Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([Cl:41])=[C:7]([C:11]2[NH:40][C:14]3[C:15]([O:29][CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[C:1]([C:5]1[C:6]([Cl:41])=[C:7]([C:11]2[NH:40][C:14]3[C:15]([O:29][CH2:30][CH2:31][OH:32])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCCO[Si](C)(C)C(C)(C)C)c2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCCO)c2[nH]1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine (390 mg, 0.641 mmol, prepared as described in the previous step) and tetrabutylammonium fluoride hydrate (914 mg, 3.21 mmol) in THF (10 mL) was stirred at 50° C. for 18 h. After cooling to room temperature, the resulting mixture was treated with EtOAc (50 mL) and washed with H2O (2×20 mL), brine (20 mL). The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (40:60-60:40 EtOAc/heptane) to yield 2-[2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy]-ethanol as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 7.67 (dd, J=7.3, 2.0 Hz, 1H), 7.48-7.56 (m, 2H), 7.39 (td, J=6.7, 1.8 Hz, 2H), 4.64-4.68 (m, 2H), 4.05 (s, 3H), 3.97-4.02 (m, 2H), 1.42-1.49 (m, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C23H23ClF3N5O2: 492.2 (M+H), Measured: 492.4.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:23])(=[O:3])[CH3:2].CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>O>[C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:10][C:9]1=[O:23])(=[O:3])[CH3:2]
Reactant: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCCCC[C@@H](/C=C/[C@H]1C(=O)C=C[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O

Procedure:
to a solution of 26 parts of methyl (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oate in 200 parts of acetone at -10° is added 100 parts of Jones reagent. The resultant mixture is stirred at -10° for 7 minutes, then diluted with 10 volumes of water. The mixture thus obtained is extracted with dichloromethane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The oily residue is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvent. From an eluate comprising 5% ethyl acetate in benzene, on evaporation of solvent, methyl (5Z,13E,15S)-15-acetyloxy-11-oxoprosta-5,9,13-trien-1-oate is obtained as a pale yellow oil. The product has the formula ##SPC3##
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:37][N:38]([CH3:44])[CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>ClCCl>[CH3:37][N:38]([CH3:44])[CH:39]1[CH2:43][CH2:42][N:41]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:40]1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CN(C)C1CCNC1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCC(N(C)C)C4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 114.2 mg of 3-(dimethylamino)pyrrolidine in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2.C>CS(C)=O.C(Cl)Cl.[Cu](I)I>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[CH:3]=[CH:4][C:5]3[C:14]4[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=4[N:7]([CH3:22])[C:6]=3[N:23]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.27 g, 0.71 mmol), 4-benzyloxy pyridinone (0.16 g, 0.78 mmol), and Cs2CO3 (0.25 g, 0.776 mmol) were suspended in DMSO (4.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (31 mg, 0.21 mmol) and copper iodide (0.17 g, 0.92 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL) and washed with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (40 mL) (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes) gave a crude product that was dissolved in CH2Cl2 (5 mL). Activated charcoal was added to the solution, and the resulting suspension was filtered through celite. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 75:25 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (0.12 g, 33%) as a clear film: 1H NMR (500 MHz, DMSO-d6) δ 7.94 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.48-7.41 (m, 4H), 7.38-7.37 (m, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.15 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 3.69-3.67 (m, 5H), 3.59-3.58 (m, 2H), 3.06-3.05 (m, 2H), 2.96-2.95 (m, 2H), 1.43-1.42 (m, 9H).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.CC(O)C.O.Br[C:47]1[N:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1>CCOC(C)=O.O>[NH2:53][C:50]1[N:51]=[CH:52][C:47]([C:14]2[C:15]([F:18])=[C:16]([F:17])[C:9]([N:4]3[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]3)=[C:10]([CH:13]=2)[CH:11]=[O:12])=[N:48][CH:49]=1
Reactant: CC1CN(c2c(C=O)cc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)CC(C)O1
Reactant: Nc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC1CN(c2c(C=O)cc(-c3cnc(N)cn3)c(F)c2F)CC(C)O1
Temperature: 85 °C
Yield: 35.9 %

Procedure:
To a suspension of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (0.500 g, 1.3 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in previously degassed toluene/IPA/water (4/4/1) mixture (2.5 mL) was added 5-bromo-pyrazin-2-ylamine (Maybridge, 0.208 g, 1.2 mmol) under nitrogen. Tetrakis(triphenylphosphine)palladium-(0) (0.055 g, 0.05 mmol) was added at room temperature and the reaction was heated at 85° C. for 3.5 hrs. The mixture was cooled to room temperature, diluted with EtOAc and water then neutralized. The phases were separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated. Purified by column chromatography eluting with ethyl acetate in hexanes (10-60%) to obtain 150 mgs of product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H), 2.97 (m, 2H), 3.34 (m, 2H), 4.18 (m, 2H), 4.78 (s, 2H), 8.08 (d, J=1.6 Hz, 1H), 8.19 (dd, J=8.4, 2.1 Hz, 1H), 8.44 (m, 1H), 10.37 (s, 1H); MS(APCl+) m/z 349 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C)[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Br[C:20]1C=CC(CC(O)C)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reactant: CC(O)Cc1ccc(Br)cc1
Product: CC(Cc1ccc(Br)cc1)O[Si](C)(C)C(C)(C)C
Yield: 87 %

Procedure:
According to the procedure for the preparation of 73C, 77A (4.90 g, 22.8 mmol) afforded 6.51 g (87%) of 77B as a colorless oil. MS (ESI) m/z 197.1 (M-OTBS)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:52][CH:53]1[C@H:57]2[C@H:58](OC3CCCCO3)[N:59](C(OC(C)(C)C)=O)[C:60]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][C:61]=3[C:62](=[O:63])[N:56]2[CH2:55][CH2:54]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[C@H:25]2[C@H:26](OC3CCCCO3)[N:27](C(OC(C)(C)C)=O)[C:28]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:29]=3[C:30](=[O:31])[N:24]2[CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:19]([O:20][CH:21]1[C@@H:25]2[CH:26]=[N:27][C:28]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:29]=3[C:30](=[O:31])[N:24]2[CH2:23][CH2:22]1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:52][CH:53]1[C@@H:57]2[CH:58]=[N:59][C:60]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][C:61]=3[C:62](=[O:63])[N:56]2[CH2:55][CH2:54]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 89.5 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15j (210 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16j (112 mg, 0.17 mmol, 89%) as a solid: [α]20D=+637° (c=0.13, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.24-1.51 (m, 16H, 14-H, 14′-H, 15-H, 15′-H, 16-H, 16′-H, 17-H; 17′-H); 1.78-1.93 (m, 4H, 13-H, 13′-H), 1.98-2.11 (m, 4H, 2-H, 2′-H), 2.25-2.38 (m, 4H, 1-H, 1′-H), 3.54-3.64 (m, 2H, 3-H, 3′-H), 3.68-3.76 (m, 2H, 11a-H, 11a′-H), 3.77-3.89 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 3.98-4.14 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.50 (s, 2H, 6-H, 6′-H), 7.64 (d, 2H, J=4.4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 28.9, 29.3, 29.5, 29.5, 29.6, 46.6, 53.7, 56.1, 69.1, 110.4, 111.5, 120.0, 140.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 3338, 2926, 1599, 1506, 1456, 1431, 1381, 1261, 1216, 1092, 1023 cm−1; MS (FAB) m/z (relative intensity) 723 ([M+2×MeOH]+., 9), 691 ([M+MeOH]+., 15), 659 (M+., 100).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][C:23]2=O)=[CH:19][CH:18]=1.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](=[CH:19][CH:18]=1)[CH2:21][CH:22]=[C:23]2[C:8]1[CH:7]=[CH:6][CH:5]=[C:2]([O:3][CH3:4])[C:1]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: O=C1CCc2ccc(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2=CCc3ccc(Cl)cc32)c1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, 45.9 ml of veratrole (49.78 g, 360.1 mol) are dissolved in 240 ml of THF and, at −78° C., 236.2 ml of a 1.6 M solution of n-butyllithium in THF (377.7 mol) are added drop wise. The reaction mixture is warmed to 0° C. and stirred at this temperature for 3 h. The mixture is cooled to −60° C., and 30.0 g of the compound from Example 16A (180.1 mol) dissolved in 150 ml of THF are added drop wise. The reaction mixture is warmed to room temperature over the course of 3 h and then acidified with 1 N hydrochloric acid and extracted with dichloromethane. The combined organic phases are dried over magnesium sulphate, and the solvent is removed in a rotary evaporator. The residue is is purified by filtration through silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). The crude product [6-chloro-1-(2,3-dimethoxyphenyl)indan-1-ol] is dissolved in 1 l of dichloromethane and, after addition of 75 mg of 4-toluenesulphonic acid monohydrate (0.39 mol), stirred at RT for. 16 h. The reaction solution is washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1). 10.5 g (20% of theory) of the title compound are obtained.
