Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].CO.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccc(C=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccc(CO)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Yield: 45.2 %

Procedure:
To a mixture of 2-benzyl-6-chloro-4-(4-formylphenyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (66 mg), methanol (1.0 ml) and THF (1.0 ml) was added sodium borohydride (6 mg) at 0° C. with stirring, and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC to give the title compound (30 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](I)=[N:11][CH:10]=1.[CH2:34]([O:36][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH2:38])[CH3:35].[F-].[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:34]([O:36][CH2:37][CH3:38])=[CH2:35])=[N:11][CH:10]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
A solution of 1.00 g (1.73 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) and 0.61 ml (1.8 mmol) 1-ethoxyvinyltri-n-butyltin in 5 ml toluene was deoxygenated by three freeze-thaw cycles. After addition of 61 mg (0.087 mmol) bis(triphenylphosphine)palladium(II) chloride the reaction mixture was heated at reflux for 16 h. The mixture was cooled to room temperature, treated with 500 mg (2.25 mmol) potassium fluoride on aluminum oxide (5.5 mmol fluoride/g) and stirred for 15 min. After filtration and washing with toluene the filtrate was concentrated. Column chromatography afforded 592 mg (66%) of the title compound as a light yellow foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17]([C:19]12[CH2:26][C:23]([CH2:27][OH:28])([CH2:24][CH2:25]1)[CH2:22][CH2:21][CH2:20]2)=O>[OH-].[Na+].CO>[OH:28][CH2:27][C:23]12[CH2:26][C:19]([C:17]3[NH:16][C:3]4[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=4[N:1]=3)([CH2:25][CH2:24]1)[CH2:20][CH2:21][CH2:22]2
Reactant: CCCn1c(N)c(NC(=O)C23CCCC(CO)(CC2)C3)c(=O)n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CO)(CC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Yield: 40.3 %

Procedure:
A solution of 5-hydroxymethyl-bicyclo[3.2.1]octane-1-carboxylic acid (6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.51 mmol, 0.20 g) in 20% NaOH (2.0 ml) and MeOH (10.0 ml) was stirred and refluxed overnight. The reaction was cooled to room temperature and then concentrated to remove MeOH. The aqueous was acidified (pH 2-3) with cone. HCl and then extracted with EtOAc. The combined EtOAc extracts were washed with saturated NaHCO3, H2O and brine, and dried (MgSO4). Filtration and evaporation followed by flash chromatography eluting with 3:2 EtOAc/CH2Cl2 provided title compound (0.077 g, 40%) as an oil. 13C NMR (100 MHz, CDCl3): 11.53 (q), 11.74 (q), 20.26 (t), 21.71 (t), 31.62 (t), 34.15 (t), 37.29 (t), 43.49 (s), 45.54 (t), 45.67 (t), 46.14 (t), 46.90 (t), 70.51 (t), 71.11 (s), 107.03 (s), 149.25 (s), 151.54 (s), 155.88 (s), 162.58 (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]([OH:16])=O)=[CH:6]2.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>C(Cl)Cl.O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]([NH:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])=[O:16])=[CH:6]2
Reactant: COC(=O)c1ccccc1N
Reactant: COc1cc2c(cc1OC)CC(C(=O)O)=C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccccc1NC(=O)C1=Cc2cc(OC)c(OC)cc2C1
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a stirred mixture of 5,6-dimethoxy-1H-indene-2-carboxylic acid (230 mg, 1.05 mmol) and DMF (20 μL) in DCM (10 mL) was added oxalyl chloride (267 mg, 2.10 mmol) dropwise at room temperature. The resulting mixture was stirred for 2 hours then concentrated and dried under high vacuum. The resulting acid chloride was then taken up into DCM (10 mL) and added dropwise to a stirred mixture of methyl 2-aminobenzoate (174 mg, 1.16 mmol) and triethylamine (159.1 mg, 1.58 mmol) in DCM (10 mL) 0° C. The mixture was then stirred overnight at room temperature before adding water and extracting with DCM. The organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography with petroleum ether/ethyl acetate 5:1 (v:v) as eluent to give methyl 2-(5,6-dimethoxy-1H-indene-2-carboxamido)benzoate (140 mg, 38%). LC-MS (ES-API); rt 9.35 min; m/z calculated for C20H19NO5 [M+H]+ 354.1, found 354.1.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C@@H:6]([OH:8])[CH3:7].CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:7][C@H:6]([O:8][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: CC(C)=CCC[C@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC[C@H](C)OS(C)(=O)=O
Temperature: 5 °C
Yield: 75.7 %

