Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(C)cc4C)CC3)nn2C(C)(C)C)cc1

Procedure:
109 mg (74%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(2,4-dimethylphenyl)piperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[O:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:18][S:19]([CH2:22][C:23]1[N:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)(=[O:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH3:18][S:19]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([O:7][CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:14]=2)=[CH:27][N:28]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cc1ccc(O)cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CS(=O)(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 4-(5-fluoro-2-nitrophenoxy)tetrahydro-2H-pyran (13.6 g) and 6-[(methylsulfonyl)methyl]pyridin-3-ol (13.9 g) in N,N-dimethylformamide (300 mL) was added potassium carbonate (39 g), and the mixture was stirred at 110° C. for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 50:50, volume ratio) to give the title compound (23 g, yield 95%) as a yellow solid.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:16]=[CH:15][C:10]2[S:11][CH:12]=[C:13]([CH3:14])[C:9]=2[CH:8]=1.[Cl:17][CH2:18][CH2:19][CH2:20]I>C1COCC1.[Cu]I>[Cl:17][CH2:18][CH2:19][CH2:20][C:12]1[S:11][C:10]2[CH:15]=[CH:16][C:7]([F:6])=[CH:8][C:9]=2[C:13]=1[CH3:14]
Reactant: ClCCCI
Reactant: Cc1csc2ccc(F)cc12
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(CCCCl)sc2ccc(F)cc12
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
n-BuLi in heptanes (1.5 ml, 2.4 mmol, 1.6M) was added drop wise to 5-fluoro-3-methyl-benzo[b]thiophene (332 mg, 2.0 mmol) in THF (5 ml) at −20° C. under argon. The reaction mixture was stirred at −15° C. for 30 min, then 1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper (I) iodide (38 mg, 0.2 mmol) were added. The reaction was stirred at −15° C. for 1 h, then NH4H4Cl (sat'd aq., 5 ml) was added. The product was extracted with diethyl ether (2×30 ml) and the organic layer was washed with brine (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0-1% diethyl ether in heptanes) to give 2-(3-chloro-propyl)-5-fluoro-3-methyl-benzo[b]thiophene (180 mg, 37%). 1H NMR (CDCl3): δ2.19 (tt, 2H), 2.22 (s, 3H), 2.94 (t, 2H), 3.57 (t, 2H), 7.04 (dt, 1H), 7.28 (dd, 1H), 7.66 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][NH:3][CH2:4][C:5]1[C:14]2([CH2:17][CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[C:8]([CH3:20])[C:9]([OH:19])=[C:10]([CH3:18])[CH:11]=2)[CH:6]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][NH:3][CH2:4][CH:5]1[C:14]2([CH2:15][CH2:16][CH2:17]2)[O:13][C:12]2[C:7](=[C:8]([CH3:20])[C:9]([OH:19])=[C:10]([CH3:18])[CH:11]=2)[CH2:6]1
Reactant: CONCC1=Cc2c(cc(C)c(O)c2C)OC12CCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CONCC1Cc2c(cc(C)c(O)c2C)OC12CCC2
Reaction time: 8 h
Yield: 17.9 %

Procedure:
A solution of 3-[(methoxyamino)methyl]-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-6-ol (300 mg) in 20 mL of ethyl acetate was treated with Pd (100 mg, 10% on activated carbon), flushed with H2, and left stirring in a hydrogen atmosphere overnight. After filtration through a pad of silica, the solvents were evaporated. The residue was purified by flash chromatography eluted with 30% ethyl acetate and hexane to give 54.0 mg of 3-[(methoxyamino)methyl]-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol as an off-white solid. 1H-NMR (300 MHz, CDCl3) δ=6.51 (s, 1H), 3.57 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H), 3.20-1.50 (m, 11H) ppm. 13C-NMR (75 MHz, CDCl3) δ=146.5, 145.9, 122.6, 122.4, 117.7, 116.3, 79.2, 62.0, 50.5, 35.4, 33.5, 31.7, 23.3, 16.2, 12.8, 11.6 ppm. MS: (m/z)=278.2 (M+H+).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=[O:4].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1>C1COCC1>[Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Product: OC(CBr)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 84.7 %

