Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12])(=O)C.C[OH:14]>N>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[OH:14]
Reactant: CO
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: N
Product: COc1ccc(O)c(F)c1
Yield: 94 %

Procedure:
A suspension of 2-fluoro-4-methyl acetophenone (10.0 g, 0.059 mol), mCPBA (26.0 g, 0.128 mol) and MgSO4 (30.0 g) in 500 mL of CHCl3 was stirred for 12 hrs. at RT. The mixture was then filtrated, washed with 2M NaOH, dried over Na2SO4 and concentrated in vacuo to give 1-acetyl-2-fluoro-4-methoxybenzene as a solid (10.7 g, 98%). A solution of the 1-acetyl-2-fluoro-4-methoxybenzene (5.3 g, 0.029 mol) in 100 mL of MeOH and 20 mL of 25% NH3 (aq) was stirred for 1 hr. at RT. The mixture was then concentrated in vacuo, diluted with water, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give 2-fluoro-4-methoxyphenol as an oil (3.85 g, 94%). 2-Ethoxy-1-fluoro-4-methoxybenzaldehyde was prepared according to method described in Example 362 of WO 93/03022 and converted to a cis/trans mixture of 2-(2-ethoxy-1-fluoro-6-methoxyphenyl)cyclopropylisocyanates according to the methods described in Examples 375 and 348 of WO 93/03022. This product was then condensed with 2-amino-5-bromo-pyridine in a manner analogous to the method in Example 7 to provide cis/trans mixture of N-2-(2-ethoxy-1-fluoro-6-methoxyphenyl)cyclopropyl-N'-(5-bromopyrid-2-yl)-ureas. The two products were separated on a silica-gel column eluated with mixtures of hexane and ethylacetate to yield N-(cis)-(3-ethoxy-2-fluoro-6-methoxyphenyl)-cyclopropyl-N'-(5-bromopyrid-2-yl)-urea: 1H NMR (250 MHz, CDCl3) δ 7.88 (s, 1H), 7.55 (dd, 1H), 6.83 (t, 1H),6.58 (dd, 1H), 4.03 (q, 2H), 3.79 (s, 3H), 3.32-3.19 (m, 1H), 1.54-1.20 (m, 2H), 1.46 (t, 3H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]([CH3:12])[CH3:11].CN(C)[CH:15]=[O:16].Cl>O1CCCC1>[Cl:9][C:7]1[CH:6]=[CH:5][C:4]([CH:10]([CH3:12])[CH3:11])=[C:3]([CH:8]=1)[CH:15]=[O:16]
Reactant: CN(C)C=O
Reactant: CC(C)c1ccc(Cl)cc1Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)c1ccc(Cl)cc1C=O
Temperature: 40 °C
Yield: 78.2 %

Procedure:
Magnesium (4.6 g, 0.189 mol) together with tetrahydrofuran (65 ml) were placed in a reaction vessel and heated while stirring to 40° C. About 5% of a solution of 2-bromo-4-chloro-1-isopropylbenzene (IV) (43 g, 0.180 mol) in tetrahydrofuran (95 ml) is then added dropwise. After the reaction has commenced, the remainder of the 2-bromo-4-chloro-1-isopropylbenzene in tetrahydrofuran was added under gentle reflux over a period of 1 hour. The mixture was then cooled to 0° C. and dimethylformamide (13.8 g. 0.189 mol) was added dropwise over a period of 1 hour. The reaction mixture obtained was stirred for another 1 hour and hydrochloric acid (86.7 g, 0.369 mol) was added in such a way that the temperature was kept below 30° C. The phases were then separated and extracted with toluene (2×50 ml). The combined organic phases were distilled under reduced pressure and the crude product obtained was recrystallized from isopropanol/water 4:1. 5-Chloro-2-isopropylbenzaldehyde (25.7 g, 99 GC-% by area, 77% of theory) was obtained as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18](O)=[O:19])[CH:9]=1>S(Cl)(Cl)=O>[CH3:12][N:11]([CH:10]([CH3:18])[CH2:9][CH3:8])[C:18]([C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)=[O:19]
Reactant: O=C(O)c1cc(-c2ccccc2F)c2ccccc2n1
Solvent: O=S(Cl)Cl
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2F)c2ccccc2n1
Reaction time: 14 h
Yield: 55.9 %

Procedure:
3.3 g of 4-(2-fluorophenyl) quinoline 2-carboxylic acid in 10 ml of thionyl chloride are brought to boiling point. After reaction, the thionyl chloride is evaporated and the residue taken up in 30 ml of toluene which is again evaporated. The residue is redissolved in 100 ml of toluene and 4.8 ml of triethylamine, then under agitation, 1.8 g of N-methyl 2-butanamine hydrochloride are added. After 14 h. the reaction mixture is taken up in 100 ml of water. The organic phase is decanted, the aqueous phase is extracted 3 times each with 100 ml of ether. The organic phases are washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel using a cyclohexane/ethylacetate (70:30) mixture as eluant. After recrystallization in isopropylether/ether (5:2) mixture, 1.16 g of N-methyl N-(1-methylpropyl) 4-(2-fluorophenyl) quinoline 2-carboxamide melting at 86° C. is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:24])[C:5]1=[O:31].[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][C:26]([CH3:29])([CH3:30])[CH2:27][OH:28])=[O:24])[C:5](=[O:31])[N:4]3[CH2:3][CH2:2][NH:1][C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Product: CC(C)(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1,1-dimethylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36 (s, 6 H), 2.03 (s, 1 H), 3.13-3.20 (m, 4 H), 3.27-3.30 (m, 2 H), 3.48 (dt, J=4.56, 2.35 Hz, 6 H), 4.13 (s, 2 H), 4.27 (t, J=6.04 Hz, 2 H), 5.09-5.15 (m, 1 H), 6.75 (t, J=5.76 Hz, 1 H), 7.10-7.18 (m, 2.04 Hz, 2 H), 7.39-7.44 (m, 2 H), 8.23 (d, J=1.54 Hz, 1 H), 8.53 (d, J=1.26 Hz, 1 H), 10.53 (s, 1 H); ES+ MS: 542 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.CS(C)=O.[I:13]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[F:8][C:5]1[CH:6]=[C:7]([I:13])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Nc1ncc(F)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a mixture of 2-amino-5-fluoropyridine (2.0 g, 17.8 mmol) and dimethyl sulfoxide (50 mL) was added N-iodosuccinimide (4.8 g, 21.4 mmol), which was stirred for 1 hour at room temperature. A suitable amount of acetic acid was added to this mixture, which was stirred for 1 hour at the same temperature, and then stirred for another 3 hours at 55° C. This reaction mixture was cooled to room temperature, after which a saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (751 mg, 18%).
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:3][N:4]1[CH2:7][CH2:6][CH2:5]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([NH2:37])=[N:27][CH:28]=[N:29][C:30]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C(#N)C>[N:4]1([CH2:3][CH:2]([N:34]2[CH2:35][CH2:36][N:31]([C:30]3[N:29]=[CH:28][N:27]=[C:26]([NH2:37])[C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[CH2:32][CH2:33]2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: Nc1ncnc(N2CCNCC2)c1-c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(C(Cl)CN2CCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncnc(N2CCN(C(CN3CCC3)c3ccc(C(F)(F)F)cc3)CC2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a microwave vial containing 1-[2-chloro-2-(4-trifluoromethyl-phenyl)-ethyl]-azetidine (32.26 mg; 0.12 mmol; 1.00 eq.) from last step in acetonitrile (2.00 ml) was added 5-(4-fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (33.43 mg; 0.12 mmol; 1.00 eq.), followed by DIPEA (0.06 ml; 0.37 mmol; 3.00 eq.). The clear solution was stirred at 60° C. overnight and then 75° C. for 3 h before the mixture was concentrated and purified with waters pre-HPLC. LC-MS: (M+1=501, obsd.=501)
