Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 93%).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)(=[O:4])=[O:3].[ClH:20].CO>CO>[ClH:20].[CH3:1][S:2]([CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)(=[O:3])=[O:4].[ClH:20]
Reactant: CC(C)(C)OC(=O)N1CCN(CCS(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)CCN1CCNCC1
Temperature: 50 °C

Procedure:
To the solution of 1,1-dimethylethyl 4-[2-(methylsulfonyl)ethyl]-1-piperazinecarboxylate (106 g, 360 mmol) in MeOH (500 mL) was added HCl/MeOH (5M, 1000 mL, 5000 mmol), and the mixture was heated at 50° C. for 1 h before evaporating most of the solvent. The residue was filtered and washed with MeOH to give the desired product as HCl salt (90.3 g, 95% yield). 1H NMR (400 MHz, D2O) δ ppm 3.30-3.72 (m, 12H), 3.09 (s, 3H).
Reaction SMILES: Br[C:2]1(Br)[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12.CC(C)=[O:25]>O.[N+]([O-])([O-])=O.[Ag+]>[I:13][C:11]1[CH:10]=[CH:9][C:6]2[O:7][CH2:8][C:2](=[O:25])[C:3]3[N:4]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=3)[C:5]=2[CH:12]=1
Reactant: CC(C)=O
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(Br)Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A solution of ethyl 4,4-dibromo-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (0.93 g, 1.71 mmol) in acetone (40 ml) and water (10 ml) was treated with silver(I) nitrate (0.78 g, 4.59 mmol) and then stirred at room temperature for 2 hours. The solids were removed by filtration through celite and carefully washed with acetone (3×50 ml). The filtrate and washings were combined and concentrated in vacuo before the residue was distributed between ethyl acetate (300 ml) and brine (100 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by FCC (silica, 0-20% ethyl acetate in heptane) to give 0.54 g (79%) of the title compound as crystalline solid. 1H-NMR (500 MHz, CDCl3) 8 ppm 1.45 (3H, t, J=7.10 Hz), 4.48 (2H, q, J=7.17 Hz), 4.78 (2H, s), 7.06 (1H, d, J=8.39 Hz), 7.67 (1H, s), 7.70 (1H, dd, J=8.54, 2.14 Hz), 8.44 (1H, d, J=2.14 Hz); M+1=399.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].Cl>C(Cl)Cl>[CH2:14]([N:16]([CH2:17][CH3:18])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH3:15]
Reactant: CCNCC
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(chlorosulfonyl)benzoic acid (1.02 g, 4.62 mmol) in CH2Cl2 (100 mL) at 0° C. was added diethylamine (2.4 mL, 23 mmol). The resulting mixture was stirred at 0° C. for 3 h then worked up by adding 2N aqueous HCl and extracting 3× with EtOAc. The combined organic was washed with brine then dried over MgSO4 and concentrated under reduced pressure. The residue was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH3:57][S:58]([C:61]1[CH:62]=[C:63]([CH:65]=[CH:66][CH:67]=1)[NH2:64])(=[O:60])=[O:59]>CN(C=O)C>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:64][C:63]2[CH:65]=[CH:66][CH:67]=[C:61]([S:58]([CH3:57])(=[O:60])=[O:59])[CH:62]=2)=[O:10])=[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]=2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: CC(C)(C)c1ccc(C(=O)O)c(Oc2cccc(C(F)(F)F)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(C)(=O)=O)c2)c(Oc2cccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4-tert-butyl-2-(6-(trifluoromethyl)pyridin-2-yloxy)benzoic acid (17 mg, 50 μmol), HATU (19 mg, 50 μmol), and triethylamine (20 μL, 0.15 mmol) in DMF (0.5 mL) was stirred for five minutes, then 3-(methylsulfonyl)aniline hydrochloride (11 mg, 55 μmol) was added. The reaction was stirred at room temperature for 20 hours and was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give 4-tert-butyl-N-(3-(methylsulfonyl)phenyl)-2-(6-(trifluoromethyl)pyridin-2-yloxy)benzamide. LC/MS: m/z 493.3 (M+H)+ at 1.97 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[C:18]1([NH:28][NH2:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].C(OCC)(=O)C>CCCCCC>[NH2:2][C:1]1[N:28]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[N:29]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nn(-c3cccc4ccccc34)c(N)c2C(N)=O)cc1
Yield: 27 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl) acrylamide (464 mg, 2.0 mmol), 1-naphthyl hydrazine hydrochloride (389 mg, 2.0 mmol) and sodium hydroxide (88 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 50-60% ethyl acetate in hexane) and was recrystallised from diethylether to give the title compound as pink crystals (185 mg) m.p. 195°. δH (CDCl3) 8.00 (1H, d, J 8.3 Hz), 7.95 (1 H., m), 7.73-7.55 (7H, m), 7.30 (2H, d, J 8.3 Hz), 5.52 (2H, br s), 5.16 (2H, br s) and 2.42 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15].[F-].[K+].O>CN(C=O)C>[CH3:19][C:13]1([CH3:20])[C:14](=[O:15])[NH:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11]1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
At room temperature, a solution of 2-amino-4-nitro-phenol (82.5 g, 0.54 mol) in DMF (660 ml) is treated with ethyl 2-bromoisobutyrate (160 ml, 1.07 mol) and KF (124.7 g, 2.15 mol), stirred at the same temperature for 1 h, warmed to 60° C., and stirred for 48 h. After pouring the mixture into H2O (3500 ml), the resulting precipitate is collected by filtration, and washed with H2O and Et2O for several times respectively to give 2,2-dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (84.8 g, 71%) as yellow solid. Rf (hexane/EtOAc 2:1) 0.42. 1H-NMR (400 MHz, DMSO-d6) 1.48 (s), 7.16 (d, J=9.0), 6.42 (d, J=0.4), 8.00 (dd, J=9.0, 0.4). 13C-NMR (100 MHz, DMSO-d6) 167.7 (s), 147.5 (s), 142.0 (s), 128.0 (s), 119.2 (d), 117.3 (d), 110.3 (d), 78.9 (s), 23.7 (2q).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][NH2:24].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][NH:24][C:32](=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCNC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
2-{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 32, 2.0 g, 5.8 mmol) in DCM (100 mL) was treated with triethylamine (2.4 mL, 17 mmol) and 4-dimethylaminopyridine (0.35 g, 2.9 mmol). The solution was cooled to 0° C. and acetyl chloride (0.82 mL, 12 mmol) was added. The mixture was stirred at room temperature for 1 hour, washed with aqueous saturated NaHCO3 (20 mL) and 1 M HCl (2×20 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (1.2 g). MS m/z 389 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:25]1([CH2:31][CH2:32]Br)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:32][CH2:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: BrCCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(SCCC2CCCCC2)nc2ccccc21

