Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([N+:19]([O-])=O)[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[O:16]1[CH2:17][CH2:18][N:13]([C:10]2[C:9]([NH2:19])=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:12][N:11]=2)[CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 25 °C

Procedure:
To a stirring solution of 4-(5-morpholino-3-nitropyridin-2-yl)morpholine (1.22 g, 4.15 mmol; described herein) and EtOAc (50 mL) was added tin(II) chloride dihydrate (4.52 g, 20.7 mmol). The mixture was stirred at rt for ten min, refluxed for 2 h, and then cooled to rt. A solid was removed by filtration and both this and the EtOAc solution were washed with water and brine. The combined aq. portions were basified with 1M NaOH and the product extracted with EtOAc, dried (magnesium sulfate), and concentrated, affording 2,5-dimorpholinopyridin-3-amine as a beige solid. Mass Spectrum (ESI) m/e=265.2 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12]>O>[N+:1]([C:7]1[C:6]([CH3:12])=[CH:5][C:10]([OH:11])=[CH:9][CH:8]=1)([O-:4])=[O:2]
Reactant: Cc1cccc(O)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1cc(O)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A reaction apparatus with a stirrer was charged with 84 ml of 99% nitric acid and 540 ml water, and the mixture was cooled to 0° C. Thereafter, at one and the same time, 54 g of m-cresol and 53 g of liquid N2O3 were added. The temperature was kept through cooling the whole time below 5° C. After the addition of m-cresol and N2O3 had been completed, the stirring was continued for 1 hour, the temperature then being kept at approx. 0° C. Thereafter the temperature was allowed to rise to approx. 30° C., and at that temperature the stirring was continued for 2 hours. The reaction mixture was thereafter cooled to 0° C. and a solid product was then precipitated. This solid product was then filtered off, washed with water and dried. In this way, 70 g of raw p-nitro-m-cresol with a melting point of 118°-122° C. was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]1[CH2:2][CH2:3][C:4]2[CH:9]=[C:8]3[C:7](=[CH:6][C:5]1=2)[C:13](=[N:17][OH:18])[CH2:12][CH2:11][CH2:10]3
Reactant: NO
Reactant: O=C(O)CCCc1ccc2c(c1)CCO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2cc3c(cc21)OCC3

Procedure:
A mixture containing 46 g of the compound of Example 1, 60 g of hydroxylamine hydrochloride and 60 g of anhydrous sodium acetate in 410 ml of ethanol is brought to reflux for 5 hours. The mixture is then cooled and diluted with water, extracted with methylene chloride, dried and evaporated to dryness. The dry residue is recrystallized in ethanol.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>P(Cl)(Cl)(Cl)=O>[CH3:25][N:22]1[CH2:21][CH2:20][N:19]([C:17]2[C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[CH2:3][CH2:2][N:1]([C:9]=34)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=2)[CH2:24][CH2:23]1
Reactant: CN1CCN(C(=O)Nc2ccccc2N2CCc3ccccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3N3CCc4cccc2c43)CC1
Yield: 10 %

