Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.[H-].[Na+].Br[CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].[Cl-].[NH4+]>CN(C=O)C>[CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:32][CH2:33][N:34]4[C:35](=[O:44])[C:36]5[C:37](=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:38]4=[O:39])[C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CC3CCCc4cccc2c43)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCn1c(=O)n(C2CCN(C3CC4CCCc5cccc3c54)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[1-(1,2,2a,3,4,5-Hexahydroacenaphthylen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol 2-one (1.00 g) was dissolved in DMF (30 ml), 60% sodium hydride (140 mg) was added, and the suspension was stirred for 1 hr. Then, N-(2-bromoethyl)phthalimide (818 mg) was added, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, and poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 2-{2-{3-[1-(1,2,2a,3,4,5-hexahydroacenaphthylen-1-yl)piperidin-4-yl]-1,3-dihydro-2-oxobenzimidazol-1-yl}ethyl}isoindole-1,3-dione.
Reaction SMILES: S[C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.Cl.C1(NC2C=CC=CC=2CCl)CCCC1>C(O)C>[NH:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[CH:2]1
Reactant: Sc1nc2ncccc2[nH]1
Agent: Cl
Agent: ClCc1ccccc1NC1CCCC1
Solvent: CCO
Product: c1cnc2nc[nH]c2c1

Procedure:
2-Mercaptoimidazo[4,5-b]pyridine and 2-(N-cylopentylamino)benzyl chloride hydrochloride were reacted in an aqueous ethanol solution to obtain 2-[2-(N-cyclopentylamino)benzylthio[-imidazo[4,5-b]pyridine in the same manner as in Example 9-(2). The obtained 2-[2-(N-cyclopentylamino)benzylthio]imidazo[4,5-b]pyridine was oxidized by m-chloroperbenzoic acid in chloroform in the same manner in Example 9-(3) to give 2-[2-(N-cyclopentylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline product. m.p.: 134° C. (decompn.)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH:31](I)([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH:31]([N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])([CH3:33])[CH3:32]
Reactant: CC(C)I
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with isopropyl iodide and cesium carbonate in N,N-dimethylacetamide to give N-isopropyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 534.8 ([M+NH4]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:15][Si](C(C)(C)C)(C)C)[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:15])[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)CC(O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCC(O)CC(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-bromophenyl)-1-(tert-butyldimethylsilyloxy)hex-5-en-3-ol (18.8 g, 44.0 mmol) in tetrahydrofuran (60 mL) is added 1 M tetrabutylammonium fluoride solution in THF (66.0 mL, 66.0 mmol). The resulting mixture is stirred at room temperature for 2 hours. The mixture is diluted with dichloromethane and is washed sequentially with water and saturated ammonium chloride aqueous solution. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product is purified by silica gel chromatography eluting with a linear gradient of 20% to 40% ethyl acetate in hexanes over 26 minutes to give the title compound as racemic diastereomeric mixture (11.8 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.38-7.36 (m, 1H), 7.28-7.24 (m, 1H), 7.22-7.17 (m, 1H), 5.83-5.75 (m, 1H), 5.15-5.11 (m, 2H), 5.03-4.89 (m, 1H), 4.00-3.90 (m, 1H), 2.32-2.21 (m, 2H), 1.96-1.89 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10]1)[CH2:4][C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:52][CH2:53][C:54]([C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=1)=[O:55].CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[Cl:62][C:59]1[CH:58]=[CH:57][C:56]([C:54](=[O:55])[CH2:53][NH:52][C:5](=[O:7])[CH2:4][CH:3]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)[CH2:10]2)[C:2]([F:25])([F:26])[F:1])=[CH:61][CH:60]=1
Reactant: NCC(=O)c1ccc(Cl)cc1
Reactant: O=C(O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)NCC(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 64.7 %