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5](=[O:46])[C@@H:6]([NH:38][C:39](OC(C)(C)C)=[O:40])[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][C:23]=3[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl>O1CCCC1.CO>[CH2:31]([C:23]1[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][S:8][CH2:7][C@:6]([N:38]=[C:39]=[O:40])([O:1][C:10]([CH3:15])([CH3:11])[CH3:9])[C:5]([OH:4])=[O:46])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)[C@H](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)O[C@](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)(N=C=O)C(=O)O
Reaction time: 1 h
Yield: 84 %

Procedure:
1N Sodium hydroxide (2 mL) was added to a stirred solution of (2R)-methyl-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylamino-propionate (100 mg) in a mixture of tetrahydrofuran (6 mL) and methanol (2 mL). The solution was stirred for 1 hour and then acidified to pH 3 with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a white solid (82 mg, 84%): mp. 89-90° C. Rf=0.50 (10% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 7.8 (2H, d, J=9 Hz, Ar—H), 7.6 (6H, m, Ar—H), 7.4 (2H, d, J=9 Hz, Ar—H), 7.28 (5H, m, Ar—H), 7.21 (2H, d, J=8 Hz, Ar—H), 6.42 (1H, d, J=8 Hz, NH), 4.26 (2H, s, PhCH2), 3.95 (1H, m, CHN), 3.75 (2H, s, PhCH2S), 2.9 (1H, dd, J=15, 5 Hz, CHHCHN), 2.74 (1H, dd, J=15, 8 Hz, CHHCHN), 1.39 (9H, s, tBu); ESI-LCMS e/z calcd for C36H35NO5S 593.74, found 617 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].O>CN1C(=O)CCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14](=[O:16])[CH3:15])[CH2:22][CH2:21]3)[CH:24]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)N1CCN(c2cccc(N)c2)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)c1ccc(Nc2cccc(N3CCN(C(C)=O)CC3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
A mixture of 1b (0.75 g, 4.1 mmol) and 2d (0.9 g, 4.1 mmol) in anhydrous NMP (2 ml) was heated to 80° C. overnight under a stream of nitrogen. After cooling water (20 ml) was added and the mixture was extracted with dichloromethane. The organic extract was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column-chromatography on silica gel using ethyl acetate as the eluent to yield 4-acetyl-N-(3-(1-acetylpiperazin-4-yl)phenyl)-2-nitroaniline as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[C:29](OC(=O)C)(=[O:31])[CH3:30].CCN(CC)CC>CC#N>[C:29]([N:24]1[C:25]2[C:21](=[CH:20][C:19]([CH2:18][N:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=4[F:17])=[C:2]([Cl:1])[C:3]3=[O:28])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1)(=[O:31])[CH3:30]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2[nH]ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)n1ccc2cc(Cn3ccc(OCc4ccc(F)cc4F)c(Cl)c3=O)ccc21
Temperature: 86 °C
Reaction time: 6 h

Procedure:
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one (Step 5, synthesis of Example 86) (0.22 g, 0.57 mmol) in CH3CN (10 mL) was added acetic anhydride (0.06 mL, 0.58 mmol) and Et3N (2 mL), and the reaction mixture was stirred at 86° C. for 6 h. The reaction mixture was cooled to room temperature, and partitioned between 1 N HCl and EtOAc. The organic solution was separated, washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. 1H NMR (300 MHz, MeOD) δ 8.35 (d, J=9 Hz, 1H), 7.77 (d, J=9 Hz, 1H), 7.70 (d, J=3 Hz, 1H), 7.54 (s, 2H), 7.31 (d, J=9 Hz, 1H), 7.01-6.99 (m, 2H), 6.66 (d, J=3 Hz, 1H), 6.59 (d, J=9 Hz, 1H), 5.29 (s, 4H), 2.63 (s, 3H). ESHRMS m/z 443.0965 (M+H C23H18ClF2N2O3 requires 443.0969).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CC(C)=O.[OH-].[Na+].Cl[CH:23]([F:25])[F:24]>O.CC(O)C>[F:24][CH:23]([F:25])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: FC(F)Cl
