Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[OH:6].CO[C:18](=O)[C@@H:19](O)[C@@H](C1C=CC=CC=1Cl)O>>[CH3:1][O:2][C:3]([C@@H:4]1[C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[O:6][CH:18]([CH3:19])[O:14]1)=[O:15]
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccccc1Cl
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccccc1F
Product: COC(=O)[C@H]1OC(C)O[C@@H]1c1ccccc1F
Yield: 70 %

Procedure:
The substantially same method as described in Example 60 was conducted, except that (2S,3R)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation example 81) was used instead of ((2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate, to obtain the title compound (3.1 g, 70˜95%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[N:19]=[C:18](Cl)[CH:17]=[C:16]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:15]=2)=[CH:9][CH:8]=1)=[O:5].[NH:32]1[CH2:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[N:32]1([C:18]2[CH:17]=[C:16]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:15]=[C:14]([S:13][C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[Cl:1])=[CH:12][CH:11]=3)[N:19]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: C1CNC1
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)c4ccccc4Cl)cc3)n2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(NC(=O)c4ccccc4Cl)cc3)n2)[nH]n1
Temperature: 90 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
A 500 mL round bottom flask was charged with 2-chloro-N-{4-[4-chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-benzamide (16.0 g, 34.0 mmol), azetidine (3.87 g, 68.0 mmol), N,N-diisopropylethylamine (13.0 mL, 74.7 mmol) and n-butanol (250 mL). The reaction mixture was stirred at 90° C. for 5 h. The reaction mixture was cooled and concentrated in vacuo. Diethyl ether (200 mL) was added and a light brown solid precipitated. The solution was filtered and the solid recrystallized from ethanol to give the pure product as a white solid (9.42 g, 52%) 1H NMR (DMSO): 2.04 (3H, s), 2.32 (2H, m), 3.87 (4H, m), 5.39 (1H, s), 5.66 (1H, br s), 7.48-7.59 (6H, m), 7.82 (2H, m), 9.87 (1H, s), 10.74 (1H, s), 11.68 (1H, s); MS (ES+): 492.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1>C1C=CC=CC=1>[Cl:11][C:12]1[C:17]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: Clc1nccnc1Cl
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1nccnc1OCc1ccccc1

Procedure:
Sodium hydride (0.10 mole) is added to 0.10 mole of benzyl alcohol in 100 ml. dry benzene and the mixture is refluxed 1-2 hours. The cooled solution is treated with 0.10 mole of 2,3-dichloropyrazine in 100 ml. of benzene. The mixture is refluxed for 20-60 hours, cooled, washed with water, dried, and evaporated and the product distilled in vacuo to give 2-chloro-3-benzyloxypyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:25][C:26]1[N:31]=[C:30]([O:32][CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:29]=[CH:28][CH:27]=1)(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[N:13]([CH2:25][C:26]4[N:31]=[C:30]([O:32][CH2:33][C@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:29]=[CH:28][CH:27]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(COS(C)(=O)=O)n1
Reactant: O=c1[nH]ncc2cc(-c3ccc(Cl)cc3)sc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(Cn2ncc3cc(-c4ccc(Cl)cc4)sc3c2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Chlorophenyl)thieno[2,3-d]pyridazin-7(6H)-one (285 mg, 1.1 mmol) was added to dry DMF (5 mL) and NaH (71 mg, 55% in mineral oil, 1.6 mmol) was added in small potions and stirred 10 min. tert-butyl (2R)-2-{[(6-{[(methylsulfonyl)oxy]methyl}pyridin-2-yl)oxy]methyl}pyrrolidine-1-carboxylate (420 mg, 1.1 mmol) dissolved in dry DMF (3 mL) was added drop wise and the reaction mixture was stirred at ambient temperature for 3 h. Water was added and the aqueous phase was extracted three times with DCM. The organic phase was evaporated and purified by flash chromatography using a gradient of EtOAc/heptane to give the title compound as a yellow solid. Yield: 380 mg (63%). 1H NMR (399.961 MHz, CDCl3) δ 8.22 (s, 1H), 7.64 (d, J=8.7 Hz, 2H), 7.53-7.42 (m, 4H), 6.72 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 5.48 (s, 2H), 4.41-4.01 (m, 3H), 3.43-3.25 (m, 2H), 1.97-1.74 (m, 4H), 1.42 (s, 9H). MS (ESI+) 553.3 (M+1H+)
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].O1CCN([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)CC1.O(C)[Na]>C1COCC1>[C:20]1([CH:21]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:23]=[CH:24][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 83.5 %

