Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](=[O:13])([O:10][CH2:11][CH3:12])N>C(O)C>[CH2:11]([O:10][C:8](=[O:13])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: Nc1ccccc1
Reactant: CCOC(N)=O
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 75.6 %

Procedure:
1024 g aniline, 980 g ethyl carbamate and 1060 g ethanol (approximately 96%) were reacted in the apparatus described in Example 1 for 6.0 hours at 200° C. When the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and distilled to remove the excess ethanol. The product was then fractionally distilled at 0.4 m bar. 1373 g N-phenyl-carbamic acid ethyl ester (75.5% of the theoretical yield), were collected and crystallized. The product had a melting point of 51° to 52° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2].Cl[CH2:18][CH2:19][CH2:20][CH2:21][P:22]([O:27][CH2:28][CH3:29])(=[O:26])[O:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][P:22](=[O:26])([O:27][CH2:28][CH3:29])[O:23][CH2:24][CH3:25])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCOP(=O)(CCCCCl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1cnc2c1c(=O)n(CCCCP(=O)(OCC)OCC)c(=O)n2C
Temperature: 70 °C

Procedure:
44.8 g (0.2 mol) of 7-ethoxymethyl-3-methylxanthine were suspended in 500 ml of DMF, treated with 55 g (0.24 mol) of diethyl 4-chlorobutane-phosphonate and 50 g (0.32 mol) of activated potassium carbonate and heated at 70° C. for 4 hours and filtered, the filtrate was concentrated under reduced pressure and the oily residue which remained was taken up in ethyl acetate. filtered again and crystallized from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:15]([CH3:14])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)cc1OC(C)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
A solution of methyl 4-chlorosalicylate (5.0 g) in dimethyl formamide (10 ml) was treated sequentially with methyl 3-bromopropionate (4.0 g) and potassium carbonate (6.0 g). The mixture was stirred at room temperature for 18 hrs and diluted with water. The mixture was extracted with ether and the organics were washed with water. The organic layer was dried and evaporated to give the desired material (6.7 g) as a low melting solid. NMR: 7.8 (d, 1H), 7.2 (m 1H), 6.9 (m, 1H), 4.8 (q, 1H), 3.9 (s, 3H), 3.8 (s, 3H), 1.7 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:6]([N+:17]([O-])=O)[CH:5]=1.CC(=O)OCC>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][C:13]([F:15])([F:16])[CH2:12]2)=[C:6]([NH2:17])[CH:5]=1
Reactant: COC(=O)c1ccc(OC2CC(F)(F)C2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC2CC(F)(F)C2)c(N)c1
Reaction time: 16 h
Yield: 79.8 %

Procedure:
1.4 g of 4-(3,3-Difluoro-cyclobutoxy)-3-nitro-benzoic acid methyl ester were dissolved using 50 ml of EA and 10 ml of acetic acid, 200 mg of Pd/C 10% (50% water) added and hydrogenated under an atmosphere of hydrogen at normal pressure for 16 h at room temperature. The reaction mixture was filtrated, 100 ml of EA added and washed twice using 30 ml of a saturated aqueous Na2CO3-solution. The organic layer was dried using MgSO4 and volatiles were evaporated to yield 1.0 g of the title compound that was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:19]2[CH:18]=[C:17]([C:20]([O:22]C)=[O:21])[NH:16][C:15]=2[CH2:14][CH2:13]1.[OH-].[Li+].CO>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:19]2[CH:18]=[C:17]([C:20]([OH:22])=[O:21])[NH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc2ccccc2c1

