Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cc[nH]c2c1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(Cn2ccc3ncc(Br)cc32)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine (400 mg, 2.030 mmol) and sodium hydride (60% in mineral oil) (89 mg, 2.233 mmol) in 4 mL N,N-dimethylformamide was stirred at ambient temperature for 10 minutes and 1-(bromomethyl)-3-fluorobenzene (384 mg, 2.030 mmol) was added. The mixture was heated at 100° C. for 3 hours. The mixture was cooled to ambient temperature, diluted with 100 mL of ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on Analogix IntelliFlash280 eluting with 10 to 70% ethyl acetate/hexanes to give the title compound.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]Cl)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].S(Cl)[Cl:25]>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([S:22][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:4])=[O:5])[CH2:2][Cl:25])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: ClSCl
Reactant: CC(C)(C)c1ccc(SCl)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(SC(CCl)S(=O)(=O)c2ccccc2)cc1
Yield: 52 %

Procedure:
A solution of 25.2 g (0.150 mole) of phenyl vinyl sulfone in 100 ml of carbon tetrachloride and 30 ml of glacial acetic acid was treated with 30.1 g (0.150 mole) of p-t-butylbenzenesulfenyl chloride. There was an exotherm of 2° within 10 minutes. The red color of the sulfenyl chloride disappeared within 24 hours. Evaporation of the solvent left 54 g (98%) of crude product m.p. 58°-69°. Recrystallization from 100 ml of ethyl acetate-petroleum ether (1:1) gave 29 g (52%) of colorless crystals, m.p. 67°-69°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:26]2)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@H](NS(C)(=O)=O)C4)n3)cc2CC1

Procedure:
rel-N-((1S,3R)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and rel-N-[(1S,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (76 mg, 42%). LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.42 (d, 1H, J=8.1 Hz), 7.20 (s, 1H), 7.07 (d, 1H, J=8.1 Hz), 6.82 (s, 1H), 5.07 (d, 1H, J=7.6 Hz), 4.18 (d, 1H, J=7.8 Hz), 4.14-4.02 (m, 1H), 3.56 (t, 2H, J=5.7 Hz), 3.53-3.42 (m, 1H), 3.39 (s, 3H), 2.99-2.88 (m, 4H), 2.95 (s, 3H), 2.81-2.67 (m, 6H), 2.58-2.48 (m, 1H), 2.21-2.11 (m, 2H), 2.00-1.89 (m, 1H), 1.56-1.43 (m, 1H), 1.31-1.11 (m, 3H).
Reaction SMILES: [C:1]([CH2:11][CH2:12]I)([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2].C(O)(=O)C>O.[Zn]>[C:1]([CH2:11][CH3:12])([C:3]([F:4])([F:5])[F:6])([C:7]([F:10])([F:9])[F:8])[F:2]
Reactant: FC(F)(F)C(F)(CCI)C(F)(F)F
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCC(F)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 56 %

Procedure:
A mixture of perfluoroisopropyl iodide (5.6 g, 0.19 mole), ethylene (5 L, 0.2 mole) and benzoyl peroxide (3.2 g) was heated in a 100 mL steel autoclave at 100° C. for 6 hours with stirring. The reaction product contained perfluoroisopropyl,iodide and (CF3)2CFCH2CH2I in a 1:1 ratio. Distillation of the reaction mixture gave (CF3)2CFCH2CH2I (b.p. 118 to 124° C.) in 33% yield. (CF3)2CFCH2CH2I (10 g) was added dropwise to a mixture of zinc dust (5 g) and acetic acid (30 mL). After the exothermic reaction was completed, the reaction mixture was stirred for 2.5 hours at 60° C., diluted with water and distilled to collect a fraction with a b.p. less than 100° C. The distillate was separated from water, dried over calcium chloride, and redistilled to give (CF3)2CFCH2CH3 (b.p. 39 to 42° C., 56% yield). The 1H and 19F NMR were in accord with the assigned structure.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:23]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=[CH:11]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCBr
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Reaction time: 1 h

