Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH:7]([CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[Cl:21])[NH:14][CH:13]=1)[C:8]([OH:10])=[O:9].[CH3:22]O>>[ClH:3].[CH3:22][O:9][C:8](=[O:10])[CH:7]([NH2:6])[CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[Cl:21])[NH:14][CH:13]=1
Reactant: NC(Cc1c[nH]c2nccc(Cl)c12)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)Cc1c[nH]c2nccc(Cl)c12
Temperature: 25 °C
Yield: 99 %

Procedure:
Thionyl chloride (27.5 mL) was added dropwise over 15 minutes to a cooled (0° C.) suspension of 2-amino-3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid hydrochloride (7.28 g, 22.3 mmol) in methanol (150 mL). On complete addition, the mixture was heated under reflux for 66 hours. The mixture was allowed to cool to ambient temperature and evaporated. The resultant residue was azeotroped with toluene (2×150 mL) to afford the title compound as a fawn solid (7.7 g, 99%). 1H NMR (400 MHz, DMSO-d6): 12.06 (s, 1H), 8.39 (s, 3H), 8.17 (d, J=5.2 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.19 (d, J=5.2 Hz, 1H), 4.07-4.06 (m, 1H), 3.54 (dd, J=14.9, 5.8 Hz, 1H), 3.30 (dd, J=14.9, 9.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11])[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(Cn1ncc2cc(Br)ccc21)OC
Temperature: 40 °C
Reaction time: 18 h
Yield: 58.4 %

Procedure:
To a solution of 5-bromo-1H-indazole (10.0 g, 51.2 mmol) in DMSO (120 mL) was added 2-bromoacetaldehyde dimethyl acetal (12.1 mL, 103 mmol) and Cs2CO3 (66.8 g, 205 mmol). The reaction mixture was stirred at 40° C. for 18 h; then the reaction mixture was diluted with H2O (100 mL) and EtOAc (175 mL). The aqueous layer was extracted with EtOAc (4×175 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (ISCO 330 g column, 95:5 hexanes/EtOAc to hexanes/EtOAc 50:50, 60 min, 40 mL/min) gave the title compound (8.52 g, 46%) as a light orange solid: 1H NMR (300 MHz, CDCl3) 7.94 (s, 1H), 7.85 (d, J=1.2, 1H), 7.48-7.42 (dd, J=8.9, 1.7 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 4.71 (t, J=5.4 Hz, 1H), 4.44 (d, J=5.5 Hz, 2H), 3.33 (s, 6H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8])(=O)C.C(SCC(CC(OC)=O)C(N[C@H](C(O)=O)CCCNC(=N)N)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Product: COC(=O)CC(CS)C(=O)N[C@@H](CCCCN)C(=O)O

Procedure:
By substituting Nα -[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-lysine for the Nα -[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-arginine in the procedure of Example 18, Nα -[3-mercapto-2-(methoxycarbonylmethyl)propanoyl]-L-lysine is obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].C[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(OCC)C>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:10]1[NH:9][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cn1cccc1
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a well stirred solution of trichloroacetyl chloride (1 kg, 5.5 mole) in 1.5 liter ethyl ether in a 12 liter flask was added dropwise over a period of 3 h a solution of N-methylpyrrole (0.45 kg, 5.5 mole) in 1.5 liter anhydrous ethyl ether. The reaction was stirred for an additional 3 hours and quenched by the dropwise addition of a solution of 400 g potassium carbonate in 1.5 liters water. The layers were separated and the ether layer concentrated in vacuo to provide 2-(trichloroacetyl)pyrrole (1.2 kg, 5.1 mol) as a yellow crystalline solid sufficiently pure to be used without further purification. To a cooled (−40° C.) solution of 2-(trichloroacetyl) pyrrole (1.2 kg, 5.1 mol) in acetic anhydride (6 L) in a 12 L flask equipped with a mechanical stirrer was added 440 mL fuming nitric acid over a period of 1 hour while maintaining a temperature of (−40° C.). The reaction was carefully allowed to warm to room temperature and stir an additional 4 h. The mixture was cooled to −30 ° C., and isopropyl alcohol (6 L) added. The solution was stirred at −20° C. for 30 min during which time a white precipitate forms. The solution was allowed to stand for 15 min and the resulting precipitate collected by vacuum filtration to provide 4-nitro-2-trichloroacetyl-1-methylpyrrole, shown as compound B-1 in Scheme B (0.8 kg, 54% yield) TLC (7:2 benzene/ethyl acetate) Rf 0.7; 1H NMR (DMSO-d6) δ 8.55 (d, 1 H, J=1.7 Hz), 7.77 (d, 1 H, J=1.7 Hz), 3.98 (s, 3 H); 13C NMR (DMSO-d6) δ 173.3, 134.7, 133.2, 121.1, 116.9, 95.0, 51.5; IR(KBr) 1694, 1516, 1423, 1314, 1183, 1113, 998, 750. FABMS m/e 269.936 (M+H 269.937 calc. for C7H5N2O3Cl3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=3)[C:21](O)=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1.CN(C)C.C[Si]([Cl:35])(C)C.S(Cl)([Cl:38])=O.NS(C1C=C(C2NC(=O)C(=CC=2)CCl)C=CC=1)(=O)=O>C(Cl)Cl>[ClH:35].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=3)[CH2:21][Cl:38])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)Nc3cccnc3)cc2)[nH]c1=O
Agent: CN(C)C
Agent: NS(=O)(=O)c1cccc(-c2ccc(CCl)c(=O)[nH]2)c1
Solvent: ClCCl
Product: Cl
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)Nc3cccnc3)cc2)ccc1CCl

