Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.O1CCCCC1[O:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[C:41](=O)[O:40][CH2:39]2.Cl>C(COC)OC.C1COCC1>[OH:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[C:41](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:40][CH2:39]2
Reactant: O=C1OCc2cc(CCCOC3CCCCO3)ccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C1Nc2ccccc2C1=C1OCc2cc(CCCO)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a stirred solution of oxindole (401 mg, 3.0 mmol) in anhydrous dimethoxyethane (20 ml) under nitrogen was added 1.0M LiHMDS/THF solution (6.3 ml, 6.3 mmol). The mixture was stirred at room temperature for 10 minutes, and 5-[3-(tetrahydro-pyran-2-yloxy)-propyl]-3H-isobenzofuran-1-one (500 mg, 1.81 mmol) was added. After stirred at room temperature for 2.5 hours, the mixture was poured into a mixture of THF (30 ml) and 2M HCl aqueous solution (30 ml) and heated at 65° C. for 1 hour. The mixture was cooled to room temperature, and then poured into an ice water (300 ml). The resulting solid was separated, rinsed with water, and dried to give 3-[5-(3-hydroxy-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (460 mg, 83%).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)CC1.[Cl:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].[C:23](=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[CH:21]=[C:20]([N:6]2[C@H:7]([CH3:23])[CH2:8][C@@:4]([OH:12])([CH3:1])[C@@H:5]2[CH3:9])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1C[C@](C)(O)[C@H](C)N1c1ccc(C#N)c(Cl)c1

Procedure:
By an operation in the same manner as in Reference Example 51 and using benzyl (2S,3S,5R)-3-hydroxy-2,3,5-trimethylpyrrolidine-1-carboxylate (450 mg), 10% palladium carbon (50% water-containing, 40 mg) and oxalic acid (77 mg), (2S,3S,5R)-2,3,5-trimethylpyrrolidin-3-ol 0.5 oxalate was obtained as a colorless solid (yield: 285.3 mg, yield: 96%). By an operation in the same manner as in Reference Example 53 and using (2S,3S,5R)-2,3,5-trimethylpyrrolidin-3-ol 0.5 oxalate (50 mg), 2-chloro-4-fluorobenzonitrile (67 mg) and lithium carbonate (46.7 mg), the title compound was obtained as a colorless solid (yield: 36.3 mg, yield: 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:12])[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:13]([N:15]1[CH2:20][CH2:19][CH:18](CO)[CH2:17][CH2:16]1)=[O:14].[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.ClCCl.C(OCC)(=O)C>[CH:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:12][CH3:23])[CH2:17][CH2:16]1)=[O:14]
Reactant: O=CN1CCC(CO)CC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCC1CCN(C=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Nitroguaiacol (2 g, 11.8 mmol), N-formyl 4-piperidinemethanol (1.13 g, 7.89 mmol) and polymer-supported triphenylphosphine (3 mmol/g, 3.94 g, 11.8 mmol) were dissolved in tetrahydrofuran (30 mL). The mixture was cooled to 0° C. and diisopropyl azodicarboxylate (2.33 mL, 11.8 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min then at 20° C. overnight. The resin was filtered off, washed with dichloromethane then methanol and the filtrate evaporated to give a deep orange oil. The oil was taken up in dichloromethane, washed with 2M NaOH, 2M HCl then brine, dried and evaporated giving a pale brown oil. This was taken up in 50:50 ethyl acetate : hexane, filtered through celite, filtrate evaporated, taken up in ethyl acetate and washed further with 1M NaOH. The organic layer was separated, dried over Na2SO4, the solvent removed under reduced pressure and the residue columned in 50:50 ethyl acetate: hexane to remove impurities. The product was then eluted with 9:1 dichloromethane : methanol to give a yellow oil, which crystallised on cooling. 1H NMR (400 MHz, CDCl3): 1.15-1.3 (2H, m); 1.85-1.9 (1H, m); 2.6-2.7 (1H, m); 3-3.1 (1H, m); 3.7-3.8 (1H, m); 4.0 (2H, d, J 7 Hz); 4.15-4.25 (1H, m); 7.2 (1H, d, J 8 Hz); 7.75 (1H, d, J 2 Hz); 7.9 (1H, dd, J 2 and 8 Hz); 8 (1H, s).
