Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH:57](N(C(C)C)CC)(C)[CH3:58].CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH2:57][CH3:58])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(CO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a solution of 78 mg (0.10 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 17, in 2 ml of dichloromethane, 340 μl (2.0 mmol) of diisopropylethylamine and 77 μl (1.0 mmol) of methanesulfonyl chloride were added, and 2 ml of ethanol was added thereto immediately after initiation of stirring at room temperature and the reaction solution was further stirred at room temperature for 0.25 hour. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=98/2-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 68 mg of the title compound as a foam (yield: 85%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C:11]2[CH:12]=[C:13]([C:16]([O-])=[O:17])[CH:14]=[CH:15][C:10]=2[C:9]2[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.CCOCC>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]2[C:9]3[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:8]=3[CH2:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:11]=2[CH:12]=1.[CH2:1]([NH:4][C@@H:5]1[C:11]2[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:10]=2[C:9]2[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:8]=2[CH2:7][CH2:6]1)[CH3:2]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(C(=O)[O-])cc1[C@@H](NC(C)=O)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN[C@H]1CCc2cc(OC)c(OC)c(OC)c2-c2ccc(CO)cc21
Product: COc1cc2c(c(OC)c1OC)-c1ccc(CO)cc1[C@@H](NC(C)=O)CC2
Yield: 33 %
Yield: 47 %

Procedure:
A suspension of (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carboxylate (2.28 ml; 5.7 mmol) and lithium aluminium hydride (0.216 g; 22.8 mmol) in a mixture of THF (10 ml) and ether (60 ml) was stirred at reflux under argon atmosphere overnight. After addition of water (60 ml), the mixture was stirred for 2 hours. The resulting solid was filtered and the filtrate was evaporated and purified by flash chromatography eluting with a 5–10% gradient of methanol/dichloromethane to give, after evaporation, N-[(5S)-3-hydroxymethyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (yield: 33%) and [(5S)-5-(ethylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]methanol (yield: 47%).
Reaction SMILES: FC(F)(F)C1C=C(C(Cl)=O)C=CC=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[NH2:18].[F:37][C:38]([F:51])([F:50])[C:39]1[CH:40]=[C:41]([C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:42]=[CH:43][CH:44]=1>C1(C)C=CC=CC=1.C(O)C>[F:50][C:38]([F:37])([F:51])[C:39]1[CH:40]=[C:41]([C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:42]=[CH:43][CH:44]=1.[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:48]([NH:47][C:45](=[O:46])[C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:37])([F:51])[F:50])[CH:40]=2)=[S:49])[CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C(N=C=S)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C(F)(F)F)c4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 88%).
Reaction SMILES: [C:1]([NH2:5])(=O)[CH:2]=[CH2:3].C([O:8]CC)C>C(O)C>[CH2:2]([C:1]#[N:5])[CH2:3][OH:8].[C:1](#[N:5])[CH2:2][CH3:3]
Reactant: C=CC(N)=O
Reactant: CCOCC
Solvent: CCO
Product: CCC#N
Product: N#CCCO

Procedure:
After the reaction, the catalyst was filtered off and the filtrate was evaporated to yield 0.85 g. of a white crystalline product. The product was dissolved in a mixture of diethyl ether and ethanol and recrystallized therefrom to obtain a white crystalline product having a melting point of 84.5°-85° C. This product was identified as acrylamide, based upon the results of gas chromatographic analysis, elementary analysis, IR analysis and NMR analysis. Very small amounts of ethylene cyanohydrin and propionitrile were obtained as by-products.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12]>CO.C1COCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N)ccc1Cl
Reaction time: 4 h
Yield: 92.6 %

Procedure:
A mixture of 36 g of 2-chloro-5-nitroanisole and Raney® nickel in 150 ml of MeOH and 200 ml of THF is hydrogenated in Par apparatus for 4 hours, at 35° C. and at a pressure of 1.3 bar. The catalyst is filtered off on Celite® and the filtrate is concentrated under vacuum. 28 g of the expected product are obtained, and are used without further purification.
Reaction SMILES: O[CH:2]([CH3:15])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][C:12]([OH:14])=[O:13].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(#N)C>[C:12]1(=[O:14])[O:13][CH:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH:9]=[CH:10][CH2:11]1
Reactant: CC(O)CCC/C=C\C/C=C\CC(=O)O
Agent: CC1CCC/C=C\C/C=C\CC(=O)O1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1CCCC=CCC=CCC(=O)O1

