Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9](OCC)=[O:10])[N:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][OH:10])[N:3]=1
Reactant: CCOC(=O)Cc1cccc(Cl)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCCc1cccc(Cl)n1
Temperature: 25 °C

Procedure:
Ester 30-1 (1.34 g, 6.7 mmol) was dissolved in 10 mL CH2Cl2 at -78°, DIBAL (1M in CH2Cl2, 17 mL, 17 mmol) was added, the mixture was warmed to RT for 15 min before quenching in a mixture of 25 mL saturated aqueous Na-K tartrate and 100 mL EtOAc. This mixture was shaken vigorously. The phases were allowed to separate, and the organic layer was washed with brine, dried (MgSO4), concentrated and chromatographed (silica, 40% EtOAc/hexane), providing 30-2 as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.O1CCCC1.C([Li])CCC.[CH3:27][N:28]1[CH2:33][CH2:32]C(=O)[CH2:30][CH2:29]1>CCCCCC.O>[CH3:27][N:28]1[CH2:33][CH2:32][C:1]2([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:2]2)[CH2:30][CH2:29]1
Reactant: COC(c1ccccc1)c1ccccc1Br
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CN1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (-60°) stirred solution of 2-bromobenzhydryl methyl ether in 38 ml. of tetrahydrofuran and 14 ml. of hexane is slowly added 53 ml. of 2.1 M n-butyllithium in hexane. After 2 hours, a solution of 10.7 g. of 1-methyl-4-piperidone in 15 ml. of tetrahydrofuran is added dropwise, and the suspension is stirred at -60° for 3 hours and at room temperature for 15 hours. Ice and water are added and the mixture is extracted with chloroform. The chloroform solution is dried over sodium sulfate and concentrated to a mixture of 4-hydroxy-4-(α-methoxy-α-phenyl-2-tolyl)-1-methylpiperidine and benzhydrol methyl ether. This oil is heated under reflux for 30 minutes if 240 ml. of acetic acid containing 60 ml. of hydrochloric acid. Dilution with water and addition of excess sodium hydroxide effects precipitation of a solid. Recrystallization from hexane provides 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], m.p. 123°-124°.
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[C:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:18].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][C:17]#[N:18])=[CH:21][CH:22]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Reaction time: 8 h

Procedure:
A suspension composed of 1.15 g (4.77 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c]-[1,2,4]benzothiadiazin-7-ol 5,5-dioxide, 1.00 g (6.21 mmol) of [4-(cyanomethyl)phenyl]-boronic acid, 1.3 g (7.15 mmol) of copper(II) acetate, 1.16 ml (14.31 mmol) of pyridine and about 500 mg of 4 Å molecular sieve in 200 ml of methylene chloride is stirred overnight. The reaction mixture is diluted by adding a further 100 ml of methylene chloride and the suspension is filtered. The filtrate is concentrated and then directly placed on a silica column which is eluted with a methylene chloride/methanol 99/1 system. The fractions containing the expected product are combined and evaporated, and the residue is taken up in a small amount of ethyl ether. After filtering off the solid, the title product is obtained in the form of beige powder.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[C:12](Cl)[N:11]=1>CCOC(C)=O>[Cl:9][C:10]1[N:11]=[C:12]([NH:7][C@H:4]2[CH2:5][CH2:6][C@H:1]([NH2:8])[CH2:2][CH2:3]2)[CH:13]=[C:14]([I:16])[CH:15]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1cc(I)cc(Cl)n1
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of trans-cyclohexane-1,4-diamine (2.085 g, 18.26 mmol) and 2,6-dichloro-4-iodopyridine (1.000 g, 3.65 mmol) was heated in a capped vial at 120° C. After 5 hours, the reaction mixture was cooled. The solids were stirred in EtOAc for 30 minutes, and the suspension was filtered. The filtrate was diluted with EtOAc and washed with 20% brine and NaHCO3. The organic layer was dried and concentrated to give 1.20 g of the title compound. The crude product was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[Cl:12][C:13]([Cl:23])([Cl:22])[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCCC1.C(O)(=O)CCCCC>C1(C)C=CC=CC=1>[Cl:12][C:13]([Cl:22])([Cl:23])[C:14](=[O:21])[C:15](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCCCCC(=O)O
Product: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)C(Cl)(Cl)Cl
Yield: 28.9 %

