Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]1[CH2:32][CH2:31][O:30][C:28](=[O:29])[CH2:27][CH2:26]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CI>O1CCCC1.CCCCCC>[CH3:1][CH:27]1[CH2:26][CH:25]([CH2:24][CH2:23][CH2:22][CH2:21][O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:32][CH2:31][O:30][C:28]1=[O:29]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCCCC1CCOC(=O)CC1
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1CC(CCCCO[Si](C)(C)C(C)(C)C)CCOC1=O
Reaction time: 0.25 h

Procedure:
To a solution of 14.3 ml (0.1 mole) of diisopropylamine in 170 ml dry tetrahydrofuran is added dropwise 37 ml (93 mmol) of a 2.5M solution of n-butyllithium in hexane. The solution is stirred for 15 min and then a solution of 13.86 g (46.1 mmol) of 4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone in 68 ml dry tetrahydrofuran is added slowly. The yellow solution is stirred at room temperature for 0.5 h and 19 ml (0.3 mole) methyl iodide is added rapidly. The exothermic reaction is controlled by cooling in a water bath. The reaction mixture is stirred for 3 h and quenched using saturated aqueous ammonium chloride solution. The mixture is extracted with ether and the organic layer is washed with water and brine. The organic phase is dried, filtered, concentrated and purified by chromatography using 3:2 hexane/ether as eluent to yield 2-methyl-4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone; NMR (CDCl3): delta 4-4.4 (m,2H), 3.6 (t,2H), 1.2 (d,3H), 0.88 (s,9H). This is converted to methyl 8-amino-2-methyl-4-[3-(3-pyridyl)propyl]-octanoate in a similar fashion as described below for the 2,2-dimethyl analog.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH3:8])[C:5]([OH:7])=[O:6])[CH3:2].S(Cl)(Cl)=O.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(OCC)(=[O:21])C>>[CH2:1]([O:3][C@@H:4]([CH3:8])[C:5]([O:7][C:15]1[CH:14]=[CH:13][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:6])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCCCCC
Reactant: CCO[C@@H](C)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCO[C@@H](C)C(=O)Oc1ccc(O)cc1
Reaction time: 20 h

Procedure:
5.6 g of the resulting (s)-2-ethoxypropionic acid was added to 10 ml of thionyl chloride, and the mixture was refluxed for 5 hours. Thionyl chloride was then evaporated under reduced pressure, and a solution of 9.0 g of hydroquinone in 50 ml of dry pyridine was added, and the mixture was stirred at 30° to 40° C. for 20 hours. The reaction mixture was dissolved in a large amount of ethyl acetate, washed with dilute hydrochloric acid several times and then with water, and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated and from the residue, 4.6 g of the desired oily product was obtained by silica gel column chromatography using hexane/ethyl acetate as an eluent.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[S:3]1.[H-].[Na+].[C:18]1([CH2:26]Br)[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1.[OH2:28]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:26][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][O:28][C:12]4[CH:11]=[CH:10][C:9]([CH2:8][CH:4]5[S:3][C:2](=[O:1])[NH:6][C:5]5=[O:7])=[CH:14][CH:13]=4)=[CH:20][CH:19]=3)=[CH:11][CH:10]=2)[S:3]1
Reactant: BrCc1ccc(CBr)cc1
Reactant: O
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccc(COc4ccc(CC5SC(=O)NC5=O)cc4)cc3)cc2)S1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A 2.23 g portion of 2,4-dioxo-5-[(p-hydroxyphenyl)-methyl]thiazolidine was dissolved in 25 ml of dimethylformamide, and the solution was mixed with 0.8 g of sodium hydride and maintained at 60° C. for 3 hours. Under cooling with ice water, 1.32 g of p-xylylene dibromide was added to the solution, and the mixture was incubated at room temperature for 3 hours and then at 80° C. for 3 hours. A 100 ml portion of water and 100 ml of ethyl acetate were added to the reaction mixture to dissolve insoluble contents, and the resulting organic layer was collected and washed with water, followed by distillation to remove ethyl acetate. Thereafter, the resulting residue was subjected to silica gel column chromatography (eluent: chloroform) to obtain 1,4-bis[[4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenoxy]methyl]benzene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[NH:22][C:21]2[CH:23]=[C:24]([O:30][CH2:31][CH:32]([F:34])[F:33])[C:25]([C:27]([OH:29])=O)=[CH:26][C:20]=2[N:19]=1.[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C1COCC1>CCOC(C)=O>[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:27]([C:25]2[C:24]([O:30][CH2:31][CH:32]([F:33])[F:34])=[CH:23][C:21]3[NH:22][C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:26]=2)=[O:29])=[CH:38][CH:37]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c(OCC(F)F)cc3[nH]2)c1Cl
Reactant: Nc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)Nc4ccc(Br)cc4)c(OCC(F)F)cc3[nH]2)c1Cl