Procedure:
To 21.1 g (0.0627 mole) of N-[2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide of Example 7a was added 500 ml of phosphorus oxychloride and this was refluxed under nitrogen overnight. The excess POCl3 was then removed at aspirator pressure with warming. The residue was boiled and triturated on the steam bath with 60 ml of absolute ethanol until solution resulted. This solution was cooled and stirred resulting in separation of a solid. This solid was collected, washed with ethanol, with ether, and finally hexane, then dried to afford 19.0 g. This was partitioned between 200 ml of chloroform and 100 ml of water, with good stirring. Addition of 2.5N-NaOH rendered the medium basic, and the product base passed into the organic phase. This was separated, washed twice with water, dried over Na2SO4 and concentrated to 6.5 g of an oil. This oil was boiled with 60 ml of acetone, filtered from some insolubles, and the filtrate concentrated under nitrogen to 20 ml and allowed to crystallize. This gave 2.6 g of solid, m.p. 144°-146° C. dec. This material was treated with 20 ml of 2N-HCl with stirring. The resulting solution was filtered from a small amount of insolubles, then made basic with 2.5N-NaOH and the product extracted into dichloromethane. The latter extract was washed twice with water, dried over Na2SO4, and concentrated to an oil which began to crystallize. This was quickly dissolved in a small volume of boiling acetone and allowed to crystallize. The crystals were collected, washed with a little acetone, and dried to afford 2.00 g (10% overall yield) of 6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine, m.p. 149°-151° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:13])[O:12][CH2:11][CH2:10]1>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12]
Reactant: Cc1ccccc1S
Reactant: O=C1CCO1
Solvent: CC#N
Product: Cc1ccccc1SCCC(=O)O
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A solution of acetonitrile (30 mL) and o-thiocresol (5.0 g, 40 mmol) was heated to reflux. Neat β-propiolactone (2.8 mL, 40 mmol) was added dropwise over 5 min. Heating was continued at reflux for 20 h at which time additional β-propiolactone (2.8 mL, 40 mmol) was added in one portion. After heating for an additional 24 h, the reaction mixture was concentrated in vacuo. The resultting solid-oil mixture was treated at 23° C. with 2N aqueous NaOH (150 mL). This basic solution was washed with Et2O (2×200 mL). The separated aqueous layer was acidified with conc. aqueous HCl until pH<1. This heterogenous solution was concentrated in vacuo to half of its original volume. Then it was allowed to stand at 23° C. for 2 h. The solid product was collected by vacuum filtration, washed with H2O (20 mL), and dried under vacuum at 65° C. for 2 h to afford 3-[(2-methylphenyl)sulfanyl]propanoic acid (4.62 g, 59%) as a white powder. 1H NMR (CHCl3, 300 MHz) δ7.31 (d, 1H, J=7.0 Hz), 7.20-7.15 (m, 3H), 3.14 (t, 2H, J=7.3 Hz), 2.69 (t, 2H, J=7.4 Hz), 2.39 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18](I)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([C:29]3[S:30][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(I)c(C(F)(F)F)nn2)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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(Cl)s3)c(C(F)(F)F)nn2)CC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
A mixture of 4-(5-iodo-6-trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D10) (0.20 g, 0.436 mmol), 5-chlorothiophene-2-boronic acid (0.082 g, 0.51 mmol), tetrakis(triphenylphosphine)palladium (0) (0.024 g, 0.021 mmol) and sodium carbonate (0.103 g, 0.96 mmol) in dimethoxyethane (3 ml) and water (0.75 ml) was stirred in a sealed tube at 110° C. for 16 h. The mixture was then filtered through a pad of diatomaceous earth and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane/10% ammonia in methanol (7M) in dichloromethane 97/3) to yield D15 (0.152 g, 67%) as a yellow syrup. C18H20ClF3N4O2S requires 448; Found 449 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].F[B-](F)(F)F.[CH3:18][O+](C)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](=[NH:9])[O:8][CH3:18]
Reactant: C[O+](C)C
Reactant: COc1ncc(Br)cc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=N)c1cc(Br)cnc1OC
Reaction time: 12 h
Yield: 124.5 %

Procedure:
To a solution of 5-bromo-2-methoxynicotinamide (4.7 g, 0.02 mol) in dichloromethane (100 mL) was added Trimethyl-oxonium tetrafluoro borate (4.6 g, 0.02 mol) at room temperature. The mixture was stirred at room for 12 hours. The solvent was moved off and the resulting residue was washed with dichloromethane (50 mL*2), then dry to provide methyl 5-bromo-2-methoxynicotinimidate (6.1 g, yield 91%). 1HNMR (400 MHz, D2O) δ 8.46 (m, 2H), 4.22 (s, 3H), 4.02 (s, 3H), 1.93 (s, 2H). MS (M+H)+: 333/335.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Under inert gas atmosphere 5.00 g (23.3 mmol) 5-bromo-2-ethoxy-pyridine are added to a mixture of 7.19 g (23.3 mmol) 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, 95 mg (1.2 mmol) PdCl2(dppf)xCH2Cl2 and 15.2 g (46.5 mol) Cs2CO3 in 50 mL DMF and 10 mL H2O. The mixture is stirred for 12 h at 80° C. After that time, the solvent is evaporated, the residue taken up in DCM and washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; gradient PE/EtOAc 20:1→10:1) to yield the desired product which was directly used in the next step.
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][C:5]([C:7]1[C:12](=[O:13])[NH:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6]>>[Br:3][CH2:4][CH:5]([C:7]1[C:12](=[O:13])[NH:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)[OH:6]
Reactant: CCOC(=O)c1cc(C(=O)CBr)c(=O)[nH]c1C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)c1cc(C(O)CBr)c(=O)[nH]c1C(=O)OCC
Temperature: 0 °C

