Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:17])[CH:3]=1.[CH:18]1(N=C=NC2CCCCC2)CCCCC1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([O:16][CH3:18])=[O:15])[CH2:12][CH2:13]2)=[O:10])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(Br)ccc1NC(=O)C1(C(=O)O)CC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: COC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CC1

Procedure:
A 4.00 gram (0.01 mole) portion of 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylic acid prepared in Example VIII (Compound 111) was recited in sequence with 80 milliliters of methanol (excess as solvent) and 2.77 grams (0.01 mole) of 1,3-dicyclohexylcarbodiimide, employing a 16-hour reaction period, in a manner similar to that described in Example XL to give 1.54 grams (0.005 mole) of methyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylate as a white powder having a melting point of 106° C.-108° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)C3C=CC=CC=3)=[N:9]2)[CH2:4][O:3]1.O.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)c3ccccc3)n2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-[1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-benzamide (150 mg, 0.5 mmol) was dissolved in methanol (2 ml), and water (1 ml) was added in one portion. The mixture was stirred at room temperature for 30 minutes. NaOH (120 mg, 3 mmol) was added. The mixture was stirred at reflux for 18 h. UPLC indicated the conversion was ˜20%, so the mixture was agitated for another 20 h. The conversation was still ˜40%. Another portion of NaOH (120 mg, 3 mmol) was added into the mixture. The mixture was agitated at reflux for another 20 h. The conversation was ˜70%. No further workup.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[N:11][C:5]=2[C:4](=[O:13])[NH:3]1.C1C=C(Cl)C=[C:16]([C:21]([O:23]O)=[O:22])C=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[C:21]([O:23][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[NH:3][C:4](=[O:13])[C:5]=2[N:11]=1)(=[O:22])[CH3:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Yield: 66 %

Procedure:
1.77 g of 1 (10 mmol) in 50 ml of glacial acetic acid containing 6.5 g of MCPBA (57-85%) was refluxed for 3 hours. Acetic anhydride (40 ml) was added to the hot reaction mixture and the refluxing was continued for another half an hour. The clear brown solution was evaporated to dryness and the solid was stirred with ether (100 ml) and filtered. The solid was crystallized from ethanol to give 1.55 g (66%) of 2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=3)[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCCC2
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CCC2

Procedure:
The title compound was prepared from methyl 3-benzyloxy-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate using a procedure similar to that found in Example 13, Step 1, except that 4-fluorobenzyl bromide was used in place of iodomethane and purification was not necessary. 1H NMR (400 MHz, CDCl3) δ 7.42-7.32 (m, 5H), 7.08-7.00 (m, 4H), 5.33 (s, 2H), 4.64 (s, 2H), 4.26-4.22 (t, 2H), 3.95 (s, 3H), 1.88-1.81 (m, 2H), 1.62 (br s, 2H); ES MS (M+1)=424.
Reaction SMILES: CC([N:5]([C@:9]([C:13]([NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]3[O:29][CH2:30][CH2:31][C:32]4([CH2:34][CH2:33]4)[C:24]=23)=[N:20][CH:21]=1)=[O:14])([CH3:12])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:32]12([C:24]3[C:25](=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:19]3[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@:9]([CH3:12])([CH2:10][CH3:11])[NH2:5])=[CH:17][N:18]=3)[O:29][CH2:30][CH2:31]1)[CH2:33][CH2:34]2
Reactant: CC[C@](C)(C(=O)Nc1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@](C)(N)C(=O)Nc1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of 1,1-dimethylethyl[(1R)-1-({[2-(2,3-dihydrospiro[chromene-4,1′-cyclopropan]-5-yloxy)-5-pyrimidinyl]amino}carbonyl)-1-methylpropyl]carbamate (Intermediate 224, 5 mg, 10.67 μmol) in dry Dichloromethane (1 mL) cooled to 0° C. TFA (0.822 μL, 10.67 μmol) was added dropwise. The reaction mixture was stirred for 2 hours at the same temperature. The reaction was allowed to reach room temperature then the volatiles were evaporated. The residue was diluted with DCM (2 mL), and washed with NaHCO3 sat. sol. (7 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound (4 mg) as a yellow oil that was used in the next step without further purification.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:13]([Cl:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([Cl:11])=[O:10])([O-])=O.[N+:16](C1C=C(C(O)=O)C=C(C=1)C(O)=O)([O-:18])=[O:17].S(Cl)(Cl)=O>CN(C)C=O>[N+:16]([C:7]1[C:8]([C:9]([Cl:11])=[O:10])=[CH:12][CH:4]=[CH:5][C:6]=1[C:13]([Cl:15])=[O:14])([O-:18])=[O:17]