Procedure:
The title compound was synthesized from methyl 4-(naphthalen-2-ylmethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.104 g, 0.34 mmol) and lithium hydroxide (0.148 g, 3.53 mmol in 5 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (10 mL) was used. The solvent was removed under reduced pressure, and the residue re-dissolved in ca. 5 mL H2O and acidified to pH 7 with 1 N HCl. The solids formed were collected, affording the title compound as a light pink solid: 77 mg, 76% yield. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.16 (ddt, J=12.34, 8.74, 5.98, 5.98 Hz, 1H), 2.50-2.76 (m, 3H), 2.92-3.03 (m, 2H), 3.37-3.47 (m, 1H), 6.31 (d, J=1.71 Hz, 1H), 7.41-7.50 (m, 3H), 7.73 (s, 1H), 7.82-7.90 (m, 3H), 10.39 (br. s, 1H); LCMS-MS (ESI−) 290.0 (M−H); HPLC (UV=93.55%), (ELSD=100%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:48][O:49][C:50]1[CH:51]=[C:52]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1>CN(C=O)C>[CH3:48][O:49][C:50]1[CH:51]=[C:52]([N:58]2[CH2:59][CH2:60][N:61]([C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[O:13])[CH2:62][CH2:63]2)[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)c3ccnc4ccccc34)CC2)c1

Procedure:
2 g (11.5 mmol) of quinoline-4-carboxylic acid were suspended in 80 ml of DMF. With stirring, 1.74 g (17.2 mmol) of N-methylmorpholine and then a solution of 8.95 g (17.2 mmol) of Py-BOP (1-benzotriazolyltripyrrolidinophosphonium hexafluorophosphate) and 2.56 g (11.5 mmol) of 1-(3,5-dimethoxyphenyl)piperazine in 25 ml of DMF were added to this mixture. The mixture was stirred at RT for 12 h, the DMF was distilled off under reduced pressure and the residue was purified on a silica gel column (Kieselgel 60, from Merck AG, Darmstadt) using the mobile phase dichloromethane/methanol/25 percent ammonia (90:10:1 v/v/v).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH:33]2[CH2:35][CH2:34]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:39]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:39])=[O:32])[C:20]([CH:33]2[CH2:34][CH2:35]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@@H]1C=C(C2CC2)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C2CC2)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-cyclopropyl-2-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 240, 2.35 g, 4.61 mmol) following the procedure described for Intermediate 19. The desired product was obtained as an orange foam (2.28 g, 94%).
Reaction SMILES: Br[C:2](=[N:8][NH:9][C:10]1[N:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C>C(O)(C)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8][N:9]=2)[N:12]=1
Reactant: CCOC(=O)C(Br)=NNc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)c1nnc2ccc(Cl)nn12
Yield: 88.3 %

Procedure:
A mixture of compound ethyl 2-bromo-2-(2-(6-chloropyridazin-3-yl)hydrazono)acetate (1.25 g, 4 mmol) in 10 mL of isopropanol with 0.5 mL of triethylamine was refluxed for 1 h. The solution was evaporated and the residue was washed thoroughly with water to give product ethyl 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate as a yellow solid (0.8 g, 67%). LRMS (M+H+) m/z: calcd 227.03; found 227. 1H NMR (300 MHz, CDCl3): δ 8.25-8.22 (d, J=9.6 Hz, 1H), 7.34-7.31 (d, J=9.6 Hz, 1H), 4.64-4.56 (q, 2H), 1.53-1.49 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](B(O)O)=[CH:7][C:6]=2[CH:13]=1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH2:33]C)=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:15]3[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=4)[N:16]=3)=[CH:7][C:6]=2[CH:13]=1
Reactant: OB(O)c1cc2cc(F)ccc2o1
Reactant: CCOC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 5-fluorobenzofuran-2-ylboronic acid (614.3 mg, 3.41 mmol) in dioxane (15 ml) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (500 mg, 1.70 mmol), K3PO4 (725 mg, 3.42 mmol), Pd(PPh3)4 (40.5 mg, 0.035 mmol) and water (1.0 ml), and the resulting mixture was stirred for 1 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (536 mg, 80%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-].[K+].[Cl-].[K+]>C(O)C>[CH2:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH:9]1[O:11][CH2:10]1
Reactant: C1CNCCN1
Reactant: ClCC1CO1
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C1CN(CC2CO2)CCN1

