Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[CH:16][C:17]([O:19][CH:20]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]4)=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].Br[CH2:35][C:36]1[O:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1>CN(C)C=O>[O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[CH:16][C:17]([O:19][CH:20]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]4)=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:35][C:36]1[O:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)OCC32C(=O)Nc3ccccc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)OCC32C(=O)N(Cc3ccc(C(F)(F)F)o3)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a stirred solution of tert-butyl 3-[(2′-oxo-1,2′-dihydrospiro[1-benzofuran-3,3-indol]-6-yl)oxy]pyrrolidine-1-carboxylate (0.19 g, 0.45 mol) in N,N-dimethyl formamide (10 mL) was added sodium hydride (0.02 g, 0.54 mmol) slowly at 0° C. After 30 min, 2-(bromomethyl)-5-(trifluoromethyl)furan (0.12 g, 0.54 mmol) was added. The mixture was stirred at ambient temperature for 16 h, and then quenched with saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexanes, 1/2) to afford tert-butyl 3-[(2′-oxo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3-indol]-6-yl)oxy]pyrrolidine-1-carboxylate (0.14 g, 55%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.29 (t, J=7.7 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.76-6.70 (m, 1H), 6.54 (d, J=8.2 Hz, 1H), 6.47 (s, 1H), 6.40-6.35 (m, 1H), 6.30 (d, J=8.2 Hz, 1H), 5.06 (d, J=16.2 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.86 (d, J=16.2 Hz, 1H), 4.80 (br s, 1H), 4.69 (d, J=9.0 Hz, 1H), 3.64-3.37 (m, 4H), 2.22-1.96 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 593.2 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].[S:24]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])(=[O:26])[NH2:25]>>[S:24]([C:28]1[CH:29]=[C:30]([NH:34][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]([F:16])[F:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:23])[CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:31]=[CH:32][CH:33]=1)(=[O:26])(=[O:27])[NH2:25]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.14) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (EI) 491.1 [M]; mp 264° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CC)=O.[NH2:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=1>>[Cl:27][C:23]1[N:22]=[C:21]([NH:20][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:26]=[N:25][CH:24]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1cncc(Cl)n1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:29]3[N:30]=[C:31]([NH:34][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)[S:32][CH:33]=3)=[C:24]([CH3:43])[CH:23]=2)[CH2:18][CH2:17]1)=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:29]3[N:30]=[C:31]([NH:34][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)[S:32][CH:33]=3)=[C:24]([CH3:43])[CH:23]=2)[CH2:20][CH2:21]1
Reactant: Cc1cc(N2CCC(OCCOCCOCCOCCN=[N+]=[N-])CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N2CCC(OCCOCCOCCOCCN)CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To a solution of N-(4-(4-(4-(2-(2-(2-(2-azidoethoxyl)ethoxy)ethoxy)ethoxy)piperidin-1-yl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (4.7 mg, 0.0077 mmol) in EtOH (1 mL) was added Pd/C (10% Pd, 3 mg). The mixture was hydrogenated overnight at room temperature under 1 atm H2 pressure. The mixture was then filtered through a pad of celite and concentrated to give N-(4-(4-(4-(2-(2-(2-(2-amino ethoxy)ethoxy)ethoxy)ethoxy)piperidin-1-yl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (1.1 mg, yield 24.5%), which was used directly without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[O:26][CH3:27])=[CH:14][CH:13]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:28][NH2:29]>C(O)CCC>[F:25][C:21]1[C:22]([F:24])=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:7]3[CH:6]=[C:3]4[C:2](=[CH:9][CH:8]=3)[NH:29][N:28]=[C:4]4[NH2:5])=[CH:17][CH:16]=2)=[C:19]([O:26][CH3:27])[CH:20]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc(F)c(C#N)c2)cc1
Reactant: NN
Solvent: CCCCO
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3[nH]nc(N)c3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of 2-fluoro-5-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzonitrile (150 mg, 0.41 mmol), aqueous hydrazine (excess) and n-butanol (3 mL) was heated to 150° C. for 30 min via microwave reactor. The mixture was then cooled to room temperature. The mixture was then purified by preparative HPLC under neutral conditions to give title compound. LC-MS (ES) calculated for C21H17F2N3O2, 381.39; found m/z 382 [M+H]+.
