Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[NH:14][CH:15]=[CH:16][C:6]=3[C:5]=2[CH:4]=1.Cl.[CH2:18]([C:20]([OH:22])=[O:21])[CH3:19].NC1C=CC2NC(=O)C3NC=CC=3C=2C=1.C(C([O-])=O)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>>[CH3:43][S:44]([N:2]([CH3:1])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[NH:14][CH:15]=[CH:16][C:6]=3[C:5]=2[CH:4]=1)(=[O:46])=[O:45].[CH2:18]([C:20]([O-:22])=[O:21])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)O
Reactant: CNc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Agent: Cl
Agent: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Product: CN(c1ccc2[nH]c(=O)c3[nH]ccc3c2c1)S(C)(=O)=O
Yield: 21.9 %

Procedure:
This compound is prepared according to synthesis 58, from 130 mg of 8-methylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 63) contaminated with 30% of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate to which 33 μL (0.42 mmol) of methanesulfonyl chloride is added. After purification by chromatography on silica (eluent dichloromethane/methanol/acetonitrile 94/3/3), 32 mg (31%) of 8-(methanesulfonyl-methyl-amino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:17][CH2:18][CH2:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]2[C:14]=1[N:13]([CH3:15])[C:12](=[O:16])[CH:11]=[CH:10]2.[H][H].[Cl:33]N1C(=O)CCC1=O.Cl>ClCCl.C1COCC1>[Cl:33][C:20]([CH2:19][CH2:18][CH2:17][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:16])[N:13]2[CH3:15])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: [H][H]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(CCCc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(Cl)(CCCc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Yield: 125.6 %

Procedure:
Sodium hydride (60% in oil) (0.33 g) was added under ice cooling to a THF solution (30 ml) of diethyl 2-[3-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)propyl]malonate (2.94 g), and stirring was carried out until the generation of hydrogen stopped. N-chlorosuccinimide (1.2 g) was added, followed by stirring for 2 hours. The reaction mixture was added to cold hydrochloric acid, and extraction with dichloromethane was performed. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 4.02 g (yield: quantitative) of diethyl 2-chloro-2-[3-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)propyl]malonate as a yellow oil.
Reaction SMILES: C=O.[B-][C:4]#N.[Na+].[NH:7]1[CH2:13][CH2:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2.[OH-].[Na+]>C(#N)C.C(O)(=O)C>[CH3:4][N:7]1[CH2:13][CH2:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2
Reactant: [B-]C#N
Reactant: CCOC(=O)C1=Cc2ccccc2NCC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2ccccc2N(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A 37% aqueous formaldehyde solution (1.50 g, 18.4 mmol), sodium cyanotrihydroborate (0.12 g, 18.4 mmol) and acetic acid (0.1 ml) were added to a solution in acetonitrile (8 ml) of the ethyl 2,3-dihydro-1H-benz[b]azepine-4-carboxylate (0.40 g, 1.84 mmol) synthesized in Reference Example 5. After stirring at room temperature for 2 hours, the reaction mixture was poured into a 1N aqueous sodium hydroxide solution and extracted twice with diethyl ether. The extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=4/96) to obtain 0.40 g of ethyl 1-methyl-2,3-dihydro-1H-benz[b]azepine-4-carboxylate.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:23](=O)[C:24]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:42]=[C:43]=[N:44][Si](C)(C)C)(C)C.Cl>C(#N)C>[NH2:42][C:43]1[N:44]=[C:23]([C:24]([N:26]2[CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:34]2)=[O:25])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([C:15]3([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]3)[CH:11]=2)[N:8]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N3Cc4ccccc4C3)c2)CC1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)C1(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
670 mg of ethyl 1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclopropanecarboxylate are dissolved in 15 ml of acetonitrile under argon. 213 mg of caesium fluoride and 380 μl of bis(trimethylsilyl)carbodiimide are added to the solution. The mixture is stirred at room temperature for 15 min, and 2.7 ml of hydrochloric acid (1N) are then added, with the product precipitating as white solid. Yield: 510 mg (91%) of ethyl 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylate; LC-MS retention time: 1.65 min (“nonpolar” gradient);
Reaction SMILES: [NH2:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[N:15][C:16]=3[NH2:18])[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[N:10]=2)=[CH:5][CH:4]=1.[C:38]1([CH2:44][CH:45]=O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][N:28]1[CH2:27][CH2:26][N:25]([CH:22]2[CH2:23][CH2:24][CH:19]([N:11]3[C:12]4=[N:13][CH:14]=[N:15][C:16]([NH2:18])=[C:17]4[C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH:2]([NH:1][CH2:45][CH2:44][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:8][CH:7]=4)=[N:10]3)[CH2:20][CH2:21]2)[CH2:30][CH2:29]1
