Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([N:21]1[CH2:26][CH2:25][CH:24](N2CCC(C3C=CC=CC=3)CC2)[CH:23](O)[CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC[OH:42]>>[C:13]([N:21]1[CH2:26][CH2:25][CH:24]([OH:42])[CH:23]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)[CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CCO
Reactant: O=C(c1ccccc1)N1CCC(N2CCC(c3ccccc3)CC2)C(O)C1
Product: O=C(c1ccccc1)N1CCC(O)C(N2CCC(c3ccccc3)CC2)C1

Procedure:
Benzoyl chloride (6.22, 44.3 mmol) was added dropwise to a cold (icebath) stirring solution containing 3.2 g (38.5 mmol) of 1,2,3,6-tetrahydropyridine in Et3N (30 ml). Following the addition, the mixture was allowed to slowly warm up to room temperature. After 24 hours, the reaction mixture was diluted with H2O (30 ml) and extracted with CH2Cl2 (85 ml). The organic extract was washed with saturated NaHCO3 (50 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to yield a chromatographically homogeneous yellow liquid (quant); 1H NMR (CDCl3) δ2.20 (d,2H), 3.46 (br s, 2H), 3.86 (br s, 2H), 4.20 (br s, 1H), 5.86 (m, 1H), 7.40 (s, 5H). The latter was redissolved in CH2Cl2 (140 ml) and cooled in an icebath. To this cold stirring solution m-CPBA (14.40 g; 50-60% pure) was added portionwise over 10 min. After completion of the addition, the reaction mixture was maintained a 4° C. for 1 hour and allowed to slowly warm up to room temperature. Sixteen hours later, the reaction mixture was diluted with CCl4 (100 ml) and filtered to remove precipitated 3-chlorobenzoic acid. The filtrate was washed consecutively with 5% aq. NaHSO3 (2×100 ml) and satd NaHCO3 (2×100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to provide 6.93 g of the crude epoxide as a brown syrup. A solution of the epoxide and 5.64 g (35.0 mmol) of 4-phenylpiperidine in EtOH (100 ml) was refluxed for 15 hours, cooled and concentrated to a brown residue. The latter was dissolved in CH2Cl2 (150 ml) and the resulting solution was washed with H2O (70 ml), dried over anhydrous Na2SO4 and concentrated to a syrup which was purified by preparative HPLC (silica gel; i-PrOH 910): hexanes (90): Et3N(1) to yield two major components. The more mobile component identified as 9a was obtained in 25% yield: The corresponding hydrochloride was recrystallized from i-PrOH-MeOH mp 220°-223° C.; 1H NMR (CDCL3) δ1.61-1.89 (m, 6 H), 2.29 (t, 1H), 1.46-1.53 (m, 2H), 2.81 (m, 4H), 2.96 (m, 1H), 3.45 (m, 1H), 3.83 (m, 1H), 4.69 (m, 1H), 4.88 (m, 1H), 7.19-7.40 (m, 10H). The less mobile component was assigned the structure 10a: mp (HCl) 248°-251° C.; 1H NMR (CDCl3) δ1.50-3.07 (m, 12H), 3.67-3.79 (m, 4H), 4.78 (m, 1H), 4.92 (m, 1H), 7.20-7.44 (m, 10H). The less mobile component was assigned the structure 10a: mp (HCl) 248°-251° C.; 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(CO[C@H]4CCOC4)cc23)c1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1cccc(-c2n[nH]c3ccc(CO[C@H]4CCOC4)cc23)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a solution of 82 mg of 3-(3-fluorophenyl)-5-{[(3S)tetrahydro-3-furanyloxy]methyl}-1-trityl-1H-indazole in 1.6 ml methylene chloride were added 0.05 ml of triisopropylsilane and 0.4 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added ethyl acetate. The mixture was sequentially washed with saturated aqueous sodium hydrogencarbonate solution (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. Then, the resulting crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:4), to give 36 mg of the title compound as a viscous colorless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A169) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[C:25]2[C:26]([N:29](C(OCC(Cl)(Cl)Cl)=O)[C:30](OCC(Cl)(Cl)Cl)=[O:31])=[N:27][O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:18][O:19][C:20]1[C:25]2[C:26]([NH:29][C:30]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:31])=[N:27][O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COc1cccc2onc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)c12
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2onc(NC(=O)N3CCN(c4nc(-c5ccccc5)ns4)CC3)c12
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.5 %

Procedure:
A mixture of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (492 mg, 2.00 mmol), bis(2,2,2-trichloroethyl) (4-methoxy-1,2-benzisoxazol-3-yl)imidodicarbonate (515 mg, 1.00 mmol), diisopropylethylamine (0.350 ml, 2.00 mmol) and dimethyl sulfoxide (10 ml) was stirred at 70° C. for 5 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to yield 325 mg (74.5%) of the desired product.
