Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][CH2:20]2)=[O:18])[CH:12]=1)C(=O)OC(C)(C)C.[ClH:29].O1CCOCC1>>[ClH:29].[CH3:1][NH:2][CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[C:17]([N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: CN(Cc1cccc(C(=O)N2CCCc3ccccc32)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCc1cccc(C(=O)N2CCCc3ccccc32)c1
Yield: 99 %

Procedure:
A solution of tert-butyl N-methyl-N-(3-(1,2,3,4-tetrahydroquinoline-1-carbonyl)benzyl)-carbamate (7.7 g, 20 mmol) in 4N hydrogen chloride/dioxan solution (20 ml) was stirred for 30 min. The mixture was reduced and azeotroped with toluene and dichloromethane to yield 1-(3-methylaminomethylbenzoyl)-1,2,3,4-tetrahydroquinoline hydrochloride as a glass (6.3 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4]O.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][Cl:23]
Reactant: COc1ccc(CO)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a solution of 2-chloro-4-methoxybenzyl alcohol (1.5 g, 8.7 mmol) in dichloromethane (10 mL) were added under ice-cooling triethylamine (2.4 mL, 17.4 mmol) and methanesulfonyl chloride (0.74 mL, 9.5 mmol) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.01 g, 61%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:36])([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:27][C:26]=1[O:37][CH3:38])(C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:32]([C:31]([C:28]1[CH:29]=[CH:30][C:25]([OH:24])=[C:26]([O:37][CH3:38])[CH:27]=1)([OH:36])[CH2:34][CH3:35])[CH3:33]
Reactant: CCC(O)(CC)c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)(CC)c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (24.7 mL, 24.7 mmol) was added to a solution of 3-[4-(t-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-pentan-3-ol (Example 176-(2); 8.0 g, 24.7 mmol) in tetrahydrofuran (30 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=1:1) to give the title compound (4.25 g, 83%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]2[C:19]#[N:20])=[O:8])=[CH:5][CH:4]=1.C(=O)(O)[O-:26].[Na+].OO>CC(C)=O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]2[C:19]([NH2:20])=[O:26])=[O:8])=[CH:21][CH:22]=1
Reactant: O=C([O-])O
Reactant: N#CC1C=Cc2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)C1C=Cc2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Yield: 40.8 %

Procedure:
The title compound was prepared by the procedure described in step 2 of Example 1 using 20.0 g of 1-(4-Trifluoromethylbenzoyl)-1,2-dihydro-quinoline-2-carbonitrile, 10.0 g of sodium bicarbonate, 500 mL of acetone, and 250 mL of 30% hydrogen peroxide solution. Crystallization from acetonitrile afforded the title compound (8.6 g) as a white solid, m. p. 158-160° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])[CH3:30]>>[CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([C:29](=[O:31])[CH3:30])=[CH:33][CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 94.7 %

Procedure:
The title compound (168 mg) was prepared according to Example 189 using 255 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 341 mg of 4-acetylphenylboronic acid. MS (ESI): exact mass calculated for C18H23N3O, 297.18; found, m/z 298.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.17-8.15 (m, 1H), 7.69-7.67 (m, 1H), 7.51-7.49 (m, 1H), 7.37-7.35 (m, 1H), 4.65 (br s, 1H), 4.46-4.38 (m, 1H), 4.00-3.50 (m, 2H), 3.48-3.42 (m, 1H), 3.25-3.17 (m, 1H), 3.13-2.81 (m, 2H), 2.67 (s, 1.5H), 1.55 (s, 1.5H), 1.44-1.40 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.C1C=CC2N(O)N=NC=2C=1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([O-])=[O:25]>CN(C)C=O>[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([CH:8]1[CH2:7][CH2:6][NH:5][CH:4]([CH2:3][CH2:2][OH:1])[CH2:9]1)=[O:25]
Reactant: OCCC1CCCCN1
Reactant: O=C([O-])CCCCl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCl)C1CCNC(CCO)C1

