Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH2:30]([O:37][C:38](=[O:48])[CH2:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:41]([N:40]([CH2:39][C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:48])[C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(CNCc1ccccc1)OCc1ccccc1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OCc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
To a solution of (2R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid (5.14 g) in dichloromethane (50 ml) was added triethylamine (8.49 ml), N-benzylglycine benzyl ester hydrochloride (5.08 g), and 2-chloro-1-methylpyridinium iodide (4.89 g) under ice-bath cooling. After being stirred at room temperature 90 minutes, the reaction mixture was concentrated under reduced pressure, and ethyl acetate (50 ml) and water (50 ml) were added to the residue with stirring, adjusted pH 1 with diluted hydrochloric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (100 g) using a mixed solvent of toluene and ethyl acetate (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give N-benzyl-N-(benzyloxycarbonylmethyl)-(2R)-2-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propionamide (8.57 g) as a syrup.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.CCOC(C)=O>[N:26]([CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[N+:27]=[N-:28]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CCl)c(C)nc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CN=[N+]=[N-])c(C)nc2n1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a stirred solution of crude ethyl 6-(chloromethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (448 mg, 1.12 mmol) in DMF (5 mL) was added NaN3 (110 mg, 1.69 mmol). The reaction was heated to 50° C. for 1 h. After cooling, the reaction was diluted with EtOAc and extracted with H2O and brine before drying over MgSO4. Filtration and concentration under reduced pressure gave ethyl 6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (450 mg, 100% crude yield) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([CH2:10][NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:6][CH:5]=1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([O:21][C:19]([N:11]([CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:3])[N:9]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CNCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Sodium hydride (88 mg, 2.20 mmol) was suspended in DMF (2.93 mL) and cooled to 0° C. Ethyl N-[(6-bromopyridin-2-yl)methyl]glycinate (200 mg, 0.73 mmol) was added and the solution was stirred for thirty minutes at 0° C. Benzyl chloroformate (0.11 mL, 0.73 mmol) was added and the solution was heated at 50° C. and allowed to stir until completion. The reaction was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][C:31]1[C:40]([N+:41]([O-:43])=[O:42])=[C:39](Cl)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][N:37]=2)[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.NO>>[CH2:1]([O:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH2:32])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][C:31]1[C:40]([N+:41]([O-:43])=[O:42])=[C:39]([NH2:10])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][N:37]=2)[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1c(OCc2ccccc2)nc2ccccc2c1Cl
Reactant: O=[N+]([O-])c1c(OCc2ccccc2)nc2cccnc2c1Cl
Agent: NO
Product: Nc1c([N+](=O)[O-])c(OCc2ccccc2)nc2ccccc12
Product: Nc1c([N+](=O)[O-])c(OCc2ccccc2)nc2cccnc12

Procedure:
In step (5) of Reaction Scheme IV, a benzyloxy-4-chloro-3-nitroquinoline or benzyloxy-4-chloro-3-nitro[1,5]naphthyridine of Formula XXXIX is treated with an amino alcohol of Formula XVI to provide a benzyloxy-3-nitroquinolin-4-amine or benzyloxy-3-nitro[1,5]naphthyridin-4-amine of Formula XL. The reaction is conveniently carried out according to the methods described in step (1) of Reaction Scheme I.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH2:53])[CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCCN
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCCCCCNC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with hexylamine (MCB) to give the title product. LC-MS (ES+) 748 [(M+H)+].
