Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][S:29]C(=O)C)[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][C:44]([CH3:47])([OH:46])[CH3:45].CO.[OH-].[K+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][S:29][CH2:42][CH2:43][C:44]([OH:46])([CH3:47])[CH3:45])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:35])[CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)CCSC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(acetylthiomethyl)androsta-5,7-diene (135 mg, 0.223 mmol) and 4-bromo-2-methylbutan-2-ol (186 mg, 1.12 mmol) in tetrahydrofuran (1.5 ml), was added a 1M potassium hydroxide methanol solution (1.5 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by the addition of a saturated aqueous ammonium chloride solution and the extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was purified by preparative thin layer chromatography (4 sheets (each 0.5 mm thickness), dichloromethane:ethyl acetate=9:1, developed once) to give the titled compound (131 mg, 90%) as a colorless oil.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].[CH3:7][Si:8]([CH3:14])([CH3:13])[O:9][CH2:10][CH2:11]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:7][Si:8]([CH3:14])([CH3:13])[O:9][CH2:10][CH2:11][C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)OCCBr
Reactant: c1cc[cH-]c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCC1=CC=CC1
Reaction time: 12 h
Yield: 64 %

Procedure:
150 ml of a 2.3 M sodium cyclopentadienide solution in tetrahydrofurane (346 mmol) is slowly added to a solution of 68.2 g (346 mmol) 2-trimethylsiloxy-1-bromo-ethane in tetrahydrofurane. The immediate formation of a pinkish solid is observed. The reaction is maintained under stirring for 12 hours. Then, an ammonium chloride aqueous solution is added. The organic phase is extracted, dried with magnesium sulphate and the volatile part is distilled under vacuum, obtaining an orange oil. This oil is distilled in order to obtain a colourless oil. (Tb.: 63–65° C., 0.02 bar (15 mmHg.)). (40.3 g, 221 mmol. Yield:64%). 1H-NMR (CDCl3): 6.50–6.00 (m,3H), 3.75 (m, 2H), 2.95 (m, 2H), 2.65 (m, 2H), 0.15 (s, 9H).
Reaction SMILES: O.[NH2:2]N.C[N:5](/[CH:7]=[N:8]/[C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([I:17])[CH:11]=1)C>C(O)(=O)C>[I:17][C:12]1[CH:11]=[C:10]([C:9]2[NH:8][CH:7]=[N:5][N:2]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(C(=O)/N=C/N(C)C)cc1I
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2nnc[nH]2)cc1I
Temperature: 90 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Hydrazine monohydrate (0.30 g, 6.0 mmol) was added to a stirred solution of (E)-N-((dimethylamino)methylene)-3-iodo-4-methylbenzamide (preparation 48b, 1.20 g, 3.8 mmol) in acetic acid (6 mL) and the mixture was stirred and heated to 90° C. After 2 hours, the mixture was concentrated in vacuo and water and 2N aqueous sodium hydroxide solution were added to the residue. The solid that formed was filtered, washed with water and dried in vacuo to give the title compound (0.98 g, 91%) as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[NH:25][C:26](=[O:41])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]2[NH:25][C:26](=[O:41])[CH2:27][C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N:35]4[CH:39]=[CH:38][N:37]=[N:36]4)[CH:30]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C#Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C#Cc1ccccc1)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example M5) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (76 mg).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2].Cl.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)#[N:11]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:3]([C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCNCCC(=O)O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CCC(=O)O)C(=O)c1ccc(C#N)cc1
Yield: 56 %

Procedure:
A suspension of ethyl β-alanine.HCl (2.81 g, 18.3 mmol) and 4-cyano-benzoyl chloride (3.03 g, 18.0 mmol) in DCM (30 mL) was stirred overnight at RT. The mixture was diluted with EtOAc, washed with aq. citric acid (3%), sat. aq. NaHCO3 and H2O. Drying (MgSO4) and evaporation of the solvent gave compound 2 (2.52 g, 56%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.Br[CH2:13][CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH:14]([CH3:16])[CH3:15]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)CBr
Product: COc1ccc(C=O)cc1OCC(C)C

