Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:28])[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21](=O)[CH2:20]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24][C:19]([CH3:28])([CH3:18])[CH2:20]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)c(Cl)c1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(Br)cc2)c2ccc(O)c(Cl)c2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.2 %

Procedure:
To a stirred suspension of zinc powder (0.59 g, 8.99 mmol) in THF (20 mL) was slowly added TiCl4 (0.50 mL, 4.50 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-bromophenyl)(3-chloro-4-hydroxyphenyl)methanone (105) (0.35 g, 1.12 mmol) and 3,3,5,5-tetramethyl cyclohexanone (0.53 g, 3.37 mmol) in THF (6 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (20 mL). The reaction mixture was filtered through a pad of Celite and the pad washed with EtOAc (50 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (30:1) to give 0.38 g (78%) of 127 as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.91 (s, 6H), 0.93 (s, 6H), 1.29 (s, 2H), 1.92 (s, 2H), 1.95 (s, 2H), 5.42 (s, 1H), 6.88-6.98 (m, 2H), 7.01 (d, J=8.3 Hz, 2H), 7.08 (s, 1H), 7.39 (d, J=8.2 Hz, 2H). LCMS (ESI): m/z 431 (M−H)−.
Reaction SMILES: [CH3:1][Mg]I.[CH3:4][N:5]1[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]=2[N:9]=[CH:8][C:7]2=[CH:16][CH:17]=[CH:18][N:6]12>O1CCCC1>[CH3:4][N:5]1[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]=2[NH:9][CH:8]([CH3:1])[C:7]2=[CH:16][CH:17]=[CH:18][N:6]12
Reactant: CN1c2ccncc2N=Cc2cccn21
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC1Nc2cnccc2N(C)n2cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To 8.4 ml of a solution of methyl magnesium iodide (3.2M in diethyl ether, diluted with 10 ml tetrahydrofuran) was added a solution of 4.1 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 70 ml of tetrahydrofuran. After stirring at ambient temperature for 20 hours, the reaction mixture was quenched into 200 ml of an iced ammonium chloride solution and extracted with ethyl acetate (2×). The combined organics were washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The crude product was preadsorbed on silica (230-400 mesh) and flash chromatographed (elution with diethyl ether) to afford a solid, recrystallization of which from toluene yielded 2.1 g (48%) of 10,11-dihydro-5,10-dimethyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp 157°-160° C.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[C:28](=[O:29])[CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[N:25]=[C:24]1[O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:22][N:23]1[C:28](=[O:29])[CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[N:25]=[C:24]1[O:36][CH:37]1[CH2:42][CH2:41][N:40]([C:2]2[CH:21]=[CH:20][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=2)[CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2)CC1
Reactant: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cn1c(OC2CCN(c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a mixture of tert-butyl 4-(4-bromo-benzyl)piperazine-1-carboxylate (371 mg, 1.04 mmol), 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (300 mg, 1.04 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (43.2 mg, 41.8 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (79.6 mg, 0.167 mmol) in toluene (2.09 ml) was added sodium tert-butoxide (151 mg, 1.57 mmol) under nitrogen atmosphere. The mixture was stirred at 150° C. for 30 minutes in Biotage Microwave reactor. The mixture was filtered through a pad of Celite, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; hexane/ethyl acetate=1/1) to afford tert-butyl 4-{4-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]benzyl}piperazine-1-carboxylate as a pale yellow solid (236 mg, 0.420 mmol, 40%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[S:12][C:11]3[S:13][C:14](C(O)=O)=[CH:15][C:10]=3[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C.O.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[S:12]1[C:11]2[S:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:6]([C:5]1[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C(O)c1cc2cc(C(=O)c3ccc(F)cc3)sc2s1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=C(c1ccc(F)cc1)c1cc2ccsc2s1
Temperature: 0 °C
Yield: 92.5 %

Procedure:
5-(4-Fluorobenzoyl)-thieno[2,3-b]thiophene-2-carboxylic acid (48.1 g) and copper powder (8.2 g) are suspended in quinoline (410 cc) and heated at the boiling point for 5 minutes. After cooling, decolourizing charcoal (0.5 g) is added to the reaction mixture which is then filtered. The solution obtained is added dropwise to a mixture of distilled water (620 cc) and a 12 N aqueous solution of hydrogen chloride (289 cc), cooled in an ice bath, the rate of addition being regulated in such a way that the temperature of the mixture remains below 10° C. Distilled water (500 cc) is added to the reaction mixture, which is stirred for a further 30 minutes in the ice bath, and then the resulting crystals are filtered off, washed four times with distilled water (total 2000 cc) and dried in air. Crude (4-fluorophenyl) (thieno[2,3-b]thien-2-yl) ketone (38.1 g), melting at 113° C., is thus obtained.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:18])[N:11]2[CH:19]=[N:20][C:21]([C:22]3[N:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[O:24][N:23]=3)=[C:10]2[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH:27]1([C:25]2[O:24][N:23]=[C:22]([C:21]3[N:20]=[CH:19][N:11]4[C:12]5[C:17](=[C:16]([F:18])[CH:15]=[CH:14][CH:13]=5)[NH:8][CH2:9][C:10]=34)[N:26]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21
Agent: Cl
Solvent: CO
Product: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Reaction time: 8 h

