Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1.[CH:11]([OH:14])([CH3:13])[CH3:12]>>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH:11]([CH3:13])[CH3:12])=[N:8][CH:9]=1
Reactant: CC(C)O
Reactant: Clc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1ccc(Br)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
60% NaH in oil (1.5:1, Sodium hydride:Mineral Oil, 5.20 g) was added in two portions to isopropyl alcohol (150 mL) at room temperature under N2. The mixture was stirred at 60° C. for 30 min. 5-bromo-2-chloropyridine (10.00 g, 51.96 mmol) was added in two portions and the mixture was stirred at reflux 4 h and than at 80° C. overnight. The solution was concentrated in vacuo. Water (50 mL) and EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was subjected to flash chromatography (silica, 0-50% EtOAc in heptanes) to give the title compound as a clear oil (8.74 g, 78%). 1H NMR (600 MHz, DMSO) δ 8.17 (s, 1H), 7.61 (dd, 1H), 6.59 (d, 1H), 5.23 (m, 1H), 1.33 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25]CC)=[O:24])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11](C(OC(C)(C)C)=O)[C:10]=2[C:9]1=[O:35])=O)(C)(C)C.[Li+].[OH-]>CO.O>[O:35]=[C:9]1[C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:20][CH2:21][NH:8]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)C(=O)c2c1c1ccccc1n2C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1=CCNC(=O)c2[nH]c3ccccc3c21

Procedure:
A solution of 5-ethoxycarbonylmethylene-1-oxo-1,3,4,5-tetrahydro-azepino[3,4-b]indole-2,10-dicarboxylic acid di-tert-butyl ester, (0.496 g, 1.02 mmol) and LiOH (0.246 g, 10.2 mmol) in MeOH—H2O (1:1 mixture, 50 mL) is stirred at room temperature for 2 days before it is concentrated. Water is added to the residue and it is acidified with NaHSO4 (2M). The solid that is precipitated is collected by vacuum filtration and dried to yield (1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid; 1H NMR (DMSO-d6) δ 2.50 (t, 2H, J=5.6 Hz), 2.82 (s, 1H), 5.00 (t, 1H, J=6.4 Hz), 6.18 (t, 1H, J=7.2 Hz), 6.34 (t, 1H, J=7.2 Hz), 6.56 (d, 1H, J=8.8 Hz), 6.90 (d, 1H, J=8.8 Hz), 7.21 (t, 1H, J=4.4 Hz), 10.98 (s, 1H); m/z [M++1] 257.0.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13].[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C>C(OCC)(=O)C>[C:17]1([N:23]2[CH:5]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=3[F:13])[CH2:4][C:3]([C:2]([F:16])([F:15])[F:1])=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNc1ccccc1
Reactant: O=C(/C=C/c1ccc(F)cc1F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Product: Fc1ccc(C2CC(C(F)(F)F)=NN2c2ccccc2)c(F)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
In a 50 mL beaker are introduced (E)-1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-buten-2-one(2.66 g, 11.2 mmol), monohydrated p-toluensulphonic acid (2.1 g, 11.2 mmol) and phenylhydrazine chlorhydrate (1.33 g, 12.3 mmol) and heated to 110° C. A small amount of ethyl alcohol can be used to facilitate the initial mixture. After approximately 2 h (control by CCF) the mixture is allowed to cool and it is diluted with ethyl acetate. It is then washed with a saturated solution of NaHCO3, dried with MgSO4, filtered and the solvent evaporated at low pressure. The crude thus obtained (3.9 g) is recrystallised with methanol (2 mL) to precipitate 3.67 g (65%) of the pyrazoline (±)-5: pf=83–84° C.; IR (KBr) μ max (cm−1) 1600, 1505, 1326; 1H-RMN (CDCl3) δ (ppm): 7.28–6.72 (m, 8H), 5.64 (dd, J=13 Hz, J=7.5 Hz, 1H), 3.8–3.6 (m, 1H), 2.94 (dd, J=17.2 Hz, J=7 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1.[Na+].[I-:16]>CC(=O)CC.CCOCC>[I:16][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: [I-]
Reactant: CCOC(=O)C1(CCCCCl)CCC1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C1(CCCCI)CCC1
Yield: 99.4 %

