Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[NH:24][CH:23]=[CH:22]5)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:30]I>CN(C=O)C.ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([O:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([CH3:30])[CH:23]=[CH:22]5)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CI
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc3[nH]ccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccc2cc(OC3CN(C(=O)N4CCCN(C5CCC5)CC4)C3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a stirred solution of 5-({1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}oxy)-1H-indole (30 mg, 81 μmol) in DMF (2 ml) was added NaH (4 mg of a 60% dispersion in mineral oil, 97 μmol) at room temperature in one portion. The suspension was stirred for 30 min at room temperature under a nitrogen atmosphere then cooled to 0° C. and MeI (6 μl, 97 μmol) was added. The reaction was allowed to warm to room temperature and stirred for 16 hours then diluted with dichloromethane (30 ml) and washed twice with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to provide the title compound (23 mg, 74%) as light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]4)[CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl>CO.CCOCC>[NH:18]1[CH2:17][CH:16]([N:14]2[CH:15]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH:12]=[N:13]2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(-c3c[nH]c4cc(F)ccc34)cn2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1ccc2c(-c3cnn(C4CNC4)c3)c[nH]c2c1
Reaction time: 3 h
Yield: 17.5 %

Procedure:
To a solution of tert-butyl 3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Step 1; 220 mg; 0.62 mmol) in MeOH (10 mL) was added saturated HCl in Et2O (5 mL). The mixture was stirred for 3 h, concentrated, and purified by preparative HPLC to afford 27.8 mg (18%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][CH2:21][NH:22][CH3:23])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[C:25]([OH:29])(=O)[CH2:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[OH:24])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:19][CH2:20][CH2:21][N:22]([CH3:23])[C:25](=[O:29])[CH2:26][OH:27])[N:12]=[CH:11][N:10]=1
Reactant: O=C(O)CO
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: CN(CCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)C(=O)CO
Yield: 58 %

Procedure:
2-Chloro-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol was reacted with glycolic acid using an analogous procedure to that described in Example 3 to give N-[2-({4-[3-Chloro-4-hydroxyanilino]quinazolin-5-yl}oxy)ethyl]-2-hydroxy-N-methylacetamide in 58% yield; NMR spectrum (DMSO-d6) 2.96 (s, 3H), 3.90 (t, 2H), 4.05 (m, 3H), 4.41 (t, 2H), 6.97 (d, 1H), 7.14 (d, 1H), 7.34 (m, 2H), 7.70 (t, 1H), 7.79 (d, 1H), 8.40 (s, 1H), 9.64 (s, 1H), 10.00 (bs, 1H); Mass spectrum MH+ 403.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([C:15]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([C:15]1([C:18]([O:20][CH3:26])=[O:19])[CH2:16][CH2:17]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(C(=O)C2(C(=O)O)CC2)cc1CNC(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1(C(=O)c2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)CC1
Reaction time: 0.5 h

Procedure:
Under a solution of 1.069 g of 1-(3-{[(t-butoxycarbonyl)amino]methyl}-4-methoxybenzoyl)-1-cyclopropanecarboxylic acid in 10 ml of methanol was added 8 ml of trimethylsilyldiazomethane (2N solution in hexane). After stirring for 30 minutes, the solution was treated with acetic acid until its color faded, and then concentrated. The residue was purified by silica gel column chromatography, to give 0.974 g of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.Cl>N1C=CC=CC=1.CCOCC>[C:11]([N:1]1[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(c1ccccc1)N1CCCC2CC=CC=C21
Yield: 74.7 %

Procedure:
To a solution of 26.6 g (0.02 m) of tetrahydroquinoline in 50 ml of pyridine, cooled to 0° C., there were added 28.1 g (0.02 m) of benzoyl chloride dropwise and with stirring at a rate such the temperature was kept below -5° C. After addition was complete, the mixture was stirred at room temperature for 1 hour and then poured into a separatory funnel containing 500 ml of water and 50 ml of conc. hydrochloric acid. Ethyl ether (300 ml) was added to the funnel and the mixture shaken until all of the precipitated oil had dissolved in the ether. After washing with water, the ether layer was filtered through anhydrous calcium sulfate and evaporated to a volume of about 150 ml. Petroleum ether (100 ml) was added to the solution which was then cooled in a refrigerator to give 35.7 g (75% yield) of 1-benzoyltetrahydroquinoline as colorless crystals, m.p. 80°-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].Br[CH2:12][C:13](=O)[C:14]([CH3:17])([CH3:16])[CH3:15].Cl.O>C(O)C>[C:14]([C:13]1[NH:6][C:5]2[C:7]([CH:12]=1)=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=2)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cc(N)ccc1Cl
Reactant: CC(C)(C)C(=O)CBr
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc2[nH]c(C(C)(C)C)cc2cc1Cl

