Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2.CO>ClCCl>[CH2:13]1[C:14]2[C:9](=[CH:8][C:7]([OH:6])=[CH:16][CH:15]=2)[CH2:10][CH2:11][NH:12]1
Reactant: COc1ccc2c(c1)CCNC2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCNC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of boron tribromide (1.2 mL, 12.5 mmol) in dichloromethane (12.5 mL) was added dropwise to a −78° C. solution of 6-methoxytetrahydroisoquinoline (1.0 g, 5.0 mol, prepared as described in Org. Synth 1988, 67, 60) in dichloromethane (38 mL) The mixture was stirred for 1 hour, warmed to 0° C., stirred for 1 hour, warmed to room temperature, and stirred for 1 hour. The mixture was cooled to −78° C., treated dropwise with methanol (20 mL), warmed to room temperature, stirred for 1 hour, and concentrated to provide the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([F:11])[CH:3]=1.[CH2:12](B([O-])OC(C(C)(C)C)C)[CH:13]=[CH2:14].[F-].[Cs+]>O1CCCC1.C(OCC)C.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>[CH2:14]([C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([F:11])[CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CCB([O-])OC(C)C(C)(C)C
Reactant: COc1cc(Br)cc(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCc1cc(F)c(F)c(OC)c1

Procedure:
3.06 g of 1-bromo-3,4-difluoro-5-methoxybenzene (D2), 4.54 ml of pinacolyl allylboronate, 3.04 g of tetrakis(triphenylphosphine)palladium(0) and 7.62 g of caesium fluoride are suspended in 115 ml of tetrahydrofuran under an argon atmosphere. The reaction mixture is subsequently heated under reflux for 48 h. For work-up, the mixture is diluted with 400 ml of diethyl ether and extracted with 100 ml of water and 100 ml of saturated NaCl solution. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent: cyclohexane), giving 1.59 g of the title compound as a colourless oil; MS: 184.0 (M+); TLC: Rf=0.69 (cyclohexane/ethyl acetate 8:1 parts by volume).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH:4]=[CH2:5].[Cl:12][CH:13](Cl)[C:14]([O:16][CH3:17])=[O:15].Cl>CN(C)C=O.O>[C:8]([O:7][C:3]([CH:4]1[CH2:5][C:13]1([Cl:12])[C:14]([O:16][CH3:17])=[O:15])=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)C(Cl)Cl
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(Cl)CC1C(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
80 g of 60% sodium hydride was suspended in 1,000 ml of N,N-dimethylformamide. To this suspension was dropped 352 ml of tert-butyl acrylate within 30 minutes under ice-cooling. Then 207 ml of methyl dichloroacetate was dropped into this reaction mixture within 1.5 hours while maintaining the internal temperature at 10° C. After the completion of the addition, the mixture was stirred for 2 hours while maintaining the internal temperature at 10° to 20° C. Then the reaction mixture was neutralized by adding concentrated hydrochloric acid and water was-further added thereto. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The extract was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was distilled under reduced pressure to thereby give 384 g (yield 84%) of methyl 2-tert-butoxycarbonyl-1-chloro-1-cyclopropanecarboxylate in the form of a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:36][CH2:37][CH3:38])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: CCCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Product: CCCOc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with propyl bromide
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:48])[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27]([C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[F:45])[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][C:11]([F:47])([F:46])[CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:30][C:29]1[S:28][C:27]([C:38]2[C:39]([F:45])=[CH:40][CH:41]=[CH:42][C:43]=2[F:44])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][C:9]([NH2:8])([CH3:48])[CH2:10][C:11]([F:46])([F:47])[CH2:12]1)=[O:24]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(C)(NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(C)(N)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
To a solution of tert-butyl N-(4-((5-(5-(tert-butoxycarbonylamino)-3,3-difluoro-5-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate (0.36 g, 0.51 mmol) in MeOH (5 mL) was added HCl in dioxane (4 M, 0.02 mol, 5 mL). The reaction mixture was stirred at room temperature for 16 hr and concentrated under reduced pressure. Purification via SCX cartridge washing with 1/1 MeOH/DCM (250 mL) followed by MeOH (250 mL) and eluting with 1 N NH3 in MeOH (200 mL) gave 495 as a pale yellow foam (250 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.85 (s, 1H), 7.33 (tt, J=8.4, 6.1 Hz, 1H), 7.07-6.99 (m, 2H), 6.28-6.06 (m, 2H), 3.78-3.74 (m, 3H), 3.65-3.40 (m, 3H), 3.29-3.20 (m, 1H), 2.41-2.16 (m, 2H), 1.96-1.85 (m, 1H), 1.77 (dt, J=14.7, 4.6 Hz, 1H), 1.26 (s, 3H). Exchangeables not observed. LCMS (ES+) m/z 498 (M+1)
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]2[CH3:18])=[C:11]([Cl:24])[CH:10]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[Cl:24][C:11]1[CH:10]=[C:9]([OH:8])[CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]2[CH3:18]
Reactant: CCOC(=O)c1cc2c(Cl)cc(OCc3ccccc3)cc2n1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(Cl)cc(O)cc2n1C
Yield: 92.4 %

Procedure:
In 60 ml of tetrahydrofuran was dissolved 2.20 g (6.40 mmol) of ethyl 6-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate. After 0.3 g of 10% palladium/carbon was added to the solution, catalytic hydrogenation was performed at ambient temperature under normal pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1.50 g (92.4%) of ethyl 4-chloro-6-hydroxy-1-methyl-2-indolecarboxylate.