Procedure:
(S)-6-Methyl-hept-5-en-2-ol (2.64 g, 20.58 mmol) and DIEA (6.45 mL, 37.0 mmol) were dissolved in anhydrous DCM (28 mL), the reaction mixture was cooled to 5° C., mesyl chloride (1.91 mL, 24.7 mmol) was added dropwise, and the reaction mixture was allowed to slowly warm to RT. After 18 h at RT the reaction mixture was diluted with DCM (100 mL), washed with water (3×35 mL), brine (35 mL), dried with MgSO4, solvent was concentrated to give a dark oil which was purified by SiO2 flash chromatography using Hexane-EtOAc to give the title compound as an oil (3.213 g, 76%). TLC, Hexane-DCM-EtOAc, 40:40:20, 2 Rf 0.70 (developed with KMnO4 stain). H1 NMR (CDCl3): • 5.08 (m, 1H), 4.80 (m, 1H), 2.99 (s, 3H), 2.10 (m, 2H), 1.75 (m, 1H), 1.69 (s, 3H), 1.62 (m, 1H), 1.61 (s, 3H), 1.43 (d, 3H, J=6.5 Hz).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][C:10]1([CH3:23])[C:14]([CH3:15])=[CH:13][CH2:12][CH:11]1[C:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH:17]=1>CS(C)=O.C(OCC)C>[CH3:9][C:10]1([CH3:23])[C:14]([CH3:15])=[CH:13][CH2:12][CH:11]1[C:16]1[CH2:21][CH2:20][C:19]2([O:22][CH2:2]2)[CH2:18][CH:17]=1
Reactant: CC1=CCC(C2=CCC(=O)CC2)C1(C)C
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC1=CCC(C2=CCC3(CC2)CO3)C1(C)C
Reaction time: 0.5 h

Procedure:
Trimethylsulfoxonium iodide (4.78 g, 21.63 mmol.) is added in portions to a suspension of sodium hydride (60% in mineral oil, 1.00 g, 25.54 mmol.) in DMSO (10 ml). Stirring is carried out for 30 minutes before 4-(2,2,3-trimethyl-cyclopent-3-enyl)-cyclohex-3-enone (XIII, see U.S. Pat. No. 5,189,013, 2.78 g, 13.64 mmol.), dissolved in DMSO (10 ml), is added. When the addition is complete, stirring is continued for a further 30 minutes, and then the reaction solution is poured onto ice (25 ml). The mixture is diluted with diethyl ether (50 ml), the phases are separated, and the aqueous phase is extracted three times with diethyl ether (50 ml each time). The combined organic phases are washed once with saturated NaCl solution before being dried over Na2SO4, filtered off and concentrated in a rotary evaporator. 3.08 g of crude product are obtained, which is then purified by flash chromatography (cyclohexane/EtOAc=20:1, Rf=0.22). 2.21 g of a colourless oil are obtained.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[N:32]=[C:33]([C:36]4[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=4[F:43])[S:34][CH:35]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[NH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:13]2[C:12]([NH:28][C:29]([C:31]3[N:32]=[C:33]([C:36]4[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=4[F:42])[S:34][CH:35]=3)=[O:30])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1csc(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (4.0 mg, 0.0065 mmol) was mixed with MeOH (77 μL), THF (39 μL) and 1.0 M NaOH (42 μL, 0.042 mmol). The reaction mixture was stirred at room temperature for 30 min. The organic solvents were removed under reduced pressure. The resulting aqueous solution was diluted with aq. NH4Cl and extracted twice with EtOAc. The combined organic layers were dried, filtered and concentrated to give an intermediate. The intermediate was dissolved in a mixture of DCM (0.066 mL) and TFA (0.066 mL, 0.86 mmol). The resulting solution was stirred at room temperature for 30 min., then concentrated under reduced pressure. The residue was diluted with MeOH, neutralized with NH4OH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give two diastereoisomers of the title compound as white powders.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:17][O:18]C(=O)C(C)C)[CH2:10][O:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14]>C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([CH2:10][O:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])[CH2:17][OH:18]
Reactant: CC(C)C(=O)OCC(O)(COC(=O)C(C)C)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Product: CC(C)C(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Yield: 94.8 %

