Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[Li].[Br:32]Br.O>O1CCCC1.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:23])[CH:16]([Br:32])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)c1cccc(OCc2ccccc2)c1
Reactant: BrBr
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccc(OCc2ccccc2)c1)C(Br)c1ccccc1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 1-(3-benzyloxyphenyl)-2-phenylethanone in tetrahydrofuran (30 mL) is treated with a solution of lithium diisopropylamine in tetrahydrofuran (5.5 mL, 2 M) at −35° C. under nitrogen. The resulting clear yellow solution is cooled to −70° C. and treated with a solution of bromine (1.6 g) in dichloromethane (5 mL). Stirring is continued at −70° C. and treated with a solution of bromine (1.6 g) in dichloromethane (5 mL). Stirring is continued at −70° C. for 5 minutes. Water (30 mL) is added and the reaction mixture allowed to warm to room temperature. The reaction mixture is extracted twice with ether (50 mL), the combined extracts are washed with brine (40 mL), dried over magnesium sulphate and evaporated to give (RS)-1-(3-benzyloxyphenyl)-2-bromo-2-phenylethanone (3.92 g) in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1nc(Cl)c([N+](=O)[O-])cc1C(=O)O

Procedure:
2-Amino-6-chloronicotinic acid (0.479 g) [Helvetica Chimica Acta (1976), 59(1), 222-9] was dissolved in concentrated sulfuric acid (5 mL) and cooled in an ice-saltwater bath and 2.5 mL of fuming nitric acid was then added dropwise with stirring. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 8 hours. The mixture was then added dropwise to a saturated sodium bicarbonate solution (200 mL). The mixture was acidified with 9M aqueous sulfuric acid to pH 2. The solid that formed was filtered and rinsed with water to obtain the title compound (0.340 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH:27]=1)=[O:4].[C:30](Cl)(Cl)=[O:31].C(N(CC)CC)C.O>ClCCCl>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[C:10]2[CH:27]=[C:6]([N:5]3[C:3](=[O:4])[C:2]([CH3:29])([CH3:28])[NH:1][C:30]3=[O:31])[CH:7]=[CH:8][C:9]=2[N:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[N:12]=1
Reactant: O=C(Cl)Cl
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(NC(=O)C(C)(C)N)ccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N3C(=O)NC(C)(C)C3=O)ccc21

Procedure:
2 g (0.005 mol) of 2 amino-N-[5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-2-methylpropionamide are dissolved in 50 ml of 1,2-dichloroethane and added to 1 g of phosgene in 50 ml of 1,2-dichloroethane at room temperature. The reaction mixture is stirred for 1/2 hour and subsequently made basic with triethylamine. The mixture is treated with water and extracted with methylene chloride. The organic phase is dried and evaporated. The residue gives, from ethyl acetate/ether, 3-[5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-5,5-dimethylhydantoin of melting point 286°-287°.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH3:28][C:26]1[CH:27]=[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:21])[F:22])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[N:24]([CH:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:25]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-[5-methyl-2-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as orange oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C(O[C:44]([C@@H:46]1[CH2:50][CH2:49][CH2:48][C@@H:47]1[NH:51][CH2:52][CH:53]1[CH2:55][CH2:54]1)=[O:45])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:53]1([CH2:52][N:51]2[C@@H:47]3[C@@H:46]([CH2:50][CH2:49][CH2:48]3)[C:44]([OH:45])=[C:16]([C:11]3[NH:10][C:9]4[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=4[S:13](=[O:14])(=[O:15])[N:12]=3)[C:17]2=[O:18])[CH2:54][CH2:55]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(CC3CC3)C1=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.075 g, 0.225 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.045 g, 0.236 mmol) and N-methylmorpholine (0.052 mL, 0.473 mmol) were added sequentially to a solution of (1R,2S)-2-(cyclopropylmethyl-amino)-cyclopentanecarboxylic acid ethyl ester (0.048 g, 0.225 mmol) in N,N-dimethylformamide (3 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was dissolved in ethanol (4 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (0.167 mL, 0.450 mmol) was added and the reaction mixture was heated to 60° C. for 1.5 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×75 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 30-80% ethyl acetate in hexanes) to afford the desired product, (4aR,7aS)-N-[3-(1-cyclopropylmethyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (0.065 g, 0.135 mmol, 60%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.28-0.40 (m, 2H), 0.56-0.68 (m, 2H), 1.02-1.18 (m, 1H), 1.60-1.83 (m, 4H), 1.95-2.51 (m, 3H), 2.99-3.06 (m, 1H), 3.06 (d, 3H, J=3.3 Hz), 3.16-3.26 (m, 1H), 3.58-3.64 (m, 1H), 3.92 (q, 1H, J=7.7 Hz), 7.00 (s, 1H), 7.22 (d, 1H, J=8.4 Hz), 7.62-7.66 (m, 1H), 7.68-7.70 (m, 1H). LC-MS (ESI) calcd for C20H24N4O6S2 480.11, found 481.2 [M+H+].
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1SC>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:21]2[N:20]([CH3:19])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nc2ccccc2n1C
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: Cn1c(NCCCOc2cccc(CN3CCCCC3)c2)nc2ccccc21

