Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=[C:3]([C:7]2[S:8][CH:9]=[C:10](C(O)=O)[N:11]=2)C=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:29][C:30]1[C:38]([NH2:39])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH2:34])=[O:33].[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C>[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:10]2[N:11]=[C:7]([C:3]3[NH:39][C:38]4[CH:37]=[CH:36][CH:35]=[C:31]([C:32]([NH2:34])=[O:33])[C:30]=4[N:29]=3)[S:8][CH:9]=2)[CH:41]=1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3nc(-c4cccnc4)cs3)nc12
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-(3-pyridyl)-1,3-thiazole-4-carboxylic acid (300 mg) in pyridine (5 mL) and DMF (5 mL) at ambient temperature was added CDI (248 mg). The mixture was heated at 40° C. for 2 hours, treated with 2,3-diaminobenzamide dihydrochloride (326 mg), stirred at ambient temperature for 16 hours and concentrated. The concentrate was heated in glacial acetic acid (20 mL) at 110° C. for 2 hours, cooled and concentrated. The concentrate was partitioned between ethyl acetate and sodium bicarbonate solution, and the solid that precipitated was filtered and washed with water and ethyl acetate. 1H NMR (DMSO-d6) δ 7.38 (t, J=7.8 Hz, 1H), 7.60-7.67 (m, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.81 (brs, 1H), 7.90 (dd, J=7.46, 1.0 Hz, 1H), 8.44-8.50 (m, 1H), 8.74-8.76 (m, 1H), 8.74 (s, 1H), 9.29 (brs, 1H), 9.34 (d, J=1.7 Hz, 1H), 13.44 (brs, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].CN(C=O)C.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>C1COCC1>[ClH:17].[N:33]1([CH2:32][CH2:31][O:30][C:24]2[CH:23]=[C:22]3[C:27]([C:18]([CH:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][C:2]4=[O:10])=[N:19][CH:20]=[N:21]3)=[CH:26][C:25]=2[O:28][CH3:29])[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(C3C(=O)Nc4ccccc43)ncnc2cc1OCCn1ccnc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
A solution of oxindole (164 mg, 1.23 mmol) in THF (3 ml) was added dropwise under nitrogen, to sodiun hydride (49 mg, 1.23 mmol, prewashed with hexane) in THF (3 ml). The mixture was stirred for 30 minutes at ambient temperature and DMF (2 ml) and then 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (125 mg, 0.41 mmol) was added. The mixture was heated at 60° C. for 30 minutes and the THF was removed by evaporation. The residue was partitioned between saturated aqueous ammonium chloride solution and ether. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The solid was dissolved in methylene chloride (5 ml), methanol (0.5 ml) and isopropanol (3 ml) and SM isopropanolic hydrogen chloride (0.5 ml) was added. The mixture was concentrated by evaporation to 2 ml total volume and the resulting precipitated solid was collected by filtration, washed with isopropanol followed by ether and dried under vacuum to give 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy4-(oxindol-3-yl)quinazoline hydrochloride (110 mg, 61%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:14])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(OC)N(C)C
Reactant: CNC(=O)c1ccc(C)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CN(C)C)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 46 h

