Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][NH:8][O:9][CH3:10].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH3:7][N:8]([O:9][CH3:10])[C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
To a stirred solution of butanoyl chloride (5.33 g, 50 mmol) and N,O-dimethylhydroxylamine (5.36 g, 55.0 mmol) in DCM (100 mL) at 0° C., was added dropwise pyridine (8.90 mL, 110 mmol). The resulting mixture was stirred for 1.5 h at RT, followed by work-up using aqueous HCl (2.0M) (100 mL) and DCM (200 mL), to afford the title compound (6.02 g) which was carried over to next step without further purification. LCMS (B) m/z: 132 [M+1]+, Rt 1.74 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].N.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH:4]1[CH:5]=[CH:6][C:1]([O:7][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:2][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Reaction time: 10 h

Procedure:
A steel autoclave was filled with 94 g (1 mole) of phenol and 40 g of sodium hydroxide pellets (1 mole), furthermore after sealing the autoclave 150 g of ammonia were injected. At 70° C., 157.5 g (1 mole) of p-nitrochlorobenzene were pumped into the autoclave as a liquid over a period of one hour; the mixture was stirred for a further 10 hours. After the pressure vessel was let town and the product obtained was washed with water, the 4-nitrodiphenyl ether was isolated at a more than 99% purity (by gas chromatography).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]([C:8](=O)[CH3:9])[C:6]#[N:7].O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[C:8]([CH3:9])=[N:17][NH:18][C:6]=1[NH2:7]
Reactant: NN
Reactant: CC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a solution of 2-(2,3-dichlorobenzyl)-3-oxobutanenitrile (2.19, 9.05 mmol) in ethanol (400 mL) was added hydrazine hydrate (0.452 g, 9.05 mmol) and the resulting solution was stirred under reflux for 16 h. Then the mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=1/1 then DCM:methanol=40:1) to provide the titled compound (1.21 g, 52%) as a yellow solid; LC/MS: MS (ES+) m/e 256 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.13 (s, 3H), 3.77 (s, 2H), 6.97 (dd, J=1.2, 7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 7.33 (dd, J=1.2, 7.8 Hz, 1H)
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O.C(O)=O>C1C=CC=CC=1>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14][Cl:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1ccc(CO)cc1OS(=O)(=O)c1ccc(C)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: O=CO
Product: COc1ccc(CCl)cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 17.5 °C
Yield: 90 %

Procedure:
To a cooled solution of 3-[(p-Toluenesulfonyl)oxy]-4-methoxybenzyl alcohol 22 (8.0 g, 26 mmol) in benzene (25 mL) was added thionyl chloride (1.9 mL, 26 mmol) slowly over a period of 5-10 min maintaining the temperature around 15-20° C. The reaction was maintained at those conditions for 2 h and checked TLC for the completion. The flask is connected to a high vacuum through a trap containing formic acid under mild heating to remove excess thionyl chloride. The slurry formed after complete removal of thionyl chloride and benzene, filtered, washed with hexane and dried to afford 23. Yield: 90%; white solid mp 102-105° C. 1H NMR: δ 2.43 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 4.50 (s, 2H, CH2), 6.80-7.79 (m, 7H, Ar—H). Anal. Calcd for C15H15ClO4S: C, 55.13, H, 4.63. Found: C, 53.20, H, 4.59.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1)[CH:6]=[CH:5]2.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([O:17][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](O)C3)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reaction time: 12 h

Procedure:
To a stirred solution of N-[6-chloro-2-[(3S)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 29) (0.4 g) in dichloromethane was added methanesulphonyl chloride (0.104 mL) and triethylamine (0.215 mL). The reaction was stirred for 12 hours under nitrogen and then purified (Varian Chem elute cartridge, saturated sodium hydrogen carbonate solution and dichloromethane as eluant) to afford the sub-title compound (0.45 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.[NH:12]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]1=[O:18].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([N:12]3[CH2:17][CH2:16][CH2:15][NH:14][C:13]3=[O:18])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Cn1ncc2cc(Br)ccc21
Reactant: O=C1NCCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1ncc2cc(N3CCCNC3=O)ccc21
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-1-methyl-1H-indazole (76 mg, 0.36 mmol) in 1,4-dioxane (5 mL) was added tetrahydropyrimidin-2(1H)-one (Aldrich, 216 mg, 2.16 mmol), followed by Pd2(dba)3 (16 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31 mg, 0.06 mmol) and cesium carbonate (176 mg, 0.54 mmol). The reaction mixture was degassed with nitrogen and heated at 100° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over Na2SO4 and filtered. Concentration and purification by flash column chromatography (hexanes/EtOAc) yielded 1-(1-methyl-1H-indazol-5-yl)tetrahydropyrimidin-2(1H)-one. LCMS-ESI+: calc'd for C12H14N4O: 231.2 (M+H+); Found: 231.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>CO.C(OCC)(=O)C.O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH2:12][NH:13][OH:14]
Reactant: Cc1cccc(Nc2ccccc2C=NO)c1C
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(Nc2ccccc2CNO)c1C

