Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:30][CH2:29]2)[S:26][CH:27]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Fc1ccccc1-c1csc(C2CCNCC2)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCC(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 57.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (102 mg, 0.377 mmol), 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperidine (90 mg, 0.343 mmol) and diisopropylethylamine (0.120 ml, 0.686 mmol) in dimethylsulfoxide (1.5 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized form a mixed solvent of hexane and ethyl acetate to give the desired product (75.7 mg, 57.7%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]([C:21]([C:23]1[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=1)=[O:22])[NH2:20].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([C:23]3[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=3)=[O:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)s1
Yield: 96 %

Procedure:
From 1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (200 mg, 0.70 mmol) synthesized in Synthetic Example 1, methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (0.70 mmol, 140.4 mg) of Reference Synthetic Example 39 and tosylic acid monohydrate (36.2 mg, 0.21 mmol), 314.1 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a yellow solid (yield 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C@H:12]([OH:15])[CH2:13]O)[CH2:6][CH2:5]2.N1C=CC=CC=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C@H:12]1[CH2:13][O:15]1)[CH2:6][CH2:5]2
Reactant: OC[C@@H](O)[C@H]1CCc2cc(F)ccc2O1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: Fc1ccc2c(c1)CC[C@H]([C@H]1CO1)O2
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
(R)-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethane-1,2-diol (0.27 g, 1.27 mmol) was dissolved in dichloromethane (7 ml) under nitrogen atmosphere and pyridine (100 μl) added under stirring. The reaction mixture was then cooled to 0° C. and tosyl chloride (0.24 g, 1.27 mmol) in dichloromethane (3 ml) was added over a period of 2 h. The temperature was then raised to 20° C. and left under agitation for 15 h. The reaction was quenched with water (10 ml) and further diluted with dichloromethane (10 ml). The aqueous layer was separated and further extracted with dichloromethane (15 ml). The collected organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo to furnish a colourless oil. Said oil was dissolved in methanol (3 ml) and dichloromethane (6 ml) under stirring in nitrogen atmosphere and potassium carbonate (0.32 g, 2.35 mmol) added. The reaction mixture was left to stir for 15 h at 25° C. The reaction was then diluted with water (10 ml) and dichloromethane (10 ml). The separated aqueous layer was then extracted with dichloromethane (20 ml). The collected organic layers were dried over magnesium sulfate and concentrated in vacuo to furnish crude (R)-6-fluoro-3,4-dihydro-2-((R)-oxiran-2-yl)-2H-chromene as a yellow oil. Separation via chomatography on silica, using heptane:ethyl acetate 9:1 as eluent, furnished 0.16 g of (R)-6-fluoro-3,4-dihydro-2-((R)-oxiran-2-yl)-2H-chromene as a colourless oil (66% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[NH:22][CH2:23][C:24]2[O:28][CH:27]=[CH:26][CH:25]=2)=[CH:4][CH:3]=1>[Pd].O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([S:18](=[O:20])(=[O:21])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[NH:22][CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][O:28]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Nc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(Nc2c(NCC3CCCO3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The mixture of 1.2 g of 4-(4-aminophenylamino)-3-furfurylamino-5-sulfamoylbenzoic acid (Example 3), 0.6 g of 10% palladium on charcoal and 120 ml of dioxane is hydrogenated at room temperature and atmospheric pressure until the theoretical amount of hydrogen has been absorbed (about 2 hours). It is filtered, the filtrate evaporated under reduced pressure, the residue is triturated with water, dissolved in 40 ml of 50% hot aqueous ethanol, the solution filtered hot, the filtrate cooled and the precipitate formed filtered off, to yield the 4-(4-aminophenylamino)-3-(2-tetrahydrofurylmethylamino)-5-sulfamoylbenzoic acid, melting at 253° with decomposition.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:40])[CH:22]([O:37]C=O)[C:23]4[N:24]=[C:25]([NH:28][C:29]([O:31][C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:30])[S:26][CH:27]=4)[C:18](=[O:41])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1>C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:40])[CH:22]([OH:37])[C:23]4[N:24]=[C:25]([NH:28][C:29]([O:31][C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:30])[S:26][CH:27]=4)[C:18](=[O:41])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(OC=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Agent: CCC(C)(C)OC(=O)N=c1[nH]c(C(OC=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Reaction time: 6 h