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A mixture of 100 g of 5-nitroisophthaloyl dichloride (prepared by taking a mixture of 60.0 g of 5-nitroisophthalic acid, 300 ml of thionyl chloride and one ml of dimethylformamide, stirring at room temperature for 30 minutes followed by refluxing for one hour; allowing the solution to stand 24 hours, followed by evaporation to a small volume in vacuo re-evaporating with toluene and then diluting the resulting liquid with 250 ml of hexane, followed by stirring and cooling until the resulting oil is solidified; and grinding the product to a powder, and recrystallizing twice from carbon tetrachloride to afford 47.4 g of nitroisophthaloyl chloride) 100 g of 2-methoxyethanol (dried over molecular sieves) and 400 ml of acetonitrile (dried over molecular sieves) is heated to boiling on a steam bath. Heating is continued for 15 minutes, then the mixture is cooled to room temperature and is poured into 2 liters of cold water with vigorous stirring. The precipitate formed (129 g) is collected by filtration, air dried and set aside. The above filtrate is extracted with benzene. The benzene extract is washed with water, dilute sodium dicarbonate and water and is dried over anhydrous sodium sulfate. The solvent is evaporated to give a mixture of crystals and oily liquid. This material is combined with the precipitate set aside above and dissolved in 580 ml of hot ethyl alcohol. The resultant solution is neutralized with 5.0 ml of 5N sodium hydroxide and is slowly diluted with 450 ml of water. The solution is allowed to crystallize at room temperature then is placed in a chill room for 16 hours. The product is collected by filtration, then is recrystallized and filtered as above from 450 ml of ethyl alcohol and 350 ml of water to give 92.1 g of 5-nitroisophthalic acid bis(2-methoxyethyl)ester as colorless needles.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:18]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:18]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:15](=[O:17])[CH2:14][CH:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCOCC1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOCC1CC(=O)N1CCCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
4-N-Boc-morpholine-3-acetic acid (500 mg, 2.04 mmol) and benzyl homopiperazine (388 mg, 2.04 mmol) were dissolved in DMF (20 mL) and cooled to 0° C. DIPEA (553 mg, 4.28 mmol) and HBTU (773 mg, 2.04 mmol) were added and the reaction mixture was stirred for 2 h. The solvents were removed in vacuo and the residue was partitioned between DCM (100 mL) and water (50 mL). The organic fraction was washed with 1 M aq Na2CO3 (25 mL), brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase column chromatography to give the title compound (730 mg, 86%) as a light yellow gum. LCMS (ES+): 418.4 [MH]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:22]=O)=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:24][NH2:25].[BH4-].[Na+].CO>O1CCCC1>[F:1][C:2]1[C:3]([CH2:22][NH:25][CH3:24])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.27 g) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (0.8 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. Sodium borohydride (91 mg) and methanol (7 mL) were added, and the mixture was stirred at the same temperature for further 30 min. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane-ethyl acetate=19:1→0:1). The above-mentioned operation was repeated to give the title compound (0.22 g, yield 39%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.C1CCCCC1.[Li]C(CC)C.C[O:24][B:25](OC)[O:26]C>C1COCC1>[F:11][C:2]1([F:1])[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([B:25]([OH:26])[OH:24])[C:5]=2[O:6]1
Reactant: COB(OC)OC
Reactant: FC1(F)Oc2ccccc2O1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1OC(F)(F)O2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
2,2-Difluoro-1,3-benzodioxole (960 mg, 6.1 mmol) was dissolved in THF (8 mL) and cyclohexane (4 mL) and the resulting solution cooled to −78° C. sec-BuLi 1.4M solution in cyclohexane (4.3 mL, 6.1 mmol) was added dropwise and the reaction mixture stirred for 1.5 hours at −78° C. Trimethylborate (694 mg, 6.75 mmol) was added and the mixture was allowed to warm slowly to −30° C. The reaction mixture was quenched with a 2N solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness affording the title compound as yellow oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:30]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:10][C:11]3[C:2]([F:1])=[N:3][C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:13][CH:14]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1cc2c(c(F)n1)CC(c1ccc(O)cn1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2)nc1
