Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][N:16]=2)[CH2:9][CH2:8]1)=[O:5].Cl.[CH3:32][NH:33][CH3:34]>>[ClH:1].[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:33]([CH3:34])[CH3:32])=[CH:17][N:16]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: CNC
Reactant: O=Cc1ccc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)nc1
Agent: Cl
Product: CN(C)Cc1ccc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)nc1

Procedure:
The title compound is prepared from Trans-2-Chloro-N-{4-[(5-formyl-pyridin-2-ylamino)-methyl]-cyclohexyl}-5-trifluoromethyl-benzamide and dimethylamine hydrochloride analogously to Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].COCCOC>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: OB(O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Brc1ccccc1-c1ccccn1
Temperature: 25 °C

Procedure:
To a 250 mL flask were charged 2-bromopyridine (4.8 mL, 49 mmol), 2-bromophenylboronic acid (9.85 g, 49 mmol), triphenylphosphine (1.09 g, 4.17 mmol), and ethylene glycol dimethyl ether (55 mL). A homogeneous solution was formed. To this solution was added 2 M K2CO3 (60 mL, 120 mmol). The mixture was purged with nitrogen then Pd(OAc)2 (0.24 g, 1 mmol) was added. The mixture was refluxed for 5 h then cooled to room temperature. The reaction mixture was transferred into a separating funnel and the organic layer was separated and retained. The aqueous phase was extracted with ethyl acetate (EtOAc) (4×100 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL) and dried over MgSO4. Filtration and evaporation produced a dark brown oil, which was purified by chromatography on silica gel with CH2Cl2:heptane=2:1 and CH2Cl2 to provide a light yellow oil, 7.57 g, 65%.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.[CH3:38][N:39]1[CH2:43][C@@H:42]2[NH:44][CH2:45][CH2:46][C@@H:41]2[CH2:40]1>FC(F)(F)CO>[CH3:38][N:39]1[CH2:40][C@@H:41]2[C@@H:42]([N:44]([C:11]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]4[N:26]=[C:25]([C:27]5[CH:28]=[N:29][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=56)[CH:24]=[CH:23][N:22]=4)=[C:13]([O:36][CH3:37])[CH:12]=3)[CH2:45][CH2:46]2)[CH2:43]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 140 °C
Yield: 60.9 %

Procedure:
DIPEA (0.583 mL, 3.35 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 515 mg, 1.34 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 186 mg, 1.47 mmol) in 2,2,2-trifluoroethanol (5 mL) and the mixture was heated in a microwave at 140° C. for 1 h. After cooling, the mixture was part-purified by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia, and then concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (400 mg, 61%) as an orange/red foam; 1H NMR (CDCl3): 1.87 (1H, dd), 1.90-1.98 (2H, m), 2.03-2.14 (3H, m), 2.20 (3H, s), 2.28 (1H, dd), 2.45 (2H, ddd), 2.60-2.67 (1H, m), 2.97-3.07 (1H, m), 3.18-3.34 (3H, m), 3.48-3.58 (1H, m), 3.96 (3H, s), 4.20 (2H, t), 4.40 (1H, ddd), 6.43 (1H, s), 6.86 (1H, d), 7.35 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.92 (1H, s); m/z: ES+ MH+ 491.15.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1([CH3:16])[CH2:13][CH2:12][CH:11]2[C:6](=[CH:7][CH2:8][CH2:9][C:10]2([CH3:15])[CH3:14])[CH2:5]1.C(O)C.Cl>O>[CH3:16][C@@:4]1([OH:3])[CH2:5][C:6]2=[CH:7][CH2:8][CH2:9][C:10]([CH3:14])([CH3:15])[C@@H:11]2[CH2:12][CH2:13]1
Reactant: CC1(O[Si](C)(C)C)CCC2C(=CCCC2(C)C)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C)CCC=C2C[C@@](C)(O)CC[C@H]21
Reaction time: 17 h
Yield: 73.8 %

