Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=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.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:61]=[C:60]4[C:56]([CH:57]=[N:58][NH:59]4)=[C:55]([NH:62][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=4)[CH:54]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)c1
Reaction time: 0.08 h

Procedure:
3-Methylbenzoic acid (60 mg, 0.44 mmol) was treated with HATU (168 mg, 0.44 mmol) in DMF (0.750 mL) and DIPEA (0.15 mL, 0.86 mmol). The mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.2 mmol) in DMF (0.350 mL) and was then left to stand at room temperature for 16 hrs. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 mL) prior to application on to a pre-conditioned (methanol then chloroform) NH2 cartridge (1 g). Product was eluted after 2 hr with ethyl acetate/methanol (1:1, 3.2 mL), and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method C) afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]([C:20]([OH:22])=[O:21])[N:18]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:17]3[S:16][CH:15]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:42][C:43]([Cl:47])([Cl:46])[CH2:44]O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:42][C:43]([Cl:47])([Cl:46])[CH2:44][O:21][C:20]([CH:19]1[N:18]2[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=[C:14]1[CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22]
Reactant: OCC(Cl)(Cl)Cl
Reactant: COc1ccc(CC2=CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CC2=CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)c2ccccc12

Procedure:
A solution of 10.9 g of 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetylamino-ceph-2-em-4ξ-carboxylic acid in 300 ml of methylene chloride is treated with 1.80 ml of pyridine, then successively with 2.50 ml of 2,2,2-trichloroethanol in 20 ml of methylene chloride and 4.95 g of dicyclohexylcarbodiimide in 40 ml of methylene chloride. The addition of the reagents is carried out at room temperature and while stirring. The reaction mixture is stirred for 20 hours at room temperature, freed from dicyclohexylurea by means of filtration and the filtrate is evaporated under reduced pressure. The residue is taken up in ethyl acetate and mixed with an aqueous dipotassium hydrogen phosphate buffer solution (pH 7.5). The aqueous portion is separated, washed several times with ethyl acetate and the pH adjusted to 2.5 with 20% aqueous phosphoric acid. After repeated extraction with ethyl acetate, the organic extracts from the aqueous phase having pH 2.5 are combined, washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on 450 g of silica gel, elution being carried out with methylene chloride containing 5% of methyl acetate, fractions of 500 ml being taken. The residue of the fractions 12-13 is crystallised from ethyl acetate and yields the 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetylamino-ceph-2-em-4ξ-carboxylic acid 2,2,2-trichloroethylester, which melts at 145-147°; [α]D20 = + 271° ± 1° (c = 0,918 in chloroform); ultraviolet absorption spectrum (in methanol): λmax = 210 mμ (ε = 67000), 232 mμ (ε = 41200), 298 mμ (ε = 9990) and 322 mμ (ε = 4960); infrared absorption spectrum (in mineral oil): characteristic bands at 2,90μ, 5,62μ, 5,68μ, 6,02μ, 6,27μ and 6,60μ; thin-layer chromatogram (silica gel): Rf = 0.27 (system: toluene/ethyl acetate 4:1) and Rf = 0.38 (system: toluene/acetone 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.C([O-])(O)=O.[Na+].CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Sc3ccccc3)ccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH2Cl2 (50 mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) portionwise. The mixture was allowed to slowly warm to RT (3 hrs). The reaction mixture was diluted with CH2Cl2 then neutralized with NaHCO3 (sat.). The aqueous phase was extracted three times with CH2Cl2 then the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using 0-10% CH2Cl2:MeOH to afford 7-methoxy-4-(phenylsulfinyl)quinoline (1.37 g, 94% yield) as a off-white foam. MH+=284.0.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:19])=[O:18]
Reactant: OCCC1CCOC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCOC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-(Tetrahydro-3-furanyl)ethanol (230 mg) was dissolved in dry DCM (5 mL) and triethylamine (0.552 mL) was added. The stirred solution was cooled (ice bath) under nitrogen and methanesulphonyl chloride (0.199 mL) was added dropwise over 5 mins. The mixture was allowed to warm slowly to room temperature as the ice bath melted and was left for 16 h. The mixture was shaken with saturated sodium bicarbonate solution and the aqueous layer was extracted with DCM (×2). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound (364 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([CH3:16])[C:13](O)=[S:14])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([CH3:16])[C:13]([Cl:19])=[S:14])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CSCC(C)C(O)=S)cc1
Product: COc1ccc(CSCC(C)C(=S)Cl)cc1

