Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:28][CH:29]=C)[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:35]CC1.OS([O-])=O.[Na+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.C(O)(C)(C)C.O.[Cl-].[Na+].O.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:28][CH:29]=[O:35])[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(F)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(2S)-2-(4-Fluorophenyl)pent-4-en-1-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (570 mg, 1.32 mmol) was dissolved in a mixture of acetone (10 mL), t-butyl alcohol (5 mL) and water (2.5 mL). OsO4 (2.5% in t-butyl alcohol, 0.190 mL, 0.013 mmol) was added together with 4-methylmorpholine-4-oxide (680 mg, 5.8 mmol). The solution was stirred at room temperature overnight and then saturated aqueous solution of NaHSO3 (10 mL) was added. The mixture was stirred for 15 min, diluted with water (50 mL) and then extracted three times with CH2Cl2. The organic solution was washed with brine and then the solvent was evaporated. The residue (643 mg) was dissolved in a mixture of THF (7 mL) and water (3 mL) and to the resultant solution was added sodium periodate (309 mg, 1.45 mmol). The mixture was stirred at room temperature overnight, diluted with water (75 mL) and brine (40 mL) and then extracted three times with ethyl acetate. The combined organic solutions were washed three times with water, dried over Na2SO4 and then the solvent was evaporated. The product was purified by chromatography on silica gel using a mixture of heptane and ethyl acetate as eluent (1:1). There was obtained 398 mg (69%) of ) N-[(2S)-2-(4fluorophenyl)-4-oxobutyl]-N-methyl-3,5-bis(trifluoromethyl)benzamide as an oil. 1H NMR (400 MHz, CDCl3): 2.6-3.9 (cm, 8H), 6.8-7.6 (cm, 6H), 7.9 (s, 1H), 9.8 (s, 1H); LCMS: m/z 436 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[N+:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:18]([O-:20])=[O:19])[C:9]=1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])([O-:17])=[O:16]
Reactant: NCCCCCO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A mixture of 5-amino-1-pentanol (619 mg, 6.00 mmol), 2-chloro-1,3-dinitrobenzene (1.01 g, 4.99 mmol), triethylamine (0.837 mL, 6.01 mmol) and tetrahydrofuran (20 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added 5-amino-1-pentanol (520 mg, 5.04 mmol) at room temperature and the resultant mixture was stirred at room temperature for 0.5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow oil (1.30 g, 4.82 mmol, 97%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][N:49]=1.[CH2:55]([O:57][C:58](=[O:80])[C:59]([CH:62]1[CH2:67][CH2:66][N:65]([C:68]2[S:69][C:70]([C:73]3[CH:78]=[CH:77][CH:76]=[C:75](Br)[N:74]=3)=[CH:71][N:72]=2)[CH2:64][CH2:63]1)([CH3:61])[CH3:60])[CH3:56].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:55]([O:57][C:58](=[O:80])[C:59]([CH3:61])([CH:62]1[CH2:63][CH2:64][N:65]([C:68]2[S:69][C:70]([C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([NH:47][C:48]4[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][N:49]=4)[N:74]=3)=[CH:71][N:72]=2)[CH2:66][CH2:67]1)[CH3:60])[CH3:56]
Reactant: Cc1ccnc(N)c1
Reactant: CCOC(=O)C(C)(C)C1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)(C)C1CCN(c2ncc(-c3cccc(Nc4cc(C)ccn4)n3)s2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (213 mg, 0.34 mmol) and palladium acetate (58 mg, 0.26 mmol) were suspended in toluene (10 ml), and after 2-amino-4-picoline (203 mg, 1.88 mmol) and 2-{1-[5-(6-bromopyridin-2-yl)thiazol-2-yl]piperidin-4-yl}-2-methylpropionic acid ethyl ester (748 mg, 1.71 mmol) obtained in Step 2 were sequentially added, cesium carbonate (1.11 g, 3.41 mmol) was added, and the mixture was stirred overnight at 100° C. Water was added to the reaction solution and extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over anhydrous sodium sulfate and the residue obtained by vacuum concentration was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:1 to 1:3) and the title compound (697 mg, 88%) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:46][CH2:47]3)=[O:32])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give the title compound. LC-MS: 720.3 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23]C(=O)CC2C=CC=C(C(F)(F)F)C=2)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23][C:9](=[O:10])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)Cc1ccccc1Cl