Procedure:
The title compound was prepared by reaction of isovanillin with 1-bromo-2-methyl propane as described in WO 04/000 806 A1 (Elbion AG).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CC(C)n1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-isopropylpyrazole.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:12]=[C:11]([NH:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:3]=1[C:4](OC(C)(C)C)=[O:5].COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[NH2:1][C:2]1[C:3]([CH2:4][OH:5])=[C:11]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:41])[O:42][C:43]([CH3:45])([CH3:46])[CH3:44])[CH:12]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)[N:14]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c(CO)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-4-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}nicotinate (0.113 g, 0.178 mmol) in THF (5 mL) was added a solution of Vitride® (3.4 M, 1.0 mL, 3.4 mmol). The mixture was stirred at 0° C. for 0.5 hrs, quenched with saturated aqueous potassium sodium tartaric acid solution, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a solid, which was triturated with ethyl acetate and diisopropyl ether to give tert-butyl 2-{[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]-phenyl}-3-(hydroxymethyl)-4-pyridinyl]amino}ethylcarbamate as a pink solid (0.078 g, yield; 78%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=2[O-:18])=[CH:8][CH:7]=1)=[O:5])C.N1C=CC=CC=1C1C=CC(C(O)=O)=CC=1.[OH-].[Na+]>O1CCOCC1>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=2[O-:18])=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(-c2cccc[n+]2[O-])cc1
Agent: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cccc[n+]2[O-])cc1
Yield: 87.8 %

Procedure:
2-(4-Ethoxycarbonylphenyl)pyridine N-oxide (260 mg) synthesized from 4-(2-pyridyl)benzoic acid in the same manner as in the above Referetnial Example was dissolved in 1,4-dioxane (10 ml), a 1N aqueous solution (2.00 ml) of sodium hydroxide was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (6 ml) was added to the residue, and precipitate formed was collected by filtration to obtain the title compound (202 mg) as a colorless amorphous solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[C:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C>ClCCl>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[C:24](=[CH:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
500 μl (4.6 mmol) of phenyl isocyanate are added dropwise to a solution of 1.2 g (2.3 mmol) of 5-(3′-aminobiphenyl-4-ylmethylene)thiazolidine-2,4-dione prepared as in Example 33(a) and 0.9 ml (6.4 mmol) of triethylamine in 12 ml of dichloromethane. The reaction medium is stirred at room temperature for 2 hours. It is extracted with dichloromethane and washed with water, and the organic phase is separated out after settling of the phases has taken place. The organic phase is evaporated and the residue obtained is washed with dichloromethane and dried. 950 mg (50%) of the expected product are collected.
Reaction SMILES: [C:1]1([CH:7]2[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([CH:23]=[CH2:24])=[O:22]>C(O)C>[C:1]1([CH:7]2[CH:15]3[CH:11]([CH2:12][N:13]([CH2:24][CH2:23][C:21](=[O:22])[CH3:20])[CH2:14]3)[CH2:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2c3ccccc3CC3CNCC32)cc1
Reactant: C=CC(C)=O
Solvent: CCO
Product: CC(=O)CCN1CC2Cc3ccccc3C(c3ccccc3)C2C1

Procedure:
A solution of 7.4 g of (3aRS,4SR,9aSR)-3a,4,9,9a-tetrahydro-4-phenyl-benz[f]isoindoline in 60 cc of ethanol is heated to the boil at reflux for 11/2 hours after the addition of 3 cc of methylvinylketone, and is subsequently concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate. After concentrating by evaporation, the filtrate yields the title compound as oily residue. Hydrogen maleate salt form: M.P. 121°-124° (after crystallization from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[N:9][OH:10].[Cl:11]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:11][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[N:9][OH:10]
Reactant: ON=Cc1cnccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1cnccc1Cl
Yield: 75.4 %

