Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[N:32]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][N:34]=[CH:33]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:40]3[CH2:39][CH2:38][CH:37]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH2:42][CH2:41]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: c1cn(C2CCNCC2)cn1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCC(n4ccnc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
660 mg of N,N'-carbonyldiimidazole were added to a solution of 1.52 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 15 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 538 mg of 4-(imidazol-1-yl)piperidine in 5 ml of dry acetonitrile was then added to the solution, and the mixture was stirred at room temperature for 30 minutes and then at 40° C. for a further 7 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with an aqueous solution of sodium hydrogencarbonate, with water and with an aqueous solution of sodium chloride, in that order. The organic solution was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by reverse phase column chromatography through 200 ml of Cosmo Sil 75C18 -PREP (a trade mark for a product of Nacalai Tesque), using a gradient elution method, with mixtures of acetonitrile and water ranging from 50:50 to 55:45 by volume as the eluent. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 1.45 g of the title compound, as a powder.
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[N:7][C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][N:4]=1)[NH2:2].[NH:18]1[CH:22]=[C:21]([CH2:23][CH:24]([C:30](OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]=[CH:19]1>>[CH:9]([C:8]1[C:3]2[N:4]([C:30]([CH:24]([CH2:23][C:21]3[N:20]=[CH:19][NH:18][CH:22]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:2][N:1]=2)[CH:5]=[C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:7]=1)([CH3:11])[CH3:10]
Reactant: CCOC(=O)C(Cc1c[nH]cn1)C(=O)OCC
Reactant: CC(C)c1nc(-c2cccnc2)cnc1NN
Product: CCOC(=O)C(Cc1c[nH]cn1)c1nnc2c(C(C)C)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing 2-hydrazino-3-isopropyl-5-(3-pyridyl)pyrazine with diethyl (imidazol-4-ylmethyl)malonate there is obtained ethyl rac-8-isopropyl-α-(imidazol-4-ylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 405 (M)+, which is converted into the above acid by alkaline saponification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>C(Cl)Cl>[CH:27]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)([CH3:29])[CH3:28]
Reactant: O=C1CCC(CCO)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OCCC1CCC(=O)CC1)(C(C)C)C(C)C

Procedure:
A solution of 4-(2-hydroxy-ethyl)-cyclohexanone (Intermediate R10, 6.8 g, 52.6 mmol, (obtainable as described in the publication by Ciufolini et. al. J. Amer. Chem. Soc. 1991, 113, 8016) was dissolved in CH2Cl2 (75 mL) and treated with diisopropylethylamine (9.2 mL, 52.6 mmol) followed by tri-isopropylsilyl trifluoromethane sulfonate (TIPSTf) (15.3 g, 50.2 mmol) at −30 EC. The reaction mixture was warmed to 0 EC for 1 h. The mixture was subjected to an aqueous work-up and purified by chromatography on SiO2 to give 4-(2-triisopropylsilanyloxy-ethyl)-cyclohexanone (Intermediate R11, 11.8 g (82%). Intermediate R11 was converted via Intermediate R12 to the unsaturated aldehyde, 5-(2-triisopropylsilanyloxy-ethyl)-cyclohex-1-enecarbaldehyde (Intermediate R13)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N1CCN(c2ccccc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min then 1.6 g (0.01 mole) of 1-phenylpiperazine was added. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml), dried and concentrated in vacuo to yield 5.1 g of crude dark yellow oil, which solidified when cooled to -78° C. Recrystallization from isopropyl ether yielded 2.2 g (54.3%) of pale yellow crystals, m.p. 93°-94° C.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:14])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>C1COCC1>[Cl:1][C:2]1[N:6]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[C:5]2[CH:7]=[C:8]([Cl:14])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1Cl
Reactant: COCCOCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCn1c(Cl)nc2cc([N+](=O)[O-])c(Cl)cc21
Reaction time: 2.5 h
Yield: 83.2 %

Procedure:
To a stirred solution of 2,6-dichloro-5-nitro-1H-benzoimidazole (5.43 g, 23.4 mmol), diisopropylethylamine (12.2 mL, 70.2 mmol), and THF (120 mL) was added portionwise 1-chloromethoxy-2-methoxy-ethane (3.30 mL, 28.1 mmol). The reaction mixture was stirred for 2.5 h and concentrated. Water (50 mL) was added to the residue, the mixture was extracted with EtOAc (3×125 mL). The combined organic layers were washed with brine (100 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (20-55% EtOAc/hexanes) to yield the titled compound (6.23 g, 83% yield) as a 1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C11H11Cl2N3O4, 319.0; m/z found, 320.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.24 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 5.71 (s, 2H), 5.68 (s, 2H), 3.72-3.64 (m, 4H), 3.57-3.50 (m, 4H), 3.35 (s, 3H), 3.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[OH:29])[CH3:21])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12].Br[CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([CH3:21])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[O:29][CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCN2C(=O)c3ccccc3C2=O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 60 °C
Yield: 89.1 %

