Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:10][CH2:11][CH2:12]O)[CH:8]=[CH2:9].C([O-])(O)=O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:6][CH2:12][CH2:11][O:10][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCOCCO
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOCCOC(=O)C(=C)C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
A three-necked flask equipped with stirrer, thermometer, reflux condenser and Dean-Stark trap is charged with methacrylic acid (137.7 g, 1.6 mol), ethylene glycol monoallyl ether (80.7 g, 0.8 mol), p-toluenesulfonic acid (0.76 g, 4.0 mmol) and toluene (650 mL). After allowing the reaction to proceed at 120° C. for 5 hours, 0.12 g of p-toluenesulfonic acid is added, and the reaction is further allowed to proceed at the same temperature for 6 hours. Then, 0.1 g of p-toluenesulfonic acid is added, and the reaction is further allowed to proceed at the same temperature for 9 hours, whereupon the reaction is completed. During the whole reaction period, methacrylic acid and ethylene glycol monoallyl ether are monitored with liquid chromatography. The final conversion amounted to 98%. The reaction mixture is neutralized by adding an aqueous solution of NaHCO3 and allowed to separate into two layers. The aqueous layer is extracted once with toluene. The combined organic layer is dried over CaCl2 and the volatile matter is distilled off under reduced pressure. The crude product is distilled under reduced pressure (60° C., 2 mmHg) to give 98.7 g (73% yield) of 2-allyloxyethyl methacrylate shown below. H2C═C(CH3)CO2(CH2)2OCH2CH═CH2
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Cl[CH2:42][C:43]1[C:44]([C@@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[C:57]([F:60])([F:59])[F:58])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>C1COCC1.O>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([C@@H:51]3[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]3[C:57]([F:59])([F:60])[F:58])[C:43]=2[CH2:42][O:16][CH:14]2[CH2:15][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)[CH2:50][CH2:49]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: FC(F)(F)[C@@H]1CCCC[C@H]1c1noc(C2CC2)c1CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(OCc1c([C@@H]3CCCC[C@H]3C(F)(F)F)noc1C1CC1)C2
Reaction time: 0.17 h

Procedure:
A solution of N-Boc-nortropine (579 mg, 2.55 mmol) and 18-crown-6 (808 mg, 3.06 mmol) in THF (8.5 mL) was treated with potassium tert-butoxide (343 mg, 3.06 mmol) and stirred for 10 minutes. A solution of 4-(chloromethyl)-5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazole (784 mg, 2.55 mmol) in THF was added. The resulting mixture was stirred at rt for 2 hours and then poured into water and extracted with EtOAc. Organics were collected, dried (MgSO4), filtered, concentrated and chromatographed (SiO2, linear gradient, 0-60% EtOAc in Hexanes) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 4.28 (m, 2H), 4.19 (m, 1H), 4.11 (m, 1H), 3.66 (dd, J=4.8, 4.7 Hz, 1H), 3.47 (dd, J=7.6, 3.7 Hz, 1H), 2.42 (m, 1H), 2.19 (ddd, J=25.2, 12.5, 3.4 Hz, 1H), 2.00-1.77 (m, 13H), 1.69 (m, 1H), 1.52 (m, 1H), 1.46 (s, 9H), 1.35 (m, 1H), 1.12 (m, 2H), 1.03 (m, 2H)4; MS m/z 443.2 (M-tBu+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([OH:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-]>COCCOC.CCOCC>[CH3:24][O:19][C:18](=[O:20])[CH2:17][C@@H:16]([OH:21])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Solvent: CCOCC
Solvent: COCCOC
