Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](O)[CH2:10][C@@:9]1([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([F:27])[CH2:10][C@:9]1([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCC[C@]1(C(=O)c2ccc(Cl)c(Cl)c2)CC(O)CN1C(=O)OC(C)(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC[C@@]1(C(=O)c2ccc(Cl)c(Cl)c2)CC(F)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To a stirred solution of (R)-2-(3,4-dichloro-benzoyl)-4-hydroxy-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.222 g, 0.554 mmol) in THF (3 mL) at ambient temperature under nitrogen was added perfluorobutanesulfonyl fluoride (0.195 mL, 1.11 mmol), triethylamine trihydrofluoride (0.181 mL, 1.11 mmol) and triethylamine (0.46 mL, 3.32 mmol). The reaction mixture was stirred for 18 hours, then filtered through a pad of silica, washed with EtOAc, and concentrated in vacuo to give (S)-2-(3,4-dichloro-benzoyl)-4-fluoro-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.222 g, 0.551 mmol, 99%) as a yellow foam that was used directly in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][CH3:7].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>>[CH2:5]([C:4]([CH2:8][CH2:9][CH3:10])=[CH:3][CH2:2][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])[CH2:6][CH3:7]
Reactant: CCCC(=CCBr)CCC
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CCCC(=CCS(=O)(=O)c1ccccc1)CCC

Procedure:
Using the procedure of Example I, 1-bromo-3-propyl-2-hexene was reacted with sodium phenyl sulfinate to form (3-propyl-2-hexenyl)-phenyl sulfone which was then reacted with ethyl β,β-dimethyl-acrylate to form ethyl dl-trans 3,3-dimethyl-2-(2'-propyl-1'-pentenyl)-cyclopropanecarboxylate having a boiling point of 80° C. at 0.06 mm Hg and a refractive index nD22 =1.464. The said ethyl ester was hydrolyzed under alkaline conditions to form dl-trans 3,3-dimethyl-2-(2'-propyl-1'-pentenyl)-cyclopropane carboxylic acid having a boiling point of 116° C. at 0.05 mm Hg and a refractive index nD22 =1.4755 which was then reacted with thionyl chloride to obtain dl-trans 3,3-dimethyl-2-(2'-propyl-1'-pentenyl)-cyclopropanecarboxylic acid chloride having a boiling point of 75° C. at 0.04 mm Hg and a refractive index nD24 =1.4795.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]([NH:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:18])[CH3:15].C(=O)([O-])O.[Na+]>C(O)C>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:23]1[CH2:22][CH2:21][N:20]([NH:19][C:17]([O:16][CH2:14][CH3:15])=[O:18])[CH2:25][CH2:24]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCBr)c1ccccc1
Reactant: CCOC(=O)NN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)NN1CCN(CCCCC(=O)c2ccccc2)CC1
Yield: 91 %

Procedure:
17.0 g of 1-benzoyl-4-bromobutane, 13.4 g of 1-(ethoxycarbonylamino)piperazine and 17.8 g of sodium hydrogen carbonate were heated under reflux in ethanol for 6 hours with stirring. The insoluble materials were removed from the reaction mixture by filtration. The solvent was distilled off, and water was added to the residue. The mixture was extracted with benzene. The extract was recrystallized from benzene-hexane to give 21.4 g of 4-(4-benzoylbutyl)-1-(ethoxycarbonylamino)-piperazine having a melting point of 105° to 106° C.
Reaction SMILES: Br[C:2]1[N:3]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[N:5]=2.Cl.C([OH:32])CCC>>[NH2:11][C:8]1[N:7]=[C:6]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:5]=[C:4]2[C:9]=1[NH:10][C:2](=[O:32])[N:3]2[CH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Nc1nc(NCC2CCCCC2)nc2c1nc(Br)n2CC1CCOCC1
Reactant: CCCCO
Agent: Cl
Product: Nc1nc(NCC2CCCCC2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 100 °C

