Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Ca+2].[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>O1CCOCC1>[OH:8][C:7]1[CH:6]=[C:5]([CH3:9])[CH:4]=[CH:3][C:2]=1[NH:1][C:15](=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccc(N)c(O)c1
Reactant: CCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: CCCC(=O)Nc1ccc(C)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
To 30 ml of dioxane, there were added 1.50 g (12.6 mmol) of 6-amino-m-cresol and 0.6 g (6.0 mmol) of calcium carbonate. To the solution thus obtained, there was added 1.02 g of butanoyl chloride over 10 minutes, followed by stirring at room temperature for 30 minutes. After the completion of the reaction, the inorganic salt was filtered and 150 ml of water was poured thereto. Then the mixture was extracted with 150 ml of ethyl acetate, washed with a saturated aqueous solution of common salt and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, a red oily product was obtained. This product was crystallized by adding thereto 15 ml of hexane and 6 ml of ethyl acetate, and then filtered and dried. Thus 0.62 g (3.2 mmol) of N-(2-hydroxy-4-methylphenyl)butanamide was obtained as colorless crystals. The yield was 25%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:16])/[CH:11]=[CH:12]/OCC.C1C(=O)N(Br)C(=O)C1.[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH:33][C:34]([NH2:36])=[S:35])[CH:27]=1>C1COCC1.O>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH:33][C:34]2[S:35][C:11]([C:10]([NH:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:16])=[CH:12][N:36]=2)[CH:27]=1
Reactant: Cc1nc(Cl)cc(NC(N)=S)n1
Reactant: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 21 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a slurry of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide 5B (120 mg, 0.50 mmol) in THF (0.75 ml) and water (0.5 mL) was added NBS (98 mg, 0.55 mmol) at 0° C. The mixture was warmed and stirred at 20-22° C. for 3h. To this was added 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea 5A (100 mg, 0.49 mmol), and the slurry heated and stirred at reflux for 2h. The slurry was cooled to 20-22° C. and the solid collected by vacuum filtration giving 140 mg (71% yield) of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][CH2:24][CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][C:2]([NH:10][CH2:25][CH2:24][CH2:23][CH2:22][N:13]1[C:14](=[O:21])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]1=[O:11])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3]
Reactant: CC(C)(N)c1ccccn1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1

Procedure:
Using General Procedure B, reaction of 1-methyl-1-pyridin-2-yl-ethylamine (Chakravarty, P K et al. Bioorg. Med. Chem. Lett. 2003, 13, 147-150) with 4-(1,3-Dioxo-1,3-dihydroisoindole-2-yl)-butyraldehyde and NaBH(OAc)3 gave 2-[4-(1-methyl-1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione as a colorless oil. 1H NMR (CDCl3) δ 1.46 (s, 6H), 1.50-1.56 (m, 2H), 1.60-1.74 (m, 2H), 2.31 (t, 2H, J=7.0 Hz), 3.65 (t, 2H, J=7.1 Hz), 7.07-7.14 (m, 1H), 7.39 (d, 1H, J=8.3 Hz), 7.63 (td, 1H, J=7.7, 1.8 Hz), 7.66-7.74 (m, 2H), 7.77-7.87 (m, 2H), 8.56 (d, 1H, J=3.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=O)[CH:8]=2)[N:3]=1.Cl.[O:34]([NH2:36])[CH3:35]>CO.N1C=CC=CC=1>[CH3:35][O:34][N:36]=[C:25]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[CH:10]2)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CON
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(c1ccccc1)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C

Procedure:
To a solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.090 g, 0.213 mmol) in MeOH (4.0 mL) was added methoxylamine hydrochloride, 98% (0.089 g, 1.063 mmol) followed by 3 drops of pyridine. The reaction mixture was brought up to reflux for 41 h until the conversion was completed, as determined by LCMS. The reaction mixture was cooled to RT and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA) to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone O-methyl oxime as a off-white solid. MS (ESI, pos. ion) m/z: 453 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([NH:7][C:8]2[C:9]([C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)=[C:5]([F:23])[CH:4]=1)#[CH:2]>CO.C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:22]=[CH:21][C:6]([NH:7][C:8]2[C:9]([C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)=[C:5]([F:23])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Yield: 100 %