Procedure:
3-Nitrobenzaldehyde (7.55 g, 50 mmoles), ethyl 4,4,4-trichloro-3-oxobutanoate (18.33 g, 59.5 mmoles), piperidine (0.66 ml) and hexanoic acid (0.33 ml) were heated at reflux in toluene (130 ml) for 48 hours using a Dean and Stark apparatus. The mixture was cooled, evaporated to dryness in vacuo and crystallised by trituration with ethyl acetate/petroleum ether (60°-80°). Recrystallisation from 2-propanol gave the sub-title compound (5.3 g) mp 105.5°-7°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(O)(O)[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.[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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3cccnc3)cn2)CC1

Procedure:
To a degassed solution of 4-(5-bromo-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 2.44 mmol, 1.0 equiv) in dimethoxyethane (10 mL) was added pyridyl-3-boronic acid (0.60 g, 4.87 mmol, 2.0 equiv; commercially available), tetrakis(triphenylphosphine) palladium(0) (84.6 mg, 0.07 mmol, 0.03 equiv) and an aqueous solution of 2 M sodium carbonate (5.6 mL) and the reaction mixture heated by microwave irradiation under Ar to 130° C. for 30 min. The crude reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases washed with a sat. solution of sodium chloride (2×50 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol providing 0.68 g (76%) of the title compound. MS (ISP): 356.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:6]=1)=[O:4].[OH-].[Li+]>O1CCOCC1>[Cl:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:8]=1[O:11][CH3:12]
Reactant: COC(=O)c1nn(-c2ccccc2F)c(OC)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1c(Cl)c(C(=O)O)nn1-c1ccccc1F
Temperature: 56 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The crude 4-chloro-1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid methyl ester obtained (330 mg, 1.16 mmol) obtained in step 1 was dissolved in 6 ml of dioxane and 5.8 ml of an aqueous 1 M solution of lithium hydroxide were added. The mixture was stirred for 30 min at 56° C. Acidic aqueous work-up gave 320 mg (100%) of the title compound.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([CH2:15][C:16]2([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:4]1)=O.Cl.[CH2:33]([C:35]1[C:43]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[C:38]2[CH2:39][CH2:40][CH2:41][CH2:42][N:37]2[N:36]=1)[CH3:34]>>[CH2:33]([C:35]1[C:43]([CH:44]2[CH2:45][CH2:46][N:47]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[CH2:6][N:5]([CH2:15][C:16]4([C:22]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:4]3)[CH2:48][CH2:49]2)=[C:38]2[CH2:39][CH2:40][CH2:41][CH2:42][N:37]2[N:36]=1)[CH3:34]
Reactant: O=C[C@H]1CN(CC2(C(=O)OCc3ccccc3)CCCCC2)C[C@@H]1c1cccc(F)c1
Reactant: CCc1nn2c(c1C1CCNCC1)CCCC2
Agent: Cl
Product: CCc1nn2c(c1C1CCN(C[C@H]3CN(CC4(C(=O)OCc5ccccc5)CCCCC4)C[C@@H]3c3cccc(F)c3)CC1)CCCC2

