Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:30][CH:31]([F:33])[F:32])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[F:33][CH:31]([F:32])[O:30][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:34])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A mixture of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-methanesulfonylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.82 g), methanol (33 mL), 5.0 M aqueous lithium hydroxide solution (0.7 mL) and water (1.4 mL) was stirred at room temperature for 35 minutes. The pH of the mixture was adjusted to 4 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water (4.0 mL) and the solid collected by filtration, washed with water and dried to afford to title compound as a pale cream solid, 0.60 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(Br)ccc1C(=O)O
Product: O=c1[nH]cnc2cc(Br)ccc12
Temperature: 190 °C

Procedure:
2-Amino-4-bromobenzoic acid (15.5 g) was dissolved in 100 mL of formamide and the solution was heated at 190° C. for 10 h. After the reaction was cooled to room temperature, the solid was collected via filtration, rinsed with water, and dried to give 10.5 g of 7-bromo-4-quinazolinone, LCMS ESI(+) m/z: 225/227 (M+1).
Reaction SMILES: [F:1][C:2]([F:38])([CH2:34][CH2:35][CH2:36][CH3:37])[C:3](=[O:33])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].C(O)(=O)C.O>C1COCC1>[F:1][C:2]([F:38])([CH2:34][CH2:35][CH2:36][CH3:37])[C:3](=[O:33])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCCCC(=O)OC(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCCCC(=O)OC(C)C
Reaction time: 3.5 h

Procedure:
The compound (59) (0.288 g) was dissolved in a mixed solvent (30 ml) consisting of acetic acid, water and THF (4:2:1) and the solution was kept at 45° C. for 3.5 hours. The resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (60). Yield: 0.184 g (76%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.[NH2:27][C:28]1[S:29][CH:30]=[C:31]([CH3:33])[N:32]=1.[H-].[Na+]>CC(N(C)C)=O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:27][C:28]2[S:29][CH:30]=[C:31]([CH3:33])[N:32]=2)=[C:6]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH:7]=1)=[O:20]
Reactant: Cc1csc(N)n1
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1csc(NCCOc2ccc(NC(=O)c3cccc(F)c3)cc2-c2ccnn2C)n1
Reaction time: 2 h
Yield: 5.4 %

Procedure:
To a solution of N-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamide (68.5 mg, 0.164 mmol) and 2-amino-4-methylthiazole (18.7 mg, 0.164 mmol) in DMA (4 mL) was added NaH (56.3 mg, 60% dispersion in mineral oil) and the reaction was stirred for two hours. The resulting material was purified by HPLC. The product was dried under reduced pressure to afford the title compound as a yellow solid (4.0 mg, 5%). LCMS m/z (%)=452 (M+H, 100). 1H NMR (500 MHz, DMSO-d6) δ 10.32 (bs, 1H), 7.89-7.72 (m, 3H), 7.69 (d, J=2.52 Hz, 1H), 7.62-7.56 (m, 1H), 7.48-7.42 (m, 1H), 7.41 (d, J=1.89 Hz, 1H), 7.23 (d, J=9.14 Hz, 1H), 6.45 (bs, 1H), 6.23 (d, J=1.89 Hz, 1H), 4.23-4.18 (m, 2H), 3.70-3.65 (m, 2H), 3.65 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC[O:22]C(/N=N/C(OCC)=O)=O.C([O:34][C:35](=[O:53])[CH:36]([O:51][CH3:52])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]#[C:45][CH2:46][CH2:47][CH2:48][CH2:49][OH:50])=[CH:40][CH:39]=1)C.[O:54]([C:61]1[CH:66]=[CH:65][C:64](O)=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1COCC1>[CH3:52][O:51][C@@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44](=[O:22])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][C:64]2[CH:63]=[CH:62][C:61]([O:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:66][CH:65]=2)=[CH:42][CH:43]=1)[C:35]([OH:34])=[O:53]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCCO)cc1)OC
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(C(=O)CCCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (1.8 mmol) in 50 mL of dry THF was treated at 0° C. with diethylazodicarboxylate (1.8 mmol) and stirred for 20 min. A solution of 3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 49, Step A) (1.2 mmol) and 4-phenoxyphenol (1.8 mmol) in 10 mL of dry THF was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 10:1 to 3:1). Fractions with Rfs 0.48 and 0.45 (hexanes/ethyl acetate 2:1) corresponding to the coupled compound and starting phenol, respectively, were combined and concentrated. The mixture was dissolved in 5 mL of methanol and was treated with a mixture of 0.712 mg of mercury (II) oxide and 12 ml of 4% sulfuric acid in water. The solution was stirred at 55° C. for 3 hours, cooled to room temperature, diluted with saturated aqueous NaHCO3 (20 mL), and extracted with dichloromethane (4×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was dissolved in 6 mL of methanol and 2 mL of 1N NaOH and stirred for 2 hours. The methanol was evaporated under vacuum, and the aqueous solution was diluted with brine (6 mL) and washed with diethyl ether (3×15 mL). The aqueous layer was acidified with 1N HCl (pH 1–2) and extracted with ethyl acetate (3×15 mL). The combined extracts were dried (MgSO4) and concentrated to give the title compound. MS(ES) for C28H30O6[M+H]+: 463.2.
Reaction SMILES: [S:1]([CH:5]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:6](O)=[O:7])([OH:4])(=[O:3])=[O:2].S(Cl)([Cl:16])=O.CN(C)C=O.CCCCCC>CCOCC>[S:1]([CH:5]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:6]([Cl:16])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: O=C(O)C(n1cccc1)S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cl)C(n1cccc1)S(=O)(=O)O
Temperature: 40 °C