Procedure:
A mixture of 1,2,3,4,4a,5,6,7-octahydro-2-trimethylsilyloxy-2,5,5-trimethylnaphthalene (0.78 g), ethanol (40 ml), water (4 ml) and 2 N hydrochloric acid (1 ml) was stirred at 20°-25° for 17 h. The mixture was poured onto water and extracted with hexanes. The combined organic extracts were washed with sodium bicarbonate solution and the solvent evaporated to give 0.61 g of crude product. Chromatography gave 0.42 g (75%) of α-ambrinol. Spectral and analytical data for this material was consistent with that given in Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:26]#[N:27])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=2)[S:12][C:13]=1[C:14]1[NH:18][N:17]=[N:16][CH:15]=1.COC1C=C(OC)C=CC=1C[NH2:33].CCN(C(C)C)C(C)C.C(O)CCC.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:33][C:21]1[CH:20]=[C:19]([C:11]2[S:12][C:13]([C:14]3[NH:18][N:17]=[N:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]=2[C:26]#[N:27])[CH:24]=[CH:23][N:22]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(-c2cnn[nH]2)c1-c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: ClCCl
Product: N#Cc1c(-c2ccnc(N)c2)sc(-c2cnn[nH]2)c1-c1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)-5-(1H-1,2,3-triazol-5-yl)thiophene-3-carbonitrile (0.103 g, 0.247 mmol), 2,4-dimethoxybenzylamine (0.247 g, 1.48 mmol) and DIPEA (0.0959 g, 0.742 mmol) in 1-Butanol (15 g, 2.0E2 mmol) was irradiated in microwave at 170° C. for 2 hrs. The mixture was concentrated and the residue was purified by column chromatography to afford desired intermediate. LC/MS (FA) ES+ 563, 565. To the intermediate in DCM (5.9 mL, 93 mmol) was added TFA (2 mL, 20 mmol) and the mixture was stirred for 10 min. The reaction mixture was concentrated and the residue in MeOH was treated with sodium bicarbonate and water. The mixture was concentrated and the mixture was purified by column chromatography to afford the title compound (48 mg, 47.0%). LC/MS (FA) ES+ 413, 415. 1H NMR (400 MHz, d4-methanol) δ: 8.03 (1H, d, J=6.26 Hz), 7.74 (1H, d, J=1.93 Hz), 7.54 (1H, dd, J=8.27, 1.97 Hz), 7.46 (1H, d, J=8.26 Hz), 7.05 (1H, s), 7.01 (2H, m)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10](OS(C)(=O)=O)[C@@H:9]([NH:17][C:18](=[O:20])[CH3:19])[C@H:8]([O:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:7]=1)=[O:5])[CH3:2].CS(C)=O.[N-:31]=[N+:32]=[N-:33].[Na+].C([O-])(O)=O.[Na+]>COC(C)(C)C.CCO>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:31]=[N+:32]=[N-:33])[C@@H:9]([NH:17][C:18](=[O:20])[CH3:19])[C@H:8]([O:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Temperature: 87.5 °C
Reaction time: 21 h
Yield: 20.4 %

Procedure:
To a solution of 340 mg of 22, 1.2 mL of DMSO and 1.2 mL of EtOH in a 5.0 mL round-bottom flask equipped with a magnetic stirrer, a reflux condenser and an inert gas supply was added 113 mg of sodium azide and the reaction mixture was stirred for 21 h at 85-90° C. The brown reaction mixture was cooled to RT, treated with 7.0 mL of a aqueous 1 M NaHCO3 and extracted with 7.0 mL tert-butyl methyl ether. The organic phase was dried with (Na2SO4), filtered and evaporated at 40° C./250-10 mbar to afford 280 mg of the crude product as brown crystals. The crude product was dissolved in 3.0 mL of tert-butyl methyl ether and stirred for 16 h at −20° C. which resulted in the formation of a beige suspension. The suspension was filtered over a pre cooled (−20° C.) glass filter frit and washed with 1.5 mL of pre cooled (−20° C.) tert-butyl methyl ether. The white crystals were dried at 40° C./10 mbar for 2 h to afford 60 mg of 24 as white crystals
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>COCCOC>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[N:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 120 °C
Yield: 81.2 %

Procedure:
A mixture of ethyl 6-chloronicotinate (2.67 g, 14.4 mmol), tert-butyl piperazine-1-carboxylate (2.5 g, 13.4 mmol) and N,N-diisopropylethylamine (3.5 mL, 20 mmol) in DME (15 mL) was heated at 120° C. for 12 hours. The mixture was then cooled to room temperature and partitioned with ethyl acetate and 10% aqueous citric acid. The organic layer was washed twice with 10% aqueous citric acid then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using 3:1 hexanes:ethyl acetate to 100% ethyl acetate afforded tert-butyl 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (3.65 g). 1H NMR (400 MHz, CDCl3): 8.81 (s, 1H), 8.04 (d, 1H), 6.58 (d, 1H), 4.33 (q, 2H), 3.70-3.67 (m, 4H), 3.56-3.53 (m, 4H), 1.49 (s, 9H), 1.37 (tr, 3H).
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[CH2:21]([NH2:23])[CH3:22]>O1CCCC1>[CH2:21]([NH:23][C:2]1[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[CH3:22]
Reactant: CCN
Reactant: COCOCc1nc(OC)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1ccc(OC)nc1COCOC
Yield: 73.7 %

