Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:40]([Cl:41])=[CH:39][C:10]3[N:11](COCC[Si](C)(C)C)[C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23]CC5C=CC=CC=5)=[O:22])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:40]([Cl:41])=[CH:39][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=[O:22])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1c(OC2CCCC(C(=O)OCc3ccccc3)C2)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C1CCCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)C1
Temperature: 80 °C

Procedure:
To a solution of benzyl 3-{[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (isomer A from Step A, 0.075 g, 0.112 mmol) in 1.1 mL of THF was added TBAF (0.675 mL, 0.675 mmol) dropwise via syringe. The reaction was heated at 80° C. for 16 h, and then diluted with EtOAc (50 mL) and washed with 2 N HCl (2×20 mL). The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by reverse phase Gilson™ HPLC (30-100% MeCN/H2O) afforded the title compound as a white solid. LCMS: calculated for C26H23ClN2O3 446.93, observed m/e 446.92M+ (Rt 2.19/4 min). 1H NMR (500 MHz, CD3OD): δ7.71-7.64 (m, 4H), 7.55 (brs, 1H), 7.50 (d, 2H), 7.48-7.43 (m, 2H), 7.39 (brs, 1H), 7.37-7.32 (m, 1H), 5.00-4.91 (m, 1H), 2.60-2.46 (m, 2H), 2.33-2.24 (m, 1H), 2.06-1.95 (m, 2H), 1.79-1.67 (m, 1H), 1.64-1.49 (m, 2H), 1.49-1.37 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>C1COCC1>[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]([OH:29])[CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: Cc1cc(=O)oc2ccc(C#N)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2oc(=O)cc(CC(O)c3ccc(Cl)cc3Cl)c2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-6-carbonitrile (56 mg, 0.325 mmol) in dry THF (12 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (0.6 mL). After 30 minutes 2,4-dichlorobenzaldehyde (105 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-60% ethyl acetate in hexanes to yield 4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromene-6-carbonitrile as a white powder.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:9][C:10](=[O:17])[CH2:11][C:12](=O)[CH2:13][CH2:14][CH3:15])[CH3:8].O>C1C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:17])[CH:11]=[C:12]([Cl:2])[CH2:13][CH2:14][CH3:15])[CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCC(=O)CC(=O)OCC
Solvent: c1ccccc1
Solvent: O
Product: CCCC(Cl)=CC(=O)OCC
Temperature: 0 °C

Procedure:
280 g of phosphorus pentachloride are added in portions over the course of 2 hours to a solution of 200 g of 3-oxo-hexanoic acid ethyl ester in 200 ml of absolute benzene whilst stirring at 0°C. 200 ml of water are then added dropwise with intense cooling so that the temperature never rises above 0°C. The mixture is stirred for a further 12 hours at 0°C. The organic phase is then separated off, washed with twice 100 ml of ice-cold 2 N sodium hydroxide solution and with twice 100 ml of water, dried over sodium sulphate and evaporated in vacuo. Fractional distillation of the evaporation residue gives, in the fraction boiling at 98°-102°C (20 mm), crude 3-chloro-2-hexenoic acid ethyl ester, which is used direct for further conversion.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:28][C:29]([NH2:31])=[O:30])([O-:3])=[O:2].Cl.Cl[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13]3[N:12]=[CH:11][C:10]([CH2:28][C:29]([NH2:31])=[O:30])=[C:9]([NH:8][CH2:7][C:6]4[CH:32]=[CH:33][CH:34]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:14]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1)[CH3:37]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cccc([N+](=O)[O-])c1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCN1CCN(c2ccc(Nc3cc(NCc4cccc([N+](=O)[O-])c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
40 mg of 4-[(3-nitrobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 224) was dissolved in 0.3 mL of N,N-dimethylformamide, to which 18.5 mg of 2-chloro-N,N-diethylethylamine hydrochloride and 25 mg of potassium carbonate were added, and stirred at room temperature for 3 hours. Water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 43 mg (88%) of the title compound as an orange crystalline powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:8])[CH2:5][O:6][CH3:7].I[CH2:10][C:11]([O-:13])=[O:12].[Na+].[H-].[Na+].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH:4]([O:8][CH2:10][C:11]([OH:13])=[O:12])[CH2:5][O:6][CH3:7]
Reactant: O=C([O-])CI
Reactant: COCC(O)COC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(COC)OCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of 1,3-dimethoxy-2-propanol (361.5 mg, Tyger) in tetrahydrofuran (4 ml) was added with sodium iodoacetate (624.6 mg, Spectrum), and successively added with sodium hydride (198 mg, Wako Pure Chemical Industries) as several portions at 0° C., and the mixture was stirred at the same temperature for 30 minutes, and then further stirred at room temperature for 15.5 hours. The reaction mixture was cooled again to 0° C., and then carefully added with water and then with chloroform, and the organic layer was separated. The aqueous layer was acidified (pH 4) with 1 N hydrochloric acid, and extracted three times with chloroform, and the combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain the title compound (206.5 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[F:9][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(Br)ccc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)ccc1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