Procedure:
A 200 ml reaction vessel was charged with 2 g of 2-(2,4-difluorophenyl)-1,3-diisobutyryloxy-2-propanol, 100 mg of Lipase D made by Amano Pharmaceutical Co., Ltd. (derived from Rhizopus delemer, Enzyme No. 6), 90 ml of 50 mM acetate buffer (pH 5) and 10 ml of cyclohexame The resulting mixture was stirred at 30° C. to react for 18 hours. After the reaction liquid was extracted three times with 50 ml of ethyl acetate, the organic layers were combined and the combined organic layer was washed with saturated aqueous solution with sodium bicarbonate and with saturated aqueous solution with sodium chloride and further dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by means of column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2) to give 1.51 g of oily (R)-2-(2,4-difluorophenyl)-3-isobutyryloxy-1,2-propanediol. An optical purity thereof was determined in the same manner as Example 35.
Reaction SMILES: OC1C=CC=CN=1.[Cl:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]([C:15]2[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:17][NH:18][C:19]=2[C:20]([O:22]CC)=O)=[O:14])=[C:11]([NH2:32])[CH:10]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:31]=[CH:30][C:12]2[C:13](=[O:14])[C:15]3[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:17][NH:18][C:19]=3[C:20](=[O:22])[NH:32][C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(=O)c1ccc(Cl)cc1N
Agent: Oc1ccccn1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 171.5 °C
Yield: 37.7 %

Procedure:
To a solution of 2-hydroxypyridine (1.30 g, 13.69 mmol) in toluene (400 mL) was added diethyl 4-(4-chloro-2-amino-benzoyl)-1H-pyrazole-3,5-dicarboxylate (5 g, 13.69 mmol). The mixture was refluxed for 2 days and then the solvent was distilled off and the residual solid was heated at 171-172° C. for 4 days. The solid was allowed to cool and was continuously chromatographed eluting for 2 hours with dichloromethane to remove starting material. The remaining material on the column was eluted with chloroform:2-propanol (97:3) for 4 days. After each day the solvent in the receiving flask was replaced with fresh solvent. Filtering the solvent from the first two receiving flasks gave the title compound as a white solid (1.65 g, 38%, mp 290° C.). Alternatively, the title compound can preferably be removed from the column by elution with ethanol/chloroform (7:93).
Reaction SMILES: [Si]([O:18][C:19]1[CH:64]=[CH:63][C:22]([O:23][CH2:24][C@@H:25]([OH:62])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([CH:43]4[CH2:48][CH2:47][N:46]([C:49]([NH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:50])[CH2:45][CH2:44]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:52]([NH:51][C:49]([N:46]1[CH2:47][CH2:48][CH:43]([C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:62])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:64][CH:63]=4)=[CH:61][CH:60]=3)[CH2:40][CH2:39]2)=[O:42])[CH2:44][CH2:45]1)=[O:50])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1
Yield: 16.7 %

Procedure:
4-({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}carbonyl)-N-octyl-1-piperidinecarboxamide (0.160 g, 0.180 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.02 g, 0.03 mmol).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12]C[C@@H:10]1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>O1CCCC1>[CH2:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:10]1[NH:15][CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCCC[C@@H]1OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCN[C@H]1CCC[C@@H]1OCc1ccccc1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To a solution of (1S,2S)-2-benzyloxycyclohexylamine (1.0 g, 5.2 mmol) in tetrahydrofuran (12 mL) was slowly added 1,3-propanesultone (601 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in the vacuum oven (50° C.), affording the title compound (1.15 g, 75%). 1H NMR (D2O, 500 MHz) δ ppm 7.34 (m, 5H), 4.62 (d, 1H, J=11.2 Hz), 4.42 (d, 1H, J=11.2 Hz), 3.40 (m, 1H), 2.97 (m, 2H), 2.90 (m, 1H), 2.76 (t, 2H, J=6.5 Hz), 2.26 (m, 1H), 1.92 (m, 3H), 1.66 (m, 2H), 1.18 (m, 4H). 13C NMR (D2O, 125 MHz) δ ppm 137.22, 129.34, 129.11, 128.84, 76.74, 70.26, 60.84, 48.02, 42.74, 29.49, 26.43, 23.57, 23.02, 21.53. [α]D=+74.8° (c=0.00207 in water). ES-MS 326 (M−1).
Reaction SMILES: O[C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][C@@H:2]([CH3:21])[CH2:3][C@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
1.8 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile obtained in the above Example 1 was dissolved in 36 ml of carbon tetrachloride. 3.0 g of triphenylphosphine was added thereto and the obtained mixture was stirred under reflux for five hours. After distilling off the solvent, the residue was extracted with n-hexane and desolvated. The obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and diethyl ether (9:1) as a developing solvent. Thus, 1.50 g of (S ,S) -4-[4'-(3"-chloro-1"-methylbutoxy)phenyl]benzonitrile was obtained.
Reaction SMILES: C(O[C:4]1[N:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17](OC)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)C.[CH3:21][N:22](C)C1N=CC(C2SC3C=C(O)C=CC=3N=2)=CN=1.C([O-])(O)=O.[Na+]>>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([NH:22][CH3:21])=[N:9][CH:8]=1
Reactant: CN(C)c1ncc(-c2nc3ccc(O)cc3s2)cn1
Reactant: CCOc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1ccc(-c2nc3ccccc3s2)cn1