Procedure:
A solution of 4-chloro-3-methoxyaniline (4.68 g) in ethanol (4.5 mL) was heated under reflux while stirring. To the solution was added 1-bromo-3,3-dimethyl-2-butanone (0.243 mL×5) in five portions at an interval of 5 minutes, and this mixture was heated under reflux while stirring for 4 hours. The reaction mixture was left to be cooled. To the reaction mixture were added 2 mol/L hydrochloric acid and water successively, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (893 mg). 1H-NMR (CDCl3) δ ppm: 1.37 (9H, s), 3.89 (3H, s), 6.09-6.16 (1H, m), 6.88 (1H, s), 7.50 (1H, s), 7.72-8.12 (1H, br).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:32])[CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)[C:10]2[CH:33]=[CH:34][CH:35]=[CH:36][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.ClCCl.C(OC(C)C)(C)C>C(O)C>[NH2:21][CH2:20][C:19]([N:11]1[C@@H:12]2[CH2:18][CH2:17][CH2:16][C@@H:13]2[C:14](=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]1=2)=[O:32]
Reactant: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Yield: 80 %

Procedure:
A suspension of (3aR*,10aS*)-9-benzyl-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (9.82 g, 20 mmol) and hydrazine monohydrate (2.31 g, 46 mmol) in ethanol (200 mL) was refluxed for 3.5 hours. The reaction mixture was cooled, which was subjected to filtration. The filtrate was washed with chloroform, which was concentrated under reduced pressure. The concentrate was suspended in chloroform, which was again subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was crystallized from dichloromethane-hexane to give 5.62 g (yield 80%). The sample for analytical experiment was prepared by recrystallization from dichloromethane-diisopropylether. m.p. 163°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:28]=[CH:29][C:30]=2[CH3:31])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:28]=[CH:29][C:30]=4[CH3:31])[CH2:21][CH2:20]3)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CCC2)CC1

Procedure:
Example 86 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H, J=1.6 Hz), 7.34 (s, 4H), 7.28–7.23 (m, 2H), 7.10 (d, 1 H, J=8.4 Hz), 6.45 (br s, 1H), 3.31 (dd, 2H, J=5.6, 11.6 Hz), 2.95 (d, 2H, J=11.6 Hz), 2.88–2.81 (m, 2H), 2.68 (m, 1H), 2.54–2.44 (m, 3H), 2.33 (t, 2H, J=6.4 Hz), 2.29 (s, 3H), 2.11–1.90 (m, 4H), 1.76–1.63 (m, 6H), 1.26 (d, 6H, J=7.2 Hz); ESMS m/e: 510.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]1.[CH3:16][C:17]([CH3:19])=O.ClCCl.[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-].C([BH3-])#N.[Na+].[Cl-].[Zn+2].[Cl-].C([BH3-])#N>[CH3:16][CH:17]([NH:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1)[CH3:19]
Reactant: CC(C)=O
Reactant: NCCN1CCN(c2ncccn2)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)NCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamine (2.46 g, 0.012 mol) in methanol (45 mL) was added acetone (0.9 mL, 0.012 mol) and zinc chloride/sodium cyanoborohydride solution in dichloromethane (24 mL, containing 0.006 mol zinc chloride and 0.012 mol sodium cyanoborohydride) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, and then an additional portion of the zinc chloride/cyanoborohydride solution (2 mL) was added. The mixture was then stirred at room temperature for 2 days. To the reaction mixture was added 1M aqueous sodium hydroxide solution (18 mL). The methanol was removed on a rotary evaporator, and the residue was partitioned between dichloromethane (100 mL) and brine solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. The desired intermediate, N-(1-methylethyl)-2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamine (TLC on silica gel using 30% methanol in ethyl acetate, Rf=0.31 ), was isolated as a colorless oil by chromatography of 250 gm of silica gel using 30% methanol/ethyl acetate as the eluant (1.28 g, 50% yield).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Br.O>[OH2:11].[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncccc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncccc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of 9.6 g (63 mMol) of 2-mercaptobenzimidazole and 7.7 g (62 mMol) of 3-hydroxymethyl-2-pyridinamine was dissolved in 60 ml of 48% aqueous hydrobromic acid and 60 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water and made alkaline with potassium carbonate. The oil that separated solidified upon addition of diethyl ether to the aqueous mixture. The solid was collected by filtration, washed with portions of diethyl ether and water, and air dried to yield 12.4 g of the title compound as an analytically pure hemihydrate. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis. Anal. Calc'd. for C13H12N4S*1/2 H2 0: C,58.84; H, 4.93; N, 21.11; S, 12.08. Found: C, 59.06; H, 4.48; N, 20.82; S, 12.16.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[CH3:16][C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=1.C(OCC)(=O)CCC(C)=O.O.NN.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:21]1[C:20](=[O:23])[CH:19]=[CH:18][C:17]([CH3:16])=[N:22]1)#[N:2]
Reactant: Cc1ccc(=O)[nH]n1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: CCOC(=O)CCC(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: NN
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(=O)n([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)n1
Reaction time: 48 h
Yield: 38.8 %

