Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:17]([O-:19])=O)=[C:7]([CH:16]=1)[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[H-].[Na+]>C1COCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:17]([OH:19])[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:8][C:7]=2[CH:16]=1
Reactant: CSc1ccc([N+](=O)[O-])c(NCc2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)nc(-c1cccnc1)n2O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-(methyl-thio)-2-nitro-N-(pyridin-3-ylmethyl) aniline (0.8 g, 0.002 mol) in THF (20 ml) was added NaH (60% suspension in mineral oil), (0.14 g, 0.006 mol) and the resulting solution was continued to stir at 60° C. for 8 h. The reaction was quenched with ice chips and extracted with dichloromethane (3×100 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford to afford the crude compound which was purified by chromatography to obtain title compound 5-(methyl-thio)-2-(pyridin-3-yl)-1H-benzo[d]imidazol-1-ol as an off white solid. 1H NMR (400 MHz, DMSO-d6), δ: 12.28 (bs, 1H), 9.36 (s, 1H), 8.71-8.70 (m, 1H), 8.55-8.53 (d, J=8 1H), 7.62-7.59 (m, 2H), 7.52-7.50 (d, J=8 Hz, 1H), 7.28-7.26 (dd, J=1.2 Hz, J=8 Hz, 1H), 2.53 (s, 3H). MS (M+1): 258.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]2[C:12](=[C:13](C(C)(C)C)[CH:14]=1)[O:11][CH:10]([C:19]([OH:21])=[O:20])[CH2:9][CH2:8]2)(C)(C)C.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[O:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH:10]1[C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(C(=O)O)CC2
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(O)C1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
6,8-di-t-Butyl-2-hydroxycarbonylchroman (2.90 g, 0.01 mol) obtained in Example 3 was dissolved in toluene (27 g), and the resulting solution was added dropwise to a suspension of aluminum chloride (2.67 g, 0.02 mol) in toluene at room temperature. After the dropwise addition, the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into aqueous sulfuric acid solution and the organic layer was separated. An aqueous alkaline solution was added to the organic layer and the aqueous layer was separated. An aqueous sulfuric acid solution was added to the aqueous layer and the mixture was extracted with toluene. The extract was concentrated under reduced pressure. The residue was quantitatively analyzed by liquid chromatography according to the internal standard method. As a result, 2-chroman-carboxylic acid was obtained in a yield of 90% [net 1.60 g, 0.009 mol]. The 1H-NMR data of the obtained 2-chroman-carboxylic acid are shown below.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=1[OH:18])(=[O:7])=[O:6])([CH3:3])[CH3:2].[H][H]>[Pd]>[CH:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[OH:18])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: CC(C)NS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 98.4 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-isopropyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.7 g, 2.38 mmol) was reduced with hydrogen and Pd/C (0.7 g) to form the desired product (0.62 g, 98 %). EI-MS m/z 263.5 (M-H)−.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31]
Reactant: CCNCC
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(CC)Cc1ccc2c(c1)cc(-c1cc(OC)c(O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 42.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.415 g, 0.985 mmol) was dissolved in acetonitrile (16.0 mL), and the solution was treated with diethylamine (2.04 mL, 19.7 mmol), acetic acid (1.10 mL, 19.7 mmol) and sodium triacetoxyborohydride (0.626 g, 2.96 mmol) to obtain 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(diethylaminomethyl)indol-2-yl]isoindolinone (0.202 g, 43%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29](O)(=[O:33])[CH2:30][CH:31]=[CH2:32].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][CH:31]=[CH2:32])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Reactant: C=CCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Reaction time: 27 h

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. 3-Butenoic acid (0.27 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 27 hr. at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography with gradient elution (70%→90% ethyl acetate in hexanes) affording the desired product (27) as a solid. CIMS (NH3Cl): 447 (MH+)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:10][CH:11]([CH2:18][CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:10][CH:11]([CH:12]([C:1]([OH:3])([CH3:2])[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][CH3:19]
Reactant: CCOC(=O)CC(C)CC
Reactant: CC(=O)c1cccnc1
Product: CCOC(=O)C(C(C)CC)C(C)(O)c1cccnc1

