Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C@@H:20]([NH:28][C:29](=[O:48])[C@H:30]([CH2:44][C:45](=[O:47])[NH2:46])[NH:31][C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O>C(O)=O>[OH:1][C@H:2]([C@@H:20]([NH:28][C:29](=[O:48])[C@H:30]([CH2:44][C:45](=[O:47])[NH2:46])[NH:31][C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:5]
Reactant: CC(C)(C)OC(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Solvent: O=CO
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (1.53 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[phenylmethyl]-2-[tert-butoxycarbonyl]-hydrazine (Example 100 B) is dissolved in 10 ml of formic acid under protective gas and stirred for 16 h at RT. The formic acid is removed by evaporation under HV, the residue is partitioned between 3 portions of ethyl acetate, saturated NaHCO3 solution and brine, and the organic phases are dried with Na2SO4 and concentrated by evaporation to yield the title compound: tRet (V)=10.7 min.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(O)CSCCSCCO>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[OH:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#CCO)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: OCCSCCSCCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C/C=C\CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(4-hydroxybut-2-yn-1-yl)piperidine-1-carboxylate from step 2 of this example (10.6 g, 41.8 mmol) was dissolved in 200 mL MeOH and 3,6-Dithia-1,8-octanediol (191 mg, 1.05 mmol) was added, followed by Lindlar's catalyst (5% w/w, 4.45 g, 2.1 mmol). The reaction vessel was degassed and back filled with hydrogen 3 times and further stirred under a hydrogen balloon at room temperature for 1 hour. The reaction was filtered through Celite and concentrated under vacuum to afford the crude product as colorless oil which was used directly in the next step.
Reaction SMILES: COC(=O)[CH2:4][CH2:5][N:6]([CH2:19][CH2:20][C:21]([O:23]C)=O)[C@H:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH3:8].[H-].[Na+].Cl.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CC(O)=O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[C@@H:7]([N:6]1[CH2:19][CH2:20][C:21](=[O:23])[CH2:4][CH2:5]1)[CH3:8]
Reactant: COC(=O)CCN(CCC(=O)OC)[C@@H](C)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C[C@@H](c1ccc2ccccc2c1)N1CCC(=O)CC1
Reaction time: 6 h
Yield: 47.4 %

Procedure:
To a solution of (S)-methyl-3-[(2-methoxycarbonylethyl)-(1-naphthalen-2-yl-ethyl)-amino]-propanoate (3.6 g, 10 mmol) in toluene (20 mL), NaH (0.5 g, 13 mmol) was added and the mixture was refluxed in an oil bath kept at 150° C. for 6 hours. After cool, the reaction mixture was acidified with AcOH and extracted with benzene. The organic layer was dried over MgSO4, and concentrated to afford a crude oil. The oil was boiled with 10% HCl (20 mL) for 18 hours. The aqueous solution was basified with K2CO3 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The crude oil was purified by chromatography on silica gel with ethyl acetate/hexanes (1:4) to give the title compound (1.2 g, 47%). 1H NMR (300 MHz, CDCl3) δ 1.51 (3H, d, J=6.59 Hz), 2.44 (4H, t, J=6.03 Hz), 2.71-2.90 (4H, m), 3.79 (1H, q, J=6.78 Hz), 7.42-7.60 (3H, m), 7.72-7.86 (4H, m).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=2)[NH:5]1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>O1CCCC1.CN1CCCC1=O>[OH:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:18]1[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COCCOc1ccc2c(-c3c(O)[nH]c4ccc(C(=O)OC)cc34)ncnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
Sodium hydride (58 mg, 1.45 mmol, 60% in oil) was washed with petroleum ether (3×5 mL) and dried in vacuo. The solid was suspended in tetrahydrofuran (3 mL) and methyl 2-oxo-5-indolinecarboxylate (140 mg, 0.73 mmol) in tetrahydrofuran (2 mL) and N-methylpyrrolidinone (2 mL) was added. The reaction mixture was stirred for 30 min at room temperature. A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline (183 mg, 0.77 mmol, described in WO 97/42187) in tetrahydrofuran (2 mL) and N-methylpyrrolidinone (1 mL) was added and the reaction mixture was stirred for 1.5 h at room temperature. The solvent was removed in vacuo and 1 M hydrochloric acid was added. The precipitate formed was filtered off and dried at 40° C. in vacuo over night to give 150 mg (99% yield) of the title compound as an orange solid: MS (AP+) m/z 394.2 (M++1).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CCOCC>C(O)C.O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)/C(=N\OCCCCNC(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.1 %

