Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:7]1[S:8][C:9]([CH3:12])=[CH:10][N:11]=1)C.[Li+].[OH-]>C1COCC1.CO.O>[Br:20][C:15]1[CH:14]=[C:13]([CH:6]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][N:11]=2)[CH2:5][C:4]([OH:21])=[O:3])[CH:18]=[C:17]([Cl:19])[CH:16]=1
Reactant: CCOC(=O)CC(c1cc(Cl)cc(Br)c1)c1ncc(C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnc(C(CC(=O)O)c2cc(Cl)cc(Br)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
17 g (43.73 mmol) of 3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acid ethyl ester are dissolved in 30 ml of a THF/MeOH/H2O=2:1:1 mixture and LiOH (2Eq) is added. After stirring overnight at RT, the solvent is removed in vacuo and the crude material is treated with 30 ml of EtOAc and 30 ml of water with pH=4. The organic phase is separated, dried over Na2SO4 and the solvent removed in vacuo. The crude material is recrystallized from heptane/EtOAc mixtures delivering 9.2 g (Yield=58%) of 3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH:31]=[O:32])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.[CH3:34][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)([CH2:30][CH:31]([OH:32])[CH3:34])[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[Mg+]
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC=O)(c2ccc(F)cc2)OC1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetaldehyde in THF (3 mL) was added MeMgBr (1.4 M in toluene/THF, 3 mL, 4.2 mmol) at 0° C. The mixture was warmed up to rt and stirred for 1.5 h before quenching with satd aq NH4Cl (3 mL). The mixture was diluted with CH2Cl2 and dried over Na2SO4. Removal of the solvent gave the crude alcohol as a mixture of diastereomers.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]([NH2:10])[C@@H:2]1[OH:11].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>C1COCC1>[OH:11][C@@H:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:10][C:19](=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)Cl
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Temperature: 0 °C

Procedure:
(1S, 2R)-cis-1-Amino-2-indanol (XIV, 1.5 g) was dissolved with triethylamine (1.5 mL) in dry THF (45 mL), and cooled to 0° C. Butyryl chloride (XIII, 1.05 mL) was added by syringe, and the resultant solution stirred 0° C. for 20 min, whereupon the reaction mixture was partitioned between half-saturated NH4Cl (45 mL) and EtOAc (2×45 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give a solid, which was taken to the next reaction without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])=[CH:10][C:11]([C:13]4[CH:14]=[CH:15][C:16]5[O:17][CH2:18][CH2:19][NH:20][C:21]=5N=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:33]1C=CC2OCCNC=2C=1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])=[CH:10][C:11]([C:13]4[CH:14]=[CH:15][C:16]5[O:17][CH2:18][CH2:19][NH:20][C:21]=5[CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1cc(-c2ccc3c(n2)NCCO3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Brc1ccc2c(c1)NCCO2
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)NCCO3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 18 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine as a starting material to afford 27.9 mg (18%) of (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.06 (s, 1H), 7.59 (s, 1H), 7.24 (m, 1H), 6.78 (m, 4H), 5.80 (s, 1H), 4.79 (m, 1H), 4.13 (m, 2H), 3.69 (m, 1H), 3.39 (m, 1H), 3.31 (m, 1H), 3.25 (m, 2H), 2.82 (m, 1H), 2.32 (m, 2H), 1.37 (d, J=6.4 Hz, 3H), 1.11 (m, 4H). MS (ESI+) m/z 419.2 (M+H)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][C:25]=1[O:26][CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[N:24][C:25]([O:26][CH3:27])=[C:20]([Cl:19])[CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ncc(B(O)O)cc1Cl