Procedure:
A mixture of 5-(tert-butyloxycarbonyl)-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (I, EXAMPLE 51, 3.39 g) and 50 ml of methanol saturated with HCl(g) is stirred at 20°-25° overnight. The solvent is then removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is separated and dried over sodium sulfate and taken to dryness to give the title compound, NMR (CDCl3) 1.23, 1.35, 2.26, 4.32, 4.86, 6.80, 6.95, 7.22 and 8.06 δ.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:30][OH:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C(OCC)(=O)C>C1COCC1>[CH2:23]([N:30]1[C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[CH2:9][CH:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:12]2[CH2:13][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ONCc1ccccc1
Reactant: C=CCC(CC(=O)c1cccc(Br)c1)O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC2CON(Cc3ccccc3)C2(c2cccc(Br)c2)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)hex-5-en-1-one (6.84 g, 17.8 mmol) and N-benzylhydroxylamine (2.86 g, 23.2 mmol) in THF (60 mL) is added Ti(OEt)4 (8.14 g, 35.7 mmol). The reaction mixture is heated to 70° C. in a sealed tube. After 2 h, the temperature is increased to 80° C. and stirring is continued for 3 days. The reaction mixture is cooled to room temperature. Water and ethyl acetate are added and the mixture is stirred vigorously for 15 minutes. The solids are allowed to settle and the organic and aqueous layers are decanted through a pad of diatomaceous earth. The layers are separated and the aqueous layer is extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with 0% to 20% ethyl acetate in hexanes gradient over 20 minutes to give the title compound as a diastereomeric mixture (7.42 g, 85%). ES/MS m/e (79Br/81Br) 488, 490 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O.[NH2:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([OH:28])[C:25]([NH2:27])=[O:26].O[NH-].O=[N-]>>[NH2:27][C:25](=[O:26])[C:24](=[O:28])[CH:23]([NH:22][C:14]([C@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[CH2:7][C:6]1[CH:17]=[CH:18][CH:19]=[C:4]([O:3][C:2]([F:1])([F:21])[F:20])[CH:5]=1)=[O:16])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc(OC(F)(F)F)c1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc(OC(F)(F)F)c1