Procedure:
Sodium borohydride (2.54 g, 0.066 mol) is added in portions over a 30 minute period to a stirred suspension of diethyl 5-(bromoacetyl)-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (57.2 g, 0.159 mol) at 10°-20° C. Upon completion of the sodium borohydride addition, the reaction mixture is stirred while attaining room temperature. Ice (100 g) is added and the mixture stirred until the ice has melted. The mixture is then concentrated in vacuo and the residue crystallized twice from an ethyl acetate-hexane mixture to give pure diethyl 5-(2-bromo-1-hydroxyethyl)-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate mp 134°-138° C. Stirring this compound with triethylamine (1.0 mL/g of solid) in methylene chloride for one hour, followed by washing the organic solution with dilute hydrochloric acid, water, brine and drying over anhydrous MgSO4 yields the crude furo[2,3-b]pyridine as an oil upon removing the solvent in vacuo. Crystallization from a cyclohexane-toluene mixture affords pure diethyl 2,3-dihydro-3-hydroxy-furo[2,3-b]pyridine-5,6-dicarboxylate mp 73°-77° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1.Cl>>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:12][CH2:13][C@H:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]2)[CH2:15][CH2:16]1
Reactant: O=C1CCC([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: O[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1
Temperature: -20 °C

Procedure:
First, 40 ml of a mixed solvent (methanol/tetrahydrofuran=1/7) was placed in a 200 ml flask. The solvent was cooled to -20° C., and 0.55 g of sodium borohydride was added to the solvent. Separately, 2.1 g of 4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanone was dissolved in 30 ml of a mixed solvent (methanol/tetrahydrofuran=1/7). This solution was added dropwise to the previously prepared mixed solvent, and the resultant mixture was stirred overnight. Then, 5% diluted hydrochloric acid was added to the reaction mixture so as to make it acidic. Methanol was distilled away from the mixture under reduced pressure, and the residue was extracted with ethyl acetate. The solution thus obtained was washed with water and dried over anhydrous sodium sulfate, and a solvent was distilled away. Thereafter, the residue was purified by column chromatography (eluent: hexane/ethyl acetate=7/3 to 1/1) and recrystallized from methanol to obtain 1.44 g of trans-4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanol(Y: 67%). The compound thus obtained had a purity of 98.1% by GC.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].[CH3:22][Sn](C)(C)C>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([CH3:22])[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C)c2nc(-c3ccccc3)oc2c1O
Temperature: 130 °C
Yield: 61.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (200 mg, 0.573 mmol), tetramethyltin (0.32 mL, 2.29 mmol), and dichlorobis(triphenylphosphine)palladium(II) (40.2 mg, 0.057 mmol) was suspended in 4.8 mL of anhydrous N,N-dimethylformamide. The reaction mixture was heated at 130° C. for 1 hour, cooled to room temperature, and diluted with ethyl acetate. The organic mixture was successively washed with saturated sodium bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography eluting from silica gel with a gradient of 0-100% ethyl acetate in hexanes to give 99.6 mg of the title compound as a white solid. MS: (+) m/z 285.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])[C:29]([O:31]CC)=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][C:36]([F:48])([F:47])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Yield: 71.2 %