Procedure:
To a suspension of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 53 mg, 0.2 mmol) and K2CO3 (41.4 mg, 0.4 mmol) in acetone (0.8 ml) is added 2-cyclohexylethyl bromide (28.8 mg, 22.6 μl). The reaction mixture is kept stirring at reflux for 5 h then filtered on a short plug of silica gel. The solvents are evaporated and the crude is purified by preparative HPLC yielding the title compound in 60% as a colourless oil: tR=7.39 min (LC-1), ESI-MS (pos.): m/z 321.36 [M+H]+; 1H NMR (CDCl3): δ (ppm) 0.80-0.91 (m, 2H), 1.04-1.23 (m, 3H), 1.35 (s, 9H, tBu), 1.35 (m, 1H), 1.54-1.72 (m, 6H), 1.83 (br. s, 1H), 3.32 (t, 2H, SCH2), 4.65 (s, 2H, CH2CO2), 7.07-7.17 (m, 3Harom), 7.61 (m, 1Harom).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]2[N:4]([N:5]=[C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:45])[CH:21]([O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=4[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=3)[NH:7]2)[N:3]=1.[Br:46]N1C(=O)CCC1=O>O1CCCC1.ClCCl>[Br:46][C:9]1[C:2]([CH3:1])=[N:3][N:4]2[C:8]=1[NH:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:45])[CH:21]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:36])[CH3:37])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:18]=1)=[N:5]2
Reactant: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(CCCc2nn3nc(C)cc3[nH]2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(CCCc2nn3nc(C)c(Br)c3[nH]2)cc1
Reaction time: 0.5 h