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1Cl

Procedure:
The title compound was prepared using 2-chlorophenylacetyl chloride in place of 2-phenylacetyl chloride using the procedure described for Intermediate 7: step a.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[K+]>O.C(O)C>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:18])=[O:2])=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution 4-benzyloxy-benzoic acid methyl ester (3) (1 equi.) and potassium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h., cooled to room temperature, quenched with hydrochloric acid (5%). The resulting white solid was filtered, washed with water, and dried under vacuum to give 4-benzyloxy-benzoic acid (4)) as a white solid (80%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH:25]([NH:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>CN(C)C=O>[CH:25]([N:28]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1)[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)no1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
A suspension of 1.04 g (3.0 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]-[1,4]benzodiazepin-6-one in 10 ml of N,N-dimethylformamide was treated with 1.27 ml (9.0 mmol) of diisopropylamine. After stirring at room temperature for 18 hrs. the solution obtained was concentrated and the residue was taken up in 10 ml of water and stirred in an ultrasound bath for 2 hrs. The crystals were filtered off under suction and dissolved in methylene chloride, and the solution was dried with sodium sulfate, is filtered and evaporated. The crude material was chromatographed on silica gel (ethyl acetate), dissolved in acetonitrile and acidified with ethereal hydrochloric acid. The solution was again evaporated and the residue was recrystallized from acetonitrile. After drying in a vacuum there were obtained 542 mg (38%) of 3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals of m.p. 173°-178° (dec.).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2>CN(C)C=O>[Cl:16][C:15]1[C:6]([CH2:5][S:2][CH3:1])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:17])[N:11]=[C:10]([O:18][CH3:19])[C:9]([O:20][CH3:21])=[N:8]2
Reactant: C[S-]
Reactant: COc1nc2cc(Cl)c(Cl)c(CBr)c2nc1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2cc(Cl)c(Cl)c(CSC)c2nc1OC
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Sodium methanethiolate (22 mg, 0.312 mmol) was added to a stirred solution of 5-bromomethyl-6,7-dichloro-2,3-dimethoxyquinoxaline (see Preparation 28) (100 mg, 0.284 mmol) in dry dimethylformamide (5 ml) under nitrogen at room temperature. The mixture was stirred for 10 minutes and was then quenched with brine and extracted twice with dichloromethane. The combined extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 1:1 hexane:dichloromethane) to give 6,7-dichloro-2, 3-dimethoxy-5-methylthiomethylquinoxaline (79 mg, 87%) as a white solid, m.p. 143°-5° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:27]>O1CCOCC1>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:27])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Solvent: C1COCCO1
Product: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(N)ncnc2s1
Yield: 78 %

Procedure:
6-[4-(3-iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (200 mg) and concentrated aqueous ammonia (5 mL) was stirred in 1,4-dioxane (15 mL) for 17 hours. The solvent was evaporated and the residue purified by chromatography on silica eluting with a gradient of 0-50% EtOAc/DCM then 0-20% MeOH/DCM to give the title compound as a colourless solid (136 mg, 78%);
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:34]1([CH:37]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[CH2:38][OH:39])[CH2:36][CH2:35]1.[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52][C:53](O)=[O:54]>O1CCCC1>[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52][C:53]([O:39][CH2:38][CH:37]([CH:34]1[CH2:36][CH2:35]1)[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)=[O:54]
Reactant: O=C(O)Cc1cccs1
