Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1.Cl[CH2:15][O:16][CH3:17]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:15][O:16][CH3:17])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1
Reactant: COCCl
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a slurry of sodium hydride (60% oily dispersion; 1.125 g, 28 mmol) in anhydrous DMF (80 mL), 1-(5-bromo-2-hydroxyphenyl)ethanone (4.67 g, 21.7 mmol) was added at 0° C. under a nitrogen atmosphere. After stirring for 1 h at the same temperature, methyl chloromethyl ether (tech, 90%; 2.35 g, 26 mmol) was added dropwise. The reaction mixture was allowed to gradually warm to room temperature and was stirred for 4 h. The reaction mixture was then quenched by pouring it onto saturated NH4Cl (aq) (100 mL). The reaction mixture was then extracted with 8:1 Et2O/EtOAc (2×150 mL). The combined organic layers were washed with water (4×80 mL), brine (60 mL), and dried over MgSO4. After purification by flash chromatography (9:1 hexane/EtOAc), the title compound (15) was obtained as colorless oil (4.44 g, 79% yield).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:17][CH:16]3[CH:12]2[CH2:13][N:14]([C:18](=[O:29])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH2:15]3)=[CH:7][CH:6]=1)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:18]([N:14]1[CH2:13][CH:12]2[CH:16]([CH2:17][N:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[CH:6][CH:7]=2)[CH2:15]1)=[O:29]
Reactant: CCOC(=O)c1ccc(N2CC3CN(C(=O)NCc4ccc(Cl)cc4Cl)CC32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CC3CN(C(=O)NCc4ccc(Cl)cc4Cl)CC32)cc1
Temperature: 60 °C
Yield: 58 %

Procedure:
To a solution of rac-4-[3-(2,4-Dichloro-benzylcarbamoyl)-3,6-diaza-bicyclo[3.2.0]hept-6-yl]-benzoic acid ethyl ester (55 mg, 123 μmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added aqueous sodium hydroxide (1 M, 2 mL) and the reaction mixture was heated to 60° C. for 1 h. The solvents were partly removed by concentration in vacuo, tetrahydrofuran (2 mL) was added and filtration afforded the title compound (30 mg, 58%) as a white solid. MS (EI) m/e: 420.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[C:15]2[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([O:5][C:6]2[C:15]3[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=3[N:9]=[CH:8][CH:7]=2)[CH:3]=1)=[O:29])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Reactant: Cc1nc2c(Oc3cccc(N)c3)ccnc2[nH]c1=O
Product: Cc1nc2c(Oc3cccc(NC(=O)c4cccc(C(C)(C)C)c4)c3)ccnc2[nH]c1=O

Procedure:
Method G1 was used with 8-(3-aminophenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-tertbutylbenzoyl chloride to afford the title compound as a slightly yellow solid (77 mg, 97%).
Reaction SMILES: [OH:1][CH:2]([CH:5]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11](=[O:16])[NH:10]1)[CH2:3][OH:4].[C:25](Cl)(Cl)=[O:26]>>[O:16]=[C:11]1[NH:10][CH:9]([CH2:8][CH2:7][CH2:6][CH:5]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH:2]2[CH2:3][O:4][C:25](=[O:26])[O:1]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC(CCCC1CCCCC(=O)N1)C(O)CO
Reactant: O=C(Cl)Cl
Product: CC(C)(C)OC(=O)NC(CCCC1CCCCC(=O)N1)C1COC(=O)O1

Procedure:
The product of EXAMPLE 269 is reacted with phosgene by the method of EXAMPLE 261, to generate the title material.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:23]=[C:9]2[CH:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14](=[S:16])[NH2:15])[N:8]2[N:7]=1)[CH3:2].Br[CH2:26][C:27](=O)[CH2:28][CH3:29]>CCO>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[N:23]=[C:9]2[CH:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14]3[S:16][CH:26]=[C:27]([CH2:28][CH3:29])[N:15]=3)[N:8]2[N:7]=1)=[O:24])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(N)=S)n2n1
Reactant: CCC(=O)CBr
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3nc(CC)cs3)n2n1

Procedure:
A mixture of the product of Step 1 (0.5 g, 1.47 mmol) and 1-bromo-2-butanone (0.22 g, 1.47 mmol) in EtOH (10 mL) was heated to reflux for 3 h. The solvent was removed under reduced pressure; the resulting yellow solid was dissolved in MeOH/CHCl3, and dried onto silica gel. The slurry was then purified by column chromatography on silica gel using 1-4% MeOH/CHCl3 as eluent, to afford 1-ethyl-3-[5-(4-ethyl-thiazol-2-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea as a solid. LCMS (APCI+) 394.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:26]1[C:27]([Cl:36])=[N:28][C:29]3[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:13]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>C(#N)C>[Cl:36][C:27]1[C:26]([C:14]2[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]3[C:12]([CH:13]=2)=[CH:11][C:10]([CH2:9][OH:8])=[CH:18][CH:17]=3)=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO[Si](C)(C)C(C)(C)C)ccc21
Agent: F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO)ccc21