5-Bromo-2-fluorotoluene (6 g, 31.7 mmol) was dissolved in dry THF (50 mL) and cooled to −78 C. under N2. n-BuLi (14 mL, 2.5M solution in THF) was added slowly using a dry syringe. Cloudiness appeared. The reaction was stirred for 40 minutes at −78° C. Triisopropyl borate (22 mL, 95 mmol) was slowly added while stirring. The reaction was allowed to warm to room temperature. Stirring continued for an additional 2 hours. A pale yellow, cloudy solution formed. (TLC (1:2 ethyl acetate/hexanes)) indicated disappearance of the starting material. The reaction was quenched by adding 10% aqueous NaOH (200 mL). After stirring for 45 minutes, 10% citric acid solution (300 mL) was added until, pH ˜5.0. The product was extracted with ethyl acetate (500 mL). The organic phase was washed with brine and dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an off white solid (yield: 4.1 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=C1N(C(OCC2C=CC=CC=2)=O)[C@H](C(O)=O)CN1.[H-].[Na+].FC(F)(F)S(O[CH2:42][CH:43]([F:45])[F:44])(=O)=O>CN(C)C=O>[F:44][CH:43]([F:45])[CH2:42][N:4]1[CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:6][N:2]([CH3:1])[C:3]1=[O:14]
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(C(=O)OC(C)(C)C)N(CC(F)F)C1=O
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) at −35° C. under argon was added sodium hydride (39.9 mg, 0.999 mmol). The mixture was stirred for 15 minutes, 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) was added and the reaction mixture was stirred at −35° C. for 30 minutes then slowly warmed to −15° C. After 1 hour the reaction mixture was quenched with water (10 ml), warmed to room temperature and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with sodium hydrogen carbonate saturated solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was then dried (magnesium sulfate), filtered and evaporated. The crude residue was purified by silica gel chromatography eluting with 10-100% of ethyl acetate in isohexane to give 1,1-dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg). LC/MS [M+H]+=265. (ii) 1,1-Dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg, 0.674 mmol) was dissolved in dichloromethane (3.00 ml) and trifluoroacetic acid (1 ml) was added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with dichloromethane and toluene to give a crude 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylic acid (assume 0.674 mmol) which was used for the next reaction. LC/MS [M+H]+=209.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[N:9]=[CH:8]2.[F:38][C:39]([F:44])([CH3:43])[C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:38][C:39]([F:44])([CH3:43])[C:40]([NH:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[O:18])[N:9]=[CH:8]2)=[O:41]
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)N)ccc32)c1
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)NC(=O)C(C)(F)F)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isobutyl 3-(5-((1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate (I4b) (0.5 g, 1.00 mmol), 2,2-difluoropropanoic acid (0.16 g, 1.45 mmol) and HBTU (0.567 g, 1.50 mmol) in DCM (4 mL) was treated with DIEA (0.696 mL, 3.99 mmol), the mixture was stirred at ambient temperature for 1 hour. The reaction was quenched by addition 10% NaHSO4 (aq), brine was added to help phase separation. The lower red DCM phase was separated, the waterphase was extracted with one portion of EtOAc, the combined organic solutions were dried over MgSO4 and filtered, solvents was removed by evaporation. Obtained a crude product as red oil. The crude material was further purified by flashchromatography using an 70 g prepacked silica column, an gradient of 0% to 50% EtOAc in Heptane was applied. Fractions with product was combined and solvents was removed by evaporation. An slightly yellow sticky oil was obtained after final evaporation from DCM. Yield 540 mg (91%).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-allyloxy-8-acetyl -3-methylflavone (2.5 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.3 g of product m.p. 145-47° C., 1H-NMR (CDCl3)δ:1.77 (s, 3H); 2.20 (s, 3H); 4.73 (d, 2H, J=5.1 Hz); 5.25-5.45 (m, 2H); 5.91-6.02 (m, 1 H); 7.05 (d, 1H, J=16 Hz); 7.11 (d, 1H, J=8.9 Hz); 7.38-7.48 (m, 7H); 7.53-7.59 (m, 4H); 8.34 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[N:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[CH2:10]2)=[O:4].C(N(CC)CC)C.CCCP(=O)=O.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C1C=CN=CC=1)C.ClCCCl>[F:37][C:38]([F:46])([F:47])[C:39]1[CH:40]=[C:41]([NH:42][C:18]([C:17]2[CH:16]=[C:15]([N:9]3[CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=4[CH2:7][CH2:8]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)O)c1)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