Procedure:
To a solution of 2-[(2,3-dimethylphenyl)amino]benzaldehyde oxime (2.0 g, 8.4 mmol) and methyl orange (20 mg as an indicator), in methanol (40 ml) and water (10 ml) is added sodium cyanoborohydride (4.0 g, 64 mmol) in small portions over two hours, maintaining a red color of the indicator by the dropwise addition of concentrated HCl. The reaction of mixture is diluted with ethyl acetate (200 ml) and the aqueous layer is neutralized to pH=7 with 1N NaOH. The organic layer is collected, dried (MgSO4) and the solvent is evaporated to give crude 2-[(2,3-dimethylphenyl)amino]-N-hydroxy-benzenemethanamine as an oil which is used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12](I)[CH:13]=[C:8]2[N:7]=1)[CH3:2].[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH2:1]([O:3][C:4](=[O:35])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:13]=[C:8]2[N:7]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Nc1nc2cc(-c3ccccc3)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.300 g, 0.51 mmol), phenylboronic acid (0.093 g, 0.76 mmol), and sodium carbonate (0.108 g, 1.20 mmol) in 1,4-dioxane (8 mL) and water (3 mL) was added (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.080 g, 0.11 mmol). The mixture was heated to 60° C. under a nitrogen atmosphere. After 4 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was diluted with water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (2×20 mL), dried over sodium sulfate, filtered, and concentrated. Chromatographic purification of the residue (silica gel, 2% methanol in dichloromethane elute) afforded 0.100 g (40%) of ethyl(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a white solid.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Oc1ccccc1[N+](=O)[O-]

Procedure:
Methyl salicylate (1.7 mL, 0.0131 mol), 1-chloro-2-nitrobenzene (2.30 mL, 0.01965 mol) and potassium carbonate (3.62 g, 0.0262 mol) were mixed in dimethylformamide (35 mL), under argon, at 150° C. for 16 h. The solvent was evaporated and the crude material was flash chromatographed (silica gel, ethyl acetate/hexane). Concentration in vacuo yielded the title compound. 1H NMR (250 MHz, CDCl3) δ8.0 (m, 4H), 7.58 (m, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.13 (dd, 1H), 6.85 (dd, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1c[nH]c2ccccc12
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 3-bromoacetylindole (1.19 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1.5 h the mixture was heated to 55° C. After a further 1.5 h the mixture was cooled and the resulting precipitate collected and washed with cold ethanol. Recrystallisation twice from ethyl acetate and once from ethanol gave the title pyrimidinone (660 mg), m.p. 228°-229° C., λmax (EtOH) 240 nm (ε 16,370) 300.5 nm (ε 13,090).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.Cl[Si](C)(C)C.[CH2:23]([S:31](Cl)(=[O:33])=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl.C(OCC)(=O)C>[CH2:23]([S:31]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])(=[O:33])=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: N[C@@H](CO)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCS(=O)(=O)N[C@@H](CO)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of (2R)-2-amino-2-phenylethanol (960 mg) in methylene chloride (30 ml) was added triethylamine (2.0 ml) and the mixture was cooled to −78° C. To the mixture was added dropwise chlorotrimethylsilane (0.90 ml), the mixture was stirred for 3 hours at −78° C. and then stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C. again. To the mixture was added dropwise 1-octanesulfonyl chloride (1.4 ml) and the mixture was stirred for 2 hours at −78° C. and then stirred for 15 hours at 0° C. The reaction mixture was diluted with ethyl acetate and then washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→3:2) to give the title compound (1.70 g) having the following physical data.
Reaction SMILES: O=[C:2]([CH3:16])[CH2:3][CH:4]([C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[C:10]1[O:15][C:2]([CH3:16])=[CH:3][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)C(F)(F)F
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C)oc1C(F)(F)F
Yield: 60.8 %

