Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][NH2:44])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>O1CCCC1>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][NH:44][C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: Cn1nnnc1CCCC(O)=S
Reactant: COc1ccc(CCN)cc1OC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(CCNC(=S)CCCc2nnnn2C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml), and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise 2-(3,4-dimethoxyphenyl)ethylamine (54 mmole) and the mixture is further stirred at room temperature for 2 hours. After the solvent is distilled off under reduced pressure, the resulting residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. After distilling off chloroform, the residue is subjected to column chromatography (Wakogel C-200, eluting agent, chloroform) to isolate N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 41%) which is recrystallized from hexane-chloroform, colorless flaks, m.p. 70.5°-71.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH:14]=[O:15])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:23]>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]([OH:23])=[O:15])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCCc1c(OCCCC#CC=O)ccc(C(C)=O)c1O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Product: CCCc1c(OCCCC#CC(=O)O)ccc(C(C)=O)c1O
Yield: 40 %

Procedure:
To 0.58 g of chromium trioxide in 8 ml of 10N sulfuric acid cooled at 0° was added a solution of 1.51 g of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hexynal in 15 ml of acetone over 30 minutes with stirring. The reaction mixture was allowed to warm to 25° over 30 minutes and then concentrated in vacuo to remove the acetone. Water (50 ml) was added and the product was extracted with ether. The ether phase was extracted with 1.0N sodium hydroxide, the aqueous layer was separated, acidified and extracted with ether. The dried (over sodium sulfate) extract was concentrated in vacuo to a solid which was crystallized twice from ether-hexane to give 0.63 g, mp 115-116°, (40% yield) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hexynoic acid, the titled compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:20]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH3:22])=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([CH:23]=[CH2:24])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Temperature: 120 °C
Yield: 43.1 %

Procedure:
To a degassed solution of 6-chloro-3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (400 mg, 1.267 mmol), was added Pd(Ph3P)4 (220 mg, 0.190 mmol) and tributyl(vinyl)stannane (422 mg, 1.330 mmol). The reaction mixture was heated to 120° C. for overnight. Then the reaction was quenched with NH4Cl(aq), extracted with DCM, dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with gradient Hex:EA to give 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)-6-vinylimidazo[1,2-b]pyridazine (168 mg, 43%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, 1H), 7.97 (s, 1H), 7.63 (d, 1H), 7.55 (d, 1H), 7.54 (d, 1H), 7.50 (s, 1H), 6.84 (dd, 1H), 6.31 (d, 1H), 5.72 (d, 1H), 4.37 (s, 2H), 3.98 (s, 3H). LCMS (method B): [MH]+=308, tR=2.49 min.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:15][CH:16]([C:20](Br)([CH3:24])[C:21](=[O:23])[CH3:22])[C:17](O)=[O:18].N12CCN(CC1)CC2>ClCCl>[Br:15][C:16]1[C:17](=[O:18])[O:23][C:21](=[CH2:22])[C:20]=1[CH3:24]
Reactant: CC(=O)C(C)(Br)C(Br)C(=O)O
Agent: C1CN2CCN1CC2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: C=C1OC(=O)C(Br)=C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
Phosphorus pentoxide (11.5 g) was added with stirring to a solution of 2,3-dibromo-3-methyl-4-oxopentanoic acid (4.6 g, 16.0 mmol) in dry dichloromethane (30 ml). The mixture was heated at reflux with stirring for 2 h. It was cooled to room temperature and the resulting mixture was filtered through a pad of filter aid and treated with 1,4-diazabicyclo[2.2.2]octane (DABCO) (2.24 g, 14.8 mmol). The mixture was stirred at room temperature for 1 h, washed with dilute hydrochloric acid (2N, 10 ml), brine (20 ml), dried over sodium sulfate, and chromatographed on a short plug of silica gel to yield the 3-bromo-4-methyl-5-(methylene)-2(5H)furanone as a colourless oil (2.14 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[Na+]>>[Cl:9][C:3]1[C:2]2[NH:1][C:20]([CH2:19][C:16]3[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=3)=[N:8][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccnc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Cc2nc3ccnc(Cl)c3[nH]2)cc1
Temperature: 0 °C
Yield: 76 %