Procedure:
1.65 g (8.49 mmol) of N-methyl-4-methyl-3-nitrobenzamide was dissolved into 9.9 mL of DMF and 6.49 g (50.90 mmol) of N,N-dimethylformamide dimethylacetal was added dropwise to this solution under a nitrogen atmosphere at room temperature, and the reaction mixture was heated and stirred at 80° C. for 46 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[N:22]([C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28])=[N+:23]=[N-:24]>C1COCC1>[C:1]([O:5][C:6]([C@@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=1[N:22]=[N+:23]=[N-:24])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)c1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A stirred solution of (2S)-5-oxo-proline tert-butyl ester (T. Kolasa and M. J. Miller, J. Org. Chem., 1990, 55, 1711-1721) (1.13 g, 6.13 mmol) in anhydrous THF (15 mL) was treated at −78° C. with LDA (9.19 mmol) and the reaction was stirred for 15 min. A solution of 2-azidobenzoyl chloride (T. Okawa, T. Sugimori, S. Eguchi and A. Kakehi, Heterocycles, 1998, 47, 1, 375-382) (6.13 mmol) in anhydrous THF (5 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 1 h before being quenched with saturated aq.NH4Cl. The reaction was allowed to warm to room temperature and the organic layer was washed with saturated aq.NH4Cl, dried (MgSO4), filtered and evaporated to give an oil which was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound as a pale yellow oil (1.67 g, 82%): 1H NMR (400 MHz, CDCl3) δ 1.53 (9H, s), 2.14 (1H, m), 2.43 (1H, m), 2.55 (1H, m), 2.69 (1H, m), 4.79 (1H, dd, J 9.2, 3.2 Hz), 7.19-7.22 (2H, m), 7.36 (1H, m), 7.49 (1H, m). 13C NMR (100 MHz, CDCl3) δ 22.1 (CH2), 28.3 (CH3), 31.9 (CH2), 59.3 (CH), 83.0 (C), 118.7 (CH), 125.0 (CH), 127.9 (C), 129.1 (CH), 131.9 (CH), 137.9 (C), 167.5 (C), 170.2 (C), 173.6 (C).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13](C)C(O)=O)=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C1C=CC=CC=1.FC(F)(F)C([O:32][C:33](=[O:38])[C:34](F)(F)F)=O.C1(C(O)C)C=CC=CC=1>CCOCC.O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][CH2:34][C:33]([OH:32])=[O:38])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: CC(O)c1ccccc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)CCc1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 0.5 h

Procedure:
2.78 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is stirred in a mixture of 20 ml. of benzene and 5 ml. of trifluoroacetic anhydride for 15 minutes. The mixture is evaporated to dryness and redissolved in 20 ml. of dry benzene. A mixture of 1.0 g. of pyridine and 2.44 g. (2 moles) of (+) α-phenylethanol is added. The mixture is left for 30 minutes and then water and ether is added. The organic layer is washed with dilute hydrochloric acid and water, then dried and evaporated. The residue is chromatographed on 100 g. silica gel, eluting with hexane:ether (4:1) to afford a 1:1 mixture of diastereomeric esters. Repeated crystallization of this mixture from ether-hexane yields the less soluble isomers. The purity of samples from successive recrystallizations is monitored by gas-liquid chromatography using a 1 meter × 2 mm. column packed with Chromosorb W (Regis Chemical Co., Chicago, Ill.) impregnated with 3% w/w OV101 polymeric material (Applied Sciences Laboratory, Inc., State College, Penn.) as stationary phase, and helium as the carrier gas at 220°C. The less soluble isomer is decomposed by stirring in a mixture of 5 ml. of benzene and 5 ml. of trifluoroacetic acid for 30 minutes. Water and ether are added and the ethereal layer washed with water, and then with dilute aqueous sodium carbonate. The aqueous layer is acidified with dilute hydrochloric acid and then extracted with ether. The ethereal layer is washed, dried and evaporated to give d 3-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid. 1 2-(5-Oxo-5H-dibenzo[a,d]cyclohepten-2yl)propionic acid [m.p. 105°-107°C; [α]D -47.4° (chloroform)] can be obtained in similar manner using (-) α-phenylethanol.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].Cl>C1COCC1>[Br:9][C:10]1[C:15]([CH:19]([C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])[OH:20])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=Cc1ccccc1Cl
Reactant: Brc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1cccnc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add LDA (400 mL, 0.8 mol) to 2-bromopyridine (105 g, 0.667 mol) in THF (3.2 L) at −78° C. and stir. After 2 hours, add 2-chlorobenzaldehyde (103 g, 0.733 mol) in THF (300 mL) and allow the reaction mixture to gradually warm to ambient temperature. Treat the reaction mixture with 1 M HCl (1.7 L) and extract with diethyl ether. Combine the organic layers and wash with water and brine. Dry over sodium sulfate, filter, and concentrate under reduced pressure. Purification by flash chromatography, eluting with hexane:ethyl acetate (10:1 to 1:1) gives the title compound: 1H NMR (300 MHz, CDCl3), δ8.28(dd, 1H, J=1.83, 4.73), 7.67 (dd, 1H, J=1.83, 7.63), 7.48-7.19 (m, 5H), 6.41 (s, 1H), 3.10 (bs, 1H); MS (IS) m/z 298.0 (M+1), 300.0 (M+1); Analysis for C12H9BrClNO: calcd: C, 48.27; H, 3.04; N, 4.69; found: C, 49.06; H, 3.18; N, 4.64. Rf=0.29 heptane: ethyl acetate, 2:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:41])[C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([N:38]([CH3:40])[CH3:39])[CH:33]=5)[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:39][N:38]([CH3:40])[C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:22]2[O:23][C:18]3[C:19]([N:21]=2)=[N:20][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][CH:17]=3)[CH:25]=1)=[O:41]
Reactant: CN(C)c1cccc(C(=O)Nc2cccc(-c3nc4nc(CN5CCN(C(=O)OC(C)(C)C)CC5)ccc4o3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cccc(C(=O)Nc2cccc(-c3nc4nc(CN5CCNCC5)ccc4o3)c2)c1
Reaction time: 1 h