Procedure:
A mixture of 4-(2-amino-3-nitrophenyl)carbonylamino-N-(2-hydroxy-4-methylphenyl)-3-methoxy-N-methylbenzamide (520 mg), N-(4-bromobutyl)phthalimide (326 mg) and potassium carbonate (160 mg) in N,N-dimethylformamide (10 ml) was heated at 60° C. for 8 hours. The mixture was diluted with ethyl acetate and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude oil was purified by silica gel column (1% methanol in chloroform) to give 4-(2-amino-3-nitrophenyl)carbonylamino-3-methoxy-N-methyl-N-[2-(4-phthalimidobut-1-yloxy)-4-methylphenyl]-benzamide (670 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Temperature: 5 °C

Procedure:
The crude oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)propan-2-ol, from Example 8 is dissolved in 200 ml of methylene chloride and to that mixture is added 13.2 g of triethylamine. The reaction mixture is cooled to 5° C. and 11.0 g of methanesulfonyl chloride is added slowly, maintaining the temperature between 5°-10° C. The precipitation of triethylamine hydrochloride crystals is observed. After the addition of the methanesulfonyl chloride has been completed, the reaction mixture is stirred for an additional one-half hour. Then the solution is filtered to remove the triethylamine hydrochloride crystals and the filtrate is poured into 200 ml of water. The organic layer is separated and dried over magnesium sulfate. Evaporation of the organic layer under reduced pressure yields 30.4 g of crude 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate as an oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl.O>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of (S)-1-Boc-2-hydroxymethyl-piperazine (500 mg) in DCM (15 mL) were added NaHCO3 (369 mg), water (3 mL) and benzyl chloroformate (0.464 mL) at RT. The resulting emulsion was vigorously stirred at RT overnight. The mixture was diluted with water and extracted with DCM. The combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 50 for 6CV, 50 to 70 over 3CV, 70 for 2CV) to afford 714 mg of colourless oil. LC-MS (B): tR=0.82 min; [M+H]+: 350.94.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([CH3:32])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:17]2[CH:16]=[C:15]3[C:20]([C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:33])([CH3:32])[C:6]([OH:34])=[O:5])=[O:11])[N:13]=[CH:14]3)=[CH:19][CH:18]=2)=[CH:25][C:26]=1[F:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of 3-{[7-(4-chloro-3-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid tert-butyl ester (36 mg), TFA (1 mL) and DCM (3 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (20 mg). LC MS ESI+: 433 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:17]C=O)=[O:4].[CH:20]([O:25][CH3:26])([O:23][CH3:24])OC>CO>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:17][CH:20]([O:23][CH3:24])[O:25][CH3:26])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)nc1CC=O
Reactant: COC(OC)OC
Solvent: CO
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)nc1CC(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Mix 2-(4-chloro-phenyl)-4-(2-oxo-ethyl)-thiazole-5-carboxylic acid methyl ester (96.4 g, 308 mmol), Dowex™ 50×8 ion exchange resin (33.3 g), and trimethyl orthoformate (147 mL) in MeOH (670 mL). Stir the slurry overnight at room temperature. Filter through a plug of diatomaceous earth and rinse with MeOH (3×300 mL). Stir the filtrate at 0° C. for 2 h and then concentrate to a volume of approximately 250 mL. Collect the solid by filtration, rinse with cold MeOH, and dry overnight at room temperature to obtain 88.2 g (84%) of the titled compound. ES/MS m/z (35Cl) 342.0 [M+1]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH:52]=3)[CH:46]([OH:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:70][CH:71]=[CH2:72].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH:52]=3)[CH:46]([O:61][CH2:72][CH:71]=[CH2:70])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1Oc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(napth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in 33% methylene chloride/cyclohexane is added 1.5 equivalents of allyl trichloroacetimidate, and the reagents are allowed to mix for 5 minutes. A catalytic amount of trifluoromethanesulfonic acid is then added slowly via syringe and the mixture is stirred at room temperature. After 3 hours the reaction is quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics are washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:23])[N:10]([CH3:22])[C:11](SC)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[O:24]1CCOCC1.[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:23])[N:10]([CH3:22])[C:11]([OH:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(O)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To a 250 mL RBF, was added 5-(3-bromo-phenyl)-3-methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one (9.2 g, 23.7 mmol), 28 mL dioxane, and 24 mL 5 N NaOH in H2O. The mixture was warmed up to 85° C. and stirred for 15 h. The mixture was cooled down to 0° C. and neutralized with 1 N HCl in H2O until pH 5. White solid was precipitated. After filtration and washed with water, the 5-(3-bromo-phenyl)-2-hydroxy-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one was obtained in 5.76 g as white powder. MS (ES+): 358 (M+H)+; (ES−): 356 (M−H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].[CH:16]([O-])([O-])OC.S(=O)(=O)(O)O>CO>[C:13]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:16])=[O:8])([OH:15])=[O:14]
Reactant: COC([O-])[O-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Yield: 82.2 %