Procedure:
To a solution of ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (21.21 g, 97.0 mmol) in 2-butanone (125 mL) was added NaI (19.07 g, 127 mmol). The reaction mixture was stirred under reflux for 20 h and diluted with Et2O (500 mL). The resulting mixture was washed with aqueous Na2S2O3 (10% (w/w), 250 mL), brine (250 mL), dried (Na2SO4) and evaporated in vacuo to give ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (29.91 g, 99%) as a slightly yellow oil. 1H NMR (CDCl3): δ=4.14 (q, J=7.1 Hz, 2H), 3.17 (t, J=6.9 Hz, 2H), 2.49-2.32 (m, 2H), 1.98-1.69 (m, 8H), 1.37-1.19 (m, 2H), 1.27 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3): δ=176.5, 60.3, 47.5, 36.9, 33.7, 30.1 (2×), 26.0, 15.7, 14.5, 6.8. HRMS calcd for C11H20IO2 (MH+): 311.0508, found: 311.0511.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21](O)=[O:22].C(OC([NH:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21]([N:34]1[CH2:35][CH2:36][CH:32]([NH2:31])[CH2:33]1)=[O:22]
Reactant: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)N2CCC(N)C2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid (Example 36) and 3-(tert-butoxycarbonylamino)pyrrolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([C:17]([F:20])([F:19])[F:18])([OH:16])[CH2:14][OH:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.O.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]2([C:17]([F:20])([F:18])[F:19])[CH2:14][O:15][C:24]([CH3:29])([CH3:25])[O:16]2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)(CC(O)(CO)C(F)(F)F)c1cc(Br)cc2c1OCC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(CC(C)(C)c2cc(Br)cc3c2OCC3)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 144 h
Yield: 372.1 %

Procedure:
A mixture of 7.6 g (20 mmol) of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane-1,2-diol and 0.754 g (4 mmol) of p-toluenesulfonic acid monohydrate in 200 mL of acetone was stirred at room temperature for 6 days and the volatiles removed in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The residue was extracted with diethyl ether and the filtrate concentrated in vacuo to afford 6.3 g (75%) of 5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dimethylethyl]-2,3-dihydrobenzofuran.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:29][NH:30][CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:29][N:30]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([NH:20][C:18]2[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)[N:16]3[N:17]=2)=[CH:22][CH:23]=1)[CH3:31]
Reactant: CNC
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(C=O)cc4)nn23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1ccc(Nc2nc3cccc(-c4cccc(S(C)(=O)=O)c4)n3n2)cc1
Temperature: 24 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of 4-(5-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzaldehyde (150 mg, 0.38 mmol) in dichloromethane (50 mL) was added dimethylamine (1 M in THF) (3.6 g, 28 mmol). The resulting mixture was stirred at 24° C. for 1 h. Sodium triacetoxyborohydride was then added to the reaction mixture. After 16 h, the mixture was quenched with saturated aqueous sodium bicarbonate solution. The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative thin layer chromatography afforded the desired product (61 mg, 37% yield). LCMS (ESI) m/z: 421.9.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([Cl:15])[CH:6]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18].Cl>C(O)C>[Cl:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:19][CH2:16][CH2:17][CH3:18]
Reactant: CCCN
Reactant: CS(=O)(=O)c1cc(Cl)cc(OCCBr)c1
Agent: Cl
Solvent: CCO
Product: CCCNCCOc1cc(Cl)cc(S(C)(=O)=O)c1

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-chloro-5-methylsulfonyl-benzene (0.5 g, 1.59 mmol) and propane-1-amine (1.04 ml, 12.76 mmol) in ethanol (5 ml). Yield: 368 mg (79.1%). The amine was converted to the hydrochloric acid salt and re-crystallized from ethanol/diethyl ether: M.p. 195-197° C. MS m/z (relative intensity, 70 eV) 291 (M+, 1), 264 (8), 262 (22), 73 (9), 72 (bp).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]#[CH:5].[CH2:14](I)[CH3:15]>CN(C=O)C.O>[CH2:14]([N:6]([CH2:3][C:4]#[CH:5])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:15]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A suspension of sodium hydride (354 mg, 14.2 mmol) in DMF (33 mL) at room temperature was treated with a solution of Example 516A (2.0 g, 12.9 mmol) in DMF (10 mL) and stirred for one hour at room temperature. The solution was cooled to 0° C., treated with ethyl iodide (1.24 mL, 15.5 mmol), stirred for one hour at 0° and overnight at room temperature. The solution was diluted with water (25 mL), extracted with diethyl ether (2×50 mL) and the combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 5-10% ethyl acetate/hexanes to give the 1.1 g (47% yield) of the desired product. MS (ESI(+)) m/e 184 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[O:12])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.O>CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:6][CH:7]=1)=[O:12]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCCl)cc3)c2cc1OC
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCN4CCOCC4)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
[4-(2-Chloro-ethoxy)-phenyl]-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-methanone (compound 189) (51 mg) was dissolved in N,N-dimethylformamide to prepare a solution. Potassium carbonate (84 mg) and morpholine (46 mg) were then added to the solution, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, and water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (38 mg, yield 68%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][OH:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:9][CH2:8][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1cccc1CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2cccn2C)cc1
Reaction time: 6 h
Yield: 76.8 %

