Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:25])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][C:34]1[C:39]([CH2:40]Cl)=[CH:38][CH:37]=[CH:36][N:35]=1>C(#N)C>[CH3:24][N:15]1[C:10]2[NH:11][CH2:12][CH2:13][S:14][CH:8]([C:7]3[CH:6]=[CH:5][C:4]([O:25][CH2:40][C:39]4[C:34]([CH3:33])=[N:35][CH:36]=[CH:37][CH:38]=4)=[CH:3][C:2]=3[CH3:1])[C:9]=2[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:16]1
Reactant: Cc1ncccc1CCl
Reactant: Cc1cc(O)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCc2cccnc2C)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Temperature: 60 °C
Yield: 55 %

Procedure:
A mixture of 3-methyl-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]phenol (0.078 g, 0.22 mmol, see Ex. #D.42), potassium carbonate (0.061 g, 0.44 mmol), and 2-methyl-3-chloromethylpyridine hydrochloride (0.0356 g, 0.2 mmol, US2005/124586) in acetonitrile (10 mL) was heated at about 60° C., for about 90 h. After cooling to rt the mixture was concentrated in vacuo. The residue was treated with DCM (50 mL) and water (20 mL). The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/methanol 9:1) followed by trituration with diethyl ether to give 1-methyl-4-[2-methyl-4-[(2-methyl-3-pyridyl)methoxy]phenyl]-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.050 g. 0.11 mmol, 50%) as an off white solid: LC-MS (Table 1, Method e) Rt=5.00 min; m/z 458 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 2.56 (3 H, s) 2.60 (3 H, s) 2.70 (1 H, ddd, J=14.9, 6.1, 2.2 Hz) 2.88 (1 H, ddd, J=14.9, 8.9, 2.6 Hz) 3.19-3.29 (1 H, m) 3.53-3.62 (1 H, m) 3.78 (1 H, br s) 3.84 (3 H, s) 4.97 (2 H, s) 6.63 (1 H, dd, J=8.4, 2.6 Hz) 6.64 (1 H, s) 6.82 (1 H, d, J=2.6 Hz) 7.07 (1 H, ddd, J=7.4, 4.9, 1.1 Hz) 7.11-7.16 (2 H, m) 7.58 (1 H, td, J=7.8, 1.9 Hz) 7.67 (1 H, dd, J=7.7, 1.1 Hz) 7.77 (1 H, dt, J=8.0, 1.0 Hz) 8.45 (1 H, dd, J=4.9, 1.6 Hz) 8.49 (1 H, d, J=4.9 Hz).
Reaction SMILES: O1CCCC1.[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.Cl.[CH:17]1([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:19][CH2:18]1.[OH-].[Na+]>C(OCC)(=O)C>[CH:17]1([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[N:27]2[CH2:32][CH2:31][N:30]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([I:6])=[CH:8][CH:9]=3)=[O:12])[CH2:29][CH2:28]2)[CH2:18][CH2:19]1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), bis(tricyclohexylphosphine)palladium (II) dichloride (132 mg), tripotassium phosphate (3.8 g) and cyclopropylboronic acid (688 mg) were added toluene (10 mL) and water (500 μL) and the mixture was refluxed for 5 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g). 4-(2-Cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g) was dissolved in chloroform (1 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. Filtration gave 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg). To tetrahydrofuran (2 mL) were added 4-iodobenzoyl chloride (169 mg), 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg) and 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (280 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[Br:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH:9]([C:3]1[C:4]([I:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: BrCCOCCBr
Reactant: CCOC(=O)Cc1c(Cl)cccc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOCCBr)c1c(Cl)cccc1I
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of ethyl 2-(2-chloro-6-iodophenyl)acetate (4.5 g, 14 mmol) in 12 mL DMF was stirred at room temperature and treated with sodium hydride (0.80 g, 35 mmol). The mixture turned to orange and was stirred for 10 minutes. The mixture was treated dropwise with 1-bromo-2-(2-bromoethoxy)ethane (4.2 g, 18 mmol) in 12 mL DMF. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then warmed to 60° C. and stirred for 2 hours. The mixture was cooled to room temperature and quenched carefully with 20 mL H2O, extracted with ether (3×100 mL). The combined organic layers were washed with water (3×50 mL), 20 mL saturated NaCl, dried over anhydrous Na2SO4, and concentrated to give 5.8 g of the crude product as a yellow oil. MS m/e: (M+H)+ 475/477.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[O:25]1[CH:29]=[N:28][C:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)=[N:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([C:27]4[N:28]=[CH:29][O:25][N:26]=4)=[CH:36][CH:35]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2ncon2)cc1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(-c2ncon2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.29 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 73 mg (0.43 mmol, 1.5 eq.) of 4-(1,2,4-oxadiazol-3-yl)aniline were reacted according to General Method 7. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 2-5% mixtures) and subsequently by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 81 mg (55% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].Br[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[N:36]=[CH:37][S:38][CH:39]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:34][C:35]2[N:36]=[CH:37][S:38][CH:39]=2)=[CH:23][CH:22]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Brc1ccc(N(Cc2cscn2)c2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2cscn2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 59.8 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (78.0 mg) was reacted with N-(4-bromophenyl)-N-((thiazol-4-yl)methyl)pyrimidin-2-amine (90.0 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yl-thiazol-4-ylmethyl-amino)phenyl]pent-4-enoic acid methyl ester (87.7 mg). Column chromatography (silica gel, eluent: chloroform→chloroform/ethyl acetate=3/1) and thin layer chromatography (cyclohexane/ethyl acetate=1/2) were used for purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)[CH3:10].ClC1C(Cl)=CC=CC=1C(C1N=CNC=1)=C.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:44])=CC=1>O1CCCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][C:13](=[S:44])[NH:14][CH:15]=1)[CH3:10]
Reactant: CC(c1c[nH]cn1)c1cccc(Cl)c1Cl
Reactant: S=C(Cl)Oc1ccccc1
Agent: C=C(c1c[nH]cn1)c1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1c[nH]c(=S)[nH]1)c1cccc(Cl)c1Cl
Reaction time: 5 h