Product: COC(=O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 450 mg (1.52 mmoles) of (S)-7-benzyloxycarbonylamino -3-hydroxyheptanoic acid in 1,2-dimethoxyethane, while being cooled in ice, was added dropwise 7 ml (4.56 mmoles) of a solution of diazomethane in ether. The mixture was stirred for 30 minutes. The reaction mixture was evaporated to dryness to yield 461 mg (98% yield) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid methyl ester;[α]D21 +1°.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:27](=[O:28])[C:19]3([CH2:21][CH:20]3[C:22]([O:24]CC)=[O:23])[C:14]3=[N:15][N:16]=[C:17]([CH3:18])[N:13]3[C:12]3[CH:29]=[CH:30][CH:31]=[CH:32][C:11]2=3)=[CH:6][CH:5]=1.Cl>CO.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:27](=[O:28])[C:19]3([CH2:21][CH:20]3[C:22]([OH:24])=[O:23])[C:14]3=[N:15][N:16]=[C:17]([CH3:18])[N:13]3[C:12]3[CH:29]=[CH:30][CH:31]=[CH:32][C:11]2=3)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CC12C(=O)N(c1ccc(Cl)cc1)c1ccccc1-n1c(C)nnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C21CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaOH (48 mg, 1.2 mmol) was added to a solution of ethyl 6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane]-2′-carboxylate (100 mg, 0.24 mmol) in MeOH (10 mL) and water (4 mL). It was stirred at room temperature overnight. The solution was adjust to pH=5 using HCl solution (1 M), then concentrated, adding dichloromethane (5 mL), filtered and the filtrate was concentrated to give crude 6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane]-2′-carboxylic acid, which was used in the next step directly. LRMS (M+H)+: 394 m/z.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](=[CH:18][C@@H:19]2[CH2:39][CH2:38][C:21]3([O:25][C@@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@H:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:22]3)[CH2:20]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:11][CH2:10]1.C(=O)([O-])[OH:41].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH2:56]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:12](=[CH:18][C@@H:19]2[CH2:39][CH2:38][C:21]3([O:22][C@@H:23]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:25]3)[CH2:20]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH:9]1[CH2:11][CH2:10]1)(=[O:41])=[O:56]
Reactant: O
Reactant: CCOC(=O)C(=C[C@@H]1CCC2(C1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2)c1ccc(SC2CC2)c(Br)c1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=C[C@@H]1CCC2(C1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-[3-bromo-4-(cyclopropylsulfanyl)phenyl]-3-[(2S,3S,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]acrylate (2.58 g, (E)/(Z)-mixture) was dissolved in dichloromethane (77 mL), followed by ice-cooling. To this solution was added sodium hydrogen carbonate (7.87 g) and then m-chloroperbenzoic acid (2.31 g). It was stirred for 30 minutes under ice-cooling, and further warmed to room temperature, followed by stirring for 3 hours. Dichloromethane (55 mL) and m-chloroperbenzoic acid (0.32 g) were further added thereto, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture to stop the reaction and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 2-[3-bromo-4-(cyclopropylsulfonyl)phenyl]-3-[(2S,3S,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]acrylate (2.52 g) as an (E)/(Z)-mixture of olefin.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11].C(N(CC)CC)C.[N+](C1C=CC([O:39][C:40]([N:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:45][CH2:44][CH2:43]2)=O)=CC=1)([O-])=O>>[F:21][C:19]([F:22])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:40]([N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44][CH2:43]1)=[O:39])(=[O:12])=[O:11]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reactant: NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
To a solution of N-(6-Aminohexyl)-2-trifluoromethylbenzene sulfonamide Hydrochloride (0.1 g, 0.27 mmol) dimethyl formamide (3 mL) and triethylamine (0.1 g, 1 mmol) was added 3, 4-Dihydro-2H-quinoline-1-carboxylic acid 4-nitrophenyl ester (0.09 g, 0.3 mmol) and the reaction mixture was stirred at room temperature for 4 h. Solvent was evaporated and purification by preparative TLC afford the titled compound as an oil (0.08 g, 61%).
