Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:20]([NH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[S:21])(=[O:10])=[O:11]
Reactant: S=C=NC1CCCCC1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: Nc1cc(Cl)sc1S(=O)(=O)NC(=S)NC1CCCCC1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and cyclohexyl isothiocyanate by a procedure analogous to the procedure described in example 3-a (yield 78%); 1H-NMR (DMSO-d6): δ1.1-1.9 (m, 10H), 4.0 (m, 1H), 6.45 (br s, 2H), 6.66 (s, 1H), 8.05 (br d, 1H), 11.2 (br s, 1H).
Reaction SMILES: [Mg].CI.[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:14])[CH3:13])[C:6]=1[NH2:7].[CH2:15](Cl)Cl>C(OCC)C>[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH3:15])([OH:14])[CH3:13])[C:6]=1[NH2:7]
Reactant: ClCCl
Reactant: CC(=O)c1cccc(C)c1N
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: Cc1cccc(C(C)(C)O)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In this example 234.93 g (9.66 moles) of magnesium was placed under nitrogen and then mixed with 583 ml of ethyl ether at room temperature. A small amount of methyl iodide was then added with gentle stirring followed by the addition of another 468 ml of ethyl ether. A methyl iodide solution containing 1,371.72 g (9.66 moles) of methyl iodide in 468 ml of ethyl ether was slowly added at reflux over a 21/4-21/2-hour period. (During this period the mixture was diluted with another 583 ml of ethyl ether to reduce the reaction rate.) The mixture was cooled to room temperature and then a solution containing 433.9 g of 2-methyl-6-acetylaniline dissolved in 698 ml of ethyl ether was slowly added over 11/4-11/2 hours. During this addition the temperature of the mixture was maintained at about or below 25° C. The mixture was then stirred at room temperature for another hour. Three liters of methylene chloride was then added at about 25° C. and the reaction was then quenched by the addition of solid ammonium chloride and water. The mixture was then allowed to stand overnight (about 15 hours). The ether phase of the mixture was then separated and filtered. The water phase was mixed with three liters of methylene chloride filtered. The methylene chloride filtrate and the ethyl ether filtrate were each evaporated affording 2-methyl-6-(1-methyl-1-hydroxyethyl)-aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([F:33])[CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.[NH2:43][C:44]1[CH:45]=[C:46]([Cl:52])[C:47](=[O:51])[N:48]([CH3:50])[CH:49]=1>C(Cl)Cl>[Cl:52][C:46]1[C:47](=[O:51])[N:48]([CH3:50])[CH:49]=[C:44]([NH:43][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:33])[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])[CH:45]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1F
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
A solution of 485 mg (0.944 mmol) ethyl 4-((4-chloro-2-fluorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (product from step 184.3), 0.658 ml (4.72 mmol) TEA in 19 ml CH2Cl2 was cooled down to 0° C. 411 mg (1.41 mmol) methanesulfonic anhydride was added and the solution was allowed to warm to RT. 229 mg (1.416 mmol) 5-amino-3-chloro-1-methylpyridin-2(1H)-one (intermediate W1) was added and the solution was stirred for 1.5 hour. The mixture was diluted with CH2Cl2 and washed with 1M NaHCO3 solution. The water phase was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (Silicagel, heptane, EtOAc) to give 474 mg (0.758 mmol, 80% yield) of the title compound as a brown oil. LCMS: (M+H)=619/621; tR=1.13 min (LC-MS 4). HPLC: tR=5.52 min (HPLC 7). TLC: Rf=0.09 (Heptane/EtOAc 1:2).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])=[CH:8][C:7]([Cl:21])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=1>CN(C=O)C>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:29][C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=3)[N:17]=[N:18][C:19]=2[C:11]=1[O:10][C:9]1[CH:8]=[C:7]([Cl:21])[CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4Cl)c(Cl)ccc32)c2cccnc21
Reaction time: 1 h

Procedure:
2,5-dichloro-3-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (1.00 g, 2.94 mmol) and cesium carbonate (1.15 g, 3.53 mmol) were suspended in dry DMF (10 mL) under N2 and tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.965 g, 3.09 mmol) was added as a solution in DMF (5 mL) at room temperature. After 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and diluted with water (50 mL). The mixture was then extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with water (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (120 g) eluting with 25-50% EtOAc/hexanes. LRMS (M+1)=569.6.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:21][C:20]([CH2:22][CH2:23][CH3:24])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.Br.[OH-].[Na+]>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:21][C:20]([CH2:22][CH2:23][CH3:24])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1
Reactant: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2s1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCc1nc2cnc3cc(O)ccc3c2s1
Temperature: 65 °C
Yield: 81.6 %

Procedure:
To 7-benzyloxy-2-propylthiazolo[4,5-c]quinoline (prepared as described in Part F of Example 1, 4.52 g, 13.5 mmol) was added a 45 wt. % solution of hydrogen bromide in acetic acid (40 mL). The resulting solution was heated at 65° C. for 1.5 h, then cooled in an ice bath. Aqueous NaOH (50% w/w solution) was added slowly until the pH=7 and a light yellow solid formed. The solid was isolated by filtration, dried, and then suspended in boiling ethanol (25 mL) for 5 min. The mixture was allowed to cool to rt and a tan solid was isolated by filtration. The solid was washed with cold ethanol and dried in a vacuum oven to yield 7-hydroxy-2-propylthiazolo[4,5-c]quinoline (2.69 g, 82%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11].B(Br)(Br)Br.CO>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:4]3[C:3]([C:8](=[O:20])[CH:9]=2)=[CH:2][CH:7]=[CH:6][CH:5]=3)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)CC(=O)c2ccccc2O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2cc(=O)c3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a solution of 1-(2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (200 mg, 0.74 mmol) in dichloromethane (15 mL) was added BBr3 (185 mg, 0.74 mmol, 1M solution in dichloromethane) slowly at 0° C., and then stirred for overnight at rt. Then MeOH was added at 0° C. to quench the unreacted BBr3. The organic layer was washed with water, dried and concentrated to give a crude product, which was purified by column chromatography using 30% EtOAc in hexane to afford 50 mg (26%) of 2-(4-methoxy-phenyl)-4H-chromen-4-one. MS (ES) m/z: 253.08 (M+1), and 149.00.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[CH:6][N:5]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: COc1ccccc1C(=O)c1cnc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N

Procedure:
The same procedure was used as described in Example 9 starting from (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone, Example 6, and 3-amino-piperidine-1-carboxylic acid tert-butyl ester (Astatech) to give 3-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. MS (M+H)+, 428.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>Br.C(O)(=O)C>[CH3:18][C:16]1[CH:15]=[CH:14][N:13]2[C:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)=[CH:10][N:11]=[C:12]2[CH:17]=1
Reactant: COc1cccc(-c2cnc3cc(C)ccn23)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccn2c(-c3cccc(O)c3)cnc2c1
Yield: 100.3 %

Procedure:
A solution of 3-(3-methoxyphenyl)-7-methylimidazo[1,2-α]pyridine (19 g, 80 mmol) in hydrogen bromide (160 ml of a 45% w/v solution in acetic acid) was heated at reflux for 18 hours. The cooled reaction was poured into sodium hydroxide solution (800 ml of a 4M aqueous solution), the pH adjusted to 7 with acetic acid and the resulting cream-coloured solid filtered and dried under vacuum at 60° C. to yield 3-(7-methylimidazo[1,2-α]pyridin-3-yl)phenol (18 g, 95%). 1H NMR (400 MHz, CDCl3) δH 6.79-6.83 (2H, m), 6.96-7.01 (2H, m), 7.30-7.33 (1H, m), 7.41 (1H, s), 7.62 (1H, s), 8.42 (1H, d, J 7); m/z (ES+) 225 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([N:20]=[C:21]=[O:22])=[CH:15][C:14]=2[Cl:23])=[N:4][CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:26]=1[C:27]([N:29]=[C:30]=[O:31])=[O:28]>CCCCCCC>[Cl:1][C:2]1[C:3]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([N:20]3[C:21](=[O:22])[O:28][C:27]([C:26]4[C:25]([F:24])=[CH:35][CH:34]=[CH:33][C:32]=4[F:36])=[N:29][C:30]3=[O:31])=[CH:15][C:14]=2[Cl:23])=[N:4][CH:5]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:7]=1
Reactant: O=C=Nc1cc(Cl)c(Oc2ncc(OC(F)F)cc2Cl)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCCCCCC
Product: O=c1nc(-c2c(F)cccc2F)oc(=O)n1-c1cc(Cl)c(Oc2ncc(OC(F)F)cc2Cl)c(Cl)c1
Yield: 86 %

Procedure:
0.8 g (2.2 mmol) of 4-(3-chloro-5-difluoromethoxy-2-pyridyloxy)-3,5-dichlorophenyl isocyanate and 0.4 g (2.2 mmol) of 2,6-difluorobenzoyl isocyanate were stirred for 16 hours at 70° C. with the exclusion of moisture, and, after cooling, the solid formed was stirred with 5 ml of absolute n-heptane, filtered off under suction and recrystallized from cyclohexene/toluene; melting point 154°-6° C., yield: 86%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[C:12]([C:17]([NH2:19])=[O:18])=[N:13][C:14]=1[CH2:15][CH3:16].N1(CO)C2C=CC=C[C:43]=2N=N1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.O1CCCC1.C(O)C>[CH2:15]([C:14]1[N:13]=[C:12]([C:17]([NH2:19])=[O:18])[C:11]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][CH:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[N:10][C:9]=1[NH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[NH:1][CH3:43])[CH3:16]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1N[C@@H]1CCCC[C@@H]1N
Reactant: OCn1nnc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1N[C@@H]1CCCC[C@@H]1NC
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.6 %

Procedure:
To a mixture of 5-{[(1R,2S)-2-aminocyclohexyl]amino}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (62 mg), ethanol (5 mL), and tetrahydrofuran (3 mL) were added 1H-benzotriazol-1-yl methanol (18 mg) and sodium acetate (15 mg), followed by stirring at room temperature for 7 hours. Sodium triacetoxyborohydride (50 mg) was added thereto under ice-cooling, followed by stirring at room temperature for 12 hours. To the reactant were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, followed by liquid separation. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=500:10:1-200:10:1) to obtain 6-ethyl-5-{[(1R,2S)-2-(methylamino)cyclohexyl]amino}-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (43 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:26][N:27]4[CH2:32][CH2:31][C@@H:30]([N:33]=[N+]=[N-])[C@H:29]([OH:36])[CH2:28]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:26][N:27]4[CH2:32][CH2:31][C@@H:30]([NH2:33])[C@H:29]([OH:36])[CH2:28]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: [N-]=[N+]=N[C@@H]1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C[C@H]1O
Temperature: 70 °C
Yield: 113.9 %

Procedure:
19A (78.0 mg, 0.15 mmol) was dissolved in a mixture of THF/H2O (1.2 ml/0.2 ml) and PPh3 (60.0 mg, 0.23 mmol) was added. The mixture was heated at 70° C. for 2 h. After cooled to rt, the reaction mixture was concentrated in vacuo and purified by prep HPLC to give 19B (85.0 mg, 93%) as a TFA salt. It has an analytical HPLC retention time=1.84 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=498+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:14]=1[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:16]
Reactant: COc1ccc2c(c1)c(=O)oc(=O)n2C
Reactant: Oc1n[nH]c2ccccc12
Product: CNc1ccc(OC)cc1C(=O)n1nc(O)c2ccccc21
Yield: 40.6 %

Procedure:
1H-Indazol-3-ol was reacted with N-methyl-5-methoxy isatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 40.6% yield; m.p. 161°-163° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCCCCC.O.P(Cl)(C(C)(C)C)C(C)(C)C>[C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccn1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 24 mg (0.044 mmol) of (t-Bu)2PCl)2PdCl2, 1.0 (8.8 mmol) of 2-chloropyridine, 1.3 g (10.66 mmol) of Ph—B(OH)2, 3.7 g (26.77 mmol) of K2CO3 in 5 mL of THF. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 220 mL of hexane and 150 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (100 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.3 g (95% yield) of 2-phenylpyridine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14](F)=[C:15]([CH:18]=1)[C:16]#[N:17]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: OC1CCOCC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OC1CCOCC1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a solution of tetrahydro-pyran-4-ol (3.3 g, 33.0 mmol) in DMF (60 ml) at 0° C. is added sodium hydride (1.4 g, 33.0 mmol). 5-Bromo-2-fluoro-benzonitrile (5.5 g, 27.5 mmol) in DMF (30 ml) is added dropwise at 0° C. The reaction is stirred at 45° C. for 16 h. The reaction is cooled to room temperature and quenched by pouring the reaction into water (500 ml). The precipitate is filtered and dried under vacuum; yield: 6.8 g 5-bromo-2-(tetrahydro-pyran-4-yloxy)-benzonitrile; HPLC/MS: 2.27 min, [M+H]=283.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([NH:25]C(OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([NH2:25])[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Reaction time: 2.5 h

Procedure:
To a solution of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-(t-butoxycarbonylamino)succinamic acid benzyl ester (389 mg, 0.851 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL). After 2.5 h at ambient temperature, the solvent was removed in vacuo to give 3(R)-amino-N-(1(S)-benzyl-2-hydroxyethyl)succinamic acid benzyl ester trifluoroacetate salt as a yellow foam that was placed with 3-(biphenyl-4-yl-)2,5-dimethoxytetrahydrofuran (182 mg, 0.641 mmol) in HOAc (1 mL) and heated to 50° C. After 2 hours, the mixture was allowed to cool, carefully stirred with saturated aqueous NaHCO3 (25 mL), and extracted into CHCl3 (3×15 mL). The combined organic layers were dried over Na2SO4 and evaporated to give a brown oil, 685 mg. Flash column chromatography with 10% MeOH/CH2Cl2 as eluant provided 276 mg (64%) of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-(3-(biphenyl-4-yl)-1H-pyrrol-1-yl)succinamic acid benzyl ester as a yellow solid. 1H NMR (CDCl3): δ 7.70-7.48 (m, 10H), 7.44 (dd, 2H, J=7.2, 7.8 Hz), 7.38-7.12 (m, 5H), 7.08-6.98 (m, 2H), 6.89 (bm, 1H), 6.63 (dd, 1H, J=2.5, 2.5 Hz), 6.54 (dd, 1H, J=1.2, 1.2 Hz), 5.76 (d, 1H, J=7.5 Hz), 5.10 (dd, 2H, J=12.1, 15.9 Hz), 4.95 (dd, 1H, J=5.0, 8.7 Hz), 4.34-4.00 (bm, 1H), 3.66 (dd, 1H, J=3.7, 11.2 Hz), 3.49 (dd, 1H, J=5.3,11.2 Hz), 3.37 (dd, 1H, J=5.0, 16.8 Hz), 3.18 (dd, 1H, J=8.7, 16.8 Hz), 2.74 (ddd, 2H, J=6.5, 13.7, 15.9 Hz). IR (KBr): 3314, 3029, 2925, 1731, 1658, 1548, 1495, 1355, 1196, 1165, 761, 698 cm-1 ; Anal. calculated for C36H34N2O4.0.5H2O: C, 76.17; H, 6.22; N, 4.94. Found C, 76.24; H, 6.18; N, 4.97.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8].C(OC([NH:34][CH2:35][CH2:36][CH:37]1[CH2:40][NH:39][CH2:38]1)=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].Cl.O1CCOCC1>C(N(CC)CC)C>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([N:39]4[CH2:40][CH:37]([CH2:36][CH2:35][NH2:34])[CH2:38]4)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CC(C)(C)OC(=O)NCCC1CNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: NCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4cc(N)c(F)cc4F)c3c2Cl)C1

Procedure:
Reaction was carried out as in Example 231 except that 1-(3-amino-4,6-difluorophenyl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-t-butoxycarbonylaminoethylazetidine, and triethylamine were used. For deprotection, trifluoroacetic acid was used rather than 4N hydrochloric acid/dioxane to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:15]1[N:24]2[N:25]=[C:26]([NH2:28])[N:27]=[C:23]2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[N:24]2[N:25]=[C:26]([NH2:28])[N:27]=[C:23]2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccccc1)c1nc2ccccc2c2nc(N)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c3ccccc3nc([C@H](N)c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a suspension of [(R)-(2-amino-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)-phenyl-methyl]-carbamic acid tert-butyl ester (0.05 g, 0.13 mmol), prepared as described in Example 49, in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 h, then the solvent was evaporated and the residue was diluted with ethyl acetate and washed with NaHCO3 satured solution then with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to provide the title compound (0.02 g, 65% yield).
Reaction SMILES: F[C:2]1(F)[C:11]2[C:6](=[CH:7]C=C[CH:10]=2)[C:5](=[O:12])[C:4]([C:13](F)(F)F)=[CH:3]1.F[C:19]1(F)C2C(=CC=CC=2)C(F)(F)C=C1C(F)(F)F>CC(C)=O>[CH3:13][C:4]1[C:3]([CH3:19])=[CH:2][C:11]([CH3:10])=[C:6]([CH3:7])[C:5]=1[OH:12]
Reactant: FC(F)(F)C1=CC(F)(F)c2ccccc2C1(F)F
Reactant: O=C1C(C(F)(F)F)=CC(F)(F)c2ccccc21
Solvent: CC(C)=O
Product: Cc1cc(C)c(C)c(O)c1C

Procedure:
Anal. Calcd. for C30H39F3OS2 : C, 67.16; H, 7.28; F, 10.63; S, 11.94. Found (A): C, 63.64; H, 5.37; F, 12.85; S, 7.69; MW, 2737; Found (B): C, 67.62; H, 5.37; F, 11.62; S, 11.80; MW, 5785; Found (C); C, 65.00; H, 5.72; F, 12.61; S, 12.98; MW, 928;