Procedure:
4-(4-Ethynyl-2-fluoroanilino)-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH/THF in the presence of 5% Pd/C as for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-(4-ethyl-2-fluoroanilino)-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (100%), m.p. (EtOAc/MeOH) 256-258° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.29 (br s, 1H), 10.00 (s, 1H), 8.43 (t, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.33 (t, J=8.4 Hz, 1H), 7.19 (dd, J=11.9, 1.5 Hz, 1H), 7.08 (dd, J=8.2, 1.5 Hz, 1H), 5.32 (s, 1H), 4.71 (t, J=5.7 Hz, 1H), 3.49 (q, J=5.9 Hz, 2H), 3.29-3.24 (m, 2H), 2.62 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H). Anal. Calcd for C16H18FN3O3: C, 60.2; H, 5.7; N, 13.2. Found: C, 60.2; H, 5.7; N, 13.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[Cl:13][C:14]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17]>CN1CCCC1=O>[Cl:13][C:14]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:15]=1[C:16]([NH:18][C:19]([NH:5][C:4]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:20])=[O:17]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CN1CCCC1=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Yield: 96.7 %

Procedure:
1 g (5.9 mmol) of 2-methoxy-5-nitroaniline were admixed with 1.3 g (5.9 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate from stage a in 2 ml of N-methylpyrrolidone and reacted at room temperature for one hour. The precipitate was filtered off, washed twice with 5 ml of acetonitrile each time and dried under high vacuum. 2.2 g of the desired product were obtained which were used in stage c without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[S:21][C:20]2[CH:22]=[C:23]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])[CH:24]=[CH:25][C:19]=2[CH:18]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:34])[C:2]([CH3:35])([CH3:36])[CH3:1])=[C:7]([CH3:33])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)NCC(=O)O)cc2s1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)NCC(=O)O)cc2s1
Yield: 99.6 %

Procedure:
[(2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-6-carbonyl)-amino]-acetic acid (135 mg, 0.265 mmol) is reduced using NaBH4 (20 mg, 0.530 mmol) as in example 2 to afford the title compound (135 mg, 99%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]S(C)(=O)=O)[CH2:5]1)(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][NH:26]2)=[CH:22][CH:21]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:32]2[CH2:33][CH2:34][CH:29]([C:24]3[C:23]4[C:27](=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=4)[NH:26][CH:25]=3)[CH2:30][CH2:31]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CC(=O)N1CC(CCS(C)(=O)=O)c2ccccc21
Product: CC(=O)N1CC(CCN2CCC(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
From 19a and 6-chloro-3-(piperidin-4-yl)-1H-indole (EP Patent publication No 465398-A1). Mp 188-90° C. 1H NMR (DMSO-d6) d 1.70-1.90 (m, 3H), 1.95-2.20 (m, 5H), 2.25 (s, 3H), 2.40-2.55 (m, 2H), 2.80 (tt, 1H), 3.00-3.10 (m, 2H), 3.40-3.55 (m, 1H), 3.75 (dd, 1H), 4.20 (t, 1H), 6.95 (d, 1H), 7.05 (ddd, 1H), 7.25 (dt, 1H), 7.35 (d, 1H), 7.55 (d, 1H), 8.00 (s, 1H), 8.25 (d, 1H). MS m/z (%): 422 (MH+, 100%), 249 (15%), 146 (19%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C([Li])CCC.[CH3:17][N:18](C=O)[CH3:19].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH2:17][NH:18][CH3:19])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1csc2ccc(Cl)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CNCc1sc2ccc(Cl)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.4 %