Procedure:
A mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (1.49 g.) and 5% sodium bicarbonate aqueous solution (100 ml.) was allowed to stand for 6 hours. After the reaction, the reaction mixture was washed with ethyl acetate. To the reaction mixture was added ethyl acetate, and the mixture was adjusted to pH 7 with dilute hydrochloric acid and then the aqueous layer was separated. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 1 to 2 with dilute hydrochloric acid, and the ethyl acetate layer was separated. The remaining aqueous layer was subjected to salting-out and then extracted with ethyl acetate. The ethyl acetate layer and the ethyl acetate extract were combined together, washed with water, dried over magnesium sulfate, and then the solvent was distilled off. To the residue (2.0 g.) was added diethyl ether, and the mixture was stirred for overnight, collected by filtration and then dried to give pale brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.90 g.).
Reaction SMILES: NN.[CH2:3]([C:6]1[CH:7]=[C:8]([N:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH2:13])[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5].[O-:19][C:20]#[N:21].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:21][C:20]([NH:13][N:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:3][CH2:4][CH3:5])[CH:7]=1)=[O:19]
Reactant: N#C[O-]
Reactant: CCCc1cccc(N(N)CC(=O)OC)c1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCc1cccc(N(CC(=O)OC)NC(N)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
The hydrazine (Intermediate 33; 910 mg, 4.1 mmol) was dissolved in dry toluene (30 ml) under nitrogen at room temperature. Sodium cyanate (880 mg, 13.5 mmol) was added to the reaction mixture, followed by trifluoroacetic acid (0.95 ml, 12.3 mmol). The reaction was stirred at room temperature for 3 h, then poured into sodium bicarbonate solution (30 ml, 8%) and extracted with ethyl acetate (3×75 ml). The combined dried (Na2SO4), organic phases were concentrated in vacuo to give a yellow oil. The crude material was triturated with ether and hexane to give the title compound (Intermediate 34; 500 mg, 46%) as a white powdery solid m.p. 111°-116°.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Br[C:43]1[C:48]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=2[F:56])=[C:47]([F:57])[C:46]([O:58][CH:59]([CH3:61])[CH3:60])=[C:45]([CH:62]=[O:63])[CH:44]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:1]1([C:43]2[C:48]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=3[F:56])=[C:47]([F:57])[C:46]([O:58][CH:59]([CH3:61])[CH3:60])=[C:45]([CH:62]=[O:63])[CH:44]=2)[CH2:3][CH2:2]1
Reactant: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Oc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2F)c1F
Reaction time: 16 h
Yield: 96 %

Procedure:
Cyclopropylboronic acid (424 mg), a 2 M aqueous sodium carbonate solution (3.29 mL), tris(dibenzylideneacetone)dipalladium(0) (151 mg), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (135 mg) were added at room temperature to a toluene (15 mL) solution of 6-bromo-3-isopropoxy-2,2′,4′-trifluorobiphenyl-4-carbaldehyde (615 mg), and the mixture was stirred at 100 C for 16 hours in an argon atmosphere. Water was added to the reaction mixture, and then, the mixture was filtered through celite. The filtrate was subjected to extraction with ethyl acetate. The organic layer was separated, then washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (529 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)C(C)C
Yield: 25.8 %

Procedure:
1-(2-Aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.01 mL, 7.26 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372-376. The crude product was recrystallized from isopropanol (4 mL/g) and then triturated with acetonitrile (12.5 mL/g), isolated by filtration, and dried overnight in a drying oven to provide 0.61 g of N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 228-230° C.
Reaction SMILES: [CH3:1][CH:2]([CH:5]([CH3:11])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=[O:4].[CH3:12][C:13](C)([O-])[CH3:14].[K+].C(Cl)C=C>CN(C=O)C>[CH3:1][C:2]([CH:5]([CH2:6][C:7]([CH3:9])([CH3:8])[CH3:10])[CH3:11])([CH2:14][CH:13]=[CH2:12])[CH:3]=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: CC(C=O)C(C)CC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCCl
Product: C=CCC(C)(C=O)C(C)CC(C)(C)C
Yield: 12.2 %

