Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[CH:9][C:10]=1[OH:11].C(OC(=O)C)(=O)C>O>[OH:11][C:10]1[CH:9]=[C:8]([CH3:12])[CH:7]=[CH:6][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: Cc1ccc(N)c(O)c1
Reactant: CCO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(C)cc1O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a mixture of 40 ml of ethanol with 60 ml of water, there was added 20.0 g (16.3 mmol) of 6-amino-m-cresol, followed by heating to 80° C. To the obtained solution, there was added dropwise 17.4 g (17.1 mmol) of acetic anhydride over 10 minutes and the mixture was stirred at 80° C. for 15 minutes. After the completion of the reaction, the mixture was cooled to 10° C. The crystals thus precipitated were filtered, washed with water and dried. Thus 23.9 g (15.0 mmol) of N-(2-hydroxy-4-methylphenyl)acetamide was obtained as pale brown crystals. The yield was 89%. A 20.0 g portion of this product was recrystallized from acetonitrile to thereby give 17.9 g of N-(2-hydroxy-4-methylphenyl)acetamide as colorless crystals. The recovering yield was 90%.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=2[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.CCOC(C)=O>[CH2:1]([O:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([Cl:9])[S:11][C:12]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2nc(Cl)sc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Clc1nc2ccc(OCc3ccccc3)cc2s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Benzyl bromide (0.921 g, 5.39 mmol) was added to a mixture of 2-chlorobenzo[d]thiazol-6-ol (1.00 g, 5.39 mmol) and cesium carbonate (1.76 g, 5.39 mmol) in CH3CN (15 mL). After 2 h at rt, the reaction mixture was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×75 mL) and brine (75 mL). The EtOAc layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 8% EtOAc in Hexanes gradient), yielding 1.396 g (94%) of the title compound as a reddish, waxy solid. LC-MS: RT=10.51 min., [M+H]+=275.9. Rf=0.41 in 10% EtOAc/Hexanes.
Reaction SMILES: Cl[C:2]([CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])[N:9]=[CH:8][C:7]=1[C:22]#[N:23])=[O:3].[CH2:24]([NH2:26])[CH3:25]>C(C(C)=O)C>[Cl:21][C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=1[N:10]1[C:6]([NH:5][CH2:4][C:2]([NH:26][CH2:24][CH3:25])=[O:3])=[C:7]([C:22]#[N:23])[CH:8]=[N:9]1
Reactant: N#Cc1cnn(-c2ccc(C(F)(F)F)cc2Cl)c1NCC(=O)Cl
Reactant: CCN
Solvent: CCC(C)=O
Product: CCNC(=O)CNc1c(C#N)cnn1-c1ccc(C(F)(F)F)cc1Cl
Reaction time: 1 h

Procedure:
A solution of 5-chlorocarbonylmethylamino-1-(2-chloro-4-trifluoromethylphenyl)-4-cyanopyrazole (4.72 g) in dry methyl ethyl ketone (25 ml) was added over 5 minutes to a stirred solution of ethylamine (20 ml) in methyl ethyl ketone (100 ml) at 0° C. (maintained by external cooling). The resulting suspension was stirred for 1 hour whilst the reaction mixture attained laboratory temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in a mixture of diethyl ether (100 ml) and water (100 ml). After separation of the organic layer, the organic layer was washed successively with aqueous 2N hydrochloric acid (2×100 ml) and water (3×50 ml) and dried over anhydrous sodium sulphate. Evaporation of the solution to dryness gave a fawn coloured powder (3.6 g. m.p. 144°-145° C.) which was chromatographed using dichloromethane-ethyl acetate (4:1) as eluent. Evaporation of the eluate containing the major component gave a yellow oil which was crystallised from a mixture of toluene (5 ml) and hexane (40 ml) to give 1-(2-chloro-4-trifluoromethylphenyl)-4-cyano-5-ethylaminocarbonylmethylaminopyrazole, m.p. 150°-151° C. in the form of colourless crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cc1cncc(C)c1
Reactant: CCCCC#CCCCCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1cc(C)cc(C)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 3,5-lutidine (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 3,5-lutidine was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (78%). 1HNMR (300 MHz, CDCl3, ppm), 9.06 (s, 2H), 8.00 (s, 1H), 4.86 (t, 3H), 2.48 (s, 3H), 1.98-2.16 (m, 6H), 1.32-1.48 (br, 10H), 0.88 (t, 3H); 13CNMR, 146.12, 141.38, 138.64, 80.43, 79.53, 61.46, 31.70, 31.17, 28.68, 28.07, 25.55, 21.92, 18.57, 18.42, 13.63.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5].[CH:10]1(O)[CH2:15][CH2:14]C[CH2:12][CH2:11]1.S(=O)(=O)(O)O>CO>[CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH:7]1[CH2:14][CH2:15][CH2:10][CH2:11][CH2:12]1)=[O:5]