Procedure:
Analysis of the pyrolysis product mixture by gas chromatography and preparative thin layer chromatography indicates that the mixture consists of 12 milligrams of the hydroxy ester starting material, and 85 milligrams of a 1:1 mixture of 3-acetylpyridine and ethyl β-methylvalerate.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.[CH3:15][OH:16].[ClH:17]>C(Cl)Cl.O1CCOCC1>[ClH:17].[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[C:11](=[NH:12])[O:16][CH3:15])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CC(O)c1cccc(OC(F)F)c1
Reactant: CO
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=N)C(O)c1cccc(OC(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 131A (1.83 g, 9.2 mmol) in anhydrous CH2Cl2 (30 mL) at 0° C. was added MeOH (2.24 mL) and 4.0 N HCl in dioxane (9.2 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 4.0 h. Solvent was removed to give methyl 2-(3-(difluoromethoxy)-phenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (10 mL) was added H2O (10 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude prouduct was purified by silica gel chromatography to give 131B (700 mg, 33% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.70 (s, 3H) 5.22 (s, 1H) 6.82 (t, J=74.04 Hz, 1H) 7.09 (dd, J=7.91, 2.20 Hz, 1H) 7.23 (s, 1H) 7.28-7.34 (m, 1H) 7.38 (t, J=7.91 Hz, 1H).
Reaction SMILES: COC([C:5]1[CH:16]=[C:15](C)[C:8]2[N:9]=C(CCC)[NH:11][C:7]=2[CH:6]=1)=O.[C:18]([O:21]CC)(=[O:20])[CH3:19]>>[N:9]1[C:8]2[CH:15]=[CH:16][CH:5]=[CH:6][C:7]=2[NH:11][C:19]=1[C:18]([OH:21])=[O:20]
Reactant: CCOC(C)=O
Reactant: CCCc1nc2c(C)cc(C(=O)OC)cc2[nH]1
Product: O=C(O)c1nc2ccccc2[nH]1

Procedure:
An acidic solution (e.g., HCl:water, 30:70) is added to compound (1a) dissolved in a solvent such as methanol. The mixture is refluxed until completion (˜12-36 hours), then concentrated under reduced pressure or in vacuo to afford compound (1b) as a solid. The recovered material may be used without further processing. Alternately, the solid may be dissolved in ethyl acetate, washed with saturated NaHCO3, dried over MgSO4 and concentrated. Acidic solutions used include sulfuric acid and a hydrogen chloride solution (30:70, HCl:H2O). Examples of compound (1a) include 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (R2=methyl, R3=propyl), which is commercially available, and is particularly well-suited for use in preparing compounds of the invention. If desired, different R2 and R3 groups can be introduced in later steps. Examples of compound (1b) include 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[C:10](=N/[S@@](C(C)(C)C)=O)/[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]([O:22][CH3:23])(=[O:21])[CH3:20]>>[CH3:23][O:22][C:19](=[O:21])[CH2:20][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:11]
Reactant: COC(C)=O
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cccc([N+](=O)[O-])c1
Product: COC(=O)CC(C)c1cccc([N+](=O)[O-])c1

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(3-nitro-phenyl)-(E)-ethylidene]-amide and methyl acetate, the product (S)-3-(R)-2-methyl-propane-2-sulfinylamino)-3-(3-nitro-phenyl)-butyric acid methyl ester was obtained as a pale yellow oil. MS (ESI): m/z=343.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:21])[CH2:15][C:16](OCC)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH3:21])[CH2:15][CH2:16][OH:17])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)N1CCC(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CCO)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of ethyl 3-(4-benzylpiperidin-1-yl)butyrate (0.60 g, 2.0 mmol) in dry THF (10 mL) was added portionwise LiAlH4 (0.15 g, 3.9 mmol). The resulting heterogeneous mixture was stirred at 25° C. for 2 h then quenched with MeOH. The resulting mixture was diluted with EtOAc (100 mL), washed with NH4Cl (100 mL) and brine (100 mL), dried and was concentrated under reduced pressure. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as solvent to afford the title compound as a colorless solid (0.38 g, 80%): mp 74-76° C.; 1H NMR (CDCl3) δ1.00 (d, J=6.6 Hz, 3H), 1.15-1.45 (m, 3H), 1.50-1.65 (m, 1H), 1.65-1.80 (m, 2H), 1.85-2.15 (m, 3H), 2.40-2.60 (m, 3H), 2.82 (bd, J=11.1 Hz, 1H), 2.90-3.10 (m, 2H), 3.80-4.00 (m, 2H), 6.55 (bs, 1H), 7.19 (t, J=7.2 Hz, 2H), 7.24 (d, J=6.9 Hz, 1H), 7.32 (t, J=7.2 Hz, 2H); MS (m/z) 247, 248, 232, 202, 91. Anal. Calcd for C16H25NO: C, 77.68, H 10.18; N, 5.66. Found C, 77.56; H 10.22; N, 5.63.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.[I:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:15][C:14]=1[C:24]([OH:26])=[O:25].[C:27](O)([CH3:30])([CH3:29])[CH3:28].C(=O)(O)[O-]>ClCCl>[C:27]([O:25][C:24]([C:14]1[S:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:17][C:13]=1[I:12])=[O:26])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)c1sc(-c2ccccc2)cc1I
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1sc(-c2ccccc2)cc1I
Reaction time: 19.5 h
Yield: 44.1 %