Procedure:
To a solution of 10 g of adenosine in 400 ml of dimethyl formamide was added 2.25 g of 60% sodium hydride (oil). After one hour, 8.5 ml of 1-bromononane was added. The reaction was stirred for 16 hours. Ice was added and the solution evaporated in vacuo. Water and ethyl acetate were added. The organic phase was separated, dried, and evaporated in vacuo to give a white solid, which was recrystallized from ethanol to yield 4.8 g of the title compound, m.p. 143-144° C. analysis for: C19H31N5O4. Calculated: C, 57.99; H, 7.94; N, 1779. Found: C, 58.13; H, 7.93; N, 17.83.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17]([NH2:19])=[S:18])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[CH3:20]N(C)C=O.CI.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17](=[NH:19])[S:18][CH3:20])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: NC(=S)NCc1ccc2c(c1)Nc1nccnc1S2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CI
Product: CSC(=N)NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 g of N-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)thiourea in acetone (10 ml)/N,N-dimethylformamide (10 ml) was added 1.0 ml of methyl iodide and the resulting mixture was stirred at room temperature for 0.5 hour. Next, the reaction mixture was distributed into an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was extracted and washed with water. After distilling off the solvent under reduced pressure, the crystals thus precipitated were taken up by filtration and washed with ethyl acetate to thereby give 0.900 g of the title compound as yellow crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4.30 g (11.2 mmol) of t-butyl 4-(4-methoxycarbonylbenzenesulfonyl)-piperazine-1-carboxylate was stirred in 15 ml of methanol and 15 ml of THF. 17 ml of 1 N aqueous sodium hydroxide solution was added to the resultant mixture, and they were stirred at 60° C. overnight. The reaction liquid was evaporated under reduced pressure, and 1 N hydrochloric acid was added to the residue. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH:19][C:20]1[CH:72]=[C:23]2[N:24]=[C:25]([CH3:71])[C:26]([C@H:60]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[C:61]([O:63][CH2:64][CH3:65])=[O:62])=[C:27]([N:28]3[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH3:41])([CH3:34])[CH2:30][CH2:29]3)[N:22]2[N:21]=1)C1C=CC=CC=1.[H][H].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(O)C.C1COCC1.[Pd]>[C:67]([O:66][C@@H:60]([C:26]1[C:25]([CH3:71])=[N:24][C:23]2[N:22]([N:21]=[C:20]([CH2:19][CH2:18][CH2:17][C:10]3[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=3[OH:8])[CH:72]=2)[C:27]=1[N:28]1[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([OH:42])[CH3:41])([CH3:34])[CH2:30][CH2:29]1)[C:61]([O:63][CH2:64][CH3:65])=[O:62])([CH3:68])([CH3:69])[CH3:70]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)c(F)cc3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3cc(F)c(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Yield: 66.3 %

Procedure:
To a solution of (S)-ethyl 2-(2-(3-(2-(benzyloxy)-4,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol) in ethanol (4 mL) was added 10% Pd—C (60.6 mg, 0.057 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vacuum. The residue was then treated with 1M TBAF (0.949 mL, 0.949 mmol) in THF (4 mL) for 16 h. Mixture was then concentrated and purified by Biotage (5-70% EtOAc/hexane) to afford to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(4,5-difluoro-2-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (85 mg, 0.126 mmol, 66.4% yield) as thick paste. 1H NMR (500 MHz, CDCl3) 6.96-6.89 (m, 1H), 6.68 (dd, J=11.7, 7.1 Hz, 1H), 6.34 (s, 1H), 5.90 (br. s., 1H), 4.31-4.09 (m, 2H), 3.93-3.81 (m, 1H), 3.44 (br. s., 2H), 2.88-2.70 (m, 4H), 2.63 (s, 4H), 2.12-1.94 (m, 4H), 1.90 (br. s., 2H), 1.57-1.42 (m, 6H), 1.41-1.31 (m, 3H), 1.27-1.18 (m, 18H). LCMS (M+H)=675.6.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2F)[CH:4]=1.[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][OH:32])[CH2:28][O:27]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][O:32][CH2:2][C:3]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[N:5]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:4]=2)[CH2:28][O:27]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: COC(=O)c1cc2c(CCl)cn(Cc3ccc(F)cc3F)c2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(COC[C@@H]3COC(C)(C)O3)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 40 °C
Reaction time: 24 h
Yield: 82.9 %

