Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10](=[O:30])[NH:11][NH:12][CH2:13][CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:15]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CI.[CH3:39]N(C)P(N(C)C)(N(C)C)=O>O1CCCC1.C(OCC)(=O)C.O>[CH3:39][N:12]([CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:15]1)[NH:11][C:10]([N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:30]
Reactant: COC(=O)COc1cccc2c1CCC(CNNC(=O)N(c1ccccc1)c1ccccc1)C2
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1cccc2c1CCC(CN(C)NC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (6.1 mg) in tetrahydrofuran (1.5 ml) was added a solution of the compound prepared in example 15 (70 mg) in tetrahydrofuran (3 ml) under an atmosphere of argon. The mixture was stirred for 30 min at room temperature. To the mixture were successively added methyl iodide (261 mg) and hexamethylphosphoramide (1 ml), After stirred for 2 h at room temperature, the mixture was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane =2:3) to give the title compound (27 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]=O)[CH:10]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][C:12]=2[CH2:21][NH:26][CH2:24][CH3:25])[CH:10]=1
Reactant: COC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1

Procedure:
[5-(2-Formyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester and ethylamine (2M in MeOH) were reacted as described in Example 8, Step 1 to provide [5(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:16].[CH3:17]O>>[ClH:16].[CH3:17][O:12][C:11](=[O:13])[C@H:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:10]
Reactant: CO
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
4-Nitrophenylalanine (1) (24 mmol) was treated with methanol (100 ml) saturated with HCl (g) and left to stir at room temperature for 18 hours. The solution was concentrated by evaporating to ⅓ of original volume and the precipitate was collected and dried under vacuum for 18 hours. The yield was 85%.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([OH:15])=[C:8]([CH3:14])[C:9]=2[CH3:13])[C:4]1=[O:16])[CH3:2].Br[CH2:20][C:21]([O:23]CC)=[O:22].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].Cl>CN(C)C=O.CO>[O:16]=[C:4]1[C:5]2[C:10](=[C:9]([CH3:13])[C:8]([CH3:14])=[C:7]([O:15][CH2:20][C:21]([OH:23])=[O:22])[CH:6]=2)[C:11](=[O:12])[C:3]1([CH2:1][CH3:2])[CH2:17][CH3:18]
Reactant: CCC1(CC)C(=O)c2cc(O)c(C)c(C)c2C1=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCC1(CC)C(=O)c2cc(OCC(=O)O)c(C)c(C)c2C1=O
Temperature: 65 °C

Procedure:
A stirred mixture of 2,2-diethyl-4,5-dimethyl-6-hydroxy-indan-1,3-dione (3.5 g., 0.014 mole), ethyl bromoacetate (2.7 g., 0.016 mole) and potassium carbonate (2.2 g., 0.016 mole) in dimethylformamide (20 ml.) is heated at 65°C. for 2 hours, treated with methanol (40 ml.) and potassium hydroxide (1.1 g., 0.02 mole) refluxed for 1/2 hour then poured into dilute hydrochloric acid (500 ml.) affording 4.2 g. of (1,3-dioxo-2,2-diethyl-4,5-dimethyl-6-indanyloxy)-acetic acid which melts at 134°-136°C. after recrystallization from acetic acid-water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:20])([CH3:19])[C:8]3[C:13]([O:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3.C([Li])CCC.[CH:26](N1CCCCC1)=[O:27]>CCOCC>[CH3:18][O:17][C:11]1[CH:10]=[CH:9][C:8]2[C:7]([CH3:20])([CH3:19])[C:6]3[C:15]([O:14][C:13]=2[C:12]=1[CH:26]=[O:27])=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3
Reactant: O=CN1CCCCC1
Reactant: COc1ccc2c(c1)Oc1cc(OC)ccc1C2(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc2c(c1)Oc1c(ccc(OC)c1C=O)C2(C)C
Temperature: 0 °C
Yield: 59.5 %