Procedure:
A solution of tert-butyl 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-1, 2.50 g, 4.78 mmol, 1 equiv) and triethylamine trihydrofluoride (3.89 mL, 23.9 mmol, 5.00 equiv) in acetonitrile (100 mL) was heated at 50° C. for 3 h. The reaction mixture was carefully partitioned between saturated sodium bicarbonate solution and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to give tert-butyl 2-(2-chloro-3-quinolinyl)-5-(hydroxymethyl)-1H-indole-1-carboxylate (7-2) as a tan foam. 1H NMR (500 MHz, CDCl3) δ 8.31 (d, 1H, J=8.5 Hz), 8.19 (s, 1H), 8.08 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=8.1 Hz), 7.78 (br t, 1H, J=8.0 Hz), 7.63 (s, 1H), 7.62 (br t, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.5 Hz), 6.66 (s, 1H), 4.82 (d, 2H, J=4.9 Hz), 1.81 (br s, 1H), 1.27 (s, 9H).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:95]=[CH:96][CH:97]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[C:53]([CH3:94])=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:95]=[CH:96][CH:97]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([CH:71]5[CH2:72][CH2:73][N:74]([C:77]([O:79][C:80]([CH3:82])([CH3:83])[CH3:81])=[O:78])[CH2:75][CH2:76]5)=[CH:67][CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)[C:53]([CH3:94])=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (100 mg, 0.138 mmol) was hydrolyzed by lithium hydroxide (17 mg, 0.416 mmol) in THF/methanol/water (2/2/1 ml) to yield 100 mg (crude) of the titled compound.
Reaction SMILES: CI.[CH2:3]([S:5]([C:8]1[C:9]([C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH3:4].[C:31](=O)([O-])[O-].[K+].[K+].CC(C)=O>O.CN(C=O)C>[CH2:3]([S:5]([C:8]1[C:9]([C:14]([N:16]([CH3:31])[C:17]2[CH:18]=[C:19]([C:27]([F:30])([F:28])[F:29])[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH3:4]
Reactant: CCS(=O)(=O)c1cccnc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccnc1C(=O)N(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
0.50 g of methyl iodide was added to a mixture of 0.20 g of 3-ethylsulfonyl-N-(3,5-bistrifluoromethylphenyl)picolinamide (Compound of Present Invention 14), 0.12 g of potassium carbonate and 3 mL of acetone, and the mixture was stirred at room temperature for 1 hour. 1 mL of DMF was added to the reaction mixture, and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.18 g of 3-ethylsulfonyl-N-methyl-N-(3,5-bistrifluoromethylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 38).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH3:15])=[CH:10][CH:9]=1.[CH3:17][O:18][C:19](=[O:22])[CH2:20][SH:21].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:17][O:18][C:19](=[O:22])[CH2:20][S:21][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][CH:10]=1)[CH3:15]
Reactant: COC(=O)CS
Reactant: CC(Cl)c1ccc(-c2ccccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CSC(C)c1ccc(-c2ccccc2Cl)cc1

Procedure:
294 gm (1.17 mol) of 1-(2'-chloro-4-biphenylyl)-1-chloro-ethane and 149.2 gm (1.4 mol) of thioglycolic acid methyl ester were dissolved in 1 liter of dimethyl sulfoxide, and 194.3 gm (1.4 mol) of potassium carbonate were added to the solution in small portions, while stirring vigorously and cooling on ice water. After stirring the mixture for 4 hours, 3 liters of water were added. The reaction product was extracted with toluene, and after washing the extract with water and drying it over magnesium sulfate, the solvent was removed in vacuo. Yield: 359:0 gm (95.5% of theory). Rf -value: 0.6 on carrier 1 with cyclohexane/ethyl acetate=4:1.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:6])([CH3:5])[CH3:4].[O:20]=[C:21]1[NH:25][CH:24]([CH2:26][C:27](O)=[O:28])[C:23](=[O:30])[NH:22]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:15][CH2:16][N:17]([C:27](=[O:28])[CH2:26][CH:24]2[NH:25][C:21](=[O:20])[NH:22][C:23]2=[O:30])[CH2:18][CH2:19]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1ccc(N2CCNCC2)c(C(C)(C)C)c1
Reactant: O=C(O)CC1NC(=O)NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)CC3NC(=O)NC3=O)CC2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
A mixture of 1-(2-tert-butyl-4-methylphenyl)piperazine dihydrochloride (Reference Example 10, 0.31 g, 1.0 mmol), (2,5-dioxoimidazolidin-4-yl)acetic acid (0.19 g, 1.2 mmol), triethylamine (420 μL, 3.0 mmol), EDCI (0.23 g, 1.2 mmol) and HOBt (0.18 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.33 g, 89%) as a orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=[O:11])[NH:6]2.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:14][NH2:15])[C:5](=[O:11])[NH:6]2
Reactant: NN
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Solvent: CCO
Solvent: O
Product: NN=C1C(=O)Nc2cccc(Cl)c21

