Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C=O.BrC1C=C2C(C(CCN)=CN2)=CC=1F.[OH-].[Na+].[Br:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]3[CH2:35][CH2:34][NH:33][CH2:32][C:28]=3[NH:29]2)=[CH:25][C:24]=1[F:36].BrC1C2NC3CCNCC=3C=2C=CC=1F.[C:52](=O)([O:58]C(C)(C)C)[O:53][C:54]([CH3:57])([CH3:56])[CH3:55]>Cl.ClCCl.CN(C1C=CN=CC=1)C>[Br:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]3[CH2:35][CH2:34][N:33]([C:52]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:58])[CH2:32][C:28]=3[NH:29]2)=[CH:25][C:24]=1[F:36]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Fc1cc2c3c([nH]c2cc1Br)CNCC3
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: Fc1ccc2c3c([nH]c2c1Br)CCNC3
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c([nH]c3cc(Br)c(F)cc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
Glyoxylic acid (8.6 g, 95 mmol) was added to a solution of 2-(6-bromo-5-fluoro-1H-indol-3-yl)ethanamine (8.1 g 31 mmol) in 2 N HCl (150 ml), and the pH of the resulting solution was adjusted to pH 3.5 with 6 N NaOH solution. The reaction mixture was stirred at ambient temperature for 18 h. The solution was adjusted to pH 5.5 with 6 N NaOH solution. The resulting precipitate was collected by filtration and dried under vacuum to afford a yellow solid. The yellow solid was suspended in 2 N HCl (100 mL), and the resulting mixture was stirred at reflux for 4.5 h. The reaction mixture was cooled to ambient temperature and was adjusted to pH 10 by addition of 2 N sodium hydroxide solution. The resulting precipitate was collected by filtration and dried under vacuum to afford a crude mixture of 7-bromo-6-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and 6-bromo-7-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.0 g, 23%) as a yellow solid. The mixture (1.9 g, 7.1 mmol) was suspended in dichloromethane (100 mL) and di-tert-butyl carbonate (1.85 g, 8.7 mmol) was added, followed by addition of DMAP (100 mg, 0.82 mmol). The reaction mixture was stirred at ambient temperature for 18 h and concentrated under vacuum. The residue was purified twice by column chromatography (silica gel, hexanes/ethyl acetate, 0:1 to 1:1) to afford the title compound (300 mg, 12%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=5.7 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 4.61 (s, 2H), 3.75 (br m, 2H), 2.73 (br m, 2H), 1.56 (s, 9H); ESI MS m/z 369 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].CN(C=O)C.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1C(=O)c2cccnc2N(Cc2ccccc2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a mixture of 4.0 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 100 ml of dry DMF was added 1.2 g of 50% NaH in mineral oil. The resulting solution was heated to 60° C. for one hour. The dark red solution was cooled to 30° C. and 2.5 ml of benzyl bromide was added and stirred overnight under nitrogen. Methanol was added slowly until bubbling ceased, and the reaction mixture was then poured into 400 ml of water. The product was extracted with ether, dried over MgSO4, then concentrated and purified by column chromatography over silica gel. Elution of the material with 2% ethyl acetate/methylene chloride gave a white solid, which was recrystallized from methylene chloride/ether/petroleum ether to give 2.2 g (39% of theory) of 6,11-dihydro-11-benzyl-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazapin-5-one, m.p. 168°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:24][CH:25]=[CH2:26])[C:9](=[N:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][Li]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:24][CH:25]=[CH2:26])[C@:9]([NH:17][S@@:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](C(=N[S@](=O)C(C)(C)C)c1ccc(Cl)cc1)c1cccc(Cl)c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(N[S@](=O)C(C)(C)C)c1ccc(Cl)cc1

