Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]([C@H:6]([C:8](O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C1(C)C=CC(S(OCCC#C)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[CH3:11])[CH2:4][C:6]#[CH:8]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: C[C@@H]1CCCN1
Agent: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC[C@H]1C
Temperature: 85 °C

Procedure:
To a sealed flask was added 2-(R)-methylpyrrolidine L-tartrate (21.1 g, 90 mmol), 3-butynyl p-toluenesulfonate (15.7 mL, 89 mmol), potassium carbonate powder (18.5 g, 134 mmol) and CH3CN (160 mL). The resulting mixture was heated to 85° C. for 24 hours and the reaction was monitored by GC for the complete consumption of the tosylate. The reaction mixture was cooled to room temperature and filtered; the wet cake was washed with CH3CN (40 mL). The combined filtrate was used in the next step without further processing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[O:16][C:15]([CH2:17][N:33]2[CH2:34][CH2:35][CH:30]([C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2Cl)o1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccc(C(F)(F)F)cc4Cl)o3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[2-chloro-4-(trifluoromethyl)phenyl]-2-furaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 505.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16](OC)=[O:17])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][OH:17])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2ccc(NCCO)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[N-glycyl]-1H-pyrazole-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide (0.14 g, 0.27 mmol) in tetrahydrofuran at −20° C. was added triethylamine (0.038 mL, 0.27 mmol) and ethyl chloroformate (0.026 mL, 0.27 mmol). This mixture was stirred for 30 min and then there was added sodium borohydride (20 mg, 0.54 mmol) in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h and then was quenched with 10% aq HCl. After diluting with ethyl acetate, the organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 35 mg (26%) of the title compound as a white powder. LRMS (ES+): 507.9 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][OH:10])=[O:8].[H-].[Na+].[CH2:13](I)[CH3:14]>C(O)C>[CH2:13]([O:10][N:9]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[OH:8])[CH3:14]
Reactant: CCI
Reactant: O=C(NO)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCON=C(O)c1ccccn1
Yield: 98.7 %

Procedure:
7 g (0.05 mol) of pyridine-2-hydroxamic acid and 1.4 g (0.05 mol) of sodium hydride were dissolved in 100 ml of ethanol, and 8 g (0.05 mol) of ethyl iodide was gradually dropwise added thereto with stirring. After the dropwise addition, the reaction solution was stirred for 2 hours under reflux condition. After completion of the reaction, the ethanol was distilled off under reduced pressure. To the residue were added suitable amounts of methylene chloride and water, whereby the desired product was extracted with the methylene chloride. The extract was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After the drying, the solvent was distilled off under reduced pressure to obtain 8.2 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.C(N)C.CN(C(ON1N=[N:32][C:27]2[CH:28]=CC=N[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:32][CH:27]([CH3:28])[CH3:26])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (250 mg, 1.03 mmol), ethanamine (0.2 mL 2.2 mmol) and HATU (456 mg, 1.2 mmol) in 20 mL of dry THF was stirred for 4 hours at room temperature. The reaction mixture was evaporated to dryness, the residue was suspended in 20 mL of 0.5 N HCl, product extracted with ethyl acetate (3×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. Residue purified by column chromatography (silica gel, 200-300 mesh, eluting with ethyl acetate/petroleum ether 2:1) to give 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 43%). LCMS: (M+H)+=269/271; 1H NMR (300 MHz, CD3OD): δ 12.95 (s, 1H), 8.50 (s, 1H), 8.43 (s, 1H), 7.77-7.72 (m, 1H), 3.42-3.36 (m, 2H), 1.25-1.12 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.C([O-])(O)=O.[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:7])[CH2:3]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2CC(=O)C2)cc1
Yield: 37 %

Procedure:
To a solution of 3-oxocyclobutanecarboxylic acid (20.0 g, 175.3 mmol) in DCM (500 mL) was added satd. aq. NaHCO3 (293 mL), tetrabutyl ammonium bromide (75.3 g, 227.9 mmol) and 4-methoxybenzyl chloride (33.0 g, 210.4 mmol) and the mixture was stirred at RT overnight. After the reaction was completed, the mixture was diluted with water and twice extracted with DCM (250 mL). The organic layer was washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (8:1) to afford 15.2 g (37%) of 4-methoxybenzyl 3-oxocyclobutanecarboxylate as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)C(=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[I:32]C1C=CN=CC=1N>>[I:32][C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[NH:2][CH3:1]
Reactant: Nc1cnccc1I
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CNc1cnccc1I