Procedure:
PPA (0.223 mL, 50% in EtOAc, ˜0.38 mmol) is slowly added to a mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-5-carboxylic acid (0.150 g, 0.291 mmol), 4-bromoaniline (50 mg, 0.291 mmol), TEA (0.101 mL, 0.728 mmol) and THF (10 mL). The mixture is refluxed for 3 d, concentrated and purified via prep. HPLC (column: Zorbax stable bond C18, 5 μm, 30×100 mm, gradient: water+0.15% HCOOH/MeOH 95:5→10:90) to furnish the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:39]2[CH:51]=[CH:50][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:40]=[CH:41][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:50][CH:51]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Reaction time: 0.13 h

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/water mixture (70 mL/14 mL) was added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (13.4 g, 44.2 mmol) followed by addition of Na2CO3 (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd(PPh3)4 (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100° C. for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71%). Analytical Data: LCMS: 573.35 (M+1)+; HPLC: 99.5% (@254 nm) (Rt; 3.999; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-1.2 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz),3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8 Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of 1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxylic acid (0.2 g, 0.56 mmol) and aniline (0.052 mL, 0.56 mmol) in DMF (5 mL) was added diisopropylethylamine (0.198 mL, 1.12 mmol) under argon. The mixture cooled to 0° C., HATU (0.212 g, 0.56 mmol) was added at that temperature and then stirred at room temperature for 4 h. After completion of reaction (by TLC), H2O (5 mL) was added drop by drop. The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish 1-(3-(benzylamino)-4-nitrophenyl)-N-phenyl piperidine-4-carboxamide (0.21 g), 87% yield. 1H NMR (500 MHz, DMSO): δ 1.57 (m, 2H), 1.82 (m, 2H), 2.65 (m, 1H), 2.99 (m, 2H), 3.98 (m, 2H), 4.60 (d, J=5.7 Hz, 2H), 5.97 (d, J=2.5 Hz, 1H), 6.44 (dd, J=2.5 Hz, 1H), 7.03 (m, 1H), 7.29 (m, 3H) 7.37 (m, 2H), 7.43 (m, 2H), 7.60 (m, 2H), 7.92 (d, J=9.7 Hz, 1H), 8.84 (m, 1H), 9.9 (bs, 1H). HRMS (ESI) calculated for C25H27N4O3: 431.2078, Found: 431.2005.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:26])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:36]1[N:40]2[CH:41]=[C:42]([O:45][C@H:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C@@H:49]([NH2:56])[CH2:48][CH2:47]3)[CH:43]=[CH:44][C:39]2=[N:38][N:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:56][C@@H:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:46]([O:45][C:42]3[CH:43]=[CH:44][C:39]4[N:40]([C:36]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:37][N:38]=4)[CH:41]=3)[CH2:47][CH2:48]2)=[O:26])[N:8]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccnc(OCCO)c2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccnc(OCCO)c4)c4ccccc43)cn12
Temperature: 60 °C
Yield: 84.6 %

