Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH2:17][CH3:18])[S:15][C:9]=2[NH:8][C:7]1=[O:19].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][C:29]=1[F:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:19]=[C:7]1[N:8]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][C:29]=2[F:42])[C:9]2[S:15][C:14]([CH2:16][CH2:17][CH3:18])=[CH:13][C:10]=2[C:11](=[O:12])[NH:6]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.7 g), 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (2.6 g), potassium carbonate (2.1 g) and acetonitrile (100 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (50 mL), and the mixture was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (50 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (50 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (2 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([OH:34])[C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-(4-bromo-phenyl)-2,2,2-trifluoro-ethanol White solid. MS (ESI): 503.1 MH+).
Reaction SMILES: [ClH:1].NC1CNC(=N)CC1.[NH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-])=O)=[CH:13][N:12]=1>>[ClH:1].[ClH:1].[NH2:18][CH:14]1[CH2:13][NH:12][C:11](=[NH:10])[CH2:16][CH:15]1[CH3:17]
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Agent: Cl
Agent: N=C1CCC(N)CN1
Product: CC1CC(=N)NCC1N

Procedure:
The method of preparation of 5-amino-2-iminopiperidine hydrochloride was used to convert 2-amino-4-methyl-5-nitropyridine to the title compound. Product was obtained as a white solid, shown to be two isomers by 1H NMR analysis. Recrystallization from EtOH/H2O gave a white solid, shown to be one isomer (A) by 1H NMR and tentatively assigned the trans configuration. The mother liquor was concentrated in vacuo and redissolved in warm EtOH. Upon cooling, the first crop was obtained which contains more (A). The second crop contains a mixture of (A) and (B). The third crop is pure (B), which was tentatively assigned the cis configuration. The analysis of the product was found to be consistent with the proposed structure. 1H NMR (D2O) of (A): δ3.8-3.7 (m, 1H); 3.68-3.58 (m 1H); 3.50-3.40 (m, 1H); 2.90-2.75 (m, 1H); 2.45-2.35 (m, 2H); 1.00 (d, J=7 Hz, 3H). 1H NMR (D2O ) of (B): δ3.75-3.65 (m, 1H); 3.45-3.25 (m, 2H); 2.85-2.70 (m, 1H); 2.50-2.35 (m, 1H); 2.20-2.15 (m, 1H); 1.05 (d, J=7 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([O:22][CH3:23])=[C:12]3[C:16]([C:17](=[O:21])[C:18]([OH:20])=O)=[CH:15][NH:14][C:13]=23)[N:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31]2[CH2:39][CH2:38][NH:37][CH2:36][C:32]=2[N:33]=[CH:34][N:35]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[OH:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([O:22][CH3:23])=[C:12]3[C:16]([C:17](=[O:21])[C:18]([N:37]4[CH2:38][CH2:39][C:31]5[C:30]([C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=6)=[N:35][CH:34]=[N:33][C:32]=5[CH2:36]4)=[O:20])=[CH:15][NH:14][C:13]=23)[N:4]=1
Reactant: COc1cnc(-n2cnc(CO)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(CO)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a solution of 2-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (23 mg, 0.072 mmol), 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (15.39 mg, 0.072 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (27.9 mg, 0.087 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.127 mL, 0.725 mmol). The mixture was stirred at room temperature for 2 hours, diluted with MeOH and purified by prep. HPLC to give 1-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione (9 mg, 0.016 mmol, 22% yield). LCMS: m/z 512.2 (M+H)+, 1.34 min (method 8). 1H NMR (500 MHz, DMSO-d6) d ppm 12.39-12.48 (m, 1H) 9.30-9.33 (m, 1H) 9.06-9.16 (m, 1H) 8.64-8.76 (m, 1H) 8.29-8.39 (m, 1H) 7.98-8.10 (m, 2H) 7.87 (s, 1H) 7.49-7.58 (m, 1H) 4.70-4.92 (m, 2H) 4.65-4.67 (m, 2H) 3.83-3.90 (m, 3H) 3.68 (t, J=5.80 Hz, 2H) 3.16 (t, J=5.65 Hz, 2H).