Procedure:
In a similar manner to Example 6, 100 g of the aldehyde from Example 72 at a purity of 96% (0.61 mole) in 50 ml of DMF, 80 g of potassium t-butoxide (0.68 mole) in 500 ml of DMF, and 53 g of allyl chloride (0.69 mole) in 50 ml of DMF were reacted in the usual manner. In this way 90.5 g of crude O- and C-alkylates (65.7:9.6) and 12.2% of starting material were produced. The crude product was heated at 155°-170° C. for 3 hours to afford 87 g of crude aldehyde. This material was distilled to afford 51 g of purified product (43% yield). BP 45° C./0.15 mmHg; 1H-NMR (300 MHz), δ 0.89 (9H, s), 0.93 (3H, s), 0.94 (1H, m), 0.98 (3H, d, J=6.84 Hz), 1.2 (1H, m), 1.84 (1H, m), 2.18 (1H, m), 2.35 (1H, m), 5.06 (2H, m), 5.67 (1H, m), 9.45 (1H, s); 13C-NMR (75 MHz), δ 13.99, 16.69, 18.15, 30.03, 32.54, 38.98, 46.38, 53.29, 118.23, 133.47, 207.26; IR (Neat), 2960, 2700, 1730, 1640, 1480, 1370, 920 cm-1 ; MS (m/e), 181 (M+ -15), 98, 83, 69, 57 (Base);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(C(C)C)CC)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1ccc(C)c(CCN)c1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNCCc1cc(C)ccc1C
Yield: 49.1 %

Procedure:
(2,5-Dimethylphenyl)ethylamine 18 (5.36 gm, 0.036 moles), ethyl 4-bromobutyrate (9.11 gm, 0.046 moles) and diisopropylethylamine (6.07 gm, 0.047 moles) were heated at 110-120° C. overnight, cooled, and partitioned between 100 ml DCM and 100 ml water. The aqueous layer was extracted twice with 50 ml portions of DCM. The combined organic extracts were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with a gradient mixture of methanol and DCM. Ethyl 4-[(2,5-dimethylphenyl)ethylamino]butanoate 19 (4.66 gm, 49% yield) was isolated as a slightly yellow oil after removing the solvent. 1H NMR (CDCl3) δ 7.07, 1H, d; 6.88, 1H, br s; 6.79, 1H, d; 4.10, 2H, q; 2.9, 4H, m; 2.35, 2H, t; 2.29, 3H, s; 2.24, 3H, s; 1.74, 2H, m; 1.24, 3H, t; 0.98, 3H, t.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O.[CH:32]([C:35]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:42]([CH3:44])[CH3:43])[C:36]=1[NH2:37])([CH3:34])[CH3:33]>CN(C=O)C>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:37][C:36]1[C:38]([CH:42]([CH3:43])[CH3:44])=[CH:39][CH:40]=[CH:41][C:35]=1[CH:32]([CH3:34])[CH3:33])=[O:31]
Reactant: O=C(O)CCCCCCBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.1 %

