Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.[F:26][C:27]([F:31])([F:30])[S:28]Cl.O>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[S:22][C:23]([S:28][C:27]([F:31])([F:30])[F:26])=[CH:24][CH:25]=1
Reactant: FC(F)(F)SCl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cccs1
Solvent: O
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccc(SC(F)(F)F)s1
Reaction time: 48 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(thien-2-yl)pyrazole (0.806 g) in dry dichloromethane (25 ml) at room temperature was added a solution of stannic chloride (500 μl) in dry dichloromethane (5 ml). To this was added 7.2 ml of a 50 mg/ml solution of trifluoromethylsulphenyl chloride in dichloromethane and the mixture was stirred for 48 hours after which it was poured onto a mixture of ice, water and dichloromethane. The aqueous layer was separated and washed with dichloromethane. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, dried and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane:hexane (1:1). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 162-3° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:35])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=O.CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:1][C@@H:2]([CH3:35])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][Si:19]([CH:23]([CH3:24])[CH3:25])([CH:20]([CH3:21])[CH3:22])[CH:26]([CH3:28])[CH3:27])[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
N-[(2R)-2-hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxamide (48.7 g, 96.5 mmol) synthesized in Example (116b) was dissolved in tetrahydrofuran (600 mL), and anhydrous methanesulfonic acid (33.6 g, 193 mmol) and triethylamine (40.4 mL, 289 mmol) were added, followed by stirring at 50° C. for 3 hours under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (500 mL) was added, and extraction was carried out twice with ethyl acetate (500 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diisopropylether (300 mL) was added to the resulting residue, and the slurry was stirred to give a white solid, which was filtered off. Under reduced pressure, the solvent in the mother liquor was distilled off, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%). This was vacuum-dried together with the filtered product to afford the desired compound (34.8 g, yield 74%) as a white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[CH:30][C:21]([NH:20][S:2]([C:5]2[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3])=[CH:22][CH:23]=1)=[O:26]
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a mixture of 1.04 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate and 10 mL of pyridine was added 512 mg of methyl 4-aminobenzoate, followed by stirring at room temperature for 1 hour. To the reaction mixture was added a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1.25 g of 2-(trimethylsilyl)ethyl 3-{[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoate as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]1[CH:35]=[C:34]([CH:36]=O)[C:33]([O:38][CH3:39])=[CH:32][C:31]=1[O:40][CH3:41])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]1[CH:35]=[C:34](/[CH:36]=[CH:2]/[C:1](=[O:3])[C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)[C:33]([O:38][CH3:39])=[CH:32][C:31]=1[O:40][CH3:41])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 40 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2-(5-formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester (Ex-36A) in a similar manner as described in Ex-22. Yellow solid, 40% yield, mp 120–122° C. 1H-NMR (CDCl3) δ 8.01–8.19 (m, 6H), 7.68 (s, 1H), 7.56 (d, J=8 Hz, 1H), 7.46 (d, J=16 Hz, 1H), 7.21–7.35 (m, 2H), 6.53 (d, J=14 Hz, 2H), 5.01 (s, 2H), 4.00 (s, 3H), 3.85 (s, 3H), 1.42 (s, 9H), MS m/z=563 ([M+H]+). HRMS (ES+) Calcd. for C30H30N2O7S: 563.1852. Found: 563.1862.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][CH:8]([OH:37])[C:9]([CH3:36])([CH3:35])[C:10](=[O:34])[CH:11]([CH3:33])[CH:12]([O:24][C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:44](Cl)([CH2:49][CH3:50])([CH2:47][CH3:48])[CH2:45][CH3:46]>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH:8]([O:37][Si:44]([CH2:49][CH3:50])([CH2:47][CH3:48])[CH2:45][CH3:46])[C:9]([CH3:36])([CH3:35])[C:10](=[O:34])[CH:11]([CH3:33])[CH:12]([O:24][C:25]([O:27][CH2:28][C:29]([Cl:30])([Cl:32])[Cl:31])=[O:26])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(COCc1ccccc1)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)C(=O)C(C)(C)C(O)CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)COCc1ccccc1
Reaction time: 3 h
Yield: 510.4 %