Procedure:
The title compound was prepared in analogy to example 25, intermediate b, from 4-iodo-pyridin-3-ylamine. Brown oil (22%) which was pure enough to be used in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:26]([O-:28])=[O:27])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:13][N:14]=1)=[O:8].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[N+:26]([C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:6]=1[C:7]([NH:9][C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:13][N:14]=1)=[O:8])([O-:28])=[O:27]
Reactant: O=C(Nc1ncc(-c2cccc(C(F)(F)F)c2)s1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(-c2cccc(C(F)(F)F)c2)s1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Yield: 76 %

Procedure:
To a solution of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide (2.6 g, 6.08 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) was added and piperidine (20 mL) and the resulting solution was stirred for 3 h at 100° C. in an oil bath. The mixture was diluted with 200 mL of ethyl acetate, washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and then concentrated under vacuum to give 2.2 g (76%) of product as a yellow solid.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH2:17])[CH2:14][CH2:15][NH2:16]>CO>[CH2:13]([NH:17][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][NH:16][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: NCCCN
Solvent: CO
Product: CCCCCCCCCC(O)CNCCCNCC(O)CCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-undecene oxide (104.6 g.) and 1,3-propanediamine (22.7 g.) and two recrystallizations of the resulting product from methanol gave N,N'-(1,3-propylene)-bis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = (CH2)3, Z = H) (29.0 g., m.p. 94.0°-103.0° C.).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]=[C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:22][C:23](OCC)=[O:24]>C1C=CC=CC=1>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:23](=[O:24])[CH2:22][C:21](=[O:20])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)C(c1ccc(NC(=O)CC(=O)c2ccccc2)c([N+](=O)[O-])c1)n1ccnc1
Yield: 44.8 %

Procedure:
A solution of 10 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrobenzenamine, 20 parts of ethyl β-oxobenzenepropanoate and 174 parts of benzene was stirred for 36 hours at reflux temperature. After cooling, the reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 7 parts (44.8%) of N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrophenyl]-β-oxobenzenepropanamide; mp. 106° C. (interm. 96).
Reaction SMILES: [CH:1](O)=O.[NH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[NH2:15])[CH:8]=[CH:7][CH:6]=1.N>O>[NH:4]1[C:5]2=[C:14]3[C:9](=[CH:8][CH:7]=[CH:6]2)[CH:10]=[CH:11][CH:12]=[C:13]3[N:15]=[CH:1]1
Reactant: O=CO
Reactant: Nc1cccc2cccc(N)c12
Agent: N
Solvent: O
Product: C1=Nc2cccc3cccc(c23)N1
Temperature: 100 °C

Procedure:
95.0 g of formic acid are added to 15.8 g of 1,8-diaminonaphthalene and the mixture is stirred at reflux temperature (100° C.) for 1 hour. Then 200 ml of water are added, and the mixture is cooled to 15-20° C. and adjusted to a pH of 8.5 by addition of 25% strength by weight ammonia. It is cooled to 10° C. and subsequently stirred at 10° C. for 1 hour. The product which is precipitated is isolated by filtration, washed with water and dried in vacuo at 800 C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:26]([CH2:27][N:28]2[CH2:48][CH2:47][C:31]3([O:36][CH2:35][CH2:34][N:33]([C:37]([C:39]4[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=4)=[O:38])[CH2:32]3)[CH2:30][CH2:29]2)=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17]>C(Cl)Cl>[F:8][C:9]1[C:26]([CH2:27][N:28]2[CH2:29][CH2:30][C:31]3([O:36][CH2:35][CH2:34][N:33]([C:37]([C:39]4[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=4)=[O:38])[CH2:32]3)[CH2:47][CH2:48]2)=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4F)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4F)CC3)C2)cs1
Reaction time: 2 h

