Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([O:26][CH3:27])[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>>[C:33]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([O:26][CH3:27])[CH:12]=2)[N:9]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(-c2nc([C@@H]3CCCN3)n3ccnc(N)c23)ccc1C(=O)Nc1ccccn1
Product: C=CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)c(OC)c2)c2c(N)nccn12
Yield: 35.5 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxy-N-(pyridin-2-yl)benzamide (intermediate 19) and acryloylchloride, to afford the title compound (14 mg, 35.5%). Data: UPLC (C) Rt: 1.74 min; m/z 484.3 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][N:16]([CH2:29][CH2:30][C@@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[CH2:33])[C:12]=2[N:13]=[CH:14][N:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:17]([Br:1])[N:16]([CH2:29][CH2:30][C@@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[CH2:33])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C[C@@H](CCn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@@H](CCn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Yield: 83.3 %

Procedure:
A solution of N-bromosuccinimide (1.35 g) in THF (23 ml) was added to a solution of (R)-tert-butyl (5-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pent-1-en-3-yl)carbamate (3.21 g) obtained in Step 6 in THF (26 ml) under ice-cooling over 30 minutes. The mixture was stirred under ice-cooling for 30 minutes. After adding a 5% aqueous sodium thiosulfate solution, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate, ethyl acetate/methanol) to obtain the title compound as a light-brown solid (3.15 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=2[F:30])[C@@H:13]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]2=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:31]([OH:33])[CH3:32]>>[ClH:2].[CH2:31]([O:33][C:28](=[NH:29])[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[C@@H:13]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]2=[O:20])=[C:23]([F:30])[CH:24]=1)[CH3:32]
Reactant: CCO
Reactant: N#Cc1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Agent: Cl
Product: CCOC(=N)c1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Dry HCl gas was slowly bubbled through a solution of 4-chloro-N-(4-cyano-2-fluoro-benzyl)-N-((R)-2-oxo-azepan-3-yl)-benzenesulfonamide (0.09 g, 0.20 mmol) in dry ethanol (3 ml) for 30 min at 0° C. The reaction mixture wa allowed to stir for a further 20 h at r.t. and then concentrated under reduced pressure. Trituration of the residue in diethyl ether yielded the HCl salt: 0.09 g; MS: m/e=482.2 (MH+).
Reaction SMILES: [N:1]([C:4]1[C:5]([C:11]#[N:12])=[N:6][C:7]([F:10])=[CH:8][N:9]=1)=[N+]=[N-].[H][H]>CO.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[NH2:1][C:4]1[C:5]([C:11]#[N:12])=[N:6][C:7]([F:10])=[CH:8][N:9]=1
Reactant: N#Cc1nc(F)cnc1N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: N#Cc1nc(F)cnc1N
Yield: 38.6 %

