Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:21])[N:4]=1.I([O-])(=O)(=O)=[O:23].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:21][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:3]([CH:2]=[O:23])=[N:4]2
Reactant: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluorophenyl)quinoxaline (Prepared in Example 100, 0.5625 g, 1.457 mmol) and sodium metaperiodate (0.1613 mL, 2.914 mmol) in DMF (9.714 mL, 1.457 mmol) was heated at 150° C. with stirring. After 3 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Seplivi column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 3 min as eluent to give 5-chloro-3-(2-chloro-5-fluorophenyl)quinoxaline-2-carbaldehyde as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (1 H, s), 8.35-8.41 (1 H, m), 8.29-8.34 (1 H, m), 8.07 (1 H, dd, J=8.4, 7.6 Hz), 7.68 (1 H, dd, J=8.8, 4.9 Hz), 7.44-7.58 (2 H, m); LC-MS (ESI) m/z 321.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12](Br)[C:13]#[CH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:14][C:13]#[CH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCOc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
To a solution of 2-(tert-butyl)phenol (21.0 g, 140 mmol) and propargyl bromide (18.8 mL, 168 mmol) in acetonitrile (250 mL) was added potassium carbonate (23.3 g, 168 mmol). The reaction was stirred at ambient temperature for two days. The reaction mixture was diluted with water (50 mL) and extracted diethyl ether (2×150 mL). The combined organic extracts were concentrated to provide 23.7 g (90%) of the title compound which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 7.26-7.14 (m, 2H), 7.02 (d, J=8.0 Hz, 1H), 6.94-6.86 (m, 1H), 4.83 (d, J=2.4 Hz, 2H), 3.55 (t, J=2.4 Hz, 1H), 1.34 (s, 9H).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(-c2ccc(O)nc2)cc1
Product: COC(=O)c1ccc(-c2ccc(Cl)nc2)cc1

Procedure:
A solution of Example 252E (1.2 g, 5 mmol) in POCl3 (30 mL) was heated to reflux for 30 minutes. The excess POCl3 was removed under vacuum and the remaining product was purified by flash column chromatography on silica gel with 4:1 ethyl acetate/hexanes to provide the desired product. MS (ESI) m/e 248 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:34])([F:33])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:30][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][C:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C:7]([F:6])([F:33])[F:34])=[N:9][N:10]=4)[N:13]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
A solution of methanesulfonyl chloride (2.74 mL, 35.46 mmol) in DCM (40 mL) was added dropwise to a stirred solution of 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (12.04 g, 29.55 mmol) and triethylamine (8.24 mL, 59.11 mmol) in DCM (120 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes then warmed to room temperature and stirred for a further 15 minutes. The reaction mixture was diluted with DCM (100 mL), and washed with water (250 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to give 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (14.32 g, 100%) as a solid.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[O:26])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1>C(OC(=O)C)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([N:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[C:29](=[O:30])[CH:28]=[CH:27][C:25]4=[O:26])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:1](=[O:3])[CH3:2])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: O=C(O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(c1cccc(Br)c1)c1ncnc2ccc(N3C(=O)C=CC3=O)cc12
Temperature: 25 °C
Yield: 39 %

Procedure:
Sodium acetate (0.10 g, 1.2 mmol) was added to a suspension of 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid (Z) (0.25 g, 0.61 mmol) in 5 mL of acetic anhydride, and the mixture was heated under reflux for 30 minutes. After cooling to room temperature, the reaction was filterd and the filtrate concentrated to dryness in vacuo. The residue was taken up in EtOAc and washed sequentially with saturated sodium bicarbonate, water, and brine. The EtOAc portion was dried over magnesium sulfate, filtered and concentrated to afford a faintly pink solid. The solid was recrystallized twice from EtOAc to afford N-(3-bromo-phenyl)-N-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-quinazolin-4-yl]-acetamide (0.104 g, 39%) as an off-white powder, mp 174-175° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:13]=1[NH2:14])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:12]([CH:9]([CH3:11])[CH3:10])[C:13]=1[NH:14][C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH3:20]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(=O)OCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.2 %