Reaction SMILES: C([O:8][CH2:9][C@:10]12[S:18](=[O:20])(=[O:19])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=3)[CH2:16][C@H:15]1[C@@H:14]1[CH2:33][C@H:11]2[CH:12]=[CH:13]1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CO.[Pd]>[OH:8][CH2:9][C@:10]12[S:18](=[O:20])(=[O:19])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:31])([F:32])[F:30])[CH:22]=3)[CH2:16][C@H:15]1[C@@H:14]1[CH2:33][C@H:11]2[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: N#Cc1ccc(N2C[C@H]3[C@H]4C=C[C@H](C4)[C@@]3(COCc3ccccc3)S2(=O)=O)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(N2C[C@H]3[C@H]4CC[C@H](C4)[C@@]3(CO)S2(=O)=O)cc1C(F)(F)F
Yield: 82.3 %

Procedure:
A solution-suspension of Example 30 (50 mg, 0.11 mmol) and Degussa-type Pd/C (10 mg; 20 wt %) in 4 mL EtOAc/MeOH (2:1) was stirred under 1 atmosphere of hydrogen at ambient temp for 5 hrs. The reaction vessel was then purged with N2 to give a black suspension that was then filtered. The resulting colorless filtrate was concentrated in vacuo to give 35 mg of a mixture of starting material and product in a 2:1 ratio. The mixture was dissolved in CH2Cl2, loaded onto a preparative TLC plate, and eluted with 30% acetone/heptane to afford 15 mg Example 32 (36% yield) as a colorless film. HPLC: 98% at 3.015 min (retention time) (YMC ODS-A column 4.6×50 mm eluting with 10-90% aqueous MeOH over 4 min containing 0.1% H3PO4, 4 mL/min, monitoring at 220 nm); and MS (ES): m/z 445.11 [M−H+ OAc]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6](Br)[CH:5]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1.COC(=O)C1C=C(NC2C=NC=CC=2)C=C(C2C=CC=C3C=2C=CN3)C=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: COC(=O)c1cc(Br)cc(Br)c1
Reactant: Nc1cccnc1
Agent: COC(=O)c1cc(Nc2cccnc2)cc(-c2cccc3[nH]ccc23)c1
Product: COC(=O)c1cc(Br)cc(Nc2cccnc2)c1

Procedure:
3-Bromo-5-(pyridin-3-ylamino)-benzoic acid methyl ester was prepared from 3,5-dibromo-benzoic acid methyl ester and pyridin-3-ylamine in low yield as described for Example 36, except that the reaction was run at 130° C. This material was converted to 3-(1H-indol-4-yl)-5-(pyridin-3-ylamino)-benzoic acid methyl ester by the method of Example 35. 1H NMR (400 MHz, CDCl3): δ 8.43 (d, J=14.4 Hz, 2H), 8.20 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.29-7.24 (m, 2H), 7.22-7.16 (m, 2H), 6.69 (s, 1H), 5.93 (s, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].ClC(OCC(C)C)=O.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=[O:36])=[CH:26][C:25]=1[F:37]>C1COCC1.CN1CCOCC1.CN(C=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@@H:7]1[C:12](=[O:14])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=[O:36])=[CH:26][C:25]=1[F:37])=[O:5])[CH3:2]
Reactant: C=C1C[C@H](C(=O)O)[C@@H](C(=O)OCC)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=C1C[C@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)[C@@H](C(=O)OCC)C1
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 1.0 g of 41b in 10 ml of THF and 0.61 ml of N-methylmorpholine was added at −12° C. 0.72 ml of isobutyl chloroformate and stirring was continued at −15° C. for 30 min and at 20° C. for 1 h. The suspension obtained was added to a hot (60° C.) solution of 1.13 g of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C. F. Bigge et al., patent application WO 2003045912) in 8 ml of DMF and stirring was continued at 60° C. for 1 h. The reaction mixture was evaporated and the residue partitioned between 1 N HCl and AcOEt, the organic layer was washed with HCl and brine, dried and evaporated. The residue was chromatographed on silica using heptane/AcOEt (1:2) to give 1.28 g of the title compound 54a. MS: 385.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: CCCCCCCCNC