Procedure:
In a mixture of 50 ml of ethanol and 7.1 ml of dioxane is dissolved 4.46 g of ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(4-tert-butoxycarbonylaminobutoxyimino)acetate, followed by addition of 7.1 ml of 2 N-aqueous sodium hydroxide solution. The mixture is stirred at room temperature for 10 hours. To this reaction mixture was added 500 ml of ether and the resulting precipitates are collected by filtration. The precipitate is dissolved in water and under ice-cooling the solution is adjusted to p 2 with 3 N-HCl and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride solution and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. To the residue is added ether-petroleum ether (1:3) and the resulting light yellow powders are collected by filtration. The above procedure yields 4.01 g of 2-(2-tritylaminothiazol-4-yl)-(Z)- 2-(4-tert-butoxycarbonylaminobutoxyimino)acetic acid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6][C:5]=2[S:4][CH:3]=1.O1CCCC1.C([Li])CCC.[C:23](=[O:25])=[O:24]>CCCCCC>[CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6][C:5]=2[S:4][C:3]=1[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: Cc1csc2c1C(C)(C)CCS2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2c1C(C)(C)CCS2
Temperature: -65 °C
Reaction time: 1 h

Procedure:
8.20 g (0.041 mol) of the title compound of Step B was added to 200 mL of tetrahydrofuran under nitrogen. The solution was cooled to about -65° C. and 21 mL (0.053 mol) of 2.5M n-butyllithium was added dropwise while keeping the reaction temperature below -55° C. After stirring for 1 h, an excess of solid CO2 was added in portions and the mixture was allowed to warm to room temperature over 2 hr. The mixture was then diluted with 150 mL of hexane and the precipitate was collected by filtration. The precipitate was added to a mixture of 300 mL of water and 300 mL of methylene chloride, cooled to about 0° C., and then acidified to pH 1 with concentrated hydrochloric acid. The layers were separated and the aqueous layer was extracted with diethyl ether (2×300 mL). The combined organic layers were dried (MgSO4), filtered, and evaporated to dryness to yield 6.36 g of the title compound of Step C as a solid melting at 176°-178° C. 1H NMR (DMSO-d6): δ 1.3 (s,6H), 1.95 (m,2H), 2.6 (s,3H), 3.08 (m,2H), 12.7 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C:17]([F:20])([F:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C:17]([F:20])([F:19])[CH2:16][C@H:12]1[C:13]([NH2:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 1-[(benzyloxy)carbonyl]-4,4-difluoro-L-proline, pyridine (0.6 eq.) and di-t-butyl dicarbonate (1.3 eq) in dioxane, ammonium bicarbonate (1.26 eq) was added and the mixture was stirred at room temperature for 20 hours. Dioxane was concentrated and the residue dissolved in ethyl acetate and washed with HCl 1 N, saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and evaporated in vacuo to obtain a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[N:51]1(C(OC(C)(C)C)=O)[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:51]3[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4CCCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (47 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). This solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined extracts were washed with sat. aq. NaCl, dried (Na2SO4) and concentrated to a glassy foam (238.7 mg). The glassy foam was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky solid [73 mg (60%)]. LC-MS m/z 754.3 (M+H)+.
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1)#[N:2].C(/C=C\C1CCN(C(OCC2C=CC=CC=2)=O)C1)#N.C1CCN2C(=NCCC2)CC1.[NH:50]1[CH:54]=[C:53]([C:55]2[C:56]3[CH:63]=[CH:62][N:61]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:57]=3[N:58]=[CH:59][N:60]=2)[CH:52]=[N:51]1>C(#N)C>[C:1]([CH2:3][CH:4]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:6]1)[N:50]1[CH:54]=[C:53]([C:55]2[C:56]3[CH:63]=[CH:62][N:61]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:57]=3[N:58]=[CH:59][N:60]=2)[CH:52]=[N:51]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#C/C=C/C1CCN(C(=O)OCc2ccccc2)C1
Agent: N#C/C=C\C1CCN(C(=O)OCc2ccccc2)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCN(C(=O)OCc5ccccc5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of benzyl 3-[(E)-2-cyanovinyl]pyrrolidine-1-carboxylate and benzyl 3-[(Z)-2-cyanovinyl]pyrrolidine-1-carboxylate (241 mg, 0.940 mmol) and DBU (234 μL, 1.57 mmol) in ACN (13 mL) was added 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (250 mg, 0.78 mmol). The mixture was stirred at ambient temperature for 3 hours. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, and the organic layer was washed sequentially with 1N HCl, water, saturated NaHCO3, and brine. The washed solution was dried over sodium sulfate and the solvent was removed in vacuo. Purification via flash column chromatography (eluting with a gradient of 0-100% [5% MeOH/DCM] in hexanes) afforded the product as a mixture of diastereomers (400 mg, 89%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([C:12]1[C:17]([O:18]COCCOC)=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:15]=[C:14]([CH:29]=[O:30])[N:13]=1)([CH3:11])[CH3:10].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][C:9]([C:12]1[C:17]([OH:18])=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:15]=[C:14]([CH:29]=[O:30])[N:13]=1)([CH3:8])[CH3:10]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.8 %