Procedure:
2-Sulfo-2-(1-pyrryl)acetic acid is treated with thionyl chloride in ether at room temperature according to the general procedure in J. Med. Chem., 15, 1105 (1972) until the evolution of gas stops. Dimethylformamide is added, the solution is warmed to about 40° C. for 1 hour. Then ether is added, followed by hexane and the solution cooled to about -25° C. 2-Sulfo-2-(1-pyrryl)acetyl chloride is isolated from the solvent by decantation.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[CH3:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[O:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.Cl.C1C[O:30]CC1>CO>[CH3:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[O:13][C:14]1[CH:15]=[CH:17][CH:22]=[CH:21][C:20]=1[C:19]([CH2:18][C:1]([O:4][CH3:5])=[O:6])=[O:30]
Reactant: C1CCOC1
Reactant: COC(=O)OC
Reactant: Cc1cccc(OCC(=O)c2ccccc2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(=O)c1ccccc1Oc1cccc(C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
1H-NMR (CDCl3): δ=2.35 (s, 3H); 2.65 (s, 3H); 6.79-7.84 (m, 8H) ppm. b) 38.7 g (0.43 mol) of dimethyl carbonate are added to a suspension of 10.3 g (0.43 mol) of sodium hydride in 230 ml of THF and then, at 50° C., a solution of 67.2 g (0.30 mol) of 2-(3-methylphenoxy)acetophenone is added dropwise. The mixture is stirred at 50° C. for 3 hours, left to cool, 60 ml of methanol are added, and the mixture is stirred at room temperature overnight. It is acidified (pH 2) with 10 percent hydrochloric acid and extracted with MTB ether. The organic phase is washed with water, dried and concentrated. 79.5 g (93% yield) of methyl 2-(3-methylphenoxy)benzoylacetate remain as dark oil.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3](=[O:24])[CH2:4][O:5][C:6]([C:8]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12]CN[CH2:9]1)=[O:7].[F:27][C:28]1[CH:33]=[C:32]([C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:52]=[CH:51][C:42]([CH2:43][N:44]([CH2:48]CO)CCO)=[CH:41][CH:40]=3)[N:35]=2)[CH:31]=[CH:30][C:29]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.N(CCO)CCO>>[CH3:25][C:2]([CH3:1])([CH3:26])[C:3](=[O:24])[CH2:4][O:5][C:6]([C:8]1([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:13][CH2:12][N:44]([CH2:43][C:42]2[CH:51]=[CH:52][C:39]([C:36]3[N:35]=[C:34]([C:32]4[CH:31]=[CH:30][C:29]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)=[C:28]([F:27])[CH:33]=4)[O:38][N:37]=3)=[CH:40][CH:41]=2)[CH2:48][CH2:9]1)=[O:7]
Reactant: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCCNC1
Reactant: OCCN(CCO)Cc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(F)c3)n2)cc1
Solvent: OCCNCCO
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1