Procedure:
To a stirred and cooled (±5° C.) mixture of 20.7 parts of 1-methyl-1H-pyrrole-2-ethanol and 200 parts of dry pyridine are added portionwise 35.9 parts of 4-methylbenzenesulfonyl chloride. Upon completion, stirring is continued for 6 hours at about 5° C. The reaction mixture is allowed to stand overnight at 0° C. and poured onto water. The product is extracted with benzene. The extract is washed successively with a 20% hydrochloric acid solution, water, a 10% sodium carbonate solution and with water, dried, filtered and evaporated, yielding 33.4 parts (76.8%) of 2-(1-methyl-1H-pyrrol-2-yl)ethyl 4-methylbenzenesulfonate as an oily residue.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17].[N+:19]([O-])([OH:21])=[O:20]>>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:19]([O-:21])=[O:20])[C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17]
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)NC(=O)C2(C)C
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Yield: 85 %

Procedure:
220 gm of 4,4-dimethyl-7-acetamino-2H,4H-isoquinoline-1,3-dione were added in portions to 800 ml of fuming nitric acid at -20° C. while stirring. The mixture was stirred for one hour at this temperature. Then, the reaction mixture was poured over ice, the precipitate was suction-filtered off, washed neutral with water, dried in the air, and boiled with isopropanol. After cooling, the crystals were suction-filtered off and washed with ether, yielding 222 gm (85% of theory) of 4,4-dimethyl-7-acetamino-8-nitro-2H,4H-isoquinoline-1,3-dione, m.p. 249° C. (decomp.).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:32]#[N:33])=[N:18][C:19]=3[NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:34][O:35]C(=O)C)(=O)C.N.[H][H]>C(O)C.[Pd]>[NH3:14].[NH2:33][CH2:32][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:34][OH:35])[O:7]2)=[C:19]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCO
Product: NCc1nc(NCCc2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[2-cyano-6-(phenethylamino)-9H-purin-9-yl]tetrahydro-3-furanyl acetate (1.0 g, 1.91 mmol) (Preparation 11) in ethanol (40 ml) saturated with ammonia gas was treated with 5% w/w palladium on charcoal (0.50 g), pressurised to 1034 kPa (150 psi) with hydrogen in a sealed vessel and stirred at room temperature for 18 hours. TLC analysis showed that some starting material still remained and therefore further 5% w/w palladium on charcoal (0.25 g) and ethanol (20 ml) saturated with ammonia were added and the mixture was again pressurised to 1034 kPa (150 psi) with hydrogen in a sealed vessel and stirred at room temperature for 18 hours. The mixture was filtered through a pad of Arbocel (trade mark) and the filtrate was evaporated under reduced pressure. The residue was azeotroped from dichloromethane, then purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (90:10:0.5 by volume) to afford the title compound as a white solid (340 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:44]=[C:43]([S:45](=[O:65])(=[O:64])[N:46](CC2C=CC(OC)=CC=2OC)[C:47]2[CH:52]=[CH:51][N:50]=[CH:49][N:48]=2)[C:42]([F:66])=[CH:41][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)[CH:23]=1>O1CCOCC1.CO>[ClH:2].[Cl:2][C:3]1[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[CH:23]=2)=[CH:41][C:42]([F:66])=[C:43]([S:45]([NH:46][C:47]2[CH:52]=[CH:51][N:50]=[CH:49][N:48]=2)(=[O:65])=[O:64])[CH:44]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnc(N3CCNCC3)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 163.6 %