Procedure:
Trifluoroacetic acid (1.05 g, 9.2 mmol) is added to a solution of 4,6-bis (1,1-dimethylethyl)-5-[(2-methoxyethoxy) methoxy]-2-pyrimidine carboxaldehyde (1. 0 g, 3.1 mmol) in methylene chloride and the reaction mixture is stirred at room temperature for 5 hours. The reaction mixture is neutralized by the addition of saturated aqueous NaHCO3 and the layers separated. The organic layer is washed with brine (50 mL), dried over MgSO4, and evaporated. Recrystallization of the residue from hexane gives pure 4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (0.24 g, 33%); mp 187°-189° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47](OC)[CH2:46]2)[CH:8]([CH3:55])[CH:7]=[CH:6][C:5]1=[O:56])[CH:2]=[CH2:3].[N+](=C)=[N-].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.B(F)(F)F.CCOCC.C(OCC)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]3[O:51][CH:47]3[CH2:46]2)[CH:8]([CH3:55])[CH:7]=[CH:6][C:5]1=[O:56])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC4OC4C3)C(C)C=CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
To a solution of the title compound of Example 14 (823 mg, 1.05 mmole) in dry dichloromethane (50 ml) was added boron trifluoride diethyl etherate (1 drop) followed by portionwise addition of a dried solution of diazomethane in diethyl ether until no starting material remained. Sodium carbonate was then added, and the resulting mixture stirred for 30 minutes at room temperature. The reaction mixture was then filtered, concentrated in vacuo, and chromatographed on silica eluting with 40°-60° petroleum ether/ethyl acetate [3:1] to give the title compound as an oil (45 mg).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:23])[C:13]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[C:6]([Cl:34])[CH:5]=1)(=O)[CH3:2].[S:35]1[CH2:39][C:38](=[O:40])[NH:37][C:36]1=[O:41].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:34][C:6]1[CH:5]=[C:4]([C:1](=[C:39]2[S:35][C:36](=[O:41])[NH:37][C:38]2=[O:40])[CH3:2])[CH:33]=[CH:32][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)c1ccc(OCCOc2c(-c3ccc(F)c(F)c3)n(C)c3ccccc3c2=O)c(Cl)c1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=C1SC(=O)NC1=O)c1ccc(OCCOc2c(-c3ccc(F)c(F)c3)n(C)c3ccccc3c2=O)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of compound 3-[2-(4-Acetyl-2-chloro-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-1-methyl-1H-quinolin-4-one (97 g, 200 mmol), thiazolidine-2,4-dione (141 g, 1200 mmol), benzoic acid (44 g, 361 mmol) and piperidine (35 g, 411.7 mmol) were taken a single neck round bottomed flask, to this toluene (1000 mL) was added. The round-bottomed flask 20 was fitted with dean stark apparatus, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25° C. and was allowed to pass through a silica gel column. The product was eluted by using 0.3-0.9% MeOH/CHCl3 to afford the title compound, 37 g (32%) as off white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:16]=1[NH:30][CH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[C:18]1[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[C:16]([NH:30][CH:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH:17]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(NC3CCC(O)CC3)c2)OC1(C)C
Reactant: Clc1nccc2c(Br)cccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccc(-c2nccc3c(Br)cccc23)cc1NC1CCC(O)CC1
Yield: 153.8 %

