Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.B(F)(F)F.[CH3:16][CH2:17]OCC>C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:16][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)cc1

Procedure:
A solution of 8.2 g. of 4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate dried and evaporated to yield ethyl 4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 15-(trifluoromethyl)pentadecyl bromide, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl 4-[15-(trifluoromethyl)pentadecylamino]phenylacetate. A mixture of 6.0 g. of this ester, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with concentrated hydrochloric acid. The mixture is diluted with water, cooled and filtered. Recrystallization of the precipitate yields the product as a white solid.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].Cl[C:11]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[CH:12][C:13]#[N:14]>CO>[NH2:14][C:13]1[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[S:6][C:5]=1[C:4]([O:8][CH3:9])=[O:7]
Reactant: N#CC=C(Cl)c1ccncc1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(-c2ccncc2)cc1N
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a stirred solution of sodium methoxide (2.12 g, 39.3 mmol) in methanol (59 mL) was added methyl thioglycolate (3.51 mL, 39.3 mmol). After 10 min, 3-chloro-3-(pyridin-4-yl)acrylonitrile (6.47 g, 39.3 mmol) was added, and the mixture was heated at 50° C. After 1 h, the mixture was concentrated to about a half volume at reduced pressure and poured into water (500 mL). Extraction with ethyl acetate/tetrahydrofuran (4:1, 500 mL), washing with brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave the title compound (8.81 g, 96%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][N:26]([CH:27]([CH3:29])[CH3:28])[C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:36][CH:37]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CNC(C)C)cc1OC
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CN(C(=O)c2ccc(NS(C)(=O)=O)cc2)C(C)C)cc1OC

Procedure:
In a manner similar to Preparation 3, react 4-(3-chlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-N-(1-methylethyl)-2-piperazinemethanamine with 4-[(methylsulfonyl)amino]benzoyl chloride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH:12]([CH2:17][O:18][CH3:19])[CH2:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4]([CH3:20])[N:3]=1.C(O)(=O)C>CO.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:20])=[CH:5][C:6]=1[NH:11][C@H:12]([CH2:17][O:18][CH3:19])[CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCC(COC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: COCC[C@@H](COC)Nc1cc(C)nc(Cl)c1N