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCCCCCCCN(C)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A mixture of 9.23 g. of 3-nitro-4-chloro-benzophenone, 10 ml. of ethanol and 10.3 g. of N-methyl-N-octylamine is stirred at 80° to 85° C for 30 minutes, and then the mixture is poured onto 100 ml. of ice water. The aqueous phase is extracted with 2x75 ml. of benzene. The benzene phases are combined, washed with distilled water with chloride-free, dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. 11.57 g. of 3-nitro-4-(N-methyl-N-octylamino)-benzophenone are obtained in the form of an oily residue. On the basis of thin layer chromatographical examination, a pure, uniform product is obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([O:29][CH3:30])=[O:28])[CH2:4][C@@H:3]1[OH:31].S(=O)(=O)(O)O.[CH2:37](O)[CH2:38]C>>[OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([O:29][CH2:30][CH2:37][CH3:38])=[O:28])[CH2:4][C@@H:3]1[OH:31]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C

Procedure:
A solution of methyl 2β,3α-dihydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (437 mg) in propan-1-ol (30 ml) was heated at 100° C. with conc. sulphuric acid (0.2 ml) for 40 h. The cooled mixture was concentrated by evaporation and the residue diluted with water (150 ml) and brought to pH 10 by the addition of 0.88 ammonia solution. The suspension was extracted with ethyl acetate (3×) and the extracts washed with brine, dried and evaporated to give a solid. This was crystallised from ethyl acetate to give the title compound (70 mg), m.p. 140°-142° C., [α]D +17.2°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=2)=[CH:3][N:2]=1.[OH-].[Na+].O.Cl>CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=2)=[CH:3][N:2]=1
Reactant: CCOC(=O)c1ccc(-c2ccnnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccnnc2)cc1
Yield: 98.9 %

Procedure:
Ethyl 4-(4-pyridazinyl)benzoate (580 mg) was dissolved in methanol (12.5 ml) and 1.0M NaOH (12.7 ml) and heated at 60° C. for 4 hours. The resulting mixture was reduced to low volume then water (25 ml) added, the solution neutralised to pH 7 with 1.0M HCl, the resulting precipitate filtered and dried over P2O5 to give 4-(4-pyridazinyl)benzoic acid as a light brown solid (503 mg); mp>330° C.; 1H NMR (300 MHz, DMSO-d6) δ=8.05 (m,5H), 9.32 (d,1H), 9.67 (s,1H) ppm; MS: m/z 201 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([O-:21])=[O:20].[K+].N>>[CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[C:9]([N+:19]([O-:21])=[O:20])[C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCc1nc2c(C)c([N+](=O)[O-])c(C)nc2[nH]1
Temperature: 80 °C
Yield: 37 %

Procedure:
2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (2.17 g) was added to stirred fuming sulphuric acid (7 ml) and the resulting solution was warmed to 80° C. Potassium nitrate (3.0 g) was added in portions over a period of 10 minutes and the resulting mixture was heated am between 95 and 100° C. for 10 minutes, cooled, then poured onto ice (approx. 25 g). The mixture was neutralised with concentrated aqueous ammonia solution and then extracted with dichloromethane (2×50 ml). The combined extracts were dried over magnesium sulphate and the solvent was then evaporated. Recrystallization of the resulting residue from ethyl acetate (15 ml) gave the intermediate compound 2-ethyl-5,7-dimethyl-6-nitro-3H-imidazo-[4,5-b]pyridine (1.01 g; m.p. 146°-149° C.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10])[N:3]=[N:2]1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=3)=[O:20])[CH2:17][CH2:18]2)=[O:10])[N:3]=[N:2]1
Reactant: O=C(Cl)CCCc1c[nH]nn1
Reactant: Cc1cc(C)cc(COC(=O)N2CCC(N)CC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)cc(COC(=O)N2CCC(NC(=O)CCCc3c[nH]nn3)CC2)c1