Procedure:
Condensation of piperidine-3,3-dicarboxylic acid 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester onto 3-(4-chloromethylphenyl)-5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazole is performed as described in step II for the preparation of 2-[{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}(2-hydroxyethyl)amino]-ethanol, with piperidine-3,3-dicarboxylic acid 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester replaced by diethanolamine. This procedures affords 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester 3,3-dimethyl-2-oxobutyl ester.
Reaction SMILES: [C:1]([CH2:4][C:5]1[O:6][C:7]([SH:10])=[N:8][N:9]=1)([OH:3])=[O:2].CC(O[CH2:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27])=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[NH2:23][CH:20]1[C:21](=[O:22])[N:18]2[C:17]([C:26]([OH:28])=[O:27])=[C:16]([CH2:15][S:10][C:7]3[O:6][C:5]([CH2:4][C:1]([OH:3])=[O:2])=[N:9][N:8]=3)[CH2:25][S:24][C@H:19]12
Reactant: O=C(O)Cc1nnc(S)o1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Reaction time: 3 h

Procedure:
A solution of 9.61 g (0.06 mol) of 2-carboxymethyl-1,3,4-oxadiazole-5-thiol in 120 ml of acetone is added to a warm (45°) solution of 10.9 g (0.04 mol) of 7-aminocephalosporanic acid in a mixture of 220 ml of water, 50 ml of acetone and 13.44 g (0.16 mol) of sodium bicarbonate. The temperature is raised to 65° and the pH maintained at 7.4-7.6 by addition of aqueous sodium carbonate solution. After 3 hours, the acetone is removed in vacuo and the reaction mixture is cooled to 10° and adjusted a pH 3.5 by addition of dilute hydrochloric acid. The product is collected, washed with water and then acetone to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9](CC(OCC)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH2:25][CH2:26][CH2:27][NH2:28].[CH2:29]([OH:31])[CH3:30]>>[NH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH2:30][N:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[N:9]1
Reactant: CCO
Reactant: NCCCN
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Product: NCCCNC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Reaction time: 3 h

Procedure:
A mixture of 7.96 g (0.026 mol) of ethyl 3,4-diphenyl-1H-pyrazole-1-acetate and 19.2 g (0.26 mol) of 1,3-diaminopropane in 13 mL of ethanol was stirred at 84°-87° C. for 3 hours and the solvent removed in vacuo. The resulting solid was chromatographed on 34 g of silica gel eluting with 1% isopropylamine in chloroform and a gradient from 0-30% methanol. The impurities came off at 2-4% methanol followed by 6.95 g of pure product. It was crystallized three times from isopropyl acetate to yield 6 09 g of N-(3-aminopropyl)-4,5-diphenyl-1H-pyrazole-1-acetamide (1:4) hydrate, mp 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])C(F)(F)F)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].[F:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1C(Cl)=O.C(O)C(N)(CO)CO>CN(C=O)C.O.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[C:36]4[C:35]([F:34])=[CH:43][CH:42]=[CH:41][C:40]=4[F:44])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: NC(CO)(CO)CO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
A solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (370 mg, 0.83 mmol) and 1M LiOH (4.97 mL, 4.97 mmol) in 10:1 THF:H2O (10 mL) was heated at 50° C. overnight. The reaction was washed with brine (25 mL), the aqueous layer was extracted with EtOAc (25 mL) and the organic layers were combined, filtered through a cotton plug, and solvent removed by rotary evaporation. After high vacuum removal of residual solvent, the crude mixture was dissolved in THF (25 mL) and to this was added 2,6-difluorobenzoyl chloride (920 mg, 5.25 mmol). After stirring 3 h at ambient temperature, DMF (25 mL) was added to dissolve any suspended solids followed by the addition of excess polymer-bound trisamine resin. Upon overnight stirring, the amine resin was removed by vacuum filtration, rinsed with MeOH (50 mL) and filtrate concentrated under reduced pressure to afford the desired amide (410 mg, 79%) as an off-white solid. ESIMS (M+H)+=492.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNCC2COc3ccc4c(c3O2)CC(=O)N4)cc1
Temperature: 85 °C
Yield: 56.3 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.00 g, 2.66 mmole) and 4-methoxybenzylamine (1.40 ml, 10.7 mmole) were combined in 10 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 2% methanol/CH2Cl2 as eluant. The free base of the title compound (0.51 g, 64%) was obtained as an oil upon concentration in vacuum. The product was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.44 g of the (S) enantiomer of the title compound as an off-white solid fumarate, one-quarter hydrate, m.p. 205-205.5° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]2[CH:8]([OH:15])[C:9]([CH3:14])([CH3:13])[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1.I[CH3:19]>CN(C=O)C>[CH3:19][O:15][CH:8]1[C:7]2[CH:16]=[CH:17][C:4]([Br:3])=[CH:5][C:6]=2[S:10](=[O:11])(=[O:12])[C:9]1([CH3:13])[CH3:14]
Reactant: CC1(C)C(O)c2ccc(Br)cc2S1(=O)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1c2ccc(Br)cc2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.07 h