Procedure:
Intermediate 67d (74 mg, 0.16 mmol) and Intermediate B (62 mg, 0.16 mmol) were suspended in 1,4-dioxane (5 mL) and DIPEA (32 mg, 42 μL, 0.25 mmol) added and the reaction heated to 60° C. for 18 h. The reaction was cooled, concentrated in vacuo and subjected to FCC, eluting with 0-5% 2M NH3 in MeOH/DCM, to afford the title compound (92 mg, 83%). LCMS (Method 3) Rt 3.51 min, 680.4 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[Br-].[CH2:26]([Zn+])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.CCOC(C)=O>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (800 mg, 2.06 mmol), benzylzinc bromide (10.3 mL, 5.14 mmol, 0.5 M in THF), and Pd(PPh3)4 (238 mg, 0.206 mmol) in THF (20 mL) was refluxed under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., 1 M HCl and EtOAc were added. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes+2% AcOH) to give 470 mg of the title compound as a yellow solid. MS: (+) m/z 401.12 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:24]([N:26]=[C:27]=[O:28])=[O:25]>O1CCOCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:24](=[O:25])[NH:26][C:27](=[O:28])[N:19]([CH3:20])[C:17]4=[O:18])=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CNC(=O)Nc1ccc(Sc2nc3ccc(Cl)cc3s2)cc1
Reactant: O=C=NC(=O)Cl
Solvent: C1COCCO1
Product: Cn1c(=O)[nH]c(=O)n(-c2ccc(Sc3nc4ccc(Cl)cc4s3)cc2)c1=O
Yield: 77.6 %

Procedure:
Methyl isocyanate (0.41 g) was added to a solution of 4-(6-chlorobenzothiazol-2-ylthio)-aniline (2.0 g) in pyridine (20 ml), with stirring. The mixture was stirred at room temperature for 12 hours and evaporated to dryness. The residue was dissolved in a minimal volume of boiling ethanol and the solution was cooled in a refrigerator. The resulting solid substance was collected by filtration and dried to give N-[4-(6-chlorobenzothiazol-2-ylthio)phenyl]-N'-methylurea (1.5 g), which had a melting point of 289°-291° C. This urea (1.4 g) was dissolved in 1,4-dioxane (50 ml), and chlorocarbonyl isocyanate (0.47 g) was added. The mixture was heated at the boiling point for 5 hours and evaporated to dryness. The solid residue was dissolved in a minimal volume of boiling ethanol and the solution was cooled in a refrigerator. The resulting solid substance was collected by filtration and dried to give 1.3 g of 1-[4-(6-chlorobenzothiazol-2-ylthio)phenyl]-3-methyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione of melting point 232°-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[OH:15].[H][H]>[Pd].C(OCC)(=O)C>[NH2:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:15]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)F)cc(Cl)c1O

Procedure:
A mixture of 5.01 g of a mixture containing 2-chloro-4-(trifluoromethyl)-6-nitrophenol, 15 ml of ethyl acetate and 1.0 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for 15 hours. The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.78 g of 2-amino-6-chloro-4-(trifluoromethyl)phenol.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].O>CS(C)=O>[CH3:13][O:12][C:11]1[C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=2[O:17][CH3:16])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2
Reactant: COc1ccc2nc(Cl)c(OC)nc2c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc3ccc(OC)cc3nc2OC)c(OC)c1
Temperature: 60 °C
Reaction time: 118 h
Yield: 76.7 %

Procedure:
To 2-chloro-3,6-dimethoxyquinoxaline (3.87 g, 17.2 mmol) dissolved in dimethyl-sulfoxide (70 ml), 2,4-dimethoxybenzylamine (6.07 g, 36.3 mmol) was added at room temperature. The mixture was stirred at 60° C. for 118 hours and then water was added thereto. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (6:1) mixture and concentration gave 4.69 g of the titled compound (yield, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[Br:14]Br>>[Br:14][CH2:12][C:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])=[O:13]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: BrBr
Product: O=C(CBr)c1cc([N+](=O)[O-])ccc1Cl
Yield: 96 %

Procedure:
Procedure A was performed with 2′-chloro-5′-nitro-acetophenone (4.0 g, 20 mmol) and bromine (1.13 ml, 22 mmol). The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (0:1 to 1:4) to afford the desired 2-bromo-2′chloro-5′-nitroacetophenone (5.4 g, 19.2 mmol).
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][C:15]([NH:18]C(=O)OCC1C=CC=CC=1)([CH3:17])[CH3:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[OH-].[OH-].[Pd+2].CO>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16])=[O:7]
Reactant: CC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(N)COP(=O)(OC(C)(C)C)OC(C)(C)C
Yield: 94.8 %