Procedure:
The title compound was prepared from 1-{[(3R,4S)-3-formyl-4-(3-fluorophenyl)pyrrolidin-1-yl]methyl}cyclohexanecarboxylic acid, benzyl ester (from Step C) and 4-(2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-piperidine, hydrochloride salt (Prepared as Piperidine 9 above) using a procedure analogous to that described in Example 1, Step D. 1H NMR (500 MHz, CDCl3) δ 1.22 (t, 3H, J=7.6 Hz), 1.23–1.50 (m, 6H), 1.50–1.70 (br m, 5H), 1.70–2.00 (m, 8H), 2.17 (br d, 2H, J=12.3 Hz), 2.20–2.40 (m, 5H), 2.57 (q, 2H, J=7.3), 2.61–2.96 (m, 9H), 4.07 (t, 2H, J=6.0 Hz), 5.16 (m, 2H), 6.85 (dt, 1H, J=1.8, 8.5 Hz), 7.02–7.10 (m, 2H), 7.20 (q, 1H, J=6.5 Hz), 7.25–7.40 (m, 5H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15](=[O:31])[NH:16][C@H:17]([C:25](=[O:30])N(OC)C)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][C:15](=[O:31])[NH:16][C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:25]=[O:30])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Lithium aluminum hydride (0.95 mL of a 1.0 M solution in THF, 0.95 mmoles) was added to a room temperature solution of [(S)-1-(Methoxy-methyl-carbamoyl)-2-phenyl-ethyl]-carbamic acid benzyl ester (0.30 g, 0.86 mmoles) in THF (10 mL). The resulting mixture was stirred at room temperature for 2 h, then was quenched by dilution with EtOAc (200 mL), and washed with 1% aqueous HCl (200 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was repeatedly diluted with CH3CN (2×200 mL) and concentrated in vacuo to give 0.24 g (approximately quantitative yield) of ((S)-1-Benzyl-2-oxo-ethyl)-carbamic acid benzyl ester as a colorless oil, which was carried on without further purification: ES+ LC/MS m/e 284 (M+H), RT=4.75 min.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:28])=[N:25][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN
Reactant: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)nc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)nc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a mixture of 5-{[cyclohexyl(2-methyl-5-phenylthiophen-3-yl)methyl]amino}pyridine-2-carboxylic acid (386 mg) synthesized above, ethyl β-alaninate hydrochloride (218 mg), 1-hydroxybenzotriazole monohydrate (218 mg), triethylamine (397 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (272 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30-50% ethyl acetate/hexane) to give a white solid. To a mixture of the obtained solid, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (311 mg, 69%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C@@H:18]([N:20]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C:9](=[O:38])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C@@H:18]([N:20]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:21][CH2:22][OH:23])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CCC/C=C\CCCC(=O)OCc1ccccc1)N(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](CCC/C=C\CCCC(=O)OCc1ccccc1)N(CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a stirred solution of (5Z,10S)-(−)-N-tert-butoxycarbonyl-N-[2-tert-butyldimethylsilyloxyethyl]-10-amino-5-undecenoic acid benzyl ester (8) (100 mg, 0.18 mmol) in 1 mL of THF was added 0.2 mL of a 1M THF solution of tetrabutylammonium fluoride. The mixture was stirred at rt for 16 h, then concentrated, and purified by flash chromatography (11 mm×6″ column, eluted with 20% v/v EtOAc/hexane) yielding 76 mg of the title compound (9) as a colorless oil (0.17 mmol, 97% yield). 1H NMR (conformeric mixture, 500 MHz, C6D6): δ7.23-7.20 (m, 1H, ArH), 7.13-6.98 (m, 4H, ArH), 5.39-5.33 (m, 1H, RCH═CHR′), 5.32-5.26 (m, 1H, RCH═CHR′), 5.01 (s, 2H, ArCH2O2CR), 3.85-3.78 (m, 0.5H, NCHCH3), 3.76-3.50 (m, 2.5H, NCHCH3 and OCH2CH2N), 3.21-3.00 (m, 2H, OCH2CH2N), 2.15 (t, J=7.3 Hz, 2H, RO2CCH2), 2.01-1.90 (m, 4H, CH2CH═CHCH2), 1.63 (p, J=7.3 Hz, 2H, RO2CCH2CH2), 1.42 (s, 9H, Boc), 1.31-1.20 (m, 3H, CHaHbCH2CHN), 1.16-1.05 (m, 1H, CHaHbCH2CHN), 0.93-0.82 (m, 3H NCHCH3).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH:22][CH3:23])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:22]([CH3:23])[S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(NC)nc3C)c(C)nc12
Solvent: CCN(CC)CC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)S(=O)(=O)CC)nc3C)c(C)nc12
Yield: 75 %