Procedure:
3-[[(4-Methoxy)phenylmethyl]thio]-2-methylthiopropanoic acid prepared according to the procedure of Example 10 in U.S. Pat. No. 4,116,962 is treated with thionyl chloride to yield 3-[[(4-methoxy)phenylmethyl]thio]-2-methylthiopropionyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[Cl:16][C:17]1[C:27]([Cl:28])=[CH:26][C:20]2[NH:21][C:22](CCl)=[N:23][C:19]=2[CH:18]=1>CN(C)C=O>[Cl:28][C:27]1[C:17]([Cl:16])=[CH:18][C:19]2[N:23]=[C:22]([CH2:11][O:10][C:8]3[C:7]([O:12][CH3:13])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=3)[NH:21][C:20]=2[CH:26]=1
Reactant: ClCc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)cc1OCc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (38, 0.364 g, 2.14 mmol) was dissolved in N,N-dimethylformamide (10.0 mL) and sodium hydride (60% dispersion in mineral oil, 100 mg, 2.50 mmol) was added. After 20 minutes, 5,6-dichloro-2-chloromethyl-1H-benzoimidazole (208, 0.420 g, 1.78 mmol) was added. The reaction was stirred at 80° C. overnight. The reaction was concentrated, then washed with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography, eluting with methanol/dichloromethane, to provide the desired compound, consistent by 1H-NMR (209, 140 mg, 21%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH2:35][CH3:36]>>[NH2:32][C:23]1[C:22]2[N:21]=[C:20]([CH2:33][CH2:34][CH2:35][CH3:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][S:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
According to the general method of Example 5, 4-nitrobenzenesulfonyl chloride and 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine were combine. N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-nitro-1-benzenesulfonamide was isolated as the hydrochloride salt (white solid), m.p. 96.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.70 (very broad s, 2H), 8.38-8.34 (m, 2H), 8.19 (d, J=8.2 Hz, 1H), 8.09 (t, J=5.6 Hz, 1H), 8.03-7.99 (m, 2H), 7.80 (d, J=7.4 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 4.55 (t, J=7.4 Hz, 2H), 2.94 (t, J=7.7 Hz, 2H), 2.86 (q, J=6.2 Hz, 2H), 1.80 (m, 4H), 1.58 (m, 2H), 1.45 (q, J=7.5 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H); IR (KBr) 3283, 3100, 2957, 2870, 2782, 1670, 1606, 1528, 1347, 1311, 1162, 1092, 854, 746, 737, 686 cm−1; MS (EI) m/e 496.1902 (496.1893 calcd for C24H28N6O4S). Anal calcd for C24H28N6O4*HCl*0.85H2O: C, 52.57; H, 5.64; N, 15.33. Found: C, 52.57; H, 5.46; N, 15.33.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=O)(C)(C)C.[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[C:38]1[N:39]=[N:40][N:41]([C:43]2[CH:50]=[CH:49][C:46](C=O)=[CH:45][CH:44]=2)[CH:42]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CC(N(C)C)=O>[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[C:38]1[N:39]=[N:40][N:41]([C:43]2[CH:44]=[CH:45][C:46]([CH2:20][N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[CH:49][CH:50]=2)[CH:42]=1
Reactant: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCNCC5)cc4)nn3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) was added to a solution of tert-butyl-1-piperazinecarboxylate (1.22 g; 6.59 mmol; 10 eq.) and 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) in DMA (4 mL) and the reaction mixture was stirred overnight at RT. Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) and glacial acetic acid (75.42 μl; 1.32 mmol; 2.00 eq.) then sodium cyanoborohydride (83 mg; 1.32 mmol; 2. eq.) were added to complete the reaction which was quenched with water and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting gum was stirred at RT in a solution of HCl in dioxane (5 mL, 4N) for 2 hours. The reaction mixture was basified to pH=9-10 and extracted with EtOAc. Organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a formic acid salt. It was dissolved in MeOH and passed through a SPE-NH2 cartridge. The fractions containing the desired compound were concentrated to dryness affording a yellow gum, which was twice sonicated in 3 mL of Et2O. The suspension obtained was concentrated then dried overnight under high vacuum to afford the title compound as a beige solid. 1H NMR (300 Mz, DMSO-d6) δ: 13.23 (brs, 1H), 9.25 (s, 1H), 8.14-8.13 (m, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5 Hz, 1.5 Hz, 1H), 3.52 (s, 2H), 2.72-2.69 (m, 4H), 2.487 (s, 3H), 2.32-2.30 (m, 4H). HPLC (Condition A): Rt 2.22 min (purity 95.4%). MS (ESI+): 374.3, MS (ESI−): 372.3.
Reaction SMILES: C([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)#N>Br>[CH3:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[N:7]1[CH:8]=[CH:3][C:4](=[O:18])[NH:5][C:6]1=[O:17]
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Agent: Br
Product: Cc1cccc(C)c1-n1ccc(=O)[nH]c1=O