Procedure:
TFA (10 mL) was cautiously added to a solution of tert-butyl 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate [Example 7, step c] (3.95 g) in DCM (40 mL). The resulting mixture was stirred for 2 h. The solvent was evaporated and the residue azeotroped twice with acetonitrile. The residue was dissolved in freshly distilled 2-methyltetrahydrofuran (100 mL) and washed 3 times with a mixture of brine and saturated sodium bicarbonate solution (10:1, 100 mL). The organic phase was dried over sodium sulphate, filtered and evaporated. The residue was azeotroped 3 times with isohexane to give the subtitled compound as a white foam. Yield 2.92 g.
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C@H:9]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[NH2:7][C@@:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])[C@H:9]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@]12CC1CN(C(=O)C(F)(F)F)[C@H]2c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@]12CC1CN(C(=O)C(F)(F)F)[C@H]2c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask containing the racemic Intermediate 53, one enatiomer being [(1S,2S)-2-phenyl-3-(2,2,2-trifluoro-acetyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester (4.3 g, 11.5 mmol) and methylene chloride (75 mL) was immersed in a 0° C. bath, trifluoroacetic acid (8.0 mL, 103 mmol) was added dropwise, and the reaction stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stir for 5 hours. The solvent was removed at reduced pressure and the material dried in vacuo to give the title compound as a trifluoroacetic acid salt. (quantitative yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Cl)[N:11]=[C:10]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Cl)[N:9]=1)=[O:6].CN(C=O)C.CC(C)([O-])C.[K+]>C(Cl)Cl>[N:7]1([C:8]2[N:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[N:11]=[C:10]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:27])[N:9]=2)[CH2:2][CH2:3][CH2:4][C:5]1=[O:6]
Reactant: O=C(CCCCl)Nc1nc(NC(=O)CCCCl)nc(NC(=O)CCCCl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCN1c1nc(N2CCCC2=O)nc(N2CCCC2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
400 mg of N,N',N"-tris(4-chlorobutyryl)melamine was placed in a flask equipped with a magnetic stirring bar, a reflux condenser, an argon inlet and a rubber septum. To the flask was added 6 ml DMF followed by 450 mg potassium tert-butoxide, while stirring the reaction mixture at room temperature for about 30 minutes. It was then diluted with CH2Cl2 and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was then purified by column chromatography (silica gel) to give 180 mg of pure 2,4,6-tris(pyrrolidin-2-on-1-yl)-1,3,5-triazine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[ClH:7].C([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH2:14]/[C:13]/1=[CH:31]\[C:32]1[N:36]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:35]=[N:34][N:33]=1)(=O)C>CO>[ClH:7].[CH:21]1([C:19](=[O:20])[CH:18]([N:15]2[CH2:16][CH2:17][CH:12]([SH:11])/[C:13](=[CH:31]/[C:32]3[N:36]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:35]=[N:34][N:33]=3)/[CH2:14]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:23][CH2:22]1
Reactant: COC(=O)Cn1nnnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cn1nnnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
Potassium carbonate (74 mg) was added to a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-tetrazol-5-yl]methylidene}piperidine hydrochloride (128 mg) in methanol (5 ml). After being stirred at room temperature for 15 minutes, the mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a residue, which was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024N hydrochloric acid, 30/70, v/v) to give (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-tetrazol-5-yl]methylidene}-4-sulfanylpiperidine hydrochloride (57 mg, gross yield: 49%, a part of this product had been hydrolyzed at the methyl ester moiety). This product (40 mg) was treated with hydrochloric acid in a similar manner to that described in Example 134, and the resulting product was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v) to afford the title compound (13 mg, yield: 34%) as a colourless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C([Li])CCC.[O:18]1CCC[CH2:19]1>>[Br:12][C:9]1[C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]=2[C:2]([CH:19]=[O:18])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(Br)c2cnccc12
Agent: [Li]CCCC
Product: O=Cc1ccc(Br)c2cnccc12
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 5,8-dibromoisoquinoline (4.0 g. 13.9 mmol) in tetrahydrofuran (120 mL) at −78° C. under nitrogen atmosphere was added dropwise a solution of n-butyllithium (2.3 M in hexane, 7.3 mL, 16.8 mmol). The reaction mixture turned dark. After stirring for 15 minutes, the reaction mixture was quenched by adding N,N-dimethylformamide (4.0 mL). After stirring at −78° C. for an additional 1 h, the reaction mixture was quenched with water, extracted with mixture of ethyl acetate/hexane (2:8), washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to afford the 8-bromo-5-isoquinolinecarboxaldehyde (0.10 g), followed by 5-bromo-8-isoquinolinecarboxaldehyde (1.0 g) as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(CCN2CCOCC2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, in DMF (1 mL) was added Cs2CO3 (110 mg, 0.33 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (31 mg, 0.166 mmol). The reaction mixture was stirred at 70° C. for 30 min under argon. After this time, the reaction mixture was diluted with water (5 mL). The resulting solution was extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) and saturated aqueous sodium chloride (2×5 mL). The organic layer was concentrated. The resultant crude material was purified by preparative HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(2-morpholinoethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (35 mg, 67%) as yellow solid. MS M+H=470; 1H NMR (CDCl3) δ 8.17 (1H, s), 7.28-7.34 (6H, m), 7.10 (2H, d, J=10.0 Hz), 4.44 (4H, t, J=5.0 Hz), 3.96-4.01 (4H), 3.50 (4H, t, J=5.0 Hz).
Reaction SMILES: O1[C@@:18]23[C@:19]4([CH3:28])[C:24](=[CH:25][CH2:26][C@@:2]12[C@H:3]1[C@:15]([CH3:29])([CH2:16][CH2:17]3)[C@@H:6]([C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5][CH2:4]1)[CH2:23][C@@H:22]([OH:27])[CH2:21][CH2:20]4.[C-]#N.C([Al+]CC)C>ClCCl>[CH3:13][CH:11]([CH2:10][CH2:9][CH2:8][C@H:7]([C@@H:6]1[C@:15]2([CH3:29])[C:3]([C:2]3[CH2:26][CH:25]=[C:24]4[C@:19]([C:18]=3[CH2:17][CH2:16]2)([CH3:28])[CH2:20][CH2:21][C@H:22]([OH:27])[CH2:23]4)=[CH:4][CH2:5]1)[CH3:14])[CH3:12]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@@H]2[C@]1(C)CC[C@@]13O[C@@]21CC=C1C[C@@H](O)CC[C@@]13C
Agent: CC[Al+]CC
Agent: [C-]#N
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)CC1=CC3
Temperature: 0 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
8α,9α-Epoxycholest-5-en-3β-ol (200mg) is dissolved in dichloromethane and the solution is cooled to 0° C. 1.5 ml of a diethylaluminumcyanide-solution (1 M in toluene) is added dropwise. After addition, the reaction mixture is warmed to room temperature and stirred for additional 18 hours. After basic work-up and column chromatography, cholesta-5,8,14-triene-3β-ol (51 mg) is isolated.
Reaction SMILES: [ClH:1].Cl.[C:3]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([OH:5])=[O:4].[CH:28]1(O)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:1].[CH:28]1([O:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:5])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: OC1CCCC1
Reactant: O=C(O)COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1
Agent: Cl
Product: O=C(COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1)OC1CCCC1