Procedure:
A suspension of magnesium sulfate (4.61 g, 38.32 mmol) in dichloromethane (37 ml) at 21° C., under N2, was treated with conc H2SO4 (510 μl, 9.58 mmol). After 15 min solid 3-Iodo-5-phenyl-thiophene-2-carboxylic acid (3.7 g, 9.58 mmol) was added followed by t-butanol (4.55 ml, 47.9 mmol) and the flask was stoppered and left over-night for 19.5 h. The reaction mixture was treated with saturated bicarbonate aqueous solution, and filtered. The solid was washed with CH2Cl2 and the filtrate dried and concentrated to an oil. The crude material was purified by flash chromatography using Hexane/CH2Cl2 (3:1) as eluent to give 1.63 g (44%) of 3-Iodo-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester as a colorless solid. NMR 1H (CDCl3, 400 MHz) 7.61-7.59 (m, 2H); 7.43-7.35 (m, 3H), 7.25 (s, 1H), 1.60 (bs, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:10]([C:14]([CH:16]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[CH:19]=3)[OH:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Bi]=O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)cc(C(O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2ccccc2)c1
Agent: O=[Bi]
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc(C(=O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2ccccc2)c1
Yield: 56.5 %

Procedure:
The benzil was synthesized according to the procedure of Example 41, Step 3 using the benzoin of Step 1 (1.85 g, 6.6 mmol) and bismuth oxide (3.3 g, 7.3 mmol) in acetic acid (15 ml). There was obtained 1.6 g (90%) of the desired benzil as a crystalline solid: mp 115-116° C. Anal. Calc'd. for C15H10FClO2 (MW 276.70): C, 65.11; H, 3.64. Found: C, 65.00; H, 3.48.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=2)=[O:4].[C:29]([O-:32])(=[O:31])C.[K+].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:29]([OH:32])=[O:31])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(OS(=O)(=O)C(F)(F)F)cc2c(CC2CCCC2)n1
Reactant: CC(=O)[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc(C(=O)O)cc2c(CC2CCCC2)n1
Temperature: 75 °C
Yield: 33.8 %

Procedure:
To a solution of 1-cyclopentylmethyl-7-trifluoromethanesulfonyloxy-isoquinoline-3-carboxylic acid methyl ester (0.150 g, 0.359 mmol) in DMSO (7.0 mL) was added potassium acetate (0.317 g, 3.23 mmol), dppf(0.140 mmol), dppp (50 mg), and Pd(OAc)2 (20 mg). The reaction mixture was degassed under vacuum for 5 min and then CO gas was purged through the reaction mixture for 10 min. The reaction mixture was then heated at 75° C. overnight under an atmosphere of CO gas. The reaction mixture was diluted with DCM and extracted with 10% citric acid solution. The organic phase was dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using EtOAc to give 38 mg of 1-cyclopentylmethyl-isoquinoline-3,7-dicarboxylic acid 3-methyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=O.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C1COCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1/[CH:8]=[N:16]/[S@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: Cn1ncc(C=O)c1Cl
Solvent: C1CCOC1
Product: Cn1ncc(/C=N/[S@@](=O)C(C)(C)C)c1Cl
Temperature: 25 °C
Yield: 88.7 %

