Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13].[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1F
Temperature: 80 °C
Yield: 65.9 %

Procedure:
A mixture of 2.0 g of 2-amino-5-chloro-4-trifluoromethylphenol, 1.33 g of 3-fluoroisonicotinic acid, 2.36 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for 3.5 hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.08 g of 3-fluoro-N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: Cl[C:2]1C(Cl)=CC2N=C(S)NC=2C=1.[OH-].[K+].IC.[Cl:17][C:18]1[C:28]([Cl:29])=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[NH:24][C:20]=2[CH:19]=1>C(O)C>[Cl:17][C:18]1[C:28]([Cl:29])=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[N:24]([CH3:2])[C:20]=2[CH:19]=1
Reactant: CSc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CCO
Product: CSc1nc2cc(Cl)c(Cl)cc2n1C

Procedure:
5,6-dichloro-2-mercaptobenzimidazole (8.76 g, 0.04 mol) in 50 ml 95% ethanol was treated with 10 ml of 45% aqueous potassium hydroxide to give a solution. Iodomethane (7 ml, 0.096 mol) was added. The reaction mixture was refluxed for two hours. Cooling overnight yielded precipitant, which was filtered, water-washed, and dried to yield 5.61 g, mp 115° C. The reaction filtrate was rotary evaporated and the residue reslurried in water. After filtration and drying, an additional 3.52 g was obtained, mp 110° C. NMR analysis indicated the presence of some 5,6-DiChloro-2-(methylthio)benzimidazole as an impurity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[N:20]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[CH:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[N:21]=[N:22][CH:23]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[CH:33]=[CH:34][N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:20]3[N:21]=[N:22][CH:23]=[N:19]3)=[CH:29][CH:28]=2)[C:31]1=[O:35])[CH3:12]
Reactant: O=c1[nH]ccn1-c1ccc(-n2ncnn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](n1ccn(-c2ccc(-n3ncnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 26).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[N:33][NH:34]2)=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:34]3[C:35]4[C:31](=[CH:30][CH:29]=[C:28]([C:27]([F:26])([F:38])[F:37])[CH:36]=4)[CH:32]=[N:33]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: FC(F)(F)c1ccc2cn[nH]c2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(C(F)(F)F)cc43)nc12
Temperature: 125 °C
Yield: 49.1 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (180 mg, 421 μmol) and 6-(trifluoromethyl)-1H-indazole (78.4 mg, 421 μmol) in dioxane (2 mL) was added sodium tert-butoxide (89.0 mg, 927 μmol) and bis(tri-tert-butylphosphine)palladium(0) (21.5 mg, 42.1 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-Butyl-2-(6-(trifluoromethyl)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (110 mg, 49%). 1H NMR (CDCl3) δ: 9.05 (s, 1H), 8.74 (d, J=0.5 Hz, 1H), 8.42 (s, 1H), 8.38 (d, J=1.0 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 5.74 (s, 2H), 3.57-3.62 (m, 2H), 1.53 (s, 9H), 0.93-0.98 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9]O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[C:25]([OH:28])(=[O:27])[CH3:26]>>[C:25]([O:28][CH2:9][CH2:10][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:27])[CH3:26]
Reactant: c1ccc(C2CCOC2(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
30.0 g of 2,2,3-triphenyltetrahydrofuran are dissolved in 125 ml of acetic acid, after which 25 ml of 40% hydrogen-bromide in acetic acid are added. The mixture is stirred for 1 h at 75° C. The solvent is evaporated, and 1 M sodium carbonate solution is added in excess. The product is extracted in toluene. The toluene solution is dried over sodium sulfate and the solvent is evaporated. The product is recrystallized from aqueous methanol and then has m.p. 81°-3° C. The yield is 28.7 g (84%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:26]2[NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=2[C:24]([O:33][CH3:34])=[CH:23][CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:26]3[NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=3[C:24]([O:33][CH3:34])=[CH:23][CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(N)c2c1CCCC(=O)N2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(OC)c3c2NC(=O)CCC3)ncc1Cl