Procedure:
To a stirred slurry of 43.3 g of 4-chloroisatin in 350 ml of ethanol was added 17.3 ml of hydrazine hydrate, and then the reaction mixture was heated under reflux for 2 hours. The reaction mixture was cooled, and the precipitate was recovered by filtration to give 43.5 g of 4-chloro-3-hydrazono-2-oxindole, mp 235°-236° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([NH2:8])=[O:7])[N:3]=[CH:2]1.[H-].[Na+].[CH2:11]([O:18][C@@H:19]([CH3:36])[C@@H:20](OS(C)(=O)=O)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:18][C@H:19]([C@H:20]([N:1]1[CH:5]=[C:4]([C:6]([NH2:8])=[O:7])[N:3]=[CH:2]1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][CH3:30])[CH3:36])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CSc1ccccc1CC[C@H](OS(C)(=O)=O)[C@H](C)OCc1ccccc1
Reactant: NC(=O)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccccc1CC[C@H]([C@H](C)OCc1ccccc1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.1 %

Procedure:
A suspension of imidazole-4-carboxamide (313 mg) in DMF (3.8 ml) was treated with sodium hydride (60% in mineral oil, 129 mg) at ice-bath temperature and the mixture was stirred at room temperature for 20 min. A solution of 2-[(3S,4S)-4-benzyloxy-3-methanesulfonyloxypentyl]thioanisole (0.92 g) in DMF (7.5 ml) was added and the mixture was stirred at 85° C. for 3 days. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo. Column chromatography (dichloromethane:methanol=30:1) gave 1-[(2S,3R)-2-benzyloxy-5-(2-(methylthio)phenyl)-3-pentyl]imidazole-4-carboxamide (1) (96.4 mg, 11.6%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][CH3:19].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.O>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:6]=[C:5]3[NH:18][CH3:19])=[CH:24][CH:23]=1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(Br)cc12
Reactant: COc1ccc(B(O)O)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OC)nc3)cc12
Temperature: 90 °C
Yield: 50.1 %

Procedure:
To a 1 dram reaction vial was added 6-bromo-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine (35 mg, 0.111 mmol), 6-methoxypyridin-3-ylboronic acid (20.4 mg, 0.133 mmol), Pd(APhos)2Cl2 (3.2 mg, 0.0041 mmol) and potassium phosphate monohydrate (77 mg, 0.33 mmol) in a mixture of dioxane-water (9:1, 2 mL). The reaction mixture was heated to 90° C. for 14 h after which it was cooled to room temperature and diluted with water (5 mL). The resultant precipitate was collected by filtration and recrystallized from methanol to give 6-(6-methoxypyridin-3-yl)-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine as a pale yellow solid (19.1 mg, 51%). LCMS m/z=344 (M+1) (Method C) (retention time=2.01 min) 1H NMR (300 MHz, DMSO) δ 9.64 (d, J=1.3 Hz, 1H), 8.84-8.74 (m, 1H), 8.68 (dd, J=6.2, 1.7 Hz, 2H), 8.57 (d, J=1.6 Hz, 2H), 8.16 (ddd, J=14.4, 8.7, 2.2 Hz, 2H), 7.85 (d, J=8.7 Hz, 1H), 7.54 (dd, J=7.9, 4.8 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 3.18 (d, J=4.3 Hz, 3H).
Reaction SMILES: [C:1]([CH:4]([C:12](=[O:14])[CH3:13])[CH:5]([C:9](=[O:11])[CH3:10])[C:6](=[O:8])[CH3:7])(=O)[CH3:2].Cl>>[CH3:7][C:6]1[O:8][C:1]([CH3:2])=[C:4]([C:12](=[O:14])[CH3:13])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Agent: Cl
Product: CC(=O)c1c(C)oc(C)c1C(C)=O

