Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[N+:18]([O-])=O.[Cl-].[NH4+]>CO.[Zn]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[NH2:18]
Reactant: Cc1ccc(OCC2CN(C)CCN2C)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1ccc(OCC2CN(C)CCN2C)c(N)c1
Reaction time: 0.5 h

Procedure:
1,4-Dimethyl-2-(4-methyl-2-nitro-phenoxymethyl)-piperazine (1.02 g, 3.65 mmol) was dissolved in MeOH (75 mL) and treated with sat'd aqueous ammonium chloride solution until the mixture became turbid. Zinc (0.24 g, 3.65 mmol) was added. The resulting warm reaction mixture was allowed to stir for an additional 30 min at which time LCMS indicate that starting material had been consumed. The reaction was diluted with EtOAc and aqueous Na2CO3 and the layers were separated. The organic layer was washed with saturated NaCl solution and dried over solid anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo to afford the desired aniline.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C1C[O:28][CH2:27]C1>>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([CH:27]=[O:28])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: C1CCOC1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C=O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butylithium at −78° C. After stirring at −78° C. for 10 min, n,N-dimethylformamide was added and the resulting mixture was stirred at −78° C. for 20 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with diluted HCl, water and adjusted to pH 7.5 and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 9.93(s, 1H), 7.60(s, 2H), 6.10(s, 1H), 3.75(d, 1H), 3.35(m 1H), 2.17(s, 6H), 2.13(s, 3H), 2.12(s, 3H), 1.4-1.8(m, 4H), 0.97(t, 6H) ppm.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:19][C:20]([NH2:22])=[O:21].[OH-].[Na+]>CN1CCCC1=O.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:19][C:20]([NH2:22])=[O:21])=[O:16])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CCCCCCCCOc1ccc(C(=O)NC(N)=O)cc1
Reaction time: 3.5 h

Procedure:
A 500 ml 3-neck round bottom flask containing a magnetic stirrer, thermometer, and a reflux condensor with a gas egress tube for a nitrogen blanket is charged with a one part apiece of p-(n-octyloxy)benzoic acid and urea dissolved in 15 parts N-methylpyrrolidone containing 0.01wt percent triphenylphosphite. The mixture is heated to 120 deg C. for approximately 2-5 hours and then cooled. The addition of a copious amount of 3M aqueous sodium hydroxide to a cooled solution precipitates the product, which is isolated by filtration. Infrared absorbance at 3250 cm-1 (urea N--H stretching) and at 1705 cm-1 and 1640 cm-1 (amide and urea C=O stretching, respectively) in addition to the conspicuous absence of any absorbance at 3490 cm-1 (acid O--H stretching) confirm the chemical transformation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: Oc1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-chlorophenol was dissolved in dichloromethane. Triethylamine (1 eq) and acetic anhydride (2 eq) were added. The mixture was stirred at room temperature for 5 hours. Solvent was eliminated by vacuum evaporation. The evaporation residue was taken up in dichloromethane, dried on magnesium sulfate and the solvent was eliminated by vacuum evaporation. Purification was by chromatography on silica gel (elution:cyclohexane/ethyl acetate 95:5).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[Br:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Br:25][CH2:26][C:27]([N:5]([CH2:4][C:3]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:2]=1[F:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:28]
Reactant: O=C(Cl)CBr
Reactant: CCCCCCCNCc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CBr
Reaction time: 2 h
Yield: 80.2 %