Procedure:
In 5.0 mL of methanol was dissolved 0.24 g of 3-azido-6-fluoro-2-pyrazinecarbonitrile. After adding 0.075 g of lead-poisoned palladium-calcium carbonate at room temperature, hydrogen gas was introduced into the mixture at room temperature under a pressure of 1 atmosphere until the mixture became showing no further adsorption of hydrogen. After filtering off the insoluble matter from the reaction mixture, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: chloroform] to obtain 0.078 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]2)[CH2:9][CH2:8]1.[C:21]1([Li])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:21]1([C:16]2[CH2:15][CH:14]([CH2:13][N:10]3[CH2:11][CH2:12][N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:8][CH2:9]3)[CH2:19][CH2:18][CH:17]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCC(CN2CCN(c3ccccn3)CC2)C1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CC(CN2CCN(c3ccccn3)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5.14 g of 3-[[4-(2-pyridinyl)piperazinyl]methyl]cyclohexanone (Example B) in 250 mL of tetrahydrofuran at 0° C. under nitrogen is added dropwise a solution of phenyllithium (23.5 mL, 2.0M in cyclohexane/diethyl ether, 70/30). The solution is stirred at 0° C. for 1 hour, quenched with dropwise addition of 250 mL of saturated potassium phosphate monobasic solution. The solvent is evaporated in vacuo, the residue is basified with concentrated ammonium hydroxide to a pH of 9 and extracted into chloroform. The chloroform extract is dried over magnesium sulfate and filtered. A solution of the filtrate in 250 mL of chloroform containing 14.5 mL of trifluoroacetic acid is stirred at room temperature under nitrogen for 12 hours. The solvent is evaporated in vacuo, the residue is dissolved into ethyl acetate (250 mL) and washed with 1N sodium hydroxide solution and brine (250 mL of each). The ethyl acetate extract is dried over magnesium sulfate, filtered, and concentrated. The crude product is purified by medium pressure chromatography (silica gel, 90% hexanes - 10% ethyl acetate) to give (±)-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]-4-(2-pyridinyl)piperazine (Example 4) as an off-white solid; mp 96°-98° C. and (±)-1-[(3-phenyl-2-cyclohexen-1-yl)methyl]-4-(2-pyridinyl)piperazine (Example 4a) as an off-white solid; mp 78°-82° C.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([C:18](=[O:37])[CH2:19][C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]2[CH2:38][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[O-]CC.[Na+].Cl>C(O)C>[OH:3][C:4]1[C@H:6]2[C@H:11]([C@H:10]3[CH2:38][C@@H:7]2[CH2:8][CH2:9]3)[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:18](=[O:37])[C:19]=1[C:20]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][C:23]=2[S:22](=[O:36])(=[O:35])[N:21]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Temperature: 60 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
The crude (1S,2R,3S,4R)-3-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester was dissolved in ethanol (7 mL) and a 21 wt. % solution of sodium ethoxide in ethanol (1.15 mL, 3.25 mmol) was added into the above solution. The mixture was stirred at 60° C. for 4 h and cooled down to 25° C. The mixture was poured into 0.5 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (Teledyne Isco RediSep column; 100% ethyl acetate) to afford the desired product, (1R,2S,7R,8S)—N-{3-[6-hydroxy-3-(3-methyl-butyl)-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.19 g, 0.364 mmol, 56.1% over two steps), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.89-0.93 (6H, m), 1.16-1.23 (2H, m), 1.28-1.32 (1H, m), 1.35-1.62 (7H, m), 1.99-1.99 (1H, m), 2.52-2.54 (1H, m), 2.63 (1H, bs), 3.06 (3H, s), 3.62-3.72 (2H, m), 7.50 (1H, dd, J1=8.9 Hz, J2=2.2 Hz), 7.57-7.59 (2H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C23H30N4O6S2 522.16, found 523.6 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Yield: 144 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.3 g, 1.67 mmol) in N,N-dimethylformamide (4.0 mL) was added sodium hydride (60% in oil, 0.073 g, 1.83 mmol) with stirring under ice-cooling, and the mixture was stirred at the same temperature for 15 min. 3-Bromobenzyl bromide (0.44 g, 1.75 mmol) was added to the mixture with stirring under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.84 g, yield 72%) as a colorless powder. 1H NMR (CDCl3) δ: 2.60 (2H, t, J=7.8 Hz), 2.90 (2H, t, J=7.8 Hz), 3.67 (3H, s), 5.01 (2H, s), 6.88 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz), 7.25 (1H, m), 7.35 (1H, d, J=7.5 Hz), 7.45 (1H, d, J=7.5 Hz), 7.59 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11])[CH3:2].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]1=[S:11])[CH3:2]
Reactant: CCc1ccccc1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccccc1N1C(=O)CN(C)C1=S
Yield: 87.4 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 16.3 g of 2-ethylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 20.2 g of triethyl amine, and 300 mL of chloroform. The title compound (20.4 g) was obtained as an off-white solid, m.p. 135°-137° C. Anal. Calcd. for C12H14N2O S: C, 61.51; H, 6.02; N,11.96. Found: C, 61.11; H, 5.92; N, 11.71. Mass spectrum (El, M.+) m/z 234.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:36])([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[CH3:28])=[C:23]([F:37])[CH:22]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:28])([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[CH3:36])=[C:23]([F:37])[CH:22]=3)=[CH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(C(C)(C)OC3CCCCO3)c(F)c1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(C(C)(C)OC4CCCCO4)c(F)c3)cc2c1
Yield: 65.1 %

Procedure:
A mixture of 1-benzenesulfonyl-2-(2-cyclopentyl-1-{3-fluoro-4-[1-methyl-1-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl}-vinyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (6 g, 9.1 mmol) in tetrahydrofuran (5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 15 mL, 15 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(2-cyclopentyl-1-{3-fluoro-4-[1-methyl-1-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl}-vinyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (3 g, 63.8%) as a white solid: LC/MS m/e calcd for C30H35FN2O4 [M+H]+ 507.62, observed 507.0.
Reaction SMILES: [CH2:1]1[CH2:8][NH:7][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Br)[CH:17]=1>CN(C=O)C.CCOC(C)=O>[Br:11][C:12]1[CH:17]=[C:16]([CH2:18][N:7]2[CH2:8][CH2:1][CH2:2][CH2:3][S:4]2(=[O:6])=[O:5])[CH:15]=[N:14][CH:13]=1
Reactant: BrCc1cncc(Br)c1
Reactant: O=S1(=O)CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S1(=O)CCCCN1Cc1cncc(Br)c1
Reaction time: 0.25 h

Procedure:
To a vial is added 1,4-butanesultam (81 mg, 0.60 mmol) in 2 ml of DMF, followed by the addition of 60% NaH (24 mg, 0.6 mmol) at 0° C. The reaction mixture is stirred for 15 minutes, followed by the addition of To a vial is added 3-bromo-5-bromomethyl-pyridine, Intermediate E (100 mg, 0.40 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 86 mg of 2-(5-bromo-pyridin-3-ylmethyl)-[1,2]thiazinane 1,1-dioxide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][NH2:16])=[N:3][CH:4]=1
Reactant: CC(C)(C)COc1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1ccc(NN)nc1