Procedure:
Dissolve 4-chloropyridine-3-carboxaldehyde oxime (2.60 g, 0.017 mol) in N,N-dimethylformamide (20 mL). Add N-chlorosuccinimide (2.48 g, 0.018 mol) in small portions and stir overnight at ambient temperature. Pour the mixture into water and extract with ethyl acetate. Wash the combined extracts with water and dry over sodium sulfate. Concentrate in vacuo to give 2.45 g (75%) of crude product as a yellowish solid. 1H NMR was consistent with structure.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH:6]1[C:14]([F:22])([F:21])[C:15]([F:20])([F:19])[S:16]([O-:18])=[O:17])=[O:4].[Na+:23].[OH:24]O>[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH:6]1[C:14]([F:22])([F:21])[C:15]([F:19])([F:20])[S:16]([O-:24])(=[O:18])=[O:17])=[O:4].[Na+:23]
Reactant: OO
Reactant: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)S(=O)[O-])C1
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)S(=O)(=O)[O-])C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a glass flask equipped with a thermometer and a capacitor were charged the aqueous solution of crude sodium 2-(2,4-bis(methoxycarbonyl)cyclopentyl)-1,1,2,2-tetrafluoroethanesulfinate obtained as described above, and a catalytic amount of sodium tungstate (IV) dihydrate. Thereto, a 35% by mass hydrogen peroxide solution 3.00 g was added dropwise. After the mixture was stirred at room temperature for 5 hrs, the disappearance of the raw material was confirmed by 19F-NMR to decide completion of the reaction. After the completion of the reaction, 20 mL of water was further added thereto, and the aqueous layer was washed with 30 mL of dichloromethane five times to obtain an aqueous solution of sodium 2-(2,4-bis(methoxycarbonyl)cyclopentyl)-1,1,2,2-tetrafluoroethanesulfonate (precursor compound (a-5)) represented by the following formula (a-5), which was used for the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10]C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[CH:28][CH:29]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC(C)(C)CO)cc2)c2ccccc21
Temperature: 95 °C

Procedure:
(±)-Cis-N-(4-chloro-phenyl)-N-{1-[4-(3-hydroxy-2,2-dimethyl-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide (210 mg, 0.484 mmol) was dissolved in DMF (10 mL) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimethyl-propan-1-ol (813 mg, 4.84 mmol), the reaction was heated to 95° C. and stirred over night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate-70/30 dichloromethane/ethyl acetate) to afford the pure ester (110 mg, 44%)
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)=[O:11].O>ClCCl>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:2][CH3:1])=[O:11]
Reactant: CN
Reactant: O=S(Cl)c1ccccc1Br
Solvent: O
Solvent: ClCCl
Product: CNS(=O)c1ccccc1Br
Temperature: -10 °C
Yield: 82.7 %