Procedure:
N-(2,4-difluorobenzyl)-N-heptylamine (2.004 g, 8.304 mmol) was dissolved in DCM (30 ml). It was then cooled in an ice-bath. Triethylamine (1.092 g, 10.796 mmol) was added and then bromacetyl chloride (1.438 g, 9.135 mmol) was dropped in. The mixture was stirred for 2 hours (ice-bath). It was then washed with water (with additional of 1% hydrochloric acid, pH-3), water and brine, and dried (magnesium sulphate) and evaporated. The crude oil product was dissolved in DCM, then loaded onto a column (ISOLUTE®SI 5 g/25 ml) and eluted with more DCM. Oil product 2.412 g was obtained, yield 80%
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:4]([CH2:14][CH2:15][CH3:16])[CH:3]=1.[F:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:24]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[N:23]=2)=[O:25])=[C:4]([CH2:14][CH2:15][CH3:16])[CH:3]=1
Reactant: O=C(O)c1cccc(F)n1
Reactant: CCCc1cc(Cl)nnc1CNCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(Cl)nnc1CN(CC(C)C)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (6-chloro-4-propyl-pyridazin-3-ylmethyl)-isobutyl-amine (940 mg, 3.89 mmol) and 6-fluoro-pyridine-2-carboxylic acid (663 mg, 4.7 mmol) in CH2Cl2 (10 ml) is added EDCI (783 mg, 4.7 mmol) and DMAP (244 mg, 2 mmol). The mixture is stirred at room temperature overnight. Water (10 ml) is added and the layers are separated. The organic layer is washed with brine (10 ml), then dried (Na2SO4) and evaporated. Flash column purification of the residue (2:1 of hexane: ethyl acetate) provides the title product. 1H NMR (CDCl3) (mixture of rotamers) 7.89 (q, 0.7H), 7.81 (q, 0.3H), 7.69 (dd, 0.3H), 7.53 (dd, 0.7H), 7.34 (s, 0.7H), 7.20 (s, 0.3H), 6.99 (dd, 0.7H1), 6.91 (dd, 0.3H), 5.19 (s, 0.6H), 5.07 (s, 1.4H), 3.41 (d, 0.6H), 3.31 (d, 1.4H1), 2.75 (t, 1.4H1), 2.48 (t, 0.6H), 2.08-2.17 (m, 1H), 1.69-1.75 (m, 1.4H1), 1.54-1.60 (m, 0.6H), 1.02 (t, 2.11H), 0.99 (d, 1.8H), 0.97 (t, 0.9H), 0.80 (d, 4.2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][C:16]1[C:17]([CH2:23][NH2:24])=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][CH2:23][C:17]2[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cnc(CN)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B, reaction of N-Boc-4-piperidone, C-(3,5-dimethylpyridin-2-yl)-methylamine and NaBH(OAc)3 in CH2Cl2 gave 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][C:6](=[O:7])[CH2:5][CH2:4]1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(Cl)Cl.N1C=CN=C1>[Si:9]([O:1][CH2:2][C@@H:3]1[O:8][C:6](=[O:7])[CH2:5][CH2:4]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=C1CC[C@H](CO)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)O1

Procedure:
The methodology of Taniguchi et al. (Tetrahedron, 30, 3532, 1974) and Farina et al. (Tetrahedron Lett., 29, 1239, 1988) for the syntheses of D-ribose derivatives provided a model for our synthetic approach to the syntheses of the corresponding L-ribose derivatives. Nitrous acid deamination of D-glutamic acid (1) gave lactone 2, which was then converted to the corresponding ester 3 by treatment of compound 2, with ethanol and catalytic amount of p-toluenesulfonic acid (See Scheme 1). Reduction of compound 3 with NaBH4 in ethanol gave (R)-4-(hydroxymethyl)-4-butyrolactone (4). Protection of the hydroxy group of compound 4 with tert-butyldimethylsilyl chloride in methylene chloride using imidazole as catalyst produced (R)-4-{[(tert-butyldimethylsilyl)oxy]methyl}-4-butyrolactone (5), which was then converted to the corresponding lactol 6 by reduction with diisobutyaluminum hydride (DIBAL) in toluene at -78° C. Acetylation of 6 with acetic anhydride and triethylamine afforded the key sugar intermediate, 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (7) as a mixture of alpha and beta anomers: MS, m/e 231 (M+--CH3CO), 215 (M+--CH3COO); NMR(CDCl3)) delta 0.10 (s, 6H, SiMe2), 0.95 (s, 9H, tert-butyl), 1.85-2.15 (m, 7H, CH2CH2 and COCH3), 3.50-3.65 (M, 2H, 5-H), 4.10-4.30 (m, 1H, 4-H), 6.20-6.30 (m, 1H, 1-H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15](=[O:17])[CH3:16])([OH:3])=[O:2].[CH3:18]O>>[C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15](=[O:17])[CH3:16])([O:3][CH3:18])=[O:2]
Reactant: CC(=O)CCc1ccccc1CCCC(=O)O
Reactant: CO
Product: COC(=O)CCCc1ccccc1CCC(C)=O
Yield: 89.4 %

