Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.[N:41]1([CH2:47][CH2:48][NH2:49])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>ClCCl>[C:29]1([CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:27][NH:26][C:9]2[N:8]=[C:7]([CH2:6][NH:49][CH2:48][CH2:47][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCCN1CCCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (150 mg, 0.26 mmol) (Preparation 25) was dissolved in stirred dichloromethane (5 ml) and 2-(1-piperidinyl)ethylamine (0.2 ml, 1.3 mmol) added. The reaction mixture was stirred for 24 hr at room temperature. The solvent was removed from the reaction mixture under reduced pressure and the residue partitioned between dichloromethane (100 ml) and water (50 ml). The organic layer was separated and washed with water (50 ml), followed by removal of solvent under reduced pressure and purification of the residue by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (95:5) increasing in polarity to dichloromethane:methanol:ammonia (90:10:1). This gave title compound (40 mg) as a gum. MS: 603 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH:41]=[CH:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCn1c(=O)ccc2ccc(CCl)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCn1c(=O)ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.262 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.148 g of 7-chloromethyl-1-(3-methoxypropyl)-1H-quinolin-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.28 (2:1 EtOAc-heptane); Rt=5.91.
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:14]([O-])([OH:16])=[O:15].[N+](C1C=CC=CC=1)([O-])=O>C(Cl)(Cl)Cl>[N+:14]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:13])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A 100g portion of soluble anhydrite was added to a solution of 32.9g toluene in 100 ml chloroform. Then a 22.6g portion of anhydrous nitric acid was added to the dispersion over a 30-minute period. Stirring at 25°C was continued for an additional 2 1/2 hour period. Nitrobenzene was added before the last half hour period and was used as the internal standard. Gas chromatographic analysis showed a 93.2% yield of nitrotoluene with the proportion being 49.1% ortho, 2.1% meta, and 48.8% para.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:28][CH:29]([CH3:32])[CH:30]=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:28][CH:29]([CH3:32])[CH3:30])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CC(C)C=O
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 150 °C
Yield: 37.6 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (24 mg, 0.06 mmol, 1.0 equiv; Example 122) in anhydrous DMF (1 mL) was added 2-methyl-propionaldehyde (17.3 mg, 22 μL, 0.24 mmol, 4.0 equiv; [CAS RN 78-84-2]), dibutyltin dichloride (1.8 mg, 0.006 mmol, 0.1 equiv; [CAS RN 683-18-1]) and phenylsilane (13.0 mg, 15 μL, 0.12 mmol, 2.0 equiv; [CAS RN 694-53-1]). The reaction mixture was heated by microwave irradiation to 150° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 10.3 mg (38%) of the title compound as a light yellow powder. MS (ISP): 456.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:18])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13][C:12]3=[NH:17])=[CH:10][C:4]=2[O:3]1.[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>C(#N)C.C(Cl)Cl>[F:18][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13]/[C:12]/3=[N:17]\[C:19]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[O:20])=[CH:10][C:4]=2[O:3]1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)C(=N)S1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: ClCCl
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)n2ccnc2)S1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-methylenethiazolidin-2-imine (Example 115, 0.2 g, 0.74 mmol) and carbonyldiimidazole (0.14 g, 0.92 mmol) in dry acetonitrile (5 mL) was stirred at 70° C. for 16 hours. After cooling down, the mixture was diluted with 150 mL of CH2Cl2 and washed successively with saturated sodium bicarbonate (75 mL), water (75 mL) and brine (75 mL). The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed over silica using 100% CH2Cl2 to CH2Cl2:MeOH 95:5 as mobile phase to give the titled compound. 1H NMR (CD3OD) δ ppm 5.00 (2H), 5.40 (1H), 5.50 (1H), 6.90 (1H), 7.35 (2H), 7.44 (1H), 7.50 (1H), 8.05 (1H); MS (ESI) m/z 365(M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([B-](F)(F)F)=[CH2:12].[K+].C(N(CC)CC)C>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C=C[B-](F)(F)F
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1ccc([N+](=O)[O-])cn1
Temperature: 120 °C