Reactant: OC1CCCCC1
Reactant: COC(=O)C(=O)N(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Product: CN(C)C(=O)C(=O)OC1CCCCC1
Temperature: 80 °C

Procedure:
In a 1,000 mL reactor, are mixed at 20-25° C., methyl 2-(dimethylamino)-2-oxoacetate) (compound 1) (393 g, 3 mol), cyclohexanol (360 g, 3.6 mol) and 98% sulfuric acid (66 g, 0.67 mol). The temperature of the mixture is brought to and maintained at 80° C. for 36 hours. Progression of the reaction is followed by gas chromatography analysis. At the end of the reaction, the methanol formed is removed from the reaction medium by distillation under reduced vacuum (P min=150 mbars) and an aqueous solution of sodium hydrogen carbonate is then added to the reaction medium so that the final pH is 7. The organic phase is separated from the aqueous phase. The latter is counter-extracted with 500 mL of dichloromethane. The organic phases are collected and the reaction medium is then concentrated for removing the dichloromethane. To the residue are added 5 g of potassium carbonate and the thereby obtained medium is then distilled under partial vacuum (Tbp 115-120° C., P<1 mbar). The expected product is obtained with a purity of more than 98.2% (466 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([CH:9]([C:14]([CH3:16])=[CH2:15])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[N:8]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)C)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O
Yield: 98.3 %

Procedure:
A mixture containing 6.7 g (17.2 mmol) of (2R) methyl 2-((3S,4S)-4-acetoxy-3-benzyloxycarbonylaminoazetidine-2-on-1-yl)-3-methylbut-3-enoate and 1.8 ml of triethylamine in 180 ml of methylene chloride is refluxed for 60 minutes in a nitrogen atmosphere. After cooling of the solution it is washed subsequently with 100 ml aqueous 1N hydrogen chloride solution and 100 ml of saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and evaporated in vacuo. In this way, 6.6 g (98%) of title compound as a pure, noncrystalline solid is obtained. IR spectrum in methylene chloride: 3400, 3000, 1790, 1730, 1510 and 1210 cm-1.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]3)[S:14][C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)(=O)=O.Cl.[NH:26]1[CH2:30][C@H:29]([OH:31])[C@H:28]([OH:32])[CH2:27]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:23][C:20]1([CH3:24])[CH2:21][CH2:22][CH:17]([C:15]2[S:14][C:9]3[N:10]=[C:11]([CH3:13])[N:12]=[C:7]([CH2:6][N:26]4[CH2:30][C@H:29]([OH:31])[C@H:28]([OH:32])[CH2:27]4)[C:8]=3[CH:16]=2)[CH2:18][CH2:19]1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: O[C@@H]1CNC[C@@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CN2C[C@@H](O)[C@@H](O)C2)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 50 °C
Reaction time: 12 h
Yield: 8.8 %

Procedure:
A suspension of [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (100 mg), cis-pyrrolidine-3,4-diol hydrochloride (57 mg), and K2CO3 (75 mg) in DMF (3 mL) was stirred at 50° C. for 12 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH). The obtained purified product was suspended in IPE, and the precipitate was collected by filtration to obtain cis-1-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}pyrrolidine-3,4-diol (9 mg).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH3:11])=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:13]>C(Cl)Cl>[CH:1]([C:4]1[C:5]([CH2:11][OH:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(C(C)C)ccc[n+]1[O-]
Solvent: ClCCl
Product: CC(C)c1cccnc1CO
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of 3-isopropyl-2-methyl-pyridine 1-oxide (26.05 g, 173 mmol) in CH2Cl2 (690 mL) was added dropwise TFAA (51.83 mL) over 30 min. under N2 then stirred for an additional 3 h. Caution: exothermic reaction on addition of TFAA. The mixture was concentrated in vacuo to a minimum volume. Brine (200 mL) was added, basified to pH 9 with solid K2CO3 slowly, then the aqueous mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford (3-isopropyl-pyridin-2-yl)-methanol (26 g, 99%) as an orange oil. 1H NMR (CDCl3) δ 1.24 (d, 6H, 7.0 Hz), 2.92 (sep, 1H, J=6.6 Hz), 4.79 (s, 2H), 7.02-7.25 (m, 1H), 7.61 (d, 1H, J=7.9 Hz), 8.41 (d, 1H, J=4.8 Hz).