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cnc(OC)c(Cl)c3)cccc2c1N
Yield: 41.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (119 mg, 0.385 mmol) and (5-chloro-6-methoxypyridin-3-yl)boronic acid (144 mg, 0.77 mmol) were reacted to afford the title compound (59 mg, 42% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.25 (t, J=6.0 Hz, 1H), 8.43-8.46 (m, 2H), 8.34 (d, J=2.0 Hz, 1H), 7.95 (apparent d, J=7.0, Hz, 1H), 7.80 (apparent t, J=7.8 Hz, 1H), 4.03 (s, 3H), 3.31 (apparent q, J=7.0 Hz, 2H), 1.59 (apparent sextet, J=7.0 Hz, 2H), 0.91 (t, J=7.0 Hz, 3H). MS APCI, m/z=372(M+H) HPLC 2.17 min.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[C:22]([C:31]([F:34])([F:33])[F:32])=[CH:21][C:20]=1[NH:35][C:36](OC1C=CC(Cl)=CC=1)=[O:37]>O1CCOCC1>[CH3:30][N:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:23]1[CH:24]=[C:19]2[C:20](=[CH:21][C:22]=1[C:31]([F:32])([F:33])[F:34])[NH:35][C:36](=[O:37])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:18]2=[O:17]
Reactant: COC(=O)c1cc(-c2cccn2C)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cccc1-c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
CH3SO2NHNH2 (25.5 mg, 1.5 equiv) and i-Pr2NEt (26.5 μL, 1 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-5-(1-methyl-1H-pyrrol-2-yl)-4-trifluoromethyl-benzoic acid methyl ester (70 mg, 0.155 mmol) in dioxane (2 mL). The mixture was stirred for 2 h (TLC control) at 95° C. CH3SO2NHNH2 (25.5 mg, 1.5 equiv) and i-Pr2NEt (26.5 μL, 1 equiv) were then added. The mixture was stirred for 48 h at 95° C. The mixture was evaporated to dryness. The crude product was purified by column chromatography (silica gel 60, EtOAc/hexanes 7/3) to give N-[6-(1-methyl-1H-pyrrol-2-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (50 mg, 80%) as a yellow solid. ESI-MS: m/z 420 [M+NH4]+, rt: 4.83 min. 1H-NMR (DMSO-d6, 400 MHz) 7.91 (s, 2H), 7.57 (s, 1H), 7.54 (s, 1 H), 3.88 (s, 3 H), 3.14 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([F:16])[C:11]=2[CH3:15])[C:6]1=O)(=[O:3])[CH3:2].[CH2:19]([C@:21]1([OH:37])[C:33]2[CH:32]=[C:31]3[N:27]([CH2:28][CH2:29][C:30]3=O)[C:26](=[O:35])[C:25]=2[CH2:24][O:23][C:22]1=[O:36])[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]1[C:6]2=[C:29]3[CH2:28][N:27]4[C:31](=[CH:32][C:33]5[C@:21]([CH2:19][CH3:20])([OH:37])[C:22](=[O:36])[O:23][CH2:24][C:25]=5[C:26]4=[O:35])[C:30]3=[N:17][C:8]3[CH:9]=[C:10]([F:16])[C:11]([CH3:15])=[C:12]([C:7]=32)[CH2:13][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCc2c(C)c(F)cc(N)c2C1=O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(NC(C)=O)CC3
Temperature: 120 °C
Yield: 59.1 %

Procedure:
To 150 mg of 2-acetylamino-8-amino-6-fluoro-5-methyl-1-tetralone and 158 mg of (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione, 30 ml of toluene and then 150 mg of pyridinium p-toluenesulfonate were added, followed by heating at an external temperature of 120° C. under reflux for 28 hours. After completion of the reaction, the solvent was removed under reduced pressure. Acetone was added to the residue and crystals so precipitated were collected by filtration, whereby 169 mg of the title compound were obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:9][C:10](=[O:21])[CH2:11][C:12]([O:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20])=[O:13])[CH2:4][CH:5]=[CH:6][CH2:7][CH3:8].[CH3:22][C:23]1[CH2:28][CH2:27][CH2:26][C:25]([CH3:30])([CH3:29])[C:24]=1[CH:31]=[CH:32][C:33](Cl)=[O:34]>C1COCC1.CCOCC>[CH2:3]([O:9][C:10](=[O:21])[CH:11]([C:33](=[O:34])[CH:32]=[CH:31][C:24]1[C:25]([CH3:29])([CH3:30])[CH2:26][CH2:27][CH2:28][C:23]=1[CH3:22])[C:12]([O:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20])=[O:13])[CH2:4][CH:5]=[CH:6][CH2:7][CH3:8]