Procedure:
A 4M solution of hydrogen chloride in 1,4-dioxane (10 mL) was added to a solution of tert-butyl 4-(4-(4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(pyrimidin-4-yl)sulfamoyl)-5-fluorophenoxy)-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 109, 310 mg, 0.332 mmol) in methanol (2 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile/water with 0.1% formic acid) to afford the title compound (196 mg, 82%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.ClC(O[CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=O>O1CCCC1>[Cl:35][C:34]([Cl:37])([Cl:36])[CH2:33][O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)C(=O)N1
Reaction time: 0.5 h

Procedure:
In 50 ml of tetrahydrofuran was dissolved 6.2 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and, following addition of 1.2 ml of pyridine, a solution of 5.4 g of 2,2,2-trichloroethyl chloroformate in 30 ml of tetrahydrofuran was added dropwise under cooling at 0°-5° C. The reaction mixture was stirred at the same temperature as above for 30 minutes and under reflux for 5 minutes and then concentrated to dryness under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-ethyl acetate (3:1). The eluate was concentrated under reduced pressure, and the residue was dissolved in a small amount of ethyl ether. After addition of petroleum ether to the solution, the mixture was allowed to stand in a refrigerator overnight to give crystals. Yield 1.1 g.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](O)=[O:21]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:20]([C:19]2[C:18]([F:17])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[OH:21])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1c(F)cccc1F
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1c(F)cccc1F)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2,6-difluorobenzoic acid
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A procedure similar to step 2 of 5.3.1 was used. 4-Phenylbutyryl chloride prepared in the step 1 and methylphenyl ether were used as starting materials, allowed to react in dichloromethane with AlCl3 as catalyst, stirred at −10° C. to −15° C. for 30 minutes and then at room temperature for 3 hours, a crude product was obtained, purified under a reduced pressure by silica gel column chromatography eluted with a gradient of petroleum ether and ethyl acetate at a ratio of 20:1-10:1 (V:V) to obtain a product as a white crystal in a yield of 57.5%, mp: 60-61 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.07 (2H, quintuple, J=7.56 Hz), 2.72 (2H, t, J=7.56 Hz), 2.93 (2H, t, J=7.56 Hz), 3.86 (3H, s, OCH3), 6.91 (2H, d, J=7.00 Hz, ArH), 7.16˜7.21 (5H, m, ArH), 7.91 (2H, d, J=7.00 Hz, ArH); FAB-MS: 255.2 (M+1, 100), 150.1 (27), 135.1 (22), 91.1 (7).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:17])[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)([F:9])[F:8])C>CO.O.O>[Br:16][C:12]1[CH:11]=[C:10]([C:7]([F:8])([F:9])[C:6]([OH:17])=[O:5])[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(F)(F)c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(F)(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Lithium hydroxide (0.13 g, 3.12 mmol) is added to a solution of (3-bromo-phenyl)-difluoro-acetic acid ethyl ester (0.29 g, 1.04 mmol) in methanol/water (8 mL, 3:1) and the reaction mixture is stirred overnight at room temperature. The mixture is diluted with water and volatiles are removed in vacuo. The aqueous is extracted once with diethyl ether, acidified to pH 2, and extracted twice with ethyl acetate. The combined extracts are dried over magnesium sulfate, filtered and concentrated in vacuo to afford (3-bromo-phenyl)-difluoro-acetic acid (250 mg), which is used in the next step without further purification. LCMS: RT=2.26 minutes; MS: 249, 251(M−H).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]([F:15])([F:14])[C:11]([OH:13])=[O:12].O>C(Cl)Cl>[N:7]([C:1]1([O:13][C:11](=[O:12])[C:10]([F:15])([F:14])[F:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(O)C(F)(F)F
Reactant: ON=C1CCCCC1
Solvent: O
Solvent: ClCCl
Product: O=NC1(OC(=O)C(F)(F)F)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of cyclohexanone oxime (4.88 g, 43.16 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (19.14 g, 43.16 mmol) and trifluoroacetic acid (49.22 g, 431.6 mmol) in methylene chloride (200 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was purified by column chromatography to give 1-Nitroso-1-trifluoroacetoxycyclohexane as a bright blue liquid (30% yield): Rf 0.57 (pentane); 1H NMR (300 MHz, Benzene-d6) δ 1.1-1.9 (m, 10H); 13C NMR (300 MHz, Benzene-d6) δ 19.9 (2CH2), 22.9 (CH2), 27.4 (2CH2), 113.8 (q, J=286.2 Hz), 127.2 (O—C—N), 153.7 (q, J=42.5 Hz); 19F NMR (300 MHz, Benzene-d6) δ −75.7 (CF3).