Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH:3]([CH:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.S(Cl)(C)(=O)=O>>[OH:2][CH:3]([CH:9]1[O:14][CH2:13][CH2:12][N:11]([C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=2)[CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C(O)C1CNCCO1
Agent: CS(=O)(=O)Cl
Agent: Cl
Product: CCOC(=O)C(O)C1CN(C(=O)c2ccc(C)cc2)CCO1
Yield: 31.2 %

Procedure:
According to the Step 28-1 in synthetic method for EXAMPLE 28, compound 115-3 (0.2 g) and 4-methylbenzoyl chloride (164 mg) were used instead of 26-5 and mesyl chloride to obtain compound 115-4 (85 mg) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:19](=[O:21])[NH2:20])[NH:11][C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:19](=[O:21])[NH2:20])[N:11]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c3cccc(C(N)=O)c3c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 78 mg of [5-carbamoyl-1-chlorocarbazol-4-yl]oxyacetic acid methyl ester in 0.8 ml of dry dimethylformamide was added to 10 mg sodium hydride (60% in mineral oil) in 0.2 ml of dimethylformamide and stirred for 15 minutes. Benzyl bromide (0.031 ml) was then added and the reaction was stirred overnight. The reaction mixture was poured into water and acidified with 1 ml of 1 N HCl solution and extracted twice with ethyl acetate. The extracts were washed with water (3×) and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with methanol/0-2% in dichloromethane to afford 40 mg of the subtitle compound. ESIMS m/e 423 (M++1) 425 (M++3) NMR (300 MHz, CDCl3): δ7.43-7.22 (m, 7H); 7.06 (d, J=7.3, 2H); 6.51 (d, J=8.6, 1H); 6.05 (s, 2H); 5.80 (br, 2H); 4.88 (s, 2H); 3.83 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11]COC)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl>C1COCC1.O>[OH:11][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[N:10][CH:9]=1
Reactant: COCOc1cnc(OC)cc1C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=O)c(O)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 0.05 mol) in THF (100 mL) was added 3 N HCl (150 mL). The reaction was stirred at 50° C. for 30 min, cooled to rt, and diluted with water (100 mL). The mixture was neutralized to pH 7-8 and extracted with EtOAc (200 mL) three times. The organic layer was dried over Na2SO4 and concentrated to give 5-hydroxy-2-methoxyisonicotinaldehyde (4.2 g, 55%) as a yellow solid. 1H NMR (400 MHz; DMSO) δ=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19]([Cl:26])[C:18]=1[CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]([Si:44](Cl)([CH3:46])[CH3:45])([CH3:43])([CH3:42])[CH3:41].Cl>C(Cl)Cl>[Si:44]([O:30][CH2:29][CH:28]([OH:31])[CH2:27][C:18]1[C:19]([Cl:26])=[N:20][C:21]2[N:22]([N:23]=[CH:24][CH:25]=2)[C:17]=1[N:7]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1)[C:6](=[O:32])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(O)CO)c(Cl)nc3ccnn23)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(O)CO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To a methylene chloride (3.6 mL) solution containing tert-butyl[5-chloro-6-(2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (500 mg, 1.08 mmol), triethylamine (300 μL, 2.16 mmol), tert-butylchlorodimethylsilane (195 mg, 1.30 mmol) and N,N-dimethylpyridine (13 mg, 0.108 mmol) were added. After the reaction mixture was stirred at room temperature for 5 hr, 1 mol/L hydrochloric acid was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography to obtain the title compound (503 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[S:15][C:14]([N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:13][N:12]=3)[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:45].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[NH:4][C:3](=[O:45])[N:2]([CH3:1])[C:6]=3[CH:7]=2)=[N:12][N:13]=1
Reactant: Cn1c(=O)[nH]c2ccc(-c3nnc(N(C[C@H](Cc4ccc(C(F)(F)F)cc4)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)[nH]c2ccc(-c3nnc(NC[C@@H](N)Cc4ccc(C(F)(F)F)cc4)s3)cc21
Yield: 74.3 %