Procedure:
To a solution of 5-chloro-3-methyl-benzo[b]thiophene (4.98 g, 27.3 mmol) in THF (50 mL) at −40° C. was added n-butyllithium (18.7 mL of a 1.6 M solution in hexanes, 30.0 mmol) dropwise. The resulting yellow solution was stirred for 1 h and then DMF (6.3 mL, 81.9 mmol) was added in one portion. The solution was warmed slowly to room temperature and stirred overnight. Saturated aqueous NH4Cl was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.62 g, 89%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.0 Hz, 1H), 2.74 (s, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:36]=[CH:35][C:8]([C:9]([O:11][CH2:12][C:13]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[O:30][CH3:31])=[CH:21][CH:20]=[C:19]3[C:14]=2[C:15]([CH3:34])=[CH:16][C:17]([CH3:33])([CH3:32])[NH:18]3)=[O:10])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:13]([CH2:12][O:11][C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:36][CH:35]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([CH3:32])([CH3:33])[CH:16]=[C:15]3[CH3:34])=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1COC(=O)c1ccc(OC(C)=O)cc1)C(C)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(F)ccc1-c1ccc2c(c1COC(=O)c1ccc(O)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
5-(4-Acetoxybenzoyloxymethyl)-6-(4-fluoro-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 12-5, 40.9 mg, 0.0835 mmol) and potassium carbonate (24.0 mg, 0.174 mmol) were suspended in anhydrous methanol (1 mL), and the mixture was stirred at room temperature for 1.5 hours. After the unsoluble materials were filtered, the filtrate was concentrated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added thereto, and then separated. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with hexane to give the titled compound (28.8 mg) as a colorless solid. (Yield 78%)
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([N+:38]([O-])=O)[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=3)[CH2:17][CH2:18][N:19]([CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:38][C:36]1[CH:35]=[CH:34][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=4)[CH2:17][CH2:18][N:19]([CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[S:13][C:6]=23)=[C:2]([F:1])[CH:37]=1
Reactant: COCCN(CCc1cccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COCCN(CCc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Yield: 85.8 %

Procedure:
To nitro compound 155 (0.44 g, 0.78 mmol) and zinc dust (0.65 g, 10 mmol) in methanol (50 mL) was added ammonium chloride (0.075 g, 1.4 mmol) in water (6 mL). The resulting mixture was heated to reflux for 2 h, then cooled, filtered through celite and concentrated. Silica gel chromatography (70% ethyl acetate/hexanes) afforded title compound 156 (0.36 g, 88% yield). MS (m/z): 538.3 (M+H).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:11]([CH:13]([CH3:15])[CH3:14])=[O:12])=[C:8]([OH:10])[CH:9]=1>C(O)(C)C.C(OC)(C)(C)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:11]([OH:12])[CH:13]([CH3:14])[CH3:15])=[C:8]([OH:10])[CH:9]=1
Reactant: CC(C)C(=O)c1ccc(Br)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CC(C)C(O)c1ccc(Br)cc1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
40.8 g (1.08 mol) of sodium borohydride are added to 1,100 ml of isopropanol, and 261 g (1.08 mol) of the 5-bromo-2-(1-methylethylcarbonyl)phenol from Example 2, dissolved in 300 ml of isopropanol, are added dropwise. The mixture is subsequently stirred at 80° C. for 2 hours and cooled, the solvent is removed, and the residue obtained is taken up in methyl tert-butyl ether (MTBE) and ice water. The mixture is extracted by shaking, the organic phase is separated off, and the aqueous phase is back-extracted several times with MTBE. The combined organic phases are dried and freed from solvent at 20° C. under reduced pressure. The residue obtained in this way is recrystallized from n-hexane, an optimum yield being obtained by cooling the mixture to -40° C. for crystallization.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:11]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C)C=O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:12]2[C:11]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:10]([CH2:9][N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[N:15]=[C:14]3[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=23)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
Sodium hydride (60% in oil, 0.171 g) was added to a solution of 1H-1,2,4-triazole (0.271 g) in N,N-dimethylformamide (DMF) (15 ml). The mixture was stirred for 15 minutes at room temperature, to which was added ethyl 6-chloromethyl-4-(3,4-dimethoxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.5 g). The mixture was stirred for 35 minutes at 80° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (30:1, v/v), ethyl 4-(3,4-dimethoxyphenyl)-2,3-dimethyl-6-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate (1.0 g, 62%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.136°-137° C.
Reaction SMILES: O1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:11]/[OH:12])/[CH2:3][CH2:2]1.[CH3:13][O:14]C1C=C2C(=CC=1)C(=O)CC2>>[CH3:13][O:14][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: O/N=C1\CCOc2ccccc21
Product: COc1ccc2c(c1)CCC2=NO

