Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:11]=O>>[CH:1]1([CH:7]([CH3:10])[C:8]([OH:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C=O)C1CCCCC1
Reactant: O=O
Product: CC(C(=O)O)C1CCCCC1
Yield: 35 %

Procedure:
Into a 500 ml round bottom flask was charged 300 g of 2-cyclohexylpropanal and was fed a stream of oxygen at a rate of 100 ml per minute at 60° C. for 80 hours through a sintered liquid filter for liquid chromatography. The reaction mixture was analyzed by means of gas chromatography and confirmed that 2-cyclohexylpropionic acid was obtained in an yield of 65% and 35% of the 2-cyclohexylpropanal remained unreacted in the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C=O.[C:36]([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:29][CH2:30][N:31]([CH3:36])[CH2:32][CH2:33]5)[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(c1ccc2ncccc2c1Cl)c1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(c1ccc2ncccc2c1Cl)c1cnc2ccc(-c3cnn(C4CCN(C)CC4)c3)nn12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To (rac)-5-chloro-6-{1-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-ethyl}-quinoline (131 mg, 0.287 mmol), a 37% aqueous solution of formaldehyde (0.107 mL, 1.434 mmol) and 85% sodium cyanoborohydride (106 mg, 1.434 mmol) in MeOH (5 mL) was added acetic acid to adjust pH at 5-6. The RM was stirred at rt for 2.5 h, filtered and purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to yield the title compound as a white foam (tR 2.29 min (conditions 8), MH+=472).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:13]Br.O.C(Cl)Cl>CC(O)=O>[Br:13][CH:8]([CH2:9][CH2:10][CH2:11][CH3:12])[C:2](=[O:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: BrBr
Reactant: CCCCCC(=O)C(=O)OCC
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCCC(Br)C(=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cold solution of ethyl 2-oxoheptanoate (2 g, 11.62 mmol) in AcOH (20 mL), was added Br2 (596 μL, 11.62 mmol). The mixture was stirred 20 minutes at 0° C., then the mixture was allowed to warm to rt. After the mixture was stirred for 3 h, water and CH2Cl2 were added. The organic phase was separated, dried (MgSO4), and evaporated to give crude ethyl 3-bromo-2-oxoheptanoate as a dark oil; 1H NMR (400 MHz, CDCl3) δ 5.05-5.01 (m, 1 H), 4.45-4.20 (m, 2 H), 2.18-1.94 (m, 2 H), 1.74-1.57 (m, 2 H), 1.48-1.17 (m, 5 H), 0.95-0.82 (m, 3 H). This compound was used without purification for the preparation of compounds of the invention such as 1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidinyl)-5-butyl-1H-imidazole-4-carboxamide hydrochloride (Table entry 20).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[N:14][CH:13]=1)C.O(CC)[Li].CC([O-])=O.[Na+]>C1COCC1.C(O)(=O)C>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C:11]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[O:10])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C1CNCCNC1
Agent: CC(=O)[O-]
Agent: [Li]OCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)nc1)N1CCCNCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of homopiperazine (12.5 g, 125 mmol) and ethyl-6-chloronicotinate (9.28 g, 50 mmol) in THF (150 mL) was cooled to 0° C. and LiOEt (1 M in THF, 50 mL, 50 mmol) was then added over 20 minutes. The resulting mixture was stirred at 0° C. for 2 h, then warmed to 20° C. and held at this temperature for 17 h. The resulting mixture was then treated with 162 mL of an aqueous solution containing 1.53 g of NaOAc and 8.2 mL of acetic acid. The resulting layers were separated and the organic was diluted with hexane (50 mL) and extracted again with the same aqueous solution as utilized above. The aqueous pH was then increased to 10 through addition of 50% NaOH(aq) (15 mL). After extraction with dichloromethane (3×250 mL) the combined organics were dried over sodium sulfate, filtered, and concentrated to yield the title compound as an oil.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 0.5 h

