Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+].O.[C:14]1(S(OCC#C)(=O)=O)[CH:19]=CC=C[CH:15]=1>C1(C)C=CC=CC=1>[CH2:19]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[C:14]#[CH:15]
Reactant: NC1CCc2ccccc21
Reactant: C#CCOS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCNC1CCc2ccccc21
Yield: 62 %

Procedure:
To a mixture of racemic 1-aminoindan (64 g), 15% aqueous sodium hydroxide solution (141 g), water (107 mL) and toluene (192 mL) there was added propargyl benzenesulfonate (94.3 g) during 20 minutes at ambient temperature. The resulting mixture was heater to 45° C. for 4 hours, at which time the pH was confirmed to be >12(45% sodium hydroxide added if necessary) and the phases were separated. To the organic phase water (64 mL) was added and the pH was adjusted to 2 with 33% aqueous sulfuric acid. The aqueous phase was separated, diluted with water and mixed with toluene. The pH was adjusted to 6 with 25% aqueous sodium hydroxide and the phases separated. The aqueous phase was extracted again with toluene, ensuring a pH=6. The combined organic layers were concentrated in vacuo to yield 51 g of crude racemic N-propargyl-1-aminoindan as a yellow oil.
Reaction SMILES: Cl.[SH:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[OH-].[Na+].[CH:13]1([C:19]2[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)C>C(Cl)(Cl)Cl>[CH:13]1([C:19]2[CH:26]=[CH:25][C:22]([CH2:23][S:2][C@@H:3]3[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]3)=[CH:21][CH:20]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(O)[C@@H]1C[C@H](S)CN1
Reactant: ClCc1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@H](SCc2ccc(C3CCCCC3)cc2)CN1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
To (4S)-4-mercapto-L-proline hydrochloride (300 mg) is added 2 N sodium hydroxide (1.6 ml) aqueous solution, and the mixture is stirred at 0° C. A solution of 4-cyclohexylbenzyl chloride (340 mg) in a mixed solvent of ethanol (5 ml)/chloroform (1 ml) is added thereto, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and deposited crystals are filtered off. The crystals are washed with water, ethanol and diethyl ether successively to give 470 mg (91%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrBr>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1
Reactant: CC(=O)Cc1cccc(F)c1
Agent: BrBr
Product: CC(=O)C(c1ccc(F)cc1)c1cccc(F)c1
Reaction time: 1 h

Procedure:
A solution of 16.5 g. of m-fluorophenyl-2-propanone [Z. Eckstein and J. Plenkiewicz, Rocznik. Chem., 37, 907 (1963)] in 70 ml. of fluorobenzene is cooled and stirred as 5.5 ml. of bromine are added dropwise. Argon gas is bubbled through the mixture for one hour. The solution is then added dropwise to a mixture of 29.6 g. of aluminum chloride and 70 ml. of fluorobenzene, stirred at 80°-90° C. Stirring is continued at this temperature for one hour then the mixture is poured into ice and 45 ml. of concentrated hydrochloric acid. Toluene is added, the organic layer is separated, washed with dilute sodium hydroxide and then water and distilled, giving the desired product as a liquid, b.p. 106°-112° C./0.15 mm.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:22])[C@H:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]([CH3:10])[CH3:9].C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>>[CH:8]([C@@H:7]1[C:6](=[O:22])[NH:5][CH:4]=[CH:3][N:11]1[C:12]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:21])([CH3:9])[CH3:10]
Reactant: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)[C@@H]1C(=O)NC=CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
(R)-benzyl (1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (335 g, 0.99 mol) was added in portions to a cooled TFA-H2O (temperature <5° C., VTFA/VH2O=7/3, 2 L), and the solution was stirred at rt for 12 h. The solution was added slowly into stirring cooled sat. aq. Na2CO3 (2.5 L) to keep the pH >8. The mixture was extracted with EtOAc (5×2 L). The combined organic layers were washed with brine (2 L), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give (R)-benzyl 2-isopropyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate as a white solid (259 g, 95.4%), which was used for next step without further purification. LC-MS m/z 274.9 [M+H]+. 1H NMR (CD3OD 300 MHz): δ7.36-7.34 (m, 5H), 6.33-6.30 (m, 1H), 5.79-5.68 (m, 1H), 5.26-5.13 (m, 2H), 4.38-4.29 (m, 1H), 2.01-1.96 (m, 1H), 1.00-0.84 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH:16](C)[CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33]C[CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:49]([N:56]1CCNCC1)C1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:49][N:56]3[CH2:33][CH2:34][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[CH2:30][CH2:31]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(C(C)CC=O)on2)cc1OC
Reactant: COc1ccccc1N1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCCN3CCN(c4ccccc4OC)CC3)on2)cc1OC
Yield: 60.8 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]butanal (33.2 mg, 0.121 mmol) and 1-(2-methoxyphenyl)piperidine (23.3 mg, 0.121 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (76.9 mg, 0.363 mmol), cold acetic acid (8.3, 0.145 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 3 hr and followed the same processes as in Example 1 to obtain 33.2 mg (60.8%) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].[C:12]1([C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(Cl)Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1[C:3]2[O:11][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(Br)c(O)c1O
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Br)c2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
3-Bromo-6-methoxycatechol (3.87 g) and diphenyl-dichloromethane (4.61 g) were heated at 170° C. with stirring without a solvent. After being allowed to stand for cooling, a saturated aqueous solution of sodium bicarbonate was added to the mixture, followed by extraction with ether. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with methanol to give Compound IIbl-a (4.7 g, 69%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[C:8]([CH3:12])[C:7]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:6]=3[C:5]=2[C:4](=O)[CH2:3]1.N1C=CC=CC=1.Cl.[NH2:28][OH:29]>C(O)C>[CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[C:8]([CH3:12])[C:7]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:6]=3[C:5]=2[C:4](=[N:28][OH:29])[CH2:3]1
Reactant: Cc1nc2c(c3c1[nH]c1ccccc13)C(=O)CC(C)C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nc2c(c3c1[nH]c1ccccc13)C(=NO)CC(C)C2
Yield: 60.9 %