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][NH:5][CH3:6].[CH2:7]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[CH3:8].[OH-].[Na+]>CCOCC>[CH3:4][N:5]([CH2:1][C:10]1[N:9]([CH2:7][CH3:8])[CH:13]=[CH:12][CH:11]=1)[CH3:6]
Reactant: C=O
Reactant: CCn1cccc1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCn1cccc1CN(C)C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A mixture of a 35% aqueous formaldehyde solution (9.0 mL, 105 mmol) and dimethylamine hydrochloride (9.0 g, 110 mmol) was added to 1-ethylpyrrol (10.0 g, 105 mmol) under ice-cooling with stirring over 1 hour and 30 minutes and the mixture was stirred at room temperature for 6 hours. A 10% aqueous sodium hydroxide solution (150 mL) and ether were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (methylene chloride:methanol, 9:1) to obtain 2-(N,N-dimethylaminomethyl)-1-ethylpyrrol (15.6 9, yield: 97%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][O:4][C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[C:8]2([CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)[O:7][O:6]1.N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[F:26][C:2]([F:1])([F:25])[CH2:3][O:4][C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:33](=[O:35])[CH3:34])[CH:19]=2)[C:8]2([CH:15]3[CH2:14][CH:13]4[CH2:12][CH:11]([CH2:10][CH:9]2[CH2:17]4)[CH2:16]3)[O:7][O:6]1
Reactant: Oc1cccc(C2(OCC(F)(F)F)OOC23C2CC4CC(C2)CC3C4)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C2(OCC(F)(F)F)OOC23C2CC4CC(C2)CC3C4)c1
Reaction time: 2 h

Procedure:
A solution of dioxetane 3 (78.2 mg) in 15 mL of CH2Cl2 was placed under argon. Dry pyridine (40 μL, 2.3 eq.) was added followed after 5 min by 16.6 μL (1.1 eq.) of acetyl chloride. The reaction was judged complete by TLC after 2 hours, showing a new material which emitted blue-green light when the plate was heated. The volatiles were removed in vacuo leaving a yellow oil which was purified by preparative TLC using CH2Cl2 as eluent. A colorless oil (44 mg) was obtained: 1H NMR (CDCl3) δ 0.98 (m, 1H), 1.29 (m, 1H), 1.46-2.00 (m, 10H), 2.20 (br s, 1H), 2.325 (s, 3H), 3.06 (br s, 1H), 3.624 (dq, 1H), 3.938 (dq, 1H), 7.20 (dd, 1H), 7.28-7.64 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[CH3:23][NH:24][CH3:25].Cl>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[N:24]([CH3:25])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CNC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
3.84 ml of triethylamine was added, at -15° to -20° C., to a solution of 5.8 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 85 ml of dry tetrahydrofuran, and then a solution of 2.63 ml of ethyl chloroformate in 25 ml of dry tetrahydrofuran was added to the resulting mixture at the same temperature. The reaction mixture was then stirred for 2 hours, after which 19.75 ml of 50% by volume aqueous dimethylamine was added to it at -20° to -25° C. The mixture was then stirred for 3 hours under ice cooling, after which is was allowed to stand overnight at room temperature. At the end of this time, the mixture was poured into a mixture of 30 ml of concentrated hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 429 mg of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:18])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([OH:17])=[CH:11][C:8]=2[C:9]=1[CH3:10].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C.C(Cl)(Cl)Cl>[OH:17][C:12]1[C:13]([O:15][CH3:16])=[CH:14][C:7]2[O:6][C:5](=[O:18])[C:4]([CH2:3][CH2:2][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)=[C:9]([CH3:10])[C:8]=2[CH:11]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc2oc(=O)c(CCCl)c(C)c2cc1O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4OC)CC3)c(C)c2cc1O
Yield: 14 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-6-hydroxy-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 27) and 1-(2-methoxyphenyl)piperazine; yield 14%; m.p. 235°-237° C. (from ethanol/chloroform).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:7]=CC=CC=1.ClCCC[S:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[CH3:20][O:19][C:18]1[C:17]2[N:16]=[C:15]([NH2:21])[N:14]3[CH2:22][CH2:23][N:24]=[C:13]3[C:12]=2[CH:11]=[CH:10][C:9]=1[O:8][CH2:1][CH2:2][CH2:7][S:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Reactant: O=S(=O)(CCCCl)N1CCOCC1