Reactant: CCC=CCCOC(=O)CC(=O)OCCC=CCC
Reactant: CC1=C(C=CC(=O)Cl)C(C)(C)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC=CCCOC(=O)C(C(=O)C=CC1=C(C)CCCC1(C)C)C(=O)OCCC=CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a suspension of 2.10 g 60% sodium hydride in 20 ml of THF, a solution of 14.00 g malonic acid dihex-3-enyl ester in 20 ml of THF were dropped in at 0-5° C. The reaction mixture was stirred 1 hour at room temperature. Then a solution of 11.9 g 3-(2,6,6-trimethyl-cyclohex-1-enyl)-acryloyl chloride (Shimasaki et al., Chem. Pharm. Bull., 43 (1995) 1, 100-107) in 40 ml of THF was dropped in and the reaction mixture was stirred at room temperature for 21 hours. Then the reaction mixture was diluted with ether and the organic phase was washed with water, dried, filtered and evaporated to dryness. The resulting yellow oil was purified by chromatography to yield 4.22 g of a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:22]=1[NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][N:23]([C:22]1[CH:30]=[CH:31][C:32]([C:34]#[N:35])=[CH:33][C:21]=1[Br:20])[C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NC(=O)C(F)(F)F)c(Br)c1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Product: N#Cc1ccc(N(CC=C[C@H]2CCCN2C(=O)OCc2ccccc2)C(=O)C(F)(F)F)c(Br)c1

Procedure:
(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene and 2-bromo-4-cyano-N-trifluoroacetylaniline were used. Column chromatography using elution with a gradient of diethyl ether (5%-100%) in methylene chloride afforded the title compound as a clear, colorless oil: IR (CHCl3) 2231, 1702, 1157 cm-1 ; LRMS (m/z, relative intensity) 537 ([MH+ with 81Br], 13), 535 ([MH+ with 79Br], 13), 402 (29), 400 (30), 294 (55), 292 (57), 244 (80), 213 (89), 91 (100); Anal. calcd for C24BrF3H21N3O3.0.2 H2O: C, 53.39; H, 3.99; N, 7.78. Found: C, 53.25; H, 3.95; N, 7.98.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][C:20]=3[Br:41])[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.C(OCC)C>[Br:41][C:20]1[O:21][C:22]2[C:27]([O:28][C@@H:29]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[Cl:39])[CH3:30])=[C:26]([NH2:40])[N:25]=[CH:24][C:23]=2[C:19]=1[C:17]1[CH:16]=[N:15][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]=1
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-{6-amino-2-bromo-7-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-furo[3,2-c]pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 mg, 0.0030 mmol) in DCM (0.1 mL) was added 1N HCl in diethyl ether (0.2 mL). The resulting mixture was stirred at rt overnight. Evaporation afforded the title compound as a light-yellow gum. LC-MS (ES+): 567.97/569.97/571.99 [MH+].
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[OH:14][CH:13]([C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1)[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: Cn1cncc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.42 h

Procedure:
A solution of 5-bromo-1-methyl-1H-imidazole (25.0 g, 155 mmol; dried over 3 Å molecular sieves, then filtered) in DCM (310 mL) was stirred on an ice bath while iPrMgCl (72 mL, 2.01 M solution in THF, 145 mmol) was added rapidly dropwise under argon via pressure-equalizing addition funnel. Residual iPrMgCl was rinsed down with 50 mL THF, and the ice bath was removed and the reaction stirred for 25 minutes. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (27.6 g, 130 mmol) (PharmaCore) in THF (65 mL) was added dropwise over ˜5 minutes via pressure-equalizing addition funnel at room temperature. After stirring 1 hour at room temperature, the yellow mixture was quenched with 5 M aqueous NH4Cl (250 mL) in one portion. The organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear light amber oil.