Reaction SMILES: [C:1]1([CH:11]=[C:12]2[CH2:18][CH2:17][C:16](=[O:19])[O:15][C:13]2=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:23]1[CH2:24][CH2:25][N:20]([C:16](=[O:19])[CH2:17][CH2:18][C:12](=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:13]([OH:15])=[O:14])[CH2:21][CH2:22]1
Reactant: C1COCCN1
Reactant: O=C1CCC(=Cc2cccc3ccccc23)C(=O)O1
Solvent: ClCCl
Product: O=C(O)C(=Cc1cccc2ccccc12)CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
7.5 g (30 mmole) of 2-(1-naphthylmethylene)glutaric anhydride (prepared as described above) were dissolved in 70 ml of methylene chloride, and 2.85 ml (33 mmole) of morpholine were added to the resulting solution. The mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was washed with a 5% v/v aqueous solution of citric acid and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate and freed from the solvent by evaporation under reduced pressure, to give 10.0 g (30 mmole) of 5-morpholino-2-(1-naphthylmethylene)-5-oxopentanoic acid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[CH3:15][N:16]([CH3:18])[NH2:17]>O1CCCC1>[CH3:15][N:16]([CH3:18])[NH:17][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([NH2:1])(=[O:4])=[O:3])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CN(C)N
Solvent: C1CCOC1
Product: CN(C)NS(=O)(=O)c1ccccc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
A solution of 1.28 g of 2-(aminosulfonyl)benzenesulfonyl chloride in 12 mL of dry tetrahydrofuran (THF) was cooled to -65° C. and a solution of 0.88 mL of 1,1-dimethylhydrazine in 12 mL of dry THF added dropwise. The resulting mixture was allowed to warm to room temperature, filtered, and the filtrate concentrated in vacuo. The solid residue was partitioned between water and ethyl acetate, the organic phase was separated, washed with water, washed with brine, dried (MgSO4), concentrated in vacuo, and the residue triturated with 1-chlorobutane to provide 1.07 g of the subject compound, m.p. 122°-124° C. (dec).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[C:26]([Cl:35])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[C:26]([Cl:35])[CH:25]=1)#[N:7]
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H](O)CN4CCCC4)c(C#N)cc23)cc1Cl
Temperature: 60 °C

Procedure:
After adding tetrahydrofuran (1.0 ml) and pyrrolidine (0.10 ml) to N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea (110 mg), the mixture was heated at 60° C. for 2 hours. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (65 mg) as light yellow crystals.