Procedure:
A solution of 117 g (0.5 mol) of 4-[2-(3-carboxypropyl)phenyl]-2-butanone, 9, in 200 ml of absolute methanol containing 2 equivalents (1.0 mol) of boron trifluoride methanol complex was refluxed for 16 hours. It was concentrated and the residue washed with H2O, then aqueous sodium bicarbonate solution. After drying, it was distilled to give 111 g of the keto ester 10, bp 132°-136° C/0.2 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[OH:14].[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:12])([F:13])[F:11])[CH:5]=[CH:4][C:3]=1[O:14][CH2:18][CH2:17][CH2:16][Br:15]
Reactant: Oc1ccc(OCC(F)(F)F)cc1Cl
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(OCCCBr)c(Cl)c1
Temperature: 70 °C
Yield: 56.9 %

Procedure:
To a 110 ml DMF solution of 2-chloro-4-(2,2,2-trifluoroethoxy)phenol (5 g, 22.1 mmol) was added 1,3-dibromopropane (11.2 ml, 110 mmol) and cesium carbonate (9.34 g, 28.7 mmol). The resulting suspension was heated to 70° C. for 5 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 10% dichloromethane/hexanes to give the title compound as a clear oil 4.37 g (57%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O>CN(C)C=O.C(OCC)(=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 95.9 %

Procedure:
Methyl 4-hydroxybenzoate (10 g, 66 mmoles) was dissolved in N,N-dimethylformamide (200 mL). Potassium carbonate (45 g, 0.33 moles) and 4-(2-chloroethyl)morpholine hydrochloride (18.3 g, 99 mmoles) were added and the resulting mixture was stirred vigorously at room temperature for 5 days. The reaction mixture was poured into water (500 mL) and extraction with ethyl acetate (2×250 mL), washing of the combined organic phases with water (200 mL), drying over MgSO4 and evaporation afforded 16.8 g (96%) of methyl 4-(2-morpholin-4-ylethoxy)benzoate as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[CH:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1>CO.[C].[Pd]>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCC(=O)NCC=C1CCc2ccc3nc(C)oc3c21
Agent: [Pd]
Solvent: CO
Product: CCC(=O)NCCC1CCc2ccc3nc(C)oc3c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
N-[2-(2-Methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]propionamide (135 mg, 0.499 mmol) was dissolved in methanol (5 mL), a 10% palladium-carbon powder (27 mg) was added, and the mixture was stirred at room temperature for 2.5 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (115 mg, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[CH:9]1[C:14]2([C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH2:12][C:11](=[O:32])[NH:10]1.C[Si]([C:37]#[CH:38])(C)C.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.CO.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:37]#[CH:38])=[CH:4][C:3]=1[CH:9]1[C:14]2([C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH2:12][C:11](=[O:32])[NH:10]1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(I)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(N)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 149.9 %

Procedure:
In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-2′-(2-amino-5-iodophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 203 (0.2 g, 0.35 mmol) was reacted with trimethylsilyl acetylene (68 mg, 0.69 mmol), CuI (0.13 g, 0.69 mmol), triethylamine (70 mg, 0.69 mmol), and dichlorobis(triphenylphosphine)palladium (49 mg, 0.069 mmol) in anhydrous tetrahydrofuran, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-2′-(2-amino-5-ethynylphenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 84%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][N:17]2[C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)=[CH:13][CH:12]=1.O.O.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[C:20]3[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=3)=[CH:13][CH:12]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1ccc2ccn(-c3cc(N)ncn3)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)cc1-c1ccc2ccn(-c3cc(N)ncn3)c2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
6-(6-(2-Methyl-5-nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine (130 mg, 0.38 mmol) was dissolved in ethanol and, after adding SnCl2.2H2O (425 mg, 1.88 mmol), the mixture was stirred at 100° C. for 3 hours. The reaction mixture was added to sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, MC:MeOH=20:1) yielded 6-(6-(5-amino-2-methylphenyl)-1H-indol-1-yl)pyrimidin-4-amine (83 mg).
Reaction SMILES: [CH3:1][CH:2]([C:9]1[N:21]2[C:12]([C:13](=[O:37])[NH:14][C:15]3[C:16]([CH2:35][CH3:36])=[N:17][C:18]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4C(C)CCC=C(C)C)=[N:19][C:20]=32)=[CH:11][N:10]=1)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].N1C=CN=C1>>[CH3:1][CH:2]([C:9]1[N:21]2[C:12]([C:13](=[O:37])[NH:14][C:15]3[C:16]([CH2:35][CH3:36])=[N:17][C:18]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[N:19][C:20]=32)=[CH:11][N:10]=1)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7]
Reactant: CCc1nc(-n2ccnc2C(C)CCC=C(C)C)nc2c1[nH]c(=O)c1cnc(C(C)CCC=C(C)C)n12
Agent: c1c[nH]cn1
Product: CCc1nc(-n2ccnc2)nc2c1[nH]c(=O)c1cnc(C(C)CCC=C(C)C)n12