Procedure:
In a mixture of 100 ml of tetrahydrofuran and 500 ml of dichloromethane was dissolved 50.0 g of 6-methyl-2-(3-(4-(2-(2,4-di-tert-amylphenoxy)octaneamido)phenyl)propyl)-1H-pyrazolo(1,5-b)(1,2,4)triazole (J). Thereto, 13.8 g of N-bromosuccinimide was added at room temperature, and stirring was continued for 30 minutes. The resulting reaction mixture was washed with 500 ml each of water for three times, and dried over anhydrous magnesium sulfate. An oily substance obtained by removing the solvent from the reaction mixture by distillation under reduced pressure was fractionated by chromatography on a column of silica gel (eluting solvent; hexane-ethyl acetate (3/1) mixture), and the eluate was concentrated and evaporated to dryness. Thus, the desired intermediate (K), 7-bromo-6-methyl-2-(3-(4-(2-(2,4-di-tert-amylphenoxy)octaneamido)phenyl)propyl)-1H-pyrazolo(1,5-b)(1,2,4)triazole, was obtained. Yield: 49.3 g (87%).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[F:23][C:24]1[CH:29]=[C:28](O)[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35]C)=[O:34]>>[F:23][C:24]1[CH:29]=[C:28]([O:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(OC)cc1
Reactant: COC(=O)CCc1ccc(O)cc1F
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(F)c2)cc1)c1ccc(OC)cc1
Yield: 71 %

Procedure:
Compound 40 was synthesized from (1Z)-2-[4-(hydroxy methyl)phenoxy]-1-(4-methoxyphenyl)ethanone O-methyloxime (0.25 g, 0.84 mmol) and methyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.2 g, 0.94 mmol) by following the procedure described in scheme 18 (0.1 g, yield: 71.00%); Purity: 98.10%.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[C:15](#[N:18])CC>CN(C)C1C=CN=CC=1>[C:15]([C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1)#[N:18]
Reactant: CCC#N
Reactant: CSc1nc(Cl)c(I)c(C(F)(F)F)n1
Agent: CN(C)c1ccncc1
Product: CSc1nc(C#N)c(I)c(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
4-Chloro-5-iodo-2-methylthio-6-trifluoromethylpyrimidine (5.00 g) was dissolved in propionitrile (125 ml) and 4-(dimethylamino)-pyridine (1.81 g) was added at room temperature with stirring. After several minutes, precipitates appeared, however, it was stirred over night at room temperature. The slurry was cooled to ice bath temperature, and then added sodium cyanide (1.04 g) water (10 ml) solution. The mixture was warmed to room temperature and stirred 3 hr. The reaction mixture was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica get column chromatography (hexane-ethyl acetate) to give 4-cyano-5-iodo-2-methylthio-6-trifluoromiethylpyrimidine (2.56 g) as yellow solid, mp 68-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH:9](C(O)=O)[CH2:8]2)=[O:4].C1(P([N:32]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH:9]([NH2:32])[CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(C(=O)O)CO2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc2c(c1)CC(N)CO2
Temperature: 80 °C
Reaction time: 12 h
Yield: 28.7 %

Procedure:
To a solution of XXXIII (1 g, 4.2 mmol) and TEA (1 mL) in 10 mL of tert-butylalcohol was added 1.15 g of diphenyl phosphoryl azide (4.2 mol). The reaction mixture was stirred at 80° C. for 12 h before concentrated in vacuo. The residue was dissolved in 20 mL of HCl/MeOH (1 N) and the mixture was stirred for at rt for 2 h. After solvent removal, the residue was partitioned between water and EtOAc. The aqueous layer was neutralized to pH 8 by addition of Na2CO3, and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to give 0.25 g of 3-amino-chroman-6-carboxylic acid methyl ester XXXIV (Yield 29%). MS: calc'd 208 (MH+), exp 208 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[F:31][C:32]1[CH:46]=[CH:45][C:35]([CH:36]([NH2:44])[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH:36]([NH:44][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[CH:45][CH:46]=1
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4,4'-di-fluorobenzhydrylamine (prepared as described in Preparation 12) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 91%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[C:14]([CH3:19])[N:13]=2)[C:10]=1[CH3:11])=[O:5])C.C(O[C:23]([C:25]1[CH:26]=NN(C2C=CC(Br)=CC=2)C=1C)=O)C>>[CH:26]1([C:15]2[CH:16]=[CH:17][C:12]([N:9]3[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)=[N:13][C:14]=2[CH3:19])[CH2:25][CH2:23]1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C
Reactant: CCOC(=O)c1cnn(-c2ccc(I)c(C)n2)c1C
Product: Cc1nc(-n2ncc(C(=O)O)c2C)ccc1C1CC1