Procedure:
To a solution of 8-bromo-N2-(cyclohexylmethyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine-2,6-diamine (110 mg) in dry n-butanol (1.5 ml) was added 37% grade hydrochloric acid (1.5 ml) at RT. The reaction was heated to 100° C. for six hours. The reaction was concentrated in vacuo, taken up in water (5 ml) and neutralised by the addition of 2.0M sodium hydroxide solution. The resulting white precipitate was filtered. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford a white solid (20 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([F:20])[CH:22]=2)(=[O:29])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Product: Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3-fluoro-4-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[S:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)=[O:16])=[CH:4][C:3]=1[N+:34]([O-])=O.CO.[S-2].[Na+].[Na+]>O>[NH2:34][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[S:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=2)=[O:16])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c(N)c2)c(-c2ccc(N)c(N)c2)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a suspension of 21.2 g. (0.076 moles) of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide in 80 ml. of methanol a solution of 22 g. (0.17 moles) of sodium sulfide of 60% purity in 25 ml. of water is added in one hour, under boiling. The reaction mixture is refluxed for 3 hours, and the progress of the reaction is monitored by thin layer chromatography. Thereafter 1 g. of celite is added to the reaction mixture, which is then filtered while hot. The filtrate is diluted with 50 ml. of water, and is slowly cooled to room temperature. The precipitate is filtered off, and the substance remaining on the filter is washed base-free with water. The product is then dried at 50° to 60° C. to yield 17 g. of the title compound, melting at 131° to 132° C.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.[Cl:9][C:10]([Cl:15])([Cl:14])[C:11](Cl)=[O:12].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[Br:8][C:5]1[S:6][CH:7]=[C:3]([NH:2][C:11](=[O:12])[C:10]([Cl:15])([Cl:14])[Cl:9])[N:4]=1
Reactant: Nc1csc(Br)n1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1csc(Br)n1)C(Cl)(Cl)Cl
Yield: 53.9 %

Procedure:
4-Amino-2-bromo-thiazole hydrobromide (15.6 g) and trichloroacetyl chloride (14.3 g) were suspended in methylene chloride (100 ml) with stirring and treated dropwise with pyridine (16 ml) over 15 minutes maintaining reaction temperature at 0° C. with an ice bath. After completing the addition, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate (250 ml) and stirred for 30 minutes. The mixture was separated and the organic layer washed with 2N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo and the residue treated with charcoal in hexane and recrystallised from hexane to give the title compound (10.5 g) m.p. 77°-80° C. (Found: C, 19.0; H, 0.7; N, 8.5. C5H2Cl3BrN2OS requires C, 18.5; H, 0.6; N, 8.6%)
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH:7]=[CH2:8])C.[OH-].[Na+].CCOC(C)=O>CCO.C1COCC1>[CH3:12][C:11]([CH3:14])([CH3:13])[C:10]([NH:9][CH:5]([CH2:6][CH:7]=[CH2:8])[C:4]([OH:16])=[O:3])=[O:15]
Reactant: C=CCC(NC(=O)C(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(NC(=O)C(C)(C)C)C(=O)O
Reaction time: 1 h
Yield: 91.8 %

Procedure:
10.50 g of the above prepared 2-(2,2-dimethyl-propionylamino)-pent-4-enoic acid ethyl ester (46.19 mmol) were dissolved in 146 ml of a 1:1 mixture of EtOH and THF and treated under cooling with an ice bath with 46.19 ml of 2N NaOH (2 eq.). After 1 h, the reaction mixture was poured onto crashed ice/AcOEt/HCl, the aqueous phase reextracted once more with AcOEt, the combined organic layers washed with water, dried over sodium sulfate, and evaporated to dryness. Thereby, 8.45 g of the title product was obtained as white solid of mp. 87–88°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=1>CN(C=O)C.C(Cl)Cl>[Br:24][C:22]1[CH:23]=[C:18]([NH:17][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH2:13][CH2:12]2)=[O:16])[CH:19]=[N:20][CH:21]=1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: Nc1cncc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)Nc2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
Oxalyl chloride (8.67 mmol) followed by DMF (2 drops) was added to a solution of 1-methyl piperidine-4-carboxylic acid (XLIII) (5.78 mmol) in DCM and stirred 30 min at room temperature under argon. The volatiles were evaporated under vacuum by avoiding contact with air. Pyridine was added to the residue followed by addition of 3-amino-5-bromopyridine (XL) (5.20 mmol). The solution was further stirred at room temperature for 3 h under argon. The pyridine was evaporated under vacuum. The residue was treated with water, basified by saturated NaHCO3 solution and washed with DCM. The aqueous layer was extracted with n-butanol. The combined organic layer was evaporated. The residue was dissolved in DCM with the addition of few drops of MeOH. The insoluble inorganic solids were filtered off. The filtrate was concentrated under vacuum to get N-(5-bromopyridin-3-yl)-1-methylpiperidine-4-carboxamide (XLIV) as a brown viscous liquid (0.74 g, 43% yield). 1H NMR (DMSO-d6) 1.61-1.69 (m, 2H), 1.77-1.79 (m, 2H), 1.93-1.97 (m, 2H), 2.20 (s, 3H), 2.29-2.35 (m, 1H), 2.84-2.87 (m, 2H), 8.36 (d, J=1.6 Hz, 1H), 8.39 (m, 1H), 8.66 (d, J=1.6 Hz, 1H), 10.33 (s, 1H); ESIMS found C12H16BrN3O m/z 299 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.C(N(CC)CC)C.O>ClCCl>[C:1]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 16 h