Procedure:
A solution of (R)—N—((R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)pent-4-enylidene)-2-methylpropane-2-sulfinamide (Example 418, Step B, 9.97 g, 24.41 mmol) in THF (98 ml) was cooled to −78° C. Methyllithium (1.6M in ether, 16.78 ml, 26.9 mmol) was added over a period of six min. The reaction was removed from the cold bath and diluted with 500 mL ether and quenched with 150 mL of saturated aqueous ammonium chloride solution. The organic layer was separated and washed with brine, then dried with anhydrous magnesium sulfate and concentrated to afford a colorless oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through (3×80 g) RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.), eluting with 30% ethyl acetate in hexane. Fractions containing the desired product, eluting as the bottom spot on silica gel TLC in hexane/ethyl acetate, were combined and concentrated under reduced pressure to provide the title compound as a glass.
Reaction SMILES: C1([Li])C=CC=CC=1.Br[CH:9]=[CH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1.C1C=CC=CC=1>O>[C:10]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1)#[CH:9]
Reactant: COc1ccc(C=CBr)c2ccccc12
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: C#Cc1ccc(OC)c2ccccc12

Procedure:
Phenyllithium (164 ml. of 2.1 M, 0.345 mol.) was added dropwise to a solution of 35.9 g. (0.138 mol.) of 1-(2-bromoethenyl)-4methoxynaphthalene in 120 ml. of refluxing dry benzene under a nitrogen atmosphere. After addition the reaction mixture was refluxed for 30 minutes, then ice and water were slowly added. The mixture was shaken, the layers separated and the organic phase was washed with water and saturated sodium chloride solution, dried (MgSO4) and evaporated to give 1-ethynyl-4-methoxynaphthalene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]CO)[CH2:14][CH2:13]3)[C:9]3[CH:22]=[C:23]([CH:26]([CH3:28])[CH3:27])[CH:24]=[CH:25][C:8]=3[S:7][C:6]=2[CH:29]=1.[C:30]([O:33]C(=O)C)(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[C:30]([O:33][CH2:19][CH2:18][N:15]1[CH2:14][CH2:13][N:12]([CH:10]2[C:9]3[CH:22]=[C:23]([CH:26]([CH3:27])[CH3:28])[CH:24]=[CH:25][C:8]=3[S:7][C:6]3[CH:29]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH2:11]2)[CH2:17][CH2:16]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccc(F)cc1S2
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCN1CCN(C2Cc3ccc(F)cc3Sc3ccc(C(C)C)cc32)CC1
Reaction time: 8 h

Procedure:
A solution of 1.0 g of 3-fluoro-10-[4-(2-hydroxyethyl)piperazino]-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin base (Example 3) in 5 ml chloroform was treated with 0.5 g acetic anhydride and the mixture allowed to stand overnight at room temperature. It was then diluted with 20 ml of chloroform, washed with water and with ice-cold sodium hydroxide solution, dried with potassium carbonate, and the chloroform evaporated under reduced pressure. The remaining oil (1.1 g, 100%) was dissolved in 3.5 ml of acetone and the solution neutralized under heating with 0.6 g maleic acid. On cooling, 1.3 g (77%) of dimaleate crystallized which was then recrystallized from acetone and melted at 153°-155.5° C.; it was identical with the product obtained by a different way according to Example 14.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8]>ClC(Cl)(Cl)Cl>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Br:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrBr
Reactant: CON=C(C(=O)OC)c1ccccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CON=C(C(=O)OC)c1ccccc1CBr
Yield: 45.7 %

Procedure:
21.4 g (0.133 mol) of bromine are added to a stirred solution of 27.5 g (0.133 mol) of methyl 2-methylphenylglyoxylate O-methyloxime in 400 ml of tetrachloromethane. The mixture is then refluxed while irradiating with a 300W Hg vapor lamp for four hours. It is then concentrated, the residue is taken up in ethyl acetate/water, and the organic phase is washed with H2O, dried with sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel with cyclohexane/ethyl acetate (9/1). 17.4 g (46%) of the abovementioned compound are obtained as an oil.
Reaction SMILES: NCCC1CCCN1C.[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([S:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[S:31][CH2:32][C:33]([N:35](C)[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:34])[CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)([CH3:13])[CH3:12]>>[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([S:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[S:31][CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][N:39]2[CH3:40])=[O:34])[CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)([CH3:13])[CH3:12]
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: CN1CCCC1CCN
Product: CN1CCCC1CCNC(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1