Procedure:
To a solution of 165 mL (0.544 mol) of palmitoyl chloride in 1 L of chloroform while cooled with ice with stirring, 69.8 g (0.598 mol) of N-hydroxysuccinimide was gradually added, and 83.1 mL (0.598 mol) of triethylamine was added dropwise thereto over 30 minutes. The resultant solution was stirred for 30 minutes while cooled with ice and for another 7 hours during which the resultant solution gradually reached room temperature. After washed with 500 mL of water three times, the resultant solution was dried over magnesium sulfate and was then concentrated under reduced pressure to obtain 260.3 g (quant) of a colorless solid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18][Cl:19].CC(O)(C(Cl)(Cl)Cl)C>C(Cl)(Cl)Cl.O>[Cl:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: OC(CCl)CCCl
Agent: CC(C)(O)C(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: OC(CCCl)COc1cccc2ccccc12
Temperature: 65 °C

Procedure:
To a mixture of 1 mole (147 g.) of 1-naphthol, 350 ml. of water and 2 moles (112 g.) of potassium hydroxide was added at 54° C. 1 mole (143 g.) of 1,4-dichloro-2-butanol. The temperature of the reaction mixture was kept below 60° C. during the addition of the chlorobutanol. The reaction mixture was heated at 65° C. for 12 hr., then mixed with 500 ml. of water and 350 ml. of chloroform. The chloroform layer was separated, washed with water, dried over sodium sulfate, concentrated and the residual oil distilled under reduced pressure to give 128 g. of a crystalline solid which was distilled at 162°-165° C./0.01 mm. The solid was recrystallized with ether and pet. ether (30°-60°) to give material melting at 75°-77° C.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5][OH:6])=[O:4].C(N(C(C)C)CC)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:7][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:1])[C:3]([CH2:5][O:6][S:29]([CH3:28])(=[O:31])=[O:30])=[O:4]
Reactant: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)COS(C)(=O)=O
Temperature: 0 °C
Yield: 63 %

Procedure:
N-(1',1'-dimethyl-3'-hydroxyacetonyl)-3,5-dichlorobenzamide (1.0 gm, 0.00345 m) was dissolved in methylene chloride (25 ml) and diisopropylethylamine (0.44 gm, 0.0035 m) and cooled to about 5° C. under a nitrogen atmosphere. While the solution was stirred magnetically, methanesulfonylchloride (0.475 gm, 0.0041 m) was added dropwise. After its addition, the mixture was stirred about an hour longer while maintaining the temperature at 5°-10° C. The mixture was then poured into ice water (500 ml) containing methylene chloride (100 ml). The organic layer was separated and was washed with cold 1% hydrochloric acid, saturated sodium bicarbonate, water and brine, and then dried over anhydrous potassium carbonate. The solvent was removed and 800 mg of the desired product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13]O.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[C:36]([O:40][C:41](=[O:48])[NH:42][CH2:43][CH:44]1[CH2:47][NH:46][CH2:45]1)([CH3:39])([CH3:38])[CH3:37]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][N:46]1[CH2:47][CH:44]([CH2:43][NH:42][C:41](=[O:48])[O:40][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:45]1