Procedure:
A solution of 10.8 g (40 mmol) of 3,6-dimethoxy-9,9-dimethylxanthene [prepared according to Coll. Czech. Chem. Commun. 24 (1959), 1061] in absolute ether was cooled to 0° to -5°. 50 ml of a 1.6M butyllithium solution (in hexane) were added dropwise while stirring. 9.04 g (80 mmol) of N-formylpiperidine were added dropwise after 15 hours and the mixture was subsequently stirred at 0° for 1 hour and at room temperature for 2 hours. Thereafter, the reaction mixture was poured into acidic (pH 1) ice-water, whereupon it was extracted twice with 200 ml of ether each time. The combined extracts were washed neutral with ice-water, dried over Na2SO4 and concentrated. The residual oil was purified on silica gel with hexane/ethyl acetate and thereafter crystallized from t-butyl methyl ether/hexane. There were obtained 7.1 g of 3,6-dimethoxy-9,9-dimethylxanthene-4-carboxaldehyde of m.p. 84.5°-86°; IR 2966, 1688, 1637, 1605, 1568, 1515, 1486 cm-1.
Reaction SMILES: [CH:1]12[C:11]3([Cl:15])[C:12]([Cl:14])([Cl:13])[C:8]([Cl:18])([C:9]([Cl:17])=[C:10]3[Cl:16])[CH:2]1[C:3]([O:5][C:6]2=[O:7])=O.C1(C)C=CC=CC=1.[SH:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>O.O1CCOCC1>[SH:26][C:27]1[CH:33]=[CH:32][C:30]([N:31]2[C:6](=[O:7])[CH:1]3[CH:2]([C:8]4([Cl:18])[C:12]([Cl:13])([Cl:14])[C:11]3([Cl:15])[C:10]([Cl:16])=[C:9]4[Cl:17])[C:3]2=[O:5])=[CH:29][CH:28]=1
Reactant: O=C1OC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reactant: Nc1ccc(S)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C2C(C(=O)N1c1ccc(S)cc1)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
A 1000 ml 3-neck flask, equipped with a Dean-Stark water trap and a mechanical stirrer, was charged with 102 g (10% molar excess) of chlorendic anhydride, 400 ml toluene and 300 ml of dry dioxane. Thirty-one grams of 4-mercaptoaniline were then added to the resultant solution, whereupon a pale yellow solid formed instantly. The reaction mixture was heated gradually until the solvent began to reflux, at which point the evolution of water commenced and the solid disappeared. About 4.5 ml of water were collected in about 3 hours. Solvent was then distilled to reduce the volume to about one-half its original volume. The resultant solution, when cooled to room temperature, deposited white crystals of the carboximide. The crystals were separated by filtration and dried overnight at room temperature. The melting point of the carboximide was 237°-240° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:38])=[CH:4][C:5]([O:36][CH3:37])=[C:6]([CH:35]=1)[CH2:7][N:8](CC1C=CC(OC)=CC=1OC)[C:9]([CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:38])=[CH:4][C:5]([O:36][CH3:37])=[C:6]([CH:35]=1)[CH2:7][NH:8][C:9]([CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)=[O:10]
Reactant: COc1ccc(CN(Cc2cc(Br)c(Cl)cc2OC)C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)c(Br)cc1CNC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude tert-Butyl 4-((5-bromo-4-chloro-2-methoxybenzyl)(2,4-dimethoxybenzyl)carbamoyl)piperidine-1-carboxylate was dissolved in 50% TFA in DCM (10 mL) and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between DCM and saturate NaHCO3 aqueous solution. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][CH2:10][C@@H:11]([C:13]([O:15][CH3:16])=[O:14])[NH2:12])=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH3:17][CH:18]([CH3:21])[CH:19]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[C:2]([O:6][C:7]([NH:9][CH2:10][C@@H:11]([C:13]([O:15][CH3:16])=[O:14])[NH:12][CH2:17][CH:18]([CH3:21])[CH3:19])=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NCC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-[(tert-butoxycarbonyl)amino]-L-alaninate hydrochloride (2.00 g), 2-methylpropanal (860 μl) and acetic acid (450 μl) were dissolved in 1,2-dichloroethane-methanol (5:1, 60 ml), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (4.00 g) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:0) was concentrated under reduced pressure to give the object compound (1.76 g).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:29](=[O:36])[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[CH:13][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH:50]1[C:62]2[CH:61]([CH2:63]OC(ON3C(=O)CCC3=O)=O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1>C(Cl)Cl>[CH:50]1[C:62]2[CH:61]([CH2:63][O:5][C:6]([NH:8][C@H:9]([C:29](=[O:36])[N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:10][C:11]3[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:16]=3)=[O:7])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)CCCCCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCCc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (S)-6-(4-(2-((tert-butoxycarbonyl)amino)-3-oxo-3-(piperidin-1-yl)propyl)phenyl)hexanoate (Compound SP426) (5.65 g, 11.24 mmol) was dissolved in DCM (30.0 ml), trifluoroacetic acid (15.0 ml, 195 mmol) was added and the mixture was stirred for 30 minutes at room temperature, after which the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in dioxane (40 ml) and a 10% aqueous sodium carbonate solution (80 ml), N-(9-fluorenylmethoxycarbonyloxy)-succinimide (3.68 g, 10.90 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made acidic by adding a 5 N aqueous HCl solution and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound SP427 (6.39 g, 100%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH2:11]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>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]>[CH2:19]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Brc1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: c1ccc(CN(Cc2ccccc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), dibenzylamine (0.231 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1 but purified by flash chromatography on silica using a CHCl3/MeOH gradient; Yield: 0.127 g (41%); 314.1 MS m/z: [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.67 (s, 4H); 6.70 (br s, 1H); 6.73 (dd, 1H, 4J=2.4 Hz, 3J=8.9 Hz); 7.19-7.23 (m, 2H); 7.28-7.33 (m, 9H); 7.90 (s, 1H); 11.91 (br s, 1H); HPLC (METHOD [A]): rt 14.79 min (99.2%)
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48])C>CCOCC>[F:33][C:30]([F:31])([F:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:48][C@H:47]([C:46]([OH:50])=[O:45])[CH3:49])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCC(F)(F)F)C(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)O

