Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Na].[CH2:5]([C:9]1[NH:10][C:11]([C:18]([O:20][CH3:21])=[O:19])=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=1)[CH2:6][CH2:7][CH3:8].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1>CO.CN(C)C(=O)C.O.C(OCC)(=O)C>[C:39]([O:38][C:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:13]2[C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([C:18]([O:20][CH3:21])=[O:19])[N:10]=[C:9]2[CH2:5][CH2:6][CH2:7][CH3:8])=[CH:25][CH:26]=1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A sodium methoxide solution prepared from 0.69 g of sodium and 40 ml of methanol was added to a solution of 7.2 g of dimethyl 2-butylimidazole-4,5-dicarboxylate (prepared as described in Preparation 4) in 40 ml of methanol, and the resulting mixture was concentrated by evaporation under reduced pressure. The resulting residue was mixed with benzene, and the mixture was concentrated by distillation under reduced pressure. After this operation had been repeated three times, the solid thus obtained was dissolved in 72 ml of N,N-dimethylacetamide. A solution of 10.41 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate in 100 ml of N,N-dimethylacetamide was then added dropwise to the resulting solution. The reaction mixture was then stirred at room temperature for 1 hour and at 50°-55° C. for 2 hours. At the end of this time, it was mixed with ethyl acetate and water, and the ethyl acetate layer was separated, and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 15.1 g of the title compound as a gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].Cl[C:15]1[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH:22][CH2:23][CH3:24])[CH:16]=1>>[NH2:21][C:19]1[N:20]=[C:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=2)[CH:16]=[C:17]([NH:22][CH2:23][CH3:24])[N:18]=1
Reactant: CCNc1cc(Cl)nc(N)n1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Product: CCNc1cc(-c2cc(F)c(C=O)c(F)c2)nc(N)n1
Yield: 42.8 %

Procedure:
The title compound was prepared following the General Procedure A using: (3,5-difluoro-4-formylphenyl)boronic acid (2.54 g, 13.7 mmol) and 6-chloro-N4-ethyl-2,4-pyrimidinediamine (2.36 g, 13.7 mmol). The solid was triturated with EtOAc and filtered to afford the title compound (1.63 g, 43%) as a yellow solid. LC-MS (ES) m/z=279 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[N:4][C:3]=1[C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:27])=[O:33])=[CH:24][CH:25]=1
Reactant: CSc1ccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc2Br)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
tert-Butyl 4-{5-bromo-4-[4-(methylsulfanyl)phenyl]-1,3-oxazol-2-yl}piperidine-1-carboxylate (705 mg, 1.55 mmol) was dissolved in methylene chloride (15.5 nit) under argon atmosphere. 3-Chloroperoxybenzoic acid (383 mg, 1.55 mL) was dissolved in methylene chloride (3.1 mL) and added via syringe to the stirring solution. The resulting solution was stirred at 25° C. for 1 hour. The solution was then diluted with methylene chloride (15 mL) and washed with saturated sodium bicarbonate followed by brine. The organics were dried over sodium sulfate and concentrated in vacuo to yield 680 mg of the desired product as colorless oil. LCMS (M+1)=469.40
Reaction SMILES: [C:1]([C:5]1[C:9]([NH:10][C:11]([NH:13][CH2:14][CH2:15]Cl)=[O:12])=[CH:8][S:7][CH:6]=1)([O:3]C)=O.Cl.[F:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+].[I-].[Na+]>C(O)(C)C.O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:15][CH2:14][N:13]3[C:1](=[O:3])[C:5]4=[CH:6][S:7][CH:8]=[C:9]4[NH:10][C:11]3=[O:12])[CH2:27][CH2:26]2)=[O:24])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COC(=O)c1cscc1NC(=O)NCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC(C)O
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Yield: 7.4 %

Procedure:
N-(3-Carbomethoxythien-4-yl)-N'-(chloroethyl)urea (U.S. Pat. No. 4,670,560) (5.24 g, 20 mmol) was dissolved in isopropanol (100 ml) and treated successively with 4-(4-fluorobenzoyl)piperidine hydrochloride (9.71 g, 40 mmol), sodium bicarbonate (3.7 g, 44 mmol) and sodium iodide (1.90 g, 12 mmol) and the mixture was heated to reflux under a nitrogen atmosphere for 12 hours. The reaction mixture was reduced to half volume, diluted with water, and concentrated to remove the remainder of the alcohol solvent. The residue was extracted with methylene chloride and the combined organic extracts were dried with saturated brine and magnesium sulfate. After concentration of the extracts, the residue was purified on silica gel using methylene chloride/ethanol/ammonium hydroxide (96:3.5:0.5) as eluant. The title compound was recrystallized from ethanol to give 0.598 g (7.4% yield) of beige crystals, mp 208°-215° C. (dec). IR(KBr): 1707, 1672, 1159, 1033, 974, 860, 835, 766, 671 and 460 cm-1 ; MS (DCI), 402 m/z (MH+); 1H NMR (DMSO-d6): δ 1.5-1.7 (m, 4 H), 2.1 (br t, J=7 Hz, 2H), 2.9 (br d, 2H), 3.2-3.55 (m, 3H), 3.9 (t, J=6.2 Hz, 2H), 6.8 (d, J=4 Hz, 1H), 7.3 (t, J=9 Hz, 2H), 8.0 (dd, H=5.8 Hz, 2H), 8.2 (d, J=4 Hz, 1H) and 11.5 (br s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5]1=[O:15])([CH3:3])=[CH2:2].C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.[I-]>CN(C=O)C.C(OCC)(=O)C>[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N:6]2[C:7]3[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=3[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]2=[O:15])=[CH:24]1
Reactant: C=C(C)n1c(=O)[nH]c2cc(C)c(C)cc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 1-Isopropenyl-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.25 g, 1.2 mmol) in DMF (10 mL) was added K2CO3 (0.51 g, 3.7 mmol). The reaction mixture was heated to 90° C. and stirred for 20 min. (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium; iodide (0.64 g, 1.8 mmol) was then added to the reaction mixture and stirred for another 3 h. The reaction mixture was treated with ethyl acetate and washed with water. The resulting residue was purified by silica gel prep TLC using 4:1 Hexane:ethyl acetate as an eluent to afford 0.35 g the desired product as an off-white solid. LCMS (ESMS): m/z 360.33 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.[OH-].[Na+].[C:13]([OH:17])(C)(C)[CH3:14].C(Cl)CO>O>[OH:17][CH2:13][CH2:14][N:3]1[C:4]([CH3:10])=[C:5]([CH3:9])[N:6]=[C:7]([CH3:8])[C:2]1=[O:1]
Reactant: CC(C)(C)O
Reactant: Cc1nc(C)c(O)nc1C
Agent: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(C)c(=O)n(CCO)c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
2-Hydroxy-3,5,6-trimethylpyrazine (13.8 g, 0.1M) and 5N NaOH (100 ml, 0.5M) were added to t-butanol (200 ml). Ethylene chlorohydrin (40.3 g, 0.5M) was added thereto and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction mixture, which was then extracted 10 times with chloroform (100 ml), and the extract dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (Wako Pure Chem. Co., C-200) and eluted with chloroform-methanol (300:1) to obtain the product (14.4 g, yield: 79.1%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=O)=[O:14])=[CH:9][CH:8]=1.[Na+]>CN(C)C=O>[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:3])(=[O:16])=[O:14])=[CH:9][CH:8]=1
Reactant: C=Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 3 °C
Reaction time: 2 h

Procedure:
A flask containing 300 ml dry dimethyl formamide was cooled in an ice/salt bath to 3° C. Thionyl chloride (250 ml) was added dropwise with stirring over a period of 2 hrs. Sodium styrene p-sulphonate (200 g) was added in aliquots over a further 1 hour. The reaction mixture was allowed to stand for 24 hours at room temperature. The solution was poured onto ice and extracted with toluene (1000 ml . The extract was neutralised with sodium carbonate, washed with water, dried over magnesium sulphate and the solvent removed by evaporation under vacuum at 30° C. Finally the purified styrene p-sulphonyl chloride was filtered and stored at 5° C. in the dark.