Procedure:
To a solution of 70 (37.6 mg, 6.3 μmol) and imidazole (9.4 mg, 13.8 μmol) in DMF (0.4 mL) at 0° C. was added TESCl (11.6 μL, 69.3 μmol). After 3 h, the mixture was diluted with sat aq NaHCO3. The aqueous layer was extracted three times with hexanes. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 93:7) to yield, in order of elution, 71 (22.9 mg, 51%), and recovered 70 (12.9 mg, 34%) as clear oils. 7: 1H NMR (400 MHz, CDCl3) δ 0.66 (q, J=7.9 Hz, 6H), 0.96 (t, J=7.9 Hz, 9H), 1.01 (s, 3H), 1.05 (d, J=5.2 Hz, 3H), 1.07 (d, J=5.3 Hz, 3H), 1.35 (s, 3H). 1.44 (s, 9H), 2.05-2.11 (m, 2H), 2.50 (dd, J=3.5 and 17.2 Hz, 1H), 3.35 (dd, J=5.9 and 9.0 Hz, 1H), 3.49 (dd, J=4.0 and 9.0 Hz, 1H), 3.53 (dd, J=3.8 and 6.7 Hz, 1H), 4.18 (dd, J=3.5 and 6.5 Hz, 1H), 4.45 (s, 2H), 4.65 (d, J=11.9 Hz, 1H), 4.79 (d, J=11.9 Hz, 1H), 4.97 (dd, J=3.7 and 8.1 Hz, 1H), 7.29-7.52 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 5.3, 7.3, 10.9, 14.9, 21.3, 22.6, 28.4, 35.9, 41.1, 42.7, 53.7, 71.9, 73.7, 75.7, 80.1, 80.9, 95.1, 127.9, 128.0, 128.7, 138.6, 154.3, 171.7, 215.7; IR (film, NaCl, cm−1) 2956, 2876, 1732, 1694, 1456, 1366, 1257, 1154, 1098, 988, 835, 774, 741; LRMS (ESI) calcd for C33H53O8SiCl3Na [M+Na+] 733.2, found 733.3. [α]23D=−16.1 (c=0.1, CHCl3).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:15]/[N+:12]([O-:14])=[O:13])=[CH:5][C:4]=2[O:9]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])/C=C/c1ccc2c(c1)OCO2
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a stirred solution of piperonal (75 g, 500 mmol) in methanol (120 mL) at 10° C. was added nitromethane (27.1 mL, 500 mmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while maintaining the temperature between 10-15° C. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon completion of the addition, and the mixture was then diluted with ice-water (˜350 mL) maintaining the temperature below 5° C., until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops) into a rapidly stirred solution of 36% hydrochloric acid (100 mL) in water (150 mL). A yellow solid precipitated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filtrate was neutral. The filter cake was air dried and then recrystallized from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 55%). 1H NMR (300 MHz, CDCl3) δ 7.94 (1H, d, J=13.5 Hz), 7.47 (1H, d, J=13.5 Hz), 7.09 (1H, dd, J=7.5&2 Hz), 7.01 (1H, d, J=2 Hz), 6.87 (1H, d, J=7.5 Hz), 6.06 (2H, s). MS (DCl/NH3) m/e 194 (M+H)+, 211 (M+H+NH3)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][NH:13][CH3:14])=[CH:4][CH:3]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:31].[N:32]1([CH2:38][CH2:39][N:40]2[CH2:45][C:44]3[CH:46]=[C:47](/[CH:50]=[CH:51]/[C:52]([OH:54])=O)[CH:48]=[N:49][C:43]=3[NH:42][C:41]2=[O:55])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[ClH:31].[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][N:13]([CH3:14])[C:52](=[O:54])/[CH:51]=[CH:50]/[C:47]2[CH:48]=[N:49][C:43]3[NH:42][C:41](=[O:55])[N:40]([CH2:39][CH2:38][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH2:45][C:44]=3[CH:46]=2)=[CH:4][CH:3]=1
Reactant: CNCc1ccc(F)c2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CN(Cc1ccc(F)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Yield: 43 %