Procedure:
To a 20 ml, microwave tube was added 2-bromo-5-nitropyridine (0.20 g, 0.98 mmol), potassium vinyltrifluoroborate (145 mg, 1.1 mmol), PdCl2(dppf)-CH2Cl2 complex (40 mg, 0.049 mmol), and a stir bar. The tube was sealed, and ethanol (6 mL) and triethylamine (0.41 mL, 3.0 mmol) was added via syringe. The mixture was purged three times with nitrogen and then heated to 120° C. for 30 minutes. LC at that point showed mostly product. The reaction was diluted with DCM, adsorbed onto silica gel, and purified by silica gel flash chromatography (Hexane:EtOAc). LC-MS (IE, m/z): 151 [M+1]+.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][CH:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25]>O>[Si:10]([O:19][CH:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NCCC1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCNC1=O
Reaction time: 1 h
Yield: 11.4 %

Procedure:
In an ice bath, 300 mg of imidazole and 497 mg of tert-butyldimethylchlorosilane were added to a dimethylformamide (2 ml) solution of 255 mg of 3-hydroxypyrrolidin-2-one, and stirred for 1 hour. Water was added to the reaction liquid, extracted with ethyl acetate, and washed with hydrochloric acid (1 N) and saturated saline water. The organic layer was dried to obtain 370 mg of a crude product. 208 g of the product was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 2/8) to obtain 62 mg of the entitled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.[S].C>C1C2C(CCCC2)CCC1>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1
Reactant: Cc1ccc(C2=CCCn3c2cnc3C)cc1
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Product: Cc1ccc(-c2cccn3c(C)ncc23)cc1

Procedure:
Combine 20 g (89.2 mmol) of the product of Example VIII with 5 g (0.16 mol) of sulfur in 250 ml of decalin and heat to 180°-190° C. under nitrogen for 7 hr. Extract the reaction with 2 liters of 2N sulfuric acid solution. Charcoal treat the extract and neutralize with potassium carbonate. Extract the aqueous portion with 800 ml of ethyl acetate, dry over magnesium sulfate, treat with charcoal, and remove the solvents under vacuum. Crystallize from ether to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([C:9](Cl)=[O:10])[O:5][C:6]=1[CH2:7][Cl:8].[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([C:9](=[O:10])[N:14]([CH3:15])[CH3:13])[O:5][C:6]=1[CH2:7][Cl:8]
Reactant: O=C(Cl)n1oc(CCl)c(Cl)c1=O
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)C(=O)n1oc(CCl)c(Cl)c1=O
Temperature: 25 °C
Yield: 62.5 %

Procedure:
254 mg of 4-chloro-2-chlorocarbonyl-5-chloromethyl-4-isoxazolin-3-one were dissolved in 5 ml of benzene, and then a solution of 48 mg of dimethylamine and 107 mg of triethylamine in 2 ml of benzene were added, with stirring, at room temperature. The mixture was stirred for a further 10 minutes, after which it was washed, in turn, with 2 ml of 0.1N sulphuric acid and water (twice, 5 ml each time). The organic phase was dried over anhydrous sodium sulphate and the solvent was distilled off. The residue was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of benzene and acetone. The solvent was distilled from the eluate and the residue was recrystallized from diisopropyl ether, to give 159 mg (yield 62.8%) of the title compound in the form of crystals, melting at 107°-108° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:6]
Reactant: Cc1cc(F)cc(C(=O)O)c1Br
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)cc(C(=O)N2CCCC2)c1Br
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-5-fluoro-3-methylbenzoic acid (140 mg, 0.60 mmol), pyrrolidine (99 μL, 1.20 mmol) and Hunig's base (210 μL, 1.20 mmol) in DMF (2 mL) at RT was added HATU (457 mg, 1.20 mmol) and the reaction stirred at this temp overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-60% Hex/EtOAC) to yield (2-bromo-5-fluoro-3-methylphenyl)(pyrrolidin-1-yl)methanone as a clear oil.
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][CH3:5].FC(F)(F)S(O[C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH:25]3[CH2:30][CH2:29][Si:28]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(C4C=CC=CC=4)[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(=O)=O>>[CH2:37]([Si@H:28]1[CH2:27][CH2:26][C@H:25]([C@H:22]2[CH2:21][CH2:20][C@H:19]([C:16]3[CH:15]=[CH:14][C:13]([CH2:2][C@@H:3]([CH3:6])[CH2:4][CH3:5])=[CH:18][CH:17]=3)[CH2:24][CH2:23]2)[CH2:30][CH2:29]1)[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CC[C@H](C)CBr
Reactant: CCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CC2)CC1
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C[C@@H](C)CC)cc3)CC2)CC1