Procedure:
2-(6-Ethoxypyridin-3-yl)-6-methoxy-1,3-benzothiazole (23 mg, 80 μmol) was reacted according to the procedure used for the preparation of 2-[2-(dimethylamino)pyrimidin-5-yl]-1,3-benzothiazol-6-ol, with the following exceptions: The reaction mixture was allowed to reach rt on. sat. aq. NaHCO3 was added and the mixture was extracted with EtOAc. The organic phase was dried and concentrated under reduced pressure. Preparative HPLC of the residue gave the title compound (4 mg). 1H NMR (CHLOROFORM-d: CD3OD) δ 8.69 (d, 1 H) 8.20 (dd, 1 H) 7.79 (d, 1 H) 7.29 (d, 1 H) 6.99 (dd, 1 H) 6.86 (d, 1H) 4.39 (q, 2 H) 1.41 (t, 3 H); MS m/z (M+H) 273.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[CH2:28][CH2:27]1)#[N:25].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN(C)C(=O)C>[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]3[CH:10]=[CH:11][C:12]4[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]5[CH2:22][CH2:23]5)=[O:20])[N:17]=4)[N:14]=3)[CH:3]=2)=[O:33])[CH2:27][CH2:28]1)#[N:25]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Sc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CC1
Yield: 80.1 %

Procedure:
Using N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (130 mg, 0.399 mmol), 3-(1-cyanocyclopropyl)benzoic acid (89 mg, 0.479 mmol), oxalyl chloride (70 μL, 0.799 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as starting materials and in the same manner as in Example 412, the title compound (158 mg, 80%) was obtained as a pale-brown powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=O)(C)(C)C.[ClH:30]>ClCCl.C(OCC)(=O)C>[ClH:30].[ClH:30].[ClH:30].[CH3:29][N:27]([C:24]1[CH:23]=[CH:22][C:21]([C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:26][CH:25]=1)[CH3:28]
Reactant: CN(C)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)c1ccc([C@H]2CNCCN2)cc1
Reaction time: 8.5 h
Yield: 96 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-(N,N-dimethylamino) phenyl)piperazine (556 mg, 1.37 mmol) in dichloromethane (4 mL) was added 4 N hydrogen chloride in ethyl acetate (4 mL). After stirring for 8.5 h, the white precipitate was collected and dried in vacuo to afford (S)-2-(4-(N,N-dimethylamino) phenyl)piperazine trihydrochloride (413 mg, 96%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH:14]([CH3:17])[CH:15]=C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[O+][O-].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH:14]([CH3:17])[CH2:15][OH:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=[O+][O-]
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(CO)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
A solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1-methylallyl)piperidine-1-carboxylic acid 1-tert-butyl ester (25.5 g) in chloroform/methanol (250 ml/250 ml) cooled to −78° C. was flowed ozone air for 30 minutes. To the reaction mixture was added sodium borohydride (7.5 g) in small batches, and the mixture was warmed to room temperature. To the mixture was added 5% aqueous sodium bicarbonate solution (250 ml), and the mixture was extracted with chloroform (125 ml). The separated aqueous layer was extracted with chloroform (125 ml) again. The combined organic layer was sequentially washed with a mixed aqueous solution of sodium bicarbonate/sodium thiosulfate (12.5 g/25.0 g, 275 ml), water (125 ml) and 10% aqueous sodium chloride solution (125 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 2/3) to give the titled compound (21.9 g).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: BrCCc1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc2c(c1)CCO2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3--see Preparation 3), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.242 g--see Preparation 20), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (30 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.26 g.