Procedure:
A mixture of 5-cyano-1-(2,6-dimethylphenyl)uracil (0.01 mol) and 30 ml of 48% HBr is heated at reflux for about 10 hours. After cooling, the solid product is collected by filtering, washed with water and dried to yield 1-(2,6-dimethylphenyl)uracil.
Reaction SMILES: [OH:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[C:16](Cl)(=O)C>CO>[OH:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([O:5][CH3:16])=[O:4]
Reactant: O=C(O)C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C(O)C12CC3CC(CC(C3)C1)C2

Procedure:
As shown in Scheme II, in this method, adamantyl bromide (Formula A) is alkylated via zinc chloride catalysis to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B) is then esterified using acetyl chloride in methanol to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C) is then converted to α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula D) by Swern oxidation. α-Oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula D) is then hydroxylated to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula 1a), which is then hydrolyzed to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:17][O:18]C(=O)C)[N:13]=[CH:12][C:11]=2[C:10]([CH3:23])([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:17][OH:18])[N:13]=[CH:12][C:11]=2[C:10]([CH3:23])([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(CO)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.4 %

Procedure:
To 6-acetoxymethyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.261 g, 0.82 mmol), in MeOH (8.2 mL) was added potassium carbonate (0.45 g, 3.3 mmol) at ambient temperature. The reaction was stirred for 2 h at ambient temperature. Water (10 mL) was added and the reaction extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (0.268 g) as a pale yellow oil, used without further purification. MS: [M+H]+=279.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]c2cc(Br)ccc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-1H-indole-3-carbaldehyde (300 mg, 1.34 mmol) in THF (10 mL) was added LiAlH4 (100 mg, 2.63 mmol) at 0° C. The mixture was heated to 70° C. and stirred for 4 h at this temperature. Upon cooling, the reaction solution was quenched with 40% of NaOH and filtered and the filtrate concentrated to give crude product which was used in next step without further purification. LCMS (m/z): 210.1 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:28]([O:29]C(=O)C)[C@H:27]([O:33]C(=O)C)[C@@H:26]([CH2:37][O:38]C(=O)C)[O:25][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=O)C.[OH-].[Na+].O>C(O)C>[O:7]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[C@@H:6]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:33])[C@H:28]([OH:29])[C@H:5]1[OH:4]
Reactant: COc1ccc(Cc2c(C)cc(C)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cc2c(C)cc(C)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a suspension of 2-(4-methoxybenzyl)-3,5-dimethylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7.4 g) in ethanol (150 mL) was added 2 mol/L aqueous sodium hydroxide solution (65 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 2-(4-methoxybenzyl)-3,5-dimethylphenyl β-D-glucopyranoside (5.2 g).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1>COCCO>[CH2:1]([NH:4][C:5]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1)=[O:6])[CH2:2][CH3:3]
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCCN=C=O
Solvent: COCCO
Product: CCCNC(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
Propyl isocyanate (2.38 g) was added dropwise to 5.13 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 60 ml of 2-methoxyethanol. The mixture was stirred at room temperature for 10 minutes. Crystals precipitated were collected by filtration and recrystallized from methanol-acetonitrile to obtain 4.91 g of 2-(propylcarbamoyl)amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[C:13]([C:16]1[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:21])(=[O:15])[CH3:14]>>[CH3:21][C:17]12[CH2:18][CH2:19][CH2:20][CH:16]1[C:13](=[O:15])[CH2:14][C:4](=[O:5])[CH2:3]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C1=C(C)CCC1
Agent: [Na]
Product: CC12CCCC1C(=O)CC(=O)C2