Procedure:
A mixture is prepared which contains 1 g of 6-cyano-2,2-dimethyl-3,4-epoxychromane and 1.1 g of 6-methylpyridazin-3-one (prepared by the method described in J. Chem. Soc., 1947, p. 241, by reacting ethyl levulinate with hydrazine hydrate) in 10 ml of dioxane containing 0.1 ml of a 35% methanolic solution of benzyltrimethylammonium hydroxide. After 2 days at room temperature, the mixture is diluted with water and filtered, the material on the filter is dissolved in ethyl acetate, the water is then decanted and the organic phase is dried and concentrated. After recrystallization from an ethyl acetate/isopropyl ether mixture, 0.6 g of the expected product is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12](Br)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:28][CH2:29][CH2:30][CH3:31].[Na+]>>[CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12]([O:28][CH2:29][CH2:30][CH3:31])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2Br
Reactant: CCC[O-]
Agent: [Na+]
Product: CCCOc1c2c(nc3c1cnn3Cc1ccccc1)C(=O)c1ccccc1CC2

Procedure:
By treating the product of Example 11 according to the procedure of Example 3, replacing the sodium ethoxide with sodium propoxide, 1-benzyl-4-propoxy-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)one is obtained.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([OH:27])=[O:26])=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].[N+](=[CH2:33])=[N-]>ClCCl.C(OCC)C>[CH3:33][O:26][C:25](=[O:27])[CH2:24][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:10]([CH2:9][C:8]2[CH:28]=[CH:29][CH:30]=[C:6]([O:5][CH:1]([CH2:3][CH3:4])[CH3:2])[CH:7]=2)=[N:11][CH:12]=1
Reactant: C=[N+]=[N-]
Reactant: CCC(C)Oc1cccc(Cc2ncc(CC(=O)O)c3cc(OC)c(OC)cc23)c1
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(C)Oc1cccc(Cc2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid (200 mg, 0.49 mmol) in dichloromethane (4 Ml) was added 0.2N diazomethane in diethyl ether solution (6 mL). The reaction mixture was stirred at room temperature for 15 hrs. The solvent was evaporated to afford of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester (200 mg, 96% yield) as a light yellow oil. The crude product was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[C:22]([Cl:24])[CH:23]=1>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Clc1cc(Cl)cc([Mg]Br)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2cc(Cl)cc(Cl)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 0.5 M 3,5-dichlorophenylmagnesium bromide in THF (0.6 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(3,5-dichloro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [CH:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:10]>CO>[CH:1]1([S:6]([NH2:10])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: N
Solvent: CO
Product: NS(=O)(=O)C1CCCC1
Yield: 66 %

