Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[C:14]([F:15])=[CH:13][NH:12][CH:11]=1.B(F)(F)F>C(Cl)Cl>[F:9][C:10]1[C:14]([F:15])=[C:13]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]3[N:12]=[C:11]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:13]4[NH:12][C:11](=[C:1]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:11]5[C:10]([F:9])=[C:14]([F:15])[C:13](=[C:1]([C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)[C:11]=1[NH:12]2)[N:12]=5)[C:10]([F:9])=[C:14]4[F:15])[C:10]([F:9])=[C:14]3[F:15]
Reactant: O=Cc1ccccc1
Reactant: Fc1c[nH]cc1F
Agent: FB(F)F
Solvent: ClCCl
Product: FC1=C(F)c2nc1c(-c1ccccc1)c1[nH]c(c(F)c1F)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3[nH]c(c(F)c3F)c2-c2ccccc2)C(F)=C1F
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
Benzaldehyde (0.35 mL, 3.5 mmol), 3,4-difluoropyrrole (0.33 g, 3.2 mmol), and 250 mL of distilled CH2Cl2 were placed under N2 in a 500 mL round-bottom flask equipped with a magnetic stir bar. The reaction was stirred while BF3 etherate (0.5 mL, 3.9 mmol) was added via syringe. To monitor the reaction, aliquots were periodically removed from the reaction vessel, oxidized with DDQ, neutralized with pyridine, and chromatographed by silica gel TLC using CHCl3 as eluent. After 30 minutes, DDQ (1 g) and pyridine (5 mL) were added. The reaction was stirred for 12 hours, filtered through a short silica gel column using CH2Cl2 as eluent, and evaporated. The resulting solid was washed three times with 10 mL of pentane followed by three washes with 10 mL of ethanol. The product was recrystallized from toluene/hexane by layering to yield 127 mg of pure 2,3,7,8,12,13,17,18-octafluoro-5,10,15,20-tetraphenylporphyrin in 21% yield (first crop). A second crystallization using identical conditions yielded an additional 75 mg for a total isolated yield of 33%. The product is characterized by the following data: 1H NMR (360 MHz, CDCl3) δ 8.03 (d, 8H, J1 =6.7 Hz), 7.74 (m, 12H), -4.18 (s, 2H); 19F NMR (500 MHz, CDCl3, -50° C.) δ -141.1 (s, 4F), -146.4 (s, 4F); UV-vis (CH2Cl2) 402 (5.31), 499 (4.21), 532 (3.71), 581 (3.55), 637 (3.60); low resolution FAB MS 758 (calcd 758). Anal. Calcd for C44H22F8N4 : C, 69.66; H, 2.92; N, 7.38. Found: C, 69.43; H, 2.90; N, 6.95.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][OH:20])=[CH:16][O:17][C:13]=2[CH:12]=1.CCN(C(C)C)C(C)C.[O:32](S(C)(=O)=O)[S:33]([CH3:36])(=O)=[O:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][O:20][S:33]([CH3:36])(=[O:34])=[O:32])=[CH:16][O:17][C:13]=2[CH:12]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: OCCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.5 %

Procedure:
To a solution of 2-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-yl]-ethanol (0.4 g, 1.3 mmol) in DCM (13 mL) was added 4-dimethylaminopyridine (16 mg, 0.13 mmol), DIEA (0.27 mL, 1.5 mmol) and Ms2O (0.27 g, 1.5 mmol) and the resulting solution was stirred (rt, 15 min). The reaction mixture was diluted with DCM (40 mL). The organic layer was washed with saturated NH4Cl (2×50 mL), brine (2×50 mL), dried, filtered and concentrated in vacuo to provide the title compound as a clear oil (0.52 g, 100%). MS (ESI): mass calcd. for C17H14N2O5S2, 390.4; m/z found, 391.1 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16](=[O:41])[CH:17]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])([CH3:14])([CH3:13])[CH3:12].[CH2:42](I)[CH:43]=[CH2:44]>O1CCCC1>[C:11]([O:15][C:16](=[O:41])[CH:17]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:18]([CH2:44][CH:43]=[CH2:42])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])([CH3:13])([CH3:14])[CH3:12]
Reactant: COc1ccc(S(=O)(=O)NC(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCc1ccccc1)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 1 h

Procedure:
100 ml dry Tetrahydrofuran (THF) are cooled to −78° C. 1M THF-solution of Lithium bis(trimethylsilyl)amide (47.35 ml, 47.35 mmol) are added while the temperature is maintained. 2-(4-Methoxy-benzenesulfonylamino)-succinic acid 4-benzyl ester 1-tert-butyl ester (10.1 g, 22.5 mmol) are dissolved in 45 ml THF and added dropwise to the reaction solution. The reaction mixture is allowed to stir for 1 h and then warmed briefly to −40° C. After re-cooling to −78° C. Allyliodide (3.1 ml, 33.8 mmol) dissolved in 30 ml THF are added drop-wise. The reaction mixture is allowed to warm to −40° C. and is quenched with a NH4Cl-solution. The organic phase is separated dried over MgSO4 and filtered. The solvent is evaporated and the product is purified with a short flash-chromatography column. Hexane/Ethylacetate (9:1): Cal. 489.6 Found. (M)+ 490.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].C(=O)([O-])[O-].[K+].[K+].C([O:16][C:17](=O)[CH2:18][C:19]([CH2:21][Cl:22])=O)C>O>[Cl:22][CH2:21][C:19]1[N:5]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[N:4]=[C:17]([OH:16])[CH:18]=1
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1cc(CCl)nc(C(Cl)(Cl)Cl)n1
Reaction time: 18 h
Yield: 36.1 %

Procedure:
A mixture of 30.0 g (0.18 mole) trichloroacetamidine, 25.2 g (0.18 mole) potassium carbonate, 30.3 g (0.18 mole) ethyl-4-chloroacetoacetate and 400 ml water was stirred 18 hours. The aqueous solution was filtered and acidified with hydrochloric acid to give a precipitate. The precipitate was washed and dried to give 17.0 g (36% yield) of crude product. An analytical sample recrystallized from ligroin had mp 138°-144° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](O)=[O:28])=[CH:23][NH:24]2)=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:27]([C:22]4[C:21]5[C:25](=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=5)[NH:24][CH:23]=4)=[O:28])[CH2:14][CH2:15]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccc(Br)cc2C12CCNCC2
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Product: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)C(=O)Nc1ccc(Br)cc12

Procedure:
Following the general procedure I as described above, the acylation of 5-bromospiro[indole-3,4′-piperidin]-2(1H)-one with 6-chloro-1H-indole-3-carboxylic acid (preparation described in example 5 above), gave the title compound. ES-MS m/e (%): 458.3 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C>[CH3:32][O:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:25]([F:28])([F:26])[F:27]
Reactant: OC(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanol (Example 34, 0.05 g, 0.132 mmol) was taken into DMF (3 mL). Next, NaH (0.011 g, 0.264 mmol, 60% dispersion) was added and stirred for 1 hour at room temperature. Next, iodomethane (0.04 ml, 0.66 mmol) was added and allowed to stir for 30 minutes. The reaction was quenched with water then extracted with ether. The combined organics were dried over magnesium sulfate and concentrated. The resulting material was purified via column chromatography using 5% ethyl acetate in hexane as the eluent to yield 0.039 g (75%) of desired product as a white solid. MS (ESI) m/z 394 ([M+H]+); Anal. Calcd for C24H18F3NO: C, 73.27; H, 4.61; N, 3.56. Found: C, 73.15; H, 4.16; N, 3.41.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].[CH2:24](Br)[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][C:6]1[C:7]2[O:8][CH2:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:1][C:2]=2[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:10])[CH:5]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2N=C(c2ccccc2)CO3)c1=O
Reaction time: 1 h
