Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=2)=[O:17])=[CH:11][C:10]=1[C@:26]12[CH2:34][O:33][C@H:32]([CH3:35])[C@H:31]1[C:30](=[O:36])[N:29]([CH3:37])[C:28]([NH:38]C(=O)OC(C)(C)C)=[N:27]2>C(Cl)Cl>[NH2:38][C:28]1[N:29]([CH3:37])[C:30](=[O:36])[C@@H:31]2[C@@H:32]([CH3:35])[O:33][CH2:34][C@:26]2([C:10]2[CH:11]=[C:12]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[O:17])[CH:13]=[CH:14][C:9]=2[F:8])[N:27]=1
Reactant: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C)[C@H]3C(=O)N(C)C(NC(=O)OC(C)(C)C)=N4)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C)[C@H]3C(=O)N(C)C(N)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a stirred solution of tert-butyl ((4aS,5R,7aS)-7a-(2-fluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (210 mg, 0.40 mmol) in DCM (2 mL) at RT. The mixture was stirred at RT for 1 h. The reaction mixture was evaporated and the residue was loaded on to a SCX cartridge (5 g). The cartridge was eluted with methanol (2×20 mL) and then 2M NH3 in MeOH (1×20 mL). The ammonia-methanol fraction was evaporated. The residue was treated with Et2O/hexanes and the resulting solid was collected by filtration and dried in vacuo to give the title compound (105 mg, colourless solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (d, J=6.06 Hz, 3H) 2.99 (d, J=8.84 Hz, 1H) 3.10 (s, 3H) 4.02 (s, 3H) 4.05-4.14 (m, 1H) 4.14-4.22 (m, 2H) 6.04 (br. s., 2H) 7.16 (dd, J=10.99, 9.22 Hz, 1H) 7.70-7.83 (m, 2H) 8.41 (d, J=1.26 Hz, 1H) 8.88 (d, J=1.26 Hz, 1H) 10.58 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)CCC.C([Si](C(C)C)(C(C)C)[N:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1)(C)C.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH:28]1[CH:32]=[CH:31][C:30]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:29]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 100 mL round bottom flask was charged with 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 3.52 mmol), 1-butanol (25.0 mL), [1-(triisopropylsilyl)-1H-pyrrol-3-yl]boronic acid (1.41 g, 5.28 mmol), water (25.0 mL) and potassium carbonate (1.27 g, 8.8 mmol). This solution was degased 4 times, filling with nitrogen each time. Tetrakis(triphenylphosphine)-palladium(0) (0.41 g, 0.35 mmol) was added and the mixture was degased 4 times, filling with nitrogen each time. The reaction was stirred overnight at 100° C. and cooled to room temperature. The mixture was filtered through a bed of celite and the celite was rinsed with ethyl acetate (42 mL). The filtrate was combined and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined and concentrated under vacuum with a bath temperature of 30-70° C. to give the title compound 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine. Yield: 83%; LC-MS: 315.2 (M+H)+.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[CH:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:3]1.[CH3:19][C:20]1([CH3:26])[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5]([C@H:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:3][C@H:2]2[N:24]2[CH2:23][CH2:22][NH:21][C:20]([CH3:26])([CH3:19])[CH2:25]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CC(Cl)c3cc(Cl)ccc32)cc1
Reactant: CC1(C)CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CN([C@@H]2C[C@@H](c3ccc(F)cc3)c3ccc(Cl)cc32)CCN1
Yield: 75.2 %

Procedure:
A mixture of 1,6-dichloro-3-(4-fluorophenyl)-2,3-dihydro-1H-indene (28 g, 0.1 mol), 2,2-dimethylpiperazine (15 g, 0.13 mol) and potassium carbonate (30 g) in acetone (250 mL) was refluxed for 18 h. The reaction mixture was evaporated in vacuo and treated with water and ether. The ether phase was separated and extracted with 1M methane sulfonic acid. The base was liberated with 10M sodium hydroxide, extracted with ether and dried (MgSO4). After filtration and evaporation in vacuo the residue was dissolved in acetone and treated with fumaric acid. The fumarate salt was filtered to give 27 g of 1 as the hemifumarate salt, mp 240°-241° C. A sample recrystallized from ethanol had mp 242°-244° C. Isomeric purity (TLC): 95% trans isomer (racemate).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]([CH3:15])=[C:6]([CH3:14])[C:7]=1[NH:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11].[CH2:23]([O:25][CH2:26][C:27](Cl)=O)[CH3:24]>N1C=CC=CC=1>[CH2:23]([O:25][CH2:26][C:27]1[N:8]([CH2:9][C:10]([CH3:11])([OH:12])[CH3:13])[C:7]2[C:6]([CH3:14])=[C:5]([CH3:15])[N:4]=[C:3]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:2]=2[N:1]=1)[CH3:24]
Reactant: CCOCC(=O)Cl
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCC(C)(C)O)c1C
Solvent: c1ccncc1
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)(C)O
Temperature: 5 °C