Procedure:
To a suspension of 3-nitrophthalic acid (211 g) and methyl orthoformate (127 g) in methanol (420 ml) was added conc. sulfuric acid (20 ml) dropwise with stirring. The reaction mixture was heated under reflux for 18 hours and concentrated to dryness. After addition of water (30 ml) to the residue, the mixture was stirred at 3-10° C. for one hour. The precipitated crystals were recrystallized from ethyl acetate-hexane to give pale yellow prisms (185 g, 82%), m.p. 166-168° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:34][N:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)N>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:35]([CH3:34])[C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc([N+](=O)[O-])c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 539.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>C(OCC)(=O)C>[N+:17]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)([O-:19])=[O:18]
Reactant: Cc1cccc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])c2ccccc12

Procedure:
To a cold (0° C.) suspension of 1-methylnaphthalene (5 g) in HNO3 was added H2SO4 (5 mL) dropwise. After stirring the reaction for one hour, the solution was diluted with ethyl acetate and washed with water (3×), aqueous saturated NaHCO3 (2×) and brine, dried over MgSO4, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate:hexane (5:95) and recrystallized from methanol to give yellow needles.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=[CH:4][C:3]=1[C:10]#[N:11]
Reactant: N#Cc1cnn(CCO)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: N#Cc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Temperature: 60 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
To a suspension of 5-amino-1-(2-hydroxyethyl)pyrazole-4-carbonitrile (10 g, 65.7 mmol) and pyridine (100 ml) was added triphenylmethyl chloride (22.3 g, 78.9 mmol) at room temperature. After stirring at 60° C. for 6 hours, the reaction mixture was concentrated in vacuo. To the residue were added tetrahydrofuran and brine, and the separated organic layer was washed with brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate to give 5-amino-1-[2-(trityloxy)ethyl]pyrazole-4-carbonitrile (25.4 g) as a colorless solid.
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:32][C:17]=2[C:18]([C:25]2[C:26]([CH3:31])=[N:27][O:28][C:29]=2[CH3:30])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH3:31][C:26]1[C:25]([C:18]2[C:17]3[CH2:32][N:33]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[C:34](=[O:35])[C:16]=3[C:15]([OH:14])=[C:24]3[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]3)=[C:29]([CH3:30])[O:28][N:27]=1
Reactant: Cc1noc(C)c1-c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1-c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 279 dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was dissolved in DMSO (1 mL) and purified by prep-HPLC to remove Ph3PO. The crude mixture was diluted with EtOAC and extracted with 1N HCl. The aqueous phase containing product 280 was re-purified by HPLC to afford 5-(3,5-dimethyl-isoxazol4-yl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 280, (0.4 mg) as a TFA salt solid: 1H NMR (CD3OD) δ 9.0 (d, 1H), 8.1 (d, 1H), 8.0 (s, 1H), 7.7 (m, 1H), 7.4 (dd, 1H), 7.1 (t, 2H), 4.8 (s, 2H), 4.2(s, 2H), 2.0 (s, s, 2×3H); MS: 404 (M+1). HPLC conditions: mobile phase A was 0.1% TFA in water, mobile phase b was 0.1% TFA in CH3CN; gradient from 5% to 60% B in 20 min; flow rate was 20 mL/min; column was Phenomenex, luna 5μ, C18 (2), 150 mm×21.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([CH3:17])[C:13](OC)=[O:14].O.[NH2:19][NH2:20]>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([CH3:17])[C:13]([NH:19][NH2:20])=[O:14]
Reactant: NN
Reactant: COC(=O)C(C)c1cc2cccnc2cc1F
Solvent: O
Solvent: CO
Product: CC(C(=O)NN)c1cc2cccnc2cc1F
Yield: 100 %

Procedure:
A solution of methyl 2-(7-fluoroquinolin-6-yl)propanoate (756 mg, 3.24 mmol) and hydrazine monohydrate (1.5 mL) in methanol (5 mL) was heated at 50° C. overnight. After cooling, the solvent was removed in vacuo to afford the title compound (756 mg, 100%) which was used without further purification. LCMS (method A): [MH]+=234, tR=3.14 min.