Procedure:
According to Reference Example 9-7, by use of cyclopentanesulfonyl chloride (300 mg, 1.8 mmol) and a 7 mol/L solution of ammonia in methanol (2 mL), the mixture was stirred and reacted at room temperature for 4 hours. After slurry purification using chloroform, purification by silica gel column chromatography (chloroform/methanol=1/0 to 20/1) was performed to give cyclopentanesulfonamide (Compound FP) (173 mg, yield: 66%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([NH:25][C:26]3[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=3)[N:17]=[C:18]2[O:21][CH:22]([CH3:24])[CH3:23])=[CH:13][C:12]=1[O:32][CH3:33]>>[CH:22]([O:21][C:18]1[C:19]2[C:14](=[CH:13][C:12]([O:32][CH3:33])=[C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:20]=2)[CH:15]=[C:16]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:17]=1)([CH3:24])[CH3:23]
Reactant: OCCN1CCCCC1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1F
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1OCCN1CCCCC1

Procedure:
Similar procedure as described in example 378 was used, starting from 2-Piperidin-1-yl-ethanol and (7-Fluoro-1-isopropoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-Isopropoxy-6-methoxy-7-(2-piperidin-1-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 440(MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C(Cl)Cl>[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27]([NH:1][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of 1.5 g of methyl 6-aminopyridine-3-carboxylate in 100 ml of methylene chloride is added 3 ml of N,N-diisopropylethylamine at room temperature. To the stirred reaction mixture is slowly added a solution of 2.5 g of [1,1'-biphenyl]-2-carbonyl chloride. The reaction mixture is stirred at room temperature for 4 hours and then quenched with water. The organic layer is washed well with water and dried over anhydrous MgSO4, filtered and evaporated in vacuo to a solid residue. The residue is stirred with ether, filtered and dried to give 3.0 g of the desired product:M+ =332.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(S(C)(=O)=O)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)nc1
Temperature: 25 °C

Procedure:
Into a round-bottom flask were charged methyl 3-(5-methylpyridin-2-yl)-5-(methylsulfonyl)benzoate (0.60 g, 1.96 mmol), barium hydroxide octahydrate (1.23 g, 3.90 mmol) and methanol (50 mL). The mixture was stirred at room temperature until the completion of the reaction. The mixture was acidified with HCl (2M ethyl ether solution, 20 mL). The mixture was concentrated to afford a mixture of the desired product and BaCl2 as a white solid (1.4 g, 40% purity). LC-MS: 291.5 [M+1]; 1H NMR (400 MHz, DMSO-d6): 8.90 (s, 1H), 8.80 (d, J=1.7 Hz, 1H), 8.63 (s, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.64-7.55 (m, 1H), 3.38 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1>>[C:8]1([C:6]2[N:5]=[C:4]3[CH2:14][CH2:15][CH2:16][C:3]3=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=3)[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(C2=CCCCC2)nc2c1CCC2
Product: CCOC(=O)Cc1ccc(Nc2cc(C3=CCCCC3)nc3c2CCC3)cc1
Yield: 38.3 %

Procedure:
Following general procedure B1, 4-chloro-2-(cyclohex-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (1.03 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.150 g, 0.84 mmol) to afford the title compound (0.121 g, 31% over two steps) as an orange oil. MW=376.49. APCI MS m/z 377 [M+H]+.
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[O:18]=[O+][O-].O=O>ClCCl.CO>[N:16]1[C:17]2[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: C(=C1CCCc2cccnc21)c1ccccc1
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CO
Solvent: ClCCl
Product: O=C1CCCc2cccnc21
Temperature: 0 °C

Procedure:
A solution of (2) in dichloromethane (100 mL) and methanol (500 mL) was cooled to −78° C. and charged with ozone/oxygen (3 psi, 1.5 ampere). The dark brown solution turned yellow after several hours. When (2) was consumed (TLC), ozone/oxygen flow was stopped. The reaction mixture was purged with nitrogen for 10 m. Methyl sulfide (6 mL) was added, and the mixture was stirred for 30 m at 0° C. The solvents were removed under vacuum and the residue was dissolved in 1 N HCl (500 mL) and washed with diethyl ether (4×150 mL). The aqueous layer was basified to pH ˜7 with NaOH (s), and extracted with ethyl acetate (2×200 mL). The pooled ethyl acetate layers were dried over magnesium sulfate. The mixture was filtered and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 90% EtOAc 10% hexane to give 6,7-Dihydro-5H-quinolin-8-one (3) as a solid. The aqueous layer was extracted with chloroform/isopropanol (3:1) several times. The pooled chloroform/isopropanol layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum to give (3). The combined weight of (3) was 17.9 g (122 mmol, 89% over 2 steps).