Procedure:
4-{2-[3-(3-Dimethylamino-benzoylamino)-phenyl]-oxazolo[4,5-b]pyridin-5-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (25 mg, 0.045 mmol) was dissolved in 1 mL of 25% TFA in CH2Cl2 and allowed to stand at room temperature for 1 hour. It was then concentrated and the resulting residue was triturated with Et2O to afford essentially quantitative yield of 3-dimethylamino-N-[3-(5-piperazin-1-ylmethyl-oxazolo[4,5-b]pyridin-2-yl)-phenyl]-benzamide as the TFA salt.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](N1C=CN=C1)=[O:12].[NH2:18][CH2:19][C:20]#N.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:12])[CH2:20][C:19]#[N:18]
Reactant: O=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: N#CCN
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: C1CCOC1
Product: N#CCC(=O)Nc1nc2ccccc2s1
Temperature: 30 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
0.3 g of benzothiazole was dissolved in 50 ml of tetrahydrofuran, and then 0.32 g of carbodiimide was added thereto in a dropwise manner in ice-bath. The obtained reaction mixture was stirred at room temperature for 10 hours. The produced white solid was filtrated, to obtain N-(benzo[d]thiazole-2-yl)-1H-imidazole-1-carboxamide (0.261 g, 54%). N-(benzo[d]thiazole-2-yl)-1H-imidazole-1-carboxamide (30 mg) was dissolved in 5 ml of tetrahydrofuran, and 11.1 mg of 2-aminoacetonitrile and then 29 μl of acetic were added thereto in a dropwise manner. The obtained reaction mixture was stirred at 30° C. for 18 hours, to produce N-(benzo[d]thiazole-2-yl)-2-cyanoacetamide (10 mg) in a light brown solid phase
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22](I)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C[O:44][C:45](=[O:48])[CH2:46][SH:47].C(O)CO.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.[Cu](I)I.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([S:47][CH2:46][C:45]([OH:48])=[O:44])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: COC(=O)CS
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCO
Solvent: CC(C)O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(SCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (400 mg) is dissolved in isopropyl alcohol (2 ml), then thereto are added thioglycolic acid methyl ester (120 μl), copper iodide (20 mg), ethylene glycol (62 μl) and potassium carbonate (156 mg), and the mixture is stirred at 80° C. under nitrogen flow overnight. After allowing to cool to room temperature, water is added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is washed with a saturated brine twice, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in methanol (6 ml), then thereto are added 1M-aqueous sodium hydroxide solution (3 ml) and tetrahydrofuran (6 ml), and the mixture is stirred at room temperature for 10 minutes. Ten % aqueous citric acid solution is added to the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine twice, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxymethylsulfanyl-pyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (153 mg).MS (m/z): 674 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[N:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:39])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[N:13][O:12][C:9]2=[C:10]([I:39])[N:11]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: CCOC(=O)c1ncc2onc(-c3cccc(Cl)c3)c2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)c1nc(I)c2onc(-c3cccc(Cl)c3)c2c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
A mixture of 3-(3-chloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (377 mg, 1.18 mmole), bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.22 g, 2.36 mmole), and dichloromethane (12 ml) was stirred at room temperature for 20 h before it was concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a white solid (440 mg); MS: (+) m/z 445.02 (M+H+).
Reaction SMILES: ClC1C=CC([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]=3)=C(C=O)C=1.[C:32]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1B(O)O)(=[O:34])[CH3:33]>>[C:32]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:14][CH:13]=[C:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]=2)(=[O:34])[CH3:33]
Reactant: COc1ccc(B(O)O)c(C(C)=O)c1
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(Cl)cc3C=O)[nH]c2c1
Product: COc1ccc(-c2[nH]c3cc(C(=O)OC(C)(C)C)ccc3c2C2CCCCC2)c(C(C)=O)c1