Reactant: O=CCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(C2CCC(n3nc(-c4ccc(C(NCCc5ccccc5)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a solution of cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.10 mmol), phenylacetaldehyde (13 mg) and glacial acetic acid (0.013 mL) in 1,2-dichloroethane (1 mL) under nitrogen was added sodium triacetoxyborohydride (2 equivs., 43 mg). The solution was stirred for 18 h then concentrated in vacuo, partitioned between dichloromethane (10 mL) and saturated aqueous NaHCO3 (10 mL) and the organic layer separated. The aqueous layer was further extracted with dichloromethane (4×10 mL) and the combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness. Purification was effected using mass actuated preparative RP-HPLC (Micromass/Gilson, Hypersil BDS C18, 5 μm, 100×21.2 mm column; 0-100% acetonitrile and 0.05M ammonium acetate, buffered to pH 4.5, over 12.5 min at 25 mL/min) to afford 1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(phenethylamino)(phenyl)methyl]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (28 mg); RP-HPLC (10 to 90% CH3CN in 0.1 N aqueous ammonium acetate, buffered to pH 4.5, over 12 min at 2 mL/min using a Waters Symmetry C18, 250×4.6 mm column) Rt=12.269 min, 95.2%; m/z (MH+) 601.3.
Reaction SMILES: [C:1]([N:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:7]([CH2:16][N:17]([C@@H:25]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[NH:37]1[CH2:47][CH2:46][CH:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38]1>C(O)C.C(Cl)(Cl)Cl>[C:20]([O:19][C:18]([N:17]([CH2:16][C@@H:7]1[C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:37]2[CH2:47][CH2:46][CH:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38]2)[CH2:6]1)[C@@H:25]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[CH3:26])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C1CCNCC1
Reactant: C=CC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(CCC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)CC1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A mixture of 750 mg of tert-butyl {[(3R,4S)-1-acryloyl-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 8 ml of an ethanol:chloroform (4:1) mixed solvent was mixed with 487 mg of ethyl isonipecotate and stirred at 60° C. for 6Hours, and the reaction solution was concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 700 mg of ethyl 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3-oxopropyl}piperidine-4-carboxylate as a pale yellow amorphous substance. By carrying out the Boc-elimination from the thus obtained compound in the same manner as in Example 2, ethyl 1-{3-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3-oxopropyl}pyridine-4-carboxylate dihydrochloride was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:14](=[C:16]1[N:20]=[CH:19][N:18]=[C:17]1[C:21]([NH2:23])=[O:22])=[N-:15]>CS(C)=O>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:12](=[O:13])[N:20]2[CH:19]=[N:18][C:17]([C:21]([NH2:23])=[O:22])=[C:16]2[N:14]=[N:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: CC(C)(C)[Si](C)(C)OCCN=C=O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Crude 2-(tert-butyldimethylsilyloxy)ethyl isocyanate (422 mg, 2.097 mmol) was added drop wise to a solution of 5-diazoimidazole-4-carboxamide (250 mg, 1.823 mmol) in dimethylsulfoxide (2.5 mL) and the reaction mixture was stirred at room temperature. After 16 hours, the crude reaction mixture was applied to reverse phase silica (C18 silica) and eluted with water and then acetonitrile. The acetonitrile fractions were combined and purified by flash column chromatography (SiO2, gradient 0-100% acetonitrile in dichloromethane) to furnish the title compound as a white solid. Yield: 40 mg, 0.12 mmol, 6.5%. LCMS (ES+) m/z 339 (M+H)+ at 3.19 minutes. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (1H, s), 7.83 (1H, br s), 7.70 (1H, bs), 4.41 (2H, t), 3.98 (2H, t), 0.78 (9H, t), −0.03 (6H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:20][CH2:19]1)[C:12](O)=[O:13])=[O:7].C(N(CC)CC)C.[C:38]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[C:38]1([CH2:44][CH2:45][CH2:46][NH:47][C:12]([C:11]2[CH:15]=[CH:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH2:19]3)=[C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH:10]=2)=[O:13])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)O)cc2NC(=O)c2ccco2)CC1