Reaction SMILES: [Na].C([C:4]([CH2:11][CH3:12])([C:8]([O-:10])=[O:9])C([O-])=O)C.Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30]CC>C(O)CCC>[C:8]([OH:10])(=[O:9])[CH2:4][CH2:11][CH2:12][CH2:30][CH2:29][CH2:28][CH2:27]/[CH:26]=[CH:25]\[CH2:24]/[CH:23]=[CH:22]\[CH2:21]/[CH:20]=[CH:19]\[CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCCCl
Agent: [Na]
Solvent: CCCCO
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Temperature: 140 °C
Reaction time: 20 h

Procedure:
To 15 ml. of n-butanol under nitrogen was added 211 mg. of sodium in pieces. The mixture was heated gently until all the sodium had dissolved, then 1.2 ml. of diethylmalonate was added and the mixture was refluxed one hour, then cooled, and a solution of 2.0 g. of 1-chloro-cis,cis,cis-7,10,13-nonadecatriene in 7.5 ml. of n-butanol was added. The resulting reaction mixture was refluxed for 3 hrs. under nitrogen, then allowed to stand for about 20 hrs., and concentrated under reduced pressure. The thus obtained residue was dissolved in a solution of 1.9 g. of potassium hydroxide in 38 ml. of 95% ethanol and heated under reflux for 3.5 hrs., then was concentrated to about 1/3 volume, diluted with water, and extracted with ether. The ether solution was extracted with 1N aqueous sodium hydroxide. The sodium hydroxide solution was made acid with 3N hydrochloric acid and extracted twice with ether. The ether extracts were washed with water, then with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated to give 1.72 g. of a pale yellow oil. The thus obtained oil was heated in a short path distillation tube at 140°C. under reduced pressure until decarboxylation was complete, then was distilled at a bath temperature of 180°-200°/0.006 mm., thus obtaining a distillate comprising cis,cis,cis-9,12,15-heneicosatrienoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCOCC1.[OH-].[Li+].Cl>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(CNC(=O)C(C)(C)C)ccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
Add methyl 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoate (1.05 kg, 3.7 mol), 1,4-dioxane (5.25 L) and water (3.15 L) together and then add lithium hydroxide (407.8 g, 9.6 mol). Stir the resulting suspension at room temperature for one hour. Acidify the mixture to pH 1 with 5 N aqueous HCl in a dropwise fashion at a rate such that the internal temperature does not exceed 30° C. Concentrate the solution to remove approximately 6 L of solvent, and cool the resulting suspension to 10° C. Filter, wash the resulting solid material with water (8 L), and allow to dry on the sinter for 3 h. Collect the solid, and dry the material in a vacuum oven at 40° C. for 48 h to give the title compound as a free-flowing white solid (775 g, 77.7%). MS (m/z) (35Cl/37Cl) 270/272 (M+1).
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:7]
Reactant: COc1ccc(CN2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)OC[C@@H]2[C@@H](C)O)cc1
Yield: 79 %

Procedure:
A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(4-methoxybenzyl)oxazolidin-2-one (5.90 g, 19.2 mmol) in CH2Cl2 (40 mL) was treated with TFA (40 mL) at room temperature for 20 min. The reaction mixture was concentrated in vacuo, then diluted with CH2Cl2 (˜50 mL), and again concentrated. This procedure was repeated three times to remove TFA. Flash column chromatography (EtOAc/Heptane 30-100%) gave 3.81 g of the desired product. 1H NMR (400 MHz, MeOD) δ 7.31-7.21 (m, 2H), 7.00-6.87 (m, 2H), 4.67 (d, J=15.0 Hz, 1H), 4.34-4.18 (m, 3H), 3.95 (q, J=6.2 Hz, 1H), 3.80 (s, 3H), 3.68 (dt, J=8.7, 5.5 Hz, 1H), 1.09 (d, J=6.4 Hz, 3H). MS m/z 252.2 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12](Br)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].[OH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=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>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:16][OH:15])[CH:22]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(Br)c2ncccc2c1
Reactant: OCc1cccc(B(O)O)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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-c2cccc(CO)c2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 6-isopropyl-8-Bromoquinoline (11.1 g, 44.4 mmol) (described in International Patent Publication WO 94/22852), 3-(hydroxymethyl)phenylboronic acid (8.70 g, 57.2 mmol), Na2CO3 (2M, 71 mL, 142 mmol) and Pd(PPh3)4 (2.51 mg, 2.17 mmol) in 280 mL of DME was stirred at 80° C. for 5 h. The resulting mixture was cooled to r.t., diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex/EtOAc, 1/1) and stirring in CH2Cl2/hexane (1/9) yielded 6-Isopropyl-8-[3-(hydroxymethyl)phenyl]quinoline as a white solid.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH:12]2[CH:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[C:23]1([C:29]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[C:36]3[C:31](=[CH:32][C:33](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:35]=3)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>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.O>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH:15]2[CH:12]([C:4]3[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]4=[C:2]([C:33]4[CH:32]=[C:31]5[C:36]([C:37]([C:39]([F:42])([F:40])[F:41])=[CH:38][C:29]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)=[N:30]5)=[CH:35][CH:34]=4)[N:3]=3)[CH2:13][CH2:14]2)[CH2:17][CH2:18]1