Reactant: OCC(c1ccc(Cl)cc1)C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)OCC(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A stirred solution of 11.7 grams (0.045 mole) of triphenylphosphine in 75 mL of dry tetrahydrofuran was cooled to 0° C., and 9.0 grams (0.045 mole) of diisopropyl azodicarboxylate was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes. Successively, 4.4 grams (0.022 mole) of 2-cyclopropyl-2-(4-chlorophenyl)ethanol (prepared in Example 1, Step B) and 3.4 grams (0.045 mole) of thiolacetic acid were then added. The exothermic reaction caused the reaction mixture temperature to rise to 39° C. After cooling to ambient temperature the reaction mixture was stirred for 16 hours. The reaction mixture was then concentrated under reduced pressure to a residual oil. The oil was subjected to chromatography on silica gel using methylene chloride:heptane (1:4) as eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.6 grams of 2-cyclopropyl-2-(4-chlorophenyl)ethyl thiolacetate as an oil. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=1>C1COCC1>[CH3:23][O:22][C:18]1[N:17]=[C:16]([CH2:13][C:12]#[N:14])[CH:21]=[CH:20][CH:19]=1
Reactant: CC#N
Reactant: COc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(CC#N)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
1.6M n-Butyllithium/hexane solution (300 mL, 479.43 mmol) was added to a solution of acetonitrile (21.87 g, 532.70 mmol) in THF (630 mL) at −78° C. under argon atmosphere, and the mixture was stirred at −78° C. for 30 min. 2-Bromo-6-methoxypyridine (25.04 g, 133.18 mmol) was added dropwise thereto over 15 min at −78° C., and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water (900 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 2→20% ethyl acetate/hexane) to give 2-(6-methoxypyridin-2-yl)acetonitrile (11.37 g, 77 mmol, 58%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:10]2[CH:8]3[O:9][CH:7]3[CH2:6][C:5]=2[CH:4]=1.[CH3:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[OH:9][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[CH:8]1[N:21]1[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C@@H:16]1[CH3:15]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: FC(F)(F)c1ccc2c(c1)CC1OC21
Solvent: CCO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1c2ccc(C(F)(F)F)cc2CC1O
Temperature: 95 °C

Procedure:
A mixture of 4-(trifluoromethyl)-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (1.2 g, 6.0 mmol) and tert-butyl (3S)-3-methylpiperazine-1-carboxylate (1.4 g, 7.2 mol) in ethanol (20 mL) was refluxed overnight. Another gram of tert-butyl (3S)-3-methylpiperazine-1-carboxylate was added. The mixture was transferred into a sealed flask and heated to 95° C. for 2 days. The solvent was concentrated and the residue was purified by flash chromatography eluting with 25% EtOAc/hexane, followed by 5% MeOH/EtOAc+0.5% concentrated NH4OH. Two isomers were isolated. Isomer 1 (fast moving isomer): 0.45 g; MS calculated for the C20H27F3N2O3 (M+H)+ 401. found 401.1. Isomer 2 (slow moving isomer): 0.38 g; MS found 401.1.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Cl:13])=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].BrC[C:18]([CH2:26][CH3:27])([CH2:22][CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20].Cl>O>[NH2:6][C:5]1[CH:7]=[C:8]([Cl:13])[C:9]([O:11][CH3:12])=[CH:10][C:4]=1[S:3][CH2:2][C:18]([CH2:26][CH3:27])([CH2:22][CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20]
Reactant: CCCCC(CC)(CBr)C(=O)O
Reactant: COc1cc2sc(N)nc2cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCC(CC)(CSc1cc(OC)c(Cl)cc1N)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4 (20.0 g) in H2O (200 ml) was added KOH (100 g). The slurry was refluxed for 7 h and allowed to cool to RT. To the dark solution was added 2 (33.2 g) in one portion. The reaction mixture was stirred for 18 h at which point the pH was adjusted to 4 with HCl. The mixture was transferred to a separatory funnel and extracted three times with ethyl acetate. The organic layer was dried and concentrated. The product was purified by column chromatography on silica gel eluting the product with 10% ethyl acetate/petroleum ether giving 5 (30.1 g).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1.C[O-].[Na+].Cl>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]5)=[N:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NNC(=O)CN1CCC(O)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: OC1CCN(Cc2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 7.3 %