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.41 g) and 1-methyl-2-methylthiobenzimidazole (1.57 g) were fused at 150° C. for 6 hours. The cooled residue was subjected to column chromatography on silica (chloroform:methanol 19:1) to give the title compound as an oil. This was treated with maleic acid to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-1-methylbenzimidazole dimaleate (0.87 g), m.p. 153°-4° C. (recrystallised from isopropanol).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Br.Br[CH:8]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.C(N(CC)CC)C>C(#N)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:5]=[C:3]([NH:2][CH3:1])[S:4][C:8]=2[C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1
Reactant: CNC(N)=S
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNc1nc(-c2ccc(OC)cc2)c(-c2cccnc2)s1
Yield: 84.6 %

Procedure:
In 18 ml of acetonitrile was dissolved 242 mg of N-methylthiourea. In the solution was suspended 1.0 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide. To the suspension was added dropwise slowly 0.4 ml of triethylamine while stirring. The mixture was stirred for three hours at refluxing temperature, and the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract was dried, then the solvent was evaporated off. The residue was recrystallized from ethyl acetate isopropyl ether to yield 650 mg (85%) of 4-(4-methoxyphenyl)-2-methylamino-5-(3-pyridyl)-1,3-thiazole, m.p. 158°-159° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:60]([O:62][C:63](=[O:71])[CH2:64][C:65]1[N:66]=[C:67]([NH2:70])[S:68][CH:69]=1)[CH3:61]>C(Cl)Cl>[CH2:60]([O:62][C:63](=[O:71])[CH2:64][C:65]1[N:66]=[C:67]([NH:70][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[S:68][CH:69]=1)[CH3:61]
Reactant: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1cccnc1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(NC(=O)c3cccnc3)cc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-[(pyridine-3-carbonyl)-amino]-phenyl}-propionic acid (prepared in Example 10, 169 mg, 0.50 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.21 mL, 1.3 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), and (2-amino-thiazol-4-yl)-acetic acid ethyl ester (140 mg, 0.75 mmol). The reaction mixture was stirred at 25° C. for 20 h. At this time, the reaction was diluted with methylene chloride (50 mL). This solution was washed with a 1N aqueous hydrochloric acid solution (1×15 mL), water (1×15 mL), and a saturated aqueous sodium chloride solution (2×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded [2-(3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]-phenyl}-propionylamino)-thiazol-4-yl]-acetic acid ethyl ester (100.1 mg, 39.5%) as white solid: mp 195-200° C.; EI-HRMS m/e calcd for C27H30N4O4S (M+) 506.1987, found 506.1985.
Reaction SMILES: [Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[N:38]4[CH:39]=[CH:40][CH:41]=[C:42]([CH:43]([F:45])[F:44])[C:37]4=[N:36][CH:35]=3)[C:31]([C:46]#[N:47])=[CH:30][N:29]=2)[CH3:26])=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:45][CH:43]([F:44])[C:42]1[C:37]2[N:38]([C:34]([C:32]3[C:31]([C:46]#[N:47])=[CH:30][N:29]=[C:28]([NH:27][CH:25]([C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:24][CH:23]=4)[CH3:26])[N:33]=3)=[CH:35][N:36]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
208 mg of the 2-{[1-(4-{[t-butyl(diphenyl)silyl]oxy}phenyl)ethyl]amino}-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine-5-carbonitrile [111-1] was dissolved in 5 mL of tetrahydrofuran, then 320 μL of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution) was added under an ice-cold condition, and stirred at room temperature for 1 hour. The reaction solution was diluted in 200 mL of ethyl acetate, and washed with phosphate buffer pH6.8 and saturated brine in the subsequent order. The obtained organic layer was dried over anhydrous magnesium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in a small amount of mixture solvent of chloroform and methanol (chloroform:methanol=9:1) and solidified by hexane, to obtain 107 mg of 4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-{[1-(4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carbonitrile [111-2] as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:5]2[N:6]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:7][CH2:8][CH2:9][C@H:10]([NH:11][C:12]3[N:13]=[N:14][N:15]([CH3:17])[N:16]=3)[C:4]=2[CH:3]=1.[H-].[Na+].CC(C)([O-])C.[K+].[F:39][C:40]([F:54])([F:53])[C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:44]Br>CN(C=O)C.C1COCC1>[F:39][C:40]([F:53])([F:54])[C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([C:49]([F:52])([F:50])[F:51])[CH:48]=1)[CH2:44][N:11]([C:12]1[N:13]=[N:14][N:15]([CH3:17])[N:16]=1)[C@H:10]1[CH2:9][CH2:8][CH2:7][N:6]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:5]2[C:28]([CH3:30])=[CH:29][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Cc1cc(C)c2c(c1)[C@@H](Nc1nnn(C)n1)CCCN2C(=O)OCc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 121.5 %