Procedure:
To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (7.43 mL, 0.197M in CH2Cl2, 1.4645 mmol)) [prepared as described in step 2 of example 40] in anhydrous DMF (10 mL) was added (R)-(−)-2,2-Dimethyl-1,3-dioxolane-4-methanol (7.32 mmol, 0.91 mL, 5 eq.) followed by i-Pr2NEt (5.86 mmol, 1.02 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was diluted with EtOAc (40 mL) and washed with water (4×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the target compound, which was purified by chromatography on a column of silica gel (40 mm OD, 150 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc-MeOH 70:30:2 v/v, 2.0 L, 25 mL fractions) using the flash technique. Fractions were combined to afford 0.520 g (83%) of methyl 3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}methyl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT-2.98 min, m/e=429.1 (M+H+, base). 1H-NMR (300 MHz, CDCl3): o=1.38 (s, 3H), 1.42 (s, 3H), 3.53 (m, 2H), 3.72 (m, 1H), 4.04 (m, 4H), 4.27 (m, 1H), 4.78 (q, 2H), 5.38 (s, 2H), 7.05 (t, 2H), 7.17 (m, 2H), 7.32 (s, 1H), 8.56 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.Cl>>[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(C(=O)OC)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
Dioxane (100 mL) was purged with nitrogen gas for 10 min. Phenanthrolene (1.0 g) and copper (1) iodide (1.0 g) were added to the dioxane, the suspension was allowed to stir under a nitrogen atmosphere for 5 min, and then cesium carbonate (18.72 g, 57.45 mmol), dimethyl malonate (5.46 g, 50.6 mmol), and 1-iodo-3-(trifluoromethyl)benzene (12.5 g, 46.0 mmol) were added. The reaction mixture was heated to reflux for 18 h and then cooled to room temperature. Aqueous 1 N HCl was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and filtered. Celite® diatomaceous filter aid (5 g) was added to the filtrate, and the resulting suspension was concentrated under reduced pressure at 50° C. to yield a solid consisting of the crude product adsorbed onto Celite®. This solid was purified by silica gel chromatography eluting with a gradient of 100% hexanes to 25% ethyl acetate in hexanes to yield 7.36 g (58.0%) of the title product.
Reaction SMILES: FC(F)(F)C1C=C([C@H]2OC(=O)N(C[C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46]C)=[O:45])=[CH:40][C:39]=4C)[CH:33]=[CH:34][C:35]=3OC)[C@H]2C)C=C(C(F)(F)F)C=1.[OH-].[K+].C(O)C>C(O)(=O)C>[F:27][C:26]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([C:30]2[CH:31]=[C:32]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][CH:39]=3)[CH:33]=[CH:34][CH:35]=2)=[CH:20][CH:25]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (20 mg, 0.0276 mmol), aqueous potassium hydroxide (300 μL, 3M, 0.90 mmol) and ethanol (2 mL) were stirred at 20° C. for 2 hours and 20 minutes to complete the hydrolysis. The reaction mixture was acidified by acetic acid. The mixture was purified by preparative TLC on silica gel, (eluted with AcOH/EtOAc/hexanes=5/25/70, v/v) to afford 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl)-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=711.17; found=712.10 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR (CDCl3, 500 MHz) δ 7.99 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.85 (d, J=5 Hz, 1H), 7.72-7.68 (m, 1.5H), 7.67-7.60 (m, 2.5H), 7.47-7.36 (m, 2H), 7.32 (d, J=8.0 Hz, 0.5H), 7.28 (d, J=8.0 Hz, 0.5H), 7.15 (s, 1H), 7.08 (d, J=8.5, 7.0 Hz, 1H), 5.58 (d, J=8.0 Hz, 0.5H), 5.29 (d, J=6.5 Hz, 0.5H), 4.97 (d, J=15.5 Hz, 0.5H), 4.94 (d, J=14 Hz, 0.5H), 4.16 (d, J=16 Hz, 0.5H), 3.96 (d, J=15.5 Hz, 0.5H), 3.87 (s, 3H), 3.83-3.74 (m, 1H), 2.38, 2.33 (s, 3H), 0.55 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=7 Hz, 1.5H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]#[N:15])=O)(C)(C)C.O.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(#N)C>[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:14]#[N:15])[CH2:10]1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([O-:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C#N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: N#C[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
6.40 g (30 mmol) of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-pyrrolidine-2-carbonitrile was dissolved in 100 ml of acetonitrile and 8.56 g (45 mmol) of 4-methylbenzenesulphonic acid monohydrate was added to the solution. The mixture was stirred at room temperature for 24 hours and was evaporated under reduced pressure. 500 ml of diethyl ether was added to the resulting brown oil. It was stirred 10 minutes and kept in the refrigerator for a night. The resulting white crystalline material was filtered off and washed with diethyl ether. 6.31 g (73%) of the above product are obtained. M.p.: 110-113° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])#[N:2].[CH3:12][Li]>C1COCC1>[F:11][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:10][C:7]=1[CH:8]([OH:9])[CH3:12]
