Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[N:9]([CH3:26])[N:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][N:12]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:6][NH:7][C:8]1[N:9]([CH3:26])[N:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][N:12]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25]
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3NC(=O)OC(C)(C)C)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of [2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-carbamic acid tert-butyl ester (0.150 g, 0.40 mmol) dissolved in THF (3 mL) was treated with the slow addition of 1M lithium aluminum hydride in THF (0.80 mL, 0.80 mmol). The mixture was placed under a nitrogen atmosphere and heated to reflux for 8 h. The mixture was cooled to room temperature and the excess reagent was quenched by the dropwise addition of 10% potassium sodium tartrate solution. Ethyl acetate (40 mL) was added and washed sequentially with 10% Rochelle salt solution (40 mL) and brine (25 m), dried over magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (3:2) to afford 0.056 g (48% yield) of methyl-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine (5-49): mp 143.3-144.9° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C1(C)C=CC(S(O[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:25]=2)(=O)=O)=CC=1.C(N(CC)CC)C.O>C(Cl)Cl>[OH:36][CH:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCC(O)c1cccc(COS(=O)(=O)c2ccc(C)cc2)c1
Reactant: OCc1ccc2ccccc2n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(O)c1cccc(COCc2ccc3ccccc3n2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
A mixture of 2-hydroxymethylquinoline (8 g, 0.05 mol) and 3-(1-hydroxyhexyl)benzyl p-toluenesulfonate (18.2 g, 0.05 mol; prepared as in Example 17) in methylene chloride (200 ml) containing triethylamine (15 ml) was stirred at 0° C. for 4 hours, and then allowed to warm up to room temperature. This mixture was stirred for two more hours at this temperature, and then poured into water. The organic layer was separated and washed with dilute sodium hydroxide solution, water and brine. After drying the organics, all volatiles were removed to obtain the crude product as a yellowish brown liquid. This was purified by chromatography on silica gel using 15% ethyl acetate in hexanes to get the pure product as a clear, light yellow liquid (9 g, 52% yield).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:31])[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:16]2[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:15]=2[O:14]1>ClCCl>[C:29]([C:26]1[CH:27]=[CH:28][C:15]2[O:14][C:13]([CH3:31])([CH3:12])[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N+:20]=3[O-:9])[C:16]=2[CH:25]=1)#[N:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 2 h
Yield: 64.3 %

Procedure:
406 mg of m-chloroperbenzoic acid were added to a solution of 528 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile in 15 ml of dichloromethane at room temperature. After 2 hours at room temperature, the mixture was washed with sodium bicarbonate solution and the organic phase was dried over sodium sulphate and evaporated. The residue was crystallized from t-butyl methyl ether and was recrystallized from toluene to give 360 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 158°-160° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[N:6]=1>C(O)(C)C>[Cl:11][C:7]1[CH:8]=[N:9][CH:10]=[C:5]([N:2]([CH3:3])[CH3:1])[N:6]=1
Reactant: CNC
Reactant: Clc1cncc(Cl)n1
Solvent: CC(C)O
Product: CN(C)c1cncc(Cl)n1
Reaction time: 3 h

