Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]#[N:32]>CC(C)=O>[C:1]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:30][C:31]#[N:32])=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 13.1 %

Procedure:
The O-alkylation procedure described for 190 was followed. To stirred mixture of 4,4′-(cycloheptylidenemethanediyl)diphenol (189) (1.18 g, 4 mmol), K2CO3 (0.691 g, 5 mmol) and acetone (50 mL) was added bromoacetonitrile (0.418 mL, 6.0 mmol). The reaction mixture was refluxed for 3.5 h. Standard work-up and purification by silica gel chromatography afforded 0.175 g (13%) of compound 216 as a white solid and 0.700 g (47%) of the bis-alkylated material 2,2′-[(cycloheptylidenemethanediyl) bis(benzene-4,1-diyloxy)]diacetonitrile as a white solid. IR (film): 3413, 2921, 1605, 1504, 1210, 1170, 828, 729 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.1 Hz, 2H), 5.0 (br, 1H), 4.74 (s, 2H), 2.33 (br s, 4H), 1.60 (s, 8H). LCMS (ESI): m/z 332 (M−H)−. Anal. Calcd for C22H23NO2, C, 79.25; H, 6.95; N, 4.20. Found: C, 79.14, H, 6.90; N, 4.21.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:30]1([C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=3)=[CH:22][CH:23]=2)=[O:29])[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: O=C(Nc1ccc(O)cc1)C1CCCC1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(NC(=O)C3CCCC3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and cyclopentanecarboxylic acid (4-hydroxy-phenyl)-amide via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C24H29NO6 [M+H]+: 428.3.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:14][C:15]=3[N:16]([CH2:21][C:22]([O:24]C)=[O:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[ClH:34]>O1CCCC1.O>[ClH:34].[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:14][C:15]=3[N:16]([CH2:21][C:22]([OH:24])=[O:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C3CCCC3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
Compound 66 (1.87 g, 4.21 mmol) obtained in Example 66 was dissolved in 1,4-dioxane (30 mL), to the solution was added 2 mol/L aqueous sodium hydroxide (15 mL), and the mixture was stirred with heating at 70° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and then the residue was neutralized by addition of concentrated hydrochloric acid. The deposited crystals were collected by filtration, washed with water and dried to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77a, 1.61 g, 90%). Compound 77a (500 mg, 1.08 mmol) was dissolved in N,N-dimethylformamide (5 mL), to the solution were added potassium carbonate (192 mg, 1.41 mmol, 1.2 equivalents) and bromoacetic acid methyl ester (140 μL, 1.41 mmol, 1.2 equivalents), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the concentrate, the mixture was extracted with chloroform, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=90:10) to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77b, 400 mg, 69%). From Compound 77b (850 mg, 1.71 mmol), (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77c, 220 mg, 29%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40. Compound 77c (200 mg, 0.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (1 mL), to the solution was added lithium hydroxide hydrate (0.04 g, 0.98 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH 3 with 1 mol/L hydrochloric acid, and the resulting solid was washed with ethanol and collected by filtration to obtain the title compound (180 mg, 93%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.B(F)(F)F.CCOCC.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-].O>CCOCC>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3][CH:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: -50 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.2 g, 16 mmol, 1.0 equiv) in Et2O (20 mL) at −50° C. were added BF3.Et2O (2.3 g, 16 mmol, 1.0 equiv) in dropwise. After completion of addition of BF3.Et2O, ethyl 2-diazoacetate (2 g, 17.6 mmol, 1.1 equiv) was added dropwise. The reaction was then stirred at −50° C. for an hour and kept at room temperature overnight. Then the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (3×100 mL), combined of the organic layers and dried over Na2SO4. The solvent was removed under reduced pressure to give the desired product (4 g), which was purified by silica gel chromatography. MS (ESI): 286 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34]O>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][N:25]([CH3:34])[CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Reactant: CO