Reactant: COC(=O)C(c1ccc(O)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C(c1ccc(OC(F)F)cc1)C(C)C
Temperature: 30 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
A mixture of methyl 2-(4-hydroxyphenyl)-3-methylbutyrate (44.42 g of 93.8% pure material=41.67 g; 0.20 mol), acetone (83.3 ml), 2-propanol (83.3 ml), and water (62.8 ml) is stirred at 30° C. in a closed system. After the system is evacuated, chlorodifluoromethane is introduced into the reaction mixture under a pressure of 0.49 kg cm-2. After about 5 minutes, one equivalent of 50.6% of aqueous sodium hydroxide (10.4 ml; 0.2 mol) from a pressurized reservoir is added all at once causing the reaction mixture to exotherm to 34° C. with a concomitant rise in pressure to 0.7 kg cm-2. Slow addition of the rest of 50.6% aqueous sodium hydroxide (31.6 ml; 0.60 mol) then commences and is completed in about 60 minutes. About 5 minutes after the beginning of the slow addition of the base, the pressure under which the chlorodifluoromethane is introduced into the reaction mixture is increased to 1.05 kg cm-2. In about 45 minutes a total of 0.60 mol of chlorodifluoromethane (51.66 g) is added. After the addition of the sodium hydroxide is completed, the reaction mixture is stirred for an additional hour. The system is then evacuated to remove any unreacted chlorodifluoromethane from the reaction mixture. Next, a 1:1 mixture (by volume) of acetone:2-propanol (100 ml) is added while washing down the reactor. The reaction mixture is filtered and the organic layer is separated yielding 334.6 g of an orange liquid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19](O)[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[N:27]=[N:28][NH:29][N:30]=4)[CH:21]=3)=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:32](=[O:34])[CH3:33].[SiH](CC)(CC)CC.B(F)(F)F>C(Cl)Cl>[OH:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[N:27]=[N:28][NH:29][N:30]=4)[CH:21]=3)=[CH:17][CH:18]=2)[CH:5]=[CH:4][C:3]=1[C:32](=[O:34])[CH3:33]
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4nn[nH]n4)c3)cc2)c(C(C)C)c1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccc(Cc3cccc(-c4nn[nH]n4)c3)cc2)c(C(C)C)c1O
Reaction time: 1.5 h
Yield: 29.8 %

Procedure:
To 1-[2-Hydroxy-4-(4-{hydroxy-[3-(2H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-3-isopropyl-phenyl]-ethanone (100 mg, 0.22 mmol) in anhydrous CH2Cl2 (5.4 mL) is added Et3SiH (281 μL, 1.76 mmol) and BF3.ether complex (56 μL, 0.44 mmol). The reaction mixture is stirred for 1.5 h. The reaction mixture is quenched into saturated aqueous NH4Cl (10 mL) and extracted with a 50% tetrahydrofuran/ethyl acetate solution (3×30 mL). The organic layers are combined, washed with brine, dried over sodium sulfatesodium sulfate, and concentrated to an oil. The residue is purified by reverse phase HPLC using a gradient of 90:10 to 20:80 (H2O/0.1% TFA):CH3CN as eluent to give the title compound (29 mg, 30%). LC-MS (m/e): 441 (M−1); 1H NMR (DMSO-d6) δ 13.1 (1H, s), 7.82-8.00 (2H, m), 7.78 (1H, d), 7.30-7.55 (6H, m), 6.72 (1H, d), 5.22 (2H, s), 4.08 (2H, s), 3.57 (1H, m), 2.57 (3H, s), 1.26 (3H, s), 1.23 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:13][OH:14])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1C=NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-nitrobenzaldehyde (115 g) and hydroxylamine hydrochloride (6.6 g) in ethanol (110 ml) and water (4 ml) was added sodium acetate (13.6 g) and the mixture was stirred at room temperature for 4 hours. The mixture was poured into water (500 ml) and the mixture filtered to give the title product.