Procedure:
The title product tert-butyl 2-(2-acetyl-4-methoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate 37d was synthesized by following a similar procedure to that used for the synthesis of tert-butyl 2-(4-chloro-2-formylphenyl)-3-cyclohexyl-1H-indole-6-carboxylate 34b, using 2-acetyl-4-methoxyphenylboronic acid 37c instead of 4-chloro-2-formylphenylboronic acid 34a.
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4][CH3:5].[CH3:8][C@@:9]12[C@H:19]3[CH2:20][CH2:21][C@:22]4([CH3:30])[C@:26]([OH:29])([C:27]#[CH:28])[CH2:25][CH2:24][C@H:23]4[C@@H:18]3[CH2:17][CH2:16][C:15]1=[CH:14]C(=O)[CH2:11][CH2:10]2.O.C([O-])(=O)C.[Na+]>C(O)CO.CO>[CH2:7]1[CH2:5][O:4][C:3]2([CH2:11][CH2:10][C@@:9]3([CH3:8])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:19]3[CH2:20][CH2:21][C@@:22]3([CH3:30])[C@H:23]4[CH2:24][CH2:25][C@@:26]3([OH:29])[C:27]#[CH:28])[CH2:14]2)[O:6]1
Reactant: COC(OC)OC
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: OCCO
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@H]3CC[C@@]21C)OCCO5

Procedure:
Trimethylorthoformate (20 ml.) and p-TSA monohydrate (1.9 g.) is added to a slurry of ethisterone (I, 31.34 g.) in ethylene glycol (100 ml.) and methanol (200 ml.). The mixture is heated to 50° until the reaction is complete (about 5 hours) as measured by TLC. The mixture is cooled to 5° and water (200 ml.) containing sodium acetate (6.6 g.) is added. The resulting suspension is filtered to recover the solids which are dried at 50° under reduced pressure (20 mm) for 6 hours to give the title compound, m.p. 245°-250°; NMR (CDCl3) 0.87, 1.03, 2.57, 3.97 and 5.23δ.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: NCCCO
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: O=C(NCCCO)c1ccc2c(c1)OCO2
Yield: 65 %