Procedure:
Cuprous chloride (50 mg) is added to a solution of dimethylamine (36 g., 0.8 mole) in 260 ml of isopropanol. 2,6-Dichloropyrazine (49.9 g., 0.33 mole) is added to the mixture with stirring and cooling to maintain the temperature at 35°-40° C. After 3/4 hr. the cooling bath is removed and the reaction mixture is stored at ambient temperature for 16 hours and finally at 42°-48° C. for 3 hours. The solvent is removed under vacuum and the residue is dissolved in dilute hydrochloric acid. The aqueous solution is extracted with ether and then made basic with solid sodium bicarbonate and extracted with methylene chloride. The organic extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to obtain 49 g. of product, melting point 46°-8° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]#[N:22])=[CH:19][CH:20]=[C:3]12.[OH-:23].[Li+].OO>O1CCCC1.O>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]([NH2:22])=[O:23])=[CH:19][CH:20]=[C:3]12
Reactant: N#Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A mixture of 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbonitrile, (Example 2), (0.03 g, 98.9 82 mol), suspended in tetrahydrofuran (1 mL) was treated with a solution of lithium hydroxide (7.11 mg, 0.29 mmol) in water (500 μL) and 30 wt % aqueous hydrogen peroxide (40.4 μL, 0.39 mmol). The reaction was stirred at room temperature overnight. At this time, the reaction was concentrated in vacuo. The resulting residue was triturated with water. The resulting solid was collected by filtration and then dried in vacuo to afford 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxylic acid amide (20 mg, 61%) as light yellow solid. 1H NMR (methanol-d4) δ ppm 7.94 (d, J=1.5 Hz, 1H), 7.85-7.90 (m, 2H), 7.80-7.84 (m, 2H), 7.77 (s, 1H), 7.52 (d, J=0.8 Hz, 1H). LC-MS calcd. for C15H11F3N3O2 [(M+H)+] 322, obsd. 322.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH:9]C(OC(C)(C)C)=O)=[C:6]([F:17])[C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[I:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=[O:35])=O)=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])=[C:6]([F:17])[C:7]=1[N:8]1[C:34](=[O:35])[NH:33][C:31]([C:30]2[CH:36]=[CH:37][C:27]([I:26])=[CH:28][CH:29]=2)=[N:9]1
Reactant: O=C=NC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1F
Yield: 42.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate (Intermediate-57, 0.250 g), 4-iodobenzoyl isocyanate (Intermediate-67, 0.250 g), DCM (10 mL) and trifluoro acetic acid (0.5 mL) to afford 0.150 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.19 (s, 9H), 4.30 (d, J=3.3 Hz, 2H), 7.39 (m, 1H), 7.45 (d, 1H), 7.62 (d, 2H), 7.90 (d, J=3.6 Hz, 2H), 8.19 (t, 1H), 13.0 (br s, 1H); MS (m/z): 528.98 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](C2C=CC=CC=2)=[C:6]([NH:14][CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[N:5]=[C:4](N=NC2N=CC=CN=2)[N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:40]([NH2:42])=O>>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:7]=1[N:42]=[CH:40][N:14]2[CH2:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23]
Reactant: NC=O
Reactant: Nc1nc(N=Nc2ncccn2)nc(NCc2c(F)cccc2Cl)c1-c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 42 %

Procedure:
In formamide (60 ml) was suspended 4-amino-6-(2-chloro-6-fluorobenzyl)amino-5-phenylazopyrimidine (1.07 g, 3 mmols). To the suspension was added portionwise sodium dithionite (3.28 g, 15 mmols; purity 80%) with stirring at 120°-130° C. After stirring at the same temperature for 30 minutes, the mixture was stirred at 140°-150° C. for another 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, the residue washed with ether (2×30 ml), and water (50 ml) added. After ice-cooling, the insoluble matter was collected by filtration and washed. This product was put in 2 N NaOH (10 ml) and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was collected by filtration, dissolved in chloroform, and purified by silica gel column chromatography [100 g, eluent: chloroform and, then, chloroformmethanol (19:1)]. Recrystallization from ethanol gave 6-amino-9-(2-chloro-6-fluorobenzyl)purine as colorless crystals (350 mg, yield 42%), m.p. 249°-250° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29].CO[Na].CO>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:27][C@@H:28]([CH3:29])[C:30]([OH:32])=[O:31])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)=[CH:21][CH:22]=1
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(F)cc3)ccc2c1O
Agent: CO[Na]
Solvent: CO
Product: C[C@H](NC(=O)c1ncc2cc(Oc3ccc(F)cc3)ccc2c1O)C(=O)O
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
A mixture of 7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (154 mg, 0.43 mmol), (S)-alanine (225 mg, 2.5 mmol) and a 0.5 N solution of MeONa in MeOH (5 ml, 2.5 mmol) was heated in a microwave oven with stirring for 20 min at 130° C. before the mixture was concentrated in vacuo. To the residue was added water (15 ml) and the mixture was washed with Et2O (3×30 ml). The purified aq. solution was acidified by the addition of 6 N HCl and extracted with EtOAc (1×30 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (79 mg); MS-(−)-ion M−1=369.1.
Reaction SMILES: C([CH2:4][C:5]1[C:6]([F:19])=[C:7]([C:16]([OH:18])=[O:17])[C:8](=[C:12]([F:15])[C:13]=1[F:14])C(O)=O)(O)=O.C(N(CC)CC)C>CS(C)=O>[F:19][C:6]1[C:5]([CH3:4])=[C:13]([F:14])[C:12]([F:15])=[CH:8][C:7]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 140 °C
Reaction time: 64 h
Yield: 58.5 %