Procedure:
2.15 g (15.8 mmol) of 2-hydroxyacetophenone, 2.8 g of 4-morpholinobenzaldehyde (14.5 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 2.52 g (56%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.99 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.93-7.84 (m, 3H), 7.52-7.48 (m, 2H), 7.03 (d, d, J=0.9, 8.4 Hz, 1H), 6.97-6.92 (m, 1H), 6.68 (d, J=9.0 Hz, 1H), 3.86-3.83 (m, 4H), 3.69-3.66 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH2:22].CO>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:22]([CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NCc1ccccn1
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccccn1
Temperature: 150 °C
Yield: 49.8 %

Procedure:
Into a microwave vial was combined 5-nitro-isochromen-1-one (1 g, 0.005 mol), 2-pyridinemethanamine (1 g, 0.009 mol), and methanol (20 mL, 0.5 mol). The mixture was heated at 150° C. for 2 hours. The mixture was cooled to room temperature. The usual work up of the reaction mixture gave a crude product which was then purified using a flash chromatography over silica gel to give the pure product as a yellow solid (0.7 g). MS m/z=282.4 (M+1).
Reaction SMILES: I[C:2]1[N:3]([CH3:13])[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1.[CH3:14][C:15]1[S:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CN(C=O)C>[CH3:13][N:3]1[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=[C:2]1[C:18]1[S:19][C:15]([CH3:14])=[CH:16][CH:17]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1ccc(-c2cn(C)c(I)n2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn(C)c(-c3ccc(C)s3)n2)s1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 2-iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 6 (1.31 g, 4.31 mmol), 5-methylthiophene-2-boronic acid pinacol ester (1.35 g, 6.03 mmol), Na2CO3 (1.80 g, 17.2 mmol) in H2O (10 mL) and DMF (40 mL) was degassed (N2 bubbling). Pd(PPh3)4 (125 mg) was added and the mixture was heated to reflux for 5 h. The mixture was allowed to cool to room temperature and concentrated. The mixture was diluted with EtOAc and H2O and the organic phase was separated. The aqueous phase was re-extracted (EtOAc) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 10:90 then 15:85 then 20:80) to give 1-methyl-2,4-bis(5-methylthiophen-2-yl)-1H-imidazole 7 (930 mg, 79%) as a colourless solid. A portion of this material was further purified by, firstly, recrystallisation (EtOAc/hexanes) and, secondly, by sublimation (130° C., 10−6 mBar): m.p. 138-140° C. 1H NMR (CDCl3, 400 MHz) δ2.48 (d, J=0.7 Hz, 3H), 2.51 (d, J=0.7 Hz, 3H), 3.76 (s, 3H), 6.64-6.67 (m, 1H), 6.73-6.77 (m, 1H), 7.00 (s, 1H), 7.10 (d, J=3.4 Hz, 1H), 7.14 (d, J=3.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ15.2, 15.3, 34.5, 117.0, 122.1, 125.5, 125.6, 126.7, 136.3, 137.7, 141.5, 142.4; HRMS (EI) m/z 274.0589 C14H14N2S2 [M]+. requires 274.0593.
Reaction SMILES: C([Li])CCC.C1(PC2C=CC=CC=2)C=CC=CC=1.C[O:20][C:21]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([O:35][CH2:36][CH2:37][CH3:38])=[CH:27][C:28]=1[C:29]2=[O:34]>C1COCC1>[OH:20][C:21]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([O:35][CH2:36][CH2:37][CH3:38])=[CH:27][C:28]=1[C:29]2=[O:34]
Reactant: CCCOc1ccc2c(c1)C(=O)c1cccc(OC)c1-2
Agent: [Li]CCCC
Agent: c1ccc(Pc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Reaction time: 0.5 h