Procedure:
A mixture of 3,6-dimethyl-2,3,4,7-tetrahydroindolo[2,3-c]quinolin-1-one of Example 12 (0.26 g, 1 mmol), ethanol (4 mL), pyridine (0.15 mL, 1.85 mmol) and hydroxylamine hydrochloride (0.1 g, 1.5 mmol) was refluxed for 3 h. The mixture was cooled, the solid product was filtered off, washed with ethanol, dried, and dissolved in hot water (20 mL). Aqueous ammonium hydroxide was added to pH 9. The precipitate was collected, washed with water, dried and crystallized from ethanol-water, 1:1 to give 0.17 g (61%) of colorless crystals; m.p. 282-283° C.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[C@@:36](C)([OH:37])[C@@H:23]5[O:24]C(C6C=CC(OC)=CC=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N[C@@H]1C2C(=CC=CC=2)CC1.O.CC(O)=O>C1COCC1>[C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@@H:20]4[CH2:21][C@@H:22]([CH2:27][OH:26])[C@@H:23]([OH:24])[C@H:36]4[OH:37])[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)[C@@](C)(O)[C@@H]3O2)cc1
Agent: N[C@H]1CCc2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of (4aS,6R,7R,7aR)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)-7-methylhexahydrocyclopenta[d]-[1,3]dioxin-7-ol (312 mg, 0.594 mmol, as prepared following the procedure in Example 1a-d, using (S)-(+)-1-aminoindan in step c) in THF (1.17 mL) and water (1.17 mL) was added AcOH (3.51 mL, 61.7 mmol) under an atmosphere of nitrogen. The mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound as a white solid (182 mg, 76%). LC/MS: Rt=0.85 min, ES+ 381 (FA standard).
Reaction SMILES: [NH2:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:9](Cl)(Cl)=O.S(=NC1C=CC=CC=1)=O.S(Cl)Cl>C(O)C.C1(C)C=CC=CC=1>[S:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[N:2]=[N:1]1
Reactant: NNc1ccccc1
Reactant: O=S(Cl)Cl
Agent: ClSCl
Agent: O=S=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc2snnc2c1