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].O>O1CCCC1>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:18]([C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:21][CH:20]=2)[O:19]1
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cl)OC1c1ccc([N+](=O)[O-])cc1
Yield: 71.6 %

Procedure:
5.55 g of tert.-butyl dichloroacetate in 30 ml of tetrahydrofuran and 4.99 g of 4-nitrobenzaldehyde in 30 ml of tetrahydrofuran were cooled to -20° C. and, over 20 minutes, 30 ml of a molar solution of potassium tert.-butylate in tetrahydrofuran were added dropwise at -20° C. The reaction mixture was stirred while the temperature was allowed to rise to 20° C., and it was then poured into 100 ml of water and ice, and was extracted with ether. The organic phase was washed with water saturated with sodium chloride, then with water, dried, and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with methylene chloride to obtain 6.44 g of 1,1-dimethylethyl 2-chloro-3-(4-nitrophenyl)oxirane carboxylate melting at 60° C.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[CH:1]1([CH2:6][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)C2CCCC2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CC2CCCC2)cc1OC
Yield: 98.7 %

Procedure:
A suspension of cyclopentyl(3,4-dimethoxyphenyl)methanone (10.8 g, 0.046 mol), wet Pd/C (1 g) in 10 ml of acetic acid and 10 ml of ethyl acetate was put in an autoclave at 60° C. with 20 bars of hydrogen during 24 hours. Filtration over Celite® and concentration gave 10 g of pale brown oil. This oil was purified by vacuum distillation (100-120° C., 0.02 mbar) through a short path to give 7.1 g (70%) of a colorless liquid.
Reaction SMILES: [CH3:1][C:2](=[O:22])[C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][CH2:12][CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1.[CH3:23][Al](C)C.O>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:23][C@@H:4]1[CH2:5][C@@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18][C@H:17]3[C@H:7]2[CH2:8][CH2:9][C:10]2[C@:15]3([CH3:16])[CH:14]=[CH:13][CH2:12][CH:11]=2)[C@H:3]1[C:2](=[O:22])[CH3:1]
Reactant: C[Al](C)C
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CCC=C[C@]4(C)[C@H]3CC[C@]12C
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CCC=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.1 g (10 mmol) of pregna-1,4,16-trien-20-one is mixed in 25 ml of dioxane with 143.4 mg of CuBr. 9.4 ml (11 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction under nitrogen and stirred for 30 minutes at 20-30° C. For hydrolysis, 0.54 ml of water dissolved in 5 ml of dioxane is added to the reaction. It is stirred for 10 minutes more and the precipitate is filtered off. The precipitate is washed again with a little dioxane. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 2.6 g of 16α-methyl-pregna-1,4-dien-20-one (80% of theory) of a melting point of 175° C. is obtained.
Reaction SMILES: [CH2:1](NC(=O)C(C)O)CCCCCCC.[OH-].[K+].C(O)(=O)C(C)O.C1OC1.[CH2:26]([C:34](C)([OH:38])[C:35]([NH2:37])=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:27]([CH2:26][CH:34]([OH:38])[C:35]([NH2:37])=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:1]
Reactant: CCCCCCCCC(C)(O)C(N)=O
Reactant: CCCCCCCCNC(=O)C(C)O
Agent: CC(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CO1
Product: CCCCCCCCCC(O)C(N)=O
Temperature: 25 °C

Procedure:
100 g of N-octyllactamide were admixed with 1 g of 45% KOH in a pressurized reactor and dried for one hour at 115° C. and reduced pressure. Then, at 130° C., 3 mol equivalents of ethylene oxide were metered in over 40 minutes and the product was kept for a further 45 minutes at this temperature for a post reaction time. After cooling to room temperature, the mixture was neutralized with lactic acid. The product was obtained in the form of a clear, brownish liquid. Using 1H-NMR analysis, an addition of 3.1 mol of ethylene oxide per mol of octyllactamide was determined.