Procedure:
To a 0° C. solution of 13 g (49 mmol) 2-bromo-1-(3,4-dichlorophenyl)ethanone in 250 ml THF was added 17 g (53 mmol) (+)-B-chlorodiisopinocampheyl-borane. The reaction mixture was stirred 6 hours at 0° C., then allowed to warm to room temperature and stir 14 hours. An additional 2 g (6 mmol) of (+)-B-chlorodiisopinocampheyl-borane was added and the reaction mixture stirred 4 more hours, then concentrated in vacuo. To this was added 250 ml ether and 10 ml diethanolamine and the resulting slurry stirred for 2 hours, then filtered through celite. The filtercake was washed 2×200 ml ether and the combined filtrates washed with 500 ml 10% aqueous KHSO4, 500 mL saturated aqueous NaHCO3, and 500 mL brine, then dried over MgSO4, filtered and concentrated. Purification by flash chromatography (9×20 cm silica gel, 100% CH2Cl2) afforded 11.2 g 2-bromo-1-(3,4-dichlorophenyl)ethanol. 1H NMR(300 mHz, CDCl3) 7.52 (d, 1H, J=3 Hz); 7.45 (d, 1H, J=9 Hz); 7.22 (dd, 1H, J=9and 3 Hz); 4.70 (dt, 1H, J=9 and 3.4 Hz); 3.62 (dd, 1H, J=11 and 3.4 Hz); 3.49 (dd, 1H; J=11 and 9 Hz); 2.66 (d, 1H; J=3.4 Hz)
Reaction SMILES: [Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=[O:17])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([OH:10])[C:4]=2[C:3]=1[C:19]1[C:20]([OH:29])=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH2:23][CH2:22]2.C[O-].[Na+:32].O>CO.O1CCCC1>[Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=[O:17])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([O-:10])[C:4]=2[C:3]=1[C:19]1[C:20]([OH:29])=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH2:23][CH2:22]2.[Na+:32]
Reactant: O=c1[nH]c2sc(Cl)c(-c3ccc4c(c3O)CCCC4)c2c(O)c1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2sc(Cl)c(-c3ccc4c(c3O)CCCC4)c2c([O-])c1-c1ccccc1

Procedure:
2-chloro-4-hydroxy-3-(5-hydroxytetralin-6-yl)-5-phenyl-7H-thieno[2,3-b]pyridin-6-one (4.0 g, 9.44 mmol) was dissolved in a mixture of methanol/tetrahydrofuran (25 ml/25 mL). Sodium methoxide solution (30% in methanol) (1.75 mL, 9.44 mmol) was slowly added followed by water (15 ml). Organic solvents were removed under reduced pressure. The remaining aqueous solution was lyophilized to give a grey solid (4.80 g, 100%, compound crystallized with 4 water molecules).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][S:8][C:9]([CH2:12][O:13][Si](C(C)(C)C)(C)C)=[CH:10][CH:11]=1)(=[O:3])[CH3:2].F.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([NH:4][CH2:5][C:6]1[S:7][S:8][C:9]([CH2:12][OH:13])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC1=CC=C(CO[Si](C)(C)C(C)(C)C)SS1
Agent: F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NCC1=CC=C(CO)SS1
Temperature: 0 °C
Yield: 72.7 %