Procedure:
A solution of 3-bromo-6-methoxy-2-(methoxymethyloxy)methylpyridine (1.5 g, 5.72 mmol), tris(dibenzylideneacetone)(chloroform)dipalladium(0) (592 mg, 0.572 mmol), (2-biphenyl)di-t-butylphosphine (680 mg, 2.28 mmol), sodium t-butoxide (1.65 g, 17.2 mmol) and ethylamine (2.0 mol/L solution in tetrahydrofuran, 15 mL, 30 mmol) in tetrahydrofuran (15 mL) was heated to 135° C. over 3 minutes under microwave irradiation (500 W). The reaction mixture was cooled, and then filtered through Celite, and washed with ethyl acetate. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain 3-ethylamino-6-methoxy-2-(methoxymethyloxy)methylpyridine (954 mg, 74%) as yellow oil.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]([C:21]1[C:29]2[O:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)([CH3:20])[CH2:12][C:13]1([C:16]([F:19])([F:18])[F:17])[CH2:15][O:14]1>CCO>[O:28]1[C:29]2[C:21]([C:11]([CH3:20])([CH3:10])[CH2:12][C:13]([CH2:15][NH:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])([OH:14])[C:16]([F:18])([F:19])[F:17])=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: C[C@@H](NCC(O)(CC(C)(C)c1cccc2c1OCC2)C(F)(F)F)c1ccccc1
Temperature: 50 °C
Yield: 104.5 %

Procedure:
To an ice-cooled solution of (R)-(+)-1-phenylethylamine (4.43 mL, 34.9 mmol) in anhydrous EtOH (3 mL) was added, dropwise, racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (1 g, 3.49 mmol), which may be prepared according to WO04/063163. The reaction mixture was then heated at 50° C. overnight, cooled to room temperature and evaporated in vacuo. The residue was applied to a 50 g silica SPE cartridge and eluted with 0.5% NH3 in toluene. The appropriate fractions were combined and evaporated in vacuo to give a colourless oil (1.486 g). This oil was subjected to mass-directed autopreparation to give Intermediate 22 (2S isomer, 314 mg), Intermediate 23 (2R isomer, 334 mg) plus a mixed fraction (480 mg). The mixed fraction was re-subjected to mass-directed autopreparation to give further Intermediate 22 (90 mg), Intermediate 23 (125 mg) plus a mixed fraction (160 mg). The fractions containing Intermediate 22 were combined with each other as were the fractions containing Intermediate 23.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([F:16])([F:15])[CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[F:15][C:10]1([F:16])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OC1CCN(Cc2ccccc2)CC1(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: OC1CCNCC1(F)F
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar, a suspension of 1-benzyl-3,3-difluoropiperidin-4-ol (1.73 g, 7.62 mmol) and Pd(OH)2 (20% Pd, 107 mg) in dry EtOH (50 mL) was stirred at rt under a H2 atmospheric pressure until completion of the reaction. The mixture was then filtered, washed with EA/EtOH, and the filtrate concentrated under reduced pressure to give the title compound as a beige solid. LC-MS-conditions 08: tR=0.15 min; [M+H]+=138.27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][N:42]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:29])([F:31])[F:30])[C:9]=4[CH:17]=3)[CH:19]=2)=[O:22])[CH2:41][CH2:40]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ccccc2Cl)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.96 (M+H+); retention time=1.05 minutes.
Reaction SMILES: C([O:4][CH2:5][CH3:6])(=O)C.[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:9]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:6][CH2:5][OH:4])[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: OCCCCCCCCCCCCCc1ccccc1

Procedure:
melting point=34°-36° C. Rf value: 0.24 (ethyl acetate:hexane=1:5); 1H-NMR (CDCl3 /TMS) δ: 1.28 & 1.57 (23H, 2br.s), 2.62 (2H, t, J=7.5 Hz), 3.65 (2H, t, J=6 Hz), 7.23 (5H, m); IR(KBr): 3344, 3259, 2918, 2848, 1468 cm-1 ; MS(EI): 276 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[CH:37][O:36][N:35]=2)=[CH:30][CH:29]=1.ClC1C=CC(S(N(CC2C=CC(C3OC=CN=3)=C(F)C=2F)[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1>>[O:36]1[CH:37]=[N:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][N:11]([C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[CH2:18][OH:19])[S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:29][CH:30]=2)=[N:35]1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ncon2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Yield: 48.1 %