Procedure:
Substituting 2-(2-aminoethyl)-1-methylpyrrolidine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-[(1-methylpyrrolidin-2-yl)ethyl]acetamide.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(OC([N:29]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[CH3:38])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH2:39]([N:29]1[C:10]2[C@:9]3([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:18](=[O:19])[N:30]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[CH3:38])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1cccc(NN(Cc2ccccc2)C(=O)OC(C)(C)C)c1C
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(-n2c(=O)c3c(n2Cc2ccccc2)[C@@]2(C)CC[C@@H]3C2(C)C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
Triethylamine (440 μL, 3.2 mmol) was added to solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 329 mg, 1.5 mmol) in 1,2-dichloroethane (6 mL) over 1 min. Then a solution of N-benzyl-N′-(2,3-dimethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (450 mg, 1.38 mmol) in 1,2-dichloroethane (12 mL) was added over 2 min. The reaction mixture was stirred at room temperature for 15 min and then heated in an oil bath at 50° C. for 2 h and then at 60° C. for 1 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 1 h. The reaction mixture was allowed to cool, silica gel was added, the solvent was evaporated and the mixture was purified using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes and then 5% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, and then treated with methanol and charcoal. This mixture was stirred for 20 min, filtered through Celite and evaporated to give an orange gum. The gum was purified for a second time using an ISCO 40 g column, eluting with 2-4% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, co-evaporated with diethyl ether and petroleum ether, and then dried under high vacuum at room temperature to give (4R,7S)-1-benzyl-2-(2,3-dimethyl-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (57 mg, 11%) as an off-white foam. ES(+)-MS (M+H) 387.
Reaction SMILES: Cl.[CH:2]12[CH:7]([CH2:8][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)=[O:11])[CH:6]1[CH2:5][NH:4][CH2:3]2.[CH:30]1([CH:33]=O)[CH2:32][CH2:31]1>ClCCCl>[CH:30]1([CH2:33][N:4]2[CH2:5][CH:6]3[CH:2]([CH:7]3[CH2:8][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:28])([F:29])[F:27])[CH:20]=3)[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)=[O:11])[CH2:3]2)[CH2:32][CH2:31]1
Reactant: O=CC1CC1
Reactant: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CNCC32)c1
Agent: Cl
Solvent: ClCCCl
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CN(CC4CC4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 1-Methyl-1H-imidazole-4-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-trifluoromethoxy-benzyl)-amide Hydrochloride prepared above (0.8 gm, 1.9 mmol) in 18.5 mL of DCE at room temperature was added Cyclopropanecarbaldehyde (0.1 mL, 1.6 mmol) and NaHB(OAc)3 (0.8 gm, 3.7 mmol). The reaction stirred at room temperature for 16 hours, was quenched by the addition of saturated NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to yield the crude material, which was purified via flash chromatography with 5-30% MeOH/CH2Cl2. The product containing fractions were collected and concentrated to yield 1-Methyl-1H-imidazole-4-carboxylic acid (3-cyclopropylmethyl-3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-trifluoromethoxy-benzyl)-amide 0.5 gm. 400 MHz 1H NMR (CDCl3) δ 7.5 (s, 1H), 7.3 (m, 2H) 7.2-7.0 (m, 3H), 5.5 (brs, 1H) 4.8 (brs, 1H), 4.0 (brs, 1H), 3.7 (s, 3H), 3.3 (brs, 1H), 3.0 (m, 2H), 2.2 (m, 4H), 1.5 (brs, 1H), 1.3 (m, 2H), 0.8 (m, 1H), 0.4 (m, 2H), 0.0 (m, 2H); MS (M+1) 449.3.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[C:20]=2[NH2:25])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.CCOC(C)=O.O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[C:20]=2[NH:25][C:1](=[O:10])[CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:17][CH:18]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrocinnamoyl chloride (0.73 mL, 4.9 mmol) was added to a mixture of 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine (4.1 mmol), triethylamine (1.14 mL, 8.2 mmol), and a few drops of DMF in CH2Cl2, and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and H2O and the organic layer was separated, washed with brine, and concentrated. The residue was purified by dry-load silica gel chromatography (28-48% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>O1CCCC1.[Ru]>[CH3:1][CH:2]([CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:8]1[NH2:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: [H][H]
Reactant: CC(C)CC(C)c1ccccc1N
Agent: [Ru]
Solvent: C1CCOC1
Product: CC(C)CC(C)C1CCCCC1N
Temperature: 25 °C