Reaction SMILES: C(N(CC)C1C=CC([C:8]([C:10]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:11]=2[C:12]([OH:14])=[O:13])=O)=CC=1)C.CN(C)C1C=CC=C(N(C)C)C=1.C(OC(=O)C)(=O)C>CO>[Cl:19][C:18]1[C:17]([Cl:20])=[C:16]([Cl:21])[C:15]([Cl:22])=[C:11]2[C:10]=1[CH2:8][O:13][C:12]2=[O:14]
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Agent: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: O=C1OCc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 90 °C
Yield: 103 %

Procedure:
A mixture of 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (8.70 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (3.61 g.) and acetic anhydride (5 ml.) was heated (to 90° C.). Addition of methanol (10 ml.) and slurrying the resulting product with methanol afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=(CH3)2N, Y2 =H, Y4 =(CH3CH2)2N, Z4 =Z5 =Z6 =Z7 =Cl) (5.60 g., m.p. 206°-207.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COc1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound, white solid, m.p. 133° C. and MS: m/e=352 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-methoxy-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[C:20]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:19]=[CH:18][C:17]=1[S:28]([NH2:31])(=[O:30])=[O:29])=[O:15].[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[N:37]=[C:36]([NH:42][C:43](OC2C=CC=CC=2)=[O:44])[N:35]=1.C1(S(N)(=O)=O)C=CC=CC=1.N1C=CC=NC=1>C(#N)C>[CH3:41][O:40][C:38]1[CH:39]=[C:34]([O:33][CH3:32])[N:35]=[C:36]([NH:42][C:43]([NH:31][S:28]([C:17]2[CH:18]=[CH:19][C:20]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:16]=2[C:14]([O:13][CH3:12])=[O:15])(=[O:30])=[O:29])=[O:44])[N:37]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)CNc1ccc(S(N)(=O)=O)c(C(=O)OC)c1
Agent: NS(=O)(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1cncnc1
Solvent: CC#N
Product: COC(=O)CNc1ccc(S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC)n2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.6 ml of DBU are added dropwise at 0° C. to a mixture of 0.87 g of 2-methoxycarbony1-4-(N-methoxycarbonylmethyl-amino)benzenesulfonamide and 0.90 g of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine in 10 ml of acetonitrile. The reaction solution is then stirred at room temperature for 6 h. After removal of the solvent by distillation the residue is taken up in water and washed with diethyl ether. After acidification of the aqueous phase with concentrated hydrochloric acid (pH=1) the sulfonylurea which is separated out is stirred in a little methanol. The colorless solid is separated off by filtration and dried to give 1.18 g of N-[(4,6-dimethoxpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbony1-4-(N-methoxycarbonyl-methylamino)benzenesulfonamide7 m.p.: 184°-186° C. (decomposition). The above process is repeated using the following starting quantities: 31.8 g of the benzene-sulfonamide employed, 58.0 9 of the pyrimidine employed, 150 ml of acetonitrile and 39.4 ml of DBU. After reaction at room temperature for 4 h and work-up as described above, 45.0 g of product with a melting point of 187°-189° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Li+].[Li+].Br[CH2:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[F:27]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[F:27]
Reactant: Fc1cccc(F)c1CBr
Reactant: CC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2c(F)cccc2F)c(O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3′,4′-dihydroxyacetophenone (25.0 g, 164.3 mmol), lithium carbonate (12.1 g, 164.3 mmol), and α-bromo-2,6-difluorotoluene (34.0 g, 164.3 mmol) in dimethyl formamide (400 mL) is stirred at room temperature for 2 days. The mixture is then filtered through celite, and the filtrate is concentrated in vacuo. The residue is diluted with H2O(200 mL), and the mixture is filtered. The collected solid is recrystallized from ethanol to give 3′-hydroxy-4′-(2,6-difluorobenzyloxy)-acetophenone.