Procedure:
From 4.0 g. of 6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 150 ml. of methylene chloride, 1.55 ml. of trimethylamine, 1.4 ml. of trimethylsilyl chloride and 1.6 ml. of thionyl chloride, following the procedure of (a) above, there is obtained 6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride hydrochloride.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:35]([N:37]1[C:49]2[CH:48]=[CH:47][C:46]([NH2:50])=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36]>>[C:29]1([CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:50][C:46]2[CH:47]=[CH:48][C:49]3[N:37]([CH2:35][CH3:36])[C:38]4[C:43]([C:44]=3[CH:45]=2)=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:18])=[O:7])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)C(c3ccccc3)c3ccccc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 77% purity by LC/MS. MS(ESI+): m/z=545.4.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]#[N:15])=[N:5][N:4]=1)[NH2:2].C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1>O1CCOCC1>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]2[N:4]3[N:5]=[C:6]([CH2:13][C:14]#[N:15])[C:7]4[C:12]([C:3]3=[N:1][N:2]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:27][CH:26]=1
Reactant: N#CCc1nnc(NN)c2ccccc12
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(-c2nnc3c4ccccc4c(CC#N)nn23)cc1

Procedure:
A mixture of 4-hydrazino-1-phthalazin-acetonitrile (0.7 g), triethylamine (0.4 g), p-methoxybenzoylchloride (0.68 g), dioxane (10 ml), is heated at reflux for 5 h, then it is cooled, the solvent is evaporated under reduced pressure, the residue is taken up with water, recovered by filtration and crystallized from ethanol/chloroform, yielding 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazin-6-acetonitrile. M.p. 252°-254° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].C(N(CC)CC)C.[CH:20]#[C:21][CH3:22]>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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:20]([C:12]1[CH:2]=[C:3]2[C:4](=[CH:10][CH:11]=1)[C:5](=[O:6])[O:7][C:8]2=[O:9])#[C:21][CH3:22]
Reactant: C#CC
Reactant: O=C1OC(=O)c2c(Br)cccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC#Cc1ccc2c(c1)C(=O)OC2=O
Temperature: 50 °C
Yield: 97.9 %

Procedure:
Bromophtalic anhydride (50.0 g, 0.22 mol), triethylamine (33.8 mL, 0.24 mol) and toluene (220 mL) were mixed in a glass reactor over nitrogen (g) atmosphere at room temperature. Bis(triphenylphosphine)palladiumchloride (0.77 g, 0.001 mol), CuI (0.42 g, 0.002 mol) and triphenylphosphine (0.87 g, 0.003 mol) were added and the temperature was raised to 50° C. Propyne (18.0 g, 0.45 mol) was slowly added through a gas inlet during 3 hours. The reaction mixture was filtered through a glass filter funnel and the solution was concentrated to dryness to give crude solid product (40.1 g, 98%). The product was re-crystallized from toluene to give a light yellow solid (24.7 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13]O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].CN(C=O)C.S(Br)([Br:22])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][Br:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: O=S(Br)Br
Reactant: OCc1ccc(OC(F)(F)F)c(Br)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(CBr)cc1Br
Temperature: 23 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
To a solution of (3-bromo-4-(trifluoromethoxy)phenyl)methanol 19.1 (6.78 g, 25 mmol) in 30 mL of DCM, was added DMF (0.5 mL) and thionyl bromide (2 mL, 26 mmol). The mixture was stirred at 23° C. for 4 hours. DCM (120 mL) was added to the reaction mixture, and the resulting mixture was washed with aqueous saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give 19.2 (8.3 g, 99% yield) as a yellow oil, which was used directly in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.74 (1 H, d, J=2.0 Hz), 7.38-7.53 (2 H, m), 4.53 (2 H, d, J=5.6 Hz).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[F:24].O>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[O:12][CH2:11][CH:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)=[CH:18][C:17]=1[F:24]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: CCCC1CCC(C(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCC[C@H]1CC[C@H](C2COC(c3ccc(Br)c(F)c3)OC2)CC1