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][CH3:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[CH2:15]([NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:16][CH3:17]
Reactant: CCCNCC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCNCC1CCNC1
Yield: 83.2 %

Procedure:
A mixture of 14.0 g (60.0 mmole) of 1-(phenylmethyl)-N-propyl-3-pyrrolidinemethanamine, 1.0 g of 20% palladium on carbon and 140 ml of methanol was shaken in an atmosphere of hydrogen at about 4.5×105Pa and room temperature for 24 hours. The catalyst was removed by filtering through Celite, the filtrate concentrated and distilled in vacuo to give 7.1 g of N-propyl-3-pyrrolidinemethanamine, bp 49°-50° C./0.25 mm.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][OH:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][OH:17])[CH2:9]1
Reactant: OCCNCC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCCNCC1CCNC1
Yield: 57.5 %

Procedure:
A mixture of 32.3 g of 2-[[[1-(phenylmethyl)-3-pyrrolidinyl]methyl]amino]ethanol, 330 ml of methanol and 3 g of 20% palladium on charcoal was shaken in an atmosphere of hydrogen at about 4.5×105Pa and at room temperature for 18 hours. The solvents were then removed at reduced pressure. The residue was distilled under vacuum (bp 129°-131° C., 1.5 mm Hg) to give 11.43 g of 2-[(3-pyrrolidinylmethyl)amino] ethanol.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH2:20][C:19]4=[N:23][N:24]([CH3:26])[CH:25]=[C:18]34)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH2:20][C:19]4=[N:23][N:24]([CH3:26])[CH:25]=[C:18]34)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc2c(n1)CCCN2c1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc2c(n1)CCCN2c1cnc2[nH]cc(C(=O)NC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
To a stirred solution of N-tert-butyl-2-(2-methyl-6,7-dihydro-2H-pyrazolo[4,3-b]pyridin-4(5H)-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 180 μmol) in CH2Cl2 (4 mL) was added TFA (740 mg, 500 μL, 6.49 mmol). After 24 h, the mixture was concentrated in vacuo and the residue was re-dissolved in 5 mL of a mixture of (CH2Cl2/methanol/ammonium hydroxide; 60:10:1) and the mixture stirred at room temperature for 24 h, then evaporated to a yellow solid, which was purified by chromatography (spherical silica 20-45 m, 23 g, Versaflash Supelco, 0 to 5% 9:1 methanol:ammonium hydroxide in CH2Cl2, 30 min) to give a residue that was dissolved in CH2Cl2 then precipitated with cyclohexane. The yellow solid was obtained by decanting the mother liquor and dried under high vacuum to give N-tert-butyl-2-(2-methyl-6,7-dihydro-2H-pyrazolo[4,3-b]pyridin-4(5H)-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 36%). 1H NMR (CHLOROFORM-d) δ: 9.46 (br. s., 1H), 8.08-8.21 (m, 2H), 7.97 (br. s., 1H), 7.82 (s, 1H), 3.88 (m, 5H), 2.89 (t, J=6.2 Hz, 2H), 2.14-2.28 (m, 2H), 1.56 (s, 9H). MS (EI/CI) m/z: 354.1 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH2:7](N(CC)CC)C.[NH2:14][C:15]1[C:16](=[O:31])[N:17]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:18]=[CH:19][C:20]=1[CH3:21]>C(Cl)Cl.CN(C)C=O.CN(C1C=CN=CC=1)C>[C:1]([NH:14][C:15]1[C:16](=[O:31])[N:17]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:18]=[CH:19][C:20]=1[CH3:21])(=[O:5])[CH2:2][CH3:7]
Reactant: CCN(CC)CC
Reactant: COc1ccc(Cn2ncc(C)c(N)c2=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(=O)Nc1c(C)cnn(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a stirred solution of 2-(R,S)-(2-naphthylacetyl)amino-3-[4'-(1"-t butoxycarbonyl-1"-methyl)ethyl]benzenepropanoic acid (0.31 g, 0.66 mmol) in methylene chloride (5 mL) at rt was added dimethylformamide (3drops) followed by oxalyl chloride (2 M in methylene chloride, 0.30 mL, 0.66 mmol). The mixture was stirred at rt for 1 hour. Triethylamine (0. 13 mL), 4-amino-2-(4-methoxybenzyl)-5-methyl-3-pyridazinone (0.12 g, 0.47 mmol) and DMAP (0.005 g)were added. The mixture was stirred overnight at rt, and heated at reflux for 6 hours. The solvents were evaporated, and the residue was fractionated over silica gel (ethyl acetate/hexane 1/1) to give 4-[2'-(R,S)-2""-naphthylacetyl)amino-3'-[4"-(1'"-t butoxycarbonyl-1'"-methyl)ethyl]benzene]propanoylamino-2-(4-methoxybenzyl)-5-methyl-3-pyridazinone (0.08 g, 0.11 mmol, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])[C:4]=2[CH:3]=1.C[N:25]1CCOCC1.C1[CH2:35][O:34][CH2:33]C1>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([NH:25][CH2:33][O:34][CH3:35])=[O:16])=[O:12])[C:4]=2[CH:3]=1