Procedure:
A solution of hydroxy-acid 14 (0.64 g, 3.1 mmol) and dry triethylamine (2.42 g, 24 mmol) in dry acetonitrile (200 mL) was added over 20 hr via a fixed-rate addition funnel and a high dilution head to a refluxing solution of 2-chloro-N-methyl-pyridinium iodide (3.18 g, 12.4 mmol) in dry acetonitrile (200 mL), under argon. The resulting solution was refluxed a further 2 hr, cooled, and concentrated in vacuo. The residue was taken up in pentane (50 mL) and washed with water (50 mL). The aqueous phase was extracted twice more with pentane (25 mL), and the combined pentane extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was flash chromatographed (hexane:EtOAc, 40:1), yielding 45 mg (7.5% yield) of macrolide II. ##STR3##
Reaction SMILES: C(O)(=O)CCCCC(O)=O.C(OC)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(#N)CCCC[C:28]#[N:29]>CO>[C:28]([CH:15]([CH2:14][CH2:13][CH3:12])[C:16]([O:18][CH3:19])=[O:17])#[N:29]
Reactant: COC(=O)CCCCC(=O)OC
Reactant: N#CCCCCC#N
Agent: O=C(O)CCCCC(=O)O
Solvent: CO
Product: CCCC(C#N)C(=O)OC
Temperature: 230 °C
Reaction time: 2.5 h
Yield: 203.7 %

Procedure:
Into a 1-liter, stainless autoclave were introduced 301.2 g of Solution A, 39.4 g (0.270 mole) of adipic acid, 51.8 g (0.298 mole) of dimethyl adipate and 29.2 g (0.270 mole) of adiponitrile. The content of the autoclave was stirred at 230° C. for 2.5 hours. After cooling the reaction mixture, 160.0 g of methanol was added and the resulting mixture was stirred at 200° C. for 2 hours. Then, the liquid reaction mixture was distilled under reduced pressure to obtain 77.5 g (0.550 mole) of methyl cyanovalerate. The yield thereof corresponded to 203.7% based on the adipic acid charged.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[Si:8]([O:25][CH2:26][C@@H:27]([N:30]1[C@H:35]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C@@H:34]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[CH2:33][CH:32]([CH3:50])[C:31]1=[O:51])[CH2:28][CH3:29])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:52](Br)C=C>>[CH2:50]([C@@:32]1([CH3:52])[CH2:33][C@H:34]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[C@@H:35]([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[N:30]([C@@H:27]([CH2:28][CH3:29])[CH2:26][O:25][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:31]1=[O:51])[CH:1]=[CH2:2]
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C=CCBr
Reactant: CC(C)NC(C)C
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of 37.3 mL (266 mmol) of diisopropylamine in dry, degassed THF (150 mL) was added 100 mL (250 mmol) of a degassed 2.5 M solution of n-butyllithium in hexanes slowly via cannula. The light yellow solution was stirred at −78° C. for 15 min, then was warmed to 0° C. and stirred for an additional 5 min. To the ice-cooled LDA solution was added a solution of 85.7 g (133 mmol) of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 185, Step D) in dry, degassed THF (210 mL) via cannula over a 15 min period. The dark orange solution was stirred at 0° C. for 30 min and then 34.5 mL (399 mmol) of allyl bromide was added quickly via syringe. After 20 sec, the ice bath was removed and the reaction was placed in a room temperature water bath and stirred for an additional 15 min. The reaction was quenched with saturated aq. ammonium chloride, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.), 6-14% EtOAc/hexanes, gradient elution) provided the title compound as a white foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.Br[C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][CH:11]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:10]2[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1cccc(Br)n1
Reactant: CN1CCC(O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCC(Oc2cccc(C#N)n2)CC1
Temperature: 130 °C
Yield: 45.5 %