Procedure:
Prepared from 1-(4-carboxymethyloxyphenyl)-4-[2-(piperidin-4-yl)ethyl]piperazine dihydrochloride and cyclopentanol.
Reaction SMILES: [CH2:1]([C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[CH2:12][C:11]2[CH:17]=[C:18]([C:21](OC(C)(C)C)=[O:22])[CH:19]=[CH:20][C:10]=2[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH2:38][NH:39][CH3:40].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH2:1]([C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[CH2:12][C:11]2[CH:17]=[C:18]([C:21]([N:39]([CH3:40])[CH2:38][C:30]3[N:29]([CH3:28])[C:37]4[C:32]([CH:31]=3)=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:22])[CH:19]=[CH:20][C:10]=2[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2N[C@H](Cc2ccccc2)C1=O
Reactant: CNCc1cc2ccccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](Cc1ccccc1)N2
Yield: 99 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-benzyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.75 g, 2.1 mmole), 1-methyl-2-(methylaminomethyl)indole (0.34 g, 2.1 mmole), Et3N (0.59 mL, 4.2 mmole), HOBt H2O (0.28 g, 2.1 mmole), and EDC.HCl (0.41 g, 2.1 mmole), the title compound (0.97 g, 100%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 80-90% EtOAc/hexanes): MS (ES) m/e 467.1 (M+H)+.