Procedure:
Coupling of (R)-1-(3-trifluoromethoxy-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[C:15]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH2:36][CH3:37])[CH3:35])[CH:28]=2)=[N:14][CH:13]=1)=O)C>O1CCCC1>[CH:34]([O:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][C:15]1[C:16]2[C:21](=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:12]([CH2:10][OH:9])=[CH:13][N:14]=1)([CH2:36][CH3:37])[CH3:35]
Reactant: CCOC(=O)c1cnc(Cc2cccc(OC(C)CC)c2)c2cc(OC)c(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C)Oc1cccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a suspension of lithium aluminum hydride (309 mg, 7.73 mmol) in anhydrous tetrahydrofuran (15 mL) was added a solution of 1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (2.3 g, 5.44 mmol) in tetrahydrofuran (10 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and the excess lithium aluminum hydride was quenched with addition of water (1 mL), 15% aqueous sodium hydroxide solution (1 mL) and water (3 mL) at 0° C. The mixture was filtered through a Celite® pad and the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-methanol (2.1, 99% yield). The crude product was used without further purification.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH2:21])=[N:17][NH:18]2)=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:21][C:4](=[O:6])/[CH:3]=[CH:2]/[C:1]([O:8][CH2:9][CH3:10])=[O:7])=[N:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: CCOC(=O)/C=C/C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
865 mg of monoethyl fumarate are added to 1 g of 6-chloro-1H-indazole-3-amine in 50 cm3 of dichloromethane. 1.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are then introduced and the mixture is stirred for 30 minutes at about 20° C. The resulting mixture is washed with 50 cm3 of distilled water and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and then evaporated under reduced pressure (2 kPa; 40° C.). 2 g of a brick-coloured gummy mass are obtained, and are purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume) and collecting 40 cm3 fractions. The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. After drying (90 Pa; 45° C.), 900 mg of ethyl 4-[(6-chloro-1H-indazol-3-yl)amino]-4-oxo-2-butenoate, (E form), melting at 220° C., are obtained.
Reaction SMILES: [CH3:1][N:2]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:28])[CH2:23][C:24]([F:27])([F:26])[F:25])=[C:18]([N+:29]([O-])=O)[CH:17]=1)(=[O:15])=[O:14])C(=O)OCC1C=CC=CC=1>CO.[Pd]>[NH2:29][C:18]1[CH:17]=[C:16]([S:13]([NH:2][CH3:1])(=[O:14])=[O:15])[CH:21]=[CH:20][C:19]=1[N:22]([CH3:28])[CH2:23][C:24]([F:26])([F:25])[F:27]
Reactant: CN(CC(F)(F)F)c1ccc(S(=O)(=O)N(C)C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)c1ccc(N(C)CC(F)(F)F)c(N)c1
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of phenylmethyl methyl({4-[methyl(2,2,2-trifluoroethyl)amino]-3-nitrophenyl}sulfonyl)carbamate (539 mg, 1.17 mmol) in MeOH (10 mL) at 25° C. was treated with 10% palladium on carbon (124 mg, 0.117 mmol) and stirred under an atmosphere of hydrogen (balloon) overnight before being filtered through celite. The filtrate was again filtered through a 0.45 micron syringe filter and concentrated to give 3-amino-N-methyl-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide (320 mg, 92%) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.14-7.20 (m, 2 H), 7.12 (d, J=2.26 Hz, 1 H), 6.95 (dd, J=8.28, 2.26 Hz, 1 H), 5.23 (s, 2 H), 3.82 (q, J=9.87 Hz, 2 H), 2.83 (s, 3 H), 2.39 (d, J=5.02 Hz, 3 H). MS (m/z) 298.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4=[CH:18][S:19][C:20]([C:21]([OH:23])=[O:22])=[C:16]4[N:15]=[C:14]3[C:24](=[O:35])NC3CCN(C4CC4)CC3)[CH:8]=2)=[CH:4][CH:3]=1.NCC[OH:39]>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4=[CH:18][S:19][C:20]([C:21]([OH:23])=[O:22])=[C:16]4[N:15]=[C:14]3[C:24]([OH:35])=[O:39])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1scc2c1nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Reactant: NCCO
Product: O=C(O)c1scc2c1nc(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1

Procedure:
6-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 96 mg (0.18 mmol) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 11.0 μl (0.18 mmol) 2-amino-ethanol. The title compound was obtained as its formiate in form of a white amorphous solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.C(OCC)(=O)C>C1COCC1.CN(C=O)C>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:21]([NH:22][C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
Under ice cooling, after a solution of phenyl chloroformate (2.0 mL, 16 mmol) in THF (2.0 mL) was added dropwise to a solution of 3-benzyloxyaniline (3.7 g, 16 mmol) and pyridine (6.0 mL) in DMF (25 mL), the mixture was stirred at room temperature for 3 hours. Ethyl acetate (200 mL) was added thereto, and then the whole was washed with water (200 mL) twice and brine (200 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with diisopropyl ether, and dried under reduced pressure to give 3.7 g of the title reference compound as a white solid. (Yield 73%)
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=O)C.[OH-].[Na+].[Cl-].[NH4+].Cl>CO.C(OCC)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][OH:4])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: CC(=O)OCCc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cc(Br)ccc1CCO
Yield: 83.8 %

Procedure:
4-Bromo-2-nitrophenethyl acetate (270 mg, 0.96 mmol) was dissolved in 4 ml of methanol. A 5 N aqueous NaOH solution (0.97 ml, 4.82 mmol) was added to the solution at room temperature with stirring, and the mixture was stirred at room temperature for 2 hr. A 10% aqueous ammonium chloride solution (5 ml) was added to the reaction solution, and the mixture was neutralized with a 1 N aqueous HCl solution. The resultant precipitate was dissolved in 20 ml of ethyl acetate, and the solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give 198 mg (yield 83%) of the title compound.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>CCCCCC>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([O:4][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH3:5])[CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 31.9 mL (0.25 mole) of ethyl acetoacetate is stirred in hexane (350 mL) at room temperature. Triethylamine (42 mL, 0.30 mole) is added, followed by dropwise addition of trimethylsilyl chloride (35 mL, 0.276 mole) keeping the internal temperature below 25° C. using a water bath (about 18° C.). The thick white slurry is stirred overnight at room temperature. 200 mL of hexane is then added and the mixture stirred in an ice bath for 1 hour. The mixture is filtered and the solids are washed with 50 mL of cold hexane. Evaporation of the combined filtrate and washings gives 46 g of 3-trimethylsilanyloxy-but-2-enoic acid ethyl ester as a colorless, slightly cloudy oil. This material is used without further purification in the following step.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C:16]([C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1)#[N:17]>>[CH3:15][C:3]1[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]3[CH:29]=[CH:30][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)[CH2:24][CH2:25]2)=[N:7][N:6]2[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=[C:5]2[CH:4]=1
Reactant: Cc1cc2nnc(C(F)(F)F)n2nc1Cl
Reactant: N#Cc1ccc(CN2CCNCC2)cc1
Product: Cc1cc2nnc(C(F)(F)F)n2nc1N1CCN(Cc2ccc(C#N)cc2)CC1
Yield: 74.7 %