Procedure:
In a 10 mL pear-shaped flask, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanoic acid (40 mg, 104 μmol) and HATU (39.7 mg, 104 μmol) were combined with DMF (1 ml) to give a colorless solution. After 5 min of stirring, 2-amino-1-(4-chlorophenyl)ethanone HCl (21.5 mg, 104 μmol) was added followed by drop-wise addition of DIEA (47.2 mg, 63.8 μl, 365 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (30 ml), washed with brine and H2O, dried over MgSO4, filtered and concentrated in vacuo to give an oil. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% ethyl acetate in CH2Cl2) to afford 36 mg (65%) of N-(2-(4-chlorophenyl)-2-oxoethyl)-4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanamide as an oil. MH+=535.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]1([CH2:14][O:15][CH2:16][CH:17](O)[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[Cl:2][CH:17]([CH2:16][O:15][CH2:14][C:8]1([CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1(COCC(O)CN2CCCC2)CCCCC1
Solvent: Cc1ccccc1
Product: CC1(COCC(Cl)CN2CCCC2)CCCCC1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
A 500 ml three necked round bottom flask was equipped with a mechanical stirrer, addition funnel, thermometer and an argon inlet and outlet. PCl5 (33 g; 0.159 m) and 18 ml of dry toluene was added to the reaction vessel. 38.5 g (0.151 m) of alpha-[((1-methylcyclohexyl)methoxy)methyl]-1-pyrrolidineethanol (the compound of Example 1b.) was added to the addition funnel along with 45 ml of toluene. Hydrogen chloride gas was bubbled into the addition funnel until the solution was acidic. The PCl5 suspension was cooled to 10° C. and the amino alcohol hydrochloride solution was added dropwise, maintaining the temperature between 10°-15° C. After the addition was complete, the ice bath was removed and the mixture stirred at RT for 1.5 hr. A two liter beaker containing 116 ml of 45% potassium hydroxide and 210 g of ice was cooled in an ice bath. The reaction mixture (a clear yellow solution) was transferred to a separatory funnel and added portionwise at a rate to keep the reaction temperature at 25°-35° C. Stirring was continued for 0.5 hr after the addition. The reaction was transferred to a two liter separatory funnel and diluted with water and ether. The water layer was extracted twice with ether and the combined ether extracts were washed twice with water, once with brine, dried over anhydrous potassium carbonate and concentrated in vacuo to give 29.12 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:12]1)=[O:5])[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]1[CH:29]=[CH:28][CH:27]=[C:9]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:19]=[CH:20][C:21]([CH2:22][OH:23])=[CH:25][CH:26]=3)=[N:12]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=O)O)cc3)ccc2=O)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CO)cc3)ccc2=O)c1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
3 g (7.6 mmol) of 4-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzoic acid are suspended in 90 ml of THF, and 19.1 ml (19.1 mmol) of borane/THF complex (1M) are added dropwise under a nitrogen atmosphere with ice-cooling. The mixture is stirred at 0° C. for 15 h. 9 ml of 2N HCl are added to the reaction mixture, which is then stirred at room temperature for 12 h. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, dried over sodium sulfate and evaporated. The product is purified by means of preparative HPLC.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][NH:8][C:9](=[O:21])[N:10]2[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH:4]=1.[CH2:29]([O:31][P:32]([O:36]CC)[O:33][CH2:34][CH3:35])[CH3:30].CCOCC.CCCCCC>CN(C=O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:5]1[CH:4]=[C:3]([CH2:2][P:32](=[O:36])([O:33][CH2:34][CH3:35])[O:31][CH2:29][CH3:30])[CH:12]=[C:11]2[C:6]=1[CH2:7][NH:8][C:9](=[O:21])[N:10]2[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20]
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(CBr)cc2N1c1c(Cl)cccc1Cl
Reactant: CCOP(OCC)OCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2)OCC
Temperature: 100 °C
Reaction time: 1.75 h