Reaction SMILES: CC(OC([NH:8][C@@H:9]([CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:20][CH:19]=1)=O)[C:10]([O:12][CH3:13])=[O:11])=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[CH2:15][CH2:14][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[N:8]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2F)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3F)cc2)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-5-oxopentanoate (D31, 339 g) in dry DCM (3390 mL), at 0° C., was added trifluoroacetic acid (TFA) (640 mL) dropwise. The mixture was allowed to warm to room temperature and stirred for 2 hrs. Solvent and excess TFA were removed under vacuum and the resulting dark oil was stripped with EtOAc (1700 mL) and left overnight under high vacuum. The title compound was obtained as a red oil (818 g). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.16 (m, 2H); 7.60 (td, 1H); 7.46 (m, 1H); 7.34 (m, 2H); 7.27 (m, 2H); 5.32 (s, 2H); 5.25 (m, 1H); 3.77 (s, 3H); 3.57 (m, 2H); 2.60 (m, 1H); 2.34 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a suspension of 2-amino-3-fluorobenzoic acid (5 g, 32.2 mmol) in chloroform (200 mL) was added dropwise bromine (1.1 equiv.) in chloroform (125 mL) solution. The mixture was stirred at room temperature for 16 hrs. The resulting white solid was collected by filtration and washed thoroughly with methylene chloride until the filtrate was colorless. The solid was air-dried to give 9.6 g of white powder as HBr salt of 2-amino-5-bromo-3-fluorobenzoic acid (95% yield). ES/MS m/z 234/236 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[C:3]([F:24])[CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)c(F)c3)CC2)c(C)c1
Yield: 34.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-3-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (783 mg) described in Preparation Example 2 and oxazolidin-2-one (174 mg), the title compound (273 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[S-:11][C:12]#[N:13].[NH4+].BrBr.O>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a well-stirred mixture of 108 g of o-nitroaniline and 128 g of ammonium thiocyanate in 400 ml of acetic acid there is added dropwise a solution of 128 g of bromine in 160 ml of acetic acid below 20° C. The mixture is stirred for 4 hours at room temperature and then poured into 4 liters of water. The resulting solid is filtered off and crystallized from ethanol to yield 86.7 g, m.p. 111°-114° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C(O)(=O)C>CO.[Rh]>[CH:2]1([C:1]([OH:12])=[O:11])[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a suspension of isophthalic acid (500 g, 3 mol) in methanol (2.81) was added 5% Rhodium-on-alumina catalyst (50 g) and acetic acid (150 ml). The reaction mixture was shaken under hydrogen (50 psi) at room temperature overnight. The mixture was filtered through celite. To this solution was added fresh 5% Rhodium-on-alumina catalyst (25 g), and the mixture was shaken under 50 psi of hydrogen for another 24 hours. The final reaction mixture was filtered through celite. The solution was concentrated under vacuum to give 493 g of the title compound as a white powder (96.3% yield). m.p. 163-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([CH2:12]/[C:13](=N/N(C)C)/[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11])[C:5]([F:8])=[N:6][CH:7]=1.Cl.C([O-])(O)=[O:31].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([CH2:12][C:13](=[O:31])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CN(C)/N=C(/C[C@](CF)(N[S@](=O)C(C)(C)C)c1cc(Br)cnc1F)C(F)(F)F
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](CF)(CC(=O)C(F)(F)F)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
(R)-N-((S,Z)-2-(5-bromo-2-fluoropyridin-3-yl)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoropentan-2-yl)-2-methylpropane-2-sulfinamide (0.510 g, 1.034 mmol) was dissolved in THF 5 mL. Hydrochloric acid 1N solution (1.034 ml, 1.034 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and worked up with saturated aqueous NaHCO3 and extracted with EtOAc three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 15-50% EtOAc/hexane to give (R)-N-((S)-2-(5-bromo-2-fluoropyridin-3-yl)-1,5,5,5-tetrafluoro-4-oxopentan-2-yl)-2-methylpropane-2-sulfinamide (0.356 g, 0.789 mmol, 76% yield). MS m/z=490.9 [M+CH3CN]+. Calculated for C14H16BrF5N2O2S: 451.250.