Procedure:
Analogous to the procedure described in Example 1, the reaction of 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 9-amino-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one gave 2-[5-chloro-2-(6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-9-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide, upon purification by flash chromatography (Dichloromethane: MeOH 97:3) followed by PLC (hexane:EtOAc 1:1), as solid (6%): 1H NMR (400 MHz, CD3OD) δ8.3 (br s, 1H), 7.60 (dd, J=7.70 Hz, 1.44 Hz, 1H), 7.26 (d, J=8.78 Hz, 1H), 7.06 (m, 1H), 7.04 (m, 1H), 6.93 (d, J=8.83 Hz, 1H), 3.89 (s, 3H), 2.90 (s, 3H), 2.82 (m, 2H0, 2.06 (m, 4H); MS (m/e) 467, 468 (M+H);
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[N:13][N+:14]([O-:16])=[O:15])[S:11][CH3:12])=[CH:4][CH:3]=1.C(#N)C.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10](=[N:13][N+:14]([O-:16])=[O:15])[S:11][CH3:12])(=[O:22])[CH3:21]
Reactant: CSC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(Cc1ccc(Cl)nc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a mixture of N-(6-chloro-3-pyridylmethyl)-S-methyl-N'-nitroisothiourea (1.3 g) and acetonitrile (10 ml) was added pyridine (1.6 g) and further dropwise acetyl chloride (0.79 g) under ice-cooling. After stirring for 1 hour under ice-cooling, the mixture was warmed to room temperature and stirred at the same temperature for 2 hours. The reaction mixture was concentrated and 50 ml of ether and 5 ml of 2N hydrochloric acid were added to the mixture which was then partitioned. The resultant organic layers were dried over anhydrous magnesium sulfate and concentrated to afford 1.6 g of N-acetyl-N-(6-chloro-3-pyridylmethyl)-S-methyl-N'-nitroisothiourea as a red oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[N:19]([CH3:20])[C:18](S(C)(=O)=O)=[N:17][N:16]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH:37]([OH:39])[CH3:38])[CH:33]=2)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[N:19]([CH3:20])[C:18]([O:39][CH:37]([C:34]3[CH:33]=[C:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=4)[O:36][N:35]=3)[CH3:38])=[N:17][N:16]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccnc(OCc3ccccc3)c2)nnc1S(C)(=O)=O
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(Oc1nnc(-c2ccnc(OCc3ccccc3)c2)n1C)c1cc(-c2cccc(Cl)c2)on1
Temperature: 65 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
The title compound from example 29.1 (103 mg, 0.298 mmol), the title compound from example 7.1 (100 mg, 0.4471 mmol) and cesium carbonate (291 mg, 0.894 mmol) were combined in a screw cap vial which was purged with nitrogen. Dimethylformamide (3 mL) was added and the reaction was stirred at 65° C. overnight. The reaction mixture was then cooled to room temperature, diluted with water and extracted three times with dichloromethane. The combined organics were dried over magnesium sulfate, filtered and concentrated, then chromatographed in dichloromethane followed by ethyl acetate on silica gel to give the title compound (129.4 mg, 58%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]1=[O:29].[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].[I-]>CN(C)C=O>[O:35]=[C:33]1[CH2:32][CH2:31][C:30](=[O:36])[N:34]1[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]1=[O:29]
Reactant: O=C1CCC(=O)N1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCCl)c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-(3-chloropropyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (24 mg, 0.057 mmol) in N,N-dimethylformamide (700 μL) was added succinimide (23 mg, 0.23 mmol), potassium carbonate (32 mg, 0.23 mmol), and possium iodide (38 mg, 0.23 mmol), respectively. The reaction mixture was stirred at 70° C. overnight. The reaction mixture was cooled and quenched with cold 1 N aqueous hydrochloric acid and extracted with toluene. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided ethyl 1-[3-(2,5-dioxo-1-pyrrolidinyl)propyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1 H), 7.31 (s, 1 H), 7.19 (dd, J=8.5, 5.3 Hz, 2 H), 7.04 (t, J=8.6 Hz, 2 H), 4.50 (q, J=7.1 Hz, 2 H), 4.17-4.12 (m, 4 H), 3.58 (t, J=7.1 Hz, 2 H), 2.71 (s, 4 H), 1.90 (m, 2 H), 1.47 (t, J=7.1 Hz, 3 H); MS m/z 504 (M+Na)+.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]([CH2:17][O:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.Cl[C:45]([O:47][CH3:48])=[O:46]>C(Cl)Cl>[CH2:1]([O:13][CH2:14][CH:15]([CH2:17][O:18][C:19]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:16][C:45]([O:47][CH3:48])=[O:46])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COC(=O)Cl
Reactant: CCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)OC
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of (rac)-1-O-dodecyl-3-O-trityl-glycerol (16.0 g) and dry pyridine (7.54 g) in dry methylenechloride (200 ml) was added, dropwise over 20 minutes, a solution of methyl chloroformate (5.70 g) in dry methylene chloride (40 ml) at 5° C. After 3 hours, the solution was allowed to stand for 17 hours at ambient temperature, and then washed with aqueous hydrochloric acid and water, dried, and evaporated. The residue was purified by column chromatography on silica gel (240 g, elution by chloroform) to yield 17.33 g of (rac)-1-O-dodecyl-2-O-methoxycarbonyl-3-O-trityl-glycerol as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[N:7]=[C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)=[CH:16][C:15]4=[O:29])=[CH:10][N:9]3[C:30]=2[CH2:31][OH:32])[CH2:5][CH2:4]1.I[CH3:34]>C1COCC1>[CH:3]1([C:6]2[N:7]=[C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)=[CH:16][C:15]4=[O:29])=[CH:10][N:9]3[C:30]=2[CH2:31][O:32][CH3:34])[CH2:4][CH2:5]1
Reactant: CI
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc2nc(C3CC3)c(CO)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (40% oil dispersion, 22 mg) in THF (9 ml) was added a solution of 1-(2-cyclopropyl-3-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (100 mg) in THF (1 ml) at 0° C., and then the mixture was allowed to warm to room temperature and stirred for 30 min. Iodomethane (22 pa) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-water and extracted with DCM. The combined DCM layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) followed by recrystallization from DCM/hexane to give the title compound (40 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[CH3:50][NH:51][CH3:52]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:24])([F:25])[F:26])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:51]([CH3:52])[CH3:50])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: CNC
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN(C)C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 500 mg of the compound obtained in Example 219, a solution of 2 mol/L dimethylamine in THF (0.76 ml) as starting material, 300 mg of the title compound (light yellow amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.C(OC(N1C2=CN=CC([C:37]3[CH:42]=[C:41]([C:43]([O:45][CH3:46])=[O:44])[CH:40]=[CH:39][C:38]=3[C:47]#[N:48])=C2C=C1)=O)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:46][O:45][C:43](=[O:44])[C:41]1[CH:40]=[CH:39][C:38]([C:47]#[N:48])=[C:37]([C:2]2[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]3[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=23)[CH:42]=1
Reactant: COc1ncc2c(ccn2COCC[Si](C)(C)C)c1Br
Reactant: COC(=O)c1ccc(C#N)c(-c2cncc3c2ccn3C(=O)OC(C)(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C#N)c(-c2c(OC)ncc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Yield: 68.8 %