Procedure:
The method of Example 12 was repeated using a mixture of 6-chloro-7-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.078 g, 0.33 mmol) and 1-(4-cyanobenzyl)-piperazine (0.199 g, 0.99 mmol) to give 4-((4-(7-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)methyl)benzonitrile (0.099 g, 75%).
Reaction SMILES: [CH3:1][C:2]1([NH:5][CH2:6][C@@H:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:13](N=N[N:17]=3)[CH:14]=2)[OH:8])[CH2:4][CH2:3]1.[Cl:18][Sn]Cl>CO.Cl>[ClH:18].[ClH:18].[NH2:17][C:12]1[N:13]=[CH:14][C:9]([C@H:7]([CH2:6][NH:5][C:2]2([CH3:1])[CH2:4][CH2:3]2)[OH:8])=[CH:10][CH:11]=1
Reactant: CC1(NC[C@H](O)c2ccc3nnnn3c2)CC1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CO
Product: CC1(NC[C@H](O)c2ccc(N)nc2)CC1
Yield: 30.2 %

Procedure:
To a solution of 319 mg (1.37 mmol) of (R)-α-[[(1-methylcyclopropyl)amino]methyl]tetrazolo [1,5-a]pyridine-6-methanol in 25 ml of methanol, 0.12 ml of 12 N HCl and 622 mg (2.75 mmol) of SnCl2 ·2H2O were added. This mixture was heated at reflux for 8 hours and then concentrated to dryness. The residue was partitioned between 80:20 methylene chloride:methanol and 5 ml of 2.5 N NaOH solution. The layers were separated and the aqueous layer repeatedly extracted with 80:20 methylene chloride:methanol. The combined extracts were dried with anhydrous magnesium sulfate and concentrated under reduced pressure, wt. 355 mg. Purification was accomplished by preparative Tlc on silica gel (90:10:1 methylene chloride:methanol:conc. ammonium hydroxide) to give 116 mg of product which was converted into its hydrochloride salt in ethanolic HCl. The salt was precipitated with ether, 105 mg; [α]25D=-28.5 (MeOH, c=1.5); Analysis: Calcd. for C11H17N3O·2HCl:
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.O.OO>CO>[CH3:7][N:6]1[C:2]([S:1][S:1][C:2]2[N:6]([CH3:7])[N:5]=[N:4][N:3]=2)=[N:3][N:4]=[N:5]1
Reactant: Cn1nnnc1S
Agent: OO
Solvent: O
Solvent: CO
Product: Cn1nnnc1SSc1nnnn1C

Procedure:
Within a flask having a capacity of 1000 ml, 5-mercapto-1-methyltetrazole of 1000 mmol is solved in methanol of 450 ml, and the solution thus formed is cooled by water bathing. Into the solution thus prepared, 34.5% hydrogen peroxide of 20 ml is dropped slowly. At several minutes after dropping, the reaction generates heat, thus creating precipitate.
Reaction SMILES: C([Li])CCC.N1CCOCC1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1.C([Li])(CC)C.[CH:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl>CCCCCC.O1CCCC1.C1CCCCC1>[OH:30][CH:24]([C:16]1[O:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC=O
Reactant: O=Cc1ccoc1
Agent: Cl
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CCCCCC
Product: CCCCCC(O)c1cc(C=O)co1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (a 2.5M solution in hexane; 4.37 ml, 10.9 mmol) was added to a solution of morpholine (0.91 ml, 10.9 mmol) in tetrahydrofuran (30 ml) at -78° under argon. After 20 min., 3-furaldehyde (0.9 ml, 10.4 mmol) was added. After another 20 min., sec-butyl lithium (a 1.3M solution in cyclohexane; 8.4 ml, 10.9 mmol) was added dropwise and stirring continued at -78° for 7 hours before 1-hexanal (1.31 ml, 10.9 mmol) was added. Stirring was continued overnight (16 hours) while the cooling bath was allowed to attain room temperature. The solution was poured into ice cold 10% (v/v) hydrochloric acid (30 ml) and after stirring at 0° for 10 min., the layers were separated. The aqueous phase was extracted with diethyl ether. All the organic phases were combined, dried (magnesium sulfate) and evaporated down to give a brown oil, which was purified by flash chromatography on silica using 40% ethyl ether/hexane. Fractions with Rf of about 0.08 on evaporation gave the title compound as a yellow oil.