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:24]([NH2:27])([CH3:26])[CH3:25]>CS(C)=O.O>[CH:24]([NH:27][C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1NC(C)C
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 27.8 mg, 0.090 mmol) and isopropylamine (0.023 mL, 0.269 mmol) in DMSO (0.8 mL) was heated under argon in a sealed flask at 60° C. for 1 h. The reaction was cooled to 25° C. and diluted with water (10 mL). The precipitated solid was collected by vacuum filtration, washed with water (2×5 mL), and dried in vacuo to provide rac-2-(3-(isopropylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (19.6 mg, 0.056 mmol, 63% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (1H, br. s.), 7.90 (1H, d, J=7.2 Hz), 7.56 (1H, d, J=7.4 Hz), 7.31 (1H, t, J=7.8 Hz), 7.03 (1H, d, J=1.8 Hz), 6.97 (1H, br. s.), 6.89 (1H, d, J=7.2 Hz), 4.35 (1H, dq, J=13.3, 6.4 Hz), 3.46 (1H, dt, J=10.0, 3.4 Hz), 3.05-3.19 (2H, m), 2.54 (3H, s), 1.36 (3H, d, J=6.5 Hz), 1.32 (3H, d, J=6.5 Hz), 1.29 (3H, d, J=6.3 Hz). m/z (ESI, +ve) 350.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([Br:21])=[CH:10][CH:11]=3)[N:6]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:33](I)[C:34]([CH3:37])([CH3:36])[CH3:35]>O.C(OCC)(=O)C>[Br:21][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(C)CI
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1ncc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2′-amino-7-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-3-ol (390 mg, 1.120 mmol) in DMF (4481 μL, 1.120 mmol) in a sealed tube was added cesium carbonate (912 mg, 2.80 mmol). After stirring for 1 minute neopentyl iodide (223 μL, 1.680 mmol) was added, the reaction vessel was sealed and heated at 100° C. for 2.5 hours. Reaction was cooled to RT to prevent over alkylation. The reaction was diluted with water (25 mL) and 10 mL of ethyl acetate and stirred for 30 minutes before being poured into a separatory funnel containing ethyl acetate (100 mL) and water (250 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The aqueous layer was then extracted with DCM (3×50 mL). The organic layers were each washed with water and then brine, at which point all the organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown foam that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-bromo-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.B.CO>O1CCCC1.C(OCC)(=O)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2([CH2:14][OH:15])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Agent: B
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (9.5 g, 29.3 mmol) was suspended in tetrahydrofuran (60 mL) and cooled to 0° C. To this solution was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 59 mL, 59 mmol) cautiously over 15 min. The reaction mixture was allowed to warm to room temperature overnight and then heated at reflux for 24 h. The mixture was cooled to 0° C., treated with excess methanol, diluted with ethyl acetate, washed with 1 N sodium hydroxide (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (40% ethyl acetate/hexanes) gave 6.6 g (72%) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.24-7.29 (m, 2H), 7.00-7.05 (m, 2H), 3.66-3.71 (m, 2H), 3.49 (s, 2H), 2.96-3.05 (m, 2H), 2.06-2.10 (m, 2H), 1.69-1.77 (m, 2H), 1.40 (s, 9H). Mass spec.: 310.21 (MH)+.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[N:32]1([CH2:31][CH2:30][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCN2CCOCC2)C3)nc1