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Reactant: O=[N+]([O-])c1ccc(Oc2ccncc2C#CCO)c(F)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CN(CC#Cc2cnccc2Oc2ccc([N+](=O)[O-])cc2F)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A solution of 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol (43 mg, 0.15 mmol) and DIPEA (45 μL, 0.26 mmol) in anhydrous THF (1.5 mL) was cooled to 0° C. and treated with methanesulfonyl chloride (15 mg, 0.11 mmol) in portions. After stirring at 0° C. for 1 h, the mixture was concentrated under reduced pressure. The residue was treated with DMF (1.0 mL), DIPEA (45 μL, 0.26 mmol) and azetidin-3-ylmethyl-carbamic acid tert-butyl ester (Beta Pharma Inc., 145 mg, 0.78 mmol) and stirred at rt for 2 h. The reaction mixture was partitioned between EtOAc and saturated aq. NaHCO3 solution and the EtOAc phase separated, washed with brine dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 eluting with 1-5% MeOH/CH2Cl2 to afford the title compound (33 mg, 48%) as a colorless oil. 1H NMR (DMSO-d6) δ 8.74 (s, 1H), 8.51 (d, 1H, J=5.6 Hz), 8.41 (dd, 1H, J=10.7, 2.5 Hz), 8.15 (d, 1H, J=9.2 Hz), 7.53 (t, 1H, J=8.6 Hz), 7.09 (d, 1H, J=6.1 Hz), 6.86 (t, 1H, J=5.6 Hz), 3.39 (s, 2H), 3.24-3.14 (m, 2H), 3.07-2.98 (m, 2H), 2.94-2.87 (m, 2H), 2.37-2.26 (m, 1H), 1.33 (s, 9H); MS(ESI+): m/z 401.20 (100), [(M-C4H9)]+; m/z 457.20 (25), (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[C:20]([CH2:21][C:22]([OH:24])=O)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].[CH3:27][N:28]([CH3:31])[CH:29]=O>>[CH3:27][N:28]([CH:31]=[C:21]([C:20]1[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:13][N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=12)[CH:22]=[O:24])[CH3:29]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1c(-c2ccccc2)nn2ccccc12
Reaction time: 20 h

Procedure:
Phosphorus oxychloride (27.6 g) was added dropwise to N,N-dimethylformamide (16.6 ml) for 20 minutes under ice-cooling, 2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acetic acid (9.08 g) was added to the solution thus obtained and the reaction mixture was stirred at 90°-100° C. for 20 hours. After cooling, the reaction mixture was poured onto ice (20 g). The mixture was made alkaline with 24% aqueous solution of sodium hydroxide (pH≈9) and stirred at 90° C. for 1 hour and 20 minutes. After cooling, the resulting mixture was extracted with ethyl acetate three times. The combined extract was washed with water and dried over magnesium sulfate. The solvent was removed and recrystallized from a mixture of ethyl acetate and isopropanol to give 3-(N,N-dimethylamino)-2-(2-phenylpyrazolo[1,5-a]pyridine-3-yl)acrylaldehyde (cis and trans mixture) (5.00 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9]2)#[N:5].C([O-])([O-])=O.[K+].[K+]>CO.ClCCl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:11]2[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4](=[N:2][OH:3])[NH2:5])[CH:7]=3)[C:12]2=[O:16])=[CH:18][CH:19]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C#N)ccc2c(=O)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Hydroxylamine hydrochloride (183 mg, 2.64 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(6-cyano-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (185 mg, 0.440 mmol) and K2CO3 (365 mg, 2.64 mmol) in MeOH (20 mL) and the mixture was stirred at room temperature for overnight. The mixture was diluted with dichloromethane (60 mL), washed with aqueous ammonium chloride (saturated, 1×20 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give tert-butyl 5-(2-(4-fluorophenyl)-6-(N′-hydroxycarbamimidoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (200 mg, 0.441 mmol) as an off white solid.