Procedure:
A mixture of 7-(bromomethyl)-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydroquinazolin-2(1H)-one (55 mg, 0.11 mmol) and triethylphosphite (0.8 mL, 4.66 mmol) in DMF (0.5 mL) was stirred at 100° C. for 1.75 h. After it was cooled to rt, the resulting mixture was treated with ether and hexane to form a precipitate. Filtration of the precipitate provided diethyl [5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylphosphonate as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.20 (m, 6H), 3.01 (s, 1H), 3.06 (s, 1H), 3.97 (m, 4H), 4.34 (abq, 2H, J=14.1 Hz), 5.12 (s, 1H), 6.12 (s, 1H), 6.86 (s, 1H), 7.26-7.60 (m, 7H). MS (API-ES+): 553 (M+H).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]2[C:15]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=3[F:32])=[C:16]([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCOCC1.[OH-].[Pd+2].[OH-]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:15]2[C:12]3[C:13](=[O:14])[NH:8][CH:9]=[N:10][C:11]=3[N:18]([CH3:19])[C:17](=[O:20])[C:16]=2[CH3:21])=[C:24]([F:32])[CH:25]=1
Reactant: Cc1c(Nc2ccc([N+](=O)[O-])cc2F)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: Cc1c(Nc2ccc(N)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
3-Benzyl-5-(2-fluoro-4-nitrophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (4.1 mg, 9.42 mmol), palladium hydroxide (20% on carbon, 4 g) and ammonium formate (4 g, 63.4 mmol) were stirred in dioxane (200 mL) at 90° C. for 4 hours in a sealed pressure vessel. The suspension was filtered and the solid refluxed in DMF (20 mL) for 1 hour then filtered. This was repeated 3 times. The filtrates were combined and evaporated. The residue was dissolved in DMF (50 mL) and Quadrapure palladium scavenger (20 g) was added and the mixture stirred at 60° C. overnight. The mixture was filtered and evaporated, ether was added and a precipitate formed. This solid was filtered to give 2 g of the title compound (67%). [M+H] calc'd for C15H14FN5O2, 316. found, 316.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(O)C.[Pd]>[CH3:13][S:14]([NH:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)(=[O:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc2sccc2c1
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
A solution of 5.00 g (0.028 mol) of 5-nitrobenzothiophene (Bordwell, J. Am. Chem. Soc., 77, 5939 (1955)) in 175 mL of ethanol was hydrogenated at 50 psi over 0.5 g of 10% Pd/c for 1.5 hours. The catalyst was removed by filtration, and the solvent was removed under reduced pressure. The residue, 4.39 g, was dissolved in a mixture of 8.4 g of pyridine and 50 mL of methylene chloride. The solution, treated with 3.45 g (0.03 mol) of methanesulfonyl chloride, was stirred overnight at room temperature. The solution was washed with water, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give 1.74 g of crystalline 5-methanesulfonamidobenzothiophene.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([OH:24])([C:20]([F:23])([F:22])[Cl:21])[C:16]([F:19])([F:18])[Cl:17])=[CH:10][C:9]=1[CH3:25])=[O:5])C.Cl>[OH-].[Na+]>[C:4]([CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([OH:24])([C:20]([F:23])([F:22])[Cl:21])[C:16]([F:18])([F:19])[Cl:17])=[CH:10][C:9]=1[CH3:25])([OH:5])=[O:3]
Reactant: CCOC(=O)CNc1c(C)cc(C(O)(C(F)(F)Cl)C(F)(F)Cl)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(O)(C(F)(F)Cl)C(F)(F)Cl)cc(C)c1NCC(=O)O

Procedure:
Dissolve the ethyl ester of Example 8 (3.0 g=7.4 mmol) in 70 ml 1.0 N NaOH. After 30 minutes acidify with concentrated HCl to pH 4. Extract the product with Et2O, dry and concentrate. Recrystallize from Et2O-hexane to obtain the title product as a white solid, melting at about 139°-142° (dec.)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[S:6](Cl)([CH3:9])(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[NH2:5][CH:3]([CH3:4])[CH2:2][NH:1][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CC(N)CN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(N)CNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,2-Diaminopropane (1.00 g, 13.5 mmol, 1.15 mL, 1.1 eq.) was placed in CH2Cl2 (30 mL) and cooled to 0° C. Mesyl chloride (1.40 g, 12.3 mmol, 0.95 mL, 1.0 eq.) was added over a period of five minutes followed by triethylamine (3.72 g, 36.9 mmol, 5.17 mL, 3.0 eq.). The reaction was stirred for 30 minutes and then concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-15% MeOH/CH2Cl2 as the eluting solvent to obtain N-(2-amino-propyl)-methanesulfonamide as a clear, colorless oil (504 mg, 27%). 1H-NMR (CDCl3, 400 MHz) δ 3.17-3.03 (m, 2H), 2.98 (s, 3H), 2.88-2.80 (m, 1H), 1.12 (d, 3H, J=6.3 Hz).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>O1CCOCC1>[C:2]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Ic1cccc2ccccc12
Solvent: C1COCCO1
Product: O=Cc1cccc(Oc2cccc3ccccc23)c1
Temperature: 90 °C

Procedure:
1-iodonaphthalene (2.000 g) and 3-hydroxybenzaldehyde (1.442 g) were added to dioxane (25 mL). The solution was degassed and flushed with nitrogen three times. Cesium carbonate (5.13 g), N, N-dimethylglycine hydrochloride (82 mg), and copper (I) iodide (30 mg) were added, and the solution was heated at 90° C. overnight. The solution was cooled, added to 1M aqueous HCl, extracted with diethyl ether, dried with brine and anhydrous sodium sulfate. The solution was concentrated and purified by flash column chromatography on silica gel with 10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][N:11]=[C:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[C:24](OC(=O)C)(=[O:26])[CH3:25]>S(=O)(=O)(O)O>[C:24]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][N:11]=[C:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccccc1NC(=O)NN=c1c(=O)c2ccccc2c1=O