Reaction SMILES: [Si:1]([O:8][C:9]([C:24]([F:27])([F:26])[F:25])([C:20]([F:23])([F:22])[F:21])[C:10]([O:12][Si](C(C)(C)C)(C)C)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:34][C:35]1[CH:41]=[C:40]([S:42][C:43]2[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[CH:45][CH:44]=2)[CH:39]=[CH:38][C:36]=1[NH2:37]>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[F:34][C:35]1[CH:41]=[C:40]([S:42][C:43]2[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[CH:45][CH:44]=2)[CH:39]=[CH:38][C:36]=1[NH:37][C:10](=[O:12])[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([C:20]([F:23])([F:22])[F:21])[C:24]([F:26])([F:25])[F:27]
Reactant: CSc1ccc(Sc2ccc(N)c(F)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CSc1ccc(Sc2ccc(NC(=O)C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)c(F)c2)cc1
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a stirred solution of 2-t-butyldimethylsilyloxy-2-trifluoromethyl-3,3,3-trifluoropropanoic acid, t-butyldimethylsilyl ester (Method 56) (1.05 g) in DCM (10 ml) was added DMF (2 drops) and oxalyl chloride (0.23 ml). The reaction mixture was stirred for 17 hours and was then added to a solution of 2-fluoro-4-(4-methylsulphanylphenylsulphanyl) aniline (Method 6) (0.63 g) in DCM (5 ml) and pyridine (0.22 ml). The reaction mixture was stirred at ambient temperature for 48 hours, evaporated under reduced pressure and the residue purified by chromatography on a silica gel Mega Bond Elut column eluting with 5-20% ethyl acetate/iso-hexane to give the title compound (0.278 g) as a yellow gum. NMR (CDCl3): 0.29 (s, 6H), 0.98 (s, 9H), 2.48 (s, 3H), 6.96-7.0 (m, 1H), 7.06 (d, 1H), 7.2 (d, 2H), 7.31 (d, 2H), 8.23 (t, 1H), 8.62 (brs, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[CH3:18][C:19]1([N:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:9]([CH2:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[NH:1][CH:35]1[CH2:34][CH2:33][N:32]([C:19]2([CH3:18])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[CH2:37][CH2:36]1)#[N:10]
Reactant: N#CC[C@H]1CCCC[C@@H]1N
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3CC#N)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 2-[(1R,2S)-2-aminocyclohexyl]acetonitrile (HCl salt, 0.7 g, 3.32 mmol) in MeOH (10 mL) was added triethylamine (0.48 mL, 3.47 mmol) followed of tert-butyl 4-methyl-4-(4-oxo-1-piperidyl)piperidine-1-carboxylate (1 g, 3.38 mmol) at room temperature. A solution containing sodium cyanoborohydride (0.34 g, 4.93 mmol) and zinc(II) chloride (0.22 g, 1.62 mmol) in MeOH (2 mL) was then added dropwise and the mixture stirred at room temperature overnight. Concentrated in vacuo, the residue was diluted in dichloromethane (100 mL) and washed with 1N NaOH (10 mL). The aqueous phase was separated and was extracted with dichloromethane (2×20 mL). The combined organic phase was washed with brine and concentrated in vacuo to provide the title compound, which was used for the next step without any purification. MS (M+1): 419.37.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]2=[N+:13]=[N-:14].[CH2:17]([OH:20])[C:18]#[CH:19]>CCOCC>[OH:20][CH2:17][C:18]1[CH:19]=[C:8]2[N:13]([C:9](=[O:12])[NH:10][C:11]3[C:3]([C:2]([F:16])([F:15])[F:1])=[CH:4][CH:5]=[CH:6][C:7]=32)[N:14]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2c1cccc2C(F)(F)F
Reactant: C#CCO
Solvent: CCOCC
Product: O=c1[nH]c2c(C(F)(F)F)cccc2c2cc(CO)nn12
Reaction time: 0.5 h

Procedure:
2.0 g (0.0088 mole) of 7-(trifluoromethyl)-3-diazooxindole and 10.2 g (0.176 mole or 20 equivalents) of 97% propargyl alcohol are refluxed under N2 for 4 hours, cooled, diluted with ether (200 ml) and stirred for 30 minutes. The light pink solid that forms is filtered off. Yield: 1.3 g; 52.2% crude yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([O:14][C:15]([F:18])([F:17])[F:16])[CH:3]=1.[C:19]([C:21]1[N:25]([CH3:26])[C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:19]([C:21]1[N:25]([CH3:26])[C:24]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([O:14][C:15]([F:18])([F:17])[F:16])[CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCNS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 18.2 %

Procedure:
According to general procedure B, 4-bromo-N-ethyl-2 (trifluoromethoxy)benzenesulfonamide (208 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethoxy)benzenesulfonamide (40 mg, 18%) was provided after purification. MS (ESI) m/z 373. HPLC purity 99.4% at 210-370 nm, 9.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Br[C@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O.O>[N:23]([C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1)=[N+:24]=[N-:25]