Procedure:
To a stirred solution of 52 mg (0.152 mmol) of the (silyloxy)amide 19 in 1.0 mL of acetonitrile, previously cooled in an ice-water bath, was added 500 μL of a 1:3 solution of 30% aqueous hydrofluoric acid solution in acetonitrile. The resulting solution was stirred for 15 minutes in the ice bath, after which time TLC analysis showed the reaction to be complete. The acid was neutralized by cautious addition of about 15 mL of a 10% aqueous potassium carbonate solution to the reaction mixture. The reaction mixture was partitioned between 20 mL of water and 40 mL of ethyl acetate. The layers were separated and the aqueous phase was extracted with 40 mL of ethyl acetate. The combined organic phases were washed with two 50-mL portions of saturated aqueous sodium chloride, dried (Na2SO4) and concentrated in vacuo. The residue (33 mg) was chromatographed over 20 g of silica gel (ethyl acetate) to give 24 mg (71%) of acetamide 20 as an orange oil. 1H NMR (CDCl3) δ6.792 (m, 2H, C=CH; minor isomer), 6.309 (d, J=6.4 Hz, 1H, C=CH; major isomer), 6.269 (d, J=5.6 Hz, 1H, C=CH; major isomer), 6.82 (br s, 1H, NH), 4.276 (br s, 2H, CH2O; minor isomer), 4.512 (d, J=5.6 Hz, 2H, CH2N; minor isomer), 4.228 (br s, 2H, CH2 0; major isomer), 4.023 (d, J=6.0 Hz, 2H, CH2N; major isomer), 2.05 (s, 1H, OH), 1.998 (s, 3H, COCH3 ; major isomer); 13C NMR (CDCl3) δ170.116, 144.100 (minor isomer), 141.214 (minor isomer), 134.827 (major isomer), 132.384 (major isomer), 126.528 (major isomer), 125.815 (minor isomer), 125.254 (minor isomer), 125.178 (major isomer), 64.499 (major isomer), 60.099 (minor isomer), 43.690 (major isomer), 38.631 (minor isomer), 23.140 (major isomer), 21.011 (minor isomer); MS (LSIMS) m/z=57 (100%), 217 (M+).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][CH2:11][CH:12]([OH:25])[CH2:13][O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[O-]CC.[Na+].[F:30][C:31]([F:54])([F:53])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=3)[CH2:42][CH2:41]2)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C(O)C>[N+:7]([C:5]1[N:6]=[C:2]2[N:3]([CH:4]=1)[CH2:10][CH2:11][CH:12]([CH2:13][O:14][C:49]1[CH:48]=[CH:47][C:46]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:54])[F:53])=[CH:37][CH:36]=4)[CH2:41][CH2:42]3)=[CH:51][CH:50]=1)[O:25]2)([O-:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CCn2cc([N+](=O)[O-])nc2Cl)cc1
Reactant: Oc1ccc(N2CCN(CCc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: CC[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(N3CCN(CCc4ccc(C(F)(F)F)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
Toluene-4-sulfonic acid 4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (1.12 g) was suspended in an ethanol (14 ml). An ethanol solution (1.13 ml) of 20% sodium ethoxide was added to the suspension, and the mixture was stirred at room temperature for 30 minutes. 4-{4-[2-(4-Trifluoromethylphenyl)ethyl]piperazin-1-yl}phenol (0.72 g) and tripotassium phosphate (0.61 g) were added to the reaction mixture and heated for 4 hours under reflux. After the reaction mixture was cooled to room temperature, water was added thereto, followed by extraction with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→hexane:ethyl acetate=0:1) and recrystallized from methanol to afford the title compound as a pale yellow powder (0.72 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+].C(O)(=O)/C=C/C(O)=O.[NH2:31][CH2:32][CH2:33][C:34]#[N:35]>O.C(Cl)(Cl)Cl>[C:32]([CH2:33][CH2:34][NH:35][C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:16])#[N:31]
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: N#CCCN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)NCCC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
4'-methylbiphenyl-2-carboxylic acid (50.00 g, 0.236 mol,), thionyl chloride (87.5 ml, 1.20 mol) and chloroform (500 ml) were mixed and refluxed for 4 hours. The thionyl chloride and solvent were removed in vacuo, and the residue suspended in toluene (300 ml). The mixture was evaporated in vacuo and the residue suspended once more in toluene and evaporated to insure removal of traces of thionyl chloride. The resultant acid chloride was dissolved in tetrahydrofuran (100 ml) and slowly added in five equal portions alternatingly with five equal portions of 1.0N NaOH (236.0 ml, 0.236 mol) to a solution of β-aminopropionitrile fumarate (30.3 g, 0.236 mol) in 1.0 N NaOH (236.0 ml, 0.236 mol) at 0° with stirring. The reaction was allowed to warm slowly to room temperature. After 24 hrs, water (500 ml) was added and the aqueous mixture extracted with ethyl acetate (3×500 ml). The organic layers were combined and dried (MgSO4), and the solvent removed in vacuo to yield a crude solid which, after recrystallization from methylcyclohexane/butyl chloride, yielded 53.5 g of a white solid. M.P.=102.0°-103.5°. NMR (200 MHz, CDCl3) δ: 7.68 (d, 1H, J=7Hz); 7.56-7.19 (m, 7H); 5.65 (bm, 1H); 3.43 (d of t, 2H); 2.39 (t, 2H, J=7Hz). Anal. calcd. for C17H16N2O; C, 77.25; H, 6.10; N, 10.60. Found: C, 77.42; H, 6.40; N, 10.68.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][O:19][C:13]4=[CH:12][C:11]=3[N:10]=[C:9]([C:20]([O:22]CC)=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][NH2:26].CO>>[CH3:25][NH:26][C:20]([C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:16]2[CH:15]=[C:14]3[O:17][CH2:18][O:19][C:13]3=[CH:12][C:11]=2[N:10]=1)=[O:22]
Reactant: CN
Reactant: CCOC(=O)c1cc(N2CCCCC2)c2cc3c(cc2n1)OCO3
Solvent: CO
Product: CNC(=O)c1cc(N2CCCCC2)c2cc3c(cc2n1)OCO3