Product: Cc1ccc(-c2nn(C)cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 55 starting from [4(4methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and methanol.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]([OH:10])=[C:8]([CH:11]=O)[C:7]([CH2:13][OH:14])=[CH:6][N:5]=1.[ClH:15].Cl.Cl.[O:18]([CH2:20][CH:21]([F:25])[CH2:22][NH:23][CH3:24])[NH2:19]>C(O)C>[ClH:15].[OH:10][C:9]1[C:4]([CH3:3])=[N:5][CH:6]=[C:7]([CH2:13][OH:14])[C:8]=1[CH:11]=[N:19][O:18][CH2:20][CH:21]([F:25])[CH2:22][NH:23][CH3:24]
Reactant: CNCC(F)CON
Reactant: Cc1ncc(CO)c(C=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCC(F)CON=Cc1c(CO)cnc(C)c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 ml of 1N sodium hydroxide solution and 408 mg (2 mmol) of pyridoxal hydrochloride are added to a solution of 390 mg (2.0 mmol) of N-(3-aminoxy-2-fluoropropyl)-methylamine dihydrochloride in 10 ml of ethanol and the mixture is stirred for 16 hours at room temperature. The reaction mixture is then concentrated to dryness by evaporation and the title compound is crystallised from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:13][O-:14].[Mg+2].C[O-]>C1(C)C=CC=CC=1.CO>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]=1[CH:13]=[O:14]
Reactant: C[O-]
Reactant: COCCOc1ccc(O)cc1
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CO
Product: COCCOc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(2-methoxyethoxy)phenol in toluene (350 ml) was added to a solution of magnesium methoxide in methanol (8% by weight solution, 331 mls), under an atmosphere of argon. The reaction mixture was heated at reflux for 2 hours. Toluene (350 mls) was added and the reaction mixture distilled at atmospheric pressure until the internal temperature reached 92° C. A mixture of paraformaldehyde in toluene (300 ml) was added to the reaction mixture and the reaction mixture was heated at reflux for 3.5 hours. The mixture was cooled to ambient temperature and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with toluene (400 ml), washed with 2M aqueous hydrochloric acid (2×150 ml) and water (to pH 1). The residue was distilled under vacuum to give 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde as an oil (35 g), bp 104-130° C. [0.01 mm Hg]; NMR(CDCl3): 3.45(3H,s), 3.75(2H,m), 4.12(2H,m), 6.92(1H,d), 7.05(1H,d), 7.2(1H,dd), 9.84(1H,s) and 10.63(1H,s); m/z 197(M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[C:2]2[NH:1][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2cc(Cl)ccc21
Product: CS(=O)(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 38 from 3-amino-5-chloro-2-(3-chlorobenzoyl)-1-ethoxycarbonyl-1H-indole (step 1) and methanesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[N:8][N:9]([CH3:11])[CH:10]=2)[N:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]([S:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:13]([NH:12][C:2]2[C:3]3[C:4](=[N:8][N:9]([CH3:11])[CH:10]=3)[N:5]=[CH:6][CH:7]=2)[CH:18]=1
Reactant: Cn1cc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nn(C)cc23)c1
Temperature: 25 °C
Yield: 20.7 %

Procedure:
A mixture of the product of Example 8c (62.1 mg, 0.371 mmol), the product of Example 6c (85.7 mg, 0.371 mmol), Pd2(dba)3 (16.9 mg, 0.0185 mmol), sodium t-butoxide (89.0 mg, 0.926 mmol), and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicycl[3,3,3]undecane (25.4 mg, 0.0741 mmol) in toluene (3 mL) was degassed, left under a positive pressure of nitrogen, and heated under reflux for 2 h. Additional amounts of Pd2(dba)3 (7.0 mg, 0.0076 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicycl[3,3,3]undecane (15 mg, 0.044 mmol) were added the reaction mixture was heated under reflux for an addition 2 h. The mixture was then cooled to room temperature and partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a 2-5% MeOH/CH2Cl2, gradient to provide the title compound (0.0279 g, 21% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.27 (s, 3H), 4.11 (s, 3H), 5.92 (d, J=5.15 Hz, 1H), 6.75-6.85 (m, 3H), 7.02 (dd, J=8.27, 0.92 Hz, 1H), 7.14 (s, 1H), 7.18-7.27 (m, 2H), 8.09 (d, J=5.15 Hz, 1H), 8.20 (s, 1H), 8.77 (s, 1H), 9.82 (s, 1H); MS (ESI+) m/z 363.0 (M+H)+ (ESI−) m/z 360.9 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=1)=[O:11].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[Na].CN(C)C(=O)C>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(Cc1ccc(F)cc1F)c1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1C