Reaction SMILES: [ClH:1].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:35]CC2C=CC=CC=2)=[C:26]([NH:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:27]=1)[OH:21].CO.C(OCC)(=O)C>CO.[Pd]>[ClH:1].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:35])=[C:26]([NH:28][S:29]([CH:32]([CH3:33])[CH3:34])(=[O:31])=[O:30])[CH:27]=1)[OH:21]
Reactant: CC(C)S(=O)(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)S(=O)(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1O

Procedure:
According to the procedures described in Example 2, the compound of Example 53 (369 mg) was dissolved in 39.9 ml of methanol and subjected to a hydrogenolysis using 10% Pd-C (190 mg). The catalyst was filtered on celite at room temperature and washed with hot methanol. After the filtrate and the washed liquor were brought together, the solvent was distilled off under a reduced pressure, whereby the above-identified compound (267 mg) was obtained. Rf=0.27(methanol/ethyl acetate of 1/3).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13](OC)(OC)OC.C(O)(=O)C.[NH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=1[CH3:37])[C:28]([NH:30][CH:31]1[CH2:33][CH2:32]1)=[O:29]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:31]1([NH:30][C:28](=[O:29])[C:27]2[CH:34]=[CH:35][C:36]([CH3:37])=[C:25]([N:24]3[C:4](=[O:6])[C:3]4[C:2](=[CH:10][CH:9]=[C:8]([O:11][CH3:12])[CH:7]=4)[N:1]=[CH:13]3)[CH:26]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: COC(OC)OC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1

Procedure:
A stirred mixture of 2-amino-5-methoxybenzoic acid (10 g), trimethyl orthoformate (13.1 ml), and acetic acid (0.34 ml) in toluene (240 ml) was heated under reflux for 6 hours. 3-Amino-N-cyclopropyl-4-methylbenzamide (10.23 g) was added to the reaction mixture and stirring continued at reflux for 16 hours. The reaction mixture was allowed to cool and then was diluted with ethyl acetate. The organic solution was then washed with 1N HCl solution, 2N NaOH solution (×2), brine, dried (magnesium sulfate), and concentrated to a cream coloured foam/solid. Recrystallisation from ethyl acetate gave N-cyclopropyl-3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (AZ12239719) (11.33 g) as a white solid; NMR Spectrum: (DMSOd6) 0.62 (m, 2H), 0.75 (m, 2H), 2.19 (s, 3H), 2.90 (m, 1H), 3.95 (s, 3H), 7.56 (m, 2H), 7.63 (s, 1H), 7.78 (d, 1H), 7.89 (s, 1H), 7.95 (d, 1H), 8.23 (s, 1H), 8.48 (d, 1H); Mass Spectrum: M+H+ 350. B) To a solution of N-Cyclopropyl-3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (4.62 g) in methylene chloride (90 ml) was added 1M boron tribromide in methylene chloride (53 ml) and stirred for 20 hours. The reaction was quenched with water and then diluted with 2N NaOH solution until the solid dissolved. The aqueous layer was washed with methylene chloride (2×) and then acidified to pH 1 with 2N HCl solution and extracted with ethyl acetate (3×). The combined organic extracts were concentrated and the solid was dried by azeotropic removal of water using toluene to yield N-cyclopropyl-3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (AZ12266450) (3.06 g) as a white solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.70 (m, 2H), 2.12 (s, 3H), 2.85 (m, 1H), 7.35 (d, 1H), 7.50 (s, 1H), 7.52 (d, 1H), 7.66 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.11 (s, 1H), 8.42 (d, 1H), 10.20 (broad s, 1H); Mass Spectrum: M+H+ 336.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.C[O-].[Na+].[N+:20]([CH3:23])([O-:22])=[O:21].Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH:8]2[C:13](=[O:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH2:23][N+:20]([O-:22])=[O:21])[CH:2]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1C2CCN(CC2)C1C(C[N+](=O)[O-])c1cccnc1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (6.4 g, 0.024 mol) in dry methanol (45 mL) was added drop-wise to sodium methoxide (produced in situ, 0.036 mol). Nitromethane (3.7 mL, 0.068 mol) was then added, and the mixture was heated at reflux for 3 h. After cooling to room temperature, 1 N HCl was slowly added to adjust pH to 8. The mixture was concentrated by rotary evaporation to yield a solid brown residue. The residue was purified by column chromatography, using ethyl acetate/hexane (1:1, v/v), followed by chloroform/methanol/ammonia (90:10:1, v/v), as