Procedure:
2 N Jones' reagent (20 ml) was gradually and dropwise added to an acetone (20 ml) solution of 7-bromoheptanol (1.95 g, 10 mmols) with cooing with ice, and then stirred at room temperature for 10 minutes. The reaction mixture was extracted three times with ether (80 ml). The organic layer was washed with water, and then extracted three times with an aqueous saturated solution of sodium hydrogencarbonate (120 ml). The aqueous layers were combined, then made acidic (pH=1) with 5% sulfuric acid added thereto, and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. 1.45 g (70%) of 7-bromoheptanoic acid was obtained as colorless needle-like crystals. WSC (891 mg, 4.7 mmols) and HOBt (628 mg, 4.1 mmols) were added to a DMF (20 ml) solution of the resulting carboxylic acid (1.06 g, 5 mmols) and 2,6-diisopropylaniline (738 mg, 4.2 mmols), and stirred at room temperature for 12 hour. The reaction mixture was extracted with ether. The organic layer was washed with water, 1N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated Then, the residue was purified through silica gel colt chromatography (developer:hexane/acetone=5/1), and the resulting crystals ware recrystallized from ether-hexane to obtain 466 mg (yield: 30%) of 7-bromo-N-(2, 6-diisopropylphenyl) heptanamide as colorless needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=1.[CH3:20][O:21]C(Cl)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:11]=1[C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:6]([CH:5]=1)[CH:20]=[O:21]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(-c2nc3cccnc3[nH]2)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Ex-76B: To a suspension of 2-(2,4-dimethoxy-phenyl)-3H-imidazo[4,5-b]pyridine (0.44 g, 1.7 mmol) in 20 ml of CH2Cl2, 1,1-dichlorodimethyl ether (0.55 g, 4.8 mmol) was added. The mixture was cooled to 0° C. with a water-ice bath, and 7 ml (7 mmol) of TiCl4 (1.0 m in CH2Cl2) was added dropwise. The mixture was stirred at 0° C. for 2 hrs, then room temperature for overnight. The reaction mixture was poured into ice-water and the precipitate was filtered to give 0.31 g (63%) of 5-(3H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde as a white solid. 1H-NMR (DMSO-d6) δ 10.22 (s, 1H), 8.67 (s, 1H), 8.56 (d, J=5 Hz, 1H), 8.44 (d, J=8 Hz, 1H), 7.57–7.61 (m, 1H), 6.97 (s, 1H), 4.19 (s, 3H), 4.06 (s, 3H). HMRS (EI) calc. for C15H13N3O3: 283.0957; found: 283.0952.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:19]([CH2:20][CH2:21][C@:3]13[CH3:4])[C@:17]1([CH3:18])[C:12]3(O[CH:13]3[C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]2.[ClH:24].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:24][C:13]1[C:14](=[O:22])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]=1[CH2:11][CH2:10][C@@H:9]1[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@@:5]31[CH2:8][C@H:6]3[CH2:7][C@@H:2]2[OH:1]
Reactant: C[C@]12CCC(=O)C3OC31CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C(Cl)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Reaction time: 24 h

Procedure:
17β-hydroxy-4,5-epoxy-14α,15α-methylene-androstan-3-one (1.5 g) is dissolved in 150 mL of acetone and treated at 0° C. with 5.5 mL of concentrated hydrochloric acid. After 24 hours at 0° C., the reaction mixture is neutralized with sodium carbonate solution and the acetone is evaporated. The residue is extracted with dichloromethane. The organic extracts are dried and concentrated. After crystallization from ethanol, 4-chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one is obtained.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])C.[OH-].[K+]>O.O1CCOCC1>[C:9]([O:8][C:6](=[O:7])[CH:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:4]([OH:23])=[O:3])([CH3:12])([CH3:10])[CH3:11]
Reactant: CCOC(=O)C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(CCOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-benzyloxyethyl) malonic acid tert-butyl ester ethyl ester (31.3 g, 97.1 mmol) in water (50 mL) and dioxane (200 mL) was added potassium hydroxide (6.6 g, 0.118 mole) while cooling in an ice bath. The mixture was then stirred at room temperature overnight. The solvents were evaporated under vacuum to leave a clear oil which was dissolved in water. The solution was washed with ether and then acidified to pH 3 using 6N hydrogen chloride (HCl) solution. The mixture was extracted twice with ether; the extracts were combined, washed with brine, dried over magnesium sulfate (MgSO4) and concentrated under vacuum to leave 2-(2-benzyloxyethyl) malonic acid mono tert-butyl ester as a clear oil, 23.9 g (84%).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:8][CH2:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19]C)[C:13]=3[O:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(S)CC.CC(C)([O-])C.[K+].[Cl-].[NH4+]>CN(C=O)C>[C:21]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:8][CH2:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([OH:19])[C:13]=3[O:12][CH:11]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc2c(CSC(c3ccccc3)c3ccccc3)coc12
Agent: CC(C)(C)[O-]
Agent: CCCS
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Oc1cccc2c(CSC(c3ccccc3)c3ccccc3)coc12
Temperature: 25 °C
Yield: 60.1 %

Procedure:
Under argon atmosphere, 3-(diphenylmethylthiomethyl)-7-methoxybenzofuran (45 mg) was dissolved in DMF (3 ml) and the solution was stirred at room temperature. To this solution, n-propanethiol (0.20 ml) and potassium t-butoxide (47 mg) were added and the resulting solution was stirred at 100° C. After confirming vanishment of the materials, the reaction mixture was poured into saturated aqueous ammonium chloride solution (5 ml) and the resulting solution was extracted three times with ethyl acetate (10 ml). After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1-3/1) using silica gel to obtain the desired compound (26 mg, yield: 60%).