Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([C:21]#[C:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOCC.CCCCCC>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: Nc1ccc(C#CCCOC2CCCCO2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCCOC2CCCCO2)cc1F

Procedure:
2,3,4-Trifluorobenzoic acid and 2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]aniline were reacted in the presence of LiHMDS solution by the general procedure of Example 1, Step B. After workup, followed by purification by column chromatography on silica gel (50% EtOAc as eluant), unreacted aniline (26%), followed by 3,4-difluoro-2-{2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]anilino}benzoic acid (31%) were isolated; m.p. (Et2O/hexane) 175–178° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.55 (v br s, 1 H), 9.28 (br s, 1 H), 7.82 (ddd, J=8.2, 6.0, 1.8 Hz, 1 H), 7.25 (dd, J=12.0, 1.7 Hz, 1 H), 7.16–7.08 (m, 2 H), 6.95 (ddd, J=8.8, 8.8, 5.4 Hz, 1 H), 4.66 (t, J=3.4 Hz, 1 H), 3.83–3.70 (m, 2 H), 3.59–3.41 (m, 2H), 2.68 (t, J=6.8 Hz, 1 H), 1.78–1.58 (m, 2 H), 1.53–1.40 (m, 4 H). Anal. calcd. for C22H20F3NO4: C, 63.0; H, 4.8; N, 3.3. Found C, 63.0; H, 4.8; N, 3.5.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:20])[C:10]3[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:23](NNC=O)=[O:24]>ClCCl>[CH3:16][N:15]1[C:10]2[C:9](=[O:20])[NH:8][C:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][CH:23]=[O:24])=[CH:3][CH:4]=3)=[N:12][C:11]=2[C:13]([CH2:17][CH2:18][CH3:19])=[N:14]1
Reactant: O=CNNC=O
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC=O)cc3)nc12
Temperature: 200 °C
Reaction time: 0.92 h
Yield: 52.2 %

Procedure:
A mixture of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]-pyrimidin-7-one (297 mg, 0.0010 mol) and 1,2-diformylhydrazine (101 mg, 0.00115 mol) was heated to 200° C. The resulting melt was then stirred under a nitrogen atmosphere at this temperature for 55 minutes. On cooling, the solid was dissolved in dichloromethane:methanol, pre-absorbed onto silica and purified by flash column chromatography eluting with a solvent gradient of dichloromethane:methanol (99:1 to 96:4 by volume) then dichloromethane:methanol:0.880 aqueous ammonia (90:10:1 by volume). Crystallisation from ethyl acetate/methanol gave the title compound (170 mg), m.p.260-261° C.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[N:18]([C:19]2[N:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[N+:56]([C:59]1[S:63][C:62]([S:64](Cl)(=[O:66])=[O:65])=[CH:61][CH:60]=1)([O-:58])=[O:57]>C(Cl)Cl>[N+:56]([C:59]1[S:63][C:62]([S:64]([N:15]2[CH2:16][CH2:17][N:18]([C:19]3[N:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:28])([F:29])[F:27])=[CH:21][N:20]=3)[C@@H:13]([CH2:12][N:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:14]2)(=[O:66])=[O:65])=[CH:61][CH:60]=1)([O-:58])=[O:57]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 49.8 %

