Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1N1[C:12](=[S:13])[N:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]2=[N:9]C1=S.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:12](=[S:13])[N:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]3=[N:9][C:27]2=[O:28])=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: S=c1nc2ccccn2c(=S)n1-c1ccccn1
Solvent: CC#N
Product: O=c1nc2ccccn2c(=S)n1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
544 Mg. of 3-(2-pyridyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione is combined with p-chloro phenylisocyanate and 10 ml. of acetonitrile. The reaction mixture is heated at 70° C. for 1 hour with a precipitate appearing after 1/2 hour. The reaction mixture is allowed to cool to room temperature with stirring. The solid material is filtered, washed twice with acetone, once with ether and dried in vacuo affording 3-(4-chlorophenyl) pyrido (1,2-a) 1,3,5-triazine-2-one-4-thione m.p. 209°-212° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([C:19]2[O:20]C=CC=2)=[CH:17][C:16]([C:24]([F:27])([F:26])[F:25])=[N:15]1.CC(C)=[O:30].[OH-].[Na+]>O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([C:19]([OH:20])=[O:30])=[CH:17][C:16]([C:24]([F:27])([F:26])[F:25])=[N:15]1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
An aqueous solution of 27.94 g of potassium permanganate in 100 ml of water was added dropwise to a mixture of 18.43 g of 1-(2-chlorophenyl)-5-(2-furyl)-3-trifluoromethyl-1H-pyrazole and 250 ml of acetone with being kept at 40° C. or lower. Then, the mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered through Celite (registered trademark) to obtain a filtrate. The filtrate was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then extracted with ethyl acetate two times. The aqueous layer was adjusted to around pH 3 by an addition of 2 N hydrochloric acid, and then extracted with methyl tert-butyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 10.65 g of 1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH3:48])=[N:44][CH:45]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[N:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOc1ccc(CCl)cn1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CCOc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cn1
Yield: 72.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 5-chloromethyl-2-ethoxypyridine (0.51 g) as starting materials, 5-benzyloxy-N-({1-[(6-ethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([F:18])=[CH:12][C:13]=2[F:17])[CH2:8]1)[CH3:2].[CH:20](OC(=O)C)=[O:21]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]([CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([F:18])=[CH:12][C:13]=2[F:17])[CH2:8]1)[CH:20]=[O:21])[CH3:2]
Reactant: CC(=O)OC=O
Reactant: CCOC(=O)CNC1CCc2c(F)cc(F)cc2C1
Solvent: ClCCl
Product: CCOC(=O)CN(C=O)C1CCc2c(F)cc(F)cc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A solution of ethyl[(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-amino]acetate (7.15 g, 25.6 mmol) in 20 mL of methylene chloride under argon was cooled to approximately 0° C. Acetic formic anhydride (9.7 mL, 67.3 mmol) was cooled to 0° C. and added over 5 to 10 minutes. The mixture was stirred 0° C. for 2 hours and then allowed to warm to room temperature. The solvent was removed by co-evaporation with toluene (3×50 mL). Crystallization of the residue under high vacuum gave ethyl[(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino]acetate (7.68 g, 25.0 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[N:20]=[C:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[O:18][N:17]=3)[CH:15]=[C:10]2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[N:20]=[C:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[O:18][N:17]=3)[CH:15]=[C:10]2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(-c5noc(C6CCN(C(=O)OC(C)(C)C)CC6)n5)cnc43)cc2OC)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5noc(C6CCNCC6)n5)cnc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (0.14 g, 0.22 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (0.20 g, 1.79 mmol). The reaction mixture was allowed to stir at room temperature. After 1 h, the mixture was diluted with cold saturated sodium carbonate solution. The phases were separated, and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to provide 0.067 g (57%) of the product as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.02 (d, J=1.5 Hz, 1H), 8.75 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.5, 2.0 Hz, 1H), 7.16 (d, J=1.5 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.89 (dd, J=8.0, 2.0 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 5.48 (s, 2H), 4.98 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H), 3.26-3.21 (m, 1H), 3.02-3.00 (m, 2H), 2.65-2.61 (m, 2H), 2.02-2.00 (m, 2H), 1.75-1.67 (m, 2H) ppm; (M+1)=528.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1.NC(N)=[O:36].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:6][N+:7]=1[O-:36]
Reactant: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Reactant: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)[n+]([O-])c3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a solution of (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (200 mg, 0.44 mmol) and urea-hydrogen peroxide (125 mg, 1.33 mmol) in DCM (10 mL) at 0° C. was added trifluoroacetic anhydride (280 mg, 1.33 mmol). The resulting mixture was allowed to stir at RT overnight. The reaction mixture was concentrated under reduced pressure to afford an oily residue that was diluted with saturated sodium bicarbonate solution (10 mL), and the product was extracted with EtOAc (2×25 mL). The combined organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC to afford 10 mg of (S)-2-fluoro-5-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine 1-oxide. 1HNMR (400 MHz, CD3OD) δ (ppm): 1.20 (d, 6H), 2.02-2.18 (m, 4H), 2.21-2.36 (m, 2H), 2.75-2.93 (m, 5H), 3.60-3.70 (m, 1H), 3.77-3.84 (m, 1H), 4.77 (dd, 1H), 6.21 (s, 1H), 7.36-7.41 (m, 1H), 7.50 (s, 1H), 8.81-8.89 (m, 1H). The other enantiomer was obtained using chiral (R) starting material.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CO>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH:15]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: COC(=O)COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)Oc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Yield: 41.7 %