Reactant: NCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCc3ccccc3)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a suspension of 3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (0.1 g, 0.246 mmol) in methylene dichloride (5 ml), triethylamine (0.074 g, 0.74 mmol), (3-phenylpropyl)amine (0.044 g, 0.370 mmol) and 1-propane phosphonic cyclic anhydride (0.23 g, 0.74 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and extracted with dichloromethane (10 ml×1). The organic layer was washed with water (10 ml×2) and dried over anhydrous sodium sulfate. The organic layer was concentrated and the crude product obtained was purified by flash chromatography using silica gel column to get (0.070 g, 67.9%) of the titled compound as a brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:16]=2)[CH2:10][CH:9]1[CH3:32])=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH:9]([CH3:32])[CH2:10]2)[CH:16]=1)=[O:31]
Reactant: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1
Temperature: 100 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Combine 4-[3-(2-chloro-4-fluoro-benzoylamino)-phenoxy]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (Preparation 78, 0.60 g, 1.31 mmol), toluene (20 mL), and p-toluenesulfonic acid monohydrate (2.5 g, 13.1 mmol), stir, and heat at 100° C. After 1 hr., cool to ambient temperature. Concentrate the reaction mixture. Partition the residue between ethyl acetate (100 mL) and 1M aqueous sodium hydroxide solution (50 mL). Separate the organic layer, wash with 1M aqueous sodium hydroxide solution (2×50 mL), wash with aqueous NaCl solution (50 mL), dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M ammonia/methanol) in dichloromethane to obtain the title compound (0.26 g, 55%). Mass spectrum: Obs. m/z 363.1289; Calc. m/z 363.1275; Analysis calculated for C19H21C12FN2O2.0.9H2O: C, 54.92; H, 5.53; N, 6.74. Found: C, 54.90; H, 5.36; N, 6.55. 1H NMR (CDCl3) of free base: 7.9 (bs, 1H), 7.8 (m, 1H), 7.4 (s, 1H), 7.2 (m, 3H), 7.1 (m, 2H), 6.7 (dd, 1H), 4.3 (m, 1H), 3.2 (m, 1H), 2.75 (m, 2H), 2.15 (m, 2H), 1.45 (m, 2H), 1.1 (d, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C2C(=NC=CC=2)C=C1>O1CCCC1>[CH2:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][NH:42][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])=[CH:43][CH:44]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cnc2cc[nH]c2c1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-quinoline carboxylic acid (100 mg, 0.577 mmol) in tetrahydrofuran (50 mL) was added N,N′-dicyclohexylcarbodiimide (1.90 g, 11.7 mmol), and the solution was stirred at room temperature for 1 hour. Then, to this solution was added a solution of 4-benzyloxybenzylamine described in Preparation Example 1 (2.49 g, 11.7 mmol) in tetrahydrofuran (5 mL), and the solution was stirred overnight at room temperature. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (4.31 g, quantitatively) was obtained as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=2[OH:12])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:19][C:20]1[N:21]=[N:22][C:23]([Cl:28])=[CH:24][C:25]=1[O:26][CH3:27]>O1CCOCC1.CS(C)=O>[Cl:28][C:23]1[N:22]=[N:21][C:20]([O:12][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=2[CH:1]2[CH2:2][CH2:3]2)=[C:25]([O:26][CH3:27])[CH:24]=1.[Cl:19][C:20]1[N:21]=[N:22][C:23]([O:12][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=2[CH:1]2[CH2:2][CH2:3]2)=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1cc(Cl)nnc1Cl
Reactant: COc1cccc(O)c1C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COc1cc(Cl)nnc1Oc1cccc(OC)c1C1CC1
Product: COc1cc(Oc2cccc(OC)c2C2CC2)nnc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.8 %
Yield: 39.1 %

Procedure:
In a mixed solvent of 1,4-dioxane (2.5 mL) and dimethylsulfoxide (2.5 mL) was dissolved 190 mg (1.16 mmol) of 2-cyclopropyl-3-methoxyphenol, 146 mg (1.30 mmol) of potassium tert-butoxide was added to the solution and the resulting mixture was stirred for 10 minutes. To the mixture was added 170 mg (0.950 mmol) of 3,6-dichloro-4-methoxypyridazine and the resulting mixture was stirred overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 90.1 mg (0.293 mmol, Yield: 30.8%) of 6-chloro-3-(2-cyclopropyl-3-methoxyphenoxy)-4-methoxypyridazine and 114 mg (0.371 mmol, Yield: 39.1%) of 3-chloro-6-(2-cyclopropyl-3-methoxyphenoxy)-4-methoxypyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O)([O-:25])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19](=[N:22][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N+:23]([O-:25])=[O:24])[CH2:20][CH:21]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2nccc(OC3=CCC(=NCc4ccccc4[N+](=O)[O-])C=C3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenyloxy)quinoline (500 mg, 1.6873 mmol) was dissolved in tetrahydrofuran (64 ml), and after adding 2-nitrobenzaldehyde (320 mg, 2.1091 mmol) and acetic acid (0.58 ml), sodium triacetoxyborohydride (720 mg, 3.3746 mmol) was further added and the mixture was stirred at room temperature for 11 hours and 30 minutes. Water and saturated sodium bicarbonate were added, the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with hexane-diethyl ether, filtered out, washed with hexane and dried by aspiration at room temperature to obtain the title compound (453 mg) as light yellow crystals.