Procedure:
A cooled (0° C.) suspension of NaH (20.61 mg; 0.52 mmol; 1.00 eq.) in dry DMF was carefully treated with solution of 6-bromo-2,2-dimethyl-2,3-dihydro-1-benzothiophene-3-ol 1,1-dioxide (Intermediate 244; 150 mg; 0.52 mmol) in anhydrous DMF. The reaction mixture was stirred at RT for 4 min then treated with a 3 M solution of iodomethane (240 μl; 0.72 mmol). The mixture was stirred at RT for 2.5 h, then quenched with water. EtOAc was added, the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness to afford a residue, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([C:11]2[CH:16]=[C:15]([C:17](C)(C)C)C(OCOCCOC)=C(C(C)(C)C)[CH:12]=2)[N:3]=1.[OH-].[Na+].C[N:35]=C=S.[ClH:38]>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([C:11]2[CH:12]=[N:35][CH:17]=[C:15]([Cl:38])[CH:16]=2)[N:3]=1
Reactant: Cl
Reactant: CN=C=S
Reactant: CNC(=S)n1nc(-c2cc(C(C)(C)C)c(OCOCCOC)c(C(C)(C)C)c2)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNC(=S)n1nc(-c2cncc(Cl)c2)nc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 20 %

Procedure:
The synthesis method of Example 7-(3) was applied. The compound (3.39 g) obtained in (4) above, a 1N aqueous sodium hydroxide solution (26 ml), methyl isothiocyanate (1.9 g) and tetrahydrofuran (30 ml) were used as reagents. The mixture was stirred at room temperature for 5 hours and neutralized with 3N hydrochloric acid. The resulting powder was collected by filtration and subjected to silica gel column chromatography (chloroform-methanol) and recrystallization from chloroform-methanol to give 917 mg of white crystals (yield 20%).
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12](OCC)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]1[C:23]1[N:24]([CH2:28][CH2:29][CH3:30])[CH:25]=[CH:26][N:27]=1.[OH2:31].[NH2:32][NH2:33]>CO>[C:17]1([CH:4]2[NH:5][C:6]3[C:11]4[C:2](=[N:32][NH:33][C:12](=[O:31])[C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH:3]2[C:23]2[N:24]([CH2:28][CH2:29][CH3:30])[CH:25]=[CH:26][N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O
Reactant: CCCn1ccnc1C1C(=O)c2c(cccc2C(=O)OCC)NC1c1ccccc1
Reactant: NN
Solvent: CO
Product: CCCn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A suspension of ethyl 4-oxo-2-phenyl-3-(1-propyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (770 mg, 1.9 mmol) and hydrazine monohydrate (6 mL, 85%) were added in methanol (10 mL) and stirred at 50° C. overnight. The mixture was filtered, and the white solid was washed with methanol and dried in vacuum to obtain 8-phenyl-9-(1-propyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (260 mg, yield 37%). 1H-NMR (400 MHz, DMSO-d) δ (ppm): 0.59-0.62 (t, J=7.4 Hz, 1H), 1.23-1.40 (m, 2H), 3.62-3.72 (m, 2H), 4.58-4.61 (d, J=11.2 Hz, 1H), 4.97-4.99 (d, J=11.2 Hz, 1H), 6.79 (s, 1H), 6.89 (s, 1H), 7.16-7.59 (m, 8H), 12.15 (s, 1H); LC-MS (ESI) m/z: 372 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28]([N:20]1[CH2:21][C:17]2[S:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=4)[C:11]=3[C:18]=2[CH2:19]1)=[O:29]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: C#Cc1cccc(Nc2ncnc3sc4c(c23)CNC4)c1