Product: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(N)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bistrifluoroacetate salt (Intermediate A) and 4-[(3-chloropropyl)sulfonyl]morpholine (Intermediate E). High vacuum drying gave the title compound (100%): 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.17-2.22 (2H, m), 3.14-3.17 (4H, m), 3.22-3.27 (2H, m), 3.61-64 (4H, m), 3.83 (3H, s), 4.16-4.20 (2H, m), 4.28-4.35 (4H, m), 7.30 (1H, d), 7.89 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].CO>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: N#CCc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CO
Product: Cl
Product: NCCc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
3.188 g of crude (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile (14.5 mmol) were dissolved in 25 ml THF and cooled down to 0° C. under nitrogen. 76 ml of a 1M borane-THF complex solution in THF (76 mmol) were then added dropwise over 20 min by keeping the temperature between 0 to 2° C. After addition the reaction mixture was stirred at rt for additional 45 min, and refluxed for 17 h. The reaction mixture was then cooled down to 0° C. and treated between 2 and 5° C. with 18 ml methanol over a period of 45 min. After 1 h refluxing the reaction mixture was concentrated, the residue dissolved in DCM and the amine extracted twice with 1N aqueous HCl. The combined aqueous phases were then treated with concentrated NaOH to adjust the pH to 12, and then extracted twice with DCM. The combined organic phases were then washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo leading to 1.54 g colorless oil. This was dissolved in 50 ml diethylether, treated with 4 ml 2.6N HCl in diethylether, stirred at rt for additional 30 min, filtered and dried under high vacuo, leading to 1.52 g white solid (40%). MS (ISP) 224.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([OH:16])[CH:8]=1.O.[NH2:21][NH2:22]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:21][NH2:22])=[O:12])=[C:9]([OH:16])[CH:8]=1
Reactant: O=C(O)c1ccc(OCc2cccc(Br)c2)cc1O
Reactant: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)c1ccc(OCc2cccc(Br)c2)cc1O
Temperature: 120 °C
Yield: 16.2 %

Procedure:
A slurry of 4-(3-bromo-benzyloxy)-2-hydroxy-benzoic acid (2.15 g; 6.4 mmol) in MeOH (10 mL) was added hydrazine hydrate (3 mL; 62 mmol) and heated to 120° C. in a sealed metal cylinder for 40 min. The cylinder was cooled on ice and the slurry diluted with THF in order to dissolve precipitate. The clear solution was evaporated onto SiO2, and purified by filtration through a plug of Silica gel (SiO2—PE80-100° C./EtOAc=4:1; EtOAc then EtOAc/CH2Cl2=3:2) to yield after evaporation 0.9 g (42%). The compound was further purified by crystallization from MeOH/THF to yield 350 mg pure product. Mp. 201-203° C.; MS (ESI−): 335/337 (MH−).
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[P:18](=[S:24])(Cl)([O:21][CH3:22])[O:19][CH3:20].[H][H]>C(#N)C>[P:18](=[S:24])([O:11][C:8]1[CH:7]=[N:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[N:10][CH:9]=1)([O:21][CH3:22])[O:19][CH3:20]
Reactant: COP(=S)(Cl)OC
Reactant: [H][H]
Reactant: CC(C)(C)c1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COP(=S)(OC)Oc1cnc(C(C)(C)C)nc1

Procedure:
To a stirred mixture of 6 grams of 2-(1,1-dimethylethyl)-5-pyrimidinol, 6 grams of finely powdered potassium carbonate and 40 ml of acetonitrile was added 6.33 grams of O,O-dimethyl phosphorochloridothioate. The mixture was stirred without external heating until all O,O-dimethyl phosphorochloridothioate was consumed as shown by GLC. The solids present were removed by filtration, the filtrate concentrated under vacuum, the residue taken up in diethyl ether, the ether solution washed twice with 2% aqueous sodium hydroxide, once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, while leaving a pale amber colored oil having a refractive index at 25° of 1.5027. Elemental analysis showed the product to contain 43.82% carbon; 6.09% hydrogen and 10.10% nitrogen. Theoretical composition is 43.47% carbon; 6.20% hydrogen and 10.14% nitrogen.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[NH2:8][C:9](=[NH:38])[CH2:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[O:28])[C:17]2=[O:35])=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl-].O[NH3+]>C(O)C>[NH2:38][C:9](=[N:8][OH:4])[CH2:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[O:28])[C:17]2=[O:35])=[CH:13][CH:12]=1