Reaction SMILES: N[C:2]1[C:9]([Br:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].OS(O)(=O)=O.N([O-])=O.[Na+].CCOC(C)=O>CCO.O>[Br:10][C:9]1[CH:2]=[C:3]([CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])cc(Br)c1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)cc([N+](=O)[O-])c1
Reaction time: 13.5 h
Yield: 82.3 %

Procedure:
To a stirring mixture of 1.2 g (4.96 mmol) of 2-amino-3-bromo-5-nitrobenzonitrile and 2.8 mL of H2SO4 in 28 mL of EtOH at 90° C. was added 2.5 g (36.2 mmol) of NaNO2 in several portions. After 13.5 h, EtOAc and H2O were added. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 927 mg of 3-bromo-5-nitrobenzonitrile in 82% yield as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl>CN(C=O)C>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CN(C)CCCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution containing 2.76 g of 4-nitroaniline (20 mmol) in 20 mL DMF was added 1.60 g of NaH (60% dispension in oil, 40 mmol). After 2 hours at room temperature, 2-(dimethylamino)ethyl chloride hydrochloride (3.46 g, 24 mmol) was added, and the reaction mixture was heated at 60° C. for 12 hours. The solvent was evaporated in vacuo to yield a residue which was partitioned between ethyl acetate and brine. The organic phase was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo to yield a residue. Purification of the residue by flash chromatography with 2% MeOH in CH2Cl2 as the eluent yielded N,N-dimethyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine (2.34 g, 56%) and the title compound (1.23 g, 22%). MS (ES+) m/e 281 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:16]1=2.N1C=CC=CC=1>ClCCl>[C:1]([N:14]([CH2:13][C:12]1[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:10]([C:9]([F:8])([F:40])[F:41])[CH:11]=1)[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:16]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Br)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (5.47 g, 22.5 mmol) followed by titanium isopropoxide (5.98 mL, 20.1 mmol) to a solution of isopropyl 8-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (5.24 g, 16.1 mmol) in tetrahydrofuran (20 mL) at room temperature under nitrogen was and stir the solution for 4 h. Dilute the reaction with methanol (40 mL) and slowly add sodium borohydride (0.912 g, 24.1 mmol) over 15 min to the reaction and stir at room temperature for 3.5 h. Quench the reaction with addition of 2 N NaOH (56 mL) and water (50 mL) and stir for 0.5 h. Filter the mixture and wash the solids with ethyl acetate/ethanol (4:1, 3×100 mL). Separate the filtrate and wash the organic layer with 2 N NaOH, 2 N HCl, and brine (50 mL each), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure to afford isopropyl-5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate as a white solid. Add acetic anhydride (22.6 mL, 241 mmol) dropwise to a suspension of isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (8.89 g, 16.1 mmol) and pyridine (19.6 mL g, 241 mmol) in dichloromethane (64 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Dilute the mixture with dichloromethane (100 mL) and wash with 2 N hydrochloric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid (7.60 g, 79%, 2 steps): ESI MS 595 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:16]=[CH:17][C:10]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccnc2[nH]ccc12
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccnc2c1ccn2S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of (1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (400 mg, 1.62 mmol) in DMF (10.0 mL) was added powdered KOH (143 mg, 1.88 mmol). After 15 minutes, methanesulfonyl chloride (137 μL, 1.78 mmol) was added. After 15 hours, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over magesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% ethyl acetate in heptane to afford (1-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[CH3:29][O:28][C:4]1[CH:3]=[C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Product: COc1cc(-c2cccc(C(F)(F)F)c2)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ccncn3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 525, except that 4-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)quinazoline-7-sulfonamide and (3-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners to afford 4-(3-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)quinazoline-7-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.48 (s, 1H), 8.58 (s, 1H), 8.50 (s, 1H), 8.23 (br. s., 1H), 8.19-8.11 (m, 2H), 8.10-8.01 (m, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.85-7.72 (m, 2H), 7.62-7.53 (m, 3H), 7.01 (br. s., 1H), 3.82 (s, 6H). m/z (ESI) 538.2 (M+H)+.