Procedure:
2-(2-Hydroxyethyl)piperidine, HOBt and WSCI are added to N,N-dimethylformamide solution of 4-chlorobutyrate while being cooled with ice and the mixture is reacted at room temperature to obtain 1-(4-(chlorobutanoyl)-2-(2-hydroxyethyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20]>>[C:19]([N:18]([CH3:17])[C:14]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[CH:12][N:11]=1)=[O:16])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)ccn1
Reactant: CNC(C)(C)C
Product: CN(C(=O)c1cc(-c2cccc(Cl)c2)ccn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(3-chlorophenyl)picolinic acid (CAN 1207725-34-5) and N,2-dimethylpropan-2-amine (CAN 14610-37-8) as starting materials and isolated (10 mg, 77%) as colorless oil; MS (ESI, m/z): 303.4 (MH+).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:21]=[C:20]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[NH:19][N:18]=1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[CH:21]=[C:20]([C:22]2[CH:28]=[CH:27][C:25]([NH:26][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])=[CH:24][CH:23]=2)[NH:19][N:18]=1
Reactant: Nc1ccc(-c2cc(-c3nc4ccccc4[nH]3)n[nH]2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ccccc1)Nc1ccc(-c2cc(-c3nc4ccccc4[nH]3)n[nH]2)cc1
Yield: 35.7 %

Procedure:
Triethylamine (35 μL, 0.25 mmol) was added to a suspension of 4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]aniline (20 mg, 0.064 mmol) and phenyl isocyanate (7.6 mg, 0.064 mmol) in anhydrous acetonitrile (1.0 mL) at room temperature. After twelve hours the reaction was concentrated in vacuo and purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the title compound (9 mg, 36% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.92 (s, 1H), 7.78 (m, 4H), 7.63 (m, 2H), 7.48 (m, 4H), 7.40 (s, 1H), 7.30 (m, 2H), 7.00 (m, 1H); MS (EI) for C23H18N6O: 395.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:26])[CH3:25]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cccc(OC(F)(F)F)c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1nccc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)pyrimidine-4-carboxamide (15 mg, 0.05 mmol, Step-1, single enantiomer) and acetyl chloride (4 mg, 0.05 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[C:1]#[N:2])=[N+:21]=[N-:22]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2ccc(N=[N+]=[N-])c(C#N)c2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl 2-(3-cyano-4-fluorophenyl)isonicotinate and sodium azide were dissolved in a DMF solution, followed by stirring at 50° C. for 4 hours to obtain methyl 2-(4-azido-3-cyanophenyl)isonicotinate. NMRC: 7.38 (1H, d), 7.84 (1H, dd), 8.46 (1H, d).
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[C:12]([C:16]1[C:17](=[O:23])[CH:18]=[CH:19][C:20](=[O:22])[CH:21]=1)([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[C:12]([C:16]1[C:17](=[O:23])[CH:18]2[CH:19]([C:20](=[O:22])[CH:21]=1)[C:3]1([Cl:10])[C:2]([Cl:11])([Cl:1])[C:6]2([Cl:7])[C:5]([Cl:8])=[C:4]1[Cl:9])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)C1=CC(=O)C=CC1=O
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)C1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Hexachlorocyclopentadiene, 40 g., and 15.4 g. of tert-butyl-p-benzoquinone were dissolved in 300 ml. of toluene and refluxed for four hours. The solution solidified upon cooling to room temperature. The solid was washed with methanol and recrystallized from benzene. Yellow crystals were obtained, melting at 124°-125° C.
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=O.[CH3:24][C@H:25]([NH2:34])[C@H:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@@H:25]([NH:34][CH2:1][C:3]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)[CH3:24]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](NCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1)[C@H](O)c1ccccc1
Reaction time: 2 h
Yield: 88.2 %

Procedure:
[3-(2-Formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid (0.12 g, 0.37 mmol), (1R,2S)-(−)-norephedrine (0.056 g, 0.37 mmol), and sodium triacetoxyborohydride (0.12 g, 0.56 mmol) were combined in CH2Cl2 (10 mL) and stirred for 2 hours. After work-up, 0.15 g of the desired product was obtained.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.[H-].[Na+]>O1CCOCC1>[C:19]([C:4]1[C:3]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[C:2]([N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: c1nc[nH]n1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(-n2cncn2)c1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 15.4 %