Procedure:
Add n-butyl-lithium (4.80 mL, 0.012 mole) in THF (60 mL) dropwise to diphenylphosphine (Ph2PH, 2.34 g, 0.012 mole) at -20° C. Warm to resulting red solution to abient temperature, then stir for 30 minutes. Prepare a solution of 5-methoxy-2-propoxy-fluoren-9-one (0.88 g, 3.3 mmole) in THF (20 mL) and add to the stirred dark-red Ph2PH solution, stirring for an additional hour while the color changes from dark-red to brown, then heating at reflux for 15 minutes. Cool to abient temperature, then quench with a saturated solution of NH4Cl. Separate the THF layer, wash with brine, dry over MgSO4, filter and concentrate the filtrate to an orange oil. Dissolve the oil in CH2Cl2 and extract with 5% aq. NaOH (50 mL) as a purple solid formed in the aqueous layer.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cnccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cnccc2c1Cl

Procedure:
Prepared according to procedure E using 2,4-dichloro-3-methyl-1,7-naphthyridine (200 mg, 0.94 mmol), 2-tri-n-butylstannylpyridine (0.35 mL, 0.939 mmol), Pd(PPh3)4 (108 mg, 0.094 mmol) with heating in toluene (10 mL) for 14 h. After purification 4-chloro-3-methyl-2-(pyridin-2-yl)-1,7-naphthyridine was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[NH:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:8][C:7]=1[O:23][CH3:24])[CH3:2].[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:25])[N:5]([CH2:28][CH3:29])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:8][C:7]=1[O:23][CH3:24])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)Nc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(CC)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 12 g. of 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxycarbanilic acid ethyl ester and 2 g. of sodium hydride (50% dispersion in oil) in 100 ml. of absolute dimethylformamide was stirred at room temperature for 4 hours and then treated with 6.5 g. of ethyl iodide. After stirring at room temperature for 30 minutes, the dimethylformamide was removed at 60° C. under vacuum. The residue was taken up in 250 ml. of water and the precipitated product extracted with two 600 ml. portions of ethyl acetate. The ethyl acetate extract was washed with two 300 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on 350 g. of silica gel using ethyl acetate/alcohol (3:1) and there was obtained N-ethyl-4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-carbanilic acid ethyl ester having a melting point of 165°-167° C. (recrystallization from ethyl acetate).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][N:24]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[C:25]4=[O:28])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:6][C:5]=1[C:34]([O:36]C)=[O:35]>O1CCOCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][N:24]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[C:25]4=[O:28])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:6][C:5]=1[C:34]([OH:36])=[O:35]
Reactant: COC(=O)c1cc(-c2ccc(COc3ccc4c(c3)C(=O)N(C3CCCC3)CC4)cc2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc(COc3ccc4c(c3)C(=O)N(C3CCCC3)CC4)cc2)ccc1Cl
Temperature: 25 °C
Yield: 87.5 %

Procedure:
50% Aqueous NaOH (0.5 mL, 0.6 mmol) was added to a solution of the crude ester (0.150 g, 0.3 mmol) in dioxane (5 mL). The reaction mixture was heated to reflux for 1 h, and then cooled to room temperature. Excess solvent was removed under reduced pressure. The residue was diluted with water and then acidified using 1M HCl. Extraction using ethyl acetate, followed by silica gel column chromatography afforded 4-chloro-4′-((2-cyclopentyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)biphenyl-3-carboxylic acid as colorless solid (0.125 g, 88%). Final HPLC purification was performed using isopropyl alcohol (IPA):H2O solvent system. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 7.60-7.78 (m, 2H), 7.63-7.45 (m, 5H), 7.15 (d, 1H, J=8.6 Hz)), 7.09 (d, 1H, J=8.6 Hz), 5.17 (s, 2H), 4.97-4.93 (m, 1H), 3.34 (t, 2H, J=6.1 Hz), 2.86 (t, 2H, J=6.1 Hz), 1.65-1.50 (m, 8H). LC-MS (ESI) Calcd for C28H26ClNO4 [M+H]+: 476.16. Found: 475.95. HRMS (ESI) calcd for C28H26ClNO4 [M+H]+: 476.1623. Found: 476.1621.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]#[N:16])([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:19]>>[ClH:19].[CH3:14][C:11]1([C:15]#[N:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC1(C#N)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round-bottomed flask, 4-cyano-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.35 g, 1.56 mmol) was dissolved in hydrogen chloride, 1.0 M solution in methanol (9.0 mL, 9.00 mmol). The reaction mixture was stirred at room temperature overnight then concentrated to give 0.27 g of 4-methyl-piperidine-4-carbonitrile hydrochloride as an off-white foam which was used without further purification.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>CO.O>[OH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(C)O

