Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].NC1NC2C=C(NC(C3C=CC=CC=3C(O)=O)=O)C=CC=2N=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:32]=[C:31]([N:33](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:30](C(OC(C)(C)C)=O)[C:29]=2[CH:55]=1.[CH3:56][C:57]1([CH3:65])[CH2:62][C:61](=[O:63])[O:60][C:59](=[O:64])[CH2:58]1>>[ClH:1].[NH2:33][C:31]1[NH:30][C:29]2[CH:55]=[C:25]([NH:24][C:61](=[O:63])[CH2:62][C:57]([CH3:65])([CH3:56])[CH2:58][C:59]([OH:64])=[O:60])[CH:26]=[CH:27][C:28]=2[N:32]=1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1nc2ccc(NC(=O)c3ccccc3C(=O)O)cc2[nH]1
Product: CC(C)(CC(=O)O)CC(=O)Nc1ccc2nc(N)[nH]c2c1
Yield: 93 %

Procedure:
Following the same procedure to synthesize 2-(2-amino-1H-benzo[d]imidazol-6-ylcarbamoyl)benzoic acid hydrochloride, tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.157 g, 0.351 mmol) was reacted with 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (0.049 g, 0.351 mmol) to give the title product (0.107 g, 93% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.81 (s, 1H), δ 7.29 (m, 2H), δ 2.45 (m, 4H), 1.16 (m, 6H) ppm; 13C NMR (75 MHz, CD3OD) 174.8, 173.6, 173.1, 171.9, 171.6, 151.2, 134.7, 129.6, 111.5, 103.9, 33.2, 33.1, 29.1, 27.3, 26.9 ppm; HRMS (ESI) Calcd for C14H19N4O3 (M+) 290.1378. Found 290.1380.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].S(=O)(=O)(O)O.[F:14][C:15](I)([F:17])[F:16].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:14][C:15]([F:17])([F:16])[C:7]1[C:5]([NH2:6])=[N:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Nc1nc(=O)[nH]cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
0.11 g (1.0 mmol) of cytosine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethylcytosine (19F-NMR yield: 27%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 5-Trifluoromethylcytosine was obtained as a white solid (0.010 g, yield: 5.6%) by column chromatography.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([C:38]([O:40][CH3:41])=[O:39])[S:36][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:34]=[C:35]([C:38]([O:40][CH3:41])=[O:39])[S:36][CH:37]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
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
Solvent: O
Product: COC(=O)c1cc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cs1
Yield: 97.8 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (138 mg), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (152 mg), tetrakis(triphenylphosphine)palladium(0) (44 mg) and 2M aqueous sodium carbonate solution (0.94 mL) in DME (10 mL) was stirred under nitrogen atmosphere at 100° C. for 2 hr stirred. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (132 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:16](=[O:19])/[CH:17]=[CH:18]/[C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:15])=[N:9][C:10]=1[S:13][CH3:14]
Reactant: CSc1nc(N)nc(-c2ccco2)c1I
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1c(SC)nc(N)nc1-c1ccco1
Temperature: 100 °C
Yield: 48.6 %

Procedure:
A stirred suspension of 457 mg (1,37 mmol) 4-furan-2-yl-5-iodo-6-methylsulfanyl-pyrimidin-2-ylamine, 0.25 ml (2.77 mmol) methyl acrylate, 96 mg (0.14 mmol) bis(triphenylphosphine)palladium(II) chloride and 0.67 g (2.06 mmol) cesium carbonate in 5 ml dioxane under argon in a sealed tube was heated at 100° C. for 16 h. After cooling to room temperature, the mixture was diluted with 50 ml ethyl acetate, filtered, and the filtrate was concentrated in vacuo. Flash chromatography (1/2-1/1 ethyl acetate/hexane) followed by trituration in ether/pentane afforded 194 mg (49%) (E)-3-(2-amino-4-furan-2-yl-6-methylsulfanyl-pyrimidin-5-yl)-acrylic acid methyl ester as an off-white crystalline solid. ES-MS m/e (%): 292 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH3:18])=[N:10][S:9]2(=[O:27])=[O:26])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[CH3:15][C:13]1([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH3:18])=[N:10][S:9](=[O:27])(=[O:26])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: C[C@H](NC1=NS(=O)(=O)C(c2cccc(Br)c2)C(C)(C)O1)c1ccccc1F
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC1=NS(=O)(=O)C(c2ccccc2)C(C)(C)O1)c1ccccc1F
Reaction time: 1.75 h
Yield: 70.1 %