Procedure:
1,3-Benzodioxole-5-carboxylic acid (2.0 g, 12.0 mmol) and 3-amino-1propanol (0.8 ml, 15.6 mmol) were coupled according to the procedure of Example 17 to 1.74 g (65% yield) of a white solid. MP 112-113° C.; 1H NMR (DMSO-d6): δ 1.65 (m, CH2), 3.27 (m, CH2), 3.42 (m, CH2), 4.45 (t, NH), 6.0 (s, CH2), 6.98 (d, 1 Ar H), 7.37 (d, 1 Ar H), 7.4 (d-d, 1 Ar H), 8.28 (t, NH) Electrospray Mass Spec: m/z 224.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C:9]1[C:10]([NH2:22])=[CH:11][CH:12]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>C(OCC)(=O)C.CCCCCC>[CH2:1]([N:8]([CH3:23])[C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=[CH:11][C:10]=1[NH:22][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CN(Cc1ccccc1)c1cc(CN2CCOCC2)ccc1N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1ccc(CN2CCOCC2)cc1N(C)Cc1ccccc1)C(=O)OCC
Temperature: 120 °C

Procedure:
A mixture of N2-benzyl-N2-methyl-4-(4-morpholinylmethyl)-1,2-benzenediamine (3.1 g, 10 mmol) and diethyl ethoxymethylenemalonate (4.2 g, 20 mmol) is heated at 120° C. until HPLC shows that the reaction is complete (20 min). The product is applied in 10% ethyl acetate/hexane to a silica gel column which is eluted with 20% ethyl acetate/hexane to remove excess diethyl ethoxymethylenemalonate and then with 50% ethyl acetate/hexane to elute 3.7 g of the title compound as an oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[NH:16][C:17]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:17]2[NH:16][C:15]([C:11]3([CH3:14])[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[N:19][C:18]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(C)(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Yield: 40.8 %

Procedure:
To a stirring solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.14 mmol, 60 mg) in THF (2.0 mL) was added lithium aluminum hydride (0.56 mmol, 0.56 mL of a 1M solution). The reaction was heated to reflux for 6 h, cooled, diluted with ethyl acetate (20 mL) and quenched with water (0.5 mL). The suspension was filtered and the filtrates washed with water (20 mL), dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The resulting solid was triturated with diethyl ether and filtered to give 20 mg of the title compound as a white powder. mp=227°-229° C.
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C([O:28][B:29]([O:33]CC)[O:30]CC)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:14]([O:13][C:12]([NH:11][C:10]1[C:9]([S:19][CH3:20])=[N:8][N:7]2[C:2]([O:28][B:29]([OH:33])[OH:30])=[CH:3][CH:4]=[CH:5][C:6]=12)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOB(OCC)OCC
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1nn2c(OB(O)O)cccc2c1NC(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
After dissolving tert-butyl N-(7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl)carbamate (200 mg) in tetrahydrofuran (2 mL), the mixture was cooled to −78° C. and n-butyllithium (1.6 M; 0.66 mL) was added dropwise. The mixture was stirred for 1 hour at the same temperature, triethoxyborane (109 μL) was added and the temperature was increased to room temperature. Saturated aqueous ammonium chloride was added to the obtained reaction mixture, and extraction was performed with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (106 mg) as grayish white crystals.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:10]([O:31][CH3:32])[CH:9]=1.OO>CS(C)=O>[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:2])=[CH:15][C:14]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:10]([O:31][CH3:32])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Cl)ccc1Oc1ccc(C#N)cc1-c1cccnc1OC
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(Cl)ccc1Oc1ccc(C(N)=O)cc1-c1cccnc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.8 %

Procedure:
Potassium carbonate (0.194 g, 1.40 mmol) was added to a solution of 4-(4-chloro-2-methoxyphenoxy)-3-(2-methoxypyridin-3-yl)benzonitrile (Preparation 2, 0.257 g, 0.701 mmol) in dimethylsulfoxide (6 mL), followed by dropwise addition of 30% hydrogen peroxide aqueous solution (0.422 mL, 14.00 mmol). The mixture was stirred at room temperature for 1 hour, then quenched by addition of saturated aqueous solution of ammonium chloride (20.0 mL) and water (20.0 mL). The pH of the aqueous was adjusted to pH=7 by dropwise addition of saturated aqueous solution of potassium hydrogen sulfate and then extracted with DCM (3×20 mL). The combined organics were washed with brine (50 mL) and filtered to give the title compound as a solid (0.307 g).