Procedure:
tert-Butyl (S)-1-(5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.36 g, 0.6 mmol) in 20 mL DCM was treated with TFA (20 mL, 260 mmol) for 30 minutes. After removing the solvent, the remaining residue was dissolved in 100 mL EtOAc. The resulting solution was washed with a mixture of aqueous saturated sodium bicarbonate and 5% 5N NaOH, and then twice with saturated sodium bicarbonate. After removing the solvent, a tan solid was obtained as the pure product 6-(5-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-1,3,4-thiadiazol-2-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (0.2 g, 79% yield). LCMS (API-ES) m/z (%): 449.1 (100%, M++H); 1H NMR (400 MHz, CDCl3) δ ppm 2.72 (b, 3H), 2.97 (dd, J=13.2, 7.7 Hz, 1H) 3.27 (dd, J=13.2, 7.7 Hz, 1H) 3.36-3.46 (m, 5H) 3.56 (m, 1H) 7.03 (d, J=8.22 Hz, 1H) 7.32-7.37 (m, 3H) 7.49 (s, 1H) 7.57 (d, J=7.82 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH:8]([CH3:9])[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4][N:3]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:9][CH:8]1[CH:2]([CH3:1])[N:3]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:4][CH2:5][NH:6][CH2:7]1
Reactant: CC1CN(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1CNCCN(C(=O)OC(C)(C)C)C1C

Procedure:
To a solution of 1-3 (3.3 g, 9.1 mmol) in ethyl acetate (45 mL) was added 20% palladium hydroxide on carbon (256 mg) and the reaction was stirred at room temperature under balloon pressure of hydrogen gas overnight. The reaction was filtered through celite and concentrated in vacuo to afford 1-4.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:22]=[C:23]([C:29]2[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([CH3:38])[C:30]=2[CH3:39])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(O)C>C1(C)C=CC=CC=1>[CH3:28][O:27][C:26]1[C:25]([C:8]2[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH2:1])=[CH:6][CH:7]=2)=[CH:24][C:23]([C:29]2[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([CH3:38])[C:30]=2[CH3:39])=[CH:22][CH:21]=1
Reactant: COC(=O)c1sc(-c2ccc(OC)c(Br)c2)c(C)c1C
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)c(C)c1C
Temperature: 97.5 °C
Yield: 21.9 %