Procedure:
Under inert gas, 48 mg of [5-(3-bromophenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl]-[(S)-1-(2-fluorophenyl)ethyl]amine were initially charged in 5 ml of methanol and, with addition of 22 mg of 10% Pd/C, stirred under a hydrogen atmosphere for 1.75 hours. After filtration to remove the solid residues, the filtrate was freed of the solvent under reduced pressure and the crude product was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and freed of the organic solvent under reduced pressure, and the aqueous residue was lyophilized. This gave the product (27.8 mg) with a molecular weight of 376.4 g/mol (C19H21FN2O3S); MS (ESI): m/e=377 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][OH:20])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>N1C=CC=CC=1>[CH:1]1([C:4]2[C:12]([N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:18][CH2:19][O:20][C:32]([C:33]3[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=3[C:35]([OH:37])=[O:36])=[O:42])=[CH:11][C:10]3[C:6](=[C:7]([C:28](=[O:29])[NH:30][CH3:31])[N:8]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCOC(=O)c3ccccc3C(=O)O)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (14) (5.00 mg, 0.0112 mmol) in pyridine (0.200 mL) at RT was added phthalic anhydride (8.29 mg, 0.560 mmol). The reaction mixture was heated under microwave irradiation at 100° C. for 15 min. A further portion of phthalic anhydride (8.29 mg, 0.560 mmol) was added and the reaction mixture reheated at 100° C. for 30 min and 110° C. for 30 min. A further portion of phthalic anhydride (16.6 mg, 1.12 mmol) was added and the reaction mixture was heated at 120° C. for 15 min. The reaction mixture was concentrated in vacuo, the residue redissolved in MeOH (1 mL) and purified by preparative LCMS (40-80% ACN in 0.1% aqueous formic acid). 2-[(2-{[5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}ethoxy)carbonyl]benzoic acid (15) was isolated as a white solid (4.29 mg, 64%). ESI-MS rniz calculated for [M+H]+: 595.16; found: 594.98; 1H NMR (400 MHz, d4-MeOH) δ 7.85 (s, 1H), 7.75 (brd, J=7.4 Hz, 2H), 7.63-7.58 (m, 2H), 7.53 (ddd, J=19.3, 15.5, 6.6 Hz, 1H), 7.48-7.42 (m, 2H), 7.34 (brs, 1H), 7.33-7.26 (m, 1H), 4.51-4.37 (m, 2H), 4.32-4.23 (m, 1H), 4.11-4.02 (m, 1H), 3.10 (s, 3H), 2.92 (s, 3H), 2.39-2.30 (m, 1H), 1.06-0.94 (m, 3H), 0.66-0.59 (m, 1H).
Reaction SMILES: BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[N+:27]([C:30]1[CH:31]=[C:32]([C:41]([O:43][CH3:44])=[O:42])[CH:33]=[C:34]2[C:39]=1[NH:38][C:37](=[O:40])[CH2:36][CH2:35]2)([O-:29])=[O:28]>C(Cl)(Cl)Cl>[N+:27]([C:30]1[CH:31]=[C:32]([C:41]([O:43][CH3:44])=[O:42])[CH:33]=[C:34]2[C:39]=1[NH:38][C:37](=[O:40])[CH:36]=[CH:35]2)([O-:29])=[O:28]
Reactant: COC(=O)c1cc2c(c([N+](=O)[O-])c1)NC(=O)CC2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c2[nH]c(=O)ccc2c1
Yield: 357.9 %

Procedure:
10.7 g of N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added to a solution of 2 g of 8-nitro-6-methoxycarbonyl-3,4-dihydrocarbostyril in 200 ml of chloroform. The mixture was refluxed by heating, for 4 hours. Thereto was added an additional amount (5.0 g) of N-bromosuccinimide. The resulting mixture was refluxed by heating, for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol two times to obtain 7.1 g of 8-nitro-6-methoxycarbonylcarbostyril as light yellow needles.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:52]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH3:37]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 256 mg (1 mmole) of palmitic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 305 mg (Yield: 58%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:17])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:26](Cl)Cl.CO>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:17])[C:12](=[O:15])[N:13]([CH3:26])[N:14]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cc(C(=O)NCCCCC(=O)O)c(=O)[nH]n2)cc1
Reactant: ClCCl
Solvent: CO
Product: Cn1nc(-c2ccc(C#N)cc2)cc(C(=O)NCCCCC(=O)O)c1=O