Procedure:
To a solution of acetoxyacetyl chloride (13.5 g, 98.7 mmol) in toluene (70 mL) at 0° C. is added dropwise via a dropping funnel a solution of 2,6-diisopropylaniline (17.5 g, 98.7 mmol) and triethylamine (20.6 mL, 148.1 mmol) in toluene (20 mL). After completion of the addition, the mixture is allowed to warm to room temperature and stirred for 24 hours. The mixture is filtered through a small pad of silica gel. The filtrate is concentrated to afford 11 g of a brown solid. The precipitate is suspended in ethyl acetate and stirred overnight. After filtration, the filtrate is concentrated to give another 10 g of a brown solid. Recrystallization (ethyl acetate/hexane) of the combined material provided 12 g of the title compound as an off-white solid; mp 179°-182° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:31][C:32](Cl)=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1C=CC=CC=1>[C:32](=[O:33])([O:31][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 1.24 g. of chloroformic acid n-nonyl ester as in Example 1. The 2.026 g. of yellowish, turbid oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.646 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-nonyl carbonate obtained melts at 53.0°-53.1° and has a clearing point of 70.0°. The compound is smectic up to 68.1°. UV (EtOH): ε 271 = 26600.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:8]2=[O:10]
Reactant: O=Cc1cccs1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: CCO
Product: O=C1CC(c2cccs2)Oc2ccc(Br)cc21
Yield: 55.6 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (20 g, 0.093 mol), thiophene-2-carbaldehyde (10.46 g, 0.093 mol) and borax (35.4 g, 0.093 mol) in ethanol (120 mL) and H2O (200 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-thiophen-2-yl-chroman-4-one (16 g, 50%). 1H-NMR (CDCl3): 3.01 (m, 1H), 3.10 (m, 1H), 5.75 (dd, 1H), 6.94 (d, 1H), 7.02 (t, 1H), 7.05 (d, 1H), 7.32 (d, 1H), 7.54 (dd, 1H), 8.00 (d, 1H).
Reaction SMILES: C([O:3][C:4](/[C:6](/[CH3:30])=[CH:7]/[C:8]1[N:17]=[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:29])[CH:14]=2)[N:9]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[C:4](/[C:6](/[CH3:30])=[CH:7]/[C:8]1[N:17]=[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:29])[CH:14]=2)[N:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)/C(C)=C/c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C/C(=C\c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1)C(=O)O
Temperature: 25 °C
Yield: 92.9 %

Procedure:
1.00 g (0.0023 mol) of (E)-2-(2-ethoxycarbonylpropenyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was dissolved in a mixture comprising 5 ml of tetrahydrofuran and 20 ml of ethanol, followed by the addition of 20 ml of a 1N aqueous solution of sodium hydroxide. The obtained mixture was stirred at room temperature for several hours, neutralized with 20 ml of 1N hydrochloric acid and concentrated under a reduced pressure. The crystal thus formed was recovered by filtration, washed with water and air-dried to give 0.85 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][C:6]=1[O:13][C:14]([F:17])([F:16])[F:15])[CH3:2].[H][H]>[Pd].CO>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:6]=1[O:13][C:14]([F:16])([F:15])[F:17])[CH3:20]
Reactant: [H][H]
Reactant: C=Cc1ccc(C(=O)N(CC)CC)c(OC(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C(=O)N(CC)CC)c(OC(F)(F)F)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirring degassed solution of N,N-diethyl-4-ethenyl-2-(trifluoromethoxy)benzamide (1783 mg, 6.2 mmol) and 10% palladium on carbon (50 mg) in MeOH (30 mL) was added hydrogen (1 atm). The reaction was stirred for 1 h and then filtered. The filtrate was conc. in vacuo to a colorless oil. The oil was purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to give 1489 mg of the desired product as a colorless oil. MS (ESI) 290 (M+H).
Reaction SMILES: CO[C:3]1[C:4](=[O:17])[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH3:18]>CO>[NH2:18][C:3]1[C:4](=[O:17])[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: COc1ccccc(Oc2ccccc2)c1=O
Solvent: CO
Product: Nc1ccccc(Oc2ccccc2)c1=O
Temperature: 80 °C

Procedure:
A solution of 2-methoxy-7-phenoxy-2,4,6-cycloheptatrien-1-one (2.0 g, described above) in methanol (30 ml) is cooled to -25° C. and saturated with gaseous ammonia. The mixture is heated in a pressure bottle at 80° C. for four hours and cooled to -70° C. The bottle is opened and the solvent is removed under reduced pressure. The residue is crystallized from ethyl acetate to give 2-amino-7-phenoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(N(C)C)=O>[C:31]([N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])=[CH:17][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:13]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCNC2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27 %

Procedure:
N-[5-(2-Chloro-phenyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]2-methylpropanamide (39 mgs, 0.12 mmoles) was dissolved in dimethylacetamide (1 ml) followed by the addition of triethylamine (20 ul, 0.144 mmoles) and finally benzoyl chloride (16.7 ul, 0.144 mmoles). The reaction was stirred at room temperature for 1.5 hours and purified by C18 reverse phase automated HPLC (14 mgs, 27% yield, 100% pure, CO-AAWO0025).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH:12]1[CH2:13][CH2:14][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Into a 500-mL three neck round-bottom flask, was placed a solution of tert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1, 20 g, crude) in ethyl acetate (200 mL). Hydrogen chloride (gas) was introduced to the solution and the resulting mixture was stirred for 30 min at room temperature. The solids were collected by filtration, then washed with ethyl acetate (100 mL) and ether (100 mL) to yield the title compound as a white solid (14 g, 57% over two steps).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[Br:13]Br>C(O)(=O)C>[Br:13][C:9]1[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:11])[C:5]2=[O:12]
Reactant: BrBr
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CC(=O)O
Product: Cc1cc(Br)c2c(c1)C(=O)C(=O)N2
Temperature: 25 °C