Procedure:
1-(5-Iodo-6-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester described in Reference Example 31 was used in place of 1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester in Reference Example 26(2), and reacted and treated in a similar manner to give the titled compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH2:7]([OH:10])[C:8]#[CH:9].N1C=CC=CC=1>C(Cl)Cl>[Cl:4][C:2](=[O:3])[C:1]([O:10][C:7]#[C:8][CH3:9])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C#CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC#COC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 100 ml of methylene chloride were dissolved 10 g (79 mmol) of oxalyl chloride, to which a solution of 4.4 g (79 mmol) of propargyl alcohol and 6.4 ml (79 mmol) of pyridine dissolved in 30 ml of methylene chloride was slowly added dropwise over 1 hour with cooling with ice. The resulting mixture was stirred for 30 minutes at room temperature to produce propynyl chloroglyoxylate in the reaction system. Subsequently, a solution of 14.5 g (79 mmol) of pentafluorophenol and 6.4 ml (79 mmol) of pyridine dissolved in 30 ml of methylene chloride was slowly added dropwise to the reaction system with cooling with ice. The resulting mixture was stirred for 1 hour at room temperature and then filtered, washed with water, dried over anhydrous magnesium sulfate and concentrated. The thus obtained crude product was purified by crystallization to obtain 2.1 g of 2-propynyl pentafluorophenyl oxalate.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>C(Cl)Cl>[CH2:2]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15])[CH2:3][CH:4]=[CH2:5]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCNCc1ccc(OC)cc1OC
Reaction time: 8 h
Yield: 40 %

Procedure:
0.5 ml of 1-Bromo-3-butene (4.926 mM) and 0.94 ml of diisopropyl ethylamine (5.396 mM) were added to the reaction solution containing 0.74 ml of 2,4-dimethoxybenzylamine (a) (4.926 mM) dissolved in methylene chloride with stirring and the solution was left alone at room temperature for overnight. The reaction mixture was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with EtOAc solvent as an eluant to give 436 mg of the pure title compound (b) (yield: 40%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)C=1C(O)=O)([OH:3])=[O:2].[C:29](Cl)(=[O:31])[CH3:30]>>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)[C:30]1[C:29](=[O:31])[O:3][C:1](=[O:2])[CH2:4][C:5]2=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12
Product: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1

Procedure:
A mixture of 3-carboxymethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid (from Example 33, 0.5 g) in acetylchloride (6.2 ml) was heated to reflux for 5 h. The solution was evaporated and the residue triturated with diethylether to give 6-fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as a pale yellow solid. MS: 377.4 ([M+NH4]+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1.Cl[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+]>C1COCC1.CCOC(C)=O>[N:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:5]3[N:6]([CH:36]=[C:3]([CH2:2][O:1][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:8][N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(-c4ccncc4)c4nc(CO)cn34)cn2)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(-c4ccncc4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of compound 87d (80.0 mg, 0.164 mmol), 2-chloroquinoline (40.3 mg, 0.246 mmol) and 18-crown-6 (43.8 mg, 0.164 mmol) in 5 mL of THF at rt was added potassium tert-butoxide (0.328 mL, 0.328 mmol, 1.0M in t-BuOH). The resulting mixture was heated to 60° C. and continued to stir for 0.5 h. After cooling to rt, the mixture was treated with 30 mL of EtOAc and washed with water (2×10 mL) and brine (10 mL). Removal of the solvent under reduced pressure followed by purification of the resultant residue by flash column chromatography on silica gel (0-4% MeOH/DCM) gave compound 87e as a yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.82 (br. s., 2H), 8.70 (br. s., 2H), 8.51 (br. s., 1H), 7.91-8.09 (m, 3H), 7.70-7.91 (m, 3H), 7.64 (t, J=7.2 Hz, 1H), 7.41 (t, J=6.8 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 5.84 (s, 2H), 3.70 (br. s., 4H), 3.60 (br. s., 4H), 1.51 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calcd. for C35H34N8O3, 615.3 (M+H). found 615.2.