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(1H-1,2,3-triazol-4-yl)butanoic acid chloride in DCM (5 ml) at RT (168 mg, 0.967 mmol) was added 3,5-dimethylbenzyl 4-aminopiperidine-1-carboxylate (318 mg, 1.064 mmol) and Huenig's Base (0.338 mL, 1.934 mmol) and the reaction mixture was allowed to stir for 3 hrs. The reaction mixture was diluted with DCM and washed with a saturated solution of brine. The layers were separated and the organic portion dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM as eluent to afford the title product;
Reaction SMILES: [NH:1]1[CH2:3][C@H:2]1[C:4]([OH:6])=[O:5].[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17])([O-:9])=[O:8]>CC(C)=O>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N@:1]1[CH2:3][CH:2]1[C:4]([OH:6])=[O:5])(=[O:18])=[O:17])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: O=C(O)[C@@H]1CN1
Solvent: CC(C)=O
Product: O=C(O)C1C[N@@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 2 °C
Yield: 94.8 %

Procedure:
The liquid reaction mixture containing 10.01 g (115 mmol) of (S)-aziridine-2-carboxylic acid obtained in Example 1 was cooled to 2° C. and 255 mL of acetone was added thereto at an internal temperature of 2 to 5° C. While maintaining this solution at an internal temperature of −5 to 0° C., a mixture of 26.9 g (121 mmol) of 2-nitrobenzenesulfonyl chloride with 67 mL of acetone was quickly added thereto. Then the reaction was continued as such for additional 2 hours. This liquid reaction mixture contained 29.7 g (109 mmol) of (S)-N-2-nitrobenzenesulfonyl-aziridine-2-carboxylic acid (yield: 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Br[CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[CH:57]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:56][CH3:55])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester was reacted with 1-(bromo-propyl)-benzene and NaHCO3 in DMF according to General Procedure P to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester. This product, upon hydrolysis according to General Procedure B, gave the title compound (6 mg). LCMS (m/z): 852.
Reaction SMILES: O([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])S(C(F)(F)F)(=O)=O.[CH3:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH3:47])[C:25]=1[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][C:38]([CH:41]([C:44]#[N:45])[C:42]#[N:43])=[CH:37][CH:36]=2)=[CH:28][C:27]=1[CH3:46].C[O-].[Na+]>C(Cl)Cl.CO>[CH3:19][C:20]1[C:25](=[C:26]2[C:27]([CH3:46])=[CH:28][C:29](=[CH:33][CH:34]=[C:35]3[CH:40]=[CH:39][C:38](=[C:41]([C:42]#[N:43])[C:44]#[N:45])[CH:37]=[CH:36]3)[CH:30]=[C:31]2[CH3:32])[C:24]([CH3:47])=[CH:23][N:22]([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:21]=1
Reactant: Cc1cncc(C)c1-c1c(C)cc(C=Cc2ccc(C(C#N)C#N)cc2)cc1C
Reactant: CCCCCC(CCC)COS(=O)(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(CCC)CN1C=C(C)C(=c2c(C)cc(=CC=c3ccc(=C(C#N)C#N)cc3)cc2C)C(C)=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a solution of 2-propyl-1-heptanol (0.81 g, 5.1 mmol) in dry CH2Cl2 (15 mL) was added dropwise a solution of trifluoromethanesulfonic anhydride (1.77 g, 6.10 mmol) in the same solvent (5 mL). After stirring at room temperature for 20 min, the reaction mixture was poured into ice (40 mL), and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give nearly pure 2-propyl-1-heptyl triflate as purple liquid (1.40 g, 94.1%). Next, 2-propyl-1-heptyl triflate (0.319 g, 1.10 mmol) was added dropwise to a solution of 19 (0.377 g, 1.00 mmol) in dry CH2Cl2 (20 mL). The reaction mixture was stirred at room temperature for 4 h. A solution of sodium methoxide in methanol (2.4 mL, 0.5 M) was then added dropwise to the resulting solution of pyridinium salt 20. The color of the mixture immediately changed from yellow to red. After stirring at room temperature for 10 min, the solvent