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyridin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 7.55 mmol of 7-[5-(octyloxy)pyridin-2-yl]-1-fluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.[CH:25]12[CH2:31][CH:30]1[CH2:29][CH2:28][CH:27]([CH2:32][O:33][C:34]1[C:46](Cl)=[CH:45][C:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[C:36]([F:48])[CH:35]=1)[CH2:26]2>>[CH:25]12[CH2:31][CH:30]1[CH2:29][CH2:28][CH:27]([CH2:32][O:33][C:34]1[C:46]([CH:1]3[CH2:7][CH2:6]3)=[CH:45][C:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[C:36]([F:48])[CH:35]=1)[CH2:26]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3CC3C2)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-chloro-2-fluorobenzoate, the title compound was obtained as a brown oil (1.29 g, 99%, crude yield): MS (ES+) m/z 361.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>CC(C)=O.ClCCl>[Cl:20][C:21]1[N:26]=[C:25]([N:9]([CH:10]([CH3:12])[CH3:11])[CH2:8][C:2]([F:13])([F:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1
Reactant: CCOC(=O)C(F)(F)CNC(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
Ethyl 2,2-difluoro-3-(isopropylamino)propanoate (1.50 g, 7.68 mmol) was dissolved in acetone and K2CO3 (2.12 g, 15.3 mmol) was added. The solution was purged with nitrogen gas and cooled to 0° C. A solution of 2,4-dichloro-5-nitropyrimidine (1.64 g, 8.45 mmol) in acetone (10 mL) was added dropwise at 0° C. over 1 h. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. It was diluted with dichloromethane (50 mL) and filtered thru a celite plug. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1) to afford the title compound as a yellow oil (1.96 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.82 Hz, 6 H) 1.34 (t, J=7.20 Hz, 3 H) 3.63-3.75 (m, 1 H) 4.24 (t, J=13.14 Hz, 2 H) 4.34 (q, J=7.07 Hz, 2 H) 8.74 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N+:13]([O-])([OH:15])=[O:14].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2cccc(Cl)c2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c([N+](=O)[O-])ccc(Cl)c2n1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
53.3 g (0.3 mole) of the resulting 8-chloroquinaldine was dissolved in 180.2 g of 98% sulfuric acid, and at 40° C., 40.2 g of nitric acid (specific gravity 1.50) was added dropwise over the course of 1 hour, followed by further reaction for 30 minutes. The reaction mixture was poured into ice water, and neutralized with an aqueous solution of sodium hydroxide. The product precipitated was collected by filtration, washed with water, and dried to afford 64.1 g (0.29 mole) of 8-chloro-5-nitroquinaldine.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[O:6]1C[CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[Na+]>O>[CH2:1]([O:6][CH2:7][CH:8]1[O:9][CH2:10]1)[CH:3]1[O:5][CH2:4]1
Reactant: C1COCCO1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C(OCC1CO1)C1CO1

Procedure:
Glycidyl ether of novolak type substituted phenolic resin was produced from the novolak type phenolic resin synthesized in Example 1, using a 1-liter flask equipped with a thermometer, dropping funnel, stirrer, and separating tube with cooler. In the flask were placed 1.0 mol (as phenolic hydroxyl group) of novolak type phenolic resin, 7.0 mols of epichlorohydrin, and 0.4 times (by weight) as much dioxane as epichlorohydrin. Then, 48% NaOH (1.0 mol as NaOH) was added dropwise over 4 hours. During this time, epichlorohydrin, dioxane, and water were azeotropically boiled at 58° to 60° C. under reduced pressure (150 mmHg) and cooled in the separating tube, whereby the organic layer containing major amounts of epichlorohydrin and dioxane were returned to the reaction system whereas the water layer was discharged from the reaction system. After the reaction was completed, epichlorohydrin and dioxane were distilled away, and the reaction product was dissolved in methyl isobutyl ketone. Then the salt formed as a by-product was filtered out, and then methyl isobutyl ketone was distilled away. Thus, there was obtained a glycidyl ether of the novolak type substituted phenolic resin. This product was found to contain 0.029% (290 ppm) of hydrolyzable chlorine and to have an epoxy equivalent of 203, a softening point of 62° C., and a density of 1.19 g/cm3.