Reaction SMILES: [C:1](OCC[C@@H](OS(C)(=O)=O)C)(=[O:8])[C:2]1C=CC=[CH:4][CH:3]=1.CN(C)C=O.[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[C:30]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:31]=[CH:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:8][CH2:1][CH2:2][C@H:3]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[C:30]([NH:35][C:36]([CH:38]3[CH2:39][CH2:40]3)=[O:37])[N:31]=[CH:32]2)=[CH:27][CH:26]=1)[CH3:4]
Reactant: C[C@@H](CCOC(=O)c1ccccc1)OS(C)(=O)=O
Reactant: O=C(Nc1cc2ccc(O)cc2cn1)C1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@H](CCO)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 45.1 %

Procedure:
To a solution of (S)-3-(methylsulfonyloxy)butyl benzoate (82.6 mg, 0.303 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) was added N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (49.7 mg, 0.218 mmol) and cesium carbonate (147.4 mg, 0.4524 mmol). The reaction mixture was stirred at 50° C. for 4 hours. To the reaction mixture was then added 2.0 M of potassium hydroxide in methanol (1.0 mL), and the temperature was maintained at 50° C. for one hour. The reaction was neutralized with 10% aqueous citric acid and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 29.5 mg (45%) of (R)-N-(7-(4-hydroxybutan-2-yloxy)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=3.446, M+H=301.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.98 (s, 1H), 8.36 (s, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.32 (dd, J=8.9, 2.5 Hz, 1H), 4.73 (h, J=6.1 Hz, 1H), 4.52 (t, J=5.0 Hz, 1H), 3.56 (dd, J=11.5, 6.1 Hz, 2H), 2.10-1.98 (m, 1H), 1.92 (td, J=12.9, 6.2 Hz, 1H), 1.74 (td, J=12.6, 6.5 Hz, 1H), 1.33 (d, J=6.1 Hz, 3H), 0.90-0.73 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:22]([CH3:25])([CH3:24])[CH3:23])[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][N:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[N:3]=[C:4]([C:22]([CH3:25])([CH3:24])[CH3:23])[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:34][C:32]2[CH:31]=[CH:30][N:29]=[C:28]([O:27][CH3:26])[CH:33]=2)[N:8]=1
Reactant: COc1cc(N)ccn1
Reactant: CC(C)(C)c1nc(Br)c(-c2ccnc(Cl)n2)n1COCC[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cc(Nc2nccc(-c3c(Br)nc(C(C)(C)C)n3COCC[Si](C)(C)C)n2)ccn1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A mixture of 4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (500 mg, 1.1 mmol; Example 6, Step 4), 2-methoxypyridin-4-amine (153 mg, 1.2 mmol), Pd(OAc)2 (30 mg, 0.14 mmol), XANTPHOS (117 mg, 0.20 mmol), cesium carbonate (731 mg, 2.2 mmol) in dry dioxane (9 ml) was sparged with N2 for 5 min. The reaction was sealed and heated at 100° C. for 2 hr. The reaction was allowed to cool to rt and partitioned between EtOAc and water. The layers were separated and the aqueous portion was extracted with EtOAc. The combined organic portions were dried (MgSO4) and concentrated to an orange residue which as purified by column chromatography (SiO2, 100:0-0:100, hexanes-EtOAc) to provide 386 mg of 4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine: LCMS (m/z): 533.2 (MH+), tR=0.92 min.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:5]=2[N:6]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:11][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1nc2c([N+](=O)[O-])cccc2o1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2c(N)cccc2o1
Temperature: 65 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
Compound 474A (6.78 g, 38.1 mmol) was dissolved in a 1:1 mixture of 10% acetic acid/ethyl acetate (100 mL total volume) and heated to 65° C. Iron powder (10.63 g, 190.2 mmol) was added portionwise. After stirring for 3 h, TLC indicated complete consumption of starting material. The cooled reaction mixture was filtered through a pad of Celite and the pad was washed with 50 mL of ethyl acetate. The organic layer was separated, washed with water (2×25 mL), brine (1×25 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with 25% ether/CH2Cl2 to give 3.90 g (69%) of compound 474B as a light brown solid. HPLC: 95.8% at 2.43 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 149.11 [M+H]+.