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH:37]([C@H:40]1[CH2:44][O:43][C:42](=[O:45])[NH:41]1)([CH3:39])[CH3:38].C([Li])CCC.C([O-])(=O)C(C)(C)C>O1CCCC1>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([C@H:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([N:41]2[C@@H:40]([CH:37]([CH3:39])[CH3:38])[CH2:44][O:43][C:42]2=[O:45])=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)C(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (prepared in Example 1A, 1.12 g, 3.80 mmol) in dry tetrahydrofuran (36 mL) under nitrogen was cooled to −78° C. and then treated with triethylamine (606 mL, 4.35 mmol). The reaction mixture was stirred at −78° C. for 15 min and then treated dropwise with trimethylacetyl chloride (491 mL, 3.98 mmol). The resulting reaction mixture was stirred at −78° C. for 15 min, at which time, the cooling bath was removed, and the reaction mixture was allowed to warm to 25° C. where it was stirred for 45 min. At this time, the reaction mixture was cooled back to −78° C. for the addition of the chiral auxiliary. Into a separate reaction flask, a solution of (4S)-(−)-4-isopropyl-2-oxazolidinone (467.9 mg, 3.62 mmol) in dry tetrahydrofuran (18 mL) under nitrogen was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.80 mmol). After complete addition of the n-butyllithium, the reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. This cloudy white solution was then added dropwise by syringe to the previously cooled (−78° C.) pivalate solution. The resulting reaction mixture was stirred at −78° C. for 1 h and then allowed to gradually warm to 25° C. The reaction mixture was stirred at 25° C. for 15 h. The resulting reaction mixture was quenched with a saturated aqueous sodium bisulfite solution and concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 19/1 to 17/3 hexanes/ethyl acetate gradient elution) afforded the higher Rf product 3-{2(S)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopropyl-oxazolidin-2-one (679.2 mg, 92%) as a yellow oil: EI-HRMS m/e calcd for C26H31NO3 (M+) 405.2304, found 405.2310; and the lower Rf product 3-{2(R)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopropyl-oxazolidin-2-one (127.4 mg, 17%) as a yellow oil: EI-HRMS m/e calcd for C26H31NO3 (M+) 405.2304, found 405.2313.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]([CH3:13])[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[F:63][C:64]1([F:68])[CH2:67][NH:66][CH2:65]1>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:63][C:64]1([F:68])[CH2:67][N:66]([C:2]2[CH:3]=[C:4]3[N:12]([CH3:13])[CH:11]=[CH:10][C:5]3=[N:6][C:7]=2[C:8]#[N:9])[CH2:65]1
Reactant: FC1(F)CNC1
Reactant: Cn1ccc2nc(C#N)c(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1ccc2nc(C#N)c(N3CC(F)(F)C3)cc21
Temperature: 110 °C
Reaction time: 48 h
Yield: 28.9 %

Procedure:
To a 5 mL vial were added 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (500 mg, 2.12 mmol), Xantphos (123 mg, 0.212 mmol), palladium (II) acetate (47.6 mg, 0.212 mmol), cesium carbonate (1380 mg, 4.24 mmol) and 3,3-difluoroazetidine hydrochloride (549 mg, 4.24 mmol) in dioxane (5.0 mL). The resulting yellow suspension was heated to 110° C. for 22 hours. LC/MS showed about 50% conversion. More palladium (II) acetate (50 mg) was added and heating was continued at 110° C. for 2 days. The solution was diluted with EtOAc (up to 100 mL) and then washed with saturated aqueous ammonium chloride (100 mL) and filtered to remove solids. The layers were separated, and the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified on a silica gel column (80 g) eluting with a 0-60% ethyl acetate in hexanes to give the title compound as a yellow solid (152 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3 H), 4.55 (t, J=12.4 Hz, 4 H), 6.55 (dd, J=3.3, 0.8 Hz, 1 H), 7.38 (d, J=0.8 Hz, 1 H), 7.69 (d, J=3.5 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C12H10F2N4, 249; found 249.
Reaction SMILES: [I-].C[S+](C)C.[Li][CH2:7]CCC.[F:11][C@H:12]1[C@@H:16]2[O:17][Si:18]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[O:19][Si:20]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:21][CH2:22][C@H:15]2[C@H:14]2[O:35][C@@H:13]12>C1COCC1>[F:11][C@H:12]1[C@@H:22]2[O:21][Si:20]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[O:19][Si:18]([CH:29]([CH3:31])[CH3:30])([CH:32]([CH3:33])[CH3:34])[O:17][CH2:16][C@H:15]2[C:14](=[CH2:7])[C@H:13]1[OH:35]
Reactant: [Li]CCCC
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2[C@H]3O[C@H]3[C@@H](F)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: C=C1[C@@H](O)[C@@H](F)[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a suspension of trimethylsulfonium iodide (30.5 g, 138.4 mmol) in THF (150 mL) at −20° C., n-BuLi (2.5 M solution in hexane) (55.3 mL, 138.4 mmol) was added. After 30 min, the epoxide 13 (6.0 g, 15.5 mmol) in THF (30 mL) was introduced at −20° C. and the reaction mixture allowed slowly to warm to 0° C. over 1 h. The mixture was then stirred at ambient temperature for 2 h, quenched with water and then extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated reduced under pressure. The residues were purified on silica gel column chromatography (10% EtOAc/Hexane) to give the allylic alcohol 14 (5.1 g, 81%) as oil. [α]26D −0.54° (c 0.5, MeOH); 1H NMR (500 MHz, CDCl3) δ 0.93-1.12 (m, 28H), 1.99 (dd, J=2.5, 5.5 Hz, 1H, OH), 2.58 (m, 1H), 3.85 (dd, J=9.5, 11.5 Hz, 1H), 4.08 (dd, J=5.0, 12.0 Hz, 1H), 4.44 (m, 1H) 4.48 (m, 1H), 4.73 (dt, J=5.0, 9.0 Hz, 1H), 5.09 (s, 1H), 5.35-5.34 (m, 1H); 19F NMR (500 MHz, CDCl3) δ −203.0 (m); 13C NMR (125 MHz, CDCl3) δ 12.5, 12.9, 13.4, 13.5, 17.0, 17.03, 17.41, 17.46, 17.5, 17.6, 48.5, 50.2, 65.5, 72.6, 97.4 (d, J=185.0 Hz), 111.8, 146.8; HR-MS Calcd. For (C19H37FO4Si2+H)+ 405.2214. found 405.2202.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]3=[N:16][CH:17]=2)[N:7]=1)[C:3]([OH:5])=O.[CH3:39][NH:40][CH3:41].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>O1CCCC1.C(O)(=O)C.CO>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)[N:7]=1)[C:3]([N:40]([CH3:41])[CH3:39])=[O:5]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(O)C(=O)O)n3)cc12
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(O)C(=O)N(C)C)n3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
In a microwave vial O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate 53.9 mg, 0.14 mmol) was added to a solution of hydroxy-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid (75 mg, 0.14 mmol), dimethyl amine (2 M solution in THF, 65 μl, 0.14 mmol) and di-iso-propyl ethyl amine (75 μl, 0.43 mmol) in tetrahydrofuran (1 ml). The vial was sealed and the solution irradiated to 70° C. for 10 min in a microwave reactor. Methanol (2 ml) was then added to the solution followed by 50% w/v aqueous sodium hydroxide (200 μl) and stirred at room temperature for 2 hours. The reaction was then neutralized with acetic acid and purified by preparative high pressure liquid chromatography, to give 2-hydroxy-2-{6-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-N,N-dimethyl-acetamide (9.2 mg, 16% yield). 1H NMR (500 MHz, Dimethyl sulfoxide-d6) δ 2.86 (s, 3H) 3.32 (s, 3H); 3.82 (s, 3H)); 5.61 (m, 2H); 7.06 (t, J=8 Hz 1H); 7.15 (d, J=8 Hz, 1H) 7.31 (t, J=8 Hz, 1H); 7.44 (d, J=7.5 Hz 1H); 7.58 (d, J=8 Hz 1H); 7.73 (s, 1H); 7.58 (t, J=7.5 Hz 1H); 7.95 (d, J=7.5 Hz 1H); 7.94 (s, 1H); 8.60 (s, 1H); 8.95 (s, 1H); 11.98 (s, br, 1H) MS: m/z 403.4 (M+H+).