Procedure:
A 1:1 mixture of 4-[1-(2,3-dichloro-phenyl)-ethyl]-1H-imidazole (Intermediate A4), and 4-[1-(2,3-dichloro-phenyl)-vinyl]-1H-imidazole (Intermediate A3) (0.77 g, 3.2 mmol) in tetrahydrofuran (THF) (10 mL) and water (10 mL) was treated with NaHCO3 (1.64 g, 19.5 mmol) at rt for 10 m. Phenyl chlorothionoformate (1.1 mL, 7.95 mmol) was added and stirring was continued for 5 h. The mixture was diluted with water and extracted with hexane:ethyl acetate (3×). The organic portions were combined, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was dissolved in MeOH (20 mL) and treated with triethylamine (NEt3) (1 mL) for 18 h at rt. The mixture was concentrated onto silica gel. The material was purified by elution from silica gel with 1 to 2% MeOH: CH2Cl2. The solids were titurated with CHCl3: hexanes and collected on a glass frit to give a white solid 4-[1-(2,3-dichloro-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione (Compound 1) 40 mg.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N:7]=1)C.[O:14]1CCCC1>>[Cl:12][C:8]1[N:7]=[C:6]([CH:5]([OH:14])[CH3:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1cccc(Cl)n1
Reactant: C1CCOC1
Product: CC(O)c1cccc(Cl)n1
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of (6-chloro-pyridin-2-yl)-acetic acid ethyl ester (1.8 g, 9.05 mmol) in dry tetrahydrofuran (25 mL) was cooled to 0° C. Borane-dimethylsulfide complex (4.35 mL, 45.25 mmol) was added dropwise and the reaction mixture warmed to room temperature before heating at reflux overnight. The mixture was cooled to room temperature and quenched into saturated ammonium chloride solution and extracted with ethyl acetate. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by column chromatography over silica gel (60-120 mesh) using 30% ethyl acetate in chloroform as eluent to afford (6-chloro-pyridin-2-yl)-ethanol (0.76 g, 54%) as a liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][C@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C.CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:14][C@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CN(CCOS(C)(=O)=O)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
Methyl(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-hydroxyethyl)piperidine-3-carboxylate (Intermediate 41) (650 mg, 1.93 mmol) was reacted with methanesulfonyl chloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL, 2.7 mmol) as described for Intermediate 6. The crude product was used without delay for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:30]([CH3:33])=[N:31][N:32]=3)[N:18]=[C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:30]([CH3:33])=[N:31][N:32]=3)[N:18]=[C:19]([C:21]3[N:22]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)cc(-c3cc4ccccc4[nH]3)nn12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)cc(-c3cc4ccccc4n3Cc3ccccc3)nn12
Reaction time: 16 h