Procedure:
2—Chloro-6-methyl-3-nitro-N-(1-methoxymethyl-3-methoxypropyl)pyridin-4-amine (˜16.82 mmol) was heated at reflux with Fe powder (10 g) in methanol (120 mL) in the presence of glacial acetic acid (10 mL) for 2 h. Then the iron was filtered through celite, the celite was washed with methanol(80 mL) and the filtrate was stripped in vacuo. The residue was dissolved in 10% HCl (120 mL) and EtOAc was added (160 mL). The mixture was neutralized with solid NaHCO3 and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4) and stripped in vacuo (4.1 g).
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:20]([OH:23])[CH2:21]Br)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:24])[CH:3]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CO.Cl>C(Cl)Cl>[O:23]=[C:20]1[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[N:5]2[C:4](=[O:24])[CH:3]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:2]2[S:1][CH2:21]1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate prepared by the method of Example 4.-III(2) (70 mg) in a mixture of methylene chloride (2 ml), methanol (2 ml), and 10% hydrochloric acid (0.3 ml) is stirred at room temperature for 2 hours. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl 3-oxo-7-phenoxyacetamidocepham-4-carboxylate (44.5 mg), identical with the product of Example 4.-III(3). Yield: 74%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[C:26]([NH:31][C:32](=[O:34])[CH3:33])[N:27]=[CH:28][CH:29]=3)[CH:24]([CH3:35])[O:23][C:21]=2[CH:22]=1>>[C:32]([NH:31][C:26]1[N:27]=[CH:28][CH:29]=[C:30]2[C:20]3[CH:19]=[CH:18][C:17]([O:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:4][CH:5]([CH3:7])[CH3:6])=[CH:22][C:21]=3[O:23][CH:24]([CH3:35])[C:25]=12)(=[O:34])[CH3:33]
Reactant: CC(=O)Nc1nccc2c1C(C)Oc1cc(Cl)ccc1-2
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Product: CC(=O)Nc1nccc2c1C(C)Oc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Yield: 51 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-5-methyl-5H-chromeno[3,4-c]pyridin-4-yl)acetamide to afford tert-butyl ((2S)-1-((4-acetamido-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.6 g, 0.882 mmol, 51% yield) as a yellow solid. LCMS (ESI) m/e 470.2 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method C): tR=1.89 min.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C.Cl>CN(C=O)C>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.0 mmol) and 4-(tert-butyl) phenyl isocyanate (0.18 g, 1.0 mmol) in DMF (20 mL) was added triethylamine (0.22 g, 2.2 mmol) at rt under nitrogen. After 2 h, 4% aqueous HCl (30 ml) was added and the solids were filtered and dried in vacuo providing 1-(4-tert-butyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid, (0.34 g, 76% yield); mp 254-256° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.71 (96.94%); 1H NMR (DMSO-d6) δ 1.24 (s, 9H), 1.97-2.01 (m, 1H), 2.35-2.45 (m, 1H), 2.54-2.62 (m, 1H), 2.85-2.97 (m, 1H), 4.30 (d, 2H, J=17.3 Hz), 4.45 (d, 2H, J=17.3 Hz), 5.10 (dd, 1H, J=12.9 Hz, J=4.5 Hz), 6.68 (t, 1H, J=4.8 Hz), 7.23 (dd, 2H, J=8.4 Hz, J=1.5), 7.31 (dd, 2H, J=8.4 Hz, J=1.5 Hz), 7.44 (d, 1H, J=7.8 Hz), 7.51 (s, 1H), 7.69 (d, 1H, J=7.8 Hz), 8.54 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 31.3, 33.8, 42.7, 47.1, 51.6, 117.6, 121.8, 122.9, 125.2, 126.9, 130.3, 137.7, 142.4, 143.4, 144.9, 155.3, 167.9, 170.9, 172.8; LCMS: MH=449; Anal. Calcd for C25H28N4O4+0.5H2O: C, 65.63; H, 6.39; N, 12.25. Found: C, 65.24; H, 6.17; N, 12.29.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C.CC(O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:9]([F:11])[CH:10]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1c(F)cc(Br)cc1F
Yield: 47 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzoic acid (800 mg, 3.38 mmol) in MeOH (11 mL) at room temperature, trimethylsilyldiazomethane (5.63 mL, 3.38 mmol) was slowly added until yellow solution was turned on. The small amount of AcOH was added until yellow color disappered. All volatile materials were removed in vacuo yielding methyl 4-bromo-2,6-difluorobenzoate (47%). LCMS (m/z): 251.1 (MH+), 0.86 min.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3C1CCCCO1)[CH3:15])=[N:9]2>O1CCOCC1.CO>[F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][NH:21]3)[CH3:15])=[N:9]2
Reactant: CC(Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1CCO3
Solvent: CO
Solvent: C1COCCO1
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c3c2n1CCO3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
Hydrogen chloride, HCl (384 μL of a 4M solution in dioxane) was added to a solution of [1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (130 mg, 0.31 mmol) in MeOH (1 mL) and the reaction was stirred at RT for 20 min. The crude reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give 435 (92 mg, 87%) as a pale yellow solid. LCMS (Method K): RT 2.28 min [M+H]+ 340.0. 1H NMR (CD3OD, 400 MHz): δ 8.22 (1H, s), 8.06 (1H, s), 7.06 (1H, dd, J=8.9, 3.1 Hz), 6.91 (1H, dd, J=12.0, 8.9 Hz), 5.78 (1H, br s), 4.63-4.38 (4H, m), 1.79 (3H, d, J=7.0 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:31][NH:32][CH2:33][CH:34]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[OH:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH2:20][N:32]([CH2:33][CH:34]([OH:35])[C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[CH3:31])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: CNCC(O)c1cccnc1
Reactant: COCCOCc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCc1c(CN(C)CC(O)c2cccnc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 50 °C
Yield: 92.5 %