Reaction SMILES: [C:1]([CH2:4][NH:5][CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[CH2:10]([O:17][C:18]([N:5]([CH2:6][C:7]([OH:9])=[O:8])[CH2:4][C:1]([OH:3])=[O:2])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CNCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(carboxymethyl)glycine (13.31 g, 100.00 mmol) in aqueous 2N NaOH (100 mL) was added a solution of benzylchloroformate (18.77 g, 110.00 mmol) in aqueous 2N NaOH (55 mL) at 0° C. The reaction was stirred at room temperature overnight and washed with Et2O. The aqueous layer was acidified to pH 2 with aqueous 1N HCl solution and extracted four times with Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the product as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH:26]3[CH2:28][CH2:27]3)[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([NH:35][C:4]2[C:5]3[N:6]=[CH:7][N:8]([C:9]=3[N:10]=[C:2]([Cl:1])[N:3]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH:26]3[CH2:27][CH2:28]3)[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCC1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC2CC2)O[C@H]1n1cnc2c(Cl)nc(Cl)nc21
Product: O[C@@H]1[C@H](O)[C@@H](COC2CC2)O[C@H]1n1cnc2c(NC3CCCC3)nc(Cl)nc21

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-cyclopropyl-β-D-ribofuranosyl)-purine (65, 543 mg, 1.22 mmol) and cyclopentylamine (1.83 mmol, 180 μL). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 400 mg (0.98 mmol, 80%), mp 104–106° C.; Rf 0.51 (10% MeOH in CH2Cl2). The product was re-crystallized from (C2H5)2O; 1H NMR (DMSO-d6) δ 8.34 (bs, 1H, NH), 8.28 (s, 1H, H-8), 5.81 (d, 1H, J=5.15 Hz, H-1′), 5.53 (d, 1H, J=5.84 Hz, OH-2′), 5.29 (d, 1H, J=5.15 Hz, OH-3′), 4.50 (q, 1H, J=5.15 Hz, H-2′), 4.50–4.47 (m, 1H, CH), 4.09–3.99 (m, 2H, H-3′,4′), 3.68–3.63 (m, 2H, H-5′), 1.94–1.89 (m, 2H, cyclopentyl), 1.71-1.50 (m, 4H, cyclopentyl), 0.46–0.41 (m, 4H, OCHCH2CH2); MS m/z 410 (M+H)+; Anal. (C18H24ClN5O4.0.2(C2H5)2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH3:9])[C:6]=1[CH2:7]O.[Br:10]P(Br)Br>C(Cl)(Cl)Cl>[Br:10][CH2:7][C:6]1[N:5]([CH3:9])[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: Cn1cnc(Cl)c1CO
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Cn1cnc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (1-methyl-1H-imidazol-5-yl)methanol (1.14 g, 10 mmol) in dioxane (50 mL), in a 250 mL round bottom flask, was added 1-chloropyrrolidine-2,5-dione (1.38 g, 10 mmol). The resulting mixture was stirred at room temperature overnight. Dioxane was removed under vacuum to provide (4-chloro-1-methyl-1H-imidazol-5-yl)methanol. The crude (4-chloro-1-methyl-1H-imidazol-5-yl)methanol was dissolved in 40 mL of chloroform, followed by addition of tribromophosphane (1.9 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated to provide 5-(bromomethyl)-4-chloro-1-methyl-1H-imidazole.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([F:20])[CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl>C1COCC1>[CH2:6]([O:12][C:13]1[CH:18]=[CH:17][C:16]([B:25]([OH:26])[OH:24])=[C:15]([F:20])[CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCOc1ccc(Br)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(B(O)O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of n-butyllithium (10.0M in hexane, 3.30 ml) is added dropwise to a stirred cooled (-78° C.) solution of 3A (9.0 g) in dry THF (70 ml) under dry N2. The stirred mixture is maintained under these conditions for 2.5 h and then a cooled solution of tri-isopropylborate (11.28 g) in dry THF (50 ml) is added dropwise at -78° C. The stirred mixture is allowed to warm to room temperature overnight and then stirred for 1 h at room temperature with 10 HCl (50 ml). The product is extracted into ether twice and the combined ethereal extracts are washed with water and dried (MgSO4). The solvent is removed in vacuo to afford an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][C:41]1([CH3:48])[O:45][CH:44]([CH2:46]O)[CH2:43][O:42]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:46][CH:44]2[CH2:43][O:42][C:41]([CH3:48])([CH3:40])[O:45]2)[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2]
Reactant: CC1(C)OCC(CO)O1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2COC(C)(C)O2)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2′-cyano-5-hydroxy-4′-methylbiphenyl-3-carboxylate (150 mg, 0.56 mmol), triphenylphosphine (220 mg, 0.84 mmol), 2,2-dimethyl-1,3-dioxolane-4-methanol (82 mg, 0.62 mmol) in CH2Cl2 (5 mL) at room temperature was slowly added a solution of diisopropyl azodicarboxylate (340 mg, 1.7 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH3:57][NH:58][C:59]([CH3:107])([C:61]([NH:63][C@H:64]([C:68]([N:70]([C@@H:72]([C@@H:103]([CH3:106])[CH2:104][CH3:105])[C@H:73]([O:101][CH3:102])[CH2:74][C:75]([N:77]1[CH2:81][CH2:80][CH2:79][C@H:78]1[C@H:82]([O:99][CH3:100])[C@@H:83]([CH3:98])[C:84]([NH:86][C@H:87]([C:95]([OH:97])=[O:96])[CH2:88][C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)=[O:85])=[O:76])[CH3:71])=[O:69])[CH:65]([CH3:67])[CH3:66])=[O:62])[CH3:60]>CN(C=O)C.ClCCl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:58]([CH3:57])[C:59]([CH3:107])([C:61]([NH:63][C@H:64]([C:68]([N:70]([C@@H:72]([C@@H:103]([CH3:106])[CH2:104][CH3:105])[C@H:73]([O:101][CH3:102])[CH2:74][C:75]([N:77]1[CH2:81][CH2:80][CH2:79][C@H:78]1[C@H:82]([O:99][CH3:100])[C@@H:83]([CH3:98])[C:84]([NH:86][C@H:87]([C:95]([OH:97])=[O:96])[CH2:88][C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)=[O:85])=[O:76])[CH3:71])=[O:69])[CH:65]([CH3:66])[CH3:67])=[O:62])[CH3:60])=[O:16]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC)C(C)C