Procedure:
A solution of 4.0 g (0.02 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol, 5.1 g (0.025 mol) of 4-bromo-3-fluorobenzaldehyde, and 0.2 g of TsOH in 100 cm3 of dichloromethane was refluxed over a hot water bath fitted with a Dean-Stark trap for 3 hours and the water formed was continuously removed from the reaction system. The resulting solution was washed with water and dichloromethane was distilled off. The residue was recrystallized from acetone to yield 6.2 g (0.016 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. This compound contained about 10% of the cis isomer of the 1,3-dioxane ring.
Reaction SMILES: [Cl-:1].[Li+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][CH:5]1[CH2:21][CH3:22].CO>CN(C)C=O>[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][C:5]1([CH2:21][CH3:22])[Cl:1]
Reactant: [Cl-]
Reactant: CCC1Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCC1(Cl)Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Temperature: 90 °C
Yield: 53 %

Procedure:
A stirred solution of cupric chloride dihydrate (4.25 g. and lithium chloride (0.765 g.) in dimethylformamide (10 ml.) is heated to 90° C. and to the mixture is added a solution of methyl (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)-acetate (4.7 g., 0.015 mole) in dimethylformamide. The reaction mixture is heated at 90° C. for two hours and poured onto ice. The product is extracted into ether (100 ml.), washed with water, dried over anhydrous sodium sulfate and the ether distilled at reduced pressure. There is thus obtained 2.5 g. of methyl (1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)acetate (53% yield) which melts at 111° C. after recrystallization from methanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH:9]=[O:10])=[CH:6][CH:7]=1
Reactant: O=CC(=O)c1ccc(O)cc1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
To a solution of (4-hydroxy-phenyl)-oxo-acetaldehyde (756 mg) in dry DMF (10 mL) were added 3,4-dichlorobenzylbromide (1.2 g) and potassium carbonate (1.03 g). After 4 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts were then combined and washed with brine (2×50 mL) and a saturated sodium bicarbonate solution (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give [4-(3,4-dichloro-benzyloxy)-phenyl]-oxo-acetaldehyde (1.3 g).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[CH:35]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:35]1([CH2:41][CH2:42][NH:43][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][CH:32]=[N:33][C:25]=2[S:24][CH2:23][CH2:22][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:20])=[O:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NCCC1CCCCC1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCC1CCCCC1)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
158 mg (0.93 mmol) of CDI were added to a solution of 300 mg (0.93 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (8 ml), and the mixture was stirred for 1 h at RT. A solution of 151 mg (0.93 mmol) of 2-cyclohexylethylamine hydrochloride and 157 μL (0.93 mmol) of diisopropylethyl-amine in DCM (8 ml) was then added, and stirring was continued for a further 16 h at RT. The reaction solution was then washed in each case three times with sat. aq. ammonium chloride solution and saturated aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 390 mg (0.90 mmol, 97%) of N-(2-cyclohexylethyl)-2-(2-(phenylsulfonyl)-ethyl-thio)nicotinamide were obtained as residue. MS: m/z 433.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[S:15](=[O:19])(=[O:18])([OH:17])O>>[F:1][C:2]1[C:3]([S:15]([OH:17])(=[O:19])=[O:18])=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:15]([OH:17])(=[O:19])=[O:18])[C:11]([F:14])=[C:10]([S:15]([OH:17])(=[O:19])=[O:18])[CH:9]=2)=[CH:6][C:7]=1[S:15]([OH:19])(=[O:18])=[O:17]
Reactant: Fc1ccc(-c2ccc(F)cc2)cc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1cc(-c2cc(S(=O)(=O)O)c(F)c(S(=O)(=O)O)c2)cc(S(=O)(=O)O)c1F
Temperature: 30 °C
Reaction time: 24 h