Procedure:
4-aminosulfonylbenzene boronic acid (0.54 g, 2.68 mmol) and potassium carbonate (0.67 g, 4.86 mmol) were added to the solution of methyl 5-(3-bromo-4-methoxyphenyl)-3,4-dimethylthiophene-2-carboxylate (step-4, 0.9 g, 2.43 mmol) in a mixture of toluene:ethanol (5:20 ml) in a tube at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0) palladium (0.14 g, 0.12 mmol) was added to the reaction mixture under nitrogen atmosphere and tube was sealed. The reaction mixture was heated at 95-100° C. for 1 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The celite cake was washed with ethyl acetate (30 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product. The crude product so obtained was purified by column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound 9e (0.23 g, 21.2%).
Reaction SMILES: COC1C=CC=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[F:34].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH3:35])=[S:47])=[CH:29][C:28]=1[F:34]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: COc1ccccc1C(=O)Cl
Agent: COc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4OC)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 80%).
Reaction SMILES: O1CCOCC1.Cl[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na].[CH3:22][S:23]([N:26]1[CH2:30][C@H:29](OS(C)(=O)=O)[CH2:28][C@H:27]1[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=[O:25])=[O:24]>O1CCCC1>[CH3:22][S:23]([N:26]1[CH2:30][C@@H:29]([P:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:28][C@H:27]1[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])(=[O:24])=[O:25]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1S(C)(=O)=O
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](P(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To 150 ml of dioxane were added 11.39 g (0.052 mol) of chlorodiphenylphosphine and 2.6 g (0.114 mol) of sodium, and the mixture was refluxed for 4 hours in nitrogen atmosphere. After allowing the mixture to stand for cooling, 50 ml of tetrahydrofuran was added to the reaction mixture, and a solution of 10.45 g (0.027 mol) of (2S,4R)-N-methanesulfonyl-2-tert-butyldimethylsilyloxymethyl-4-methanesulfonyloxypyrrolidine [V] in 100 ml of tetrahydrofuran was added dropwise to the mixture lest any air should enter in the reaction system. The mixture was stirred in nitrogen atmosphere at 0° C. for 2 hours and then at room temperature overnight and then any insoluble matter was removed, for example, by filtration. The filtrate was concentrated until dryness under reduced pressure and the residue was purified by column chromatography on silica gel whereby 7.93 g (yield: 62%) of an oily substance was obtained.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=3)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cn1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added 2-methoxy-5-pyridinboronic acid 63 mg, sodium carbonate 72 mg and polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 8 mg, and it was stirred at 110° C. for 15 hours. After the reaction mixture was cooled to room temperature,2-methoxy-5-pyridinboronic acid 21 mg and polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 8 mg were added to it, and it was stirred at 110° C. for 36 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-fluoroanilino)-4-(2-methoxypyridin-5-yl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][N:36]([CH3:39])[C:35]1=[O:40]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][N:36]([CH3:39])[C:35]4=[O:40])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: CN1CCN(CCCl)C1=O
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(CCN2CCN(C3Cc4cc(Cl)ccc4Sc4ccccc43)CC2)C1=O

Procedure:
8.3 g of 1-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 11.6 g of powdered potassium carbonate, 0.2 g of potassium iodide and 80 ml of toluene, with 8.6 g of β-chloroethyl-3-methyl-2-imidazolidinone and the mixture is heated under reflux for 20 hours. The mixture is then poured into water, the organic phase washed with water, dried over sodium sulphate and evaporated. There is obtained 1-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone as a brown oil. By treatment of this compound with maleic acid in ethanol/ether there is obtained the corresponding maleate which melts at 186°-188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Fc1ccc(CCl)cc1
Product: Oc1ccc(F)cc1Cc1ccc(F)cc1

Procedure:
Alkylation of 4-fluorophenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4′-fluorobenzyl)phenol. This material was converted to compound 77, mp 228-230° C., and compound 78, mp 134.5-139° C., by the procedure similar to that in Example 18 method B.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([O:23]C)=[O:22])=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([OH:23])=[O:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(C(=O)OC)c(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccccc1
Reaction time: 12 h
Yield: 98.7 %

Procedure:
To a solution of 2-benzyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid dimethyl ester (1.75 g) in THF (10 ml) were added methanol (10 ml) and 8N-aqueous sodium hydroxide solution (1 ml) at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and water was added, after which conc. hydrochloric acid (1 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (1.67 g).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[In+3].Cl[SiH](C1C=CC=CC=1)C1C=CC=CC=1.[CH2:19]([N:26]1[CH2:33][CH:32]2[CH:28]([CH:29](O)[C:30]3[CH:36]=[CH:35][S:34][C:31]=32)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClC(Cl)C>[CH2:19]([N:26]1[CH2:33][CH:32]2[CH:28]([CH2:29][C:30]3[CH:36]=[CH:35][S:34][C:31]=32)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC1c2ccsc2C2CN(Cc3ccccc3)CC12
Agent: Cl[SiH](c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [In+3]
Solvent: CC(Cl)Cl
Product: c1ccc(CN2CC3Cc4ccsc4C3C2)cc1
Temperature: 60 °C
Yield: 57 %