Procedure:
The title compound was synthesized from 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (28 mg, 0.09 mmol), cesium carbonate (36 mg, 0.11 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (26 mg, 0.11 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (20 mg, 48%). MS [M+H]+=462 HRMS [M+H]+ calc'd 462.1254, found 462.1255. Chiral LC: R.T.=16.21 min., 98.0% ee.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH2:20]([O:22]C1C=CC=C2C=1NC=C2)[CH3:21]>>[CH2:20]([O:22][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2)[CH3:21]
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: CCOc1cccc2cc[nH]c12
Product: CCOc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-ethoxy-1H-indole.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To the product from Example 186 (1.3 mg, 0.0023 mole) in H2O (15 mL) and CH3CN (15 mL) was added LiOH (290 mg, 0.0069 mole). The reaction mixture was stirred at room temperature for 1 hour. The pH was lowered to ~2.5 with TFA and the product was isolated by RPHPLC to yield the title compound (1.1 g after lyophilization) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(=S)=S>[Cl:12][C:11]1[C:6]([Cl:5])=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:10]=1[C:22](=[O:23])[CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)Cc2ccccc2)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (395 g.) is added portionwise to a stirred solution of 2,3-dichloroanisole (500 g.) and phenylacetyl chloride (392 ml.) in carbon disulfide (1200 ml.) with cooling to 5°C. in an ice-water bath. After the addition, the reaction mixture is allowed to warm to room temperature, whereupon it forms a solid mass. After standing at 20°-25°C. overnight, the reaction vessel is flushed with nitrogen for 15 minutes, and crushed ice (about 2 kg.) and 12N HCl (400 ml.) are slowly added alternately with cooling in an ice bath. The pale yellow gummy solid that precipitates is collected by suction filtration on a sintered glass funnel to remove water as well as carbon disulfide. The solid product is washed well with water and sucked dry. To remove any persistent carbon disulfide, the product is triturated with hexane and again collected by filtration. Yield after drying in a steam oven at 70°C. for 18 hours is 803.5 g. (98%), mp 125°-127°C. A sample recrystallized from benzene-cyclohexane (2:1) melts at 128°-129°C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([Br:15])[CH:9]=1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].O.CCOC(C)=O>CN(C=O)C.C(Cl)Cl.CCCCCCC>[N:24]([CH2:6][C@@H:7]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([Br:15])[CH:9]=1)=[N+:25]=[N-:26]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cc(F)cc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1cc(F)cc(Br)c1
Temperature: 70 °C
Yield: 83.1 %

Procedure:
(S)-2-((tert-butoxycarbonyl)amino)-2-(3-bromo-5-fluorophenyl)ethyl methanesulfonate (5.92 g, 14.36 mmol) was dissolved in anhydrous DMF (60 mL). Sodium azide (2.80 g, 43.1 mmol) was added, and the reaction heated to 70° C. and maintained at this temperature for 2 h. After cooling, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×80 mL). The combined organics were washed with water (50 mL) and brine (3×50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (AnaLogix, 80 g column, loaded in DCM, 0 to 40% EtOAc in heptane over 30 min) gave (S)-tert-butyl (2-azido-1-(3-bromo-5-fluorophenyl)ethyl)carbamate (4.29 g, 11.94 mmol, 83% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.73 (d, J=8.83 Hz, 1H), 7.48 (t, J=4.26 Hz, 2H), 7.29 (d, J=9.77 Hz, 1H), 4.80 (d, J=8.20 Hz, 1H), 3.47 (d, J=7.88 Hz, 2H), 1.44-1.38 (m, 9H), 1.36 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.I[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].CN1CCCN(C)C1=O.C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH2:21][CH2:24][C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: COC(=O)c1ccccc1CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -60 °C
Yield: 53.8 %

Procedure:
To a suspension of the ketone (10.0 g, 32.6 mmol) of Step 1 and the iodide (2.7 g, 47.7 mmol) of Step 2 in THF was added 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The ketone was dissolved by heating and the resulting solution was cooled to -60° C. A solution of 0.35M lithium diisopropylamide (89.7 mL, 30.9 mmol) was then added dropwise. After the addition was completed, the dry ice bath was removed and the reaction was allowed to warm to +10° C. The reaction was quenched by the addition of 25% aq. NH4OAc and the desired product was extracted with EtOAc, dried over Na2SO4 and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (toluene to 5% EtOAc in toluene) to yield 8 g (55%) of the title product.