eluent, to obtain a yellow oil (4.2 g, 64%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:21](=[O:23])[CH3:22]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 2.73 g of L-phenylalanine methyl ester hydrochloride (12.7 mmol) in 5.00 g of pyridine (63.2 mmol) is dropwise added 12.90 g of acetic anhydride (126.0 mmol) under ice cooling. The mixture is allowed to stand for 2 hours and concentrated in vacuo. The residue is extracted with ethyl acetate. The extract is washed with 5% hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine in order, dried over sodium sulfate, filtered and concentrated in vacuo to give 2.34 g of the objective N-acetylphenylalanine methyl ester 4. Yield, 83.6%.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([O:10][CH3:11])[N:5]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[N+:8]([O-:1])[CH:7]=[C:6]([O:10][CH3:11])[N:5]=1
Reactant: OO
Reactant: COc1cncc(Cl)n1
Solvent: CC(=O)O
Product: COc1c[n+]([O-])cc(Cl)n1

Procedure:
Hydrogen peroxide (1.5 ml. of 30%) is added to a solution of 10 mmole of 2-chloro-6-methoxypyrazine in 5 ml. acetic acid. The solution is heated at 60°-75° C. for 10-15 hours. The solution is concentrated to quarter volume, diluted with water and extracted with chloroform, washed, dried and evaporated to give 2-chloro-6-methoxypyrazine 4-oxide which may be crystallized from a suitable solvent such as ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[NH3:12].C[Si]([C:17]#[N:18])(C)C>CO.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[NH2:12][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH2:9][CH3:10])[C:17]#[N:18]
Reactant: N
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)C#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: CCC(N)(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4′-chloropropiophenone (5 g) in MeOH (20 ml) was treated under an argon atmosphere and at r.t. with 7M NH3 in MeOH (33.9 ml). Then, tetraisopropyl orthotitanate (10.54 ml) was added dropwise. The reaction mixture was stirred for 1 hr at r.t. Then, trimethylsilyl cyanide (3.72 ml) was added and stirring was continued at r.t. overnight. The reaction mixture was poured in ice and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The crude (RS)-2-amino-2-(4-chloro-phenyl)-butyronitrile (4.95 g) was used in the next reaction step without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=O)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:2][NH2:3])[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN=C(C(=O)c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Benzoin, 60 g, is suspended in 600 ml acetic anhydride and 60 ml concentrated sulfuric acid is added under ice cooling. Under continued ice cooling, 33 g potassium nitrate is added in small portions. The reaction is stirred at room temperature for two days and poured over ice. The aqeuous portion is decanted off and the remaining oil is taken up in ether, washed with water, sodium bicarbonate solution, dried over potassium carbonate and stripped. The oil residue is added dropwise to concentrated nitric acid at 0°, followed by heating gently on a steam bath for 2 hours. After cooling, the solution is poured over ice. The solid which forms is removed by filtration (~40 g) and recrystallized three times from glacial acetic acid, to yield 5.5 g of a yellow solid, 4-nitrobenzil. To a solution of 0.7 g hydrazine hydrate in 50 ml ethanol is added a suspension of 4-nitrobenzil, 5.1 g, in 150 ml of ethanol. The reaction is heated on a steam bath for 1 hour and cooled. Plate-like crystals separate out and are removed by filtration. Yield 3.5 g. The product is recrystallized from 200 ml ethanol. M.P. 166°-173°.
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:23])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:6]1(=[O:22])=[O:21].FC1C=CC=C[C:26]=1[N:31]1C2C=CC=CC=2NS1(=O)=O.BrC[C@@H](C)CO>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][C@H:3]([CH3:23])[CH2:2][NH:31][CH3:26])[S:6]1(=[O:22])=[O:21]
Reactant: C[C@H](CBr)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Agent: C[C@@H](CO)CBr
Product: CNC[C@@H](C)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to Example 19, step 1, 1-[(2S)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and (S)-3-bromo-2-methylpropan-1-ol giving 0.26 g of the desired product.