Procedure:
A 5-mL vial was charged with tert-butyl (3R)-3-(((methylsulfonyl)(phenyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.229 g, 0.373 mmol), TFA (1.0 mL, 13 mmol) and CH2Cl2 (2 mL). The mixture was stirred at room temperature for 35 min and then concentrated. CH2Cl2 (1 mL) was added to the residue followed by triethylamine (0.60 mL, 4.3 mmol). The mixture was stirred at room temperature for 10 min and then a solution of 5-nitrothiophene-2-sulfonyl chloride (0.104 g, 0.456 mmol, Enamine LLC, Monmouth Jct. NJ) in CH2Cl2 (1 mL) was added drop wise. After stirring at room temperature for 40 min, the mixture was concentrated and purified by column chromatography (50 g of silica gel, 0 to 60% EtOAc in hexanes) to afford N-(((2R)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.131 g) as a light-brown foam.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:2].C1COCC1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>C(Cl)Cl>[OH:2][CH:1]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(O)c2ccccc2)c2ccccn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (0.400 mg, 1.63 mmol) in 30 mL 1:1 THF:CH2Cl2 at −20° C. was added phenylmagnesium bromide (0.979 mL, 1.96 mmol, 2.0 M in THF) dropwise. The reaction was allowed to warm to rt. After 30 minutes, saturated aqueous ammonium chloride was added, and the mixture was filtered and concentrated to provide crude ethyl 1-[hydroxy(phenyl)methyl]-4-oxo-4H-quinolizine-3-carboxylate as a yellow solid. To a solution of the resultant residue (115 mg, 0.356 mmol) in 4 mL 1:2:1 DMSO:MeOH:H2O was added sodium hydroxide (0.100 g, 2.50 mmoL). The reaction was heated to 60° C. for 1 h, cooled to rt, and subjected to purification via reverse phase HPLC to yield the title compound that gave a mass ion (ES+) of 296.2 for M+H+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](SC)[N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>[Ni].C(O)C>[NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(N)nc(SC)n1C
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1c(N)ncn1C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
Ethyl 4-amino-1-methyl-2-(methylthio)imidazole-5-carboxylate (1.52 g, 7.11 mmol) and W-2 Raney nickel (3 g, 50% in water) in ethanol (25 mL) were heated at reflux for 12 hours. Additional Raney nickel (ca 1.5 g, 50% in water) was added and heating was continued for an additional 3 hours adding Raney nickel (ca 1.5 g, 50% in water) every hour. The reaction was filtered and the filtrate evaporated under reduced pressure. Chromatography of the residue on silica gel eluting with 1.5% methanol in chloroform afforded 0.72 g (60%) of the desired product as a solid. TLC (10% methanol/90% chloroform) Rf =0.47. 1H NMR (CDCl3, 300 MHz) d 1.38 (t, 3H), 3.77 (s, 3H), 4.32 (q, 2H), 4.82 (br, 2H), 7.13 (s, 1H). MS (DCl/NH3) m/e 170 (M+H)+ .
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[C:46]([O:45][C:44](=[O:50])[NH:43][C@H:40]1[CH2:39][CH2:38][C@H:37]([NH:36][C:33]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]=2[CH3:32])=[O:34])[CH2:42][CH2:41]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c15) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:17])=[O:14]
Reactant: CC(C)=O
Reactant: OCCCCCCCCCCCCBr
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCCCCCCBr

Procedure:
To this end, 12-bromo-1-dodecanol is oxidized with Jones' reagent to form 12-bromo-1-dodecanoic acid. Then the white solid acid is esterified with diazomethane to form the corresponding methyl ester. The methyl ester is treated directly with imidazole and reacted at 80° C. for five hours until it forms 12-imidazolyl-1-dodecanoic acid methyl ester. The thick mass, which is obtained in this way, is split between water and dichloromethane; and the organic phase is dried over Na2SO4 and concentrated by evaporation. The oily residue is cleaned chromatographically on silica gel and then dissolved in a mixture of methanol and tetrahydrofuran (3:4), treated with LiOH.H2O, and the mixture is heated under reflux for two hours. Following evaporation of the solvent, the white residue is dissolved again in water, extracted with dichloromethane, acidified to a pH 5-6, and extracted again with ethyl acetate. The ethyl acetate extract is dried over Na2SO4, filtered and concentrated by evaporation. The white solid is recrystallized from methanol/ether and yields 12-imidazolyl-1-dodecanoic acid.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:9](=[O:20])[C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=1F)[C:5]([O:7][CH3:8])=[O:6].[C:22]([O:26][C:27]([N:29]([CH3:31])N)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]([N:2]1[C:11]2[C:10](=[CH:15][C:14]([F:16])=[C:13]([F:17])[C:12]=2[F:18])[C:9](=[O:20])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3]1)[CH3:31])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: COC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: ClCCl
Product: COC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To methylene chloride (120 ml) solution of methyl 3-dimethylamino -2-(2,3,4,5-tetrafluorobenzoyl)acrylate (13.2 g) was added methylene chloride (12 ml) solution of 1-tert-butoxycarbonyl-1-methylhydrazine (7.59 g) with ice-cooling, and the mixture was stirred for one hour at the same temperature and then for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diisopropyl ether (132 ml). The solid formed was taken out by filtration and dried with phosphorus pentaoxide under reduced pressure to obtain methyl 1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (10.49 g).
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][S:18]([CH3:17])(=[O:20])=[O:19])=[C:4]([F:10])[CH:3]=1
Reactant: Cc1cc(N)c(F)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NS(C)(=O)=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylaniline (2.04 g, 10.0 mmol) in anhydrous CH2Cl2 (20 ml) and pyridine (3.23 ml, 40.0 mmol) was added methanesulfonyl chloride (0.86 ml, 11.0 mmol) and the resulting mixture was stirred at room temperature for 2 h. Solvent was removed in vacuo, and the residue was partitioned between EtOAc and 1M aq. HCl. The organic layer was washed with saturated aqueous NaHCO3, brine and then dried over Na2SO4. The drying agent was filtered off, and the filtrate was concentrated to give the title compound as a solid (2.80 g, 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34]Br.P([O-])([O-])([O-])=O>CN(C=O)C>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4c(Cl)cccc4Cl)C(=O)O3)ccc2O1
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(2-hydroxyethoxy)hexyl]-1,3-oxazolidin-2-one (200 mg) in DMF (4 ml) under nitrogen was treated with sodium hydride (26 mg, 60% in oil) and the mixture was stirred at 20° for 10 min. 2,6-Dichlorobenzyl bromide (122 mg) was added and the mixture was stirred at 20° for 3 h. Phosphate buffer solution (20 ml, pH6.5) was added and the mixture was extracted with EtOAc (30 ml). The extract was washed with water (2×20 ml), dried (NaSO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel 20 mm diameter column. Elution with EtOAc-cyclohexane (1:1) gave the title compound (155 mg). LCMS RT=3.97 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][CH2:20][C:21]2[C:26]([CH2:27]O)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][CH2:20][C:21]2[C:26]([CH2:27][C:31]#[N:33])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2ncccc2CO)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2ncccc2CC#N)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.4 %

Procedure:
To a mixture of [2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]methanol (2.10 g), triethylamine (1.05 g) and ethyl acetate (100 mL) was dropwise added methanesulfonyl chloride (1.19 g) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (50 mL) was added an aqueous solution (5 mL) of sodium cyanide (0.51 g) at room temperature and the mixture was stirred at room temperature for 2 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.49 g, 70%) of 2-[2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[C:3]=1[CH:14]([C:21](C)(C)C)CO[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:46]CC1>CCOCC>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[C:3]=1[CH:14]([OH:46])[CH3:21]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(Cl)c(C(CO[Si](C)(C)C)C(C)(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Product: CCOC(=O)c1ccc(Cl)c(C(C)O)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 4-chloro-2-fluoro-3-(1-t-butyltrimethylsilyloxyethyl)benzoate (25 g) and tetrabutylammonium fluoride (210 ml of 1.0M solution in THF) were dissolved in THF and stirred for 4 hours at room temperature. The mixture was diluted with ether and washed with water. The organic extract was dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding ethyl 4-chloro-2-fluoro-3-(1-hydroxyethyl)benzoate (16.8 g) as a clear oil, NMR (CDCl3) 1.3(t,3H), 1.5(d,3H), 2.5(bs, 1H), 4.3(q,2H), 5.3(q, 1H), 7.1(d, 1H), 7.7(t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH2:21][C:22]#[CH:23])=[CH:18][C:17]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[N:16]1.ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:49])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH2:21][C:22]#[CH:23])=[CH:18][C:17]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:33])([F:31])[F:32])=[N:16]1
Reactant: C#CCNc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C#CCNc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 74.6 %