Procedure:
2.1 A solution of 1.44 g of 3,4-diamino-2-chloropyridine and 9.06 g of (4-nitrophenyl)acetic acid in 10 ml of polyphosphoric acid is stirred at 80° for 16 hours. The mixture is subsequently poured into ice-water, neutralised using NaOH, the deposited crystals are separated off and subjected to conventional work-up. The organic phase yields 2.2 g of 4-chloro-2-(4-nitrophenylmethyl)-3H-imidazo[4,5-c]pyridine (“4”).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:30]=[CH2:31])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reaction time: 1 h
Yield: 52 %

Procedure:
To a degassed solution of 4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL), tributyl(vinyl)tin (760 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After being refluxed for 2 hours, the reaction mixture was concentrated in vacuo and the residue was portioned in ethyl acetate (100 mL) and a saturated aqueous solution of potassium fluoride (100 mL). After the mixture being stirred vigorously for 1 hour, the separated aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.4 g of the crude product.
Reaction SMILES: II.[C:3]([O:7][C:8]([C@H:10]([CH2:15]I)[C:11]([O:13][CH3:14])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4].I[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2C2C(OC)=CC=CC=2OC)C2CCCCC2)CCCCC1>CN(C=O)C.[Zn].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.[Pd].[Pd]>[C:3]([O:7][C:8]([C@@H:10]([CH2:15][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Iodine (0.0140 g, 0.0553 mmol) was added to zinc (0.542 g, 8.29 mmol) and the solid mixture was heated under vacuum for 10 minutes. The flask was flushed with nitrogen three times and allowed to cool. DMF (0.5 mL, degassed with nitrogen) was added and the suspension was cooled to 0° C. and stirred while (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate (1.82 g, 5.53 mmol) in DMF (2.8 mL) was added dropwise. The mixture was stirred for 30 minutes at 0° C. and then allowed to come to RT for 30 minutes. 1-Iodo-4-(trifluoromethyl)benzene (1.50 g, 5.53 mmol), tris(dibenzylideneacetone)dipalladium (0.101 g, 0.111 mmol), and dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-Phos) (0.182 g, 0.442 mmol) were added. The flask was purged with nitrogen and heated at 40° C. After 3 hours the reaction was allowed to cool and partitioned between EtOAc and an aqueous solution of ˜9:1 saturated ammonium chloride/ammonium hydroxide. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, and dried over sodium sulfate. Concentration and purification by silica gel chromatography (6:1 Hexanes/EtOAc) afforded (S)-methyl 2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[S:13](Cl)([CH3:16])(=[O:15])=[O:14].N1C=CC=CC=1>C(Cl)Cl>[S:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)([CH3:16])(=[O:15])=[O:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CS(=O)(=O)Cl
Agent: CCOC(=O)Cc1csc(=N)[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1csc(NS(C)(=O)=O)n1

Procedure:
A mixture of ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (5.6 g.), mesyl chloride (6.9 g.), pyridine (15 ml.) and methylene chloride (45 ml.) was refluxed for 5 hours. After the reaction, the reaction mixture was concentrated. The residue was poured into ice-water (150 ml.) and stirred. The precipitates were collected by filtration, washed with water and diethyl ether and dried to give pale brown powder of ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (6.3 g.).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)#[CH:25].C(NCC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]#[C:25][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][C:6]4[CH2:23][C:13]5([C:21]6[C:16](=[N:17][CH:18]=[CH:19][CH:20]=6)[NH:15][C:14]5=[O:22])[CH2:12][C:7]=4[CH:8]=3)[N:3]=2)=[CH:27][CH:28]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: O=C1Nc2ncccc2C12Cc1cc3ccc(Cl)nc3cc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cc1ccc(C#Cc2ccc3cc4c(cc3n2)CC2(C4)C(=O)Nc3ncccc32)cc1
Temperature: 120 °C