Procedure:
6-(4-cyanophenyl)-4-[(4-carboxybutyl )-aminocarbonyl]-(2H)-pyridazin-3-one Rf value: 0.30 (silica gel; methylene chloride/methanol=9:1)
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C@H:8]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C@H:6]2[N:7]=1.C(N(S(F)(F)F)CC)C.C(O)C>ClCCl>[CH3:35][N:2]([CH3:1])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([C@@H:12]([OH:14])[CH3:13])[C@@H:9]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C@H:8]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C@H:6]2[N:7]=1
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](C(C)=O)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CO[C@H]2[C@H](OCc3ccc(OC)cc3)[C@H]3N=C(N(C)C)S[C@H]3O[C@@H]2[C@H](C)O)cc1
Yield: 49.7 %

Procedure:
A solution of 1-((3aR,5S,6S,7R,7aR)-2-(dimethylamino)-6,7-bis(4-methoxybenzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanone (280 mg, 0.56 mmol) in dichloromethane (10 mL) was treated with (diethylamino)sulfur trifluoride (451 g, 2.80 mol) and ethanol (5.2 mg, 0.11 mmol) overnight at room temperature. The reaction was then quenched by addition of sat. aqueous sodium carbonate solution (50 mL), and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and condensed under vacuum to give a crude product 55 (140 mg), which was used in the next step without further purification. (ES, m/z) [M+H]+ 523.0; 1H NMR (300 MHz, CD3Cl) δ 1H NMR (300 MHz, CDCl3) δ 7.24-7.30 (m, 4H), 6.84-6.95 (m, 4H), 6.30-6.32 (m, 1H), 4.57-4.62 (m, 4H), 4.27-4.35 (m, 2H), 3.81-3.91 (m, 8H), 2.99-3.01 (m, 6H), 1.56-1.62 (m, 3H).
Reaction SMILES: C1([Li])C=CC=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Li].C1([Cu]C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+].[OH-].[Na+].C(OC([N:44]1[CH2:51][CH:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:49][C@H:45]1[C:46]([OH:48])=[O:47])=O)(C)(C)C.FC(F)(F)C(O)=O>CCOCC.C1COCC1.C(Cl)(Cl)Cl>[C:52]1([C@H:50]2[CH2:51][NH:44][C@H:45]([C:46]([OH:48])=[O:47])[CH2:49]2)[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)C[C@H]1C(=O)O
Agent: c1ccc([Cu]c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H]1C[C@@H](c2ccccc2)CN1
Reaction time: 0.25 h