Procedure:
A dinitrobenzene (I) is reacted with, for example, ammonium chloride and iron or with hydrogen gas and palladium on activated carbon in a solvent such as ethanol or toluene and at elevated temperature to give the corresponding aminoaniline (VII). The aminoaniline (VII) is reacted with, for example, thionyl chloride, N-thionyl aniline or sulfur dichloride in a solvent such as toluene or ethanol and at elevated temperature to yield a benzothiadiazole of formula (A'").
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[F:26][C:27]([F:49])([F:48])[C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]([CH:46]=O)=[CH:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:46]/[C:39]3[C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]([S:34]([C:31]4[CH:32]=[CH:33][C:28]([C:27]([F:49])([F:26])[F:48])=[CH:29][CH:30]=4)(=[O:36])=[O:35])[CH:38]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1cn(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(C(F)(F)F)cc4)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0500 g, 0.144 mmol) obtained in Example A16, Step 1 in methanol (0.6 mL) was added with 1-[4-(trifluoromethyl)phenylsulfonyl]-1H-indole-3-carboxaldehyde (0.0509 g, 0.144 mmol) and piperidine (0.00123 g, 0.0144 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (1 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-([6-hydroxy-3-oxo-2-({1-[4-(trifluoromethyl)phenylsulfonyl]-1H-indol-3-yl}methylene)-2,3-dihydrobenzofuran-7-yl]methyl)piperazine-1-carboxylate (0.0759 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17]([Cl:19])=[O:18]>O1CCCC1>[ClH:19].[CH3:12][N:8]1[CH2:7][CH2:6][C:5]2[N:4]=[CH:3][C:2]([NH:1][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([Br:13])[CH:15]=3)=[CH:11][C:10]=2[CH2:9]1
Reactant: COc1ccc(C(=O)Cl)cc1Br
Reactant: CN1CCc2ncc(N)cc2C1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cnc3c(c2)CN(C)CC3)cc1Br
Product: Cl
Reaction time: 18 h

Procedure:
3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine (300 mg; 1.84 mmol) was dissolved in dry tetrahydrofuran (10 ml) under argon and treated with a solution of 3-bromo-4-methoxybenzoyl chloride (459 mg; 1.84 mmol) in dry tetrahydrofuran (10 ml). The mixture was stirred at ambient temperatures for 18 h and the product (720 mg; 95%) collected by filtration washed with tetrahydrofuran and dried.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.3 %

Procedure:
To a suspension of LAH (750 mg, 19.7 mmol) in ether (40 ml) was added crude t-butyl-2,2,2-trifluoroethoxyacetate (2.0 g, 9.3 mmol) in ether (10 ml) at 0° C. The mixture was stirred for 45 minutes at 0° C. Then, the mixture was poured into ice-water and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give crude 2-(2,2,2-trifluoroethoxy)ethanol (1.09 g, 81%). To a solution of crude 2-(2,2,2-trifluoroethoxy)ethanol (150 mg, 11.0 mmol) in dichloromethane (3 ml) was added triethylamine (110 mg, 1.1 mmol) and p-toluenesulfonylchloride (200 mg, 1.1 mmol). The mixture was stirred at room temperature for 2 days. The mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After concentration, silica gel column chromatography (n-hexane/ethyl acetate=5/1) gave 2-(2,2,2-trifluoroethoxy)ethyl p-toluenesulfonate (188 mg, 63%)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:14]([I:16])[CH3:15].C1C(Cl)=CC=C(Cl)C=1>C(OCC)(=O)C>[I-:16].[CH2:14]([N+:6]1[C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1])[CH3:15]
Reactant: CCI
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2s1
Solvent: Clc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CC[n+]1c(C)sc2cc([N+](=O)[O-])ccc21
Product: [I-]
Temperature: 120 °C

Procedure:
To 2-methyl-6-nitrobenzothiazole (0.36 g) was added ethyl iodide (1.5 ml) and dichlorobenzene (20 ml). The mixture was heated to 120° C. for 2 days and then allowed to cool to room temperature. Ethyl acetate was added and the resulting precipitate removed by filtration. Drying in a vacuum oven gave the desired material (80 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]2[O:33][C:32](=[O:34])[NH:31][C@H:30]2[CH3:35])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:31]2[C@@H:30]([CH3:35])[C@@H:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[O:33][C:32]2=[O:34])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccc(Cl)cc1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccc(Cl)cc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]acetic acid methyl ester and (4S,5R)-5-(4-chloro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Cl.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC=CC=3OC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[O:26][CH3:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: COc1ccccc1CCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: COc1ccccc1Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: COc1ccccc1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 54.4 %