Procedure:
A mixture of 4-Bromo-5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridine (0.940 g, 2.63 mmol), 4-Cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-benzoic acid methyl ester (Example 140 Step 1 starting material) (0.840 g, 2.93 mmol, 1.1 eq), Bis(di-tertbutyl-(4-dimethylaminophenyl)-phosphine)-di-chloropalladium (II) (0.046 g, 0.066 mmol, 2 mol %), and tribasic potassium phosphate (1.12 g, 5.26 mmol, 2 eq) in a 10:1 mixture of dioxane and water was heated to 80° C. for 2.5 hr. The reaction was cooled to 23° C., the contents decanted into a separatory funnel and the residue in the vial was washed with copious amounts of ethyl acetate. The organic was washed with water, brine, dried (Na2SO4), and concentrated. The crude mixture was further purified by chromatography eluting with 30% EtOAc/Heptane giving 4-Cyano-3-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]-benzoic acid methyl ester as a yellow amorphous solid (0.790 g, 1.81 mmol, 69%). MS ESI m/z 438.4 (M+H)+. 1NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.12 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 6.20 (d, J=3.2 Hz, 1H), 5.54 (d, J=5.0 Hz, 2H), 4.04 (s, 3H), 3.98 (s, 3H), 3.55 (m, 2H), 0.95 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH2:33][OH:34])[CH:27]=1)[CH2:10][NH:11][C:12]([CH3:25])([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:35]1([CH2:40][CH2:41][CH2:42][NH2:43])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Si:1]([O:8][C@H:9]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH2:33][OH:34])[CH:27]=1)[CH2:10][NH:11][C:12]([CH3:25])([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:43][CH2:42][CH2:41][CH2:40][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: NCCCN1CCCC1
Reactant: CC(C)(Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Product: CC(C)(Cc1cccc(CC(=O)NCCCN2CCCC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Yield: 16 %