Procedure:
Piperazine (86.15 g., one mole) and ethanol (150 g. plus 1.5 g. water) were placed in a one liter 3-neck flask equipped with a stirrer, thermometer, dropping funnel and condenser. The mixture was stirred until a complete solution was obtained and then epichlorohydrin (92.53 g., one mole) was added dropwise while maintaining the temperature below 25° C., by means of an ice bath. After addition of the epichlorohydrin was complete, the temperature was maintained below 25° C. for an additional 30 minutes. Then a solution of 56.11 g. (1 mole) of potassium hydroxide in 225 g. of ethanol was added over a period of 30 minutes while maintaining the temperature below 25° C. After cooling to 15° C. the potassium chloride which had formed during the reaction was filtered from the mixture and the filtrate concentrated to 1/2 its volume by stripping under vacuum. One liter of ethyl acetate was then added to the residual filtrate. The N-glycidylpiperazine oligomer precipitated as a white solid. The resultant slurry was filtered after standing several hours. The N-glycidylpiperazine oligomer collected on the filter after drying in vacuo at room temperature amounted to 119 grams, 83.8% of the theoretical yield. Elemental analysis indicated: %C, 56.09; %H, 9.55; %N, 18.55; %O 15.77. The number average molecular weight as determined by vapor pressure osmometry was 705. This data corresponds to the formula: ##STR5##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC3CC3)c2)CCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g, 8.3 mmol) in dry CHCl3 (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)o1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (94 mg, 0.179 mmol) and ammonium hydroxide (5 mL), the title compound was obtained as a white solid (30 mg, 33%). 1H-NMR (DMSO-d6): δ ppm 10.34 (br s, 1H), 8.18-8.19 (d, J=5.2 Hz, 1H), 7.65 (br s, 1H), 7.30-7.34 (t, J=7.4 Hz, 2H), 7.21-7.24 (m, 3H), 6.56 (br s, 2H), 6.45 (d, J=5.2 Hz, 1H), 1.40 (s, 9H); MS: 504 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].CCN(CC)CC.[C:27]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:27]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([NH:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][CH:2]([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:10]=[CH:11][CH:12]=2)[N:17]=1)=[O:40])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(N)nc12
Reactant: O=C(OCc1ccccc1C(=O)Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CC(C)(C)C)Oc1cccc2ccc(NC(=O)c3ccccc3COC(=O)c3ccccc3)nc12
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial was added a stir bar, the title compound from Example 16 (100 mg, 0.388 mmol) and anhydr. THF (1.3 mL). To the resultant solution was added of Et3N (0.12 mL, 2.2 equiv), DMAP (5.0 mg, 1.06 equiv) and of 2-(benzoyloxymethyl)benzoyl chloride (116 mg, 1.1 equiv). The solution was stirred overnight, after which time the mixture was placed directly on a silica gel column and eluted with EtOAc/hexanes to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.23 (m, 1H), 8.16 (m, 1H), 7.92 (m, 2H), 7.72 (m, 1H), 7.55 (m, 4H), 7.38 (m, 4H), 7.24 (m, 1H), 5.51 (s, 2H), 4.82 (m, 1H), 1.88 (dd, 1H), 1.49 (dd, 1H), 1.34 (d, 3H), 0.92 (s, 9H); MS (DCI/NH3) m/z 497 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:19]2[S:23](=[O:25])(=[O:24])[N:22](CC3C=CC(OC)=CC=3OC)[C:21](=[O:37])[CH2:20]2)=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([N:19]2[S:23](=[O:24])(=[O:25])[NH:22][C:21](=[O:37])[CH2:20]2)=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)CN(c3cc4c(cc3OCc3ccccc3)SC(C)C4)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1Cc2cc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)cc2S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(6-benzyloxy-2-methyl-2,3-dihydrobenzo[b]thiophen-5-yl)-2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (71 mg, 0.13 mmol) in DCM (8 mL) is added TFA (10 mL) and the mixture is stirred at RT for 4 h. TFA and DCM are removed under vacuum to give the title compound and it is used directly in the next step: (M+H)+=301.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[NH2:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13]([NH:27][C:26]1[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:15]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(O)C(=C1C(=O)Nc2ccc(Br)cc21)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)C(=C2C(=O)Nc3ccc(Br)cc32)c2ccccc2)cc1OC
Yield: 16.4 %