Procedure:
Following the procedure of Example 12, the sodium salt of diethyl malonate (161.0 mmol) and 1-acetyl-2-methyl-1-cyclopentene (20.0 g, 161.0 mmol) are reacted together to give 7a-methyl-2,3,7,7a-tetrahydro-1H-indene-4,6(5H)-dione, which is then reacted with 2-chloro-4-methylsulfonyloxybenzoyloxy)-7a-methyl-2,3,7,7a-tetrahydro-1H-inden-6-one and 6-(2-chloro-4-methylsulfonyloxybenzoyloxy)-7a-methyl-2,3,7,7a-tetrahydro-1H-inden-4-one.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[CH:9]1[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][CH2:10]1>[Pd].CN(C=O)C>[NH:12]1[CH2:11][CH2:10][CH:9]([N:3]2[CH2:4][CH2:5][C:6](=[O:8])[NH:7][C:2]2=[O:1])[CH2:14][CH2:13]1
Reactant: O=C1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C(=O)N1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1CCN(C2CCNCC2)C(=O)N1
Yield: 102.7 %

Procedure:
A solution of benzyl 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)piperidin-1-carboxylate (0.18 g) obtained in Example 45d) and 20% palladium on carbon (containing 60% water, 36 mg) in DMF (10 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (0.11 g,, quantitative) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[H-].[Na+].O>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccc(F)cc2)CC1
Reaction time: 3.5 h
Yield: 96.2 %

Procedure:
To a solution of 0.75 g (6.02 mmol) of 4-fluorobenzylbromide and 0.58 g (2.7 mmol) of 1-t-butoxycarbonyl-4-hydroxymethylpiperidine in 5 mL of THF was added 0.136 g (5.4 mmol) of NaH in 3 portions over 30 min. After 3.5 h, 50 mL of H2O was added to the reaction mixture and it was extracted with ethyl acetate. The combined organic fractions were washed with sat'd Nacl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl aceate, 4:1) to give 0.84 g of the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1)=[O:2].[OH-].[Na+]>C(O)C.O>[CH:1]([C:3]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:2]
Reactant: CCOC(=O)c1ccc(COc2cccc(O)c2C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=Cc1c(O)cccc1OCc1ccc(C(=O)O)cc1

Procedure:
Ethyl 4-(2-formyl-3-hydroxyphenoxymethyl)benzoate (0.6 g. 0.002 M) was suspended in 95% ethanol (5 ml) and 1 N sodium hydroxide solution (5 ml) and stirred at room temperature (2.5 hr). The yellow solution was diluted with water, extracted with ethyl acetate, and acidified with concentrated hydrochloric acid. The precipitated solid was filtered off, washed well with water, and recrystallised from 95% ethanol to give 4-(2-formyl-3-hydroxyphenoxymethyl) benzoic acid, m.p. 239°-240° C. (Found: C. 65.99; H, 4.29. C15H12O5 requires C, 66.17; H, 4.44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1)=O.[NH2:20][C:21]([NH2:23])=[O:22].CC(C)([O-])C.[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:23][C:21](=[O:22])[N:20]=[C:10]([C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: O=C(O)c1ccc(C(=O)/C=C/c2ccccc2Cl)s1
Reactant: NC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cc(-c3ccccc3Cl)[nH]c(=O)n2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
(E)-5-(3-(2-chlorophenyl)acryloyl)thiophene-2-carboxylic acid (1.0 g, 3.4 mmol), urea (1.0 g, 16.6 mmol), and sodium t-butoxide (1.6 g, 16.6 mmol) were suspended in 17 mL of 1,4-dioxane. The reaction mixture was stirred overnight at 80° C. After cooling, the suspension was neutralized by the addition of 1M HCl. The precipitate was filtered, washed with water and air dried to give 740 mg of product. 1H NMR (400 MHz, d6-DMSO): δ 7.89 (s, 1H), 7.63 (m, 2H), 7.56 (t, 1H), 7.50 (t, 1H), 7.24 (d, 1H), 7.07 (s, 1H); MS (EI) for C15H9ClN2O3S: 332 (MH+).