Procedure:
To 304.35 g of 4-carboxymethyl-3,5,6-trifluorophthalic acid dissolved in 1.5 liters of dimethyl sulfoxide was added 0.5 liter of triethylamine, followed by 64 hours of stirring at 140° C. After cooling to room temperature, dimethyl sulfoxide was evaporated. The resulting residue was mixed with 1 liter of 1N hydrochloric acid and extracted with ether (1 liter×3). The organic layer was washed with 1 liter of water and 1 liter of saturated brine, and then dried over sodium sulfate. By evaporating the solvent, 177.94 g (0.64 mol, 60%) of the title compound was obtained as a partially purified product.
Reaction SMILES: C([O:8][C:9](=[O:22])[C@H:10]([CH3:21])[NH:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:14][CH3:15])C1C=CC=CC=1>C(O)C.[Pd]>[CH2:19]([O:18][C:16]([C@@H:12]([NH:11][C@H:10]([C:9]([OH:22])=[O:8])[CH3:21])[CH2:13][CH2:14][CH3:15])=[O:17])[CH3:20]
Reactant: CCCC(N[C@@H](C)C(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Yield: 86.7 %

Procedure:
The S,S diastereoisomer benzylester from step (b) (6.2g) in ethanol (250ml) was hydrogenated at 3 atmospheres at room temperature for 30 minutes over 10% palladium on charcoal (0.6g). The catalyst was removed by filtration and the filtrate was evaporated to near dryness. The residue was slurried with diethyl ether and the white solid was filtered off and was dried to give the required product (3.8g) mp 153°-4°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH:20]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([NH:29][C:30](=[O:32])[CH3:31])=[CH:24][C:23]=1[CH3:33])=O>CO>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[N:19]=[C:20]([C:22]4[C:23]([CH3:33])=[CH:24][C:25]([NH:29][C:30](=[O:32])[CH3:31])=[CH:26][C:27]=4[CH3:28])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: CC(=O)Nc1cc(C)c(C=O)c(C)c1
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Solvent: CO
Product: CC(=O)Nc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C)c(C)c4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (0.8 mL in 0.2 M DMSO solution), N-(4-formyl-3,5-dimethyl-phenyl)-acetamide (0.8 mL in 0.2 M toluene solution) and FeCl3 (0.4 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-(4-acetylamino-2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 427 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:16])[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C=CC=1)C(O)=[O:22]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:16])[CH2:13][CH2:12][N+:11]([O-:22])([CH2:14][CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCN1CCC(O)(c2cc(F)cc(Cl)c2)C1
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC[N+]1([O-])CCC(O)(c2cc(F)cc(Cl)c2)C1
Yield: 64.9 %

Procedure:
3-(3-chloro-5-fluorophenyl)-1-ethylpyrrolidin-3-ol (0.65 g, 2.67 mmol) was dissolved in dichloromethane (30 ml) and m-chlorobenzoic acid (1.38 g, 8.01 mmol) was added in portions. The mixture was stirred at ambient temperature for 15 h after which about 75% of the solvent was evaporated. The resulting slurry was purified with flash chromatography on basic Al2O3 eluted with methanol. The methanol was evaporated and dichloromethane (50 ml) and aqueous sodium carbonate (10%, 50 mL) was added. The organic phase was dried (MgSO4) and evaporated to give the title compound (0.45 g). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 158-160° C.
Reaction SMILES: N=[C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH2:20])[C:14]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[CH:13]2.[OH-:35].[Na+]>Cl>[NH2:20][C:15]1[C:14]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:4]3[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[O:35])[CH:11]=2)[N:16]=1
Reactant: COc1ccccc1C(=N)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccccc1C(=O)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 50 °C