Procedure:
A mixture of (5-bromo-2-oxo-1,2-dihydroindol-3-ylidene)phenyl-acetic acid (70 mg), 3,4-dimethoxyaniline (63 mg), 4-dimethylaminopyridine (25 mg), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP, 90 mg) and TEA (1 drop) in DMF (2 mL) was refluxed overnight. The reaction mixture was concentrated and then diluted with aqueous carbonate. The precipitate which formed was washed with dilute HCl and water and then dried to give 16 mg of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4C)nc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4C)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(2-methyl-3-pyridinyl)methyl]sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.61 g) in methylene chloride (18.3 ml) was added dropwise a solution of m-chloroperbenzoic acid (243 g) in methylene chloride (4.0 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(2-methyl-3-pyridinyl)methyl]sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 272) (277 mg).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:9].[Cl-:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:1]([Cl:10])([Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClC(Cl)c1ccccc1
Yield: 45 %

Procedure:
Furthermore, it is known from Liebig's Annalen der Chemie, Volume 626, pages 26 to 34 (1959) to react benzaldehyde with triphenylphosphine dichloride to give benzal chloride, but the yield is only 59%. When cyclohexanone is reacted with triphenylphosphine dichloride in the presence of an equimolar amount of triethylamine it is not the corresponding geminal dihalide which is obtained but 1-chlorocyclohex-1-ene in 45% yield (loc. cit., page 33).
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[S:21]([CH3:22])=[O:33])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Solvent: ClC(Cl)Cl
Product: CS(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 95.5 %

Procedure:
To a solution of (11β,17β)-9-fluoro-11-hydroxy-17-(methylthio)androsta-1,4-dien-3-one (701 mg, 2.0 mmole; see example 5) in chloroform (30 ml) was added a solution of 85% m-chloroperbenzoic acid (398 mg, 2.0 mmole) in chloroform (10 ml). An instantaneous reaction was observed (tlc). The solution was then washed with a 10% potassium carbonate solution and water, dried (anhydrous magnesium sulfate) and evaporated to afford the title compound as a solid (700 mg). One crystallization of this from acetone-hexane followed by drying (100° C., 0.3 mm of Hg, 10 hours) gave the analytical specimen of the title compound (600 mg) melting point 270°-272° C. dec., as a mixture of sulfoxide stereoisomers, with consistent spectral data.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][N:14]([CH3:16])C)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=C[CH:26]=[C:25](N)[CH:24]=1.Cl>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][NH:14][C:16]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=CN(C)C)C(=O)OC)CC1
Reactant: COc1cccc(N)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N1CCN(C(=CNc2cccc(OC)c2)C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of step (ii) (6.3 g), m-anisidine (2.5 ml), ethanol (65 ml) and concentrated hydrochloric acid (2.2 ml) was stirred at room temperature for 2 hours then evaporated. The residue was basified by careful addition of aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by flash chromatography on silica by elution with 70% v/v ether/hexane to yield 1-ethoxycarbonyl-4-(1-(3-methoxyphenyl)amino-2-methoxycarbonylethen-2-yl)piperazine (5.15 g) as an off-white solid: m.p. 120°-122° C.; NMR (CDCl3) δ 1.28 (3H, t), 2.90 (4H, m), 3.50 (4H, m), 3.71 (3H, s), 3.81 (3H, s), 4.18 (2H, q), 6.52 (3H, m), 7.21 (1H, t), 7.39 (1H, d), 7.80 (1H, d); m/Z 364 (H+H)+.