Procedure:
After a mixture of ethyl 8-(1-piperidinyl)-1,3-dioxolo[4,5-g]quinoline-6-carboxylate as obtained in Reference Example 31 (60 mg) and a 40% methylamine-methanol solution (5 ml) was stirred at room temperature for 3 hours, the solvent was distilled off under reduced pressure to yield the title compound as a colorless powder (33.6 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12](O)=[O:13])[CH:8]=[C:7]2[OH:15].[CH3:18][NH:19][CH3:20].C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl>CN(C=O)C.CCOC(C)=O>[CH3:18][N:19]([CH3:20])[C:12]([C:9]1[CH:8]=[C:7]([OH:15])[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:16][CH3:17])=[CH:4][CH:5]=2)[N:10]=1)=[O:13]
Reactant: CNC
Reactant: COc1ccc2c(O)cc(C(=O)O)nc2c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COc1ccc2c(O)cc(C(=O)N(C)C)nc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 8-chloro-4-hydroxy-7-methoxy-quinoline-2-carboxylic acid (500 mg, 1.97 mmol) and 2.0 M dimethylamine in THF (2 mL, 3.94 mmol) were dissolved in DMF (20 mL). HATU (1.5 g, 3.94 mmol) and NMM (697 mg, 6.89 mmol) were added and the mixture was stirred at r.t. overnight. The reaction was diluted with EtOAc and acidified with 1 N HCl. The two layers were separated. The organic layer was washed with 2% LiCl, saturated NaHCO3 and brine, dried with Na2SO4, and concentrated to give 8-chloro-4-hydroxy-7-methoxy-quinoline-2-carboxylic acid dimethylamide.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18]C)=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-:34]>O1CCCC1.CO>[NH2:2][C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[C:16]([OH:18])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)=[O:34]
Reactant: [OH-]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(C#N)cc2c(=O)n1C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(C(N)=O)ccc23)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A solution of methyl [7-cyano-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (17 mg, 0.039 mmol) in tetrahydrofuran (THF) (0.600 mL) and methanol (0.6 mL) was treated with LiOH (0.118 mL, 0.236 mmol) and stirred at 50° C. for 2 hours. Additional LiOH (300 uL) was added and the reaction was stirred at 50° C. for 4 h, and then cooled to rt overnight. The mixture was concentrated and purified with reverse phase chromatography (20-100% MeCN/H2O-0.1% TFA, 12 min) to afford [7-(aminocarbonyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetic acid (9.6 mg, 0.022 mmol, 56.0% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.02 (s, 1 H), 8.22-8.10 (m, 1 H), 7.39-7.28 (m, 4 H), 7.25-7.15 (m, 1 H), 7.09-6.99 (m, 1 H), 5.39 (d, J=1.2 Hz, 1 H), 3.76 (s, 3 H), 2.38 (s, 3 H), 2.33 (s, 3 H), 1.08 (s, 4.5 H), 1.06 (s, 4.5 H); LCMS (m/z) ES+=437 (M+1).
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](C(O)=O)=[CH:31]2.CCN=C=NCCCN(C)C.Cl.CCOC(C)=O.O(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:25][CH2:24][CH:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:16]=2[N:8]([C:6]([C:32]2[NH:33][C:34]3[C:30]([CH:31]=2)=[CH:29][C:28]([O:27][CH3:26])=[CH:36][CH:35]=3)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)cc2c1
Yield: 75.5 %