Procedure:
Liquified methylamine (36.3 mL, 0.817 mol) was added slowly to a stirred solution of 2-bromobenzenesulfinyl chloride (48.9 g, 0.204 mol) in dichloromethane (489 mL) cooled below -70° C. The reaction mixture was allowed to warm to -10° C. and was then shaken with water (489 mL). The layers were separated, and the dichloromethane layer was washed with water (2×245 mL), dried (Na2SO4), and filtered. Evaporation of the solvent left a pale yellow oil (44.4 g) that mostly crystallized on standing. This was dissolved in dichloromethane and chromatographed on a column of silica gel using 2:1 dichloromethaneether as eluant. Fractions containing product (Rf =0.52, UV) were evaporated to leave 2-bromo-N-methylbenzenesulfinamide as a white crystalline solid (39.5 g) melting at 66°-70° C.
Reaction SMILES: [ClH:1].Cl.CN1CCN(CC(C2(O)CCCCC2)C2C=CC=C(OC3C=CC=CC=3)C=2)CC1.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](=O)[CH:40]([C:54]2([OH:60])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH:40]([C:54]2([OH:60])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]2)[C:41]2[CH:42]=[CH:43][C:44]([O:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:45][CH:46]=2)[CH2:35][CH2:34]1
Reactant: CN1CCN(C(=O)C(c2ccc(Oc3ccccc3)cc2)C2(O)CCCCC2)CC1
Agent: CN1CCN(CC(c2cccc(Oc3ccccc3)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(Oc3ccccc3)cc2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 1, step 2 1-[2-(4-methylpiperazin-1-yl)-1-(3-phenoxyphenyl)ethy]cyclohexanol dihydrochloride was prepared from 1-[2-(4-methylpiperazin-1-yl)-1-(4-phenoxyphenyl)-2-oxoethy]cyclohexanol. MS(ESI) m/z 395 ([M+H]+). Anal Calcd for C25H34N2O22HCl 0.9H2O: C,62.08; H,7.88: N,5.79. Found: C, 62.26; H, 8.11; N,5.70.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[OH-:18].[Na+].OO>C1COCC1>[CH2:11]([O:10][CH2:9][CH2:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([CH2:1][OH:18])[CH2:3][CH2:4]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=C1CCC(CCOCc2ccccc2)CC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0 C) solution of ((2-(4-methylenecyclohexyl)ethoxy)methyl)benzene (9.68 g, 41.66 mmol) in THF (200 mL) was added B2H6 Me2S complex (2M in THF, 41.66 mL, 83.32 mmol) under N2. After being stirred at 0° C. for 2 h and at rt for another 2 h, the solution was cooled to 0° C. and added a mixture of 3M aqueous NaOH solution (34 ml) and 30% hydrogen peroxide solution (34 mL) dropwise. The resulting mixture was stirred at 0° C. for 1 h and at rt for 1.5 h. Aqueous workup and purification by flash column chromatography (eluent: 40% EtOAc in hexanes) gave the product as yellow oil (7.04 g, 68%). LC/MC: 249.1 (MH)+.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[C:3]1=[O:20]
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Product: COc1cccc(CC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylacetyl chloride. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p. 198°-199° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(CC)CC>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (4.18 g, 20.0 mmol), morpholine (2.09 g, 24.0 mmol), Et3N (6.07 g, 60.0 mmol) and EtOAc (30 mL) was stirred at rt for 5 h. The mixture was then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (5.0 g, 91%).
Reaction SMILES: ClC(Cl)C.[OH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:22]([N:24]([CH2:29][CH3:30])[S:25](Cl)(=[O:27])=[O:26])[CH3:23]>C(Cl)Cl>[OH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:25](=[O:27])(=[O:26])[N:24]([CH2:29][CH3:30])[CH2:22][CH3:23])[CH:12]=2)[C:7]=1[CH:16]=[O:17]
Reactant: CCN(CC)S(=O)(=O)Cl
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc2c(C=O)c(O)ccc2c1
Temperature: 50 °C
Yield: 85.1 %

Procedure:
600 ml of a dichloroethane solution containing 150 g (0.87 mole) of 2-hydroxy-1-naphthaldehyde and 250 g (1.87 moles) of anhydrous aluminum chloride was stirred with heating at 50° C. To the solution was added dropwise 172.2 g (1 mole) of N,N-diethylsulfamoyl chloride. After the completion of the dropwise addition, the mixture was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was poured into 1 liter of ice water. Methylene chloride was added to the mixture and it was extracted and separated. The organic layer was concentrated to about 500 ml. To the concentrate was added methanol to precipitate crystals. The precipitated crystals were collected by filtration, and washed with methanol to obtain 228 g (0.74 mole) of 2-hydroxy-6-(N,N-diethylsulfamoyl)-1-naphthaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2([C:13]3([CH3:21])[CH2:16][C:15]([F:18])([F:17])[C:14]3([F:20])[Cl:19])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([C:13]2([CH3:21])[CH2:16][C:15]([F:18])([F:17])[C:14]2([F:20])[Cl:19])([OH:11])[CH2:12][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:4][CH:3]=1
Reactant: CC1(C2(C#Cc3ccc(Cl)cc3)CO2)CC(F)(F)C1(F)Cl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C(O)(C#Cc2ccc(Cl)cc2)Cn2cncn2)CC(F)(F)C1(F)Cl
Yield: 77.4 %

Procedure:
31.8 g of 2-[2-(4-chlorophenyl)-ethin-1-yl]-2-(2,3,3-trifluoro-2-chloro-1-methylcyclobut-1-yl)-oxirane are added at room temperature to a stirred mixture of 6.4 g of 1,2,4-triazole, 12.6 g of ground potassium carbonate and 300 ml of acetonitrile. The reaction mixture is refluxed for 12 hours, and then cooled and filtered. The filtrate is concentrated under reduced pressure, and the remaining residue is purified by column chromatography (ethyl acetate) on silica gel. 29 g (75.5% of theory) of 1-(4-chlorophenyl)-3-(2,3,3-trifluoro-2-chloro-1-methyl-cyclobut-1-yl)-4-(1,2,4-triazol-1-yl)-but-1-in-3-ol are obtained in form of a viscous oil.