Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:13]1[CH:14]=[N:15][CH:16]=[C:17](Cl)[C:18]=1[CH2:19][CH:20]([C:22]1[C:27]2[CH2:28][C:29](C)(C)[O:30][C:26]=2[C:25]([O:33][CH3:34])=[CH:24][CH:23]=1)O>CO>[CH3:34][O:33][C:25]1[C:26]2[O:30][CH2:29][CH:28]([CH3:1])[C:27]=2[C:22]([CH2:20][CH2:19][C:18]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Solvent: CO
Product: COc1ccc(CCc2ccncc2)c2c1OCC2C
Yield: 68.4 %

Procedure:
p-Toluenesulfonic acid (1.0 g) was added to a solution (50 ml) of Compound 45a (2.0 g) obtained in Step A of Example 45 in methanol at room temperature, followed by heating under reflux. The reaction solution was cooled and then the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, followed by extraction with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give Compound 57 (1.0 g, 48.2%) as a pale-yellow oily substance.
Reaction SMILES: Br[CH2:2]/[C:3](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[C:14]([OH:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([S:21][CH2:2]/[C:3](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5])(=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC(=S)c1ccccc1
Reactant: O=C(O)/C(=C/c1ccccc1)CBr
Product: O=C(O)/C(=C/c1ccccc1)CSC(=O)c1ccccc1
Yield: 67 %

Procedure:
The (Z)-2-bromomethyl-3-phenylpropenoic acid described in Example 1 (step A) is reacted with thiobenzoic acid according to the experimental procedure described in Example 1 (step B). Yield=67% (recrystallized in ether) m.p. 160° C. 1H NMR CDCl3 /TMS): 8.15 to 7.80 (m, 3H); 7.70 to 7.20 (m, 8H); 4.20 (s, 2H)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:6]1=2.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:18][C:16]2[CH:15]=[CH:14][C:7]3[C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]=3[CH:17]=2)=[N:21][CH:22]=1
Reactant: COCCN1CCCC(C)(C)c2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)CCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 1-(2-Methoxy-ethyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a light yellow solid (23%). LCMS: m/z=527.49 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.56 (bs, 1H), 8.07 (s, 1H), 7.18 (m, 6H), 6.86 (bs, 1H), 6.74 (d, 1H, J=8.3 Hz), 3.47 (m, 2H), 3.40 (s, 3H), 2.93 (d, 3H, J=4.6 Hz), 2.73 (m, 4H), 1.72 (m, 2H), 1.53 (m, 2H), 1.34 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:22]1([CH2:28][C@@H:29]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[NH2:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:20][O:19][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:14]([CH3:18])[C:15](=[O:17])[NH:30][C@H:29]([C:31]1[S:32][CH:33]=[CH:34][N:35]=1)[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: N[C@@H](Cc1ccccc1)c1nccs1
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@H]([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of #11 (280 mg, 0.974 mmol, 1 eq.) and #15 (460 mg, 1.44 mmol, 1.48 eq.) in N,N-dimethylformamide (3 mL, 0.32 M) at 0° C. was added diethylphosphoryl cyanide (DEPC) (93% purity, 212 μL, 1.30 mmol, 1.34 eq.), followed by triethylamine (367 μL, 2.63 mmol, 2.7 eq.). After 2 hours at 0° C., the reaction mixture was warmed to room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate:toluene (2:1, 30 mL) and was washed successively with 1 M aqueous sodium bisulfate solution (35 mL) and 50% saturated aqueous sodium bicarbonate solution (4×25 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (12% to 100% ethyl acetate in heptane) to give #16 as a light amber oil (374 mg, 81%). LC-MS: m/z 474.4 [M+H+], 374.4 [(M−2-methylprop-1-ene)+H+] retention time=3.63 minutes; 1H NMR (400 MHz, DMSO-d6), characteristic signals: δ 8.66 (d, J=8.5 Hz, 1H), 7.78 (d, J=3.3 Hz, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.21-7.31 (m, 4H), 7.14-7.20 (m, 1H), 5.40 (ddd, J=11.4, 8.5, 4.0 Hz, 1H), 3.23 (br s, 3H), 2.18 (dq, J=9.7, 6.7 Hz, 1H), 1.06 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=[C:8]([CH3:20])[CH:7]=1.[O:21]1CCOCC1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=[C:8]([CH:20]=[O:21])[CH:7]=1