Procedure:
5 g of Ru/C (5%) are added to a solution comprising 20.0 g (0.113 mol) of 2-(1,3-dimethylbutyl)aniline in 300 ml of tetrahydrofuran, and the mixture is hydrogenated with 100 bar of hydrogen at 120° C. for 24 hours. After cooling to room temperature, the catalyst is filtered off through Celite 545 and the product is concentrated under reduced pressure. This gives 19.1 g (92.4% of theory) of 2-(1,3-dimethylbutyl)cyclohexanamine having a purity of 100% according to HPLC and a log P (pH 2.3) of 4.07.
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].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=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]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][C:42](=[O:44])[CH3:43])=[CH:39][CH:40]=2)[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: CC(=O)Oc1ccc(CN(c2ccc(I)cc2)c2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccc(OC(C)=O)cc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 66 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (45.6 mg) was reacted with (4-iodophenyl)-(4-acetoxybenzyl)pyrimidin-2-ylamine (67.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-acetoxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (61.7 mg). Column chromatography (silica gel, eluent: ethyl acetate/hexane=1/3→3/1) and thin layer chromatography (silica gel, developing solvent: cyclohexane/ethyl acetate=1/5) were used for purification. (2) To a solution of (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-acetoxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (61.7 mg) in THF (3.0 ml), 0.1N aqueous sodium hydroxide solution (3.0 ml) was added, and the resulting mixture was stirred at room temperature for 2 hours. Water (50 ml) was added to the reaction solution and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid thereto and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-hydroxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (43 mg).
Reaction SMILES: [O:1]1[C:5]2[NH:6][CH2:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:6]2[C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH2:10][N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: c1cc2n(c1)Cc1ccoc1NC2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccoc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml of methylene chloride under argon is added 1.5 mmol of triethylamine followed by ice bath cooling. A solution of 1.1 mmol of 4-nitrobenzoyl chloride in 5 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:19](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([NH2:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C/c1cnoc1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)/C=C/c1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a mixture of (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.97 g), triethylamine (1 ml) and tetrahydrofuran (60 ml) was added ethyl chlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (1 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give (E)-3-(5-phenyl-4-isoxazolyl)propenamide (0.86 g, yield 89%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 194–196° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][C@@H:34]1[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.O>[C:1]1([N:7]2[C:11]([S:12][CH2:33][C@@H:34]3[NH:38][C:37](=[O:39])[CH2:36][CH2:35]3)=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=C1CC[C@H](CO)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1CC[C@H](CSc2nnnn2-c2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
1-Phenyl-1H-tetrazole-5-thiol (9.0 g) and triphenylphosphine (13.2 g) were added to a solution of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (4.5 g) in tetrahydrofuran (90 mL), followed by ice-cooling. A solution of 2.2 M diethyl azodicarboxylate in toluene (23 mL) was added dropwise thereto, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1→1:1→0:1) to give (R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfanyl]methyl}pyrrolidin-2-one (1.98 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([O:21]C(=O)C)=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:25]=1)=[O:4].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:25]=1)=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccc(OC(C)=O)cc3)ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)Nc1cn2cc(Sc3ccc(O)cc3)ccc2n1

Procedure:
1.0 Gm. of the acetate derivative obtained in Example 15 is heated with a 10 ml. 50% methanol-water solution of 0.5 g. of potassium hydroxide for one hour. After evaporation of the methanol in vacuo the reaction mixture is acidified with glacial acetic acid. The resultant solids are removed by filtration, washed with water and dried to yield 2-(methoxycarbonylamino) 6-(p-hydroxyphenylthio) imidazo [1,2-a] pyridine.