Procedure:
To a solution of 5-bromo-3-cyano-1-(2,6-dichloro -4-trifluoromethylphenyl)-4-trifluoromethylsulphonylpyrazole (2.0 g) in dioxan (30 ml) was added 1,2, 4-triazole (0.74 g), and the mixture heated under reflux overnight. After cooling to ambient temperature, sodium hydride (0.125 g) was added and the mixture heated under reflux for 2 days. The solvent was evaporated in vacuo and the residue dissolved in dichloromethane (50 ml) and washed with water (50 ml). The aqueous layer was re-extracted with dichloromethane (50 ml) and the combined organics dried over anhydrous magnesium sulphate, then evaporated in vacuo to give a yellow oil. Purification by chromatography on silica, eluting with dichloromethane/hexane (1:1) gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)- 5-(1,2,4-triazol-1-yl)-4-trifluoromethylsulphonylpyrazole (0.3 g) as a white solid, m.p. 172.3°-173.7° C.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>S1(CCCC1)(=O)=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(Cl)cnc1Cl
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 60 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 100 ml of sulfolane is added dropwise at a temperature in the range from 0° C. to +10° C. Then 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at +50° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after 2 hours at +50° C. 150 ml of methylene chloride are added to the reaction mixture which is then poured into ice water. The two-phase mixture is neutralised with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phase are dried over sodium sulfate and concentrated by evaporation. The solution of the sulfolane product is separated by distillation, affording 34.3 g (82.6% of theory) of 2,5-dichloro-3-fluoropyridine.
Reaction SMILES: CN(C[C:5]1[N:6]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[N:10]=[C:7]2[S:8][CH:9]=1)C.[N+](C1C=CC=CC=1C1N=[C:31]2[N:35]([CH:36]=1)[CH:34]=C(CO)S2)([O-])=O>>[CH3:34][N:35]([CH2:36][C:9]1[S:8][C:7]2=[N:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])=[CH:12][N:6]2[CH:5]=1)[CH3:31]
Reactant: O=[N+]([O-])c1ccccc1-c1cn2cc(CO)sc2n1
Reactant: CN(C)Cc1csc2nc(-c3ccccc3N)cn12
Product: CN(C)Cc1cn2cc(-c3ccccc3N)nc2s1

Procedure:
Essentially the same procedure used during the preparation of 2-(3-dimethylaminomethyl-imidazo [2,1-b]thiazol-6-yl)-phenylamine was employed, except that [6-(2-nitro-phenyl)-imidazo[2,1-b]thiazol-2-yl]-methanol was used as the starting material.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][C:13]([CH3:15])=[CH:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: CC(C)=CCBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCOc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
3-Hydroxybenzonitrile (1.19 g, 10 mmol) and 4-bromo-2-methyl-2-butene (1.66 g, 10 mmol) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (1.66 g, 12 mmol) was added, and the solution was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The extract was washed, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5), and the title compound (1.71 g, 10 mmol, 99.4%) was obtained as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[Cl:16])=[O:4].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=2[Cl:16])=[O:4])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Product: NS(=O)(=O)c1ccc(NC(=O)CNc2ccc(Cl)cc2)c(Cl)c1

Procedure:
2-Chloro-N-(2-chloro-4-sulphamoylphenyl)-acetamide (7g) and p-chloroaniline (6.3 g) were heated together for 45 minutes on a water bath at 90°. The mixture was worked up as in Example 1(b) to yield the title product (4.5 g), m.p. 185° .
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Cu])#[N:12].CN(C=O)C>C(Cl)Cl>[CH3:10][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[C:11]#[N:12]
Reactant: COc1cccc(C)c1Br
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(C)c1C#N
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 2-bromo-1-methoxy-3-methylbenzene (7.5 g, 37 mmol), CuCN (6.7 g, 75 mmol) followed by addition of DMF (60 mL); the resulting mixture was then refluxed at 150° C. overnight. When the reaction was complete, as evidenced by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately. The solids were filtered, re-dissolved in DCM, absorbed into silica gel and loaded into column with Hexanes:EtOAc (1:1) to afford the title product.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[N:18]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][C:20](=O)[CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:1]([CH:3]=[C:20]1[CH2:21][CH:22]2[CH2:25][N:18]([CH2:24][CH2:23]2)[CH2:19]1)#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CC2CCN(C1)C2
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC2CCN(C1)C2
Temperature: 25 °C