Procedure:
A stirred mixture of (±)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (15 mg, 0.047 mmol, described in Intermediate 20), 4-ethynyltoluene (7 mg, 0.061 mmol), PdCl2(PPh3)2 (4 mg, 0.006 mmol), and diethylamine (0.073 mL, 0.70 mmol) in DMF (0.5 mL) was heated at 120° C. in a microwave reactor for 5 min. The cooled mixture was partitioned between saturated aqueous NaHCO3 (3 mL) and EtOAc (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined and concentrated to give a crude product. This was further purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=402 (M+1). HRMS: m/z=402.1609; calculated m/z=402.1601 for C27H20N3O.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](Cl)=[O:25]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:24]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]3[CH3:17])=[O:25])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: CC1CCCCC1C(=O)Cl
Product: CCC(NC(=O)C1CCCCC1C)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 120 mg (0.74 mmol) 2-methylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][N:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccc2C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-Trifluoromethylphenyl)-5-carboxypyridine (220 mg, 1.23 mmol) in tetrahydrofuran (10 mL) at 0° C. was added 1.0M lithium aluminum hydride in tetrahydrofuran (1.23 mL, 1.23 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 16 hours, cooled to 0° C., and quenched by dropwise addition of water (0.05 mL), 2.5N aq. NaOH (0.05 mL), and water (0.15 mL). Sodium sulfate was added, the reaction filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, CH2Cl2 then EtOAc) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:11]([O:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([OH:12])[CH:11]([N:21]=[N+:22]=[N-:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2OC2CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])CC1
Temperature: 75 °C
Yield: 78.6 %

Procedure:
To a stirred solution of 16.4 g 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester in 420 ml dichloromethane was added at −60° C. 35.8 g m-chloroperbenzoic acid (70% purity). The mixture was allowed to slowly warm to room temperature overnight, 1 l ethylacetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. Evaporation of the solvent and chromatography yielded 14.5 g (82%) 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester as colorless liquid; MS (EI): m/e=213 (M+,5%), 158 (22%), 140 (12%), 57 (100%). To a solution of 14.3 g 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in 750 ethanol was added 150 ml water, 35.8 g ammonium chloride and 43.6 g sodium azide. The mixture was stirred at 75° C. over night, the solvents were greatly removed by distillation under vacuum and the residue was suspended in ethanol and filtered. The ethanol was distilled off and the residue was suspended in ethylacetate and filtered. Removal of the solvent and chromatography on silicagel with ethylacetate/hexane 1:1, yielded 13.5 g (79%) 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester as a viscous oil; MS (ISP): m/e=257 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 6.32 g (20 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide, 5.68 g (14 mmol) of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide and 100 ml of toluene is heated to boiling under reflux for 4.5 hours. The solution obtained is then evaporated in vacuo and the residue is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from methylene chloride/ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile of melting point 237°-238°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1OC
Temperature: 25 °C

Procedure:
A mixture of 2-methoxyphenol (11.3 g), potassium carbonate (25 g), ethyl bromoacetate (12 ml), and acetone (113 ml) was heated under reflux for 4 hours. After cooling to the room temperature, the mixture was filtered and the solvent was distilled off under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound IIbd-a (17 g, 91%) as a pale-yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl.ClCCl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([NH:31][O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NOCc1ccccc1

Procedure:
A solution of Example 1C (0.20 g, 0.66 mmol), O-benzyl hydroxylamine hydrochloride (0.22 g, 1.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g, 0.89 mmol), 1-hydroxybenzotriazole (0.14 g, 1.0 mmol), and N-methylmorpholine (0.40 mL, 3.6 mmol) in 5:1 dichloromethane/DMF (6 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:2/dichloromethane:methanol to provide the desired product.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:24][C:25](=[O:40])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:28]([CH3:39])[CH:27]=1)[CH2:19][CH2:20][C:21]([OH:23])=O)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:72]1[CH2:78][CH2:77][CH2:76][C@H:73]1[CH2:74][OH:75].FC(F)(F)C(O)=O.ClCl>C(#N)C.C(OCC)(=O)C.C(O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C@@H:18]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[O:33])=[C:28]([CH3:39])[CH:27]=3)[CH2:19][CH2:20][C:21]([N:72]3[CH2:78][CH2:77][CH2:76][C@H:73]3[CH2:74][OH:75])=[O:23])=[N:10][C:11]=2[CH:16]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1cc(C(=O)NC(CCC(=O)O)c2nc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC#N
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@H]2CO)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 60 %

Procedure:
Prepared analogously to Example 1g from N-[1-(1-tert-butoxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, TBTU, diisopropylethylamine, (S)-prolinol in acetonitrile, and subsequent reaction with trifluoroacetic acid analogously to Example 17. Yield: 60%; Rf value: 0.25 (silica gel; ethyl acetate/ethanol=85:15); C29H34ClN5O4 (552.07); mass spectrum: (M+H)+=552/554 (chlorine isotope).