Reactant: COCCOc1cc(C)nc2c1ccc1cccnc12
Reactant: C1COCCO1
Solvent: O
Product: COCCOc1cc(C=O)nc2c1ccc1cccnc12
Yield: 53 %

Procedure:
A solution of SeO2 (1.19 g, 10.8 mmol) in a mixture of dioxane (50 mL) and water (2 mL) was heated to reflux in a two-neck 250 mL round-bottomed flask. A solution of 4-(2-methoxy-ethoxy)-2-methyl-[1,10]phenanthroline (1.16 g, 4.3 mmol) in hot dioxane (30 mL) was added through an addition funnel over a period of 10 minutes and the reaction mixture was refluxed for 30 minutes. The solvent was evaporated in vacuo and the residue was treated with methylene chloride (200 mL) and saturated NaHCO3 (200 mL). The aqueous layer was extracted several times with methylene chloride (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (SiO2, MeOH/DCM, 1:40 to 1:20) to afford the pure product as a pale solid (0.65 g, 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:26]([O-:28])=[O:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O/[N:30]=[C:31](\[NH2:42])/[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[C:38]([F:41])([F:40])[F:39]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:26]([O-:28])=[O:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]([O:14]/[N:30]=[C:31](\[NH2:42])/[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[C:38]([F:41])([F:39])[F:40])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: N/C(=N\O)c1cccnc1C(F)(F)F
Solvent: CN(C)C=O
Product: N/C(=N\OC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1)c1cccnc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a stirred solution of 3,4-bis(benzyloxy)-5-nitrobenzoic acid (0.759 g, 2 mmol) in dimethylformamide (10 mL) at room temperature was added 1,1-carbonyldiimidazole (0.34 g, 2.10 mmol) in one portion. The resulting yellow mixture was allowed to stir for ninety minutes whereupon (Z)—N′-hydroxy-2-(trifluoromethyl)nicotinimidamide (0.41 g, 2 mmol) was added in one portion. The resulting mixture was stifled at room temperature for two hours and then poured onto water (100 mL). The resulting precipitate was filtered off, washed with water and dried. After recrystallisation from dichloromethane/isopropanol, (Z)—N′-(3,4-bis(benzyloxy)-5-nitrobenzoyloxy)-2-(trifluoromethyl)nicotinimidamide was obtained as a light yellow solid, 0.88 g (78%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.Cl[CH2:34][C:35]1[N:36]=[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:38][C:39]=1[CH3:40].O>CN(C)C=O>[CH3:40][C:39]1[O:38][C:37]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[N:36][C:35]=1[CH2:34][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4nc(-c5ccccc5)oc4C)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Sodium hydride (60%, oily, 36.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (360 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (207 mg) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (304 mg, yield: 59%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[C:21]=3[CH3:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:41])=[C:22]([CH3:27])[C:21]=3[CH3:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc(N)c(C)c3C)ccnc2cc1OCc1ccccc1
Reactant: COc1ccccc1N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(OC)cc23)c(C)c1C