Procedure:
Ethyl 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (0.38 g, 0.53 mmol) and sodium hydroxide (170 mg, 4.2 mmol) were added to an ethanol/water mixture (2:1, 15 ml), followed by heating under reflux for 4 hours. After the reaction mixture was neutralized with 1N hydrochloric acid, the solvent was distilled off and the resulting residue was diluted with water, adjusted to pH 2-3 with 1N hydrochloric acid, and then extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid (260 mg, Yield 87%) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33].C(N(CC)CC)C>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:2]([NH:1][C:32]([C:23]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)=[O:33])[CH:7]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2N)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2NC(=O)c2ccc3ccccc3c2)c1=O

Procedure:
A solution of 3-(2-amino-4-chlorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.4 g), 2-naphthoyl chloride (0.29 g) and triethyl amine (0.19 g) in anhydrous tetrahydro furan (30 ml) was heated at reflux temperature overnight under nitrogen atmosphere.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C=O)C.O>[Cl:13][CH2:14][CH2:15][CH2:16][O:9][C:5]1[CH:4]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 103.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-(dimethylamino)phenol (3.50 g, 25.51 mmol) in DMF (30 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.80 g of an 80% dispersion in mineral oil, 26.79 mmol) in DMF (40 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1.25 h. The resulting brown mixture was cooled to 0-5C. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (6.26 g, 30.62 mmol). The resulting reddish brown mixture was stirred at ambient temperature for 4.25 h. Cold water (35 mL) was carefully added, followed by saturated NaCl solution (35 mL). The resulting mixture was extracted with ether (4×50 mL). The combined dull-yellow ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing a light-brown oil (5.65 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:33]([F:35])[F:34])[N:3]=1.[CH3:36][N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:35][CH:33]([F:34])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:39]3[CH:40]=[CH:41][N:37]([CH3:36])[N:38]=3)[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Cn1cc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(-c2ccn(C)n2)nc(N2CCOCC2)n1
Temperature: 20 °C
Yield: 68.5 %

Procedure:
A mixture of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (Example 64) (313 mg, 0.61 mmol), 1-methyl-1H-pyrazol-4-ylboronic acid (155 mg, 1.22 mmol), and aq. 2 M K2CO3 (4.1 mL) in 1,4-dioxane (20 mL) was degassed with N2 for 30 min and then Pd(dppf)Cl2 (30 mg) was added, and the mixture was degassed for a further 10 min. The reaction mixture was heated under reflux for 1 hr, cooled to 20° C., diluted with water, and extracted with CH2Cl2 (20 mL×3). The combined CH2Cl2 extracts were dried (Na2SO4) and the solvents were removed to gave a crude product which was purified by chromatography on silica, eluting with CH2Cl2/EtOAc (4:1) to give tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-(1-methyl-1H-pyrazol-3-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate (233 mg, 69% yield): mp (CH2Cl2/hexanes) 224-227° C.; 1H NMR (DMSO-d6) δ 9.60 (s, 1H), 8.75 (s, 1H), 8.64 (s, 1H), 8.28 (m, 1H), 7.82 (t, JHF=53.1 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 3.99-3.96 (m, 4H), 3.96 (s, 3H), 3.92 (s, 3H), 3.76 (m, 4H), 1.53 (s, 9H); Anal. Calcd. for C25H29F2N9O4.0.25H2O: C, 53.4; H, 5.3; N, 22.4. Found: C, 53.3; H, 5.3; N, 22.3%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CN(C)CCN
Product: CN(C)CCNS(=O)(=O)c1ccc(Cl)nc1
Yield: 72 %

Procedure:
The title compound was prepared as described for Example 29 using 6-chloropyridine-3-sulfonylchloride and N,N-dimethylethane-1,2-diamine. Yield: 72%: MS (MS) m/z 264 (M++1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:39][N:40]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CN(C)C(=O)CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CN(C)C(=O)CN1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-acetamide (Example 80) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine via General Procedure A. Purification on silica yielded 172. (400 MHz CDCl3): 2.61 (8H, s, CH2), 2.94 (3H, s, CH3), 3.07 (3H, s, CH3), 3.19 (2H, s, CH2), 3.82 (2H, s, CH2), 3.87 (4H, m, CH2), 4.01 (4H, m, CH2), 5.19 (2H, s, NH), 7.26 (1H, s, ar), 9.28 (2H, s, ar). MH+498.37