Procedure:
To the product from Part F (1-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-ylamino]-2-methylpropan-2-ol was added 10 ml of pyridine. Ethoxyacetyl chloride (3.014 g) was added dropwise to the resulting mixture. The resulting solution was brought to reflux for about 3 days with an intervening day of cooling at about 5° C. The solvent was removed under reduced pressure, and the resulting product dissolved in ethyl acetate containing sodium bicarbonate. The resulting mixture was extracted with water. The resulting organic layer was dried with magnesium sulfate, the solvent was removed under reduced pressure, and the product was cooled to about 5° C. The resulting solid was recrystallized from ethyl acetate. The supernatant was concentrated under reduced pressure to the point of crystallization. This was repeated, resulting in a total of three fractions of crystals in the amounts of 1.500 g, 2.370 g, and 1.527 g, respectively.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:12][CH2:13][O:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COCCOc1ccc2cc[nH]c2c1
Temperature: 75 °C
Yield: 71.8 %

Procedure:
A mixture of 1H-indol-6-ol (4.0 g, 30.0 mmol), 1-bromo-2-methoxyethane (3.53 mL, 37.6 mmol), and cesium carbonate (11.75 g, 36.1 mmol) in DMF (50 mL) was heated at 75° C. for 16 hr. DMF was removed under vacuum with a oil pump. The residue was diluted with ethyl acetate (200 mL), washed sequentially with 1 N NaOH solution (50 mL), water (2×50 mL), and brine (50 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum. The desired product (4.68 g, 21.54 mmol, 71.7% yield) was isolated as a white solid by ISCO (300 g silica gel, solid loading, 10-50% ethyl acetate/hexane).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[CH:14][CH:13]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:23])=[O:24])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(NCCCC(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCc1ccc(NCCCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
{4-[4-(3-Carbamoylpropylamino)phenyl]butyl}carbamic acid tert-butyl ester 430 (0.23 g, 0.66 mmol) was cooled to 0° C. in an ice bath. A cold solution of TFA/dichloromethane (10 mL) was added. The reaction was slowly warmed to room temperature and stirred for 30 minutes. The solvent was evaporated in vacuo to provide 440. 1H NMR (300 MHz, CD3OD) δ 1.69 (m, 4H), 1.95 (m, 2H), 2.47 (m, 2H), 2.71 (m, 2H), 2.93 (m, 2H), 3.39 (m, 2H), 7.39 (s, 4H). m/z (ESI) 250.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:16][CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[OH:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]=[C:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]=2[CH2:32][O:31][C:30]2[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:16][CH3:17])[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:10][C:9]2([CH3:15])[OH:14])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC1(c2ccc(Cl)cc2)CCNCC1(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1(C)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 37.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-methoxy-3-methyl-piperidin-3-ol (206 mg, 1.24 mmol) in acetonitrile/water (4:1, 20 mL) was added potassium carbonate (171 mg, 1.24 mmol) followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (417 mg, 1.12 mmol). The mixture was stirred at rt 40 h and concentrated. The product residue was partitioned between ethyl acetate and water and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (100% methylene chloride −90% methylene chloride/10% methanol gradient) to afford the titled compound (232 mg, 35%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([CH3:19])[C:16](=[O:18])[NH:17][C:10]=23)[CH:5]=[CH:4][C:3]=1[NH:20]C(=O)OC(C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>[NH2:20][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([CH3:19])[C:16](=[O:18])[NH:17][C:10]=23)=[CH:7][C:2]=1[F:1]
Reactant: Cn1c(=O)[nH]c2c(Oc3ccc(NC(=O)OC(C)(C)C)c(F)c3)ccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2c(Oc3ccc(N)c(F)c3)ccnc21