Reactant: CC1(C)OB(c2ccc3c(C(F)(F)F)cc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: CN1CCN(C2CCC2c2nc(I)c3c(N)nccn23)CC1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN(C2CCC2c2nc(-c3ccc4c(C(F)(F)F)cc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-Iodo-3-[4-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine (120 mg, 0.00029 mole), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-quinoline (230 mg, 0.00058 mole), cesium carbonate (330 mg, 0.0010 mole), 1,2-dimethoxyethane (6 mL, 0.06 mole) and water (1 mL) were combined in a 25 ml round bottom flask with a magnetic stir bar. The flask was subjected to three vacuum, argon cycles and charged with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.000030 mole). The flask was subjected to three vacuum, argon cycles again. The reaction was stirred under argon at 75° C. (external temperature) overnight. The product mixture was concentrated in vacuo, then allowed to stand under vacuum for 1 h. The product mixture was then chromatographed on silica gel with methylene chloride, methanol, concentrated ammonium hydroxide (140:10:1). Only the purest fractions were combined and concentration in vacuo, and placement under high vacuum for 30 minutes afforded the title compound as a yellow solid. The solid was re-crystallized from hexanes/ether to afford the title compound as a yellow solid; 1H NMR (CD3OD, 400 MHz) δ 2.14-2.62 (m, 15H), 2.78-2.82(Q, 1H, J=7.9 Hz), 3.62-3.67 (Q, 1H, J=7.9H), 6.32 (bs, 2H), 7.12-7.14 (d, 1H, J=4.8 Hz), 7.58-7.64 (m, 4H), 8.16-8.22 (m, 2H), 8.39-8.42 (m, 3H), 8.48 (s, 1H); 19F NMR (DMSO, 400 MHz) δ-60.15; MS(ES+): 557.98 (10) [MH+]; HPLC TR3.408 min. (100%) (polar—15 min).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH:46]([C:49]1[CH:54]=[C:53]([CH:55]([CH3:57])[CH3:56])[CH:52]=[C:51]([CH:58]([CH3:60])[CH3:59])[C:50]=1[S:61]([Cl:64])(=[O:63])=[O:62])([CH3:48])[CH3:47]>CN(C)C=O>[ClH:64].[O:31]=[C:29]1[NH:28][C:27](=[O:32])[CH:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([O:20][CH2:19][C:17]3[N:16]([CH3:35])[C:15]4[CH:36]=[C:11]([O:10][C:9]5[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH:3][S:61]([C:50]6[C:51]([CH:58]([CH3:59])[CH3:60])=[CH:52][C:53]([CH:55]([CH3:57])[CH3:56])=[CH:54][C:49]=6[CH:46]([CH3:48])[CH3:47])(=[O:63])=[O:62])=[CH:38][CH:37]=5)[CH:12]=[CH:13][C:14]=4[N:18]=3)=[CH:22][CH:23]=2)[S:30]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)NCCc2ccc(Oc3ccc4nc(COc5ccc(CC6SC(=O)NC6=O)cc5)n(C)c4c3)cc2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.7 %

Procedure:
To a mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), triethylamine (0.17 g) and anhydrous N,N-dimethylformamide (10 ml) was added 2,4,6-triisopropylbenzenesulfonyl chloride (0.17 g) and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1 as the eluant. To a solution of the product in ethyl acetate (15 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml) and the mixture was stirred at room temperature for 20 minutes. The precipitate was isolated by filtration and washed with ethyl acetate to afford the title compound (0.28 g, mp 134-136° C.).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][C:35]([SH:37])=[N:34][N:33]=2)=[CH:28][CH:27]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:37][C:35]3[O:36][C:32]([C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)=[N:33][N:34]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1nnc(-c2ccncc2)o1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(-c4ccncc4)o3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31].CO>CC(C)=O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:7])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: O
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(SC)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium periodate (0.214 g.; 0.001 mole) in 3 ml. of water is added dropwise to 5-methoxy-2-methyl-1-(ρ-methylthiobenzylidene)-3-indenyl acetic acid (0.352 g.) (0.001 mole) in 25 ml. methanol and enough acetone to cause solution. This solution is stirred overnight at room temperature and filtered. The filtrate is evaporated at 30° to a sufficiently small volume that causes the product to precipitate. The suspension is diluted with several volumes of water, cooled and collected. The product is dried in vacuo over potassium hydroxide pellets and then in a vacuum oven at 70° to give 5-methoxy-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenyl acetic acid (M.P. 200.5-203.5°).