Yield: 18.7 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.5 g), phenacyl bromide (0.29 g) and potassium carbonate (0.2 g) in acetone (30 ml) was stirred under reflux conditions for 1 hour. Then insoluble salt was removed through Celite and the filtrate concentrated under reduced pressure. The oily substance was purified by column chromatography on silica gel using ethyl acetate-hexane(1:4) as eluent to give the title compound (0.12 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(OCC)(=O)C>C(O)C>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[Cl:15])[N:5]=[C:4]([NH2:16])[N:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2Cl)n1
Reactant: Nc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc(Nc2ccc(Br)cc2)cc(-c2cc(Cl)ccc2Cl)n1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of the hydrochloride salt of 4-chloro-6-(2,5-dichloro-phenyl)-pyrimidin-2-yl-amine (0.03 g, 0.096 mmol) and 4-bromoaniline (0.034 g, 0.020 mmol) in ethanol (7.5 ml) was heated under reflux for 1 hour. After evaporation of the solvent under reduced pressure, the residue was treated with 1.0 N hydrochloric acid (10 ml) and stirred for 30 minutes. Filtration provided the crude product, which was treated with ethyl acetate (10 ml) and stirred for 1 hour. After filtration the solid was dissolved in methanol (10 ml) and treated with aqueous sodium carbonate solution (1.0 M, 1 ml). After stirring for 1 hour, the solvent was evaporated under reduced pressure and the solid was treated with water (10 ml). After stirring for 15 minutes, filtration provided the title compound (59% yield) as a white powder. 1H NMR (DMSO-d6) δ 6.31 (s, 1H, Ar), 6.54 (s, 2H, NH2), 7.45 (d, 2H, J=8.9 Hz, Ar), 7.52 (dd, 1H, J=8.6 Hz, J-2.6 Hz, Ar), 7.60 (d, 1H, J=8.6 Hz, Ar), 7.64 (d, 1H, J=2.6 Hz, Ar), 7.77 (d, 2H, J=8.9 Hz, Ar), 9.46 (s, 1H, NH).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.[CH:17]1([C@H:23]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH:35]=[O:36])[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N1CCCC1>C1COCC1>[CH:17]1([C@H:23]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:25]([C@H:35]([C:15]3[C:14]([Cl:16])=[CH:13][N:12]=[CH:11][C:10]=3[Cl:9])[OH:36])[CH2:24]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1C=O
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1[C@@H](O)c1c(Cl)cncc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 3.51 mL, 7.02 mmol) was added to 3,5-dichloropyridine (820 mg, 5.54 mmol) dissolved in THF (15 mL) cooled at −78° C. and stirred at this temperature for 1 h. (2S,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate (1.04 g, 3.70 mmol) and its epimer at C2 of the pyrrolidine in THF (11 mL) was added and the solution was removed from the cooling bath and allowed to warm to room temperature and stirred for 2 h. The solution was quenched with saturated ammonium chloride, the aqueous layer was extracted with EtOAc (2×50 mL) and the organic layer washed with brine (30 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-80% EtOAc in heptane) affording (2S,4S)-tert-butyl 4-cyclohexyl-2-((S)-(3,5-dichloropyridin-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate (1.20 g, 2.79 mmol, 76% yield) as a mixture of epimers. MS (ESI) 451.1, 453.1 [M+Na]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:12]([C:9]([N:19]([CH3:21])[CH3:20])([CH2:10][CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:3][CH:4]=1)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1COCCN1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Temperature: 25 °C

Procedure:
608.7 g (2.03 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-butan-1-one (Example 1, B), 354.2 g (4.06 mol) of morpholine, 562 g (4.06 mol) of K2CO3 and 2000 ml of dimethylsulfoxide are heated at 160° for 12 hours, with stirring. After this time, a sample no longer shows any starting ketone in a thin-layer chromatogram. The reaction solution is cooled to room temperature, poured onto ice and extracted with methylene chloride. The organic phase is dried over MgSO4, filtered and evaporated. The oily residue crystallizes from ethanol. The product melts at 111°-119°.