Procedure:
Prepared by treatment of the product of Example 9f with excess imidazole at 200° C.
Reaction SMILES: C([CH2:8][NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.CCO.C(OC(C)C)(=O)C>C(Cl)Cl>[CH3:8][NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCCc2ccccc2)CC1
Solvent: CCO
Solvent: CC(=O)OC(C)C
Solvent: ClCCl
Product: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 69.2 %

Procedure:
To a Parr hydrogenation flask was added biphenyl-2-ylcarbamic acid 1-[2-(benzylmethylamino)ethyl]piperidin-4-yl ester (40 g, 0.09 mol; prepared as described in Preparation 3) and EtOH (0.5 L). The flask was flushed with nitrogen gas and palladium on activated carbon (15 g, 10 wt % (dry basis), 37% wt/wt) was added along with acetic acid (20 mL). The mixture was kept on the Parr hydrogenator under a hydrogen atmosphere (˜50 psi) for 3 hours. The mixture was then filtered and washed with EtOH. The filtrate was condensed and the residue was dissolved in a minimal amount of DCM. Isopropyl acetate (10 volumes) was added slowly to form a solid which was collected to provide 22.0 g of the title compound (70% yield). MS m/z: [M+H+] calcd for C21H27N3O2, 354.2; found, 354.3. Rf=2.96 min (10-70 ACN:H2O, reverse phase HPLC).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[S:15]([C:18]1[CH:27]=[CH:26][C:25]2[NH:24][C:23](=[O:28])[C:22]3[NH:29][CH:30]=[C:31]([C:32]([OH:34])=[O:33])[C:21]=3[C:20]=2[CH:19]=1)(=[O:17])=[O:16]>ClCCl.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[O:28]=[C:23]1[C:22]2[NH:29][CH:30]=[C:31]([C:32]([OH:34])=[O:33])[C:21]=2[C:20]2[CH:19]=[C:18]([S:15](=[O:17])(=[O:16])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:27]=[CH:26][C:25]=2[NH:24]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Nc4ccccc4)cc3c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.5 %

Procedure:
30 μL (0.37 mmol) of pyridine and 20 μL (0.22 mmol) of aniline are added to 60 mg (0.18 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid suspended in 4 mL of anhydrous dichloromethane and 1 mL of anhydrous dimethylformamide. The reaction mixture is stirred for 5 hours at room temperature then diluted with a 10% aqueous solution of potassium carbonate and dichloromethane. The phases are separated and the aqueous phase is acidified with acetic acid to pH of 4. The product is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered then evaporated. The residue is diluted with water (5 mL) then the solid is filtered and dried under vacuum to give 30 mg (42%) of 4-oxo-8-phenylsulfamoyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-].[NH4+:14]>CO>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:14])[CH:8]=1
Reactant: [NH4+]
Reactant: ClCCCCOc1cccnc1
Agent: [OH-]
Solvent: CO
Product: NCCCCOc1cccnc1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
The 4-chloro-1-(3-pyridyloxy)butane (2.00 g, 10.8 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.25 g (74.2%) of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CO)CC3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCO
Product: O=CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
A mixture of 9-bromo-5-hydroxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (520 mg, 1.67 mmol) and Dess-Martin periodinane (945 mg, 2.27 mmol) in THF (140 mL) was stirred for 5 h at room temperature. The excess reagent was decomposed by addition of ethanol and the resulting mixture was concentrated. The residual solids were triturated with dichloromethane and the insoluble materials were removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography with 0.2% acetic acid/ethyl acetate to give 330 mg of the title compound (64%): 1H NMR (270 MHz, DMSO-d6) δ12.30 (bs, 1H), 9.57 (s, 1H), 7.21 (d, 1H, J=2 Hz), 7.19 (d, 1H, J=2 Hz), 5.31~5.37 (m, 1H), 2.85 (dm, 1H, J=15.8 Hz), 2.45~2.68 (m, 2H), 1.92~2.10 (m, 1H).