Reaction SMILES: CCCCCC.[CH3:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH3:7][C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2
Reactant: BrCc1ccccc1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Solvent: CCCCCC
Solvent: O
Product: Cc1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
Hexane was used to wash 80 mg 2.0 mmol) of 60% NaH/mineral oil and 6 mL of DMF was added followed by 352 mg (2.0 mmol) of 2-methyl-5-nitro-1H-indole. After 0.33 hours, 0.24 mL (2.0 mol) of benzyl bromide was added, stirred 0.5 hours and diluted with water. The mixture was extracted with EtOAc, the EtOAc washed with a saturated NaCl solution, dried (MgSO4) and on concentrating at reduced pressure, crystals formed. These were washed with MeOH to give 400 mg (75% yield) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole, mp, 150-152° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: OCc1ccc(Cl)cc1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCc2ccc(Cl)cc2)c1

Procedure:
Mitsunobu coupling of phenol 58 with 4-chlorobenzylalcohol followed by flash chromatography (5 to 30% EtOAc-hexanes gradient) gave 2-(3-(3-(4-chlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione as a colorless oil. Yield (2.82 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.79-7.82 (m, 2H), 7.67-7.69 (m, 2H), 7.31-7.38 (m, 4H), 7.15 (t, J=8.0 Hz, 1H), 6.79-6.81 (m, 2H), 6.70-6.73 (m, 1H), 4.99 (s, 2H), 3.72 (t, J=7.2 Hz, 2H), 2.65 (t, J=8.0 Hz, 2H), 2.02 (dddd, J=7.2 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.C([O-])([O-])=[O:17].[K+].[K+].[CH3:22][C:23]([CH3:25])=[O:24]>>[CH3:15][O:14][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:22][C@@H:23]([OH:24])[CH2:25][OH:17])[CH:3]=2)[CH:8]=1)=[O:13]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Agent: [K+]
Product: COC(=O)c1ccc2cc(OC[C@@H](O)CO)ccc2c1

Procedure:
To a solution of methyl 6-hydroxy-2-naphthoate (4.55 g, 22.5 mmol) in anhydrous acetone (60 ml) are added S-(−)-glycidol (2.0 g, 27.0 mmol) and K2CO3 (9.3 g, 67.3 mmol). The reaction mixture is heated to reflux for 3 days. The reaction mixture is filtered through Celite™ (filter material) and the filtrate is concentrated in vacuo to afford 6-((S)-2,3-Dihydroxy-propoxy)-naphthalene-2-carboxylic acid methyl ester as a white solid; 1H NMR (DMSO-d6): 3.49 (2H, t, J=6.0 Hz), 3.85-3.88 (1H, m), 3.89 (3H, s), 4.02 (1H, dd, J=9.9, 6.0 Hz), 4.16 (1H, dd, J=9.9, 4.0 Hz), 4.73 (1H, t, J=6.0 Hz), 5.04 (1H, d, J=5.2 Hz), 7.26 (1H, dd, J=9.0, 2.0 Hz), 7.41 (1H, d, J=2.0 Hz), 7.88-7.94 (2H, m), 8.04 (1H, d, J=9.0 Hz), 8.55 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[N:5]=[C:4]([N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[N:3]=1.C(Cl)Cl.[C:20](Cl)(Cl)=[O:21].[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[NH2:9][C:6]1[N:7]2[O:8][C:20](=[O:21])[N:1]=[C:2]2[N:3]=[C:4]([N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[N:5]=1
Reactant: C=CCN(CC=C)c1nc(N)[n+]([O-])c(N)n1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Temperature: 0 °C

Procedure:
75 g. of 2,4-diamino-6-diallylamino-s-triazine-3-oxide are suspended in 800 ml. of methylene chloride and cooled while stirring to 0° C. At this temperature there are then simultaneously added dropwise within 45 minutes 180 ml. of 20% phosgene in toluene and sufficient 10% sodium hydroxide to hold the pH at 7-7.5. The mixture is subsequently stirred for a further 1 hour. Methylene chloride and methanol are then added in order to dissolve the precipitated product. The two phases are separated and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure, there being obtained 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one, having a melting point of 211°-213° C.