:17][CH:16]=1)[CH2:12][O:11][C:10]1[C:5]2[N:6]([C:2]([Br:1])=[C:3]([CH3:27])[N:4]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:21])=[O:25])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg) in methylene chloride (2 ml) were added pyridine (17 mg), 4-dimethylaminopyridine (10 mg) and acetic anhydride (32 mg), and the mixture was stirred for 1.5 hours. The mixture was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol=5:1, V/V) to give 8-[3-[N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (74 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CCN(C(C)C)C(C)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:5])[NH2:6]
Reactant: Cc1cccc(C(N)=O)c1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1c(C)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 2-amino-3-methylbenzamide (1.50 g, 10.0 mmol) and DIEA (2.61 mL, 15 mmol) in THF (50 mL) at 0° C. was added ethyl chlorooxoacetate (1.23 mL, 11.0 mmol). The solution was allowed to warm to rt and stir for 16 h, then was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-100% EtOAc/hexanes to afford ethyl 2-(2-carbamoyl-6-methylphenylamino)-2-oxoacetate as a solid (490 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=7.1 Hz, 3H), 2.17 (s, 3H), 4.30 (q, J=7.1 Hz, 2H), 7.28 (t, 1H), 7.33-7.57 (m, 3H), 7.82 (s, 1H), 10.67 (s, 1H).
Reaction SMILES: [C-:1]#[N:2].[K+:3].[F:4][C:5]([F:9])=[C:6]([F:8])[F:7].[C:10](=[O:12])=[O:11]>CN(C)C=O>[C:1]([C:6]([F:8])([F:7])[C:5]([F:9])([F:4])[C:10]([O-:12])=[O:11])#[N:2].[K+:3]
Reactant: O=C=O
Reactant: FC(F)=C(F)F
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(F)(F)C(F)(F)C(=O)[O-]
Reaction time: 4 h

Procedure:
A mixture of 26.0 g (0.40 mole) of KCN, 150 ml of dimethyl formamide, 50 g (0.50 mole) of tetrafluoroethylene (TFE), and 50 g of CO2 was held at 50° for 4 hr., and then at 100° for 4 hr. at a maximum pressure of 1100 psi (7.6×103 kPa). The resulting mixture was dark and contained no insoluble salts. Volatile compounds were removed from the mixture under reduced pressure leaving a viscous residue of potassium 3-cyanotetrafluoropropionate, which substantially solidified to a deliquescent semisolid when triturated with ether. IR (neat): 2288 (weak covalently bound CN), 1680 (strong CO2), and 1250-1100 cm-1 (C--F, C--O) with broad H-bonded OH at 3450 and weak saturated CH at 2940 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1.C(O[C@@H:22]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]1[O:24][C:25](=[O:27])[CH3:26])(=O)C>C1(C)C=CC=CC=1>[C:25]([O:24][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[O:39][C@H:22]1[O:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](=[O:10])[NH2:11])=[CH:7][CH:6]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(=O)c1ccc(Cc2ccccc2O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(C(N)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(2-hydroxybenzyl)benzamide (0.063 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (0.33 g) in toluene (3 mL) was added boron trifluoride diethyl-ether complex (0.11 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give 2-(4-carbamoylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. To a solution of the obtained 2-(4-carbamoylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in methanol (5 mL) was added sodium methoxide (0.005 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/ethanol=5/1) to give 2-(4-carbamoylbenzyl)phenyl β-D-glucopyranoside (0.068 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[C:13]([C:14]4[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=4)=[C:9]3[C:8](=[O:34])[N:7]([CH3:35])[C:6]2=[O:36])[CH2:3][CH2:2]1.CN.[C:39](P(=O)(OCC)OCC)#[N:40]>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[C:13]([C:14]4[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([NH:40][CH3:39])=[O:22])[CH:15]=4)=[C:9]3[C:8](=[O:34])[N:7]([CH3:35])[C:6]2=[O:36])[CH2:2][CH2:3]1
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC3CC3)c2c1
Reactant: CCOP(=O)(C#N)OCC
Agent: CN
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(C)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{7-(cyclopropylmethyl)-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methylamine using diethyl cyanophosphonate as a coupling reagent Mass: 500.25 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25])#[N:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25])#[N:2]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C#N
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
40% Methanolic Triton B (0.24 mL, 0.53 mM) was added to a solution of the 9-[(2-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (140 mg, 0.41 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (130 mg, 0.82 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate/THF) to afford 116 mg (68%) of the {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.75 (d, 1H, J=8 Hz), 7.5-7.2 (m, 6H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 2H, J=8 Hz),), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.75 (s, 2H), 4.9 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 2228, 1732, and 1675. MS (ES) m/e 412, 414.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:17]=[CH:16][C:9]3[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[O:13][C:8]=3[CH:7]=2)[CH2:2]1.[CH3:18][CH:19]([NH2:21])[CH3:20]>C(O)C>[CH3:14][C:12]1[O:13][C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH:3]([OH:1])[CH2:2][NH:21][CH:19]([CH3:20])[CH3:18])[CH:17]=[CH:16][C:9]=2[C:10](=[O:15])[CH:11]=1
Reactant: Cc1cc(=O)c2ccc(OCC3CO3)cc2o1
Reactant: CC(C)N
Solvent: CCO
Product: Cc1cc(=O)c2ccc(OCC(O)CNC(C)C)cc2o1