Procedure:
Acetyl chloride (3.95 ml) was added dropwise to a stirred solution of 4-amino1-benzylpiperidine (10.0 g) and triethylamine (7.7 ml) in dry dichloromethane (100 ml) at 4° C. The mixture was allowed to reach ambient temperature and stirred for 16 hours. Water was then added, the organic phase separated and dried (MgSO4), and removal of the solvent by evaporation gave 4-acetylamino-1-benzylpiperidine, 10.23 g, as a light brown solid which was used without further purification: NMR (CDCl3) δ 7.29(5H,m), 5.29(1H,b), 3.79(1H,m), 3.49(2H,s), 2.80(2H,dm), 2.12(2H,dt), 1.95(3H,s), 191(2H,dm), 1.46(2H,dq); m/e 233 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(Cl)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 177 %

Procedure:
A solution of BH3 (34 mL, IM in tetrahydrofuran) was added dropwise to the solution of 4-bromo-3-chlorobenzoic acid (2.5 g, 11.4 mmol) in tetrahydrofuran at 0° C. The mixture was stirred at 40° C. overnight. Acetic acid (5 mL) was added dropwise to the reaction mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give (4-bromo-3-chlorophenyl)methanol as a white solid (4.47 g, 91%). 1H NMR (300 MHz, d6-DMSO): 7.69 (d, J=8.1, 1H), δ 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H), 5.38 (s, 1H), δ 4.48 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24](=[O:26])[CH3:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:25][C:24]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)=[O:26])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc1OC

Procedure:
The procedure described in Example 8 was repeated using 1.8 g of 3.4-dihydroxy-5-nitrobenzaldehyde and 1.8 g of 3',4'-dimethoxyacetophenone in 20 ml of methanol. Yield 1.7 g (50%), m.p. 206°-208° C.
Reaction SMILES: [C:1](=[O:6])([O:4]C)[O:2]C.[CH3:7][N:8]([CH3:10])[CH3:9].O>CO>[C:1](=[O:2])([O-:6])[OH:4].[CH3:7][N+:8]([CH3:1])([CH3:10])[CH3:9]
Reactant: CN(C)C
Reactant: COC(=O)OC
Solvent: O
Solvent: CO
Product: C[N+](C)(C)C
Product: O=C([O-])O
Reaction time: 3 h

Procedure:
604 g of dimethyl carbonate, 394 g of trimethylamine, 300 g of water and 500 g of methanol were introduced in the same reactor as used in Preparation Example 1 and heated with stirring. After the temperature in the reactor reached 100° C., the reaction was continued for 3 hours at 100° C. Tetramethylammonium hydrogencarbonate was obtained in a yield of 90.3 mol % (based on trimethylamine).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].[Cl-].[NH4+]>C1COCC1>[Cl:32][C:31]([Cl:34])([Cl:33])[CH2:30][O:29][C:27](=[O:28])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (16.8 g) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) and triethylamine (11.32 mL) in THF (338 mL) was added 2,2,2-trichloroethyl chloroformate (11.2 mL). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19.0 g).
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](O)=[N:21]4)=[CH:16][CH:15]=3)[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH2:24][C:25]1[C:39]([O:40][CH3:41])=[CH:38][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20]([NH:24][C:25]5[C:39]([O:40][CH3:41])=[CH:38][C:28]6[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:32][CH2:33][C:27]=6[CH:26]=5)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(=O)(NC1CC1)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: COc1cc2c(cc1N)CCN(CC(N)=O)CC2
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4cccc(S(=O)(=O)NC5CC5)c4)n3n1)CCN(CC(N)=O)CC2