Procedure:
The general procedure of Example 18 was repeated using (S)-1-bromo-2-methylbutane and (4-(trans-4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)cyclohexyl)phenyl) trifluoromethanesulfonate, thereby obtaining the intended compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:6][C:5]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1.[N+:13]([O-])([O-:15])=[O:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[O:12]=[S:2]1(=[O:1])[CH2:6][C:5]2[C:7]([Cl:11])=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:4]=2[NH:3]1
Reactant: O=S1(=O)Cc2c(Cl)cccc2N1
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)c2c1NS(=O)(=O)C2
Reaction time: 24 h
Yield: 21.9 %

Procedure:
1 ,3-dihydro-2,2-dioxo-4-chloro-2,1-benzisothiazole (1.5 mg, 0.92 mmol) was dissolved in methylene chloride (30 ml) followed by the addition of sodium nitrate (86 mg, 1.01 mmol). The addition of sulfuric acid (0.18 ml/3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture is allowed to stir. After about 24 hours, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (50% Ethyl acetate/Hexane) gave the desired product(50 mg, 21%). EI-MS m/z 263.5 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>C(O)C.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CC=C(c2ccc(N)cc2)CC1
Temperature: 80 °C

Procedure:
tert-Butyl 4-(4-nitrophenyl)cyclohex-3-enylcarbamate (2.55 g, 8.01 mmol) was suspended in ethanol (30 ml) followed by addition of sodium sulfide, nonahydrate (10.37 ml, 80 mmol) dissolved in water (30 ml). The mixture was heated to 80° C. for 1.5 h and extracted with dichloromethane; the organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]2[CH2:10][C@H:8]2[NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(O)cc1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a solution of tert-butyl-(trans)-2-(4-hydroxyphenyl)cyclopropylcarbamate (Intermediate N, 5 g, 20.0 mmol), K2CO3 (6.8 g, 50.0 mmol) in dry DMF (10 vols) was added 3-Bromo benzyl bromide (5 g, 20.0 mmol) and stirred at RT for 16 h. After completion, the reaction mixture was poured into ice water (150 mL) and extracted with EtOAc (2×75 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography to give (tert-butyl(trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropylcarbamate (5.2 g, 62%) as a white solid. The crude was carried to next step without further purification.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[NH2:2].[C:5]1([S:11]([N:14]2[CH2:19][CH2:18][CH2:17]N[C:15]2=[O:20])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(Cl)=O>>[Cl:4][C:1]([N:2]1[CH2:17][CH2:18][CH2:19][N:14]([S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:13])=[O:12])[C:15]1=[O:20])=[O:3]
Reactant: O=C1NCCCN1S(=O)(=O)c1ccccc1
Reactant: NC(=O)Cl
Agent: O=C(Cl)Cl
Product: O=C(Cl)N1CCCN(S(=O)(=O)c2ccccc2)C1=O

Procedure:
This carbamic acid chloride was produced as described in Example 27 A from 6 parts by weight of 1-phenylsulfonyl-1,3-diaza-cyclohexane-2-one and 5 parts by weight of phosgene. The product was recrystallized from acetone/petrolether.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=1>C(#N)C1C=CC=CC=1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: C#CCCCCCC
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: CCCCCCC#Cc1ccc(F)cc1
Reaction time: 45 h
Yield: 67 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 4-fluorobenzonitrile (0.242 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 45 h at 65° C. showed the presence of 1.34 mmol (67% yield) of 1-fluoro-4-(1-octynyl)benzene and no remaining 4-fluorobenzonitrile in the reaction mixture.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][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:35]=[C:34]([S:36][CH3:37])[CH:33]=[CH:32][C:31]=3[O:38][CH3:39])[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:51])C=1>C(Cl)Cl.CCOC(C)=O>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([S:36]([CH3:37])=[O:51])[CH:33]=[CH:32][C:31]=3[O:38][CH3:39])[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(SC)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(S(C)=O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: -20 °C