Procedure:
4-[6-(1H-Indol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (71.00 mg; 0.16 mmol) was suspended in 300 μl THF and treated with NaH (10.19 mg; 0.26 mmol; 60% in mineral oil). After 10 minutes of stilling, Benzyl bromide (19.17 μl; 0.16 mmol) was added and stirred for 16 hours. The crude material was purified via flash chromatography and afterwards with reversed phase chromatography under basic conditions.
Reaction SMILES: [C:1]1([C@H:7]2[O:14][CH2:13][C@H:12]3[N:8]2[C:9](=[O:15])[CH2:10][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]I.[Cl-].[NH4+]>C1COCC1.C([N-]C(C)C)(C)C.[Li+]>[CH3:16][C@@H:10]1[C:9](=[O:15])[N:8]2[C@H:12]([CH2:13][O:14][C@@H:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11]1
Reactant: O=C1CC[C@H]2CO[C@H](c3ccccc3)N12
Reactant: CI
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of (2R,5S)-2-phenyl-3-oxa-1-azabicyclo(3.3.0)octan-8-one (5.08 g, 25 mmol) in THF (30 ml), lithium diisopropylamide (a 2.0M solution in THF, 13.1 ml, 26.3 mmol) was added dropwise at −78° C. under stirring. After the reaction mixture was stirred at the same temperature for 15 minutes, methyl iodide (7.78 ml, 125 mmol) was added thereto and stirring was conducted further for 30 minutes at −40° C. The reaction mixture was poured in an ice-saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate form 4:1 to 1:1, 30 ml/min, φ 50 mm×300 mm, range 0.32) to give (2R,5S,7S)-7-methyl-2-phenyl-3-oxa-1-azabicyclo(3.3.0)octan-8-one (3.8 g, 70%) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.O>[N:17]([CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(CN=[N+]=[N-])c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of methyl 4-(bromomethyl)-1-naphthoate (30 g, 0.107 mol) in anhydrous DMSO (300 mL) was added NaN3 portion wise (14 g, 0.215 mol) at 0° C. and stirred at rt for 16 h. Then the reaction mixture was diluted with water (500 mL), extracted with EtOAc (2×250 mL), washed with water, brine and dried over MgSO4. The solvent was removed under vacuum to give methyl 4-(azidomethyl)-1-naphthoate (20 g, 77%).
Reaction SMILES: N=[N+]=[N-].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Cl)=[N:7][N:6]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [N-]=[N+]=N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: c1ccc2cnncc2c1
Temperature: 25 °C
Yield: 15.1 %

Procedure:
A mixture of the preceding hydrazoic acid (798 mg, 3.91 mmol), 1,4-dichlorophthalazine (778 mg, 3.91 mmol) and triethylamine (0.54 ml, 3.9 mmol) in xylene (28 ml) was heated at reflux under nitrogen for 20.5 h. The mixture was cooled to room temperature, the solvent evaporated in vacuo and the residue partitioned between dichloromethane and water. The aqueous was separated and re-extracted with dichloromethane (×2). The combined extracts were dried (MgSO4), evaporated in vacuo and the residue chromatographed on silica gel eluting with ethyl acetate, then 5% methanol/dichloromethane to afford the title-phthalazine (77 mg, 6%), 1H NMR (360 MHz, CDCl3/d6-DMSO) δ 7.51 (1H, m, Ar—H), 7.55 (1H, s, Ar—H), 7.99 (1H, m, Ar—H), 8.11 (1H, m, Ar—H), 8.24 (1H, m, Ar—H), 8.38 (1H, d, J=7.8 Hz, Ar—H), 8.78 (1H, m, Ar—H), 8.83 (1H, m, Ar—H), 9.18 (1H, br s, Ar—H); MS (ES+) m/e 349 [MH]+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:38](O)(=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:38](=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCCCC(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCCCC(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 31.2 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro- 6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 423 mg (3.6 mmol) of hexanoic acid, to provide 364 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[C:11]([O-])(O)=O.[Na+]>C(O)=O.O>[CH3:1][C:2]1[C:3]2[N:10]=[CH:11][NH:9][C:4]=2[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)c(N)c1C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cc1ccc2[nH]cnc2c1C