Procedure:
A solution of 1.00 g (3.23 mmol) of the product of Step B dissolved in 4 mL of toluene was stirred under a N2 atmosphere and cooled to 0° C. with an ice-water bath. To this solution was added 9.68 mL (4.85 mmol) of a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene. After a 15 minute interval, 0.46 mL (3.88 mmol) of benzyl bromide was added and the reaction mixture was allowed to warm to room temperature and stirred 1 hour. Several milliliters of methanol were added to consume excess base, and the reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with saturated NaHCO3, brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.540 g (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][C:34]([CH3:36])=O.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][N:23]([CH:34]([CH3:36])[CH3:33])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN(C(C)C)C1
Reaction time: 2 h
Yield: 47.2 %

Procedure:
The hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylazetidine-3-carboxamide (110 mg, 0.22 mmol Example 99), acetone (23 μl, 0.31 mmol) and diisopropylethylamine (78 μl, 0.45 mmol) were stirred at room temperature in 5% acetic acid in 1,2-dichloroethane (2 ml) with 3 Å molecular sieves, and sodium triacetoxyborohydride (95 mg, 0.45 mmol) was added portionwise over 0.5 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting product was purified on preparative HPLC (standard basic conditions) to give the title product (52 mg, 47%) as a white powder; 1H NMR Spectrum: (CDCl3) 0.98 (d, 6H), 2.41 (s, 3H), 2.49 (m, 1H), 2.90 (s, 3H), 3.25 (brs, 2H), 3.57 (m, 2H), 3.96 (s, 2H), 3.97 (s, 3H), 7.16 (m, 2H), 7.24 (s, 1H), 7.57 (brs, 1H), 7.78 (brs, 1H), 8.00 (brs, 1H), 8.54 (brs, 1H), 8.73 (s, 1H); Mass Spectrum: (M+H)+ 501.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].[C:11]1([C:16](Cl)=[O:17])[S:15][CH:14]=[CH:13][CH:12]=1.C1(C2NC3C(C(=O)C=2)=CC(OC)=C(OC)C=3)CC1>>[C:11]1([C:16]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:1](=[O:3])[CH3:2])=[O:17])[S:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccccc1N
Reactant: O=C(Cl)c1cccs1
Agent: COc1cc2[nH]c(C3CC3)cc(=O)c2cc1OC
Product: CC(=O)c1ccccc1NC(=O)c1cccs1
Yield: 85.4 %

Procedure:
2-Acetylaniline (2.0 g) and 2-thenoyl chloride (3.2 g) were condensed in the same manner as in the preparation of compound 95 to obtain N-(2-thenoyl)-2-acetylaniline (3.1 g). The compound (2.0 g) and potassium t-butoxide (9.1 g) were reacted in the same manner as in the preparation of compound 95 to obtain 2-(2-thienyl)-4(1H)-quinolone (compound 100, 310 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:17][OH:18])[CH2:3]1.[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1CO
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1COc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.5 %