Procedure:
The product of Example 95B (0.40 g, 0.96 mmol) and 20% palladium hydroxide on carbon (0.21 g) in a ethyl acetate (10 mL) and methanol (1 mL) was stirred under a an atmosphere of hydrogen for 0.5 hours. The reaction was filtered through a bed of celite and concentrate to give the title product (0.256 g).
Reaction SMILES: [O-][CH2:2]C.[CH3:4][C@@:5]12[C@H:15]3[CH2:16][CH2:17][C@:18]4([CH3:26])[C@:22]([OH:25])([C:23]#[CH:24])[CH2:21][CH2:20][C@H:19]4[C@@H:14]3[CH2:13][CH2:12][C:11]1=[CH:10][C:8](=[O:9])[CH2:7][CH2:6]2>C1C=CC=CC=1>[C:23]([C@:22]1([O:25][CH3:2])[CH2:21][CH2:20][C@H:19]2[C@H:14]3[C@H:15]([CH2:16][CH2:17][C@:18]12[CH3:26])[C@:5]1([CH3:4])[C:11](=[CH:10][C:8](=[O:9])[CH2:7][CH2:6]1)[CH2:12][CH2:13]3)#[CH:24]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC[O-]
Solvent: c1ccccc1
Product: C#C[C@]1(OC)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 2 h

Procedure:
Thallous ethoxide (0.8 ml.) is added to ethisterone (17α-ethinyl-17β-hydroxyandrost-4-en-3-one, 3.44 g.) in benzene (50 ml.). After mixing, the benzene is removed with the rotary evaporator and acetonitrile (50 ml.), benzene (40 ml.) and methyl iodide (1.7 ml.) are added. The mixture is refluxed and stirred for 2 hours. Additional methyl iodide (2 ml.) is added and the mixture refluxed another 2 hours. The precipitated thallous iodide is filtered off and the filtrate is concentrated to a residue which is taken up in boiling SSB and filtered thru Celite. After concentration the product is column chromatographed over silica gel eluting with increasing amounts of ethyl acetate in SSB. The appropriate fractions (TLC) are pooled and concentrated to give the title compound (recrystallized from SSB): m.p. 127°-131°; UV (ethanol) λ=240 nm (ε=16,500); MS (m/e) 326 and 311; IR (mull) 3240, 2100, 1670 and 1620 cm-1.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH:4](C(O)=O)[CH2:5][N:6]3[CH3:23].O>CN1CCCC1=O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[CH:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)C(C(=O)O)CN2C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CN2c3c(c(F)c(F)c(F)c3C1=O)CCN2C
Temperature: 160 °C
Yield: 48.1 %

Procedure:
300 mg of the compound (197) obtained in Example 68 was dissolved in 6 ml of N-methylpyrrolidone, and the solution was heated at 160° C. for 3 hours. After air-cooling, the water was added to the reaction solution, and the solution was extracted with chloroform three times. After drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by column chromatography (silica gel, eluent solvent; chloroform) to obtain 128 mg of the subject compound (198) in a 49% yield.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].BrC1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10]N=1.[CH2:15]([O:17][CH2:18][CH3:19])[CH3:16].O.[CH3:21][CH2:22][CH2:23]CC>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:14][C:11]1[CH:12]=[CH:13][C:15]([O:17][CH2:18][CH2:19][CH2:21][CH2:22][CH3:23])=[CH:16][CH:10]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCCCC
Reactant: CCOCC
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: O
Product: CCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.44 g (6.92 mmol) of a subtitled compound of Preparation 2B in 50 ml of toluene and 20 ml of methanol under nitrogen, was added 15.5 ml (31.1 mmol) a 2M sol. of sodium carbonate which resulted in the formation of a white precipitate. To the resultant mixture, was added 800 mg (0.69 mmol) of palladium tetrakis (triphenylphosphine), followed by 1.64 g (6.92 mmol) of 2,5-dibromopyridine. The resultant reaction mixture was reacted for approximately three hours, forty-five minutes at reflux temperature. When the reaction was substantially complete, as indicated by TLC, the mixture was cooled to room temperature and allowed to stir overnight. The reaction mixture was placed in a separatory funnel and combined with diethyl ether and water. The resultant layers were separated and the organic layer was dried over sodium sulfate, filtered and then concentrated in vacuo to provide a residue. This residue was redissolved in pentane and filtered to provide 0.95 g of the desired compound. The filtrate was recrystallized to provide an additional 1.4 g of the desired compound. These solids were combined and used without further purification. ##STR20##