Procedure:
A mixture of 111 mg of N-(4-chlorobenzyl)-2-(chloromethyl)-3-[(2-methoxyethoxy)methyl]-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide, 54 mg of 2-(methylamino)-1-pyridin-3-ylethanol (Arch. Pharm. (1961), 294, 453), and 62 μL of diisopropylethylamine in 1.5 mL of DMF is heated at 50° C. for 18 h, then cooled and partitioned between EtOAc and water. The organic phase is washed with two additional portions of water and brine, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica using 5% MeOH in CH2Cl2 affords 128 mg of the title compound as a white foam. Recrystallization of a sample from EtOAc provides white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:26][CH:27]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1

Procedure:
77.6 mg of solid white 3-{4-[3-(4-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-trifluoromethylphenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].O=P(Cl)(Cl)Cl.[CH3:18]O>>[CH3:18][O:7][C:6](=[O:8])/[CH:5]=[CH:4]/[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)C=Cc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a 250 ml round-bottomed flask, 2-Chlorocinnamic acid (25 g, 136.9 mmol) and MeOH(56 ml) were added. POCl3 (1.27 ml, 13.6 mmol) was added dropwise. The reaction mixture was stirred under reflux for 3˜4 h. The reaction mixture was cooled to room temperature, quenched with 1N NaOH solution. The mixture was extracted by EtOAc and washed with H2O. The aqueous layer was further extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under vacuum. (26.98 g, 85˜97%)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[N:7]=1
Reactant: NC(CO)CO
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Yield: 41.3 %

Procedure:
A solution of 4-Chloro-2-methylsulfinyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.90 g, 2.53 mmol) in dichloromethane (90 mL) was mixed with a solution of serinol (0.24 g, 2.66 mmol) in DMF (2.0 mL). The resultant mixture was stirred at room temperature for 1 hour before concentrated under vacuum. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (0.40 g, 42%): MS (ES) m/z 383 (M+H)+; 1H-NMR(CDCl3) δ 1.95 (s, br, 2H), 3.90 (m, br, 5H), 6.05 (m, br, 1H), 6.56 (d, J=9.6 Hz, 1H), 7.10 (m, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.94 (d, J=9.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][NH:17][C:16](=[S:19])[NH:15][CH2:14]1>CC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2([OH:9])[N:17]3[CH2:18][N:13]([CH3:12])[CH2:14][N:15]=[C:16]3[S:19][CH2:7]2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CN1CNC(=S)NC1
Solvent: CC(C)=O
Product: CN1CN=C2SCC(O)(c3ccc(Br)cc3)N2C1

Procedure:
A solution of 6.95 grams (0.025 moles) of p-bromophenacylbromide in 60 milliliters of acetone was mixed with a solution of 3.27 grams (0.025 moles) of 3,4,5,6-tetrahydro-5-methyl-s-triazin 2(1H) thione in 450 milliliters of acetone. 6-p-Bromophenyl-6-hydroxy-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a-]-s-triazine hydrobromide crystallized out as a colourless solid, m.p. 138°-140° C. (decomposition). The yield was 7.5 grams (75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:39])(C[Si](OC(C)C)(C)C)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:19][CH:18]=2)[C:13]1=[O:30])[CH3:11].[C:40](=O)([O-])[OH:41].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:39])([CH2:40][OH:41])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:30])[CH3:11]
Reactant: O=C([O-])O
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 68.9 %

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (0.88 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 10 ml), to which 1.57 ml of 30% aqueous hydrogen peroxide and 0.128 g of sodium hydrogencarbonate were added. The mixture was heated at 70° to 80° C. for 90 minutes, cooled and extracted with 50 ml of ethyl acetate. The extract was washed with 25 ml of water, an aqueous solution of Na2S2O3 (25 ml×2) and 25 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=2:3) and recrystallized from diisopropyl ether to give 0.5 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (yield: 69%) as colorless powdery crystals.
Reaction SMILES: [N+](=[CH:3][CH3:4])=[N-].[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH:18]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C:15]1=[O:27])([OH:7])=[O:6].C(O)C.Cl>CCOCC>[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH:18]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C:15]1=[O:27])([O:7][CH2:3][CH3:4])=[O:6]
Reactant: CC=[N+]=[N-]
Reactant: CCCCCCCSC1CCC(=O)C1CCCCCCC(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCSC1CCC(=O)C1CCCCCCC(=O)OCC
Temperature: 0 °C