Reaction SMILES: [CH3:1][C:2]1([CH:5]=O)[CH2:4][CH2:3]1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH:15]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16][NH2:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH:15]([O:18][Si:19]([CH2:20][CH3:21])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:16][NH:17][CH2:5][C:2]1([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(C=O)CC1
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(CNCC1(C)CC1)c1c(Cl)cccc1Cl
Reaction time: 0.75 h
Yield: 62.8 %

Procedure:
To a mixture of 1-methylcyclopropanecarbaldehyde (32.8 mg, 0.390 mmol) in DCM (2.0 ml) was added 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (125 mg, 0.390 mmol) followed by NaBH(OAc)3 (124 mg, 0.585 mmol). After 45 min, this was quenched with sat. aq. NaHCO3. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were concentrated then purified by prep TLC eluted with 5% MeOH/DCM to provide 2-(2,6-dichlorophenyl)-N-((1-methylcyclopropyl)methyl)-2-((triethylsilyl)oxy)ethanamine (95 mg, 0.245 mmol, 62.7% yield). 1H NMR (500 MHz, CDCl3) δ 7.28-7.30 (m, 2H), 7.12-7.16 (m, 1H), 5.65 (br. s., 1H), 3.37-3.44 (m, 1H), 2.82-2.90 (m, 1H), 2.69 (br. s., 1H), 2.48 (d, J=11.86 Hz, 1H), 1.60 (br. s., 1H), 1.15 (s, 3H), 0.87-0.92 (m, 9H), 0.51-0.63 (m, 6H), 0.28-0.44 (m, 4H); LCMS (ESI) m/z 388.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc(Cl)nc1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-6-chloropyridine gave 2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.53 (d, 1H, J=3 Hz), 8.25 (dd, 1H, J=3 and 9 Hz), 8.15 (d, 1H, J=2.4 Hz), 7.39 (d, 1H, J=8.7 Hz), 7.00 (bs, 1H); LCMS: purity: 98%; MS (m/e): 259 (M+).
Reaction SMILES: [BH4-].[CH3:2][O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[NH:22][C:16]3=[N:17][CH:18]=[C:19]([NH2:21])[CH:20]=[C:15]3[CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:23]([NH:21][C:19]1[CH:20]=[C:15]2[CH:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][CH2:4][O:3][CH3:2])[CH:8]=3)[NH:22][C:16]2=[N:17][CH:18]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COCCOc1cccc(-c2cc3cc(N)cnc3[nH]2)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Solvent: CO
Product: COCCOc1cccc(-c2cc3cc(NCc4ccccc4)cnc3[nH]2)c1
Reaction time: 16 h
Yield: 6.5 %

Procedure:
Polymer supported borohydride (706 mg, 1.8 mmol) was added to a mixture of 2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine (50 mg, 0.18 mmol) and benzaldehyde (18mg, 0.18 mmol) in methanol (3 mL). The mixture was stirred for 16 hours, filtered, concentrated in vacuo and purified by preparative HPLC to afford benzyl-{2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-amine (4.4 mg, 7%)
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>O>[CH3:13][C:12]1[NH:11][C:10](=[O:14])[NH:9][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([N:21]2[CH:22]=[C:18]([CH3:17])[N:19]=[CH:20]2)=[CH:3][CH:4]=1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Solvent: O
Product: Cc1cn(-c2ccc(C(=O)c3[nH]c(=O)[nH]c3C)cc2)cn1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
4-(4-Fluorobenzoyl)-1,3-dihydro-5-methyl-2H-imidazol-2-one (6.6 g, 30 mmol) is combined with 4-methyl-1H-imidazole (33 g, ca. 400 mmol) in a sealed flask and the mixture heated with stirring at ca. 140° C. overnight. The mixture is cooled, water (120 mL) added and the mixture stirred in an ice bath. The suspension is filtered and the filter cake washed with water and acetone. The solid is heated under reflux in a mixture of 2-propanol (300 mL) and water (200 mL) until dissolution is complete. The solution is filtered, reheated to dissolve some precipitated solid and allowed to cool slowly to room temperature. After 2.5 days the mixture is cooled in ice for 2 hr, the solid collected by filtration, washed with acetone, and dried in vacuo at 105° C. for 