Procedure:
Pd(PPh3)4 (1.39 g) was added to a solution of compound (1b) (5.83 g), 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester (7.80 g), and an aqueous sodium carbonate solution (2 M, 40 mL) in ethylene glycol dimethyl ether (80 mL) in a nitrogen atmosphere, and the mixture was stirred at 85° C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (2a) (14.8 g, yield: 62%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]2[O:9][CH2:10][CH2:11][C:12]3([CH2:17][CH2:16][CH2:15][N:14]4[CH:18]=[N:19][CH:20]=[C:13]34)[C:6]2=[CH:5][CH:4]=1.C[Si](I)(C)C.CO>C(#N)C>[CH:20]1[N:19]=[CH:18][N:14]2[CH2:15][CH2:16][CH2:17][C:12]3([C:6]4[C:7](=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=4)[O:9][CH2:10][CH2:11]3)[C:13]=12
Reactant: COc1ccc2c(c1)OCCC21CCCn2cncc21
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: Oc1ccc2c(c1)OCCC21CCCn2cncc21

Procedure:
A mixture of 1 mmol of 7-methoxy-2,3,6′,7′-tetrahydro-5′H-spiro[chromene-4,8′-imidazo[1,5-a]pyridine] and 5 ml of trimethylsilyl iodide in 20 ml of acetonitrile is heated at reflux for 24 hours. 5 ml of methanol are added cautiously and the mixture is heated at reflux for a further 30 minutes. The reaction mixture is evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[NH:27]1[CH:31]=[N:30][N:29]=[N:28]1>>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:28]2[N:29]=[N:30][CH:31]=[N:27]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1nnn[nH]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4ncnn4)=C(C=O)C[C@@H]32)C1
Yield: 16.9 %

Procedure:
The method followed that described for Synthesis Example 7, but using 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (Compound 3) (0.5 g, 1.329 mmol), 1H-tetrazole (187 mg, 1.59 mmol) and Li2CO3 (287 mg, 3.94 mmol) gave a crude product (520 mg). Flash column chromatography on elution with pet. ether/EtOAc, (5:1), gave firstly 3β-acetoxy-17-(2H-tetrazol-2-yl)-16-formylandrosta-5,16-diene (Compound 22) (92 mg, 28.2%), mp 170-172° C. (decomp.). 1H NMR (300 MHz, CDCl3): δ1.1 (3H, s, 18-Me), 1.29 (3H, s, 19-Me), 2.04 (3H, s, 3β-OAc), 4.62 (1H, m, 3α-H), 5.42 (1H, d, J=4.2 Hz, 6-H), 8.68 (1H, s, 5′-H) and 10.46 (1H, s, 16-CHO). Analysis calculated for C23H30O3N4: C, 67.28; H, 7.37; N, 13.65. Found: C, 67.15; H, 7.61; N, 13.45. Further elution with p. ether/EtOAc/Et3N (7:3:0.3) gave 3β-acetoxy-17-(1H-tetrazol-1-yl)-16-formylandrosta-5, 16-diene (Compound 23) (146 mg, 44.6%), mp 196-198° C. (decomp.). 1H NMR (300 MHz, CDCl3): δ1.09 (3H, s, 18-Me), 1.20 (3H, s, 19-Me), 2.04 (3H, s, 3β-OAc), 4.62 (1H, m, 3α-H), 5.43 (1H, d, J=4.8 Hz, 6-H), 8.93 (1H, s, 5′-H) and 9.92 (1H, s, 16-CHO). Analysis calculated for C23H30O3N4: C, 67.28; H, 7.37; N, 13.65. Found: C, 67.05; H, 7.65; N, 13.45.