Procedure:
24 g of the product of Stage A were mixed in 150 ml of toluene and 1.85 g of toluenesulfonic acid were added. The mixture was refluxed for 20 hours. The solvent was evaporated under reduced pressure at 40° C. The residue was chromatographed on silica (eluent: 95/5 hexane/ethyl acetate) to obtain 13.5 g of the expected product.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:26]2[NH:25][C:24](=[O:29])[C:23]3[NH:30][CH:31]=[CH:32][C:22]=3[C:21]=2[CH:20]=1.[CH2:33]([C:35]([O-:37])=[O:36])[CH3:34]>CN(C)C=O>[C:8]1([S:14]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[NH:25][C:24](=[O:29])[C:23]4[NH:30][CH:31]=[CH:32][C:22]=4[C:21]=3[CH:20]=2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:33]([C:35]([O-:37])=[O:36])[CH3:34]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3ccccc3)cc2c2cc[nH]c12
Temperature: 40 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
62 μL (0.44 mmol) of triethylamine and then 31 μL (0.24 mmol) of benzenesulfonyl chloride are added to 60 mg (0.22 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) suspended in anhydrous dimethylformamide (1 mL). The solution is stirred for 1 h at 40° C. The solvent is evaporated and the raw product obtained is purified by recrystallization from methanol to give 51 mg (57%) of 8-benzenesulfonylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[OH:28]O>>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:28])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1
Reactant: OO
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 2 from 6-[4-(4-acetaminophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:11][CH2:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([N:14]1[C:22]2[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)[CH2:12][CH3:13])(=[O:38])=[O:37]
Reactant: CCC(CCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(CCOS(C)(=O)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-(1-(3-(4-chlorophenyl)-1-hydroxypentan-3-yl)-1H-indol-4-yl)methanesulfonamide (20 mg, 0.05 mmol), as described in Example 40 Step I, and NMM (10 mg, 0.1 mmol) in DCM (3 mL) was added methanesulfonyl chloride (7 mg, 0.06 mmol). Then the mixture was stirred at room temperature for 1 h, quenched with saturated ammonium chloride solution (5 mL), and extracted with ethyl acetate. The organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by Prep-TLC (PE/EA=4/1) to afford the title compound as colorless oil. LC/MS m/z=485.1[M+H]+.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.C[O:13][C:14](=[O:18])[CH2:15][CH2:16]Br.O>CS(C)=O>[N:3]1([CH2:16][CH2:15][C:14]([OH:18])=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: COC(=O)CCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCn1ccc2ccccc21
Reaction time: 24 h

Procedure:
KOH (11.5 g, 0.2 mol.) was added to a solution of indole (5.0 g, 40.0 mmol.) and 3-bromopropionic acid methyl ester (4.37 ml, 40 mmol.) in DMSO (35 ml), and stirring was carried out for 24 h at RT. For working up, water (50 ml) was added to the mixture, washing was carried out with ether (5×20 ml), and the aqueous phase was adjusted to pH 4 with 1M HCl and extracted with ether (5×20 ml). The combined extracts were dried, filtered and concentrated. Chromatography with methanol yielded 3-indol-1-ylpropionic acid in a yield of 3.8 g (white solid, m.p. 54–56° C.).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:25])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC2CCCN2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyloxy-3-methylbenzoate (301.6 mg, 0.863 mmol) in CH2Cl2 (6 mL) was added TFA (1.2 mL) at 0° C., and the mixture was stirred at room temp for 1 hr. The solvent was removed under a reduced pressure, and the residue was made basic by the addition of 1 N NaOH. The mixture was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 192.5 mg (90%) methyl 3-methyl-4-(2-pyrrolidinyl)methoxybenzoate as an oil. 1H-NMR (400 MHz, CDCl3) δ 1.58–1.65 (m, 1H), 1.78–2.00 (m, 3H), 2.24 (s, 3H), 2.97 (dt, J=6.8, 10.2 Hz, 1H), 3.05 (dt, J=5.9, 6.8 Hz, H), 3.54–3.58 (m, 1H), 3.87 (s, 3H), 3.92 (dd, J=6.3, 9.3 Hz, 1H), 3.99 (dd, J=4.9, 9.3 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 7.83 (s, 1H), 7.85 (dd, J=2.0, 8.3 Hz, 1H); MS (FAB) m/z 250 (M++1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:20]3[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]3)=[N:14][C:15](Cl)=[N:16]2)=[N:11][C:10]=1[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:20]3[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]3)=[N:14][C:15]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:16]2)=[N:11][C:10]=1[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3nc(NCc4ccccc4)c(Cl)nc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3nc(NCc4ccccc4)c(Cl)nc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 7-benzylamino-2,6-dichloro-4-(1-oxido-thiomorpholino)pteridine and piperazine.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][CH:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: FC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3([O:27][CH2:26][CH2:25][O:24]3)[CH3:23])=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:26]1[CH2:25][O:24][C:22]([CH3:23])([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:11]3([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[O:27]1
Reactant: CC1(Cc2ccc(C3(O)CCN(Cc4ccccc4)CC3)cc2)OCCO1
Agent: [Pd]
Solvent: CO
Product: CC1(Cc2ccc(C3(O)CCNCC3)cc2)OCCO1
Yield: 86.7 %

Procedure:
1-Benzyl-4-[4-(2,2-ethylenedioxypropyl)phenyl]piperidin-4-ol (10.7 g) in methanol, was hydrogenated at room temperature and pressure over 10% palladium on carbon (5.0 g). After filtration through celite and evaporation of the solvent in vacuo, the residue was crystallised from ethanol:ether to give 4-[4-(2,2-ethylenedioxypropyl)phenyl]piperidin-4-ol (7.0 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.C(O)(=O)C(O)=O.[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH:60]1[CH2:64][CH2:63][NH:62][CH2:61]1>C(#N)C>[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH:60]1[CH2:64][CH2:63][N:62]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:61]1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: Clc1ccccc1C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccccc2Cl)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 3-(2-chlorophenyl)pyrrolidine oxalate (38 mg, 0.14 mmol), and stirred at 60° C. for 2 h. The residue was purified on reversed phase HPLC to yield the title compound (9 mg). HRMS (ESI, pos. ion) m/z calcd for C21H16ClF3N2O2: 420.0852, found 420.0854.