Procedure:
3.7 g 1,2-epoxy-3-(2-methyl-4H-1-benzopyrane-4-one-7-yloxy)-propane and 2.5 cm3 2-propylamine were boiled in 40 cm3 ethanol for 2 hours; the process of example 9 (a) was followed. 4.3 g 1-(2-methyl-4H-1-benzopyrane-4-one-7-yloxy)-3-(1-methylethyl-amino)-2-propanol (m.p. 80°-82° C.) was obtained in the form of a base.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17].I[CH2:19][CH3:20]>C(OCC)(=O)C.O>[CH2:19]([O:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[F:8])[CH:13]=[O:14])[CH3:20]
Reactant: CCI
Reactant: O=Cc1ccc(F)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1F
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Sodium hydride (171 mg) was added to a DMF (10 mL) solution of 4-fluoro-3-hydroxybenzaldehyde (300 mg) obtained above at room temperature, and the reaction solution was agitated for 30 minutes. Then, iodoethane (0.26 mL) was added dropwise to the reaction solution, and the reaction mixture was agitated at room temperature for 1 hour. After the reaction ended, water and ethyl acetate were added to the reaction solution under ice-cooling and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate 5:1), and 250 mg (70%) 3-ethoxy-4-fluorobenzaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [BH4-].[Na+].CCO.[CH2:6]([O:8][C:9](=[O:35])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1/[CH:23]=[CH:24]/[C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:35])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1/[CH:23]=[CH:24]/[CH:25]([OH:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH3:7]
Reactant: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Yield: 80.4 %

Procedure:
Sodium borohydride (10 mg, 0.26 mmol) followed by EtOH (0.25 mL) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid ethyl ester (110 mg, 0.25 mmol) in CH2Cl2 (1.0 mL) at 0° C. After 1 h at 0° C. the reaction was quenched with 1 N aqueous HCl. The reaction mixture was extracted with CH2Cl2 (3×10 mL), then the combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2) afforded 88 mg (80%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid ethyl ester.
Reaction SMILES: CO.[CH:3]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4]1.[BH4-].[Na+].CC(C)=O>C(Cl)(Cl)Cl>[CH:3]1([CH:6]([OH:7])[C:8]2[CH:9]=[CH:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)[CH2:4][CH2:5]1
Reactant: CSc1ccc(C(=O)C2CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(O)C2CC2)cc1
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To 200 ml of methanol solution containing 24 g of cyclopropyl (4-methylthiophenyl)ketone was added slowly 9.4 g of sodium borohydride under an ice-cooled condition, the reaction mixture was stirred for 2 hours. Then an adequate amount of acetone was added to the reaction mixture and concentrated under a reduced pressure. To the residue thus obtained was added chloroform, and the chloroform solution was washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by evaporation to yield 18 g of 1-(cyclopropyl, hydroxylmethyl)-4-methylthiobenzene as in the form of colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=1.Cl.[Li+].[OH-]>CN1C(=O)CCC1.C1COCC1.O>[O:12]=[C:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]2[C:8](=[N:9][CH:10]=[CH:11][C:2]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=2)[NH:7]1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 140 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
83 (550 mg, 2.17 mmol), methyl 2-(4-aminophenyl)acetate (376 mg, 2.28 mmol), and HCl (0.65 mL, 2.17 mmol, 4.0 M in dioxane) were suspended in NMP (5 mL), and stirred for 3 h at 140° C. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL), and stirred for 30 min. The resulting precipitate was filtered, washed with H2O, and dried under vacuum. The methyl ester intermediate (750 mg, 2.09 mmol) and LiOH (150 mg, 6.26 mmol) were dissolved in THF (4 mL) and H2O (4 mL), and stirred for 48 h at room temperature. The THF was removed, the mixture was diluted with H2O, and acidified to pH=5 with 1M HCl. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to provide 302 (550 mg, 76% yield) as a white solid. 1HNMR(DMSO-D6): 3.52(s, 2H), 6.97 (d, 1H), 7.13 (m, 2H), 7.21 (m, 2H), 7.58 (m, 1H), 7.61 (m, 1H)m 8.10 (d, 1H), 8.34(d, 1H), 8.84-8.90 (m, 2H). LC-MS (M+H=346, obsd.=346).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[C:11]([F:13])[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[F:14].[C-:15]#[N:16].[Na+].O>CS(C)=O>[C:15]([CH2:2][C:3]1[CH:12]=[C:11]([F:13])[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[F:14])#[N:16]
Reactant: Fc1cc(CCl)c(F)c2c1OCCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(F)c2c(c1F)OCCO2
Reaction time: 1 h