Reaction SMILES: CS(O[CH:6]([CH3:29])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:11][CH2:10]1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[N:30]([CH:6]([CH3:29])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:11][CH2:10]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 2-({trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexyl}oxy)-1-methylethyl methanesulfonate 283 mg) and sodium azide (271 mg) in DMF (3 mL) was stirred at 60° C. overnight. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (249 mg).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44]1([S:50](Cl)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:44]1([S:50]([NH:8][CH:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([NH:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NC(=O)OC(C)(C)C)CC2c2ccccc2)CC1
Product: C=CCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NS(=O)(=O)c3ccccc3)CC2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as Example 16, Step A and B, 1-(RS)-((t-butoxycarbonyl)amino)-3-(SR)-((4-(N-(4-nitrobenzylaminocarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane from Example 22, Step H (derived from the lower isomer from Example 20, Step E) was deblocked and acylated with phenylsulfonyl chloride to obtain the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH2:27][CH3:28])=[O:8])=[CH:5][CH:4]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].[I-].[K+]>CN(C)C=O.O>[O:36]=[C:34]1[C:33]2[C:32](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:31](=[O:41])[N:35]1[CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH2:27][CH3:28])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CCl)cc1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Yield: 57 %

Procedure:
4-(Chloromethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]benz amide (1.2 g) was dissolved in N,N-dimethylformamide (15 ml). To the solution, potassium phthalimide (0.95 g) and potassium iodide (0.09 g) were added and the mixture was stirred under heating at 60° C. for 2 hours. After adjusting to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was washed with tert-butyl methyl ether to obtain 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-methyl]-N-[2-ethyl-4-(1,1,1,2,3,3,3-hepta-fluoropropan-2-yl)-6-methylphenyl]-benzamide (0.85 g, yield 56%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([Cl:29])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cccc(Cl)c4)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3cccc(Cl)c3)c2O1
Yield: 57.2 %

Procedure:
Treatment of (±)-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.00 g, 2.24 mmol) with sodium azide (0.93 g, 14.3 mmol) generally according to the procedure described for Intermediate 98 provided 0.41 g of (±)-2-(azidomethyl)-5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (100 mg, 5 wt. %) generally according to the procedure described for Example 1 provided 0.31 g (50%) of (±)-1-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 195° C. (dec); Anal. calcd for C15H13Cl2NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 51.59; H, 4.21; N, 4.02.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]4[CH:25]=[CH:24]C([N+]([O-])=O)=C[CH:21]=4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[O:29]1CC[C@@H](O)C1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[O:29]1[CH2:24][CH2:25][C@@H:20]([O:19][C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:9]=[CH:10][N:5]4[N:4]=[CH:3][C:2]([Br:1])=[C:6]4[N:7]=3)[CH2:12][CH2:13]2)=[O:18])[CH2:21]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Reactant: O[C@@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To 112 mg (0.25 mmol) of 4-nitrophenyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate dissolved in 10 mL of THF, was added (R)-tetrahydrofuran-3-ol (44 mg, 0.5 mmol), followed by 60% NaH (40 mg, 1.0 mmol) and stirred at RT for 2 hr. After 2 hr it was diluted with 20 mL of EtOAc and slowly quench with brine. The organic layer was dried over MgSO4 and concentrated, it was purified over 12 gram silica gel column eluting with 0-10% MeOH/DCM to obtain 71 mg (72% yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O=[C:12]([CH2:16][CH2:17][C:18](O)=[O:19])[C:13]([OH:15])=[O:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:17]([CH2:16][CH2:12][C:13]([OH:15])=[O:14])[C:18](=[O:19])[NH:10]2
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCO
Product: O=C(O)CCc1nc2cc(Cl)c(Cl)cc2[nH]c1=O

Procedure:
Following the above procedure, 4,5-dichloro-o-phenylenediamine was reacted with 2-ketoglutaric acid in ethanol to yield 6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxaline propionic acid. Reaction of the free acid with ethanol in the presence of BF3 etherate yielded the corresponding ethyl ester, β-(6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxaline)propionic acid, ethyl ester melting at 183.5-184.5. The free acid had the following analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: Fc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ncccc2F)CC1
Yield: 13.3 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-fluoropyridine (78 μl, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (18 mg), a white solid, in 13% yield.