Procedure:
Deprotection of 13 (260 mg, 0.72 mmol) as in Example C, and reaction with 5-methoxyindole-2-carboxylic acid (145 mg, 0.76 mmol) and EDCI.HCl (344 mg, 1.80 mmol) in DMA (3 mL) gave 14d (237 mg, 76%), mp (2×EtOAc/iPr2O) 241-243° C. 1H NMR [(CD3)2SO] δ 11.73 (d, J=1.3 Hz, 1 H, NH), 9.16 (s, 1 H, H-4), 8.35 (dd, J=7.2, 2.5 Hz, 1 H, H-6), 8.23 (dd, J=6.9, 2.4 Hz, 1 H, H-9), 7.79-7.70 (m, 2 H, H-7,8), 7.42 (d, J=8.9 Hz, 1 H, H-7'), 7.20 (d, J=1.9 Hz, 1 H, H-3'), 7.17 (d, J=2.4 Hz, 1 H, H-4'), 6.94 (dd, J=9.0, 2.4 Hz, 1 H, H-6'), 4.93 (dd, J=10.6, 9.2 Hz, 1 H, H-2), 4.70 (dd, J=10.9, 2.4 Hz, 1 H, H-2), 4.65-4.57 (m, 1 H, H-1), 4.18-4.07 (m, 2 H, CH2Cl), 3.79 (s, 3 H, OCH3).
Reaction SMILES: [CH2:1]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:13][CH:14]([C:20]([CH3:22])=O)[C:15](OCC)=[O:16]>C1C=CC=CC=1>[OH:16][C:15]1[C:8]2[C:9](=[CH:11][CH:12]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:7]=2)[N:10]=[C:20]([CH3:22])[C:14]=1[CH3:13]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CCCCCc1ccc(N)cc1
Solvent: c1ccccc1
Product: CCCCCc1ccc2nc(C)c(C)c(O)c2c1
Yield: 42 %

Procedure:
1.63 Grams of 4-n-pentylaniline and 1.44 g of ethyl 2-methylacetoacetate were refluxed in benzene in the presence of a Lewis acid catalyst for 3 hours. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution and a saturated brine and dried over-anhydrous sodium sulfate. After the solvent was evaporated, the resultant intermediate was refluxed in diphenyl ether for 30 minutes and allowed to cool to produce precipitates, which were collected by filtration under reduced pressure to obtain 1.01 g of 4-hydroxy-2,3-dimethyl-6-n-pentyl-quinoline (yield 42%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1.Cl>CN(C)C=O.O>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[N:16]([CH2:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2
Reaction time: 18 h

Procedure:
To a solution of 0.05 mole of (cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (starting compound A12) and 0.15 mole of sodium hydride in 100 ml of dimethylformamide is stirred at RT for 30 min, after which 0.05 mole of 4-chloromethylbenzoic acid is added. This mixture is left stirring for 18 h, after which it is poured into water. This solution is acidified with hydrochloric acid and subsequently extracted with dichloromethane. The organic solution is dried over magnesium sulfate and evaporated. The compound is crystallized from diethyl ether.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1>>[NH2:32][C:18]1[N:19]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:29]3)=[CH:24][CH:23]=2)[CH:21]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]2)[N:17]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Product: CC(C)OC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared from isopropyl chloroformate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=411.4.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[OH:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30](Br)[CH:31]=[CH2:32].[OH-].[K+]>C(O)C>[CH2:32]([O:23][C:20]1[CH:19]=[CH:18][C:17]([CH:15]([OH:16])[CH2:14][N:11]2[CH2:10][CH2:9][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][CH2:12]2)=[CH:22][CH:21]=1)[CH:31]=[CH2:30]
Reactant: Oc1ccc(C(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOc1ccc(C(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 63.7 %

Procedure:
In 1.2 liters of ethanol were dissolved 120 g (0.31 mol) of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)-ethanol, 74.8 g (0.62 mol) of allyl bromide and 41 g of potassium hydroxide. The resultant solution was heated with refluxing for one hour. After cooling the solution and then removing the solvent, the residue was added with 1.0 liter of ethyl acetate. The resultant mixture was washed successively with an aqueous 1N solution of sodium hydroxide, water and saturated saline, followed by drying over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized from a mixed solvent of ethanol and n-hexane to give 84.6 g of 1-(4-allyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol (yield: 64%).