Procedure:
According to the procedure of Example 1, except substituting 4-fluoro-naphthalen-1-ylmethyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.13 g, 43%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.64-10.51 (m, 1H), 10.12 (m, 1H), 8.45-8.30 (m, 1H), 8.22-8.07 (m, 2H), 8.03-7.86 (m, 1H), 7.78-7.62 (m, 2H), 7.63-7.51 (m, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.32 (t, J=8.6 Hz, 1H), 7.21-7.12 (m, 1H), 5.03-5.02 (m, 2H), 4.57-4.42 (m, 2H), 4.01-3.91 (m, 2H), 3.80-3.63 (m, 4H), 3.53-3.43 (m, 2H), 3.40-3.25 (m, 2H), 3.09-2.96 (m, 5H); MS (ESI) m/e 504 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:3]=1.Cl.[Cl:18][C:19]1[CH:35]=[CH:34][C:22](/[CH:23]=[CH:24]/[S:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[ClH:18].[Cl:18][C:19]1[CH:20]=[CH:21][C:22](/[CH:23]=[CH:24]/[S:25]([N:28]2[CH2:33][CH2:32][N:31]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:16][CH:15]=3)[CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:34][CH:35]=1
Reactant: O=S(=O)(/C=C/c1ccc(Cl)cc1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Agent: Cl
Product: O=C(c1ccc(-c2cccnc2)cc1)N1CCN(S(=O)(=O)/C=C/c2ccc(Cl)cc2)CC1

Procedure:
In the same manner as in Example A-17 except for the use, as starting materials, of 4-(3-pyridyl)benzoic acid hydrochloride and 1-[(E)-4-chlorostyrylsulfonyl]piperazine hydrochloride, a reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([OH:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([OH:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Yield: 69.2 %

Procedure:
In a fashion analogous to Step B of Example 3A, 1.1 g of Boc-Tyr-DAla-Phe-Met-OH was treated with 10% anisole in TFA and chromatographed on Amberlite XAD-2 to give 0.64 g (60%) of H-Tyr-DAla-Phe-Met-OH, m.p. 248°-249° C., [α]D25.5 =41.06° (c, 1.00 in 50% acetic acid).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]CCCC)=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Li+]>C1COCC1.CO>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCOC(=O)c1ccc(Br)c(OCCCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1cc(C(=O)O)ccc1Br
Temperature: 23 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 5.1 (0.90 g, 2.7 mmol) in THF/MeOH (2/1) (18 mL), was added lithium hydroxide (6.0 mL, 6.0 mmol). The resulting mixture was stirred overnight at 23° C. and then quenched with excess 1N HCl. The mixture was then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by combiflash (0 to 40% EtOAc/hexanes) to afford a 20.1 (0.68 g, 91% yield).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CNC(=O)c1cc(N2CCN(C)CC2)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=O)c1cc(N2CCN(C)CC2)ncc1-c1ccccc1Cl
Temperature: 80 °C
Yield: 63.6 %

Procedure:
To a suspension of 1.20 g (3.83 mmol) 5-bromo-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide in 15 ml toluene were added successively 0.135 g tetrakis(triphenylphosphine)palladium(0), 4 ml 2 M sodium carbonate solution in water and 0.72 g (4.6 mmol) o-chlorphenylboronic acid. The mixture was heated under argon at 80° C. for 18 h. The aqueous layer was separated and washed with toluene. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.84 g (63%) of the title compound as a pale brown foam.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][O:17][CH:18]=3)[N:11]=[C:10]([C:19]3[CH:20]=[C:21]([C:25]4([NH:29]C(=O)OC(C)(C)C)[CH2:28][O:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)[CH:9]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]1[CH:18]=[C:14]([CH2:13][N:12]2[C:8]([O:7][C:6]3[CH:37]=[CH:38][C:3]([C:2]([F:1])([F:39])[F:40])=[CH:4][CH:5]=3)=[CH:9][C:10]([C:19]3[CH:20]=[C:21]([C:25]4([NH2:29])[CH2:28][O:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)=[N:11]2)[N:15]=[CH:16]1
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(Cc4cocn4)n3)c2)COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(Cc4cocn4)n3)c2)COC1
Reaction time: 1.5 h