Reactant: N=C(N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1)=NO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
37 mg (0.07 mmol) of N-{2-[4-(2-amino-2-iminoethyl)benzyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-5-chloro-2-thiophenecarboxamide trifluoroacetate are suspended in 3 ml of ethanol, and 0.09 ml (0.65 mmol) of triethylamine and 22.7 mg (0.33 mmol) of hydroxylammonium chloride are added. The reaction mixture is stirred at room temperature for 5 h and then concentrated. The residue is stirred with water and filtered. This gives 21 mg (69% of theory) of the desired product as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[N:6]1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:29][C:15]([F:14])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[CH:7]=[N:6]3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: ClCCCn1ncc2ccccc21
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCN(CCCn3ncc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
1-(3-chloropropyl)-1H-benzopyrazole (6.98 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoromethyl phenyl piperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 7.6 g compound (I-59) with a yield of 63.1%. ESI-MS [M+H]+: m/z 389.2.
Reaction SMILES: [C:1]1([C:11]2[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:17]([Zn]CC)C.ICI>ClCCl>[C:1]1([C:11]23[CH2:17][CH:12]2[CH:13]([OH:16])[CH2:14][CH2:15]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC[Zn]CC
Reactant: OC1C=C(c2cccc3ccccc23)CC1
Solvent: ICI
Solvent: ClCCl
Product: OC1CCC2(c3cccc4ccccc34)CC12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-naphthalen-1-yl-cyclopent-2-enol (1.00 g, 4.79 mmol) in dichloromethane (60 mL) was added diethylzinc (1.0 M in hexanes; 23.6 mL, 23.62 mmol, 4.9 eq.) and the reaction mixture was stirred for 10 min. The reaction mixture was cooled to 0° C. and treated with a solution of diiodomethane (1.93 mL, 24.04 mmol, 5 eq.) in dichloromethane (10 mL) in a dropwise fashion over 10 min. The reaction mixture was subsequently allowed to warm to ambient temperature and stirred for a further 2 h. TLC indicated that the reaction had gone to completion and was quenched with saturated aqueous ammonium chloride (50 mL). The reaction mixture was extracted with dichloromethane (3×100 mL) and the combined organics were dried over magnesium sulphate and concentrated in vacuo to afford the desired compound as a yellow oil. The crude material was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether. 40-60; 20%:80%) to afford the desired compound as a yellow oil (1.00 g, 93%). 1H NMR (400 MHz, CDCl3) δ ppm 0.92-0.99 (1H, m, CH), 1.43-1.44 (2H, m, CH2), 1.82-1.86 (1H, m, CH), 1.93-2.07 (2H, m, CH2), 2.15-2.23 (1H, m, CH), 5.02-5.04 (1H, m, CH), 7.24-7.35 (4H, m, ArH), 7.75 (1H, d, J 8.0 ArH), 7.87 (1H, d, J 8.0 Hz, ArH) 8.15 (1H, d, J 8.4 Hz, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [H][H]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cccc(N)c1N

Procedure:
The mixture of 206 g (1.14 mol) of 6 and 20.6 g of 10% Pd on charcoal in 824 ml of THF and 824 ml of methanol was hydrogenated with a total of 6 equivalents of hydrogen (130 l) at 2048° C. over 24 h. The mixture was filtrated and the solvents were evaporated.
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[CH2:35]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1)[CH3:36]>C1(C)C=CC=CC=1.C(O)C>[CH2:35]([C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1)[CH3:36].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([CH2:35][CH3:36])=[CH:38][CH:39]=2)=[S:47])=[C:29]([F:34])[CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: CCc1ccc(C(=O)Cl)cc1
Agent: CCc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-Ethyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-ethyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-ethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 87%).