Procedure:
1-Methylpiperidin-4-ol (1.89 g, 0.0164 mol), 6-bromo-2-pyridinecarbonitrile (3.00 g, 0.0164 mol), Pd(OAc)2 (0.184 g, 0.820 mmol), 2-(di-t-butylphosphino)biphenyl (0.303 g, 1.02 mmol) and Cs(CO3)2 were mixed in 100 mL of toluene. The reaction mixture was stirred under argon and heated to 130° C. in an oil bath for 4 days. The reaction mixture was diluted with EtOAc and washed with water, dried over Na2SO4 and evaporated. The crude product was flash chromatographed on silica gel DCM/MeOH/TEA 95/5/1 to give 1.62 g (45%) of the desired product. 1H NMR (500 MHz, CDCl3) δ 7.67 (m, 1H), 7.29 (d, 1H), 6.95 (d, 1H), 5.12 (m, 1H), 2.74 (m, 2H), 2.40-2.30 (m, 5H, thereof a singlet at 2.35), 2.09 (m, 2H), 1.86 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:26][OH:27])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=O>ClCCl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:26]=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[C:22]([F:24])([F:23])[F:25])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
Sulfur trioxide-pyridine complex (23.4 g, 147 mmol) was added to a stirred solution of {9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}methanol (8.72 g, 20.9 mmol), triethylamine (23.3 mL), and dimethyl sulfoxide (140 mL) in dichloromethane (30 mL) at room temperature, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (6.90 g, 16.7 mmol, 80%).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.S(Cl)(=O)(=O)N.[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH:20]=[C:19]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=3)=[CH:33][CH:32]=2)[N:18]=1>CN(C)C(=O)C.CO>[S:2](=[O:3])(=[O:4])([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[C:19]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][N:41]=[C:40]([C:44]([F:46])([F:47])[F:45])[CH:39]=4)=[CH:33][CH:32]=3)[N:18]=[C:17]([NH2:16])[N:22]=2)=[CH:24][CH:25]=1)[NH2:5]
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc(-c2ccc(O)cc2)n1
Reactant: O=C=NS(=O)(=O)Cl
Agent: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: O=CO
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc(-c2ccc(OS(N)(=O)=O)cc2)n1
Temperature: 25 °C

Procedure:
To neat chlorosulfonyl isocyanate (0.166 g, 1.37 mmol) was added dropwise formic acid (97%, 0.63 g, 1.37 mmol) while cooling in ice-water bath. The mixture was stirred at rt until gas evolution ceased. The resulting sulfamoyl chloride was added to a solution of 4-{2-amino-6-[(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl) amino] pyrimidin-4-yl} phenol (0.06 g, 0.14 mmol, Example 51) in dry N,N-dimethylacetamide at 0° C. The reaction mixture was then stirred at rt for 12 h. The solution was diluted with methanol and separated by preparative HPLC. The desired fractions were combined, basified with saturated sodium carbonate, and extracted with EtOAc (3×). The extracts were combined, washed with brine, dried over magnesium sulfate, and evaporated to give desired product, 0.025 g (35%). 1H NMR (DMSO-d6) δ 9.42 (s, 1H), 8.59 (d, 1H), 8.09 (d, 2H), 7.98 (m, 2H), 7.85 (m, 2H), 7.35 (m, 3H), 7.10 (m, 3H), 6.42 (s, 1H), 6.36 (s, 2H); MS ES 519 (M+H)+calcd 519.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[I:23]N1C(=O)CCC1=O>C(O)(=O)C.ClCCl.CC#N>[I:23][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1ccc(-c2ccc(C(F)(F)F)nc2)cc1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(6-(Trifluoromethyl)pyridin-3-yl)phenol (Preparation 61, 1.24 g, 5.18 mmol) was dissolved in a mixture of acetic acid (10 mL), dichloromethane (10 mL) and CH3CN (10 mL) at room temperature. Concentrated sulphuric acid (0.5 mL) was then added followed by N-iodosuccinimide (1.052 g, 4.67 mmol). The reaction was stirred at room temperature for 18 hours. A further aliquot of N-iodosuccinimide (116 mg, 0.518 mmol) was added and the reaction mixture was stirred for one hour and concentrated in vacuo. The crude oil was purified on silica gel by Biotage™ (5% to 60% of EtOAc in heptane over 20 CV) and fractions containing product were evaporated to give an inseparable mixture of product/starting material 7:3 (840 mg). This was used directly in the next stage without further purification.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[N:12]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:13]([SH:16])=[N:14][N:15]=1.[I-].[K+]>CN(C=O)C>[NH2:10][C:11]1[N:12]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:13]([S:16][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:14][N:15]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 70 °C
Yield: 27.3 %