Procedure:
Indiumtrichloride (973 mg, 4.40 mmol) and chlorodiphenylsilane (2888 mg, 13.20 mmol) were added to a solution of the product from step f) (1192 mg, 4.40 mmol) in 20 mL of dichloroethane. The reaction mixture was heated at 60° C. overnight and then was cooled to room temperature and quenched with saturated NaHCO3 (50 ml). The reaction mixture was extracted with ethylacetate (2×50 mL). The combined organic extracts were washed with brine (50 ml), dried with MgSO4 and solvent evaporated in vacuo to afford the subtitle compound (638 mg, yield: 57%) that was used without further purification. MS calculated C16H17NS+H: 256, observed: 256.
Reaction SMILES: CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[CH:21]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[CH:21]1([CH2:27][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCC2CCCCC2)cc1
Yield: 63 %

Procedure:
To 250 ml of DMF containing about 200 g of anhydrous potassium carbonate (1.5M) was added 122 g of 4-hydroxybenzaldehyde and 177 g of cyclohexylmethylbromide. The mixture was heated to reflux temperature and maintained overnight, after which was poured into cold water and extracted with ethyl acetate. The extracts were dried and evaporated under reduced pressure to yield the desired subtitled intermediate (63% yield), b.p. 133°-138° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.ClC(Cl)C.[C:24](Cl)(=[O:26])[CH3:25].[Cl-].[Cl-].[Cl-].[Al+3].Cl>O>[C:24]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:15]=[C:14]2[C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=1[CH2:13]2)(=[O:26])[CH3:25]
Reactant: COC(=O)c1ccc2c(c1)Cc1cc(C)ccc1O2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc2c(c1)Cc1cc(C)cc(C(C)=O)c1O2

Procedure:
A mixture of 130 g. of methyl 7-methylxanthene-2-carboxylate in 200 ml. of dichloroethane is cooled to -5°C and to the cooled solution are added 4.95 ml. of acetyl chloride and then 17.0 g. of aluminum trichloride. The resultant solution is stirred at room temperature for 1.75 hours. After this time, the solution is poured into a mixture of 300 g. of ice, 700 ml. of water and 20 ml. of concentrated hydrochloric acid. The mixture is then extracted with three 500 ml. portions of methylene chloride. The combined extracts are washed with 10% aqueous potassium hydroxide solution and the washed solution evaporated to give methyl 5-acetyl-7-methylxanthene-2-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([C:11]=1C(O)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:1][C:2]3[C:3]([CH3:15])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
3-Hydroxy-2-methyl-4-quinoline carboxylic acid (1.5 g), 7-benzyloxy-4-chloro-6-methoxyquinoline (2 g), and 4-(N,N-dimethylamino)-pyridine (2.4 g) were dissolved in 1,2-dichlorobenzene (70 ml) to prepare a solution which was then stirred at 150° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using hexane-acetone to give the title compound (2.4 g, yield 85%).
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[C:10][CH2:11][CH2:12]O)[CH:4]=1>O>[CH3:1][NH:2][CH2:12][CH2:11][C:10]#[C:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1
Reactant: CN
Reactant: OCCC#Cc1cccnc1
Solvent: O
Product: CNCCC#Cc1cccnc1
Reaction time: 3 h
Yield: 546.1 %

Procedure:
An aqueous methylamine solution (5 mL, 40%, 58.7 mmole) was mixed with XII (200 mg, 0.08 mmole) and stirred for 3 hr. in a sealed tube at 45° C. After the reaction was complete, water (10 mL) was added to the cooled reaction mixture, and the reaction mixture was extracted with chloroform (10×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was chromatographed on a silica gel column using methanol:chloroform (1:9) and then with a chloroform: methanol mixture containing 1% triethylamine as eluent. About 70 mg of XIII was obtained as a slightly yellow syrup, which was distilled at 110-112° C., 0.04 mm Hg. XIII was converted to its mono fumarate salt form, which exhibits a melting point of 103-104° C.