Reaction SMILES: [OH-:1].[Na+].C(C1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][S:17][CH:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)=[CH:32][C:19]2=3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#N.[CH2:45]([OH:47])[CH3:46]>>[C:45]([C:46]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][S:17][CH:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)=[CH:32][C:19]2=3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([OH:1])=[O:47]
Reactant: [OH-]
Reactant: CCO
Reactant: N#Cc1ccc(S(=O)(=O)NCCSC2c3ccccc3COc3ccc(OCc4ccc5ccccc5n4)cc32)cc1
Agent: [Na+]
Product: O=C(O)c1ccc(S(=O)(=O)NCCSC2c3ccccc3COc3ccc(OCc4ccc5ccccc5n4)cc32)cc1

Procedure:
20 ml of a 1N-sodium hydroxide aqueous solution was added to 0.4 g of 11-[2-(4-cyanophenylsulfonylamino)ethylthio]-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Example 34 suspended in 5 ml of ethanol and the mixture was refluxed under heating for 6 hours. After completion of the reaction, the solvent was removed, water was added to the residue, insolubles were removed by filtration and then the residue was adjusted to about pH 3 with 1N-hydrochloric acid. Crystals precipitated were collected by filtration and dissolved in ethyl acetate and the organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and condensed. The resulting solid was recrystallized from hexane to obtain 0.33 g of the title compound as yellowish white powder.
Reaction SMILES: [CH:1](O)=O.[CH3:4][NH:5][C:6]([O:8][N:9]=[CH:10][C:11]([CH3:15])(SC)[CH3:12])=[O:7].OO.[S:18](=[O:22])(=O)(O)[OH:19]>C(Cl)Cl>[CH3:4][NH:5][C:6]([O:8][N:9]=[CH:10][C:11]([CH3:15])([S:18]([CH3:1])(=[O:22])=[O:19])[CH3:12])=[O:7]
Reactant: CNC(=O)ON=CC(C)(C)SC
Reactant: O=CO
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: ClCCl
Product: CNC(=O)ON=CC(C)(C)S(C)(=O)=O
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
15 grams of an 88 percent aqueous solution of formic acid was added to a mixture containing 30 grams of 2-methyl-2-(methylthio)propionaldehyde O-(methylcarbamoyl)oxime in 70 grams of methylene chloride solution. To the mixture was added 56 grams of a 30 percent aqueous hydrogen peroxide over a 15-20 minute period. During the course of addition, the reaction temperature rose from 25° to 40° C. with a gentle reflux of methylene chloride. After the addition of the peroxide solution, 6.0 grams of concentrated sulfuric acid was added dropwise at a rate to maintain the reflux at 40° C. When the addition was complete, the mixture was stirred for an additional 2.5 hours at 40.45° C. When the oxidation was over, 60-70 grams of the methylene chloride solvent was removed by evaporation under reduced pressure. The mixture was cooled to 5° C. and filtered. The solid reaction product was then washed with 25-30 grams of cold water and dried to constant weight. (2-Methyl-2-(Methylsulfonyl)propionaldehyde O-(methylcarbamoyl)oxime was obtained, m.p. 144°-145° C, having a 2-methyl-2-(methylsulfinyl)propionaldehyde O-(methylcarbamoyloxime (sulfide) content of less than 0.10 percent.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([O:27]C(OC(C)(C)C)=O)=O)([CH3:23])([CH3:22])[CH3:21].[CH2:35]([N:37](CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:20]([O:24][C:25]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:35]#[N:37])[CH:10]=2)/[C:6](=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)/[C:7]1=[O:11])=[O:27])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(C#N)cc21
Yield: 93.6 %

Procedure:
In a manner similar to the method described in example 24a, E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (1.34 g, 4.77 mmol) was reacted with di-tert-butyl-dicarbonate (1.91 g, 8.73 mmol) (Aldrich), triethylamine (3.29 mL, 23.6 mmol) and 4-dimethylaminopyridine (25 mg) in dichloromethane (100 mL) to give E/Z-6-cyano-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as a yellow solid (Yield: 1.7 g, 93.4%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCC(c2ccc(F)cc2)O1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(F)cc2)O1