Procedure:
Benzyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g) [see Ceulemans et al, Chem. Eur. J. (1997), 3(12), 1997-2010] was added to a solution of phenol (1.12 g), triphenylphosphine (2.51 g) and diethylazodicarboxylate (1.51 ml) in dry tetrahydrofuran (40 ml). The reaction mixture was stirred at room temperature for 20 hours, after which time the solvent was removed under reduced pressure and the residue was dissolved in chloroform. The organic solution was washed with 15% aqueous sodium hydroxide solution, then brine, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 1:1, by volume, hexane:ethyl acetate to afford benzyl (2S,4R)-4-hydroxy-2-(phenoxymethyl)pyrrolidine-1-carboxylate (0.69 g) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:17])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.C([Li])(CC)C.CON(C)[C:26]([C:28]1([CH3:31])[CH2:30][CH2:29]1)=[O:27].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:17][C:26]([C:28]2([CH3:31])[CH2:30][CH2:29]2)=[O:27])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:8]=1
Reactant: COc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Reactant: CON(C)C(=O)C1(C)CC1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)C2(C)CC2)c(NC(=O)OC(C)(C)C)c1
Reaction time: 0.75 h
Yield: 65.8 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl (5-methoxy-2-methylphenyl)carbamate (2.00 g) in tetrahydrofuran (42 mL) was slowly added dropwise sec-butyllithium (1.08 mol/L hexane-cyclohexane solution, 22 mL) at −45° C., and the mixture was stirred for 45 minutes. Then, a solution of N-methoxy-N,1-dimethylcyclopropane carboxamide (1.33 g) in tetrahydrofuran (4.2 mL) was added dropwise thereto, and the mixture was stirred at −45° C. for 45 minutes, and then stirred at room temperature for 3 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.77 g). 1H-NMR (CDCl3) δ ppm: 0.80-0.89 (2H, m), 1.35-1.44 (5H, m), 1.52 (9H, s), 3.55 (2H, s), 3.80 (3H, s), 6.57 (1H, dd, J=2.8, 8.3 Hz), 6.97 (1H, d, J=8.3 Hz), 7.46 (1H, br s), 7.90-8.28 (1H, br).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][N:7]=1)=[O:5].[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH:17](Br)[CH3:18]>C1COCC1.O.C(=O)=O>[Br:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([C:4](=[O:5])[CH2:18][CH2:17][CH:16]([O:20][CH3:21])[O:15][CH3:14])[CH:11]=1
Reactant: COC(OC)C(C)Br
Reactant: CON(C)C(=O)c1cc(Br)ccn1
Agent: O=C=O
Solvent: O
Solvent: C1CCOC1
Product: COC(CCC(=O)c1cc(Br)ccn1)OC
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To a solution of (1) (8.86 g, 36.2 mmole) in 250 mL of anhydrous THF in a 3-neck flamed dried round bottom flask at −70° C. (acetone-dry ice bath) is slowly added the Grignard reagent prepared from bromopropionaldehyde dimethyl acetal (16.5 g, 90.4 mmol) and Mg turnings (4.39 g, 181 mmol) in anhydrous THF (250 mL), maintaining internal temperature around −68° C. to −70° C. After stirring at −70° C. for 2 hours, the reaction mixture is diluted with 200 mL of water with the dry ice bath removed. The mixture is poured into a separatory funnel, and the mixture is extracted 3 times with ethyl acetate (150 mL). The organic layers are combined and dried over Na2SO4 and the solvent evaporated leaving a thick yellow oil (11 g, 100% crude yield, MS ES+258.02).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[CH2:22][CH2:23]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: OCCN1CCNCC1
Reactant: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Product: OCCN1CCN(c2cc(Cl)nc3cc(-c4ccccc4)nn23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
There was dissolved, in 1,4-dioxana (3 mL), 5,7-dichloro-2-phenyl-pyrazolo-[1,5-a]pyrimidine (50.4 mg, 0.191 mM), then 1-(2-hydroxyethyl)-piperazine (46 μL, 0.382 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture and the resulting solid was washed with ethyl acetate to thus give the title compound in a quantitative yield.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[S:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[S:16][C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(C)(C)Sc1ccccc1-c1ccc(C2CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1ccccc1-c1ccc(C2CC2)nc1)C(=O)O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-(2-(6-cyclopropylpyridin-3-yl)phenylthio)-2-methylpropanoate (0.286 mmol) and aqueous sodium hydroxide solution (1 M, 2 mmol) in methanol is stirred at 60° C. for 12 hours. The reaction mixture is then concentrated, acidified, filtered and the isolated solid purified by to chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:33][C:34]([NH2:38])([CH3:37])[C:35]#[CH:36]>C(N(C(C)C)CC)(C)C.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>[NH2:38][C:34]([CH3:37])([CH3:33])[C:35]#[C:36][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Reactant: C#CC(C)(C)N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C#CC(C)(C)N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1

Procedure:
(5-Bromo-2-methoxy-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone (1.36 g; 3.2 mmol) is dissolved in hot diisopropylethylamine (120 ml). PdCl2(PPh3)2 (680 mg; 0.97 mmol), Cs2CO3 (6.8 g; 0.02 mmol), CuI (0.68 g; 3.57 mmol) and 1,1-dimethyl-prop-2-ynylamine (6.8 ml; 65 mmol) are added and the mixture refluxed under argon for 30 min. The reaction mixture is decanted from the solid, evaporated, taken up in water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated to dryness. Purification via chromatography (SiO2; toluene/ethanol/NH3conc 96/4/0.2>94/6/0.3) yields the title compound as a slightly colored foam (1.14 g; 84%).
Reaction SMILES: [NH2:1][C:2]1[O:3][N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH3:14].[CH:15]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[CH:15]1([C:21]([NH:1][C:2]2[O:3][N:4]=[C:5]3[C:10]=2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]3[CH3:14])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cn1c(=O)c2c(N)onc2n(C)c1=O
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: Cn1c(=O)c2c(NC(=O)C3CCCCC3)onc2n(C)c1=O
Temperature: 50 °C
Yield: 57.5 %

Procedure:
To a solution of 17.5 g of 3-amino-5,7-dimethylisoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione in 350 ml of pyridine, 26.2 g of cyclohexanecarbonyl chloride was added and the mixture was heated at 50° C. for 3 hours. The mixture was evaporated to dryness under reduced pressure and 200 ml of methanol was added to the residue. The resultant crystals were recrystallized twice from chloroform-methanol to afford 15.7 g of colorless needles, m.p. 210°-212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.COCCOC>C(O)C>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]2[CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccnc(N)c1
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccn2cc(CCl)nc2c1
Reaction time: 2.5 h
Yield: 1.8 %

Procedure:
A mixture of 2-amino-4-picoline (Aldrich; 500 g), 1,3-dichloroacetone (Aldrich; 5.89 g), and 1,2-dimethoxyethane (Aldrich; 44 mL) is stirred for 25 min at 53° C., at which time ethanol (47.5 mL) is added. After stirring for 2.5 h at reflux, the mixture is concentrated under reduced pressure and the residue is partitioned between dichloromethane and saturated sodium bicarbonate and brine. The organic layers are dried over MgSO4 and concentrated under reduced pressure. The crude material is chromatographed on silica gel using methanol/dichloromethane (1/99 to 2/98) to give, after crystallization from dichloromethane/hexane, 3.06 g of product. A portion of this material is dissolved in dichloromethane and refluxed with activated charcoal for 30 min. The activated charcoal is removed by filtration through a pad of diatomaceous earth and the filtrate is atmospherically concentrated, at which time hexane is added. The resulting solids are filtered, washed with hexane, and vacuum dried to give 0.15 g of 2-(chloromethyl)-7-methylimidazo[1,2-a]pyridine; mp 250° C. (decomp); ms m/z 180, 182; IR (mineral oil) 774, 1649, 1504, 1252, 701 cm-1 ; 1H NMR (CDCl3) δ 2.39, 4.75, 6.63, 7.32, 7.53, 7.95.