Procedure:
A solution of 6-(2-(imino(2-methoxyphenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine (0.022 g, 0.049 mmol) in 5N aq. HCl (2 mL) was heated to 100° C. in a sealed tube for 16 h, then allowed to cool to 50° C. and heated for another 70 h at that temperature. The mixture was neutralized with 10N NaOH and filtered. The precipitate was redissolved in MeOH and purified by reverse-phase HPLC (10-90% acetonitrile/H2O, TFA modifier). A single fraction was treated with NH4OH and the acetonitrile was removed in vacuo. The resulting suspension was filtered and air-dried to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(2-methoxyphenyl)methanone. MS (ESI, pos. ion) m/z: 454 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.I[C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)CCN>C1(C)C=CC=CC=1.[Cu](I)I>[CH:1]1([C:4]2[N:5]([C:14]3[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:27][CH:28]=3)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:3][CH2:2]1
Reactant: Ic1ccc(OCCCN2CCCC2)cc1
Reactant: c1ccc2[nH]c(C3CC3)cc2c1
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)cc(C1CC1)n2-c1ccc(OCCCN2CCCC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
To a solution of 2-cyclopropyl-1H-indole (17 mg, 0.11 mmol) and 1-[3-(4-iodophenoxy)propyl]pyrrolidine (36 mg. 0.11 mmol) in toluene (0.2 mL) was added copper iodide (0.2 mg), potassium phosphate (47 mg, 0.22 mmol), and N,N-dimethylethylenediamine (1.2 μL, 0.11 mmol). The reaction was stirred at 100° C. overnight. After cooling to room temperature, the reaction was filtered through a pad of silica. The reaction was concentrated and purified by preparative HPLC to give 1.6 mg of the desired indole. LC-MS (C24H28N2O calc'd 360) m/z 361 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.55-7.52 (m, 1H), 7.35-7.32 (m, 2H), 7.10-7.02 (m, 5H), 6.16 (s, 1H), 4.11 (t, J=6.3 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.59 (m, 4H), 2.08 (quint, J=7.0 Hz, 1H), 1.83 (m, 2H), 1.64 (m, 4H), 0.88-0.81 (m, 2H), 0.79-0.73 (m, 2H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:14]1)=[O:11].[NH:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:44](O)=[O:45]>>[C:47]([NH:42][CH2:43][C:44]([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:14]1)=[O:11])=[O:45])([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:48]
Reactant: CC(=O)OC[C@@H](C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@H](N)Cc2ccc(Cl)cc2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@@H](C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)CNC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Example 1 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B of Example 187 and N-BOC-Gly.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:14])=[CH:5][C:6]([OH:13])=[N:7]2.[N:15]([O-])=[O:16].[Na+].OS(O)(=O)=O>[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[C:5](=[N:15][OH:16])[C:6](=[O:13])[NH:7]2
Reactant: O=N[O-]
Reactant: Oc1cc(O)c2c(Cl)cc(Cl)cc2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2cc(Cl)cc(Cl)c2C(=O)C1=NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 147 mg (0.616 mmol) of 5,7-dichloro-2,4-quinolinediol and 126 mg (1.82 mmol) of NaNO2 in 3 mL of 0.2N NaOH in ice-bath was added dropwise 2 mL of aqueous 2N H2SO4. The mixture was stirred in ice-bath for 4 h after addition of H2SO4, filtered and dried to leave an orange solid. The solid was crystallized by boiling with 10 mL of ethanol (95% ). The solution was cooled to room temperature, filtered and dried to leave 132 mg (83%) of 5,7-dichloro-3-oximequinoline-2,4-dione as a yellow solid, mp 244°-245° C. (decomposed). 1H NMR (CDCl3 +DMSO-d6), 7.011 (d, 0.44, J=1.8) 7.080 (m, 1.54), 11.567 (sb, 0.35), 11.821 (s, 0.46). MS, 258 (100, M+), 241 (60), 214 (80), 187 (20), 160 (30). High resolution MS, Calcd for C9H435Cl2N2O3, 257.9595, found 257.9598.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:36])[C@H:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[NH2:30].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH:29]([NH:30][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:23])([F:22])[F:24])[C:28]([O:27][CH3:26])=[O:36]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC(NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: C[Li].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C@H:16](COS(C2C=CC(C)=CC=2)(=O)=O)[C@H:15]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+].N.[CH2:41](OCC)[CH3:42]>[Cu]I.O>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([CH2:41][CH3:42])[C@H:15]([NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:14]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2NC(=O)OC(C)(C)C)cc1
Reactant: CCOCC
Agent: [Cu]I
Agent: N
Agent: [Cl-]
Solvent: O
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under cooling with ice, a solution of methyllithium (121 mL, 1.02 M, diethyl ether solution) was added to a suspension of copper(I) iodide (11.8 g, 62.1 mmol) in diethyl ether (200 mL), followed by stirring for 30 minutes. The temperature of the reaction mixture was cooled to −78° C. A solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-(p-toluenesulfonyloxy)methylpyrrolidine (6.27 g, 12.4 mmol) in diethyl ether (140 mL) was added thereto. The temperature of the mixture was elevated gradually, followed by stirring for 1 hour under cooling with ice. Under cooling with ice, a saturated aqueous ammonium chloride solution (100 mL) and 28% aqueous ammonia (25 mL) were added to the resultant mixture, and then water (100 mL) was added thereto, followed by extraction with ethyl acetate (300 mL×2). The combined organic layer was washed by saturated brine (100 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:2), to thereby yield the title compound as a colorless oily substance (3.09 g, 71%).