Temperature: 90 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 4-(2-chloroethyl)morpholine hydrochloride (0.217 g, 1.16 mmol) in DMF (5.3 mL). Heat at 90° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 10% to 20% (2.0 M NH3 in methanol) in acetone to give the title compound: MS ES+ 397.2 (M+H)+, HRMS calcd for C22H29N4O3 397.2240 (M+H)+, found 397.2223, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=5.6 min, 99.0% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(C(C)C)CC)(C)C.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1>ClCCl>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:5][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[CH:24]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc(CNCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
g (5.68 mmol) of 2,4-dichlorobenzylamine was dissolved in 20 ml of dichloromethane and treated with 2.94 g (22.7 mmol) of diisopropylethylamine and 1.43 g (6.25 mmol) of 3-bromomethyl-benzoic acid methyl ester. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/4).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].O>[Fe].CO>[N:18]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[O:11][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccncc3o2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2nc3ccncc3o2)cc1
Yield: 64.4 %

Procedure:
A mixture of 2-(4-nitrophenyl)oxazolo[5,4-c]pyridine (610 mg, 2.5 mmol), NH4Cl (1.2 g, 22.4 mmol), iron powder (0.76 g, 13.6 mmol), H2O (13 mL) and methanol (51 mL) was heated to reflux for 6 h under N2. The mixture was concentrated in vacuo and purified by chromatography on silica gel (eluted with EA/PE=3:1) to give 4-(oxazolo[5,4-c]pyridin-2-yl)benzenamine as light brown powder (340 mg, yield 64%). 1H NMR (400 MHz, DMSO-d6) δ: 8.95 (1H, s); 8.46 (1H, d, J=5.2); 7.92 (2H, d, J=8.8); 7.69 (1H, d, J=5.6), 6.71 (2H, d, J=8.8), 6.19 (2H, s); MS (ESI) calcd for C12H9N3O (m/z): 211, found: 212 [M+H]+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[CH3:7][Si:8]([CH2:11][CH2:12][O:13][CH2:14]Cl)([CH3:10])[CH3:9].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:27](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.CC(C)([O-])C.[Li+]>CC#N.O>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:27]([N:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH2:14][O:13][CH2:12][CH2:11][Si:8]([CH3:7])([CH3:9])[CH3:10])(=[O:29])=[O:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: Nc1nccs1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CCOCN(c1nccs1)S(=O)(=O)c1ccc2c(Cl)nccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
A solution of thiazol-2-amine (0.134 g, 1.342 mmol) in 3 mL MeCN was treated with SEM-Cl (0.238 ml, 1.342 mmol) and was allowed to stir at room temperature for 30 minutes. LC/MS showed mostly product, so the reaction mixture was treated with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (See, Example 73, Step 1; 0.500 g, 1.220 mmol) and was cooled to −10° C. Lithium tert-butoxide (1N in THF) (2.441 ml, 2.441 mmol) was added, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 1-chloro-N-(thiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)isoquinoline-6-sulfonamide (0.220 g, 0.482 mmol, 39.5% yield). m/z (ESI) 456.0 (M+H)+;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.O.[OH-].[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[C:20]1([NH:19][C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nnn[nH]1)c1cncc(Nc2ccccc2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 5 ml of dimethylsulfoxide, 4.55 ml of aniline was added, and the mixture was heated for 17 hours at 80°-90 ° C. Water and 10%-sodium hydroxide aqueous solution were added to the reaction mixture, and the aqueous alkaline solution was washed with chloroform. The aqueous layer was filtered, and the filtrate was adjusted with 10%-hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and ethanol affording 0.80 g of the desired compound as yellow needles, m.p. 290°-293.5° C. (decomp.).