Reaction SMILES: C=O.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Na].[C:31](#N)C>CO.C(Cl)Cl>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:31])[CH2:27][CH2:28]3)[CH:22]=2)[CH:17]=1
Reactant: CC#N
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1
Agent: C=O
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CC1
Reaction time: 0.5 h

Procedure:
37% Aqueous formaldehyde (0.060 ml) was added to a stirred solution of 3-(1,3-benzothiazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.250 g) dissolved in methanol (2.5 ml) and DCM (2.5 ml). Sodium triacetoxyhydroborate (0.141 g) was added and the resulting solution was for 30 minutes. The mixture was concentrated. DCM and 7N methanol/ammonia were added. The mixture was concentrated on silica gel and the residue was purified by flash chromatography on silica gel eluting with 2 to 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to afford a solid. Acetonitrile (4 ml) was added and the solution was stirred overnight. The solid was filtered, and dried under vacuum. There was thus obtained 3-(1,3-benzothiazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.198 g); Mass Spectrum: M+H+ 391; NMR Spectrum (DMSOd6): 8.48 (d, 1H), 8.33 (s, 1H), 8.16 (d, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.93 (s, 1H), 7.88 (bs, 2H), 7.57 (dd, 1H), 7.49 (dd, 1H), 4.08-4.18 (m, 1H), 2.84-2.92 (m, 2H), 2.22 (s, 3H), 1.94-2.12 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[OH:25][CH2:26][C:27](=O)[CH3:28].[BH3-]C#N.[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:27]([CH3:28])[CH2:26][OH:25])[CH:17]=2)=[CH:3]1
Reactant: CC(=O)CO
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(CO)Nc1cccc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c1
Reaction time: 8 h

Procedure:
To a mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg, 0.32 mmol) and hydroxyacetone (0.03 mL, 1.5 eq) in CH2Cl2 (12 mL) and THF (5 mL) was added NaCNBH3 (28 mg, 1.5 eq) and the reaction mixture was stirred overnight. The volatiles were removed under vacuo and the residue was purified by preparatory TLC to give 3-(1-methylindol-3-yl)-4-[3-(2-hydroxy-1-methylethylamino)phenyl]-1H-pyrrole-2,5-dione (8 mg). LC/MS: M+ 375(85.6%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: ClCCCCn1ccc2ccccc21
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCn3ccc4ccccc43)CC2)c1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(4-chlorobutyl)-1H-indole and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 418.3 (M+H)+.
Reaction SMILES: [NH4+].[N:2]([C@H:5]1[CH2:10][C@H:9]([OH:11])[C@@H:8]([CH2:12][O:13][P:14]([OH:17])([OH:16])=[O:15])[O:7][CH2:6]1)=[N+:3]=[N-:4].[N:18]([C@H]1[C@H](O)[C@H](O)[C@@H](CO)[O:23]C1)=[N+]=[N-]>>[NH4+:2].[NH4+:18].[N:2]([C@H:5]1[C@H:10]([OH:23])[C@H:9]([OH:11])[C@@H:8]([CH2:12][O:13][P:14]([OH:17])([OH:16])=[O:15])[O:7][CH2:6]1)=[N+:3]=[N-:4]
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](COP(=O)(O)O)[C@@H](O)C1
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](CO)[C@@H](O)[C@H]1O
Agent: [NH4+]
Product: [N-]=[N+]=N[C@@H]1CO[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
Phosphate 12 is prepared similarly to phosphate 5 starting from azide 11 (0.503 g. 2.66 mmol). Coarse purification by column chromatography and silica gel (0.35% ammonia (20% aqueous solution in i-PrOH) pale yellow oil 12 (0.353 g, 46%). Rf 0.4 (i-PrOH/25%-NH4OHaq/H2O 6/4/1). This product is used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:16]([OH:17])[OH:15])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1cnc2ccccc2c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromoquinoline (Sigma-Aldrich, St. Louis, USA) (1 eq, 14.0 mmol, 1.94 ml) in toluene/THF (4:1, 25 ml), triisopropylborate (1.2 eq, 16.8 mmol, 3.94 ml) is added. The mixture is cooled to −40° C., then n-butyl lithium (1.6 M in THF, 1.2 eq, 17 mmol, 10.5 ml) is added within 30 min. After stirring for additional 30 min at this temperature, the cooling bath is removed and the reaction mixture is allowed to to warm up to −20° C. before quenching with aqueous HCl solution (2 N). The mixture is adjusted to pH 7 by using aqueous NaOH solution (4 N), then it is saturated with NaCl, and extracted with THF. The organic layer is concentrated in vacuo, and the resulting solid is recrystallized in MeCN yielding the title compound, [M+H]+=173.