Procedure:
The title compound was prepared from {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (preparation 154) and 1-pyrrolidinepropanamine, using a similar method to that of preparation 38, in 16% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cc(Br)cc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 3-(benzyloxy)-5-bromopyridin-2(1H)-one (4.4 g, 15.71 mmol) in DMF (50 mL) was added Cs2CO3 (6.65 g, 20.42 mmol) then iodomethane (1.2 mL, 19.19 mmol) at RT. After stirring overnight the mixture was concentrated. The residue was taken up in H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-100 g, 50% EtOAc/hexanes) gave the title compound (3.61 g, 78%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.43-7.30 (m, 5 H); 7.05 (d, J=2.4 Hz, 1 H); 6.69 (d, J=2.4 Hz, 1 H); 5.24 (s, 0 H); 5.10 (s, 2 H); 3.55 (s, 3 H). LC/MS (M+H)+ 294/296.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH2:20]Br)[CH:17]=[CH:18][CH:19]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([CH2:20][O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(COC2CCC3(CC2)OCCO3)c1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 9, using 4.7 grams (0.030 mole) of 1,4-dioxaspiro[4.5]decan-8-ol (prepared as in Step B of Example 8), 7.2 grams (0.030 mole) of 3-trifluoromethylphenylmethyl bromide, and 1.3 grams (0.033 mole) of sodium hydride (60% in mineral oil) in 60 mL of toluene, yielding 8-(3-trifluoromethylphenylmethoxy)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21]C=[CH:19]2)#[N:15].Cl>>[N:8]1([CH:1]2[CH2:19][C:18]3[C:22](=[CH:23][CH:24]=[C:16]([C:14]#[N:15])[CH:17]=3)[CH2:21]2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc2c(c1)C=CC2
Agent: Cl
Product: N#Cc1ccc2c(c1)CC(N1CCNCC1)C2
Reaction time: 2 h

Procedure:
To a flask containing 5-cyano-inden bocpiperazine (0.025 g, 0.076 mmol) and a stir bar was added 4M HCl (2 mL). The resulting mixture was then stirred for 2 h; LC indicated completion of the reaction. The solution was concentrated in vacuo, pumped under reduced pressure and gave the title product (LC/MS: [(M+1)]+=228.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Br.Br[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: BrCc1cccnc1
Agent: Br
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1Cc1cccnc1

Procedure:
The title compound, MS: m/e=299.2 (M+H30), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 3-(bromomethyl)pyridine hydrobromide.