Procedure:
The same procedure of Example 5 is repeated with the only differences that 1.95 g of ethyl 3-oxo-butyrate were weighed and dissolved in MeOH/H2O 19/1 (v/v) and the catalyst of Example 15 was utilized. At the end of the reaction, the ethyl 3-hydroxybutyrate resulted to be equal to 91%, while the ethyl 3-dimetoxybutyrate resulted equal to 9%. The stereoinduction was >99% in favour of the antipode (S).
Reaction SMILES: [CH3:1][C:2]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][C:6](=O)[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CCOC(=O)C1(C)CC(=O)c2ccccc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C)CCc2ccccc2O1
Yield: 80.3 %

Procedure:
A mixture of 126 parts of ethyl 3,4-dihydro-2-methyl-4-oxo-2H-1-benzopyran-2-carboxylate and 560 parts of ethanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was distilled, yielding 95.5 parts (80.3%) of ethyl 3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylate; bp. 71°-73° C. at 0.5 mm. pressure (intermediate 27).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].I[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[CH:20][N:21]=2)[CH:18]=1.C1(C2C=CC=CC=2)C(O)=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.[Cu](I)I>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[CH:20][N:21]=2)[CH:18]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: Ic1ccc2ncnn2c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc2ncnn2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
Diethyl malonate (400 μL) was added to a mixture of 6-iodo-[1,2,4]triazolo[1,5-α]pyridine (245 mg, 1 mmol), copper iodide (19 mg, 0.1 mmol), biphenyl-2-ol (34 mg, 0.2 mmol), and Cs2CO3 in THF (5 mL). The hetereogeneous solution was stirred for 16 h at 70° C. After cooling, the mixture was partitioned between chloroform (40 mL) and aq NH4Cl (20 mL). The organic layer was washed with NH4Cl (3×15 mL), NaHCO3 (20 mL), and brine (20 mL) then was dried over Na2SO4. Concentration of the solution followed by SiO2 flash chromatography purification yielded the product (170 mg, 61%) as a colorless glass.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:3]([OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([OH:9])=[N:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(O)cc(O)c1C
Agent: O=S(=O)(O)O
Product: Cc1nc(O)c([N+](=O)[O-])c(O)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
5,6-Dimethyl-pyridin-2,4-diol (6.5 g, 47 mmol) was stirred in 30 mL sulphuric acid and then cooled to 0° C. in an ice bath. Fuming nitric acid (10 mL) was added dropwise, and the mixture allowed to stir for 1 h after complete addition. The reaction mixture was poured onto crushed ice and the resulting yellow solid collected by filtration to give the title compound (3.9 g, 46%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=O)[CH3:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>O.C(O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=[N:2][OH:3])[CH3:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NO
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C)=NO)cc1OC
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of hydroxylamine hydrochloride (3.33 grams, 48 mmol) and sodium acetate (4.92 grams, 60 mmol) in 20 milliliters of water was added to a stirring solution of 3′,4′-dimethoxyacetophenone (5.41 grams, 30.0 mmol) in a mixture of water (30 milliliters) and ethanol (30 milliliters), the solution was stirred overnight. The resulting mixture was filtered and the solid was dried in vacuo (60° C., <1 mm) to afford 4.68 grams (80%) of product as a yellow solid: mp 137-138° C.; 1H NMR (CDCl3) δ7.34-7.08 (m, 2H), 6.94-6 80 (m, 1H), 3.92 (s, 3H ), 3.90 (s, 3H), 2.28 (s , 3H); 13C NMR (CDCl3) δ155.6, 150.1, 148.8, 129.2, 119.2, 110.6, 108.6, 55.8.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1>[CH2:15]([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: CCCCOc1ccccc1N