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 5-methoxyindan-1-one and making non-critical variations provided the title compound as a oil: HRMS (EI) calcd for C10H11O2 177.0790, found 177.0783. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.73; H, 6.34; N, 7.77.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH:10]([CH2:23][C:24]([OH:26])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CO.[Pd]>[O:26]=[C:24]1[NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH:10]2[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2[N+](=O)[O-])C(CC(=O)O)C1
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The product of Example 22C (658 mg, 1.801 mmol) was dissolved in methanol (50 mL) and 10% Pd/C (52 mg) was added. The flask was evacuated and purged with nitrogen (3 cycles) and then with hydrogen (3 cycles), and the reaction was stirred at room temperature under hydrogen (1 atm) for 7 hours. The flask was evacuated and purged with nitrogen (3 cycles), and the reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated under vacuum, and the residue was dissolved in tetrahydrofuran (25 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (680 mg, 1.788 mmol) and diisopropylethylamine (1 mL) were added, and the mixture was stirred at room temperature for 14 hours and then concentrated under vacuum. The residue was purified by chromatography (SiO2, eluted with hexanes-ethyl acetate, 100:0-50:50) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.18 (d, J=13.5 Hz, 1H), 2.74 (dd, J=13.3, 6.9 Hz, 1H), 2.88-3.30 (m, 5H), 4.01-4.19 (m, 2H), 6.93-6.98 (m, 1H), 7.01-7.10 (m, 2H), 7.16 (s, 1H), 7.17-7.24 (m, 1H); MS (DCI) m/z 318 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]([NH:20][NH2:21])=O)=[CH:4][CH:3]=1.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=N)[NH2:30].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[NH:30][C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)=[N:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: N=C(N)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc3ccccn3c2Cc2nnc(-c3ccccn3)[nH]2)cc1
Temperature: 120 °C

Procedure:
A mixture of 2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetohydrazide (0.55 mmol, 1.0 eq) in DMF (1-2 ml) and picolinimidamide hydrochloride (1.5 eq) was heated at 120° C. for 3 h. The mixture was cooled to rt, treated with sat. NaHCO3 (5 ml), extracted with CH2Cl2 (10 ml). The organic solution was dried with Na2SO4, evaporated under vacuum. The crude product was purified by HPLC. M/e+ 387 for C21H16ClN6 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ 9.11 (d, J=1.4 Hz, 1H), 8.56 (d, J=3.7 Hz, 1H), 8.36 (d, J=6.2 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.70 (dt, J=8.4, 2.9 Hz, 2H), 7.36 (m, 2H), 6.99 (m, 2H), 4.64 (s, 2H) ppm.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]1[CH2:26][O:25]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:27][NH:28][CH3:29]>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]([OH:25])[CH2:26][N:28]([CH3:29])[CH3:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C3CO3)cccc2c1Nc1ccccc1C
Reactant: CNC
Product: CCCC(=O)c1cnc2c(C(O)CN(C)C)cccc2c1Nc1ccccc1C
Yield: 28 %

Procedure:
A mixture of 3-butyryl-4-(2-methylphenylamino)-8oxiranylquinoline (1.0 g, 2.89 mmol) and 33% w/w dimethylamine in methylated spirits (10 ml) was heated at 95° for 2 hours in a pressure vessel. After cooling and evaporation of the solvent, the residue was purified by flash chromatography (silica gel, methanolic ammonia/dichloromethane) and crystallistion from aqueous ethanol to give 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxy-2-dimethylaminoethyl)quinoline (0.32 g, 28%), m.p. 95°-96°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([CH2:14][OH:15])[CH2:3]1.[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:16]([OH:22])=[O:17].[OH:15][CH2:14][C@@H:4]1[NH:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1C[C@@H](O)CN1

Procedure:
1,1-Dimethylethyl(2R,4R)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.185 g, 0.852 mmol) was stirred in a 1:1 solution of methylene chloride:TFA for 14 hours. The reaction was concentrated, and the crude material was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.5 (m, 1 H), 2.2 (m, 4 H), 3.0 (m, 1 H), 3.1 (m, 1 H), 3.6 (m, 3 H), 4.3 (m, 1 H), 5.3 (s,br, 2 H), 8.6 (s,br, 1 H), 9.2 (s,br, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:24]O)[CH:12]([CH2:13][OH:14])[C:11](=[O:15])[N:10]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH2:24][O:14][CH2:13][CH:12]1[C:11](=[O:15])[N:10]([C@@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:9]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)C(CO)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)COCC2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
To a cooled (0° C.) solution of (3S)-3,4-bis(hydroxymethyl)-5-oxo-1-[(R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (710 mg, 2.03 mmol) and triphenylphosphine (450 mg, 2.64 mmol) in tetrahydrofuran (10 mL) was added a solution of 40% diethyl azodicarboxylate in toluene (1.06 mL, 2.33 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 6 h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 40% AcOEt in hexane to afford the title compound (435 mg) as a white solid.