Reactant: CN1CCOCC1
Reactant: C1CCOC1
Reactant: O=C(O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: COCNC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
By the method described in Example 5, the title compound of Example 4 (1.2 g, 3.6 mmol) in 40 mL of THF was converted to its mixed anhydride with NMM (0.42 g, 3.6 mmol) and IBCF (0.49 g, 3.6 mmol) and coupled to N,O-dimethylhydroxylamine . HCl (0.35 g, 3.6 mmol) using an additional 0.36 mmol (3.6 mmol) of NMM to liberate the free base of N,O-dimethylhydroxylamine . HCl. This procedure gave 726 mg of the title compound after HPLC purification on silica gel.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[Na+].[Na+].[C:8]1([S:22]([O-:25])(=[O:24])=[O:23])[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([S:18]([O-:21])(=[O:20])=[O:19])[C:12]=2[CH:11]=[CH:10][CH:9]=1>>[C:8]1([S:22]([OH:25])(=[O:24])=[O:23])[C:17]2[CH:16]=[C:15]([S:1]([OH:5])(=[O:4])=[O:3])[CH:14]=[C:13]([S:18]([OH:21])(=[O:20])=[O:19])[C:12]=2[CH:11]=[C:10]([S:1]([OH:3])(=[O:5])=[O:4])[CH:9]=1
Reactant: O=S(=O)([O-])c1cccc2c(S(=O)(=O)[O-])cccc12
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c2c1

Procedure:
To 240 ml. of 30-33% fuming sulfuric acid at 120° C. is added, portionwise, 60 g. of 1,5-naphthalenedisulfonic acid disodium salt. The mixture is heated at 180°-190° C. for 23 hours. The solution is cooled, allowed to crystallize and filtered through a course sintered glass funnel. The product is washed with concentrated sulfuric acid to give 1,3,5,7-naphthalenetetrasulfonic acid as an off-white pasty solid. Without further purification, the solid is added, portionwise, to 150 ml. of chlorosulfonic acid and the mixture is heated at 145°-150° C. for 1.5 hours. The mixture is cooled to room temperature and filtered. The product is washed, in order, with chlorosulfonic acid, methylene chloride, acetonitrile, water, acetonitrile and finally with ether. The product is air-dried and then dried further in an Abderhalden apparatus at 76° C. to provide 33.9 g. of the desired product as a colorless powder, m.p. 263°-270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]([NH2:14])=O)=[C:9]([CH3:11])[N:10]=2)[N:7]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]#[N:14])=[C:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: Cc1nc2ccc(Cl)nn2c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nc2ccc(Cl)nn2c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a mixture of 6-chloro-2-methylimidazo[1,2-b]pyridazine-3-carboxamide (1.5 g, 7.0 mmol) produced in the above, pyridine (1.7 mL, 21 mmol) and tetrahydrofuran (20 mL) was added dropwise under ice-cooling a solution of trifluoroacetic anhydride (1.5 mL, 11 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 2 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (887 mg, 66%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]2[CH:17]=[CH:18][CH:19]=[C:9]2[CH2:8][CH2:7]1)=[O:5].O.O.Cl[Sn]Cl>C(O)C.O1CCCC1>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]3[CH:17]=[CH:18][CH:19]=[C:9]3[CH2:8][CH2:7]2)=[O:5])=[C:2]([Cl:1])[CH:23]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCc2cccn2-c2ccccc21
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
To a solution of 0.50 g of 6,7-dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 10 ml of ethyl alcohol and 2 ml of tetrahydrofuran is added 2.35 g of SnCl2.2H2O and the mixture stirred at 55° C. for 30 minutes. The solvents are evaporated in vacuo to a residue which is stirred with 20 ml of 1N NaOH and 40 ml of ethyl acetate for 15 minutes and filtered through diatomaceous earth. The filter pad is washed with 2×10 ml of ethyl acetate and the combined extracts washed with brine, dried (Na2SO4) and evaporated in vacuo to give 0.47 g of solid residue which is triturated with ether-hexane to give 0.43 g of light yellow crystalline solid. MS(CI): 338(M+H, Cl35) 340(M+H, Cl37)