23 hr to produce the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[CH:24][CH2:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][CH3:30])[CH:21]=2)[N:16]([CH2:32][CH2:33][CH3:34])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]>[Pd].C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][CH2:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][CH3:30])[CH:21]=2)[N:16]([CH2:32][CH2:33][CH3:34])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCNC(=O)CC=Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCNC(=O)CCCc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Reaction time: 6 h
Yield: 95 %

Procedure:
Palladium on carbon (0.055 g, 10% w/w) was added to a solution of methyl 3-methoxy-4-[1-propyl-5-[3-(propylcarbamoyl)prop-1-enyl]indol-3-ylmethyl]benzoate (0.545 g) in ethyl acetate (15 ml) and tetrahydrofuran (10 ml), and the mixture hydrogenated at atmospheric pressure for 6 hr. The catalyst was removed by filtration through diatomaceous earth, the filter cake washed with ethyl acetate, and the combined filtrate evaporated to give methyl 3-methoxy-4-[1-propyl-5-[3-(propylcarbamoyl)propyl]indol-3-ylmethyl]benzoate (0.52 g, 95%) as a white solid; mp 100°; partial NMR (300 MHz, DMSO-d6): 0.81(m, 6H, 2×CH3). 3.82(s, 3H, OCH3), 3.91(s, 3H, OCH3), 7.73(t, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:41])[CH:12]=[C:13]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=1)[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:44]1>C(Cl)Cl.CC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:41])[C:12]([OH:44])=[C:13]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:32]=1)[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)cc2)oc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Reactant: CC1(C)OO1
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=c1c(O)c(-c2ccc(OCc3ccccc3)cc2)oc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution containing 1.00 g (1.85 mmol) of 3 in 30 mL of CH2Cl2 at 0° C. was added 30 mL of a 0.9-0.11 M solution of DMDO in acetone. The reaction mixture was stirred at 0° C. overnight under N2.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:20]([C:22]1([OH:30])[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[C:23]1=[O:29])#[CH:21]>>[F:19][C:3]1[C:2]([C:21]#[C:20][C:22]2([OH:30])[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[C:23]2=[O:29])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC1(O)CCCN(C)C1=O
Product: CN1CCCC(O)(C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)C1=O
Yield: 16 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpiperidin-2-one (US2012/214762A 1) to give the titled compound as a white solid (20 mg, 16%).
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CCO>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH2:10][OH:11])[C:3]=2[F:12])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc(CO)c(F)c1Br
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(CO)c(F)c1-c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Into a 100 mL round bottom flask was added (3-bromo-2-fluoro-4-methoxy-phenyl)-methanol (I-31, 1.04 g, 4.0 mmol), 3-chlorophenylboronic acid (0.76 g, 4.8 mmol), Pd(PPh3)4 (0.45 g, 0.41 mmol), Na2CO3 (6 mL, 2M aq), toluene, (32 mL), and EtOH (11 mL). The reaction was degassed with N2, then stirred at 80° C. for 24 hours. Water was added and the product was extracted with ethyl acetate. The combined organics were concentrated and filtered through a SiO2 plug eluting with 50% ethyl acetate/hexanes. The solid was triturated with ether and filtered. The filtrate was concentrated and triturated with ether and filtered. The filter cakes were combined and purified by flash column chromatography eluting with 20% acetone/hexanes to give (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32, 0.79 g, 67%) as a white solid.