Procedure:
Charge a vial with (S)-benzyl 7,9-dimethyl-5-(2-methyl-2H-tetrazol-5-ylamino)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate (100 mg 246 μmoles), NaH (23 mg 60% in mineral oil, 575.1 μmoles) and THF (9.2 ml, 24.6 mmoles). (Alternatively, potassium tert-butoxide in DMF can be used in place of NaH and THF.) Stir the reaction mixture at RT for 10 m. Add 3,5 bis(trifluoromethyl)benzylbromide (173.8 mg 566.2 μmoles) dropwise over 30 min. After about 19 h, add NaH (10 mg, 60% mineral oil) and stir for an additional 1 h. Partition the reaction mixture between EtOAc (50 mL) and brine (2×25 mL). Collect the organic layers and dry over Na2SO4. Filter and then concentrate the filtrate to yield an oil. Partition the oil between ACN (50 mL) and heptane (2×25 mL). Collect the CAN layer; dry to yield an oil (189 mg) of the title compound.
Reaction SMILES: [OH-].[K+].O.C([NH:7][C:8]1[S:9][CH:10]=[C:11](/[C:13](=[CH:19]/[CH3:20])/[C:14]([O:16]CC)=[O:15])[N:12]=1)(=O)C.FC(F)(F)C(O)=O>CC(C)=O>[NH2:7][C:8]1[S:9][CH:10]=[C:11](/[C:13](=[CH:19]/[CH3:20])/[C:14]([OH:16])=[O:15])[N:12]=1
Reactant: C/C=C(\C(=O)OCC)c1csc(NC(C)=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C/C=C(\C(=O)O)c1csc(N)n1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of 16.5 parts by weight of potassium hydroxide in 111 parts by volume of water is heated up to 75° to 78° C. 14.9 parts by weight of ethyl Z-2-(2-acetamidothiazol-4-yl)-2-butenoate are added and the mixture is stirred at 75° to 78° C. for 2 hours. After cooling to 10° C., the mixture is brought to pH 7.0 with trifluoroacetic acid, the solution is filtered with suction over kieselguhr and the pH is then brought to 3.6 with further trifluoroacetic acid. The mixture is cooled to 0° C. and stirred at 0° C. for 30 minutes, and the crystals which have precipitated are isolated. After washing three times with 6 parts by volume of isopropanol each time, the crystals are dried. The product is then stirred with 62.4 parts by volume of acetone for 20 minutes, filtered off with suction, washed with 42 parts by volume of acetone and dried again. 6.3 parts by weight of pure product are obtained. Further product can be isolated from the mother liquor of the acetone extraction stirring.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:24].[OH-].[Na+].O>CO>[CH3:1][N:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:24]
Reactant: COC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(-c2ccccc2)c(CCC(=O)O)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
1.2 g (3.7 mmol) of methyl 2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-propanoate are dissolved in 80 ml of methanol in a 250 ml round-bottomed flask, 0.25 g (6.25 mmol) of sodium hydroxide pellets and 1 ml of water are added and then the mixture is stirred at room temperature for 1 h and at reflux for 2 h. The mixture is cooled, the solvent is evaporated under reduced pressure, the residue is taken up in 50 ml of water and 50 ml of diethyl ether, and 36% hydrochloric acid is added dropwise. The insoluble material is collected by filtering, is washed with water and is dried. 0.91 g (2.96 mmol) of white solid is obtained. Melting point: 138°-140° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:28])[CH2:4][CH2:3]1.[O:29]1[C:38]2[CH:37]=[C:36]([CH:39]=O)[N:35]=[CH:34][C:33]=2[O:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:29]1[C:38]2[CH:37]=[C:36]([CH2:39][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[C:15]([C:22]6[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=6)[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:28])[CH2:6][CH2:7]3)[N:35]=[CH:34][C:33]=2[O:32][CH2:31][CH2:30]1
Reactant: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
To 3 mL of a chloroform solution containing 160 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-5-(pyridin-4-yl)quinoxalin-2(1H)-one and 63 mg of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carbaldehyde, 0.04 mL of acetic acid was added, and stirred at room temperature for 4 hours. To the reaction mixture, 140 mg of sodium triacetoxyborohydride was added, and stirred for 13 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=4:1] to give 139 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-c]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-5-(pyridin-4-yl)quinoxalin-2(1H)-one as a white foam.
Reaction SMILES: CS(O)(=O)=[O:3].[OH-].[NH4+].O[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([C:15]2[S:19][C:18]([NH:20][C:21](=[O:32])[C:22]3[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=3[O:30][CH3:31])=[N:17][N:16]=2)[CH:14]=1>>[OH:3][C:10]1[CH:11]=[CH:12][C:13]([C:15]2[S:19][C:18]([NH:20][C:21](=[O:32])[C:22]3[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=3[O:30][CH3:31])=[N:17][N:16]=2)=[CH:14][CH:9]=1
Reactant: CS(=O)(=O)O
Reactant: COc1cccc(OC)c1C(=O)Nc1nnc(-c2cccc(O)c2)s1
Agent: [NH4+]
Agent: [OH-]
Product: COc1cccc(OC)c1C(=O)Nc1nnc(-c2ccc(O)cc2)s1
Temperature: 0 °C