Procedure:
0.17 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-(2-propynylamino)-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 80 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.13 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-(2-propynylamino)-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.O.S(OCC)(O[CH2:20][CH3:21])(=O)=O.[OH-].[Na+]>COCCOC>[CH2:20]([CH:2]([OH:1])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:21]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=[N+]([O-])c1cc(NCCO)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCC(O)CNc1ccc(O)c([N+](=O)[O-])c1
Temperature: 5 °C

Procedure:
39.6 g (200 mmol) 4-(2-hydroxyethylamino)-2-nitrophenol is added to a mixture of 150 ml water and 15 ml 1,2-dimethoxyethane. 33.9 g (220 mmol) diethyl sulfate is added dropwise at an internal temperature of 60° C. so that the pH of the solution is maintained between 6 and 8 by simultaneous dropwise addition of 10% sodium hydroxide (ca. 62 ml). After complete reaction, the solution is filtered through a pleated filter and cooled with stirring to 5° C. The product is allowed to crystallize.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([C:13]([N:15]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[C:11]([N+:27]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.CCOC(C)=O>CO>[NH2:27][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]([O:25][CH3:26])=[CH:23][C:12]=1[C:13]([N:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]1[CH2:21][OH:22])=[O:14]
Reactant: COc1cc(C(=O)N2C[C@H](O)C[C@H]2CO)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2C[C@H](O)C[C@H]2CO)c(N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of diol 20 (26 g, 64.6 mmol, 1.0 equiv.) and SnCl2.2H2O (72.9 g, 323 mmol, 5.0 equiv.) in MeOH (300 mL), was heated at reflux and the progress of the reaction monitored by TLC (EtOAc). After 3 h, the MeOH was evaporated in vacuo and the resulting residue was cooled and treated carefully with saturated NaHCO3 (400 mL). The mixture was diluted with EtOAc (800 mL), and after 12 h stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give a brown solid 21 which was used in the next reaction without further purification: [α]29D=−69° (c=0.13, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.70-1.82 (m, 1H, 1-H), 2.06-2.19 (m, 1H, 1-H), 3.52-3.85 (m, 9H, 3-H, 11-H, 7-OMe, 2×OH), 4.26-4.72 (m, 1H, 11a-H), 4.47-4.60 (m, 1H, 2-H), 5.10 (s, 2H, OCH2Ph), 6.26 (s, 1H, 9-H), 6.78 (s, 1H, 6-H), 7.29-7.36 (m, 7H, Ph, NH2); 13C NMR (CDCl3, 100 MHz): δ 37.0, 57.1, 58.5, 59.0, 66.2, 69.4, 70.7, 103.4, 112.4, 112.9, 127.1, 128.0, 128.6, 136.5, 140.0, 141.9, 151.0, 172.8; IR (neat): 3358, 2939, 1619, 1589, 1512, 1455, 1432, 1408, 1263, 1231, 1171, 1113, 1012, 787, 735, 698, 644 cm−1; MS (ES+) m/z (relative intensity) 395 ([M+Na]+., 4), 373 ([M+H]+., 70), 374 ([M+2H]+., 40), 256 (100), 257 (45).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:18])[CH:4]=[N:3]1.[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[O:17])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:18])[CH:4]=[N:3]1
Reactant: CCCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (180 mg, 0.68 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (262 mg, 0.68 mmol)[prepared in Preparation 6] and diisopropylethylamine (0.59 ml, 3.40 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (350 mg, 0.75 mmol) in one portion. The solution stirred at 25° C. for 2 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (243 mg, 0.41 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.