was removed under reduced pressure. The resulting purple solid was then partitioned between water (50 L) and CH2Cl2 (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 4:100 methnol: CH2Cl2, to give 0.340 g (65.7%) of the title compound as purple solid: mp 161-162° C.; NMR (400 MHz, DMSO-d6): δ 9.039 (s, 2H), 7.418 (s, 2H), 7.286 (d, 2H, J=8.0 Hz), 7.145 (d, 1H, J=16.4 Hz), 6.919 (d, 1H, J=16.4 Hz), 6.739 (d, 2H, J=7.6 Hz), 4.453 (m, 2H, J=5.2 Hz), 2.125 (m, 1H), 2.074 (s, 6H), 1.859 (s, 6H), 1.319-1.219 (m, 12H), 0.849 (m, 6H); 13C NMR (125 MHz, DMSO-d6): δ 157.523, 142.592, 141.882, 138.688, 136.859, 133.320, 131.364, 129.981, 126.942, 125.704, 125.468, 121.582, 118.070, 64.195, 38.546, 32.695, 31.366, 30.156, 29.419, 25.061, 21.894, 19.010, 18.855, 16.581, 14.215, 13.942; MS (high resolution, EI): m/z 517.3451 [M+]; calcd, 517.3457; Anal. Calcd. for C36H43N3.1/3H2O: C, 82.56; H, 8.40; N, 8.02. Found; C, 82.59; H, 8.11; N, 8.36.
Reaction SMILES: CS[C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]=2.O[O:24][S:25]([O-:27])=O.[K+].[CH2:29]1COCC1>CO.O>[CH3:29][S:25]([C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]=2)(=[O:27])=[O:24]
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)c1cccc(-c2ccc3nc(SC)sc3n2)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccc3nc(S(C)(=O)=O)sc3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution was ethyl 3-(2-(methylthio)thiazolo[5,4-b]pyridin-5-yl)benzoate (5.6 g, 16.9 mmol) in THF (25 mL) and methanol (25 mL) was added Oxone (41.55 g, 67.67 mmol) in water (25 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was filtered and concentrated to give 5.8 g (94%, yield) of ethyl 3-(2-(methylsulfonyl)thiazolo[5,4-b]pyridin-5-yl)benzoate as a bright brown solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([NH:31][CH2:32][CH2:33][CH3:34])[N:26]=[C:25]([S:35][CH2:36][C:37]3[N:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=4)[S:40][CH:41]=3)[C:24]=2[C:49]#[N:50])=[CH:19][CH:18]=1)=[O:12])[CH3:10])=O)(C)(C)C.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>ClCCl>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[NH2:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([NH:31][CH2:32][CH2:33][CH3:34])[N:26]=[C:25]([S:35][CH2:36][C:37]3[N:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=4)[S:40][CH:41]=3)[C:24]=2[C:49]#[N:50])=[CH:19][CH:18]=1)=[O:12])[CH3:10]
Reactant: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc2)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)N)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
873 mg (1.191 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(propylamino)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alaninate (Example 14A) were initially charged in 29 ml of dichloromethane. 1.84 ml (23.817 mmol) of trifluoroacetic acid were added, and the reaction solution was then stirred at RT overnight. The reaction solution was concentrated by evaporation and the residue was triturated with diethyl ether. The solid formed was filtered off and dried. This gave 914 mg (89% of theory) of the target compound.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:17](=[O:23])[CH2:18]S(C)(=O)=O.C(O)C.C(O)(=O)C>O>[CH3:18][C:17]([C:3]1[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2[C:10]([C:2]=1[OH:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:23]
Reactant: CS(=O)(=O)CC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1c(O)c2ccccc2n1-c1ccccc1

Procedure:
In a manner analogous to that of Example 5, the title compound was prepared from 1-(3-hydroxy-1-phenyl-1H-indol-2-yl)-2-(methylsulfonyl) ethanone. The product was obtained as green needles of mpt. 127°-130° from the condensed ethanol-acetic acid filtrate by the addition of warm water, followed by slow cooling.