Reaction time: 8 h
Yield: 93.3 %

Procedure:
2-Hydroxy-5-(4-fluorophenyl)-tetrahydrofuran (550 mg, 3.0 mmol), t-butyldimethylsilyl chloride (498 mg, 3.3 miol) and imidazole (450 mg, 6.6 mmol) were dissolved in 2 mL of dry DMF. This solution was stirred under dry argon overnight, poured into 200 mL of water and extracted with a 2:1 mixture of ethyl acetate( and hexane (3×100 mL). The combined organic extracts were washed with water (4×200 mL) and brine (100 mL), dried over sodium sulfate and evaporated to give 830 mg (93%) of 2-(t-butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (202, mixture of cis and trans isomers) as a colorless oil, which did not need any purification. 1H-NMR (CDCl3) δ 7.40-7.50(2H, m, minor isomer), 7.25-7.35 (2H, m, major isomer), 7.00-7.10 (2H, m, both major and minor isomers), 5.71-5.75 (1H, m, major isomer), 5.59-5.62 (1H, m, minor isomer), 5.12-5.20 (1H, m, major isomer), 4.90-4.98 (1H, m, minor isomer), 2.40-2.55 (1H, m, both major and minor isomers), 2.05-2.17 (1H, m, both major and minor isomers), 1.87-2.00 (1H, m, both major and minor isomers), 1.67-1.70 (1H, m, both major and minor isomers), 0.92 (s, 9H, both major and minor isomers), 0.16 (s, 6H, both major and minor isomers).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[N:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=3)[N:4]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)c1ccncc1
Product: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
3-bromo-1-trityl-1H-indazole-5-carboxylic acid (500 mg, 1.04 mol) was added to a vial containing pyridin-4-ylboronic acid (128 mg, 1.04 mol) and tetrakis(triphenyl-phosphine)palladium (120 mg, 0.104 mol). After purging the vial with nitrogen gas, dioxane (5 mL) and 2M sodium carbonate (5 mL) was added to the vial respectively. The reaction mixture was stirred and was heated to 80° C. for overnight. Upon completion, the mixture was concentrated under vacuo. Water (30 mL) was added and pH was adjusted to 7 by HCl. The mixture was extracted using dichloromethane (3×100 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting suspension was filtered and concentrated. The crude product was purified using prep LC/MS.
Reaction SMILES: C1[C@@H](C(O)=O)[N:4]([C:9](O)=[O:10])C[C@@H]1O.C([N:15]([CH2:18][CH3:19])[CH2:16]C)C.Cl[C:21]([O:23]C)=[O:22]>ClCCl>[OH:10][C:9]1[C:19]([C:21]([OH:23])=[O:22])=[CH:18][N:15]=[CH:16][N:4]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)O
Solvent: ClCCl
Product: O=C(O)c1cncnc1O

Procedure:
A suspension of 22.4 g (129 mmol) of N-acetyl-L-4-hydroxyproline and 300 ml of dichloromethane is stirred at -10° and 18.06 ml (130 mmol) of triethylamine is added, followed by 10.2 ml (130 mmol) of methyl chloroformate at -10° to -15° C. The silylated acid solution from above is added in aliquots keeping the temperature below -5° C. When all is added, the reaction temperature is allowed to rise to 0° C. and the reaction flask is placed in an ice bath. The reaction is stirred overnight allowing the bath temperature to rise to room temperature. The reaction is filtered and filtrate is evaporated. Water is added to the residue and the mixture is stirred for 2 hrs and filtered. The product is resuspended in water, stirred, and filtered. The solid is taken up in isopropanol and a light precipitate is filtered off. The filtrate is evaporated down and the residue is washed with isopropanol and then ether. The product is suspended in water and cooled in an ice bath. The pH is adjusted to 2.15 with dilute hydrochloric acid and the precipitate is filtered. The solid is taken up in isopropanol and the insolubles filtered off. The solids are dissolved in methanol and added to the isopropanol solution. The resulting solution is evaporated down and ether added to the residue. A light yellow solid is obtained and dried under vacuum to give 8.8 g of 2-[4-acetyl-L-hydroxyprolylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid.