Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45](O)=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C2(O)CCCC2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Pyridine (0.83 mL, 12 mmol) and trifluoromethanesulfonic anhydride (1.2 mL, 7.1 mmol) were added to a solution of 4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (Example 33-(1); 2.6 g, 6.9 mmol) in dichloromethane (26 mL) at −10° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=4/1) to give the title compound (1.8 g, 51%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[C:14]1[S:18][C:17]([N:19]([CH3:30])[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[N:16][N:15]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:30][N:19]([CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]1)[C:17]1[S:18][C:14]([C:4]2[CH:5]=[CH:6][C:7]([N:9]3[CH:13]=[CH:12][CH:11]=[N:10]3)=[CH:8][C:3]=2[OH:2])=[N:15][N:16]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(c1nnc(-c2ccc(-n3cccn3)cc2O)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of 5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Example 1) (30 mg, 0.070 mmol) in DCM (1.5 mL) was added BBr3 (1M solution in heptane, 0.352 mL, 0.352 mmol). The resulting bright yellow suspension was stirred at room temperature for 2 h. The reaction mixture was quenched by addition of MeOH (5 mL) and the resulting solution was loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (15 mL). The solvent was evaporated in vacuo. The resulting crude material was sonicated in MeOH (2 mL) and the resulting suspension was filtered under vacuum to afford the title compound as a pale yellow solid (14.9 mg, 51.4% yield). LC-MS: Rt 0.55 min; MS m/z 413.3 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (d, J=2.02 Hz, 1H), 7.99 (d, J=8.59 Hz, 1H), 7.73-7.78 (m, 1H), 7.47 (d, J=1.52 Hz, 1H), 7.36 (d, J=8.59 Hz, 1H), 6.53-6.58 (m, 1H), 4.33 (t, J=12.13 Hz, 1H), 2.99 (s, 3H), 1.58-1.69 (m, 2H), 1.47 (t, J=12.13 Hz, 2H), 1.23 (s, 6H), 1.12 (s, 6H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:29])([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:29])([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccccc1
Agent: [Na+]
Product: CCOC(=O)C(C)(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccccc1

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-methyl-2-phenoxypropionate (i1.42 g), which is the product of Reference example 8(e), and sodium azide (0.66 g) and the reaction mixture was treated to afford the desired compound (0.82 g) as a syrup.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[C:17]=2[CH3:25])[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH3:15])=[C:17]([CH3:25])[C:18]=1[CH3:24]
Reactant: COc1ccc(C(C)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(C)N2CCNCC2)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice chilled solution containing 4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (0.4 g 1.38 mmol) and 10 ml dichloromethane, was added trifluoroacetic acid (2 ml) dropwise. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated. The residue was purified by flash chromatography on silica gel eluted with 10% MeOH(NH3)/dichloromethane. 1-[1-(4-Methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine was obtained as a yellow oil (0.16 g 47%). Analysis H1 NMR (400 MHz, CDCl3): 7.23 (1H, d), 6.69 (1H, d), 3.8 (3H, s), 3.55 (1H, q), 3.484 (2H, s), 2.838 (4H, m), 2.47 (2H, m), 2.38 (2H, m), 2.271 (3H, s), 2.167 (3H, s), 1.26 (3H, d). MS (LC-MS): Calculated for C15H24N2O 248.36. Found 249.25 (M+).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>C1(C)C=CC=CC=1>[N+:22]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:6](=[O:8])[C:5]([O:12][CH2:13][CH3:14])=[O:11])([O-:24])=[O:23]
Reactant: Cc1ccncc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of freshly prepared sodium ethoxide was added diethyl oxalate (1.5 eq.) followed by 4-methyl-3-nitro pyridine (1 eq.) in toluene and reaction mixture was stirred overnight. It was then concentrated under reduced pressure and acidified with acetic acid to obtained red solid, which on further purification, by column chromatography provided the ethyl 3-(3-nitropyridin-4-yl)-2-oxopropanoate.
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.OO.[F:16][C:17]([F:47])([C:43]([F:46])([F:45])[F:44])[C:18]([F:42])([F:41])[C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([I:28])([F:27])[F:26]>FC(F)(F)C(O)=O>[F:8][C:7]([F:10])([F:9])[C:6]([O:11][I:28]([O:5][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[C:25]([F:27])([F:26])[C:24]([F:30])([F:29])[C:23]([F:32])([F:31])[C:22]([F:34])([F:33])[C:21]([F:36])([F:35])[C:20]([F:37])([F:38])[C:19]([F:40])([F:39])[C:18]([F:41])([F:42])[C:17]([F:47])([F:16])[C:43]([F:44])([F:45])[F:46])=[O:5]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: OO
Solvent: O=C(O)C(F)(F)F
Product: O=C(OI(OC(=O)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
To a mixture of 10.6 ml (75.2 mmols) of trifluoroacetic anhydride and 30 ml of trifluoroacetic acid was added dropwise 1.36 ml of a 35% aqueous hydrogen peroxide solution (H2O2, 15.7 mmols and H2O, 55 mmols) in an ice bath. After completion of addition, the mixture was stirred for 1.5 hour and 5.0 g (7.7 mmols) of heneicosafluoro-n-decyl iodide was added thereto, followed by allowing the mixture to react at 0° to 5° C. for 24 hours. The solvent was then distilled off to obtain 6.3 g (94% yield) of di(trifluoroacetoxy)iodoheneicosafluoro-n-decane as white fluffy crystals.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23](O)[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([O:12][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[O:11]
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(N)Cc1ccccc1
Yield: 99.1 %

Procedure:
To a stirred solution of DL-phenylalanine 38 (5 g, 30.26 mmol) in toluene (100 mL) was added dodecanol 2 (5.08 g, 27.24 mmol) in one lot, followed by pTSA (6.33 g, 33.29 mmol). The temperature of the reaction mixture was slowly raised to reflux temperature, and the water was separated azeotropically The reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum. The obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 39 (9 g, yield: 89.1%) as a liquid.
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:5]2[S:6](=[O:14])(=[O:13])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[Br:17][C:16]1[C:2]([NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:3][C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6](=[O:14])(=[O:13])[C:5]=2[CH:15]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc2c(cc1Br)S(=O)(=O)c1ccccc1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc2c(cc1Br)S(=O)(=O)c1ccccc1-2

Procedure:
2-Amino-3-bromo-5,5-dioxidodibenzothiophene (DE 2638081; 0.309 g, 1.0 mmol) was suspended in a solution of DCM (5 ml) and triethylamine (0.111 g, 1.1 mmol). Pivaloyl chloride (0.132 g, 1.1 mmol) was added dropwise and the resultant mixture stirred for 5 days at ambient temperature. The mixture was reduced to dryness and the residue was triturated with methanol. NMR: 9.25 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.11 (d, 1H), 7.98 (d, 1H), 7.80 (t, 1H), 7.68 (t, 1H), 1.28 (s, 9H); m/z 394/396.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:29][CH2:28][C@@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:38]2[N:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:40][N:39]=2)[CH:15]=1>C1COCC1.C(OCC)(=O)C>[CH3:12][S:13]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:29][CH2:28][C@@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:38]2[N:39]=[CH:40][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:42][N:43]=2)[CH:15]=1)=[O:6]
Reactant: CSc1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.20 g, 0.92 mmol) in THF (5 mL) was added to an ice-cooled solution of 223c) (0.54 g, 1.02 mmol) in THF (100 mL) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then diluted with ethyl acetate (50 mL) and successively washed with saturated sodium hydrogen carbonate solution (2×50 mL) and brine (1×50 mL). The organic phase was dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography [silica gel; dichloromethane with 2% methanol]. White solid. Yield: 0.28 g (51% of theory)
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[N:6]=[C:5]([S:7][CH3:8])[CH2:4][S:3]1.[N:10]([O-])=[O:11].[Na+].C(O)(=O)C>O>[N:10](=[C:4]1[S:3][C:2]([CH3:9])([CH3:1])[N:6]=[C:5]1[S:7][CH3:8])[OH:11]
Reactant: CSC1=NC(C)(C)SC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSC1=NC(C)(C)SC1=NO
Reaction time: 3 h

Procedure:
6.4 g (0.04 mol) of crude 2,2-dimethyl-4-methylthio-3-thiazoline are dissolved in 40 ml of water and the solution is treated with 3.6 g (0.052 mol) of sodium nitrite and subsequently treated dropwise at 10° C. with 6.1 ml (0.11 mol) of acetic acid. After stirring the mixture for 3 hours, 3.6 g of sodium nitrite and 6.1 ml of acetic acid are added theretoand the mixture is allowed to stir for an additional 16 hours. The mixture is then diluted with water and the precipitated crystals are filtered off,to yield 5-oxo-2,2-dimethyl-4-methylthio-3-thiazoline oxime, m.p. 168°-171° C.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.C([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([N+:22]([O-:24])=[O:23])[C:12]=1[O:25][CH3:26])(=O)C>CN(C=O)C.C1COCC1>[CH3:26][O:25][C:12]1[C:13]([N+:22]([O-:24])=[O:23])=[C:14]([CH:18]=[C:19]([O:20][CH3:21])[C:11]=1[OH:10])[C:15]([O:17][CH3:1])=[O:16]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(O)c(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
A catalytic amount of DMF (5 drops) was added to a solution of oxalyl chloride (6.3 g, 49.8 mmol) and o-nitrobenzoic acid 83 (12.4 g, 45.2 mmol) in anhydrous THF (100 mL) and the reaction mixture allowed to stir at room temperature for 16 h. The resulting acid chloride was quenched dropwise with anhydrous methanol (100 mL) at 0° C. The reaction mixture was treated with potassium carbonate and allowed to stir at room temperature for 3 h. Excess solvent was removed by rotary evaporation at reduced pressure and the residue dissolved in water. The aqueous solution was acidified to pH 8 and the resulting white precipitate was collected by filtration, washed with water (2×100 mL) and dried to afford the product as an off-white solid (10.6 g, 83%). H1 NMR (270 MHz, CDCl3) δ10.07 (br s, 1H), 7.26 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: ClCCl.[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].C(=O)([O-])O.[Na+].[I:20](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>CO>[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([I:20])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(F)c(I)cc1C(=O)O
Reaction time: 48 h
Yield: 77 %

Procedure:
To a vigorously stirred solution of dichloromethane (700 ml), methanol (320 ml), and 2-amino-4fluoro-benzoic acid (33.35 grams, 215 mmoles) was added solid sodium hydrogencarbonate (110 grams, 1.31 moles) followed by portion addition of benzyltrimethyl ammonium dichloroiodate (82.5 grams, 237 mmoles). The mixture was allowed to stir for 48 hours. The mixture was filtered to remove the insolubles. The remaining solid residue was washed with 200 ml of dichloromethane. The filtrate was concentrated and redissolved in a one to one mixture of ethyl acetate (1 litre) and a 0.2 N solution of sodium hydroxide (1 litre), added to a 2 litre separatory funnel and extracted. The organic layer was washed with an additional 200 ml of water. The aqueous layers were combined and acidified with 2N hydrochloric acid. The resulting precipitate was collected by suction filtration, washed with water and dried under vacuum at 60° C. to yield 46.5 grams (77%) of the title compound. 1H NMR (400 MHz, DMSO-6) δ: 8.04(d, 1H), 7.1(s, broad, 2H), 6.63(d, 1H). ESI-MS m/z 280 (M−1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:24][NH:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][S:40]([CH2:43][C:44](O)=[O:45])(=[O:42])=[O:41].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:27])([F:29])[F:28])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:22][N:23]([C:44](=[O:45])[CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:24]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: FC1(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)N1CC(F)(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
To a stirred solution of 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)phenyl)-3-fluoroazetidine hydrochloride (Example 1, Intermediate 3) (0.25 g, 0.535 mmol) in THF (5 mL) was added DIPEA (0.933 mL, 5.35 mmol) at room temperature and stirred for 10 minutes at room temperature. Methane sulfonyl acetic acid (0.147 g, 1.07 mmol), T3P (50% solution in ethyl acetate, 1.6 mL, 2.675 mmol) were added at room temperature. Resulting reaction mixture was stirred for 16 hours at room temperature under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (5×25 mL). Combined organic layer was washed with saturated solution of NaHCO3 (2×100 mL), dried over sodium sulphate and concentrated in vacuo to get pale yellow oil (0.32 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired product gets eluted in 0.6% MeOH in DCM to afford white semisolid (0.160 g), which was triturated with DCM: n-pentane (1:10; 2×5 mL) to afford product as off white solid. Yield: 0.145 g (49.15%). 1H NMR (400 MHz, DMSO-d6) δ: 3.11 (s, 3H), 3.20 (d, J=17.16 Hz, 1H), 3.65 (d, J=17.12 Hz, 1H), 4.24 (s, 2H), 4.34 (d, J=21.6 Hz, 2H), 4.70 (d, J=21.52 Hz, 2H), 7.27 (d, J=7.96 Hz, 2H), 7.47 (d, J=9.36 Hz, 2H), 7.73 (d, J=3.92 Hz, 3H). LC-MS (m/z): =550.1 (M−H). HPLC purity: 98.75%.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].O>C1COCC1>[CH3:8][N:9]([CH3:14])[S:10]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)(=[O:12])=[O:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydride (5.2 g, 130 mmol, 60% in mineral oil) in anhydrous THF (50 mL) was added a solution of 1H-pyrazole (5.92 g, 87 mmol) in anhydrous THF (100 mL) at 0° C. The mixture was stirred for 30 minutes at room temperature. Dimethylsulfamoyl chloride (13.9 mL, 130 mmol) was added at 0° C., and then the mixture was stirred for 1.5 hours at room temperature. Water was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the oil was passed through a short silica gel column using 20% hexane/ethyl acetate as a solvent. N,N-dimethyl-1H-pyrazole-1-sulfonamide was obtained as a yellow oil and used in the next step without further purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([O:30][C:31]([CH2:33][N:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)[CH3:35])=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([CH2:33][N:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:42][CH:43]=1)[CH3:35])=[O:32])[CH3:29]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCOC(=O)CN(C)Cc1ccc(N)cc1
Product: CCOC(=O)CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-ethoxycarbonylmethyl-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (aluminium oxide, methylene chloride/ethanol=40:1) C29H29N3O5
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:16]=[CH:17][C:10]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1ccnc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccnc2c1ccn2S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of (1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (400 mg, 1.62 mmol) in DMF (10.0 mL) was added powdered KOH (143 mg, 1.88 mmol). After 15 minutes, methanesulfonyl chloride (137 μL, 1.78 mmol) was added. After 15 hours, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over magesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% ethyl acetate in heptane to afford (1-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: O[C:2]([C:16]1[C:21]2[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([O:27][CH3:28])=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C([SiH](CC)CC)C.[C:36](=O)(O)[O-:37].[Na+]>C(Cl)Cl>[CH3:36][O:37][C:19]1([O:27][CH3:28])[C:20]2[O:24][C:23]([CH3:25])([CH3:26])[CH2:22][C:21]=2[C:16]([CH:2]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:3][C:4]2[CH:5]=[CH:6][N:7]=[CH:8][CH:9]=2)=[CH:17][CH2:18]1
Reactant: O=C([O-])O
Reactant: COc1ccc(C(O)(Cc2ccncc2)c2ccccc2)c2c1OC(C)(C)C2
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: ClCCl
Product: COC1(OC)CC=C(C(Cc2ccncc2)c2ccccc2)C2=C1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Under an argon atmosphere, a solution of Compound 47a (0.4 g) obtained in Step A in methylene chloride (3 ml) was cooled to −78° C., and then boron trifluoride ether complex (0.3 ml) and triethylsilane (0.52 ml) were successively added thereto, followed by stirring at 0° C. for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 47 (0.27 g, 56.7%) as a yellowish brown oily substance.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](=[N:6][OH:7])[NH2:5].[CH:16]1([CH2:19]Br)[CH2:18][CH2:17]1.[H-].[Na+]>CN(C=O)C>[CH:16]1([CH2:19][O:7][N:6]=[C:4]([NH2:5])[C:3]2[C:8]([C:12]([F:13])([F:14])[F:15])=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])[CH2:18][CH2:17]1
Reactant: BrCC1CC1
Reactant: NC(=NO)c1c(F)cccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=NOCC1CC1)c1c(F)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
In 100 ml of DMF was dissolved 26.6 g of 2-fluoro-6-trifluoromethylbenzamidoxime and 17.8 g of cyclopropylmethylbromide, and to the solution was added 4.8 g of sodium hydride (60% in oil) at 10° C. over 30 min. The solution was then stirred for 3 hours, and the solution reacted was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 24.8 g of the objective compound. m.p. 63-64° C.