Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:26][CH3:27])[CH2:4][N:5]1[C:14]2[C:9](=[C:10](OS(C(F)(F)F)(=O)=O)[CH:11]=[CH:12][CH:13]=2)[C:8](=[O:23])[N:7]([CH3:24])[C:6]1=[O:25])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1OB(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:23])[N:7]([CH3:24])[C:6](=[O:25])[N:5]2[CH2:4][CH:3]([CH2:26][CH3:27])[CH2:1][CH3:2]
Reactant: CCC(CC)Cn1c(=O)n(C)c(=O)c2c(OS(=O)(=O)C(F)(F)F)cccc21
Reactant: Cc1ccc(OB(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)Cn1c(=O)n(C)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
To a mixture of [1-(2-ethylbutyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl]-trifluoromethanesulfonate (29 mg, 0.071 mmol), 2,4-dimethylphenylboroic acid (21 mg, 0.14 mmol) and potassium carbonate (20 mg, 0.14 mmol) and toluene (2 ml) was added of tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.036 mmol). The mixture was stirred at 90° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution in water, 10% citric acid solution in water and brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified by column chromatography eluting with 5% ethyl acetate/n-hexane to afford 11 mg (41%) the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:22][C:21]1[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1C#Cc1c(-c2ccccc2)noc1C
Yield: 66 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-3-methylpyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 91 mg, 66%) which was obtained as a light yellow solid. MS: m/e=275.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:34]=[CH:33][S:32][CH:31]=1>CN(C=O)C.[Cu]>[CH:18]1([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:30]4[CH:34]=[CH:33][S:32][CH:31]=4)=[CH:15][CH:16]=3)=[N:9]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2C1CCCC1
Reactant: Brc1ccsc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccsc3)cc1)nn2C1CCCC1
Temperature: 153 °C
Yield: 22.3 %

Procedure:
A mixture of 4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol (0.212 g, 0.718 mmol, 1 equiv), potassium carbonate (0.060 g, 0.43 mmol, 0.6 equiv), copper powder (0.015 g, 0.24 mmol, 0.33 equiv), and 3-bromothiophene (0.09 mL, 0.9 mmol, 1.3 equiv) in DMF (7.2 mL) was heated at 153° C. for 24 hr. The reaction mixture was allowed to cool to ambient temperature, concentrated, and the residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give 1-cyclopentyl-3-[4-(3-thienyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a light brown solid (0.060 g, 0.16 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 9.77 (1H, s), 8.46 (1H, s), 8.41 (1H, s), 7.73-7.74 (1H, m), 7.57 (2H, d, J=4.5 Hz), 7.46-7.48 (1H, m), 7.15 (1H, d, J=5.2 Hz), 6.96 (2H, d, J=8.6 Hz), 5.24-5.30 (1H, m), 2.03-2.05 (4H, m), 1.89-1.93 (2H, m), 1.70-1.72 (2H, m). RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 18.76 min. MS: MH+ 378.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:25][N:26](C)C)[C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=O.[NH2:29]N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:11]2[S:24][C:14]3[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[O:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)=[N:29][NH:26][CH:25]=1
Reactant: CN(C)C=C(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Reactant: NN
Solvent: CO
Product: Clc1ccccc1-c1c[nH]nc1-c1cc2c(s1)-c1ccccc1OCC2

Procedure:
2-(2-Chlorophenyl)-1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-3-(dimethylamino)prop-2-en-1-one was treated with hydrazine in methanol to give 283. MS (ESI) 379.1
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH:5]=[CH:6]2)=O.[C:11]([CH2:13]C(O)=O)#[N:12].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:11]([CH2:13][CH:1]=[C:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH:5]=[CH:6]2)#[N:12]
Reactant: CC1C2C=CC(C2)C1C=O
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC1C(=CCC#N)C2C=CC1C2
Yield: 75.4 %