To a mixture of 3-[5-(methoxycarbonyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]benzoic acid (63 mg, 0.20 mmol), triethylamine (0.084 mL, 0.60 mmol), and catalytic DMAP in 3.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.143 mL, 0.24 mmol). After 5 min at rt, 3-(trifluoromethyl)aniline (0.037 mL, 0.30 mmol) was added and the reaction stirred at rt for 18 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, dilute aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc to give the title compound as a yellow solid (50 mg, 55%). 1H NMR (Acetone-d6) δ: 9.75 (br. s., 1H), 8.89 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.09 (d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.37-7.47 (m, 3H), 7.28-7.34 (m, 1H), 4.61 (s, 2H), 3.92 (s, 3H), 3.67-3.73 (m, 2H), 3.37 (t, J=5.9 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:28]Br)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[SH:36].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:4]1[C:5]([CH2:28][S:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(C(C)=O)c(CSc3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
A mixture of 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (1.5 g), 1-methyl-2-mercaptoimidazole (0.417 g), potassium carbonate (0.495 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over magnesium sulfate. Evaporation of the solvent gave 3-acetyl-4-(3,4-dimethoxy-phenyl)-6,7-dimethoxy-2-[(1-methylimidazol-2-yl)thiomethyl]-quinoline (1.1 g, 71%). This compound was recrystallized from ethanol to give colorless prisms, mp. 175°-176° C.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35](Br)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (170 mg, 60%). MS (ISP) 570.2 [(M+H)+]; mp 132° C.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1.ClC1C2C(=O)C3C=NC=CC=3C(=O)C=2C(O)=CC=1.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([O:18][S:43]([C:40]2[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=2)(=[O:45])=[O:44])=[CH:4][CH:3]=1
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(O)c21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C1c2ccncc2C(=O)c2c(Cl)ccc(O)c21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 1:1 mixture of 9-fluoro-6-hydroxybenzo[g]isoquinoline-5,10-dione and 9-chloro-6-hydroxybenzo[g]isoquinoline-5,10-dione, of Preparative Example 9a, (0.060 g) is dissolved in dry pyridine (2 mL) and p-toluenesulfonyl chloride (0.095 g) is added. After stirring at room temperature for one hour, triethylamine (0.25 mL) is added and stirring is continued for one additional hour. The reaction mixture is concentrated almost to dryness and partitioned between 1N HCl (4 mL)-20% ammonium sulfate (6 mL) and ethyl acetate (10 mL). The aqueous phase is separated, extracted with ethyl acetate (3×5 mL) and discarded. The combined organic solutions are dried over anhydrous sodium sulphate and concentrated to dryness to give an approximately 1:1 mixture (0.095 g) of 9-fluoro-6-(p-toluenesulfonyloxy) benzo[g] isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy) benzo[g]isoquinoline-5,10-dione which is used without further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].CC(C)([O-])C.[K+].Cl.Cl[CH2:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH3:33]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH3:33]
Reactant: COc1ccccc1CCc1ccccc1O
Reactant: CN1CCCC1CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1CCc1ccccc1OCCC1CCCN1C
Yield: 20.2 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(2-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 23), 1.47 g of potassium t-butoxide and 1.61 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 300 mg (yield 20%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
5-bromo-2-chlorobenzoic acid (E-Merck 8.14989.0101, 20 g; 84.94 mmol; 1 eq.) was dissolved in MeOH (400 mL). The solution was cooled down to 0° C. SOCl2 (18.49 mL; 254.82 mmol; 3 eq.) was added dropwise (addition took 30 min and IT increased to 9° C.). After addition, the reaction mixture was stirred at RT for 2 days. The reaction mixture was concentrated and the crude mixture was dissolved in EtOAc (400 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), brine (100 mL), dried over MgSO4 and concentrated affording the title compound as a white solid (20.15 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 7.98-7.97 (d, J=2.40 Hz, 1H), 7.80-7.67 (dd, J=8.74 Hz, 2.40 Hz, 1H), 7.56-7.54 (d, J=8.23 Hz, 1H), 3.86 (s, 3H). HPLC (Method A) Rt 4.15 min (Purity: 99.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([NH2:40])=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH:34]3[C:38]([NH2:40])=[O:39])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NC(=O)[C@@H]1CCC[C@@H]1N
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NC2CCCC2C(N)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 225, the product of Example 48 (150 mg, 0.34 mmol) and cis-2-amino-1-cyclopentanecarboxamide (139 mg, 1.02 mmol) were reacted to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by recrystallization from dichloromethane and hexane, afforded the desired product, 87 mg (52%). LC-MS: 494.0 (MH+, m/z), 2.00 (Rt, min).