Solvent: c1ccncc1
Product: CCCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Reaction time: 18 h
Yield: 60.1 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (21.5 g) and 2-butoxyaniline (24 g) are added to pyridine (50 ml), and the mixture is refluxed with stirring for 18 hours. The reaction mixture is concentrated to dryness. The residue is recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-butoxyanilino)-6-oxo-5-pyrimidinecarboxylate (20 g). M.p. 209°-211° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[CH:7][N:6](S(C3C=CC=CC=3)(=O)=O)[C:5]=2[C:18]([O:20]C)=[O:19])[CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][C:5]=2[C:18]([OH:20])=[O:19])[CH2:2][CH2:3]1
Reactant: COC(=O)c1c(C2CC2)ccn1S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1[nH]ccc1C1CC1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
To a suspension of the starting methyl 3-cyclopropyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (0.9 g, 3 mmol) in tetrahydrofurane (4.6 mL) and water (2.3 mL) was added lithium hydroxide (0.29 g, 12 mmol) and this mixture was heated to 100° C. in a microwave vial during 4 hours. Next, the reaction mixture was poured into water (50 mL) and this aqueous phase was washed with diethyl ether (2×). Afterwards, the aqueous layer was acidified until pH=3 by adding solid phosphoric acid and extracted with ethyl acetate (3×). The organic solution was washed with water and brine, dried (Na2SO4) and concentrated in vacuum to give 370 mg of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:14][C:13]2=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl.N>CCO.CO>[N+:18]([C:16]1[N:15]=[C:13]2[N:12]([CH:17]=1)[CH2:11][CH:10]([CH2:9][OH:8])[O:14]2)([O-:20])=[O:19]
Reactant: CC(C)(C)[Si](C)(C)OCC1Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCO
Product: O=[N+]([O-])c1cn2c(n1)OC(CO)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
A suspension of silyl ether 89 (503 mg, 1.68 mmol) in a solution of 1% HCl in 95% EtOH (desilylation conditions described by Cunico et al., 1980) (27 mL) was stirred at room temperature for 6 h, and then stored at 4° C. for 2.5 d. The resulting solution was neutralised by dropwise addition of 7M NH3 in MeOH (2 mL) with stirring, and then concentrated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 2-5% MeOH/CH2Cl2 gave (6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol-2-yl)methanol (90) (reported by Sehgal et al., 1981 via reaction of 2,4-dinitroimidazole and glycidol) (299 mg, 97%) as a white solid (after trituration with CH2Cl2): mp (CH2Cl2) 166-169° C.; 1H NMR [(CD3)2SO] δ 8.10 (s, 1H), 5.40 (m, 1H), 5.27 (t, J=5.6 Hz, 1H), 4.36 (dd, J=10.5, 8.8 Hz, 1H), 4.11 (dd, J=10.5, 6.4 Hz, 1H), 3.80 (ddd, J=12.8, 5.4, 3.0 Hz, 1H), 3.65 (dd, J=12.8, 5.8, 3.9 Hz, 1H). Anal. (C6H7N3O4) C, H, N.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]([F:30])([F:29])[C:14]([NH:16][C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[C@H:19]([OH:28])[CH2:18]1)=[O:15]>C(Cl)Cl>[F:12][C:13]([F:29])([F:30])[C:14]([NH:16][C@@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[C:19](=[O:28])[CH2:18]1)=[O:15]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Reaction time: 2 h

Procedure:
Step AF (1): Pyridinium chlorochromate (362 mg) was added to a stirred suspension of 4Ao MS and 2,2,2-trifluoro-N-((1S,3R)-3-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide (200 mg) from Step T (1) in DCM (6 mL) at rt. The resulting mixture was stirred for 2 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated in vacuo to give (S)-2,2,2-trifluoro-N-(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide. This crude product was carried forward without purification. 1H NMR (400 MHz, CD3OD) δ ppm 2.56 (m, 1H) 3.08 (m, 1H) 3.83 (s, 3H) 5.58 (m, 1H) 6.96 (m, 2H) 7.29 (m, 1H) 7.62 (s, 1H). Optical rotation [α]D=−124.16 (c=6.84 mg/mL, methanol).