Procedure:
This compound as a yellow solid, was prepared following the same procedure as described for the synthesis of Example 522 by coupling N-Cyclopropyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide. MP>150° C. (decomp.). LCMS (E/I+) 562.14 (M+H). 1H NMR (DMSO-d6) δ 9.00 (s, 1H), 8.60 (d, 1H, J=6.50 Hz), 8.20 (s, 1H), 7.95 (s, 1H), 7.85 (m, 2H), 7.70 (t, 1H, J=6.50 Hz), 7.20 (d, 1H, J=6.00 Hz), 7.00 (d, 1H, J=6.00 Hz), 6.80 (s, 1H), 4.30 (broad, 1H), 3.80 (s, 3H), 3.70 (broad, 1H), 2.80 (broad, 2H), 2.70 (broad, 2H), 2.60 (broad, 4H), 2.40 (broad, 2H), 2.10 (broad, 1H), 1.20 (broad, 1H), 0.50 (broad, 2H), 0.40 (broad, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:16].[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC>O1CCCC1>[BH:17]([OH:22])[OH:18].[C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][CH:2]=[C:3]([CH3:16])[CH:4]=1)(=[O:9])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(S(=O)(=O)NC(C)(C)C)c1
Product: OBO
Temperature: -78 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
4-Bromo-N-tert-butyl-3-methyl-benzenesulfonamide (10 g, 32.6 mmol) was dissolved in dry tetrahydrofurane, then cooled to −78° C. Triisopropyl borate (27.7 ml, 120.8 mmol, 3.7 equiv.) was added in one portion, followed by the dropwise addition of n-butyllithium solution 1.6M (75.5 ml, 120.8 mmol, 3.7 equiv.) at −78° C. The mixture was stirred overnight, then quenched dropwise with water. The organic solvent was evaporated and the pH adjusted to 3 with 0.5 M HCl. The residue was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesiumsulfat-dihydrate, filtered and evaporated. The crude product was purified on silica-gel with ethyl acetate/n-heptane to give 2.82 g of the title product as yellow, waxy solid. MS (ES): m/e 270 (M−H)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42][C:43]#[C:44][C:45]([CH3:55])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:46]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:42][C:43]#[C:44][C:45]([CH3:46])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:55])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Reactant: C[C@@H](O)C1=CC[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
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C#CCO[C@H](C)C1=CC[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
Yield: 92.8 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne (109 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (76.4 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1.O.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
To a solution of 0.58 g (2.5 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 30 mL anhydrous pyridine was added 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, followed by stirring for 6 hours in a heat flux condition. After cooling to room temperature, cold water (100 mL) containing HCl (10 mL) was added to the solution, which was then allowed to stand for 30 min to form precipitates. These were separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.70 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 75%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][S:13][C:7]=2[N:6]=[CH:5]1.[Br:16]Br>CN(C=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>[Br:16][C:12]1[S:13][C:7]2[N:6]=[CH:5][N:4]([CH2:3][C:2]([F:1])([F:14])[F:15])[C:9](=[O:10])[C:8]=2[CH:11]=1
Reactant: O=c1c2ccsc2ncn1CC(F)(F)F
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)sc2ncn1CC(F)(F)F
Yield: 93.5 %

Procedure:
A solution of 3-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one (2 g, 8.54 mmol) and bromine (0.484 ml, 9.39 mmol) in DMF (20 ml) at 0° C. was stirred for 60 min. The reaction mixture was diluted with 1:1 sodium thiosulfate (25% aqueous solution)/saturated sodium bicarbonate (aq) solution (100 ml) and extracted with ethyl acetate (100 ml). The concentrated crude product was purified by flash chromatography (0-60% ethyl acetate/cyclohexane) to give the title compound (2.5 g, 94%). LCMS RT=1.16 min, M+H+=312.9/314.9.