Reactant: N#Cc1ccc(F)c(C=O)c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1cc(C#N)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyano-2-fluorobenzaldehyde (1.50 g, 10.06 mmol) in THF (15 mL) cooled to 0° C. was added methyllithium (7.90 mL, 11.06 mmol). The mixture was stirred at room temperature for 2 h and quenched by the addition of saturated NH4Cl (10 mL). The mixture was partitioned between ethyl acetate (50 mL) and water (20 mL), the organic was washed with water (20 mL), dried over magnesium sulfate and concentrated in vacuo to provide a residue. Purification via flash column chromatography (30×150 mm column; elution with EtOAc: Hex, 1:2) afforded pure compound:
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[C:12]([N:14]=[C:15]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([NH:26][CH2:27][CH3:28])[CH:25]=1)OCCC)#[N:13]>CN(C=O)C>[C:12]([NH:14][C:15]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([NH:26][CH2:27][CH3:28])[CH:25]=1)=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])#[N:13]
Reactant: NCCO[N+](=O)[O-]
Reactant: CCCOC(=NC#N)c1cncc(NCC)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1cncc(C(=NCCO[N+](=O)[O-])NC#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (659 mg, 4.62 mmol) in DMF (1 ml) was added sodium methoxide (227 mg, 4.20 mmol) followed by a solution of propyl N-cyano-5-ethylamino-3-pyridinecarboximidate (195 mg, 0.84 mmol) in DMF (1 ml) described in Example 10 of Experimental Example 1, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated under reduced pressure. The residue was suspended in water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under redeuced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (208 mg, yield 89%) as colorless crystals.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2.O>CN(C=O)C>[Br:8][C:18]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:21])[C:10]=1[CH3:9]
Reactant: Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)c2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
25 g of NBS in 75 ml of DMF are added to a solution of 34.8 g of 2-methyl-1-(benzenesulfonyl)-7-azaindole in 75 ml of DMF. The mixture is stirred at room temperature for 1 h, poured into water, the precipitate which has precipitated out is separated off, washed with water and dried, giving 42 g of 3-bromo-2-methyl-1-(benzenesulfonyl)-7-azaindole, M˜351.22 g/mol, M+H found 351.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[CH3:16][C:17]1[CH:28]=[CH:27][C:20]2[NH:21]C(=O)[O:23][C:24](=O)[C:19]=2[CH:18]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[NH:21][C:20]2[C:19]([C:24]=1[OH:23])=[CH:18][C:17]([CH3:16])=[CH:28][CH:27]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(C)ccc2[nH]c1=O
Temperature: 90 °C
Yield: 36.6 %

Procedure:
Neat diethyl malonate (18.05 g, 112.7 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 4.96 mg, 124 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then the mixture was heated to 90° C. for 30 min. then cooled to room temperature. A solution of Compound 11 (22 g, 124 mmol) in dimethylacetamide was added slowly and the solution heated overnight at 110° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to yield 10.2 g (36%) of white solids. M.P. 242° C. 1H NMR (DMSO-d6): δ 1.30 (t, J=7.2 Hz, 3H), 2.35 (s, 3H), 4.34 (q, J=7.2 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.46 (dd, J=1.6, 8.4 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 11.35 (s, 1H), 13.03 (s, 1H). EIMS m/z 248 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(Cc2ccc(I)cc2)c(C)c1CC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 60.2 %

Procedure:
To a stirred solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert.-butyl ester (10 g) in dimethylformamid (50 ml) at room temperature is added 1-bromomethyl-4-iodobenzene (15.5 g) and potassium carbonate (8.0 g). After 15 h of stirring, water is added and the reaction mixture is extracted twice with ethyl acetate. The organic layer is washed several times with water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (4:1 to 3:2 cyclohexane:ethyl acetate) to yield 1-(4-iodobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (12.2 g). [M+H]=427; HPLC retention time 1.57 min (Method E).