Procedure:
The title compound (0.06 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 2-methoxybenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-methoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H22ClN3O, 367.15; found, m/z 368.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.45-7.43 (m, 2H), 7.30-7.27 (m, 2H), 7.18-7.17 (m, 1H), 6.80-6.77 (m, 2H), 6.61-6.59 (m, 1H), 5.26 (s, 2H), 3.80 (s, 3H), 2.92-2.86 (m, 4H), 2.74-2.69 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[N:10]#[C:11]Br>C(O)C.C(O)(=O)C>[BrH:1].[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([NH2:10])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: N#CBr
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: Nc1nc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 4-bromo-1,2-diaminobenzene (3.0 g, 16 mmol) in a mixture of ethanol (90 mL) and acetic acid (90 mL) was added cyanogen bromide (2.56 g, 24.0 mmol) and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was concentrated in vacuo and the residue was triturated in ethyl acetate (200 mL) to afford 5-bromo-1H-benzo[d]imidazol-2-amine hydrobromide as a brown solid in 85% yield (3.98 g): 1H NMR (300 MHz, DMSO-d6) δ12.49 (br s, 2H), 8.61 (s, 2H), 7.50 (s, 1H), 7.38-7.23 (m, 2H); MS (ES+) m/z 211.9 (M+1), 213.9 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]1([C:19]2([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)C>[CH3:1][S:2]([O:25][CH2:24][C:19]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccccc2)CCCC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reaction time: 1 h

Procedure:
659 mg (6.07 mmol) of methanesulfonyl chloride and then 838 μl (6.01 mmol) of triethylamine were added, whilst cooling in an ice-salt bath, to a solution of 1.00 g (5.67 mmol) of (1-phenylcyclopentyl)methanol [prepared as described in step (i) above] in 18 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was diluted with diethyl ether, and the diluted mixture was washed with 2N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.44 g (a quantitative yield) of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccncc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccncc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.1 %

Procedure:
p-Methoxyaniline (0.078 g, 0.639 mmol), triethylamine (0.066 g, 0.639 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.108 g, 0.639 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(4-pyridylmethyloxy)benzoic acid (0.135 g, 0.318 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) and then recrystallized from ether to obtain the titled compound (0.054 g, 0.102 mmol, 32%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=C[CH:2]=1.[C:8]([OH:11])(=[O:10])[CH3:9].[OH2:12]>>[C:8]([O:11][CH2:5][CH:6]=[C:1]([CH3:7])[CH:2]=[O:12])(=[O:10])[CH3:9]
Reactant: O
Reactant: Cc1ccccc1
Reactant: CC(=O)O
Product: CC(=O)OCC=C(C)C=O
Temperature: 75 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
1-Acetoxy-4-chloro-3-methyl-2-butene (7.8 g) was added to a suspension of hexamine (6.7 g) and acetonitrile (47 ml), and the mixture was stirred at room temperature for 16 hours. The precipitated crystals were separated by filtration to give crystals (12.5 g) of a quaternary ammonium salt. This salt (7.9 g) was dissolved in water (50 ml), and toluene (100 ml) was added. With stirring at 75° C., acetic acid (1.5 g per addition) was added 30 minutes, 1 hour and 2 hours after the beginning of the reaction. The reaction was stopped 6 hours after the beginning of the reaction. The toluene layer was separated and concentrated, and the resulting residue was purified by column chromatography on silica gel to give 4-acetoxy-2-methyl-2-buten-1-al (2.6 g, 74%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH:11]=[CH2:10]
Reactant: N#Cc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C#N)cc1
Reaction time: 4 h
Yield: 96 %

Procedure:
A mixture comprising 29.75 g of 4-cyanophenol, 33.27 g of allyl bromide, 41.46 g of potassium carbonate and 350 ml of acetone, was refluxed under stirring for 4 hours. Acetone was distilled, and water was added to the residue. The mixture was extracted with benzene. The benzene layer was washed sequentially with a 5% sodium hydroxide aqueous solution and water, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a pale yellow oily substance. The residual substance was crystallized from n-hexane-ethyl ether to obtain 38.16 g of 4-allyloxy benzonitrile as colorless crystals having a melting point of from 40.5° to 41° C.