Procedure:
Two drops of concentrated sulphuric acid were added to a solution of 1 g (0.003 mol) of 2-[4-(2-hydroxyphenyl)-semicarbazono]indan-1,3-dione (example 4) in 10 ml acetic anhydride.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[NH:8][CH:7]=[CH:6]2)[CH3:2]>[Ni]>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc2cc[nH]c2cc1[N+](=O)[O-]
Agent: [Ni]
Product: CCc1cc2cc[nH]c2cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
A suspension of 5-ethyl-6-nitro-1H-indole (1.9 g, 10 mmol) and Raney Ni (1 g) was stirred under H2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-ethyl-1H-indol-6-ylamine (B-23) (760 mg, 48%). 1H NMR (CDCl3) δ 7.90 (br s, 1H), 7.41 (s, 1H), 7.00 (s, 1H), 6.78 (s, 2H), 6.39 (s, 1H), 3.39 (br s, 2H), 2.63 (q, J=7.2 Hz, 2H), 1.29 (t, J=6.9 Hz, 3H); ESI-MS 161.1 m/z (MH+).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[C:15]([CH3:17])([CH3:16])[O:14][C:13]([NH:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH3:20])=[N:12][S:11]2(=[O:29])=[O:28])[CH:5]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C@@H:19]([NH:18][C:13]1[O:14][C:15]([CH3:16])([CH3:17])[CH:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:30])=[O:2])[S:11](=[O:28])(=[O:29])[N:12]=1)[CH3:20]
Reactant: COC(=O)c1cccc(C2C(C)(C)OC(N[C@@H](C)c3ccccc3F)=NS2(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC1=NS(=O)(=O)C(c2cccc(C(=O)O)c2)C(C)(C)O1)c1ccccc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 33493 %

Procedure:
To a solution of 3-{2-[(S)-1-(2-fluorophenyl)ethylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl}benzoic acid methyl ester (1.7 mg) in dioxane (15 ml) were added water (5 ml) and sulfuric acid (0.3 ml), and the mixture was stirred at 100° C. for 16 h. The mixture was alkalized with sodium carbonate solution, diluted with water and washed with ethyl acetate. The aqueous phase was acidified, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. This gave the product (551 mg) with a molecular weight of 420.5 g/mol (C20H21FN2O5S).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:34][CH3:35])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[C:25]([C:29]([O:31]CC)=[O:30])[NH:26]4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:34][CH3:35])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[C:25]([C:29]([OH:31])=[O:30])[NH:26]4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc2ccc(NC(=O)C(CC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Product: CCC(C(=O)Nc1ccc2cc(C(=O)O)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
75 mg (0.14 mmol) of ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-indole-2-carboxylate (racemate) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 38 mg (48% of theory)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1>>[CH3:28][O:27][C:21]1[CH:22]=[C:23]([O:25][CH3:26])[N:24]=[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[N:20]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(OC)nc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 2-amino-4,6-dimethoxypyrimidine (27 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.65 (brs, 1H), 8.71–8.70 (m, 2H), 7.54 (brs, 1H), 7.44 (dd, J=7.8, 4.8 Hz, 1H), 7.25 (s, 1H), 7.04 (s, 1H), 6.07 (t, J=5.4 Hz, 1H).
Reaction SMILES: [C:1]([C:4]([CH3:21])([CH3:20])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])([OH:3])=[O:2].CC1(C)CCC(=O)OC1=O.[N+](C1C=CC(CO)=CC=1)([O-])=O.[CH3:43][O:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Cl)=[CH:47][CH:46]=1>CN(C)C=O.O.C(N(CC)CC)C>[CH3:43][O:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][O:2][C:1]([C:4]([CH3:21])([CH3:20])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])=[O:3])=[CH:47][CH:46]=1
Reactant: CC(C)(CCC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: CC1(C)CCC(=O)OC1=O
Agent: O=[N+]([O-])c1ccc(CO)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C(C)(C)CCC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 80 °C
Reaction time: 9.5 h

Procedure:
To a solution of p-nitrobenzyl 4-carboxy-4-methylvalerate (17.26 g) in dry dimethylformamide (100 ml), prepared by the procedure similar to that described in Example 174 from 2,2-dimethylglutaric anhydride and p-nitrobenzyl alcohol, was added p-methoxybenzyl chloride (9.16 g) and triethylamine (5.91 g). The reaction mixture was stirred at 80° C. for 9.5 hours, diluted with water and extracted with diethyl ether. The extract was washed successively with aqueous potassium carbonate, water, dilute hydrochloric acid and again water, dried over anhydrous sodium sulfate and evaporated to give p-nitrobenzyl 4-p-methoxybenzyloxycarbonyl-4-methylvalerate.