Reactant: C[C@]12C=CC(=O)C=C1[C@H](Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12C=CC(=O)C=C1[C@@H](N=[N+]=[N-])C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of 6β-bromoandrosta-1,4-diene-3,17-dione (5.0 g) in 250 ml of dimethylformamide, 1,15 g of powdered sodium azide dissolved in 14 ml of water are added and the mixture is warmed to 100° C. and maintained with stirring at the same temperature for 120 minutes. The entire mixture is then poured into 1 l of water and extracted with four 200 ml portions of ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride solution and dried. The solvent is then removed in vacuum to yield a crude product which is purified by chromatography on Al2O3 (neutral activity) with ethyl acetate:n-hexane 40:60 as eluant so obtaining 3.4 g of pure 6α-azido androsta-1,4-diene-3,17-dione. The analytical sample was crystallized from methanol, m.p. 168°-170° C.; [α]D20° +93.2° (c=1, CHCl3); U.V. (95% EtOH) λmax=244; ε=17,420; N.M.R. (CDCl3) δ: 0.98 (3H, s); 1.3 (3H, s); 4.31 (1H, ddd); 6.44 (1H, dd); 6.26 (1H, dd); 7.02 (1H, d). Following analogous procedure the 6β-azido androsta-1,4-diene-3,17-dione can be prepared, starting from 6α-bromo androsta-1,4-diene-3,17-dione.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:15][CH2:16][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:22]=2[CH2:23]1)[CH3:2]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 8.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-piperidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.7 mg) was obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([C:31]([CH3:35])([CH3:34])[CH:32]=O)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:35][C:31]([C:29]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([O:22][CH3:21])[CH:30]=1)([CH3:32])[CH2:34][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:4]2[C:3]([CH3:2])=[C:11]3[C:7](=[CH:6][CH:5]=2)[C:8](=[O:12])[O:9][CH2:10]3)[CH2:16][CH2:17]1
Reactant: COc1cc(C(C)(C)C=O)ccc1C#N
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: COc1cc(C(C)(C)CN2CCN(CCc3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
4-[1,1-Dimethyl-2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-2-methoxy-benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-methyl-1-oxopropan-2-yl)benzonitrile. LC-MS (IE, m/z): 448.6 [M+1]+. (0.30 μM)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:59][C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=1>ClCCl>[C:64]([C:63]1[CH:66]=[CH:67][C:60]([NH:59][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:23])=[CH:61][CH:62]=1)#[N:65]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Reactant: N#Cc1ccc(N)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C#N)cc3)cc21
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (example 1, steps 1 to 4) (1.0 g, 2.6 mmol) in dichloromethane (50 mL) was treated with N,N-diisopropyl ethyl amine (0.34 g, 2.6 mmol) and cooled to 0° C. Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (2.4 g, 5.2 mmol) was added, and the mixture was stirred at 0° C. for 1 min. 4-Aminobenzonitrile (1.2 g, 10.4 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the crude was purified by flash chromatography (heptane/ethyl acetate gradient) yielding 4-(5-chloro-2-methoxybenzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (4-cyano-phenyl)-amide as a white solid, 0.18 g (14%), MS (ISP): m/e=482.0 (M−H).
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:19])[CH3:18].Cl>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:19])[CH3:18])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: CON(C)C(C)=O
Reactant: Brc1cccc2sccc12
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Approximately 5 ml of a solution of 4-bromobenzo[b]thiophene (4.10 g; prepared in a manner similar to that described in Bull. Soc. Chim. Fr., 1966, 111, 3667) in tetrahydrofuran (44 ml) was added under nitrogen to magnesium turnings (0.486 g). Two crystals of iodine were added and the mixture was heated to initiate the reaction. The remainder of the 4-bromobenzo[b]thiophene solution was added at reflux temperature over 20 minutes then the mixture was heated under reflux for 15 minutes and allowed to cool to ambient temperature. A solution of N-methoxy-N-methylacetamide (1.98 g; prepared in a manner similar to that described in Example 15) in tetrahydrofuran (20 ml) was added, the mixture was heated under reflux for 1 hour, then it was allowed to cool to ambient temperature. 2M Hydrochloric acid (40 ml) was added, the mixture was stirred at ambient temperature for 1 hour, then the product was extracted into ethyl acetate (250 ml). The extract was washed with water (2×50 ml) and saturated aqueous sodium chloride solution (2×50 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 97:3 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl]ethan-1-one (1.76 g) as a yellow oil which was used without further purification.