Procedure:
A solution of tert-butyl 2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)phenylcarbamate (2.18 g, 5.8 mmol) in 1 M TBAF in THF (41 mL) was refluxed overnight under an argon atmosphere. The solution was cooled and evaporated and water (20 mL) was added, upon which a precipitate formed. The precipitate was filtered, washed with water, and dried to give the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=2)=[N:4]1)[CH3:2]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[NH2:45][C:42]1[CH:41]=[CH:40][C:39]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[N:14]([S:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)(=[O:31])=[O:32])[C:15]([C:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=5)=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:44][CH:43]=1
Reactant: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(N)cc2)n1
Reaction time: 16 h

Procedure:
A solution of 1,1-dimethylethyl 4-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-1 (2H)-pyridinecarboxylate (0.46 mmol) in ethyl acetate (5 mL) was purged with nitrogen and palladium(II) hydroxide/Carbon (30 mg of 20 wt. % palladium) added. The reaction was purged with hydrogen gas and allowed to stir vigorously under 1 atm of hydrogen. After 16 h, the reaction was purged with nitrogen and filtered though a pad of Celite (rinsing with ethyl acetate). The filtrate was concentrated under reduced pressure to give the title compound as a yellow foam which was used without further purification. ESMS [M+H]+: 625.6
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].O>N1C=CC=CC=1>[C:1]1([NH:7][NH:8][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: NNc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1)c1ccccc1F
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred solution of 50.0 g of phenylhydrazine in 280 ml of dry pyridine, cooled to about 5° was added, dropwise, 80.0 g of o-fluorobenzoyl chloride. After coming to ambient temperature, the reaction mixture was stirred for about 2 hours, and then poured into water. The resultant precipitate was recrystallized from toluene to yield 82 g (77.5%) of 2-fluorobenzoic acid, 2-phenylhydrazide.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][S-:26].[Na+]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:26][CH3:25])=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C[S-]
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Agent: [Na+]
Product: CSc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 25 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-(5-methylsulfanyl-thiazol-2-yl)-urea (94 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and sodium methanethiolate (140 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [PH:1](=[O:13])([O-:12])[O:2][C@@H:3]([O:7]S(C)(=O)=O)[C@@H:4](O)[CH3:5].[Na+:14].[Na+].O[C@@H:17]([CH3:28])[C@@H:18]([O:24][PH:25](=[O:27])[O-:26])[O:19]S(C)(=O)=O.[OH-].[Na+]>O>[PH:1](=[O:13])([O-:12])[O:2][C@H:3]1[O:7][C@H:4]1[CH3:5].[Na+:14].[Na+:14].[O:19]1[C@@H:17]([CH3:28])[C@H:18]1[O:24][PH:25](=[O:27])[O-:26]
Reactant: C[C@H](O)[C@@H](O[PH](=O)[O-])OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1O[C@@H]1O[PH](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of disodium (1S,2S)-2-hydroxy-1-methanesulphonyloxypropyl phosphonate (2.78 g) in water (10 ml) an aqueous solution 1N of sodium hydroxide (10 ml, 10 mmol) was added at 15° C. The reaction mixture was kept at 15° C. for 2 hours. Evaporation of the solvent affords disodium (1R,2S)-1,2-epoxypropyl phosphonate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]3[C:18]([C:21](=[O:47])[NH:22][C:23]4[CH:28]=[C:27]([C:29](=[O:45])[NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[N:38]5[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]5)[CH:26]=[CH:25][C:24]=4[F:46])=[CH:19][N:20]=[C:14]3[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[F:48][CH2:49][CH2:50][NH2:51]>>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]3[C:18]([C:21]([NH:22][C:23]4[CH:28]=[C:27]([C:29](=[O:45])[NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[N:38]5[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]5)[CH:26]=[CH:25][C:24]=4[F:46])=[O:47])=[CH:19][N:20]=[C:14]3[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4](=[O:5])[NH:51][CH2:50][CH2:49][F:48]
Reactant: NCCF
Reactant: COC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccccc5N5CCN(C)CC5)ccc4F)cnc3c2)cc1F
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(-c5ccc(C(=O)NCCF)c(F)c5)ccn34)c2)CC1