Procedure:
A solution of 4.75 g of 4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino]benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: Cl[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:2][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:4]=1)#[N:13]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: N#Cc1cn(CCl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cn(CC(C#N)(C#N)CCC(F)(F)F)c2ccccc12
Yield: 52.5 %

Procedure:
1.70 g of 1-(chloromethyl)-3-cyano-1H-indole and 1.45 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 27 ml of N,N-dimethylformamide. 2.49 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.48 g of [{3-cyano-1H-indole-1-yl}methyl] (3,3,3-trifluoropropyl) malononitrile (referred to as the compound of the present invention (39), hereinafter) shown by below formula.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:22](Cl)(Cl)=[S:23]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][N:14]=[C:22]=[S:23])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(F)cc(CCCN)cc1F
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(F)cc(CCCN=C=S)cc1F
Yield: 52.2 %

Procedure:
3-(3,5-Difluoro-4-methoxyphenyl)propylamine (0.0693 mol), triethylamine (0.152 mol) and thiophosgene (0.076 mol) were reacted substantially as described in Example 7G to obtain 8.8 g (53%) of a yellow oil.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[CH:8]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[CH2:9].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCOCC1>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([S:10]([CH2:8][CH2:9][N:5]2[C:4](=[O:6])[CH2:3][CH2:2][C:1]2=[O:7])(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: C=CS(=O)(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)CCN2C(=O)CCC2=O)cc1
Temperature: 65 °C
Yield: 71.4 %

Procedure:
In a 100 mL round bottom flask, a mixture of 1.15 g of succinimide, 2 g of 4-ethenesulfonylphenylamine and 30 g of 1,4-dioxane was heated to 60-70° C. and stirred. To the reaction solution was added 0.75 g of 40% aqueous tetrabutylammonium hydroxide solution 3 times over a 1-hour period. Subsequently, the mixture was stirred at 60-70° C. for 2 more hours. When the solution turned into a white suspension, stirring was stopped and the reaction solution was cooled to room temperature and precipitated and dispersed in 100 mL of methanol. The resultant precipitate was filtered, redispersed in 100 mL of clean water, filtered again and washed to remove salt. Then, the product was redispersed in 500 mL of methanol, filtered and dried to obtain 2.2 g of 1-[2-(4-amino-benzenesulfonyl)-ethyl]-pyrrolidine-2,5-dione (yield=70%).
Reaction SMILES: I.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=3[C:12]3=[N:20][O:21][C:22]([CH3:23])=[C:11]3[C:10]2=[O:24])[CH2:4]1.[C:25]1([S:31]([N:34]([CH2:41][C:42](O)=[O:43])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:25]1([S:31]([N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:41][C:42]([NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH:5]([N:9]3[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=4[C:12]4=[N:20][O:21][C:22]([CH3:23])=[C:11]4[C:10]3=[O:24])[CH2:4]2)=[O:43])(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Reactant: O=C(O)CN(c1ccccn1)S(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: I
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)CN(c3ccccn3)S(=O)(=O)c3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 144 h
Yield: 47 %