Procedure:
6-Chloromethyl-5,8-difluoro-1,4-benzodioxane (36.9 g, 0.183 mole) is dissolved in 500 ml of dimethylsulfoxide and 11.2 g (0.23 mole) of sodium cyanide added. This is stirred at 25° for 1 hour, and then poured into cold water. Extraction with ether, washing the extract with water, drying and concentration gives 6-cyanomethyl-5,8-difluoro-1,4-benzodioxane.
Reaction SMILES: [C:1]([C:4]1[C:9]([OH:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([OH:13])[C:5]=1[CH3:14])(=[O:3])[CH3:2].[CH3:15][O:16][CH2:17][C:18](=O)[CH3:19].N1CCCC1>C1(C)C=CC=CC=1>[OH:13][C:6]1[C:5]([CH3:14])=[C:4]2[C:9](=[C:8]([CH3:11])[C:7]=1[CH3:12])[O:10][C:18]([CH2:17][O:16][CH3:15])([CH3:19])[CH2:2][C:1]2=[O:3]
Reactant: COCC(C)=O
Reactant: CC(=O)c1c(C)c(O)c(C)c(C)c1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COCC1(C)CC(=O)c2c(C)c(O)c(C)c(C)c2O1
Yield: 37 %

Procedure:
3.00 g (15.6 mmoles) of acetyl-trimethylhydroquinone, 1.58 g (18 mmoles) of methoxyacetone and 250 g (30 mmoles) of pyrrolidine were reacted in toluene solution by a method similar to that of Example 1 to give the above product, which was obtained as an oil. Boiling point: 250°-270° C. (bulb tube); yield: 37%.
Reaction SMILES: [F:1]/[C:2](/[CH2:13]Br)=[CH:3]/[CH2:4][NH:5]C(=O)OC(C)(C)C.[OH:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])=[CH:18][C:17]=1[Cl:31]>>[ClH:31].[NH2:5][CH2:4]/[CH:3]=[C:2](/[F:1])\[CH2:13][O:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])=[CH:18][C:17]=1[Cl:31]
Reactant: O=C(NC1CCCCC1)c1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NC/C=C(/F)CBr
Product: Cl
Product: NC/C=C(/F)COc1ccc(C(=O)NC2CCCCC2)cc1Cl

Procedure:
(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-3-chloro-N-cyclohexyl-benzamide hydrochloride was synthesized from (E)-tert-butyl 3-fluoro-4-bromobut-2-enylcarbamate and 4-hydroxy-3-chloro-N-cyclohexylbenzamide.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:24])=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NCc1ccccn1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCc3ccccn3)cn2)CC1
Yield: 70 %

Procedure:
By the same procedure as described in the example 73, synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-(aminomethyl)pyridine. And then, the product was chromatographed on column (hexane/methylene chloride/ethyl acetate=2/1/1, v/v/v) and crystallized with ether to give a desired compound.