Procedure:
The residue produced above was stirred, and 20 g. of methanesulfonic acid was added dropwise to it. After 4 hours of stirring, at room temperature, the solution was poured into 300 ml. of ice water, and the pH was adjusted with ammonium hydroxide to 7.5. A precipitate separated, which was collected and recrystallized from acetone to produce 2.5 g. of N-[5-(5-hydroxyphenyl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide, m.p. above 260°.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[N:10]=[CH:11][N:12]=[C:13](O)[C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:13]1[C:14]2[N:15]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2oc(-c3ccccc3)nc12
Product: Clc1ncnc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 67 %

Procedure:
2-Phenyl-oxazolo[5,4-d]pyrimidin-7-ol (0.10 g, 0.43 mmol) was dissolved in 3 mL POCl3, and the mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to room temperature and poured onto ice water. The resulting mixture was extracted by CH2Cl2. The combined organic layers were concentrated and the residue was purified by column chromatography (EtOAc:hexanes=1:10) to afford the title compound as a white solid (73 mg, 67%). 1H NMR 400 MHz (CDCl3) δ 8.82 (s, 1H), 7.35-7.32 (m, 2H), 7.68-7.57 (m, 3H). LC-MS (ESI) m/z 232.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3](N2C=NC=N2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C[O-].[Na+].[C:17](O)(=[O:19])C>CO>[CH3:17][O:19][C:3]1[C:2]([CH3:1])=[CH:7][NH:6][C:5](=[O:8])[N:4]=1
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(=O)[nH]cc1C
Yield: 91.7 %

Procedure:
1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are boiled under reflux with 972 mg (18 mmol) of sodium methylate in 30 ml of anhydrous methanol for 4 hours with exclusion of moisture. The cooled solution is neutralized with acetic acid, concentrated and chromatographed on silica gel using ethyl acetate/methanol 9/1. 770 mg (91.7% of theory) of 4-methoxy-5-methylpyrimidin-2(1H)-one are obtained with melting point 196°-199° C. 1H NMR (270 MHz, d6 -DMSO), δ[ppm]: 11.09 (s, 1H), 7.51 (d, 1H), 3.83 (s, 3H), 1.85 (s, 3H).