Procedure:
To a solution of 5-(3-amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide, 130 mg (0.28 mmol) in 10 mL of DMF was added 82 mg (0.28 mmol) of (benzenesulfonyl-pyridin-2-yl-amino)-acetic acid (Bionet), 46 mg (0.34 mmol) of 1-hydroxy-7-azabenzo-triazole, 66 mg (0.34 mmol) of EDC, 5 mg of DMAP and 120 μL (0.84 mmol) of TEA. The reaction mixture was stirred six days at rt. and was concentrated to dryness. The residue was dissolved in 20% isopropanol/chloroform, washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by radial chromatography using a MeOH/chloroform gradient and concentrated to dryness. The residue was slurried in ether/hexanes and concentrated to dryness to yield 79 mg (47%) of the title compound as a tan foam. MS (ion spray) 606.1 (M+).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:8](=[O:17])[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.P(Cl)(OCC)(OCC)=O.[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1>O1CCCC1>[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH:1][CH:2]([CH2:6][C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:3]([OH:5])=[O:4])=[O:40])=[CH:37][CH:36]=1
Reactant: NC(Cc1cc2ccccc2[nH]c1=O)C(=O)O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCOP(=O)(Cl)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC(Cc1cc2ccccc2[nH]c1=O)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1.2 Grams of 2-amino-3-(2-quinolon-3-yl)propionic acid and 0.8 ml of triethylamine were suspended in 10 ml of tetrahydrofuran, then under stirring condition at a room temperature, a solution containing 1.0 g of diethyl chlorophosphate in 10 ml of tetrahydrofuran was added dropwise thereto, and the reaction mixture was stirred at a room temperature for 3 hours. To this reaction mixture was added a solution containing 1.0 g of p-chlorobenzoic acid in 10 ml of tetrahydrofuran dropwise and the whole reaction mixture was further stirred at a room temperature for 10 hours. After completion of the reaction, the crystals precipitated were removed by filtration, the filtrate was concentrated and to the residue was poured a saturated sodium hydrogencarbonate aqueous solution, then extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried with sodium sulfare. The solvent was removed by distillation and the residue was recrystallized from ethanol-water to obtain 0.9 g of 2-(4-chlorobenzoylamino)-3-(2-quinolon-3-yl)propionic acid in the form of white powder product.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=1.[OH-].[Na+].[CH2:19](O)C>>[CH3:15][S:12]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH3:19])[N:7]=1)[C:3]([OH:2])=[O:16])(=[O:14])=[O:13]
Reactant: CCO
Reactant: COC(=O)c1cc(OC)nc(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(C(=O)O)cc(S(C)(=O)=O)n1
Temperature: 80 °C

Procedure:
To a solution of 2-methanesulfonyl-6-methoxy-isonicotinic acid methyl ester (4.3 g, 17.5 mmol) in ethanol (75 mL) was added 2 N aqueous sodium hydroxide (35 mL, 70 mmol). The mixture was warmed at 80° C. for 4 hours and then concentrated in vacuo to remove the ethanol. The remaining aqueous solution was acidified with 1 N aqueous HCl and extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate and concentrated to afford 2-methanesulfonyl-6-ethoxy-isonicotinic acid.
Reaction SMILES: [Na].C[C:3](C)([C:7]([O-:9])=O)[C:4]([O-])=[O:5].[C:11]1(=[CH:15]C(=O)C)[CH2:14][CH2:13][CH2:12]1.[OH-].[K+].Cl>O.CO>[OH:9][C:7]1[CH2:12][C:11]2([CH2:13][CH2:14]2)[CH2:15][C:4](=[O:5])[CH:3]=1
Reactant: CC(=O)C=C1CCC1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: O=C1C=C(O)CC2(CC2)C1
Temperature: 35 °C

Procedure:
5.75 g Sodium added in portions to 240 ml of methanol and the solution is heated to reflux for 1 hour. 28.4 ml Dimethylmalonate are added and the mixture is heated to reflux for another 10 minutes. The mixture is cooled to 35° C., 350 g 1-cyclobutylidenepropan-2-one (7% in 1,2-dichlorobenzene) are added and the mixture is refluxed for 1 hour. After recooling to room temperature a solution of 28.0 g potassium hydroxide in 130 ml water are added and the mixture is refluxed for 1 hour. The mixture is cooled to room temperature, the pH is adjusted to 1.5 by careful addition of half saturated hydrochloric acid and it is refluxed for 1 hour. The mixture is cooled to room temperature and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, concentrated in vacuo and the residue is purified by chromatography on silica gel (petroleum ether/ethyl acetate 50:50).