Procedure:
Diethyl cyanomethylphosphonate (5.67 g, 0.032 mole) in THF (75 ml) was added over 10 minutes to a stirred solution of potassium tert-butoxide (3.60 g, 0.032 mole) in THF (75 ml) at 0° C. The reaction mixture was then cooled to -20° C. before dropwise addition of 1-azabicyclo[3.2.11octan-3-one* (3.64 g, 0.029 mole) in THF (50 ml) over 15 minutes. The mixture was allowed to warm to room temperature, stirred for 1h, and then poured into 20% aqueous potassium carbonate (150 ml) and extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried (Na2SO4) and evaporated to give the title compound (D11) as a 6:5 mixture of E and Z isomers (3.88 g, 90%). The isomers could be separated chromatographically on silica using 3% methanol/chloroform as eluant to give in order of elution the Z-isomer and the E-isomer as oils.
Reaction SMILES: C[Si](C)(C)[O-:3].[Na+].[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:10](F)[CH:9]=1>C1COCC1>[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:10]([OH:3])[CH:9]=1
Reactant: C[Si](C)(C)[O-]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(Br)cc1O
Temperature: 25 °C
Yield: 205.8 %

Procedure:
A solution of 2 M sodium trimethylsilanolate (15.6, 31.1 mmol) in THF was added dropwise to 4-bromo-2,5-difluoronitrobenzene (2.47 g, 10.4 mmol) under a nitrogen atmosphere. A bright red suspension was formed, and the mixture was refluxed for 27 hours. The mixture was cooled to room temperature and concentrated. Water (6 mL) was added, and the solution was acidified with a 10% HCl solution, extracted with DCM (70 mL×2). The organic layers were combined and concentrated to give 5-bromo-4-fluoro-2-nitrophenol (5.05 g, 2.06%). MS m/z: 236(M+1). 1H NMR (400 MHz, CD3OD) δ ppm 7.48 (d, J=5.87 Hz, 1H), 7.95 (d, J=8.41 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[CH3:21][NH:22][CH2:23][CH2:24][OH:25]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][OH:25])=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CNCCO
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN(CCO)CCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 2-(methylamino)ethanol were converted to yield 2-[[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-methyl-amino]-ethanol, MS: 408 (MH+, 1Br).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([CH:15]([CH2:18][CH3:19])[CH2:16][NH2:17])[CH3:14]>>[CH2:13]([CH:15]([CH2:18][CH3:19])[CH2:16][NH:17][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:14]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CCC(CC)CN
Product: CCOC(=O)c1cccnc1NCC(CC)CC
Yield: 76.3 %

Procedure:
Ethyl 2-chloronicotinate (0.646 g, 3.48 mmol) and 2-ethylbutylamine (0.74 g, 7.31 mmol) were reacted in a sealed tube at 130° C. for 2 hours. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×50 mL). The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (19:1) to provide the title compound (0.665 g, 76%). MS (ESI+) m/z 251.1 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 0.93 (t, J=7.54 Hz, 6H), 1.41 (m, 7H), 1.55 (m, 1H), 3.46 (m, 2H), 4.32 (q, J=6.99 Hz, 2H), 6.48 (dd, J=7.72, 4.78 Hz, 1H), 7.99 (s, 1H), 8.11 (dd, J=7.72, 2.21 Hz, 1H), 8.27 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CCCC1)CC3)(=[O:4])[CH2:2][CH3:3].C(O)(=O)CC.[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]2[C@H:38]3[C@H:49]([CH2:50][CH2:51][C@:33]12[CH3:34])[C@:46]1([CH:47]=[O:48])[C:41](=[CH:42][CH2:43][CH2:44][C@@H:45]1C)[CH2:40][CH2:39]3>>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]2[C@H:38]3[C@H:49]([CH2:50][CH2:51][C@:33]12[CH3:34])[C@:46]1([CH:47]=[O:48])[C:41](=[CH:42][CH2:43][CH2:44][CH2:45]1)[CH2:40][CH2:39]3
Reactant: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CCCC[C@]4(CO)[C@H]3CC[C@]12C
Reactant: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C=O
Solvent: CCC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C=O)[C@@H]1CC[C@@H]2O

Procedure:
Substituting 4-androstene-17β,19-diol 17-propionate for the 17β-hydroxy-1α-methyl-4-androsten-19-one propionate above results in the preparation of 17β-hydroxy-4-androsten- 19-one propionate.