Reactant: O=C(O)CCCCCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)CCCCCCN1C(=O)C=CC1=O)C(C)C
Reaction time: 0.5 h

Procedure:
A stirring solution 7-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)heptanoic acid (1.2 equivalents), HATU (1.2 equivalents), and Hunig's base (3 equivalents) in DMF and dichloromethane is allowed to stir for 30 minutes. Compound #115 (1 equivalent) is then added as a solution in dichloromethane and DMF. Reaction is monitored by LC-MS. Reaction is concentrated down and purification is completed by Isco medium pressure reverse phase chromatography (Gradient: 5%-100% water in acetonitrile).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[CH2:9]([Mg]Br)[CH3:10].CCOCC>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:8])[CH2:9][CH3:10]
Reactant: CC[Mg]Br
Reactant: O=Cc1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a stirred solution of 2-pyridine carboxaldehyde (4.0 g, 37.34 mmol) in THF (50 mL) at 0° C., add 3M ethyl magnesium bromide in ether (18.7 mL, 56.0 mmol), continue stirring for 30 min at 0° C. and then at ambient temperature for 2 h. Add water (200 mL), extract three times with EtOAc, dry over anhydrous Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the desired intermediate as a yellow oil (3.39 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([NH:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:18][C:17]=2[CH3:41])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OP(O)(O)=O>O>[NH2:21][C:19]1[S:20][C:16]([C:14]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=3)[CH2:11][CH2:12][N:13]=2)=[C:17]([CH3:41])[N:18]=1
Reactant: COc1ccc(CCNC(=O)c2sc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc2C)cc1OC
Agent: O=P(O)(O)O
Solvent: O
Product: COc1cc2c(cc1OC)C(c1sc(N)nc1C)=NCC2
Temperature: 100 °C
Reaction time: 10 h
Yield: 24.9 %

Procedure:
A mixture of N-[2-(3,4-dimethoxyphenyl)ethyl]-4-methyl-2-tritylamino-5-thiazolecarboxamide (5.0 g) and polyphospholic acid (116% as H3PO4, 50 g) was stirred at 100° C. for 10 hours. After the reaction mixture was cooled, water (250 ml) was added and stirred for 1 hour. After removal of insoluble materials by filtration, and filtrate was neutralized with sodium carbonate. From the aqueous solution was extracted the desired compound with chloroform, and the extract was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated in diisopropyl ether to afford 1-(2-amino-4-methylthiazol-5-yl)-6,7-dimethoxy-3,4-dihydroisoquinoline (0.67 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:17][CH2:18][CH:19]1[O:23][C:22](=[O:24])[N:21]([CH3:25])[CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.C(#N)C>[CH3:25][N:21]1[CH2:20][CH:19]([CH2:18][CH2:17][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[O:23][C:22]1=[O:24]
Reactant: CN1CC(CCCl)OC1=O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC#N
Product: CN1CC(CCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)OC1=O
Yield: 79.3 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 4.1 g (0.02 mol) of 1-(4-nitrophenyl)piperazine, 3.3 g (0.02 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 6.4 g (0.06 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 5.3 g (79%) of yellow solid, mp 155°-156° C. (acetonitrile).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([Si](C(C)(C)C)(C)C)[CH:18]=1)(O)[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][C:11]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[CH:10]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cn([Si](C)(C)C(C)(C)C)c3ccccc13)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2c[nH]c3ccccc23)CC2CCC1N2
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To 1.25 g (2.74 mmol) tert-butyl-3-{1-[tert-butyl(dimethyl)silyl]-1H-indol-3-yl}-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate in 25 mL CH2Cl2 is added 6 mL of TFA. After stirring at 23° C. for 45 min, the reaction mixture is poured into sat. aqueous NaHCO3 (300 mL) and extracted with 3×50 mL CH2Cl2. The combined organics are washed with 1×100 mL H2O, 1×100 mL of brine, dried over Na2SO4, filtered and evaporated to give 603 mg (2.24 mmol, an 82% yield) of the title compound as a yellow/orange oil. MS (ES) m/z 269 (MH)+.