Procedure:
A stirred solution of 136 g (1.0 mole) of 2-formyl-3-methylbicyclo[2.2.1]hept-5ene, 91 g (1.05 mol) of cyanoacetic acid, 3 g (0.05 mol) of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml of benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the carbon dioxide evolution ceased (approx. 31 hrs). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 120 g (75.5% yield) of 2(2-cyanoethylidene)-3-methylbicyclo[2.2.1]hept-5-ene: b.p. 70-80° C/1 mm; nD20 1.5080; ir 3060, 2250, 1460, 1380, 760, 740, 726, 700; nmr 1.15 (3H, d, J=7 Hz, methyl), 4.9-5.5 (1H, m, vinyl H), 5.7-6.1 (2H; m, vinyl H); ms 159.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]#[CH:14])([CH3:4])([CH3:3])[CH3:2].[Cl:15]C1CC(=O)NC1=O>CC(C)=O.C([O-])(=O)C.[Ag+]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]#[C:14][Cl:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CC(Cl)C(=O)N1
Reactant: C#CCOc1ccccc1C(C)(C)C
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccccc1OCC#CCl

Procedure:
To a solution of Example 5A (18.86 g, 100 mmol) in acetone (400 mL) was added N chlorosuccinimide (16.02 g, 120 mmol) and silver acetate (1.67 g, 10 mmol) and the mixture was heated at reflux for 4 hours. After cooling, the silver salts were removed by filtration and the filtrate evaporated under reduced pressure. The residue was taken up in diethyl ether, washed with water and saturated aqueous sodium bicarbonate, dried with magnesium sulfate, filtered, and the solvent was removed under reduced pressure to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H), 4.73 (s, 2H), 6.91-6.97 (m, 2H), 7.19 (td, J=7.71, 1.86 Hz, 1H), 7.30 (dd, J=7.97, 1.53 Hz, 1H). MS (DCI) m/z 223 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH:4]1[CH2:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5]1.O1CCCC1.Cl>[Zn].O>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]1
Reactant: CC(C)(C)CC1C=C(C(=O)O)C1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CC1CC(C(=O)O)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
3-(2,2-dimethylpropyl)-1-cyclobutenecarboxylic acid (10 g), tetrahydrofuran (100 mL) and 6 N hydrochloric acid (100 mL) were mixed. To the mixture was added zinc (30 g) at ice temperature. The mixture was stirred at 70° C. overnight. After an addition of 6 N hydrochloric acid and water the mixture was filtered. The filtrate was extracted with ethyl acetate (150 mL, 100 mL). The organic layer was washed with brine (100 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (11.6 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
400 mg (1.3 mmol) of [4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 10 ml of DMF. 59 mg (1.4 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 380 mg (2.0 mmol) of t-butyl bromoacetate was added to the obtained mixture, and they were stirred at room temperature for 4 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the crude product was obtained. The crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)ccc1Br
Reactant: Cc1cncc(N)c1
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cncc(C)c1

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 3-Amino-5-methylpyridine was performed in accordance with the general method of Example 78, step 3 to yield the title compound as a light brown solid, MS (ISP): m/e=272.3 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:4]=2[O:3]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl>[Br:25][CH2:11][C:10]1[C:4]2[O:3][C:2]([F:1])([F:12])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c1OC(F)(F)O2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: FC1(F)Oc2cccc(CBr)c2O1

Procedure:
76 g of 2,2-difluoro-4-methyl-1,3-benzodioxole and 200 mg of Azobisisobutyronitrile are added to a suspension of 90 g of N-bromosuccinimide in 400 ml of methylene chloride. The mixture is then heated under reflux, with stirring, until all the undissolved material floats to the top. After cooling, the succinimide is filtered off with suction and rinsed with carbon tetrachloride and the solution is then distilled in order to separate off the carbon tetrachloride. 117 g of crude benzyl bromide remain in the residue and are employed without purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:25]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][C:19]([C:28]3[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[C:31]([CH3:38])=[CH:30][CH:29]=3)=[C:18]5[CH:17]=[CH:16][C:15]4=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Br:39]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:39][C:21]1[C:22]2[C:27]3=[C:26]4[C:25](=[CH:24][CH:23]=2)[C:12]([C:5]2[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:13][CH:14]=[C:15]4[CH:16]=[CH:17][C:18]3=[C:19]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH3:38])=[CH:30][CH:29]=2)[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)ccc5ccc2c3c54)c2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)cc(Br)c5ccc2c3c54)c2ccccc12
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixed solution of 1.7 g of 1,6-di(4-methylnaphthalen-1-yl)pyrene, 0.54 g of N-bromosuccinimide and 30 ml of dimethylformamide was stirred under a nitrogen gas stream at 60° C. for 6 hours. The solution was cooled to room temperature and 50 ml of water was poured into the solution, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then concentrated by evaporation. The resulting concentrate was recrystallized from toluene and then vacuum-dried at 70° C. to obtain 1.5 g of 1-bromo-3,8-di(4-methylnaphthalen-1-yl)pyrene as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[H-].[Na+]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)CCCCBr
Reactant: Cc1c(N)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A solution of 3-bromo-2-methylaniline (1 g, 5.37 mmol) in DCM (15 mL) was treated with TEA (0.749 mL, 5.37 mmol) and then dropwise with a solution of 5-bromopentanoyl chloride (1.072 g, 5.37 mmol) in DCM (4 mL). The mixture was stirred at rt for 30 min, then was diluted with DCM, washed with water and brine, and dried and concentrated. The residue was dissolved in THF (100 mL) and added to a suspension of sodium hydride (60% oil dispersion, pre-washed with hexane, 0.430 g, 10.75 mmol) in THF (50 mL). The resulting mixture was stirred overnight at rt. The mixture was concentrated and the residue was acidified with 1 M hydrochloric acid. The mixture was extracted with DCM and the organic phase was washed with water, dried and concentrated to give 1-(3-bromo-2-methylphenyl)piperidin-2-one as a tan oil (1.4 g, 97%). 1H NMR (400 MHz, chloroform-d) δ 7.49-7.54 (1H, m), 7.07-7.13 (2H, m), 3.38-3.60 (2H, m), 2.54-2.59 (2H, m), 2.26 (3H, s), 1.91-2.02 (4H, m). Mass spectrum m/z 268, 270 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:25][CH2:26]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Oc2c(Cl)cncc2Cl)s1
Product: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Oc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-((3,5-dichloropyridin-4-yl)oxy)-4-nitrothiophene-2-carboxylic acid (10 mg, 0.03 mmol) from above and 1-isopropylpiperidin-4-amine (17.4 mg, 0.1 mmol). The title compound was obtained as a solid (1.0 mg, 7% yield). MS m/z: 459.01, 461.01 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C:12]([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][CH:40]=1)[C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]=1)=[O:20])=[O:13])([CH3:10])C.[C:41]1([N:47]2CCN[CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:34][O:33][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][C:28]=1[O:31][CH3:32])[C:21]([C:19](=[O:20])[C:18]1[CH:38]=[CH:39][CH:40]=[C:16]([O:15][CH2:14][C:12](=[O:13])[N:11]3[CH2:49][CH2:48][N:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:10][CH2:8]3)[CH:17]=1)=[N:22][CH:23]=[C:24]2[C:35]([OH:37])=[O:36]
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)NC(C)C)c3)c2cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCN(c5ccccc5)CC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropylcarbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.060 ml of N-phenylpiperazine (0.388 mmol). The mixture was shaken for 15 minutes under argon at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 6,7-Dimethoxy-1-{3-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-benzoyl}-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (30 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(C(=O)O)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution 1-[(4-methoxy)phenyl]-3-(ethoxycarbonyl)-5-(methoxycarbonyl)pyrazole (4.0 g, 13.2 mmol) in 40 mL of tetrahydrofuran and 20 mL of water was added an aqueous solution of lithium hydroxide monohydrate (0.55 g, 13.2 mmol). The reaction was allowed to stir at ambient temperature for 1 h. The tetrahydrofuran was removed in vacuo and the aqueous was extracted with ether to remove unreacted diester. The aqueous layer was acidified with HCl and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated to afford 3.2 g (84%) of the title compound, which was used without further purification. LRMS (ES−): 289.0 (M−H)−.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[S:8][N:7]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[S:8]1)=[O:4]
Reactant: CCCCOc1nc(O)ns1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
10 ml of methyl isocyanate were added to a solution of 17.5 g of 3-hydroxy-5-n-butoxy-1,2,4-thiadiazole in 125 ml of tetrahydrofuran containing 0.5 ml of triethylamine and after stirring for 2 hours at 20° C, the mixture was evaporated to dryness. The residue was empasted with isopropyl ether and was vacuum filtered and dried to obtain 21 g of 2-(N-methylcarbamoyl)-5-n-butoxy-1,2,4-thiadiazole-3-one melting at 108° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>C1COCC1>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[N:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Fc1ccnc(F)n1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccnc(F)n2)c(OC)c1
Yield: 100 %

Procedure:
A solution of 2,4-difluoropyrimidine (1.00 g, 8.62 mmol) and 2,4-dimethoxybenzylamine (1.44 g, 8.62 mmol) in THF (28 mL) was stirred at room temperature for 1 hour. The reaction solution was vacuum concentrated, and the residue was purified with silica gel chromatography to yield the title compound (2.27 g, 62%) as a colorless amorphous solid.
Reaction SMILES: [F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[OH:23])[CH2:19][CH2:18][CH2:17]2)[S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6].Br[CH2:26][C:27]1[S:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6])[C:14]1[CH:15]=[C:16]2[C:20]([CH2:19][CH2:18][CH2:17]2)=[CH:21][C:22]=1[O:23][CH2:26][C:27]1[S:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=1
Reactant: CCOC(=O)c1cnc(CBr)s1
Reactant: Cc1csc(S(=O)(=O)N(C[C@H](C)F)c2cc3c(cc2O)CCC3)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(COc2cc3c(cc2N(C[C@H](C)F)S(=O)(=O)c2nc(C)cs2)CCC3)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
137 mg of N-[(2S)-2-fluoropropyl]-N-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,3-thiazole-2-sulfonamide was dissolved in 1.05 mL of DMF, and 139 mg of ethyl 2-(bromomethyl)-1,3-thiazole-5-carboxylate and 102 mg of potassium carbonate were added thereto, followed by stirring at room temperature for 2 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 154 mg of ethyl 2-{[(6-{[(2S)-2-fluoropropyl][(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]CC4C=CC=CC=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][N:37]3[CH3:42])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][N:37]3[CH3:42])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCCC1CCOc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CN1CCCCC1CCOc1ccc(CC2c3ccc(O)cc3CCN2c2ccc(F)cc2)cc1
Yield: 13.9 %

Procedure:
The title compound was prepared as described in Example 44. G, using 2-(4-fluorophenyl)-1-(4-[2-(1-methyl(2-piperidyl))ethoxy]benzyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.043 g, 0.076 mmol). The product was purified by radial chromatography (100% CH2Cl2, then CH2Cl2/MeOH, 95:5) to yield the title compound (0.005 g, 14% yield): ES-MS (m/z) 475 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[S:14][C:15]([F:18])([F:17])[F:16].Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[OH-].[Na+]>>[F:17][C:15]([F:18])([F:16])[S:14][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[O:1][CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1ccc(O)c(SC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(SC(F)(F)F)c1

Procedure:
In analogy to the procedure of Example XIV, the title compound is prepared from 10 g (0.036 mol) of ethyl 4-hydroxy-3-trifluoromethylthiophenylacetate, 7.7 g (0.036 mol) of 2-chloromethylquinoline and 2.88 g (0.072 mol) of sodium hydroxide.