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:16]>>[CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1Cc1ccccc1
Reactant: Br
Product: BrCc1ccccc1Cc1ccccc1
Reaction time: 20 h
Yield: 98 %

Procedure:
2-Benzylbenzyl alcohol (commercial) (1 g) was suspended in 48% aqueous hydrobromic acid (10 ml) and stirred vigorously for 20 hours. The resultant suspended solid was extracted twice with hexane and the extracts dried (MgSO4) and evaporated to give 2-benzyl benzylbromide as yellow solid (1.3 g, 98%).
Reaction SMILES: CC([O:4][C:5](=[O:42])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([NH:30]C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:21]=3)[CH:15]=2)[N:10]([C:38](=[O:40])[CH3:39])[C@@H:9]([CH3:41])[CH2:8]1)C.F[C:44](F)(F)[C:45](O)=O.[ClH:50].[Cl:51][CH2:52]Cl>CO>[ClH:51].[ClH:50].[CH3:52][CH:44]([N:6]([C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]4)[CH:21]=3)[CH:15]=2)[N:10]([C:38](=[O:40])[CH3:39])[C@@H:9]([CH3:41])[CH2:8]1)[C:5](=[O:42])[OH:4])[CH3:45]
Reactant: ClCCl
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN4CCC(NC(=O)OC(C)(C)C)CC4)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: CO
Product: CC(=O)N1c2ccc(-c3cnn(CCN4CCC(N)CC4)c3)cc2[C@H](N(C(=O)O)C(C)C)C[C@@H]1C

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(1-{2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]ethyl}-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 37) (130 mg, 0.223 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred under nitrogen. The crude product was concentrated and purified on MDAP. The product-containing fractions were evaporated to dryness, loaded onto a 2 g SCX cartridge and eluted with MeOH (15 ml) and 2M methanolic ammonia (15 ml). The basic fractions were evaporated to give a white solid which was dissolved in MeOH (1 ml) and 1.25M HCl in MeOH was added (0.1 ml). The mixture was dried to give a white solid (47 mg).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10](Cl)=[O:11].C1(C)C=CC=CC=1.[NH2:25][C:26]1[CH:38]=[C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>O>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([NH:25][C:26]1[CH:38]=[C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[O:11]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
0.089 mL of pyridine and 0.11 mL of 2,6-dichlorobenzoyl chloride were added to 3.0 mL of toluene solution containing 0.15 g of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially, and the resulting mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and 0.021 mL of pyridine and 0.037 mL of 2,6-dichlorobenzoyl chloride were added sequentially and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and water was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 2-(2,6-dichlorobenzamido)-4-phenoxybenzoate.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C(ON1N=[N:26][C:21]2[CH:22]=[CH:23][CH:24]=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:33]([N:35](CC)[CH2:36][CH3:37])[CH3:34]>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([N:26]2[CH2:37][CH2:36][N:35]([C:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]3)=[O:10])[CH2:33][CH2:34]2)[CH2:22][CH2:23][CH2:24]1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C([C@H]1CC[C@H](O)CC1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 500 mg (3.5 mmol) of cis-4-hydroxycyclohexanecarboxylic acid (commercially available), 739 mg (3.5 mmol) of 1-(2-cyclobutyl)-piperazine dihydrogen chloride (WO 2004101546), 1.23 g (3.8 mmol) of TBTU and 1.40 g (13.8 mmol) of triethylamine in 7 ml DMF was stirred for 12 h at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine, and evaporated. The residue was purified by column chromatography on NH2-silica gel eluting with CH2Cl2 and methanol=from 100:0 to 98:2. Evaporation of the combined product fractions yielded 600 mg (65%) of the title compound as light brown oil. MS (m/e): 267.1 (MH+).