Procedure:
A solution of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (521 mg, 1.63 mmol), N-amino-2-(4-hydroxypiperidyl)acetamide (850 mg, 4.9 mmol), and sodium methoxide (1.2 mL, 4.9 mmol) in methanol (8 mL) was taken up in a sealed tube and allowed to stir at room temperature for 25 minutes and then heated at 95° C. overnight. The reaction was acidified with hydrochloric acid to neutral pH. The product was extracted using ethyl acetate. The material was concentrated and purified by semipreprative HPLC. The purified material was taken up in ethyl acetate and washed with an aqueous solution of sodium bicarbonate to yield the title compound (47 mg, 7% yield). 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 8.6 (s, 1H), 8.0 (m, 3H), 7.6 (m, 1H), 7.4 (t, 2H), 3.6–3.8 (m, 2H), 3.4 (m, 2H), 3.2 (d, 1H), 2.4 (m, 2H), 2.0 (s, 4H)H, ES-MS (m/z) 393 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:24])(=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=2[CH3:25])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:33]1([CH2:36][NH:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:35][CH2:34]1>C(O)C>[CH:38]1([N:37]([CH2:36][CH:33]2[CH2:34][CH2:35]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])(=[O:24])=[O:23])=[CH:13][C:12]=3[CH3:25])=[O:9])[CH:3]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: C1CCC(NCC2CC2)CC1
Reactant: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Temperature: 160 °C
Yield: 84.3 %

Procedure:
A solution of 6-chloro-N-(4-(N-(2-methoxyethyl)sulfamoyl)-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 38, 100 mg; 0.26 mmol) and diisopropylamine (91 mL; 0.52 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (54.4 mg; 0.33 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (110 mg, 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:38]1[C:47]([S:48]([CH3:51])(=[O:50])=[O:49])=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:40]([CH3:52])[CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CC(=O)OCC.O>[CH3:51][S:48]([C:47]1[CH:46]=[C:41]([C:42]([O:44][CH3:45])=[O:43])[C:40]([CH3:52])=[CH:39][C:38]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)(=[O:49])=[O:50]
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(S(C)(=O)=O)c(-c2ccc(S(F)(F)(F)(F)F)cc2)cc1C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
150 mg of 1-bromo-4-pentafluorosulfanylbenzene were stirred together with 135 mg of bis(pinacolato)diboron, 156 mg of potassium acetate and 64 mg of Pd(dppf)2 in 4 ml of DMF at 80° C. for 2 h. Then 163 mg of methyl 4-bromo-5-methanesulfonyl-2-methylbenzoate, 337 mg of Na2CO3, 64 mg of Pd(dppf)2 and 2 ml of water were added, and stirring was continued at 80° C. for 3 h. Cooling was followed by dilution with 50 ml of EA and washing twice with 10 ml of water each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with DIP. 150 mg of a colorless oil were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[C:4](=[O:22])[N:3]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37].CC1(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(=[O:69])N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH3:1][C:2]1([CH3:42])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([C:18]([F:20])([F:21])[F:19])[CH:9]=2)[C:4](=[O:22])[N:3]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][S:31]([CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:37])([F:38])[F:39])=[O:69]
Reactant: CC(=O)Nc1ccc(N2C(=O)N(CCOCCOCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Product: CC(=O)Nc1ccc(N2C(=O)N(CCOCCOCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Yield: 75 %

Procedure:
Compound 39 described below was synthesized according to a similar method to that described in Example 2 using the compound of Example 38 as starting reagent replacing the compound of Example 1. The expected compound is obtained in the form of a pale yellow oil with a yield of 75%.