Procedure:
The title compound is prepared by a procedure analogous to Example 178. employing 50 mg of N-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methylamine (0.15 mmol), 51 mg of triethylamine (0.5 mmol) and 39 mg of ethanesulfonylchloride (0.3 mmol). 48.9 mg, Yield 75%: mass spectrum (m/e): 436 (M+1); 1H-NMR (CDCl3): 6.73 (s, 1H), 3.62 (s, 3H), 3.42 (q, 2H, J=7.4 Hz), 3.35 (m, 1H), 2.55 (s, 3H), 2.48 (s, 3H), 2.28 (s, 3H), 1.85 (m, 4H), 1.46 (t, 3H, J=7.4 Hz), 0.90 (t, 6H, J=7.5 Hz).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:44][CH2:45][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:47][CH2:48]2)=[CH:39][CH:38]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCCC12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc2N2CCCCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.43 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (103 mg, 0.41 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (95.0 mg, 0.41 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was cooled to room temperature and purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield the title compound (57.3 mg, 32%) as a white solid. 1H NMR (DMSO-d6) δ: 13.44 (br. s., 1H), 10.82 (s, 1H), 9.52 (br. s., 1H), 7.84 (d, J=2.0 Hz, 1H), 7.36-7.42 (m, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H), 4.58 (d, J=13.1 Hz, 1H), 4.21 (d, J=4.5 Hz, 2H), 3.97 (dd, J=11.6, 2.8 Hz, 1H), 3.46 (d, J=11.6 Hz, 2H), 2.96-3.07 (m, 2H), 2.79-2.85 (m, 1H), 2.67 (td, J=12.8, 2.7 Hz, 1H), 2.06-2.10 (m, 1H), 1.95-2.02 (m, 2H), 1.72-1.91 (m, 3H), 1.64-1.67 (m, 1H), 1.33-1.58 (m, 3H). [M+H] calc'd for C23H27ClN4O, 411; found, 411.
Reaction SMILES: C([O-])(=O)C.[NH4+].[F:6][C:7]1[CH:8]=[C:9]([C:17]2[C:25]3[CH2:24][CH2:23][C:22](=O)[C:21]=3[CH:20]=[N:19][CH:18]=2)[CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14].C([BH3-])#[N:28].[Na+]>CO.C(O)C>[F:6][C:7]1[CH:8]=[C:9]([C:17]2[C:25]3[CH2:24][CH2:23][CH:22]([NH2:28])[C:21]=3[CH:20]=[N:19][CH:18]=2)[CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: O=C1CCc2c1cncc2-c1ccc(C(F)(F)F)c(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ammonium acetate (117 mg, 1.52 mmol) in MeOH (1 mL) was treated with 4-(3-fluoro-4-trifluoromethyl-phenyl)-5,6-dihydro-[2]pyrindin-7-one (intermediate A-14 [C1]) (15 mg, 0.051 mmol) dissolved in ethanol (0.5 mL) and the reaction mixture stirred at room temperature for 1 h. Sodium cyanoborohydride (11.2 mg, 0.18 mmol) was added and stirring continued at room temperature. After 15 min, the reaction mixture was heated to reflux for 30 min. The solvent was removed under reduced pressure, a sat. aq. solution of ammonium chloride (2 mL) and a 1 M solution of HCl (1 mL) were added and the aq. phase washed with dichloromethane (3×5 mL). To the aq. phase was added a 1 M solution of NaOH (2 mL) and extracted with dichloromethane (3×5 mL). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The title compound was isolated as light brown solid (3.8 mg, 25%). MS: 297.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([OH:28])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:35](OS(OCC)(=O)=O)[CH3:36]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([O:28][CH2:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(-c2ccc(OCc3ccccc3)cc2)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a suspension of 5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazole 2.0 g and K2CO3 2.23 g in DMSO 20 ml was added diethylsulfate 1.24 g. After stirring at ambient temperature for 2 hours, the reaction was quenched by adding 28% aqueous ammonium hydroxide solution and ice. The mixture was partitioned between AcOEt and H2O. The organic layer was washed with H2O and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=40% and the solvent was evaporated in vacuo. The reisual solid was recrystallized from IPE to give 5-[4-(benzyloxy)phenyl]-3-ethoxy-1-(4-methoxy-phenyl)-1H-pyrazole 1.44 g as a powder.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](C(N)CCBr)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:21]([O:20][C:18](=[O:19])[NH:10][CH2:9][CH2:8][CH2:7][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Reactant: c1ccc(C2(c3cccs3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccc2)(c2cccs2)CC1
Yield: 20 %

Procedure:
A solution of 4-phenyl-4-(thiophen-2-yl)piperidine and 3-Boc-aminopropylbromide (1.0 g, 4.4 mmol) with 1 g of K2CO3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over Na2SO4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.43 g (1.1 mmol, 20% for two steps) of 3-(4-phenyl-4-(thiophene-2-yl)piperidin-1-yl)-propylcarbamic acid tert-butyl ester as colorless oil. The ester in 5 ml of CH2Cl2 was added with 1 ml of CF3CO2H and resulting solution was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO3. Concentration of the reaction mixture provided the desired product as an oil (0.29 g, 0.96 mmol, 88%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9](Cl)(=[O:11])[CH3:10]>C(OCC)(=O)C>[C:9]([N:3]1[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]1=[O:8])(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1NC(=O)OC1=O
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)OC(=O)[C@@H]1C
Reaction time: 2 h
Yield: 25 %

Procedure:
(S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of acetyl chloride (306 mg, 3.9 mmol) under ice cooling. Further, a solution of 4-dimethyl-aminopyridine (476 mg, 3.9 mmol) in ethyl acetate (15 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in ethyl acetate (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (118 mg, 25%) as a colorless clear syrup.