Procedure:
To a suspension of CuBr: ##STR10## (27.02 g, 0.13143 mole) in dry ether (600 ml) was added phenyllithium (111.58 ml, 2.355 molar solution, 0.2629 mole) dropwise keeping the inside temperature between -20° to -15° C. At the end of the addition a bright clear yellow solution was obtained which was stirred at that temperature for another 15 minutes. A solution of Title D tosylate acid (23.0 g, 0.597 mole) in THF (dry, 300 ml) was added to the diphenyl copper lithium solution at -15° C. and the reaction mixture was stirred at that temperature for 2 hours and 1 hour at 0° C. and allowed to come to ambient temperature (1 hour) followed by 1 hour at ambient temperature. It was cooled in an ice bath and saturated ammonium chloride solution (200 ml) was added to it with vigorous stirring and left overnight at room temperature. The pH of the solution was raised from 11 to 12 by adding 10% NaOH solution, and the solution was then extracted with ether. The blue aqueous phase was acidified with 10% KHSO4 to a pH of ~1 to 2 with cooling and stirring and and the solution was then extracted with ethyl acetate (4×100 ml). The combined organic phase was washed with water (2×50 ml) and brine (2×50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent on a rotavap gave 15.5 g (89%) of crude phenyl substituted material, namely, N-t-butoxycarbonyl-4-phenylproline, as heavy white crystals. The above crude material was dissolved in chloroform (50 ml) and trifluoroacetic acid (50 ml) was added to it, and the mixture stirred at room temperature for 1 hour and the solvent evaporated on a rotavap. Toluene (100 ml) was added to the residue and evaporated again on a rotavap. The residue was dissolved in 500 ml water (pH ~1) and the pH of the solution was brought to 6.3 by adding 10% NaOH solution. The precipitate was dissolved in 2 liters hot water and ~2 g of charcoal was added to it and boiled for 5 minutes, filtered and concentrated to a volume of ~500 ml. It was kept in the refrigerator overnight to complete the crystallization. It was filtered, washed with water (50 ml), acetonitrile (100 ml), and ether (100 ml) and air dried to give 6 g of title compound, m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12].ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24]([CH3:25])=[O:34])[CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) of the compound from Example 8 were introduced into 15 ml of dichloromethane at 0° C., 61.9 mg (0.25 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 91 mg (88% of theory) of the title compound as mixture of diasteromers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25](S(C)(=O)=O)[CH:24]=[CH:23][N:22]=3)[N:18]([C:31]3[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:24]=[CH:23][N:22]=3)[N:18]([C:31]3[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2cc(S(C)(=O)=O)ccn2)cn1
Product: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2cc(N3CCCC3)ccn2)cn1
Yield: 96 %

Procedure:
A solution of 4-[1-(6-methoxy-3-pyridyl)-5-(4-methylsulfonyl-2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (0.186 g) obtained in Example 48 in pyrrolidine (3.7 mL) was stirred at 100° C. for 17 hours, and then the mixture was cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (0.176 g, 96%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:4][CH:3]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:30].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:32]1([CH3:37])[C:31]([C:29]([CH2:28][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:4][CH:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]2=[O:1])=[O:30])=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)=CCN1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21
Reactant: Cc1ccccc1C(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=CCN1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (965 mg) was suspended in toluene (14 ml), 2-bromo-2′-methylacetophenone (686 mg), 1N aqueous sodium hydroxide (7 ml) and tetran-butylammonium bromide (20 mg) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was weakly acidified with 1N hydrochloric acid, extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to thereby obtain 782 mg of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cc(Br)cnc1Cl
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1
Yield: 82 %

Procedure:
Using an analogous method to that described in Example 11, 3-amino-5-bromo-2-chloropyridine was reacted with and 4-fluorobenzenesulfonyl chloride to give N-(5-bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide in 82% yield; 1H NMR Spectrum: (CDCl3) 8.21 (1H, d); 8.15 (1H, d); 7.84 (2H, m); 7.20 (2H, m); 6.97 (1H, br s); Mass Spectrum: M+H+ 365.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][N:41]2[C:42](=[O:44])[CH2:43][O:39][C:40]2=[O:45])[CH2:15][CH2:16]1
Reactant: OCCC1CCN(c2ccc3ccccc3n2)CC1
Reactant: O=C1COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1COC(=O)N1CCC1CCN(c2ccc3ccccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 5 (step 5.2). Starting with 2.22 g (8.65 mmol) of 2-[1-(2-quinolyl)-4-piperidyl]-ethanol, prepared in step 8.1, 2.50 g (9.52 mmol) of triphenylphosphine, 1.05 g (10.38 mmol) of 1,3-oxazolidine-2,4-dione and 1.75 g (8.65 mmol) of diisopropyl azodicarboxylate (DIAD), and after chromatography on silica gel, eluting with a 30/70 and then 40/60 mixture of ethyl acetate and cyclohexane, 2.63 g of product are obtained in the form of an amorphous white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5](=[O:10])[CH:4]=[N:3]1.[Br:11]Br>O>[Br:11][C:4]1[C:5](=[O:10])[N:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: Cn1ncc(=O)n(C)c1=O
Reactant: BrBr
Solvent: O
Product: Cn1nc(Br)c(=O)n(C)c1=O
Temperature: 60 °C

Procedure:
The compound 17a (13.3 g, 94.1 mmol) is placed in 100 ml of water in the presence of bromine (18 ml, 351 mmol) and then this mixture is heated at 60° C. for 12 h.