Procedure:
To a −60° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (example 124) (32.5 mg, 0.0522 mmol) in CH2Cl2 (5 mL) was added m-CPBA (14.6 mg, 77% purity, 0.0652 mmol). The reaction was warmed slowly to −20° C. and then diluted with EtOAc (35 mL), washed with aq. NaHSO3, brine, saturated NaHCO3, and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on slica gel (20 to 100% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylsulfinyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.10 (75% EtOAc/hexanes). LCMS=640.1 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.10-7.86 (m, 9H), 4.87-5.59 (m, 2H), 3.56-4.14 (m, 5H), 2.79 (s), 2.75 (s), 2.73 (s), 0.61 (d, J=6.5 Hz), 0.57 (d, J=6.4 Hz), 0.46 (d, J=6.4 Hz), 0.43 (d, J=6.5 Hz).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]([C:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[N:25]([CH3:31])[N:24]=1)([CH3:22])([CH3:21])[CH3:20]>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:28]([C:26]2[N:25]([CH3:31])[N:24]=[C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:27]=2)=[O:29])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 4 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
4-Trifluoromethylaniline (19.39 g, 120.3 mmol) and triethylamine (13.4 g ,132 mmol) was added to 400 ml of anhydrous dichloromethane in a 1-liter round bottomed flask. This stirred solution was cooled to 4° C. using an ice water bath. 3-tert-Butyl-1-methyl-1H-pyrazole-5-carbonyl chloride 26.57 g (132 mmol) was added drop wise to this cooled solution. The reaction mixture was allowed to warm to room temperature and then was stirred at ambient temperature for 18 hours. The reaction mixture was then placed in an extraction funnel and then extracted first with 400 ml of 1N HCl and subsequently with 300 ml of water. The extraction with water was repeated. The organic layer was then stirred in a 2 liter Erlenmeyer flask and 500 ml of hexane added. The mixture was stirred for 2 hours and provided a precipitate which was collected by filtration on a Buchner funnel. The white solid was then dried in vacuum oven at 40° C. for 24 hours to give 20.63 g of pure product (52% yield). 1H NMR (400 MHz CDCl3) δ: 7.85 (s 1H) 7.74 (s 2H) 7.62 (d 1H) 6.53 (s 1H) 4.16 (s 3H) 1.33 (s 9H). MS: m/z 324.2 (M−1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCN(c1c(C=O)cccc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of 1.0 g (2.865 mmol) of the product of Example 321 in 7.5 mL of DMF was added 0.143 g (3.582 mmol) of 60% sodium hydride followed by 0.74 mL (4.30 mmol) of n-octyl bromide. The reaction was stirred overnight at room temperature then diluted with ether, washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with EtOAc/hexanes (1:3) to provide 0.592 g (49%) of the product as a white solid. Electrospray Mass Spec: 462.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH3:9])[C:4]([O:6]CC)=O)#[N:2].CC(C)C(=O)[CH2:14][C:15]#[N:16]>>[CH3:10][C:3]([CH3:9])([C:4](=[O:6])[CH2:14][C:15]#[N:16])[C:1]#[N:2]
Reactant: CCOC(=O)C(C)(C)C#N
Reactant: CC(C)C(=O)CC#N
Product: CC(C)(C#N)C(=O)CC#N
Yield: 48 %

Procedure:
Prepared from ethyl 2-cyano-2-methylpropanoate (3 g, 21.25 mmol) according to the method described for 4-methyl-3-oxopentanenitrile in Example 122A Step 1, to afford 2,2-dimethyl-3-oxopentanedinitrile as a yellow oil (1.40 g, 48%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.98 (s, 2H), 1.60 (s, 6H).