Procedure:
The title compound was prepared from methyl 2-fluoro-4-(3-(2-fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)benzoate (step) and 2-fluoroethanamine analogously Example 8.1 steps 1 and 2; LC-MS: Rt 0.74 mins; MS m/z 670/671 {M+H}+; Method 2minLC_v003
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH:21](O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[CH:24]=2)=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].COCCN(S(F)(F)[F:48])CCOC.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[F:48][CH:21]([C:13]1[N:14]=[C:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:11][CH:12]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:24]=1
Reactant: COc1ccc(F)c(-c2ccc(C(O)Cc3cccc(COC4CCCCO4)c3)nc2CC(C)(C)C)c1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(C(F)Cc3cccc(COC4CCCCO4)c3)nc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)-2-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)ethanol (312.5 mg) in toluene (5.0 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (170 μL) at 0° C., and the mixture was stirred at 0° C. for 5 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as an orange oil. This compound was used for the next step without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[O:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1.[NH2:23][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C(OCC)C>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[NH:23][C:9]1[O:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1
Reactant: Nc1ncccn1
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1oc(Nc2ncccn2)nc1C(F)(F)F
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A reaction vessel was charged with 50 ml toluene, 4 g (16.4 mmol) ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate and 3.12 g (32.8 mmol) 2-aminopyrimidine. The reaction mixture was heated at a temperature of 100°-110° C. for 16 hours. The mixture was cooled to room temperature, diluted with ethyl ether, washed with 5% hydrochloric acid, and then washed with large amounts of water. The ether portion was dried over magnesium sulfate and then concentrated under reduced pressure to yield 3.14 g of a yellow oily-solid material. This material was recrystallized from an ethanol-water solution to provide a yellow solid material which was air dried at room temperature, then triturated in warm hexane, and finally recrystallized from ethanol-water solution to yield 2.06 g of a yellow solid material (m.p. 199°-205° C.) identified in Table I.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24](OB(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[CH3:20].ClCCl>C(N(CC)CC)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH3:20]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOCCOc1ccc(OB(O)O)cc1OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g), 3-ethoxy-4-(2-propoxyethoxy)phenylboric acid (0.80 g), cupric acetate (0.27 g), MS4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 16 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2→2:3) to obtain methyl 7-[3-ethoxy-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.45 g) as a light yellow, oily substance. 1H-NMR (200 MHz, CDCl3) δ0.95 (3H, t, J=7.4 Hz), 1.44 (3H, t, J=7.0 Hz), 1.56-1.70 (2H, m), 3.04-3.11 (2H, m), 3.53 (2H, t, J=6.8 Hz), 3.58-3.65 (2H, m), 3.80-3.85 (5H, m), 4.03 (2H, q, j=7.0 Hz), 4.17-4.22 (2H, m), 6.56-6.63 (2H, m), 6.94-7.04 (3H, m), 7.70 (1H, s), 8.08 (1H, d, J=8.4 Hz).
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[OH:5])[CH2:3][CH2:2]1.O[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[O:23][CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([CH:4]([C:6]2[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[O:5][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[O:23][CH3:24])[CH2:2][CH2:3]1
Reactant: COc1cc(C#N)ccc1O
Reactant: COc1ccc(C(O)C2CC2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(Oc2ccc(C#N)cc2OC)C2CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a stirred 0° C. solution of cyclopropyl(6-methoxypyridin-3-yl)methanol (3.80 g, 21.20 mmol), 4-hydroxy-3-methoxybenzonitrile (1.60 g, 10.73 mmol), and triphenylphosphine (5.60 g, 21.35 mmol) in tetrahydrofuran (10 mL) was added diethyl azodicarboxylate (3.70 g, 21.25 mmol) dropwise. The resulting mixture was allowed to warm to room temperature. After 2 h, the mixture was concentrated. Chromatographic purification of the residue (silica gel, 10% ethyl acetate in petroleum ether elute) afforded 2.70 g (80%) of 4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzonitrile as a light yellow oil.
Reaction SMILES: [C:1]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Br:14]Br>C(O)(=O)C>[Br:14][C:2]([CH3:4])([CH3:3])[C:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1)=[O:5]
Reactant: CC(C)C(=O)c1ccc(C#N)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(Br)C(=O)c1ccc(C#N)cc1
Reaction time: 72 h
Yield: 71.5 %

Procedure:
To a mixture of 4-isobutyrylbenzonitrile (2.4 g, 13.86 mmol) in acetic acid (50 mL) was added bromine (0.8 mL, 15.53 mmol). The mixture was stirred for 3 days and then concentrated in vacuo. The reaction mixture was diluted with ethyl acetate and washed with sat NaHCO3. The organic layer was dried MgSO4, filtered, concentrated, and then purified on silica gel using an EtOAc/hexanes gradient to yield 2.5 g of 4-(2-bromo-2-methylpropanoyl)benzonitrile. 1H NMR (400 MHz, chloroform-d) δ ppm 8.00-8.07 (2H, m), 7.76-7.79 (2H, m), 1.24 (3H, s), 1.22 (3H, s).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([NH:19][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and aniline as the starting materials.