Reaction SMILES: Cl.[O:2]1CCOC[CH2:3]1.[CH2:8]([O:10][C:11]1[CH:12]=[CH:13][C:14]([F:27])=[C:15]([C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]=[C:19]([C:25]#N)[CH:18]=2)[CH:16]=1)[CH3:9].C[OH:29]>>[CH2:8]([O:10][C:11]1[CH:12]=[CH:13][C:14]([F:27])=[C:15]([C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]=[C:19]([C:25]([O:2][CH3:3])=[O:29])[CH:18]=2)[CH:16]=1)[CH3:9]
Reactant: CCOc1ccc(F)c(-c2cc(C#N)nc(C)c2C)c1
Reactant: C1COCCO1
Reactant: CO
Agent: Cl
Product: CCOc1ccc(F)c(-c2cc(C(=O)OC)nc(C)c2C)c1

Procedure:
4M HCl in 1,4-dioxan (20 mL, 80 mmol) was added to a suspension of 4-(5-ethoxy-2-fluoro-phenyl)-5,6-dimethyl-pyridine-2-carbonitrile (which may be prepared as described in Description 51) (1.87 g, 6.92 mmol) in methanol (20 mL) at ambient temperature. The stirred, yellow solution was refluxed under N2 for 9 h. The reaction was concentrated to one third the volume then poured into sat. aq. NaHCO3 (100 ml). The mixture was extracted with EtOAc (3×50 ml). The combined organic extracts were dried (Na2SO4) and evaporated to a colourless oil which solidified. This was purified by SiO2 column chromatography: the oil was dissolved in DCM (15 ml) and the solution was applied to a 100 g cartridge which was then eluted on a Biotage SP4 system with a gradient of EtOAc/iso-hexane (0-80%) to afford methyl 4-(5-ethoxy-2-fluoro-phenyl)-5,6-dimethyl-pyridine-2-carboxylate (D52);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:32][CH:33]=[CH2:34]>C1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:34][CH:33]=[CH2:32])[CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)N(c1ccc(Cl)cc1)C1CCNCC1
Reactant: C=CCBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN1CCC(N(C(=O)Cc2ccccc2)c2ccc(Cl)cc2)CC1
Product: Cl

Procedure:
To a stirred solution of 5 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 3.8 parts of N,N-diethylethanamine in 200 parts of benzene are added portionwise 5 parts of 3-bromo-1-propene. After the addition is complete, the whole is heated for 21 hours at a temperature between 50°-60° C. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate solution and water, dried over potassium carbonate and evaporated. The oily residue is converted into the hydrochloride salt in 1,1'-oxybisethane and 2-propanone, yielding 4 parts of N-(4-chlorophenyl)-N-[1-(2-propenyl)-4-piperidinyl]benzeneacetamide hydrochloride; mp. 225.5° C.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[C:8]([N+:13]([O-])=O)[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:16]([C:18]1C2C(=C(N)C=CC=2)N=[CH:20][CH:19]=1)[CH3:17].C(O)C>O=[Pt]=O.[H][H]>[CH2:1]([C:3]1[C:12]2[C:7](=[C:8]3[C:9](=[CH:10][CH:11]=2)[C:18]([CH2:19][CH3:20])=[CH:16][CH:17]=[N:13]3)[N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccnc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Reactant: CCc1ccnc2c(N)cccc12
Agent: O=[Pt]=O
Solvent: CCO
Product: CCc1ccnc2c1ccc1c(CC)ccnc12

Procedure:
4-Ethyl-8-nitroquinoline is reduced to 4-ethyl-8-aminoquinoline by catalytic reduction with Adams' catalyst as follows: place a solution of 0.05 moles of 4-ethyl-8-nitroquinoline in 100 ml of rectified spirit (ethyl alcohol) together with 0.1 g of Adams' catalyst (platinum (IV) oxide, available from Aldrich Chemical Co., Inc.) in a hydrogenation flask, and shake in hydrogen. After the theoretical volume of hydrogen is absorbed, filter off the platinum with suction and rinse the reaction vessel with rectified spirits. Evaporate the alcohol from the combined filtrate and washings on a water bath. Dissolve the crude residue in rectified spirits, add a little decolorizing charcoal, boil and filter. Heat the filtrate to boiling, add hot water to initiate crystallization and allow to cool.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-])[C:10]=2[CH:11]=1.C1(C)C=CC(S(Cl)(=O)=[O:20])=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [O-][n+]1cccc2ncc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1ccc2ncc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 0.50 g of 3-bromo-1,5-naphthyridin-5-oxide in 10 mL of chloroform, 0.51 g of p-toluenesulfonyl chloride, 1.04 g of potassium carbonate and 3 mL of water were added, and the mixture was stirred at room temperature overnight. Thereto were added water and chloroform, and the solid was filtered off to obtain 0.39 g of 7-bromo-1,5-naphthyridin-2(1H)-one as a white solid.