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3sc4c(c23)CN(C(=O)/C=C/CN(C)C)C4)c1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-ethynylphenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 27A (40 mg, 0.12 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (27 mg, 0.17 mmol) to yield 11 mg (22%).
Reaction SMILES: [CH3:1]I.[CH3:3][N:4]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:7][NH:6][C:5]1=[S:14].[OH-].[Na+]>C(O)C>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:8]1[N:4]([CH3:3])[C:5]([S:14][CH3:1])=[N:6][N:7]=1
Reactant: Cn1c(-c2cccs2)n[nH]c1=S
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2cccs2)n1C
Reaction time: 14 h

Procedure:
A solution of methyl iodide (6.3 ml, 1.0×10-1 mole) in ethanol (32 ml) was added dropwise to a stirred, room temperature solution of 2,4-dihydro-4-methyl-5-(2-thienyl)-3H-1,2,4-triazole-3-thione (12.5 g, 6.34×10-2 mole) and 1 molar aqueous NaOH (142 ml, 1.42×10-1 mole). After being stirred for about 14 hours the reaction was extracted four times with EtOAc. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure giving a tacky yellow solid which was purified by flash chromatography (EtOAc). Crystallization from EtOAc gave colorless crystals: 10.5 g (78%), mp 83°-85° C.
Reaction SMILES: OOS([O-])=O.[K+].[N+:7]([C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O)([O-])=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[NH2:7][C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[C:12]1[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]=1
Reactant: Nc1ccccc1N
Reactant: Cc1ccc(C=O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3[nH]2)c(N)c1
Temperature: 20 °C

Procedure:
33.8 g (55 mmol) of oxone [70693-62-8] are added in portions to a solution of 13.5 g (100 mmol) of 2-nitro-4-methylbenzaldehyde [20357-22-6] and 11.9 g (110 mmol) of 1,2-diaminobenzene in a mixture of 150 ml of DMF and 5 ml of water with stirring and cooling to 20° C. at such a rate that the temperature does not exceed 35° C. The reaction mixture is subsequently stirred at room temperature until conversion of the aldehyde is complete (about 4 h). The reaction mixture is stirred into a solution of 40 g of potassium carbonate in 2000 ml of water, stirred for a further 15 min., extracted with three 300 ml portions of dichloromethane in each case, the organic phase is washed twice with 300 ml of water, once with 500 ml of sat. sodium chloride solution and dried over sodium sulfate. The dichloromethane solution is filtered through silica gel, and the dichloromethane is removed in vacuo. The yellow residue is taken up in 500 ml of methanol, blanketed with nitrogen with stirring, 3 g of 10% Pd/C are added, and the mixture is hydrogenated at room temperature in an autoclave at a hydrogen pressure of 2 bar. When the uptake of hydrogen is complete, the catalyst is filtered off via a Celite bed, and the methanol is removed in vacuo. Yield: 18.5 g (83 mmol), 83%. Purity: >95% according to 1H-NMR.