Procedure:
3,4-dimethylbenzene-1,2-diamine (300 mg) in 3 mL formic acid was irradiated in a microwave reactor at 150° C. for 5 min. The mixture was diluted with water, neutralized with sat. NaHCO3, then extracted with EtOAc (3×). The organic phase was washed with water and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated to afford 320 mg of Intermediate 178.1 as a tan solid. LCMS (2 min gradient) RT=0.90 min, 147.0 (M+H)+.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>CO>[CH3:24][C:20]1([CH3:23])[CH2:19][O:18][CH:17]([CH:15]([C@@H:14]2[C@:25]3([CH3:34])[C@H:11]([C:10]4[C@H:28]([CH2:27][CH2:26]3)[C@:29]3([CH3:33])[C:7]([CH2:6][C@@H:5]([OH:4])[C@@H:31]5[O:32][C@@H:30]53)=[CH:8][CH:9]=4)[CH2:12][CH2:13]2)[CH3:16])[O:22][CH2:21]1
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 5 mg (0.0106 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate in 2 ml of dry methanol was added 7.3 mg (0.0528 mmole) of anhydrous potassium carbonate and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a glass filter with the aid of Celite and the filtrate was concentrated under reduced pressure. Finally the concentrate was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:5, v/v) to give 4 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol (yield: ca. 90%).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH3:12][OH:13]>>[CH3:12][O:13][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1
Reactant: CO
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Product: COC(=O)CCC1CCC(=O)N1

Procedure:
Twenty-eight grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 100 g of methyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at reflux for 104 hours. The mixture is cooled and excess methyl alcohol is distilled at reduced pressure. The residual oil is dissolved in 1 l of anhydrous diethylether, 1 g of activated charcoal is added and the resulting suspension is filtered through filter aid. The filtrate is concentrated at reduced pressure and the resulting crystals are isolated by filtration. Recrystallization from methanol yields 5-oxo-2-pyrrolidinepropanoic acid methyl ester with a melting point of 52°-53° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:15][CH3:16])[CH:8]=2)[N:3]=1.[CH2:17]([NH2:19])[CH3:18]>>[CH2:15]([O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:19][CH2:17][CH3:18])[C:11]([CH:12]=[O:13])=[CH:10]2)[CH3:16]
Reactant: CCN
Reactant: CCOc1ccc2nc(Cl)c(C=O)cc2c1
Product: CCNc1nc2ccc(OCC)cc2cc1C=O
Temperature: 140 °C
Reaction time: 10 h
Yield: 101.7 %

Procedure:
To a stirred solution of 2-chloro-6-ethoxyquinoline-3-carbaldehyde (298 mg, 1.26 mmol) in a 20 mL microwave vial equipped with a magnetic stirrer was added ethylamine (2.0 N in THF, 13.0 mL, 26.0 mmol) and the reaction mixture was stirred for 10 h at 140° C. under microwave irradiation then for 13 h at 130° C. still under microwave irradiation. After cooling to RT, the reaction mixture was concentrated to dryness at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum, which gave 6-ethoxy-2-(ethylamino)quinoline-3-carbaldehyde SLA 41034 as an orange solid (313 mg, >100% yield).
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18].O>C(O)C>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)(=[O:19])=[O:18])\[C:21]#[N:22])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)c1ccccn1
Solvent: O
Solvent: CCO
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
2-Nitrothiophen-5-carboxaldehyde (0.157 g) and 2-pyridinesulphonylacetonitrile (0.2 g) were stirred in 2 mL of ethanol containing 0.01 mL piperidine for four hours at 100 C. The mixture was cooled to room temperature and water was added for crystalization. The crude product was filtered and recrystalized from ethanol and water to give 0.15 g of (E)-3-(2-nitrothien-5-yl)-2-[(pyridin-2-yl)sulfonyl]acrylonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1.[OH:25]O>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:25])[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1
Reactant: OO
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccccn3)cc12
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccccn3)cc12

Procedure:
Prepared analogous to Example 123 from 4-methyl-6-[4-(2-pyridyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.