Procedure:
To a suspension of 8.0 g of 5-methylisatin in 200 ml of acetic acid was added dropwise a solution of 3.3 ml of bromine in 50 ml of acetic acid with stirring at room temperature, and the mixture was heated at 50° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol-hexane to obtain 11.4 g of 7-bromo-5-methylisatin having a melting point of 176°-180° C.
Reaction SMILES: BrC1C=CC([C:8]2O[C:10](C)=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=CC=1.[F:21][C:22]1[CH:23]=[C:24]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH:25]=[CH:26][C:27]=1[C:28]1[O:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34]O)[N:32]=1>>[F:21][C:22]1[CH:23]=[C:24]([C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=2)[CH:25]=[CH:26][C:27]=1[C:28]1[O:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34][N:12]2[CH2:8][CH2:14][CH2:13][CH:11]2[CH3:10])[N:32]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)nc1CCO
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)nc1CCN1CCCC1C

Procedure:
The titled compound is prepared in substantial accordance with the procedures found in Intermediate 13 and Example 75 using 2-[2-(3-Fluoro-4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethanol (see Intermediate 38). MS (m/e): 443.3 (M+1)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.[CH3:10][NH:11][CH2:12][CH:13]=[O:14]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH:13]=[O:14])[C:8]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:9]
Reactant: O=C=Nc1ncc(Br)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-methylaminoacetaldehyde (13.5 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture was then stirred at room temperature for a period of about one hour. After this time the reaction mixture was filtered, and the filtrate was stripped of solvent under reduced pressure, leaving an oil. This oil was chromatographed on silica gel using ethyl acetate as the diluant. The eluant was dissolved in an ethanol-water mixture, and the solution was filtered. The filtrate was then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-bromothiazol-2-yl)ureido]-acetaldehyde as a crystalline solid having a melt point of 72° to 73° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH3:20])[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:24][CH3:23])[C:12]=2[O:19][CH3:20])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1cc(Br)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(Br)ccc2C#N)c1OC
Yield: 69.3 %

Procedure:
4-Bromo-2-(3-formyl-2-methoxyphenoxy)benzonitrile (0.55 g, 1.7 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (120 mg, 1.9 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (40 mL) for 17 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.20 g, 1.7 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-bromo-2-(2-methoxy-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (546 mg, 71%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:3][CH:2]([C@@H:4]1[NH:5][CH2:6][CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:9]1)[CH3:1]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)[C@@H](C(C)C)C2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCN[C@@H](C(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 100 %

Procedure:
1,1-Dimethylethyl (2S)-2-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate (0.482 g, 1.27 mmol) was dissolved in 20 mL of DCM with stirring. TFA (4.0 mL, 52 mmol) was added, and the reaction was stirred for 4 h. The reaction was cooled to 0° C. and slowly quenched with 40 mL of 3N NaOH (aq.). The mixture was poured into H2O and DCM, and the layers were separated. The aqueous layer was washed with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound of step E (0.356 g, 1.27 mmol, 100%). 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=9.5 Hz, 1H), 6.57 (dd, J=9.5, 2.6 Hz, 1H), 6.46 (d, J=2.6 Hz, 1H), 3.88 (s, 3H), 3.77-3.86 (m, 2H), 2.93-3.02 (m, 1H), 2.82 (td, J=11.9, 3.3 Hz, 1H), 2.54-2.71 (m, 2H), 2.29-2.39 (m, 1H), 2.22 (br. s., 1H), 1.55-1.67 (m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:11][C@H:10]([OH:12])[CH:9]=[CH:8]2)[CH:2]=1>CCO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:8][CH2:9][C@@H:10]([OH:12])[CH2:11]2)[CH:2]=1
Reactant: O[C@@H]1C=C[C@@H](c2cccnc2)C1
Agent: [Pd]
Solvent: CCO
Product: O[C@@H]1CC[C@@H](c2cccnc2)C1
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of (1S,4S)-4-(3-pyridyl)-2-cyclopenten-1-ol (1.86 g, 11.5 mmol) and 10% Pd/C (186 mg) in EtOH (35 mL) was stirred under hydrogen atmosphere for 3 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. (1R,3R)-3-(3-pyridyl)cyclopentanol (1.82 g, 97%) was yield as yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)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>[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2ccc(Br)c12
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: O
Solvent: CN(C)C=O
Product: Nc1ncnn2ccc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 110 °C
Yield: 75 %

Procedure:
To a stirred degassed mixture 5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (500 mg, 2.35 mmol), Intermediate C (1.18 g, 3.52 mmol), Na2CO3 (746 mg, 7.04 mmol) and H2O (3.5 mL) in DMF (18 mL) was added tetrakis(triphenylphosphine)palladium(0) (271 mg, 0.24 mmol). The reaction was heated at 110° C. for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and H2O (50 mL). The layers were separated and the aqueous was further extracted with ethyl acetate (1×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified via ISCO® chromatography using 3:1 ethyl acetate/hexanes to afford 600 mg (75%) of the desired product, which contained trace impurities. ES-MS ink 341.23 [M+H]+, HPLC RT (min) 2.91.