Procedure:
5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde (500 mg, 3.46 mmol) was suspended in THF (20 ml), Ti(OEt)4 (1.51 ml, 7.26 mmol) was added followed by (S)-(+)-2-methyl-2-propanesulfinamide (440 mg, 3.63 mmol) and the reaction heated to reflux for 6 hours. The reaction was then cooled to room temperature, poured onto EtOAc:Brine (20 ml: 20 ml) filtered through celite and washed through with EtOAc (2×20 ml). The organic layer was then separated, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to give the title compound as a brown viscous oil (760 mg, 88.7% yield). 1H NMR (400 MHz, CDCl3) 1.22-1.23 (9H s) 3.88 (3H s) 7.92 (1H s) 8.43 (1H br. s) MS (ESI/APCI) m/z 248 (M+H)+
Reaction SMILES: C([C:3]1[C:13]2[CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[O:8][C:7]=2[CH:6]=[C:5]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][CH3:32])[N:26]=2)[CH:4]=1)C.[OH-].[Na+]>CCO>[CH3:32][NH:31][C:27]1[N:26]=[C:25]([CH2:24][CH2:23][O:22][C:5]2[CH:4]=[CH:3][C:13]3[CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10]4[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=4[O:8][C:7]=3[CH:6]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCc1cc(OCCc2cccc(NC)n2)cc2c1CC(CC(=O)O)c1ccccc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cccc(CCOc2ccc3c(c2)Oc2ccccc2C(CC(=O)O)C3)n1
Reaction time: 20 h
Yield: 68.5 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-[2-[6(methylamino)pyridin-2-yl]-1-ethoxy]dibenzo[b,f]oxepine-10-acetic acid (0.26 mmole) and 0.991 N NaOH (0.525 mL, 0.52 mmole) in absolute EtOH (2 mL) was warmed in an oil bath set at 50° C. After 20 hr, the reaction was concentrated on the rotavap and the residue was dissolved in H2O (1.5 mL). The solution was filtered to remove insoluble material, and the filtrate was carefully neutralized by dropwise addition of 1.0 N HCl. The precipitate was collected and dried in high vacuum to afford the title compound (72 mg, 30% for 2 steps) as an off-white solid: MS (ES) m/e 405.0 (M+H)+. Anal. Calcd for C24H24N2O4.1.25HCl. 0.25H2O: C, 63.42; H, 5.71; N, 6.16. Found: C, 63.35; H, 5.9; N, 6.16.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:29][NH2:30])=[O:28])[CH2:23][CH2:22]1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:30][NH:29][C:27]([CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)=[O:28])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)C1CCOCC1
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CCOCC1
Yield: 54.6 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tetrahydro-2H-pyran-4-carbohydrazide (952 mg) described in Reference Example 2, 309.8 mg of the title compound was afforded (yield 54.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:29][CH3:30])[N:4]=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](O)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CC(O)C>[S:37]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][C:5]([O:29][CH3:30])=[CH:6][CH:7]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Solvent: CC(C)O
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](OS(=O)(=O)c3ccc(C)cc3)C[C@H]21
Temperature: 60 °C
Yield: 97.1 %

Procedure:
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol (1.5 g; 3.6 mmol) is dissolved in 9 ml of 2-propanol. The solution is heated up to 60° C. 723 mg (3.8 mmol) of p-toluenesulfonic acid are added. The solution is cooled down to room temperature and stirred over night. From a part of the solution seed crystals are produced and added to the remaining solution. The crystals are filtered off and dried to obtain 1.98 g (94%) of the title compound (m.p.: 218° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH:26](I)([CH3:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)I
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OC(C)C)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and isopropyl iodide, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>ClCCl>[C:8]([CH:2]([NH:1][C:23]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:24])[C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:9]
Reactant: CCOC(=O)C(N)C#N
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C#N)NC(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 18.3 g (143 mmol) of ethyl amino(cyano)acetate in 500 mL of anhydrous dichloromethane were added 30 mL (214 mmol) of triethylamine and 23 mL (171 mmol) of cyclohexanecarbonyl chloride, and the mixture was stirred for 3 hours at 0° C. Then, saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate to give the solid substance. The obtained solid substance was collected and the filtrate was removed under reduced pressure. The obtained residue was treated with ethyl acetate to give solid substance. This treatment was further repeated. The filtrate was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to give crude crystalline. The obtained crude crystalline was washed with ether and combined with the above all solid products to give 24.3 g (71%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:25])[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([C:22](O)=[O:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[O:10])[CH:7]=1.Cl.C[O:28][C:29](=[O:33])[C@H:30]([CH3:32])[NH2:31].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.CC1C=C(C=C(C)C=1)NC(CC1C=CC(OC(C)(CC)C(O)=O)=CC=1)=O>CN(C)C=O>[CH3:25][C:4]1[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:20])([CH3:21])[C:22]([NH:31][CH:30]([CH3:32])[C:29]([OH:28])=[O:33])=[O:23])=[CH:14][CH:13]=2)=[O:10])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: COC(=O)[C@H](C)N
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)O)cc2)c1
Agent: CCC(C)(Oc1ccc(CC(=O)Nc2cc(C)cc(C)c2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)NC(C)C(=O)O)cc2)c1

Procedure:
Using RSR13 acid (1.4 g, 4.1 mmol), appropriate (D or L) alanine methyl ester hydrochloride (575 mg, 4.1 mmol) and 1-hydroxybenzotriazole hydrate (610 mg, 4.5 mmol), N-methylmorpholine (622 mg, 6.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (946 mg, 4.9 mmol) in dimethylformamide (30 mL), the two isomers were prepared and isolated as described above for compound 21, in 1.67 g yield (98%).