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][O:7][C:8]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>>[CH2:1]1[C@H:5]2[CH2:6][O:7][C:8]3[CH:15]=[CH:14][C:13]([C:16]([Cl:21])=[O:18])=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)C(=O)N1CCC[C@H]1CO2
Product: O=C(Cl)c1ccc2c(c1)C(=O)N1CCC[C@H]1CO2

Procedure:
A solution of the above carboxylic acid derivative (2.38 g; 9.64 mmol) in thionyl chloride (10 ml) was heated under reflux for 1.5 h. The excess thionyl chloride was evaporated under reduced pressure to giving (S)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzoxazepine-5-one-7-carboxylic acid chloride (2.56 9) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[ClH:14].NCC1C=C(C=C(OC)C=1)C(OC)=O>>[ClH:14].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C)cc(C#N)c1
Agent: COC(=O)c1cc(CN)cc(OC)c1
Agent: Cl
Product: COC(=O)c1cc(C)cc(CN)c1

Procedure:
Methyl 3-(aminomethyl)-5-methylbenzoate hydrochloride was prepared from methyl 3-cyano-5-methylbenzoate in an analogous manner to Intermediate 2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13]Br)[CH3:11].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde (61 g) and 2-ethylhexylbromide (106 g) were added to 150 ml of dimethylformamide containing 138 g of potassium carbonate. The mixture was refluxed overnight and then poured into a volume of cold water and extracted with ethyl acetate. The extract was dried, evaporated and distilled (0.1 millimeter vacuum) to yield 4-[(2-ethylhexyl)oxy]benzaldehyde, boiling point (b.p.) 118°-121° C.
Reaction SMILES: B([O-])=O.[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1.Cl.[NH3+]N.[F:16][C:17]1[C:22]([F:23])=[C:21]([O:24][CH2:25][CH3:26])[CH:20]=[CH:19][C:18]=1B(O)O>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Br:5][C:6]1([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH3:26])=[C:22]([F:23])[C:17]=2[F:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1
Reactant: Brc1ccc(I)cc1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: N[NH3+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(C2(Br)C=CC=CC2)c(F)c1F
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
0.450 mol of sodium metaborate are introduced into 240 ml of water. 0.012 mol of bis(triphenylphosphine)palladium(II) chloride, 0.6 mol of 4-bromo-1-iodobenzene (11) and 0.012 mol of hydrazinium hydrochloride are added, and the mixture is stirred at about 20° C. for 5 minutes. 0.6 mol of 2,3-difluoro-4-ethoxyphenylboronic acid (12) dissolved in 600 ml of tetrahydrofuran are then added, and the mixture is refluxed for 4 hours, giving the compound of the formula 13.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:27]=[C:26]([NH2:28])[C:6]2[NH:7][C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[N:9][C:5]=2[CH:4]=1.[CH3:31][C:32]([CH3:38])([CH2:36][OH:37])[C:33](O)=[O:34].Cl.CN(C)CCCN=C=NCC>ClCCl>[OH:37][CH2:36][C:32]([CH3:38])([CH3:31])[C:33]([NH:28][C:26]1[C:6]2[NH:7][C:8]([N:10]3[CH2:11][CH2:12][N:13]([C:16]4[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:14][CH2:15]3)=[N:9][C:5]=2[CH:4]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:27]=1)=[O:34]
Reactant: CC(C)(CO)C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(CO)C(=O)Nc1cc(C(F)(F)F)cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a 25-mL, round-bottom flask was added 5-(trifluoromethyl)-2-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-benzimidazol-7-amine (108 mg, 0.25 mmol, Example 58), 2,2-dimethyl-3-hydroxypropionic acid (47 mg, 0.4 mmol, Aldrich), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76 mg, 0.4 mmol, Aldrich) and dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 36 h, washed with satd aq. NaHCO3 solution (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 50% EtOAc/hexane to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 531(M+1)