Product: O=C(Cc1ccc(F)cc1F)c1ccc(-n2cncn2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 17.5 %

Procedure:
A mixture of 2-(2,4-difluorophenyl)-1-(4-fluorophenyl)-1-ethanone (5.0 g, 20 mmol-see EP-A-0069442), sodium 1,2,4-triazole (2.18 g, 24 mmol) and N,N-dimethylacetamide (100 ml) was stirred at 100° C. for 18 hours. The mixture was diluted with xylene (300 ml) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and washed with water (3×50 ml). The organic solution was dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (eluting with ethyl acetate:dichloromethane 1:1) gave a white solid (1.05 g, 18%), which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH3:27])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[OH-].[Li+]>>[CH3:27][O:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([CH:28]3[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1
Reactant: COC(=O)c1sc(C2CCC(=O)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Agent: [Li+]
Agent: [OH-]
Product: CO[C@H]1CC[C@H](N(c2cc(C3CCC(=O)CC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
The product from step IV (61 mg) was hydrolyzed with lithium hydroxide as described earlier (example 3, step VIII) to afford after column purification on silica gel (CH2Cl2-MeOH) 23 mg (39%) of 3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-oxocyclohexyl)-thiophene-2-carboxylic acid.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:28]([CH3:42])[CH:27]=3)=[O:25])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]1[CH3:43])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:51][C:52]([CH3:57])([CH3:56])[CH2:53][CH:54]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:3]([N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][N:39]([CH2:54][CH2:53][C:52]([CH3:57])([CH3:56])[CH3:51])[CH2:38][CH2:37]4)=[C:28]([CH3:42])[CH:27]=3)=[O:25])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]1[CH3:43])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1OCCCN1CCNCC1
Reactant: CC(C)(C)CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1OCCCN1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride from Example E70.2 (100 mg, 0.16 mmol) was dissolved in methanol (2.45 ml) and triethylamine (0.068 ml, 0.48 mmol). Acetic acid (0.05 ml) then 3,3-dimethylbutyraldehyde (0.031 ml, 0.24 mmol) were added and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (16 mg, 0.24 mmol) was added and the mixture was stirred for 20 h at room temperature then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield the title compound (98 mg, 96%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CSc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Methyl thioglycolate was dissolved in DMF (10 ml) and this mixture was cooled to 0° C. under an atmosphere of nitrogen. NaH (750 mg of 60% mineral oil dispersion, 18.1 mmol) was then added in one portion. After 5 min., the ice bath was removed and p-fluoroacetophenone (1 ml, 8.2 mmol) was added in one portion. The reaction mixture stirred at ambient temperature for 1 hr then diluted with ethyl acetate (50 ml) and washed with water. The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organics dried over MgSO4 and concentrated in vacuo to yield (4-acetyl-phenylsulfanyl)-acetic acid methyl ester, as a white waxy solid (1.48 g, 80%). 1H NMR (250 MHz, CDCl3): δ 7.80 (d, 2H, J=9.4), 7.32 (d, 2H, J=9.4), 3.71 (s, 2H), 3.67 (s, 3H), 2.50 (s, 3H). MS [EI+] 225 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[CH:9][C:10]([Cl:36])=[C:11]([CH2:18][N:19]([C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][CH:24]=3)[CH2:20][C:21]#[CH:22])[CH:12]=2)[N:7]=1)(=O)C.[OH-].[Na+].O>O1CCCC1>[Cl:36][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:17])[N:15]([CH3:16])[C:6]([CH2:5][OH:4])=[N:7]2)=[CH:12][C:11]=1[CH2:18][N:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[CH:34][CH:35]=1)[CH2:20][C:21]#[CH:22]
