Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([N:5]([CH2:13][C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C@@H:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH3:37])[N:23]=[CH:22][N:21]=2)[CH2:16][C@@H:15]1[O:38][Si](C(C)(C)C)(C)C)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3].C1COCC1.F.N1C=CC=CC=1>N1C=CC=CC=1>[NH2:1][S:2]([N:5]([CH2:13][C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C@@H:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH3:37])[N:23]=[CH:22][N:21]=2)[CH2:16][C@@H:15]1[OH:38])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9])(=[O:3])=[O:4]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)[C@@H](O)C2)ncn1
Temperature: 23 °C
Reaction time: 19 h

Procedure:
To a solution of tert-butyl (aminosulfonyl)({(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)oxy]cyclopentyl}methyl)carbamate (331.5 mg, 0.0004094 mol) in THF (1.84 mL, 0.0228 mol) and pyridine (1.84 mL) at 0° C. was added pyridine hydrofluoride (0.25 mL, 0.0028 mol) dropwise. The mixture was allowed to slowly warm to 23° C. and stirred for 19 hours. To the reaction was added pyridine hydrofluoride (0.25 mL, 0.0028 mol) and the mixture was stirred an additional 6 hours. The reaction was quenched by the dropwise addition of saturated aqueous NaHCO3. The mixture was partitioned with additional saturated aqueous NaHCO3 and EtOAc, separated, and the aqueous was extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (30 to 70% EtOAc/hexanes) to collect 34.5 mg (15%) of the title compound. LC/MS: Rt=1.64 min, ES+ 550 (FA standard).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[N:6][CH:7]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]2[N:28]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[F:20])[N:29]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:3]=1
Reactant: O=C(C=Cc1cncc(Br)c1)C(F)(F)C(F)(F)F
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(Br)c2)c(F)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
1-(5-Bromo-pyridin-3-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (2.9 g, 8.6 mmol) prepared in Step 3, 2,4-difluorophenylhydrazine hydrochloride (2.4 g, 8.6 mmol), and piperidine (1.7 mL, 17.3 mmol) were added to ethanol (86.4 mL). The reaction mixture was stirred at 90° C. for 18 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to give 2.4 g of the titled compound as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:29])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].Br[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:29][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: Cc1ccc(Br)nc1
Reactant: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 75 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
To a solution of (2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 44) (48 mg, 0.112 mmol) and 2-bromo-5-methylpyridine (57.7 mg, 0.335 mmol) in toluene (2.5 mL) were successively added sodium tert-butoxide (107 mg, 1.117 mmol), tris(dibenzylideneacetone)dipalladium(0) (20.46 mg, 0.022 mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (17.59 mg, 0.045 mmol). The reaction mixture was stirred at 75° C. for 5 h then cooled to room temperature, and filtered through Celite. The insoluble material was washed with 5% MeOH in DCM. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient:10 to 80% AcOEt in Hexanes) gave (2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-N-(5-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine (34 mg, 0.065 mmol, 58%) as a colourless oil.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC4C(=CC=C([C:30]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:49][C:44]8([O:48][CH2:47][CH2:46][O:45]8)[CH2:43][N:42]7[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=[N:38][CH:37]=6)=[CH:32][CH:31]=5)C=4)C=3)=CN=2)CC2(CC2)C1)=O.BrC1C=C2C(=CC=1)C=C(C1NC([C@@H]3CC4(CC4)CN3C(=O)[C@@H](NC(=O)OC)C(C)C)=NC=1)C=C2.BrC1C=CC(C2NC([C@@H]3CC4(OCCO4)CN3C(=O)[C@@H](NC(=O)OC)C(C)C)=NC=2)=CC=1.Br[C:132]1[CH:137]=[CH:136][C:135]([C:138]2[NH:142][C:141]([C@@H:143]3[CH2:147][CH2:146][CH2:145][N:144]3[C:148]([O:150][C:151]([CH3:154])([CH3:153])[CH3:152])=[O:149])=[N:140][CH:139]=2)=[CH:134][CH:133]=1>>[CH3:59][O:58][C:56]([NH:55][C@@H:51]([CH:52]([CH3:53])[CH3:54])[C:50]([N:42]1[C@H:41]([C:39]2[NH:40][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:132]4[CH:133]=[CH:134][C:135]([C:138]5[NH:142][C:141]([C@@H:143]6[CH2:147][CH2:146][CH2:145][N:144]6[C:148]([O:150][C:151]([CH3:154])([CH3:153])[CH3:152])=[O:149])=[N:140][CH:139]=5)=[CH:136][CH:137]=4)=[CH:35][CH:34]=3)=[CH:37][N:38]=2)[CH2:49][C:44]2([O:48][CH2:47][CH2:46][O:45]2)[CH2:43]1)=[O:60])=[O:57]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CC2)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CC7(CN6C(=O)[C@@H](NC(=O)OC)C(C)C)OCCO7)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)N[C@H](C(=O)N1CC2(CC2)C[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]1)OCCO2)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare (S)-1-((S)-6-(5-(6-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl-carbamic acid methyl ester, except instead of methyl (S)-1-((S)-6-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate and methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate, methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (600 mg, 1.182 mmol) and (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (510 mg, 1.3 mmol). The amount for all the other reagents were adjusted accordingly. 489 mg (56%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[N:32]1[CH2:36][CH:35]=[CH:34][N:33]1[CH3:37])CCC>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([N:32]4[CH2:36][CH:35]=[CH:34][N:33]4[CH3:37])[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)N1CC=CN1C
Product: CN1C=CCN1c1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure B from 4-(4-benzyloxyanilino)6-chloropyrido[3,4-d]pyrimidine and 2-(tri-n-butylstannyl)-N-methylpyrazole (prepared according to the published method: WO 94/00825); δH [2H6]-DMSO 9.30 (1H,s), 8.80 (2H,m), 7.80 (2H,d), 7.65 (1H,d), 7.50 (6H,m), 7.20 (2H,d), 6.90 (1H,d), 5.20 (2H,s), 4.25 (3H,s); m/z (M+1)+409.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[C:10]([O:13][CH2:14][CH2:15]Br)(=[O:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:10]([O:13][CH2:14][CH2:15][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OCCBr
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(SCCOC(C)=O)cc1
Yield: 84.8 %

Procedure:
4-methoxybenzene-1-thiol (15.7 g, 0.11 mol), 2-bromoethyl acetate (18.8 g, 0.11 mol), and K2CO3 (46.6 g, 0.34 mol) in acetone (200 mL) were stirred at room temperature for 12 h. Then the mixture was filtered. After CH2Cl2 extractive work up and silica gel chromatography chromatography (PE: EA=1:0-10:1) the title compound (21.1 g, 83.3%) was obtained as a colorless oil. 1H NMR: (CDCl3, 400 MHz) δ 7.40 (dd, J1=6.8 Hz, J2=2.0 Hz, 2H), 6.86 (dd, J1=6.8 Hz, J2=2.0 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.02 (t, J=7.2 Hz, 2H), 2.03 (s, 3H). LCMS: 139.0 (M−87)+
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=1.N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.[Cu]I>[CH3:33][S:32][C:29]1[CH:30]=[CH:31][C:26]([N:3]2[CH:4]=[CH:5][C:6]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:11][CH2:10]3)=[CH:7][C:2]2=[O:1])=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Reactant: CSc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(-n2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2=O)cc1
Temperature: 145 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A mixture of benzyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (697 mg, 2.12 mmol), (4-bromophenyl)(methyl)sulfane (431 mg, 2.12 mmol, Aldrich), quinolin-8-ol (61.6 mg, 0.425 mmol, Alfa Aesar), potassium carbonate (381 mg, 2.76 mmol, EMD), Copper(I) iodide (81 mg, 0.43 mmol, Alfa Aesar) in DMSO (6 mL) was stirred at 145° C. overnight under Argon. The resulting mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to a green solid. The solid was purified by flash chromatography (SiO2, 0 to 5% MeOH in CH2Cl2) to yield 911 mg of desired product as a light green solid. MS (ESI) 451 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]([CH2:31][CH2:32][OH:33])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]([CH2:31][CH:32]=[O:33])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[CH2:34][C:35]([CH3:36])([CH3:38])[CH3:37]
Reactant: CCOC(=O)CC(CCO)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(CC=O)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
To a solution of ethyl 3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)-5-hydroxypentanoate (330 mg) and triethylamine (0.89 mL) in DMSO (5 mL) was added sulfur trioxide pyridine complex (410 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added, at room temperature, 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product (350 mg) of the title compound as a pale-orange oil. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])=[C:4]([F:6])[F:5].S(=O)(=O)(O)[OH:10]>O>[F:1][CH2:2][C:3]([OH:10])([CH2:7][F:8])[CH:4]([F:6])[F:5]
Reactant: O=S(=O)(O)O
Reactant: FCC(CF)=C(F)F
Solvent: O
Product: OC(CF)(CF)C(F)F

Procedure:
As another example, the 2-fluoromethyl-1,1,3-trifluoro-2-propanol may be prepared by oxidizing commercially available 1,3-difluoro-2-propanol to 1,3-difluoro-2-propanone which may then be reacted with a CF2 carbene to form 2-fluoromethyl-1,1,3-trifluoro-1-propene. The 2-fluoromethyl-1,1,3-trifluoro-1-propene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,3-trifluoro-2-propanol.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[S:18][C:6]2[CH2:7][NH:8][CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CCOCC>[ClH:1].[CH3:2][C:3]1[S:18][C:6]2[CH2:7][N:8]([CH3:19])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1
Reactant: Cc1cc2c(s1)CNCC2c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: Cc1cc2c(s1)CN(C)CC2c1ccc(Br)cc1
Yield: 90.6 %

Procedure:
3.45 gm (0.01 mole) of 2-methyl-4-(p-bromophenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine hydrochloride, m.p. 282°-283° C., 50 ml of ether, 2.8 gm (0.02 mol) of potassium carbonate and 1.5 gm (0.01 mol) of methyl iodide were admixed, and the mixture was heated for 2 hours on a water bath. The inorganic salts were separated by suction filtration, the solvent was evaporated out of the filtrate, and the hydrochloride was precipitated from the residue with ethereal hydrochloric acid, and recrystallized from isopropanol. 3.25 gm (91% of theory) of 2,6-dimethyl-4-(p-bromophenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine hydrochloride, m.p. 258°-260° C., were obtained.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:7]1[O:8][CH2:9][CH2:10][S:11][C:12]=1[C:13]([OH:15])=O)[CH3:6].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:28])=[C:21]([CH:27]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C(Cl)Cl.C(O)C>[Cl:28][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:13]([C:12]2[S:11][CH2:10][CH2:9][O:8][C:7]=2[CH2:5][CH3:6])=[O:15])=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1cc(N)ccc1Cl
Reactant: CCC1=C(C(=O)O)SCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(NC(=O)C2=C(CC)OCCS2)ccc1Cl
Temperature: 35 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
Thionyl chloride (4.0 g, 0.034 mole) was added to a stirred mixture of 2-ethyl-5,6-dihydro-1,4-oxathiin-3-carboxylic acid (5.9 g, 0.034 mole) and methylene chloride (100 ml). The mixture was warmed to about 35° C. for 3 hours, then evaporated under reduced pressure. The residue, crude 2-ethyl-5,6-dihydro-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (100 ml), and the ice-chilled solution treated dropwise with a solution of ethyl 5-amino-2-chlorobenzoate (6.8 g, 0.034 mole) and triethylamine (3.7 g, 0.037 mole) in methylene chloride (100 ml). The reaction mixture was stirred overnight at room temperature and then worked up by washing in sequence with water, dilute hydrochloric acid, water, 2% sodium hydroxide and water. Evaporation of the solvent left an oil, which solidified. After recrystallization from ethanol (30 ml) the product (7.0 g, 58% yield) melted at 86°-88° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][C:13](=[O:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:12][C:13]([C:26]([F:28])([F:27])[F:25])([OH:15])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (25 mg, 0.056 mmol), prepared using procedures described in Example 6, was taken into DMF (0.5 mL) followed by addition of (trifluoromethyl)trimethylsilane (40 μL, 0.28 mmol) and cesium carbonate (22 mg, 0.067 mmol) and the mixture was stirred for one hour at room temperature. The mixture was partitioned with ethyl ether and water and the organic phase washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:2 as eluent afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol (19.8 mg, 69% yield) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 8.31-8.26 (br, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.13-7.10 (m, 1H), 6.86-6.80 (m, 1H), 6.65-6.60 (m, 1H), 4.42 (br s, 2H), 4.18 (br s, 2H). MS (EI) for C17H11F6IN2O2: 517 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17](N)[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(OC(C)(C)C)=O.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[CH:17][S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(N)n1
Agent: CC(C)(C)ON=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1cscn1
Yield: 55.8 %

Procedure:
To a suspension of 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (11.5 g) in tetrahydrofuran (80.5 ml) was added dropwise a solution of t-butyl nitrite (6.5 g) in tetrahydrofuran (32.5 ml) at 50° to 57° C. under stirring, and the mixture was stirred at 50° to 55° C. for 20 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water and the solution was acidified to pH 1.0 with 10% hydrochloric acid. Water (60 ml) was added to the separated organic layer and the mixture was adjusted to pH 6.0 with 40% aqueous solution of potassium carbonate. The separated aqueous solution was washed with ethyl acetate and the solution was acidified to pH 2.8 with 10% hydrochloric acid. The acidified solution was extracted with ethyl acetate and the ethyl acetate layer was dried over magnesium sulfate and evaporated. The residue was triturated with diisopropyl ether to give 2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (6.1 g), mp. 141° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([CH:15]=[O:16])[C:12]([CH2:17][CH3:18])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([CH:15]([OH:16])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:12]([CH2:17][CH3:18])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-n2cc(C=O)c(CC)n2)c1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CCOc1cccc(-n2cc(C(O)CC(C)C)c(CC)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution (20 mL) of 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde (1.7 g) synthesized in Example 83(2) in tetrahydrofuran was added dropwise under ice-cooling, isobutylmagnesium bromide (12.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.4 g, 67%) as a pale-yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:62]=[C:63]([F:66])[C:64]=1[F:65])[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[O:27]=[C:25]([N:59]1[CH2:60][CH2:61][CH:56]([O:55][C:54]2[CH:53]=[C:52]([F:51])[C:64]([F:65])=[C:63]([F:66])[CH:62]=2)[CH2:57][CH2:58]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: Fc1cc(OC2CCNCC2)cc(F)c1F
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)c(F)c(F)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 18.9 %

Procedure:
DIPEA (135 mg, 1.0 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (69 mg, 0.3 mmol) in DMF (2.0 mL) followed by HOBt (61 mg, 0.45 mmol) and EDCI.HCl (85 mg, 0.45 mmol). After 2 minutes of stirring, 4-(3,4,5-trifluoro-phenoxy)-piperidine hydrochloride (75 mg, 0.3 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 26 mg (19% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3,4,5-trifluoro-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 459.16, 97.98%, 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.4 (m, 4H), 7.1 (m, 1H), 4.7 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 2.0 (m, 3H), 1.7 (m, 3H).