Yield: 47.4 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylaniline (260 mg) was dissolved in N,N-dimethylformamide (5 ml), and 2-methoxyphenyl isocyanate (116 mg) was then added to the solution. The mixture was allowed to react at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/acetone (211) to give 169 mg (yield 47%) of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:7][C:6]([CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([O:10][C:9](=[O:11])[CH:8]([C:6]1[S:7][C:3]([CH3:2])=[CH:4][CH:5]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Cc1ccc(C(Nc2ccccc2)C(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(C(Nc2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
To a solution of (5-methyl-thiophen-2-yl)-phenylamino-acetic acid hydrochloride (I268) (220 mg, 0.77 mmol), (R)-quinuclidin-3-ol (338 mg, 2.66 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (180 mg, 1.33 mmol) in dry THF (15 mL), is added PS-DCC (1.0 g, 1.330 mmol) and the mixture is shaken at RT for 15 hours. Then (R)-quinuclidin-3-01 (49.3 mg, 0.39 mmol) and PS-DCC (291 mg, 0.39 mmol) are added again and the reaction is shaken at RT for other 3 hours. The resin is filtered off and washed several time with EtOAc. The solvent is concentrated and washed with aq. NaHCO3, water and brine. The organic phase is dried over Na2SO4 and evaporated to obtain the title compound as a brown oil (175 mg, 63% yield).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9])C.[OH-].[Na+].C(Cl)(=O)C([Cl:18])=O>C(COC)OC>[F:11][C:5]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([Cl:18])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCC(C)(F)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CCCCC(C)(F)C(=O)Cl
Reaction time: 3.5 h
Yield: 76 %

Procedure:
To a solution of 71 g of 2-fluoro-2-methyl hexanoic acid ethyl ester in 500 ml of glyme was added 1.1 eq. of 1 N sodium hydroxide solution. After stirring for 3.5 hr., the glyme was removed under vacuum, the residue extracted with ether and the aqueous layer acidified. The mixture was then extracted with pentane and the pentane solution dried. The solvent was then removed under vacuum to give 61 g of crude acid. The crude acid was treated with 156 g of oxalyl chloride and the solution stirred at room temperature for 1.5 hr and then heated at 65° for 1.5 hr. The excess oxalyl chloride was then removed under vacuum and the residue distilled to give 51 g of 2-fluoro-2-methylhexanoyl chloride b.p. 60° (25-30 mmHg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13]CC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CCO>O>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a suspension of 73 (4.0 g, 15.6 mmol) in H2O (150 ml) were added NaOH (3.1 g, 78.0 mmol) and EtOH (5 ml). The mixture was reflux for 12 h, and cooled to 25° C. The solid was filtered out and the filtrate was acidified with 2N HCl. The precipitate was collected and washed with H2O. The crude product was recrystallized from to give 78 as white solid. (3.0 g, 13.2 mmol). Yield: 84.6%; mp 73-75° C.; MS (EI, 70 eV): m/z 228.3 (M+); 1H-NMR (CDCl3, 200 MHz): δ 5.27 (s, 2H), 7.08-7.54 (m, 8H), 6.93 (dd, J=8.0, 1.8 Hz, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 165.43, 157.40, 135.02, 134.34, 133.88, 129.16, 127.92, 122.44, 118.09, 113.11, 72.23; Anal. Calcd for C14H12O3: C, 73.67; H, 5.30.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg+].[Br-].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: C[Mg+]
Reactant: COc1ccc(C(C)=O)c(Br)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
To the mixture of 1-(2-bromo-4-methoxyphenyl)-ethanone (300 mg) dissolved in THF solution (3 ml), MeMgBr (3 M THF solution, 0.52 ml) was added at 0° C. under nitrogen atmosphere. Then, the mixture was stirred at room temperature for 6 hrs. The reaction mixture was added with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the residues obtained after concentration under reduced pressure were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (220 mg, 69%).