Procedure:
At room temperature, 70 ml. of a 0.2N diazoethane solution in ether is added to a solution of 3.4 g. of 2-(6-carboxyhexyl)-3-heptylthio-cyclopentanone in 25 ml. of dry ethanol. The reaction mixture is poured into 100 ml. of ice water, containing 5 ml. of concentrated HCl, agitated, the organic phase separated, the aqueous phase extracted three times with respectively 30 ml. of chloroform, and the combined organic phases are washed with water, dried over Na2SO4, the solvent is distilled off, and chromatographic purification of the residue (silica gel/chloroform) produces 2-(6-carbethoxyhexyl)-3-heptylthio-cyclopentanone. Rf = 0.7 (silica gel/chloroform).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.Cl.[NH2:42][OH:43].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:43]/[N:42]=[CH:1]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: NO
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3/C=N/O)cc1)C2
Yield: 89 %

Procedure:
To a solution of 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56 (0.500 g, 0.95 mmol) and hydroxylamine hydrochloride (0.132 g, 1.90 mmol) in methanol (15 mL) was added pyridine (0.155 mL, 1.90 mmol) and the reaction mixture heated to reflux under nitrogen for 1 hour. The cooled reaction mixture was then poured into 5% w/v aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white foam. Crystallization of the crude product from dichloromethane gave the title compound (0.458 g, 89%) as a white crystalline solid, m.p. 165-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:5]=[C:6]([N+:18]([O-:20])=[O:19])[C:7]=1[Cl:8]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1Cl
Temperature: 95 °C
Reaction time: 1.17 h
Yield: 18.1 %

Procedure:
3,4-Dichloro-α,α,α-trifluorotoluene (862 g. 4.0 mols) is added to a stirred mixture of concentrated sulfuric acid (4400 g.) and nitric acid (3400 g.) at 35° C. The mixture is stirred 70 minutes at 95° C. and allowed to separate. The oil layer is washed once with water and twice with 5% sodium carbonate solution, dried, and fractionally distilled to give 3,4-dichloro-5-nitro-α,α,α-trifluorotoluene (188 g. 18%) b.p. 115°-118° C./15 mm, 88% pure.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[C:3]=1[N:11]=O.OS([O-])=O.[Na+].[NH2:18]C1C(=O)NC(=O)N(C)C=1N.N([O-])=O.[Na+]>O.C(O)(=O)C>[CH3:8][N:7]1[C:2]2[NH:1][N:18]=[N:11][C:3]=2[C:4](=[O:10])[NH:5][C:6]1=[O:9]
Reactant: Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: Cn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: O=N[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(=O)c2nn[nH]c21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspersion of 2.42 g (14.3 mmol) of the 6-amino-1-methyl-5-nitrosouracil in water heated to 90° C., was added 30 mL of a 38% solution of NaHSO3 over 10 minutes and the reaction allowed to continue until the reaction mixture was completely decolourized. After cooling the reaction mixture to 0° C., 5,6-diamino-1-methyluracil crystallized from the medium. After filtering off, washing with water, ethanol and diethylether and drying 2.14 g (80%) of the intermediate 5,6-diamino-1-methyluracil was isolated. 8.71 g (55.8 mmol) of 5,6-diamino-1-methyluracil was dissolved in 100 mL water and 50 mL acetic acid upon heating. After cooling to room temperature, a solution of 3.86 g (55.9 mmol) NaNO2 in 17 mL water was added over 5 minutes. The mixture was stirred for 5 minutes and then refluxed for a short time. After standing for two days at room temperature, 3-methyl-8-aza-9H-xanthine crystallized from the mixture. After filtering off, drying, recrystallization from water/ethanol 1:1 and drying 3.57 g (38%) of 3-methyl-8-aza-9H-xanthine was obtained (m.p. 313–320° C.).