Procedure:
The same procedure as 5a is used with 9.51 g dry 4,4′-difluorobiphenyl (50 mmole, fw=190.19) and 106.8 g 30% fuming sulfuric acid (400 mmole, fw=80.06) which are stirred at 30° C. for 24 hour and then heated with stirring at 110° C. for another 72 hours. Crystallization was effected using 29.6 g distilled water and 185 mL propionitrile. Yield was 17.2 g (65%) of the tetrasulfonated product as white crystals of the monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[N:17][C:10]=3[N:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:20]=[CH:19][C:18]([CH:21]=[N:24][OH:25])=[N:17][C:10]=3[N:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C=NO)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
4-(3-Chlorophenyl)-1-ethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-7-carbaldehyde (900 mg, 2.9 mmol) was dissolved in 10 ml of methanol, 420 mg (6.0 mmol) of hydroxylamine hydrochloride and 550 mg (6.7 mmol) of sodium acetate were added thereto, followed by stirring overnight at room temperature. The insoluble matter was washed with water and chloroform and recrystallized from dimethylformamide-acetonitrile to give 171 mg (18%) of 4-(3-chlorophenyl)-1-ethyl-7-hydroxyiminomethylpyrido[2,3-d]pyrimidin-2(1H)-one.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[CH:16][C:15]([C:28]([F:31])([F:30])[F:29])=[N:14]2)=[CH:9][CH:8]=1>C(OC(=O)C)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)=[CH:16][C:15]([C:28]([F:31])([F:29])[F:30])=[N:14]2)=[CH:11][C:12]=1[N+:1]([O-:4])=[O:2]
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To acetic anhydride (20 ml) was added 70% nitric acid (2 ml) dropwise in an ice-bath. During the addition, the internal temperature of the mixture temporarily rose to 25° C. and dropped to 0° C. To the mixture was added 1-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.0 g) portionwise. The reaction mixture was allowed to stir for 5 hours and poured into ice-water. The precipitate formed was collected by filtration and dried to give 1-(4-methoxy-3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.15 g).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([C:11](=[O:28])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][C:13]=2[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:8]=[CH:7][C:6]=1[O:29][CH2:30][CH:31]([CH3:33])[CH3:32])(=O)C.[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:24]([O:23][C:13]1[CH:14]=[C:15]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:17][C:12]=1[C:11]([C:9]1[CH:8]=[CH:7][C:6]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:5]([OH:4])[CH:10]=1)=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(=O)Oc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
In 10 ml of ethanol is dissolved 0.48 g of 5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl acetate, to which is added 3.2 ml of 1 mol/L solution of sodium hydroxide. The mixture thus obtained is stirred at ambient temperature for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried on anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.40 g of (2,4-diisobutoxyphenyl)(3-hydroxy-4-isobutoxyphenyl)methanone is obtained as a light yellow solid product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)=[O:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH3:12])=[CH:16][CH:17]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 78 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (5 g, 21.2 mmol) was added to a solution of 4-hydroxyacetophenone (2.87 g, 21.1 mmol), and K2CO3 (7.28 g, 0.052 mol) in DMF (50 mL). The mixture was heated at 80° C. for 15 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by flash chromatography eluting with (hexanes/ethyl acetate 70:30) to give the title compound (4.8 g, 77.8%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[C:27]([NH:28]C(=O)OCC3C=CC=CC=3)=[CH:26][C:25]3[C:20](=[CH:21][C:22]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][C:40]4=[O:45])=[CH:23][CH:24]=3)[N:19]=2)=[O:17])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:28][C:27]1[C:18]([C:16]([NH:15][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:4]2[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([NH2:1])[CH2:3]2)=[O:17])=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][C:40]1=[O:45])[CH:21]=2
Reactant: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2N)C1

Procedure:
A mixture of benzyl [2-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3-oxomorpholin-4-yl)quinolin-3-yl]carbamate (0.0067 g, 0.011 mmol) in 3.0 mL of MeOH was hydrogenated in the presence of 8 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H30N7O3 [M+H]+: m/z=476.2. found: 476.3.