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([N:11]1[CH2:16][CH:15]2[CH:13]([C:14]2([C:18]2[CH:19]=[C:20](N)[CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:12]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(=O)([O-])O.[Na+].[ClH:30]>O.[Cu]Cl>[Cl:30][C:20]1[CH:19]=[C:18]([C:14]2([CH3:17])[CH:15]3[CH:13]2[CH2:12][N:11]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:16]3)[CH:23]=[CH:22][CH:21]=1
Reactant: Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Agent: Cl[Cu]
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A solution of sodium nitrite (97 mg, 1.4 mmol) dissolved in water (2 ml) was added to 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 0.17 g, 0.61 mmol) dissolved in aqueous hydrochloric acid (2.0 M, 2 ml) over a few minutes at 0° C. After 30 min at 0° C., the reaction mixture was added to copper (I) chloride (1.57 g, 15.8 mmol) in concentrated hydrochloric acid (4.0 ml). After stirring the reaction mixture at room temperature for 45 min, the reaction mixture was heated to 90° C. for 5 min. The reaction mixture was poured cautiously on to solid, pre-wetted sodium hydrogen carbonate and the product was extracted firstly with diethyl ether and then ethyl acetate. The combined organic extracts were dried (MgSO4) and then concentrated in vacuo. The crude residue was purified by chromatography on silica gel eluting with hexane:ethyl acetate (8:1) to give the product (69 mg, 39%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1COCC1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]#[N:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CCC(OCc2ccccc2)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: N#CC1CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a suspension of 4-(benzyloxy)cyclohexanecarboxamide (2.33 g, 10 mmol, 1.0 equiv) in THF (dry, 50 mL) was added trifluoroacetic anhydride (4.16 mL, 30 mmol, 3.0 equiv) dropwise at room temperature. The resulting clear solution was stirred at room temperature for 30 min and then concentrated to give the residue. H2O (50 mL) was added. The aqueous phase was extracted with MTBE (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated to give 2.1 g (yield 97%) of 4-(benzyloxy)cyclohexanecarbonitrile as a pale yellow oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Ca+2:13].[OH-]>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[Ca+2:13].[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Ca+2]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
To 1000 g of 5% paratoluene sulfonic acid aqueous solution stirred at room temperature, 30 g of calcium hydroxide was added. The stirring was continued while measuring the pH value. At the time when the pH value reached 6, approximately, filtration was done by using a 0.4 μm glass filter to remove the insoluble components, so as to obtain a calcium paratoluenesulfonate aqueous solution.
Reaction SMILES: [C:1](=[O:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3](Cl)[CH3:4].[Cl:11][C:12]1[C:13]([F:52])=[C:14]([C@@H:18]2[C@:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:21]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[NH:20][C@H:19]2[C:38]([NH:40][C:41]2[CH:49]=[CH:48][C:44]([C:45]([OH:47])=[O:46])=[CH:43][C:42]=2[O:50][CH3:51])=[O:39])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:11][C:12]1[C:13]([F:52])=[C:14]([C@@H:18]2[C@:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:21]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[NH:20][C@H:19]2[C:38]([NH:40][C:41]2[CH:49]=[CH:48][C:44]([C:45]([O:47][CH:3]([O:2][C:1]([O:6][CH:7]([CH3:9])[CH3:8])=[O:10])[CH3:4])=[O:46])=[CH:43][C:42]=2[O:50][CH3:51])=[O:39])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)OC(=O)OC(C)Cl
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OC(C)OC(=O)OC(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 73.8 %

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood Products, 1.99 g, 1.5 mL, 13.9 mmol) was reacted with 2-propanol (785 mg, 1 mL, 13.0 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at room temperature for 4 h to give 1-chloroethyl isopropyl carbonate. A portion of 1-chloroethyl isopropyl carbonate (221.6 mg, 1.33 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.3 mg, 244 μmol) in the presence of cesium carbonate (478 mg, 1.47 mmol) in dimethylformamide (5 mL) overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 1-(isopropoxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (134.4 mg, 73% yield). MS (ES+) m/z calcd. for C37H40Cl2F2N3O7: [(M+H)+]: 746, found: 746
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1([CH2:34][OH:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:35][CH2:34][C:28]2([F:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:7]=1
Reactant: OCC1(F)CCCCC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCC3(F)CCCCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (80 mg; 0.21 mmol), intermediate 42.1, and (1-fluorocyclohexyl)methanol (117 mg; 0.841 mmol), example 66 was prepared analogously to the procedure for the preparation of example 42.