Procedure:
A mixture of 1.0 g. of 1,1,2,2-tetraacetylethane in 10 ml. of concentrated hydrochloric acid was stirred at room temperature for about 1 hour until a clear solution was obtained. The mixture was then poured onto ice and extracted with diethyl ether. The extracts were dried over sodium sulfate, taken to dryness, and the residue recrystallized from hexane to give 2,5-dimethyl-3,4-diacetylfuran, m.p. 75°-77° C.
Reaction SMILES: [CH3:1][C:2]([NH2:27])([CH3:26])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45](=O)[O:46]C1C=CC([N+]([O-])=O)=CC=1)([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45]([NH:27][C:2]([CH3:1])([CH3:26])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[O:46])([CH3:30])[CH3:29]
Reactant: CC(C)(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC(C)(C)Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 95 using 2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine (CB28) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown oil (0.018 g, 9%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:17]([N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]([NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1C)OCC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1C)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A mixture of diethyl trans-4-methylpiperidin-3-ylphosphoramidate (0.63 g, 2.52 mmol), benzaldehyde (0.38 mL, 3.78 mmol) and acetic acid (0.29 mL, 5.03 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.24 g, 3.78 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo, and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-methylpiperidin-3-ylphosphoramidate (0.85 g, 99%), which was used directly in the next step without purification.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21].Cl.[NH2:23][OH:24]>CO>[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[N:23][OH:24])[NH2:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21]
Reactant: NO
Reactant: CN1Cc2c(C#N)ncn2-c2ccc(F)c(Cl)c2C1=O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN1Cc2c(C(N)=NO)ncn2-c2ccc(F)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 67 h
Yield: 83.3 %

Procedure:
1.0 g (0.0432 mol) of sodium was dissolved in 60 ml of methanol. 8.85 g (0.0304 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile and 3.25 g (0.0469 mol) of hydroxylamine hydrochloride were added thereto in succession at room temperature. The white suspension was stirred at room temperature for 67 hrs. and evaporated, whereupon the residue was suspended in 100 ml of water and the crystals were filtered off. By drying the crystallizate there were obtained 8.2 g (83%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime as white crystals; m.p. 228°-231°.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[N:4]([CH3:26])[CH:5]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:7]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:34][OH:35].ClCCl>C(O)C.O>[Br:1][C:2]1[C:3](=[O:27])[N:4]([CH3:26])[CH:5]=[C:6](/[C:8](=[N:34]/[OH:35])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:7]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1cc(Br)c(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1[C@H](C/C(=N\O)c1cc(Br)c(=O)n(C)c1)c1ccc(Br)cc1
Temperature: 100 °C

Procedure:
To a suspension of (R)-3-bromo-5-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-1-methylpyridin-2(1H)-one in ethanol (2.5 mL) and water (0.1 mL) were added sodium bicarbonate (30.9 mg) and hydroxylamine hydrochloride (32.0 mg) and the reaction mixture was stirred at reflux (100° C. oil bath temperature) for 2 hours. The reaction mixture was poured on water and dichloromethane and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane/ethyl acetate (100:0 to 50:50) to give the title compound as a white solid, MS (ESI+): m/z=504.99 [M+H]+.
Reaction SMILES: OO.C[O:4][C:5](=[O:52])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3[N:17]=[C:18]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[N:19]=[C:20]([C:21]4[CH:22]=[N:23][C:24]([N:27](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=[N:25][CH:26]=4)[C:15]=3[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.Cl.[OH-].[Na+:55]>O1CCCC1>[Na+:55].[NH2:27][C:24]1[N:23]=[CH:22][C:21]([C:20]2[C:15]3[CH2:14][CH2:13][N:12]([C:9]4[CH:8]=[CH:7][C:6]([C:5]([O-:52])=[O:4])=[CH:11][CH:10]=4)[C:16]=3[N:17]=[C:18]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[N:19]=2)=[CH:26][N:25]=1
Reactant: COC(=O)c1ccc(N2CCc3c(-c4cnc(N(Cc5ccc(OC)cc5)Cc5ccc(OC)cc5)nc4)nc(N4CCOCC4)nc32)cc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(C(=O)[O-])cc2)cn1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Tetrahydrofuran/5M aqueous sodium hydroxide solution/30% hydrogen peroxide solution=4/2/1 solution of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid methyl ester obtained in Example 1-D-08 was refluxed overnight, followed by neutralization with 6M hydrochloric acid. After filtering the precipitate, trifluoroacetic acid (1 ml) and concentrated sulfuric acid (2 drops) were added, followed by stirring at 40° C. for 4 hours. Concentration was carried out under reduced pressure, and water was added, followed by neutralization with 1M aqueous sodium hydroxide solution. After filtering the resulting solid, dichloromethane/hexane=9/1 was added, followed by stirring at room temperature for 30 minutes, to filter the solid. To this, 1M aqueous sodium hydroxide solution corresponding to 1 equivalent of sodium hydroxide was added, followed by stirring at room temperature for 10 minutes, and subsequently concentration was carried out under reduced pressure, to obtain the desired compound.