Procedure:
A stirred solution of tert-butyl (3-{3-[5-(4-trifluoromethylphenoxy)-1-(1,3-oxazol-4-ylmethyl)-1H-pyrazol-3-yl]phenyl}oxetan-3-yl)carbamate (48 mg, 0.086 mmol) in 0.6 mL of CH2Cl2 was cooled in an ice bath, and to the solution was added 0.6 mL of TFA. The solution was stirred for 1.5 h and then quenched with 10% Na2CO3. The organic phase was washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give 3-{3-[1-(1,3-oxazol-4-ylmethyl)-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl]phenyl}oxetan-3-amine as a glass. Calcd (M+1)+: 457.4. found: 457.1.
Reaction SMILES: C[O:2][P:3]([CH:7]=[CH:8][C:9]([CH3:26])=[CH:10][CH2:11][C:12]1[C:13]([OH:25])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24])(=[O:6])[O:4]C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>C(#N)C>[OH:25][C:13]1[C:12]([CH2:11][CH:10]=[C:9]([CH3:26])[CH:8]=[CH:7][P:3](=[O:2])([OH:6])[OH:4])=[C:20]([O:21][CH3:22])[C:19]([CH3:23])=[C:18]2[C:14]=1[C:15](=[O:24])[O:16][CH2:17]2
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)C=CP(=O)(OC)OC)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)C=CP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonic acid dimethyl ester 2B (22 mg, 0.057 mmol) and 2,6-lutidine (0.22 mL, 1.71 mmol) in acetonitrile was added trimethylsilyl bromide (0.183 mL, 1.71 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with methanol at 0° C., and the resulting mixture was concentrated. The residue was purified by preparative reverse-phase HPLC to afford, after removal of the solvent, [5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonic acid 2C as a solid (13 mg, 65%); 1H NMR (300 MHz, CD3OD) δ 1.91 (s, 3H), 2.10 (s, 3H), 3.55 (d, J=6.6 Hz, 2H), 3.75 (s, 3H), 5.2 (s, 2H), 5.6-5.8 (m, 2H), 6.9 (m, 1H) ppm.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:28](OC(=O)C)(=[O:30])C>Cl(O)(=O)(=O)=O.C(O)=O>[CH:28]([O:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[C@H:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:27])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24]1)=[O:30]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O=CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 40 °C

Procedure:
Ten grams of lithocholic acid was dissolved in 40 ml. of 89.9% formic acid and 8 drops of 70% perchloric acid, and the resulting solution heated to 55° C. with stirring. The solution was then cooled to 40° C. at which time 35 ml. of acetic anhydride was slowly added and the temperature of the reaction mixture maintained between 55°-60° C. The solution was cooled and poured into 500 ml. of water and the resulting precipitate was filtered, washed with water and dried to yield 3α-formyloxy-5β-cholan-24-oic acid.
Reaction SMILES: O.[C:2](=[O:5])([O-:4])[O-].[K+].[K+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[N:21]3[N:22]=[C:23]([N:25]4C(=O)[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]4=[O:35])[N:24]=[C:20]3[N:19]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:18]([CH3:46])=[C:17]2[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:12][CH:11]=1)#[N:9].Cl>C(O)C>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[N:21]3[N:22]=[C:23]([NH:25][C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[C:2]([OH:4])=[O:5])=[O:35])[N:24]=[C:20]3[N:19]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:45])[F:44])[CH:37]=3)[C:18]([CH3:46])=[C:17]2[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:14][CH:15]=1)#[N:9]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(N3C(=O)c4ccccc4C3=O)nn2C1c1ccc(C#N)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)c3ccccc3C(=O)O)nn2C1c1ccc(C#N)cc1
Temperature: 50 °C
Yield: 87.4 %

Procedure:
Water (1 ml) and potassium carbonate (23.1 mg, 167 μmol, 2 eq.) were added to a solution of ethyl 7-(4-cyanophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4-[3-(trifluoromethyl)-phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (50.0 mg, 83.5 μmol; Example 1) in ethanol (6.25 ml). In a closed, pressure-proof glass tube, the reaction mixture was heated at 50° C. 1 N hydrochloric acid (670 μl, 670 μmol, 8 eq.) was then added, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 10 μm, 250×30 mm; mobile phase: acetonitrile-water-0.1% TFA 10:90→100:0). This gave the product as a solid (45 mg, 87% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[O:18]([CH2:17][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COc1ccccc1
Temperature: 25 °C

Procedure:
5-Chloropyrimidin-2-one (5 mmol) and triethylamine (5 mmol) were stirred together in dichloromethane (50 ml). When all the solid had dissolved a solution of chloromethoxybenzene (see Preparation 2) (5 mmol) in dichloromethane (25 ml) was added with stirring at room temperature. The resultant mixture was stirred for 24 h at this temperature before the solvent was distilled off. The residue was triturated with water (30 ml), extracted into chloroform (3×20 ml), and the dried (MgSO4) solution evaporated to yield a mixture of the title compound and the O-alkylated isomer in the ratio 3:1; yield 7.00 g (85%). The N-isomer was separated by column chromatography on silica gel; m.p. 146° C.