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(COC(C)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#CCN(Cc1cc2c(=O)n(C)c(CO)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[N-[2-acetoxymethyl-7-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.47 g, 0.92 mmol) in tetrahydrofuran (18 ml), was slowly added 1N aqueous NaOH (1.84 ml, 1.84 mmol) followed by water (1.5 ml). The slightly cloudy solution was stirred at room temperature for 1 hour, the solvent was removed in vacuo and the residue was treated with water (35 ml). The pH was adjusted to 4.5 with 1N HCl and the mixture was extracted with ethyl acetate (3×60 ml). The organics were combined, dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography, on elution with 50% ethyl acetate in dichloromethane, afforded a white solid which was reprecipitated from dichioromethane (minimum amount)/hexanes. The solid was collected by filtration and dried in vacuo over P2O5 (0.345 g, 80%), mp 109-111° C.; 1H-NMR (DMSO-d6); 1.49 (s, 9H, CO2But), 3.50 (s, 3H, N3-Me), 3.25 (s (poorly resolved triplet), 1H, C≡CH), 4.40 (s, 2H, CH2C≡C), 4.57 (d, J=5.70 Hz, 2H, 2-CH2OH), 4.80 (s, 2H, 6-CH2), 5.67 (t, J=6.4 Hz, 1H, CH2OH), 6.78 (d, J=8.80 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.44 Hz, 2H, 2′,6′-Ar), 7.82, 7.87 (2×s, 2H, 5-H, 8-H); MS (FAB, m/z) 467, 469 (M+, 95%, 45% respectively; Cl isotopic pattern).
Reaction SMILES: [C:1]([C:4]1[C:5](=[S:15])[S:6][S:7][C:8]=1[C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)(O)=[O:2].C(OC([N:21]1C2C(=CC=CC=2)C=CC1OCC)=O)C.N>C(Cl)Cl.CO.CN(C)C=O>[C:1]([C:4]1[C:5](=[S:15])[S:6][S:7][C:8]=1[C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)(=[O:2])[NH2:21]
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: O=C(O)c1c(-c2cnccn2)ssc1=S
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1c(-c2cnccn2)ssc1=S
Temperature: 20 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
A suspension of 4-carboxy-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (12.8 g) [prepared as described in Example 32] and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (13.25 g) in methylene chloride (40 cc) is stirred for 5 hours at a temperature of about 20° C. A solution (15 cc) of 4N ammonia in methanol is added over a period of 10 minutes to the solution obtained, and the reaction mixture is stirred for a further 5 minutes at a temperature of about 20° C. The insoluble product is filtered off and washed successively with methylene chloride (50 cc), saturated aqueous sodium bicarbonate solution (25 cc), water (4 × 100 cc) and then ethyl acetate (15 cc). The residue obtained is dissolved at a temperature of about 100° C. in dimethylformamide (100 cc) and the solution, which is filtered hot, is then poured into distilled water (200 cc). After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed with ethyl acetate (2 × 10 cc) to give 4-carbamoyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (6.58 g) melting at 267° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:13]
Reactant: F[B-](F)(F)F
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1ccc2c(c1F)CCCC2=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 6-methoxy-1-tetralone (200 mg, 1.1 mmol) in ACN (20 mL) was added Selectfluor (603 mg, 1.7 mmol) at rt, and the reaction was stirred at 40° C. overnight. The reaction was filtered and concentrated. The residue was dissolved in EtOAc (40 mL), filtered, and concentrated. Purification by silica gel chromatography (PE/EtOAc/DCM=20:1:2) gave 90 mg (41%) of the title compound as a yellow solid. [M+H] Calc'd for C11H11FO2, 195. Found, 195.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Product: O=C(O)c1cccc2cc(Oc3ccnc4c(C(F)(F)F)cccc34)ccc12
Yield: 49.1 %

Procedure:
The title compound (1.43 g, 49% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4-chloro-8-(trifluoromethyl)quinoline (2.12 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 384 (M+1).