Procedure:
6.2 g (30.8 mmol) 2-chloro-5-(2,2-dimethylpropoxy)pyridine together with 60 ml (1.2 mol) hydrazine hydrate are divided into four portions of equal size and 10 ml ethanol are added to each portion. Each portion is reacted in a single mode microwave (CEM Explorer) at 170° C. (200 watt) for in each case 12 h. Thereafter, the four mixtures are combined and the solvent is removed. The residue is taken up in ethyl acetate and the mixture is washed in each case once with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture is dried over magnesium sulfate and the solvent is removed in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=C(c1ccncc1)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of 4-trifluoromethoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.21 (d, 2H, J=8.8 Hz), 7.35 (m, 2H), 7.45 (s, 1H), 7.70 (m, 2H), 7.83 (m, 2H), 8.82 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.21 (s, 1H). MS: m/z 502.3 (M++1).
Reaction SMILES: [C:1]([CH:5]1[CH2:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:13]OS(OC)(=O)=O>>[CH3:3][C:1]([CH:5]1[CH2:6][CH2:7][C:8]([O:9][CH3:13])=[N:10][CH2:11][CH2:12]1)([CH3:4])[CH3:2]
Reactant: CC(C)(C)C1CCNC(=O)CC1
Reactant: COS(=O)(=O)OC
Product: COC1=NCCC(C(C)(C)C)CC1

Procedure:
A sample of 4-tertbutylcaprolactam (Bader, 2.5 g, 14.8 mmol) was reacted with dimethylsulfate (1.4 mL, 14.8 mmol) by the method of EXAMPLE 69 to yield, after chromatography, 2.7 g of the title material.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CNCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A solution of 254A (243 mg, 0.60 mmol) in CH2Cl2 (3 mL) at 0° C. was treated with trifluoroacetic acid (0.3 mL). The reaction was stirred at room temperature for one hour, then concentrated to an oil. The crude amine was dissolved in EtOAc (10 mL), washed with saturated aqueous NaHCO3 and dried (Na2SO4), filtered and concentrated in vacuo. The product was purified by flash chromatography (10% MeOH/CH2Cl2) on silica gel to afford 95 mg (yield: 52%) of Compound 254B.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C([O-])=O.[Na+].C(O)=O>CO.[Pd]>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: Cc1nccn1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A mixture of 54.0 g of 2-methyl-1-(p-nitrophenyl)imidazole, 2.87 g of palladium black, 36 7 g of sodium formate and 47.4 ml of formic acid in 1100 ml of methyl alcohol is stirred at room temperature for 18 hours under a hydrogen atmosphere. The mixture is filtered and the filtrate evaporated to a residue. The residue is partitioned between saturated potassium bicarbonate and chloroform. The organic layer is dried and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is crystallized from ether:ethanol to give 34.9 g of the desired product as a solid, m.p. 108°-110° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[C:5]([CH3:11])[CH:4]=1)#[CH:2].[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1)[CH3:13]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:19]2[CH:20]=[CH:21][C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])=[CH:17][CH:18]=2)=[CH:4][C:5]=1[CH3:11]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(CO)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(CO)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol (Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate (Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treated with copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (20-40% EtOAc-hexanes) afforded 130.0 mg (99%) of the title compound as an orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:23])[CH:3]=1.[O:24]1[CH2:28][CH:27]=[N:26][C:25]1=[O:29]>>[F:23][C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][O:24][C:25]2=[O:29])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C1N=CCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3F)CC2)nc1
Yield: 68.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (378 mg) described in Preparation Example 184 and oxazolin-2-one (104 mg), the title compound (264 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.[Na]>CC(C)=O.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Yield: 64.9 %

Procedure:
A suspension of 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (1.23 g, 4 mmol) and sodium hydrosuffite (7.0 g, 85% pure from Aldrich, 40 mmol) in acetone and water (1:1, 20 mL) was refluxed for 3 h. Upon cooling, the volatile components (mainly acetone) were removed on rotavap, and the resulting mixture was subjected to filtration. The solid was thoroughly washed with EtOAc. The combined filtrate was extracted with n-BuOH (4×), and the combined organic layer was washed with saturated aq. NaHCO3, dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas) to provide 0.71 g of product as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([CH:21]([OH:24])[C:22]#[CH:23])=[CH:14][C:15]=3[C:16]([CH3:20])([CH3:19])[CH2:17][CH:18]=2)=[CH:5][CH:4]=1.I[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([CH:21]([OH:24])[C:22]#[C:23][C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)=[CH:14][C:15]=3[C:16]([CH3:20])([CH3:19])[CH2:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(N(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)c1ccc(C2=CCC(C)(C)c3cc(C(O)C#Cc4ccc(C(=O)O)cc4)ccc32)cc1

Procedure:
In a manner similar to that of Example 16b, by reacting 0.81 g (2.4 mmol) of 1-[5-(4-dimethylaminophenyl)-8,8-dimethyl-7,8-dihydro-2-naphthyl]prop-2-yn-1-ol with 0.496 g (2 mmol) of 4-iodobenzoic acid, 0.035 g (0.05 mmol) of trans-dichlorobis(triphenyl-phosphine)palladium and 0.019 g (0.1 mmol) of copper iodide, a beige-colored solid is obtained (0.65 g; yield=72%; m.p.=91° C.).