Procedure:
Ethyl 2-bromo-2-methylpropanoate (184 μL, 1.239 mmol) was added to a solution of 5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.35 g, 1.239 mmol) in DMF (2.5 mL) and heated at 60° C. for 20 hours after which time a few crystals of potassium iodide were added and the mixture heated at 70° C. for a further 24 h. The temperature was then increased to 90° C. and the mixture heated for an additional 6 days. The mixture was allowed to cool to room temperature, concentrated and dissolved in dichloromethane. Triethylamine and water were added and the layers separated. The aqueous layer was extracted with dichloromethane (2×) and the combined organic extracts dried over NaSO4, filtered, concentrated and purified by column chromatography (ethyl acetate) to afford ethyl 2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a tan solid (0.134 g, 27%).
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:29]([O:31]C)=[O:30])=[C:7]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1.[Br:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O.N12CCCC1=NCCC2>C(#N)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:29]([OH:31])=[O:30])=[C:7]([CH:9]=[CH:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([Br:33])[CH:35]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(Br)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Agent: C1CN=C2CCCN2C1
Agent: [Br-]
Solvent: CC#N
Product: O=C(O)c1ccc(Br)cc1C=Cc1cccc(Br)c1

Procedure:
The product of step (ii) (22.8 g). 3-bromobenzaldehyde (4.5 ml) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (5.95 g) in acetonitrile (50 ml) was heated under reflux for 0.5 hours. The solution was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with 2M HCl, dried (MgSO4) and evaporated. The residue and potassium hydroxide (5.6 g) in water (100 ml) and methanol (20 ml) was heated under reflux for 8 hours. The reaction mixture was diluted with water and washed with dichloromethane. The aqueous solution was acidified to pH 1 (2N HCl) and extracted with dichloromethane. The organic solution was dried (MgSO4), evaporated and the product purified by chromatography eluting with toluene. Yield 8.5 g. Used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26].C(O)C>[Pd].O>[ClH:26].[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:11]([Cl:26])[N:10]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cnc(-c2ccc([N+](=O)[O-])cc2)n1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2nc(Cl)c(CC(=O)O)n2Cc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 1-benzyl-2-(4-nitrophenyl)-5-imidazole-acetic acid (2.19, 5.0 mmol), 10% palladium on carbon (0.10 g), 12 M HCl (3.0 ml), 96% ethanol (50 ml) and water (50 ml) was hydrogenated at 55 psi for 1.5 hours on a Parr shaker hydrogenation apparatus. The mixture was filtered through a celite pad and then through a fluted filter paper. Evaporation left the title compound, Compound 12, as 1.0 g orange solid. Rf=0.1 (silica, ethyl acetate/hexanes 1:1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])[C:2]#[CH:3].S(Cl)([Cl:20])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:20])=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])[C:2]#[CH:3]
Reactant: O=S(Cl)Cl
Reactant: C#CCOc1c(OC)cc(C(=O)O)cc1OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To 100 ml of toluene were added 13.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoic acid, 9.5 g of thionyl chloride and 50 mg of DMF, and the resulting mixture was heated under reflux for 3 hours. Thereafter, the reaction mixture which had been allowed to cool to near room temperature was concentrated under reduced pressure. The resulting solid was washed with hexane, and 12.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride was obtained.