Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3)[C:27]3[N:28]=[CH:29][S:30][CH:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[N:28]=[CH:29][S:30][CH:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nccc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3cscn3)ccc12
Yield: 43 %

Procedure:
To a solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-4-yl)isoquinoline-6-sulfonamide (0.070 g, 0.120 mmol) in DCM (1.195 ml) was added TFA (0.276 ml, 3.59 mmol) at room temperature. The resulting mixture stirred for a total of 3 weeks, monitoring every few days by LCMS. The crude mixture was concentrated by allowing the DCM to evaporate and taken up in DMSO. The DMSO solution was injected directly onto the Gilson HPLC for purification to provide 24 mgs (43% yield) of desired product. m/z (ESI) 465.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:10]([O:12][C:13](=[O:19])[C:14](OCC)=[O:15])[CH3:11].O>C1C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:10]([O:12][C:13](=[O:19])[C:14]([C:7]1[S:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:9][CH:8]=1)=[O:15])[CH3:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCc1cccs1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CCCCc1ccc(C(=O)C(=O)OCC)s1
Temperature: 5 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a 0° C. solution containing 2-butyl-thiophene (5 g, 35.6 mmol) dissolved in benzene (90 mL) and diethyloxalate (5.1 g, 35.6 mmol) was added (dropwise) a solution containing TiCl4 (6.7 g, 35.6 mmol) dissolved in benzene (10 mL). The reaction was let stir at 5° C. for 1 h then poured into water (300 mL) and extracted with ether. The organic layer was separated, washed with brine, then dried over MgSO4, filtered and stripped. The residue was purified by flash chromatography on silica gel in hexane/ethyl acetate 20:1. A yellow oil (4 g, 46% yield) was recovered. MS m/e 241 (M)+; 1HNMR (400 MHz, DMSO-d6 300 MHz) δ 0.9 (t, 3H), 1.4 (m, 5H), 1.6 (m, 2H), 2.9 (t, 2H), 4.4 (t, 2H), 7.1 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([CH:14]([CH2:19][CH2:20][CH2:21][OH:22])[C:15]([O:17][CH3:18])=[O:16])[CH3:13].CCOCC>ClCCl>[CH2:12]([CH:14]([CH2:19][CH2:20][CH:21]=[O:22])[C:15]([O:17][CH3:18])=[O:16])[CH3:13]
Reactant: CCC(CCCO)C(=O)OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CCC=O)C(=O)OC
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 59323.1 %

Procedure:
To 50.46 g (0.234 mmol) of pyridinium chlorochromate, under argon, was added 100 mL of dichloromethane followed, with rapid stirring, by 25.0 g (0.156 mmol) of methyl 2-ethyl-5-hydroxypentanoate in 20 mL of dichloromethane. After stirring at 20° C. for 2.5 h, 15 g of silica gel was added followed by 200 mL of ether. Filtration through a 3.5×40 cm silica gel column (60-200 mesh), eluting ether and concentration at 40° C. under vacuum gave an oil, which was redissolved in 100 mL of dichloromethane. Washing with 3×100 mL of cold 1N HCl, 3×100 mL of satd. NaHCO3, drying over MgSO4, filtration, concentration at 40° C. and distillation gave methyl 2-ethyl-5-oxopentanoate 14.64 g (59%) product, b.p 104°-105° C. (16 mm Hg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
A mixture of 4,6-dichloro-pyrimidin-2-yl-amine (3.3 g, 20 mmol), p-tolylamine (3.4 g, 32 mmol) and N,N-diisopropylethylamine (12 ml) in ethanol (150 ml) was heated under reflux for 40 hours. After cooling to room temperature, filtration provided 6-chloro-N*4*-p-tolyl-pyrimidine-2,4-diamine (2.8 g, 60% yield) as a white solid.
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1>[CH:14]1[CH:15]=[C:10]([S:9][CH:2]2[S:6][C:5](=[O:7])[NH:4][C:3]2=[O:8])[N:11]=[CH:12][CH:13]=1
Reactant: O=C1NC(=O)C(Br)S1
Reactant: Sc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(Sc2ccccn2)S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To a solution of 5-bromo-thiazolidine-2,4-dione (28.24 g, 0.144 mol) and 2-mercaptopyridine [(II), 16.0 g, 0.144 mol] in dry THF (200 mL) at -78° C. was added lithium bis(trimethylsilyl)amide (1.0M in hexanes, 317 mL, 0.317 mol) dropwise over a 40 min period. After 30 min. the reaction mixture was warmed to room temperature. After an additional 3 hr, 10% HCl was added to pH=1. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×500 mL). The combined organic phase was washed with water (500 mL), brine (500 mL), dried (MgSO4) and concentrated to provide the title compound as a green solid (30.45 g, 93%): mp 118°-120° C.; NMR (DMSO, d 6): δ12.35 (s, 1H, NH), 8.39 (d, J=5.3 Hz, 1H, PyrH), 7.69 (dd, J=7.3, 8.3 Hz, 1H, PryH), 7.42 (d, J=8.3 Hz, 1H, PyrH), 7.19 (dd, J=5.3,7.3 Hz, 1H, PyrH), 6.31 (s, 1H, CH), MS(EI): 226 (MI, 12%), 155 (10%), 79 (100%); Anal. (C8H6N2O2S2): C, H, N.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=1[NH:22][C:23]([C@@H:25]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=O)[CH2:3][C:4](=[O:11])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CN(C1C=CC=CN=1)C>O1CCCC1>[OH:1][C:2]1[C:12]2[C:13](=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:16][CH:17]=2)[N:22]=[C:23]([C@@H:25]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)[C:3]=1[C:4]([NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 62.2 %

Procedure:
Using the procedure of Step C of Example 7, a solution of 28 g of the product of Step B in 280 ml of tetrahydrofuran and 5.25 g of dimethylaminopyridine were reacted to obtain 16.9 g of 1,1-dimethylethyl N-[(S) 1-[4-hydroxy-3-[(2-thiazolylamino)-carbonyl]-8-(trifluoromethyl)-quinolin-2-yl]-2-(1H-indol-3-yl)-ethyl]-carbamate melting at 270° C. and having a specific rotation of [α]D =+33°±2° (c=0.5% in CH3COOH).
Reaction SMILES: [Cl:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][CH:21]([OH:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[F:27][C:28]1[CH:29]=[N:30][NH:31][C:32]=1[Sn](CCCC)(CCCC)CCCC>>[Cl:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([C:32]3[NH:31][N:30]=[CH:29][C:28]=3[F:27])[C:15]([N:19]3[CH2:22][CH:21]([OH:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(O)C2)c(I)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(O)C2)c(-c2[nH]ncc2F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 92 using N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)-5-iodonicotinamide (Stage 88.1) and 4-fluoro-5-(tributylstannyl)-1H-pyrazole. After purification by flash chromatography on silica gel, the residue was dissolved in MeCN (2 mL), sonicated and then stirred at RT for 90 min. The resulting suspension was filtered, washed with MeCN (3 mL) and dried to afford the title product as a white solid. HPLC (Condition 7) tR=5.72 min, UPLC-MS (Condition 8) tR=0.93 min, m/z=454.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.53-3.61 (m, 2H) 3.91-4.01 (m, 2H) 4.37-4.47 (m, 1H) 5.57 (br. s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.83-7.97 (m, 3H) 8.04 (d, J=1.96 Hz, 1H) 8.78 (d, J=1.96 Hz, 1H) 10.23 (br. s, 1H) 13.03 (br. s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:7][CH2:6][CH:5]([CH2:8][C:9](OC)=[O:10])[CH2:4]1.[Li+].[BH4-].CO>C1COCC1>[CH3:14][O:13][C:3]1([O:2][CH3:1])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][OH:10])[CH2:4]1
Reactant: COC(=O)CC1CCC(OC)(OC)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COC1(OC)CCC(CCO)C1
Reaction time: 16 h
Yield: 99.2 %

Procedure:
J. Org. Chem., 1986, 51 (21), 4000-4005. A 5000 mL large neck round bottom flask was charged with a solution of methyl 2-(3,3-dimethoxycyclopentyl)acetate (238 g, 1177 mmol) in THF (1100 mL). To the solution was added LiBH4, 2.0 M in THF (706 mL, 1412 mmol) over approximately 1 min, followed by dropwise addition of methanol (57.1 mL, 1412 mmol). Note: vigorous exotherm. The reaction was stirred for 16 hrs, monitoring by 1H and 13C NMR. The reaction was quenched by the addition of sat'd ammonium chloride solution (600 mL), then diluted with Et2O (˜500 mL), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (300 mL), and the combined organic extracts were concentrated. The resulting oil was diluted with CH2Cl2 (200 mL), dried (MgSO4), filtered and concentrated to yield 2-(3,3-dimethoxycyclopentyl)ethanol (203.3 g, 1167 mmol, 99% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[Br:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:8][C:9]([F:16])([F:15])[C:10]([NH:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: NCc1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccco1)C(F)(F)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a solution of 1-(furan-2-yl)methanamine (1 g, 10.3 mmol) in 15 mL of dry DMF, ethyl bromo(difluoro)acetate (2.3 g, 11.3 mmol) and K2CO3 (2.13 g, 15.4 mmol) were added. The solution was stirred for 18 h at room temperature. The mixture was diluted with 30 mL of water and extracted with 2×20 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2-bromo-2,2-difluoro-N-(furan-2-ylmethyl)acetamide as red oil (2.3 g, 88% yield). HPLC-MS (ESI+): m/z 255.03 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]1([CH3:43])[CH2:33][CH2:32][CH2:31][CH:30]([O:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)[CH2:29]1>O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:40][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH:30]2[CH2:31][CH2:32][CH2:33][C:28]([CH3:43])([CH3:27])[CH2:29]2)=[CH:36][CH:37]=1
Reactant: CC1(C)CCCC(Oc2ccc(CN)cc2)C1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: C1COCCO1
Product: CC1(C)CCCC(Oc2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)C1
Yield: 49 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (387 mg, 0.91 mmol) with (±)-4-(3,3-dimethyl-cyclohexyloxy)-benzylamine (233 mg, 1 mmol) in anhydrous 1,4-dioxane (14 mL). Purify the crude mixture by chromatography on silica gel eluting with cyclohexane/EtOAc (19:1 to 1:1 gradient) to obtain (±)-7-chloro-6-[4-(3,3-dimethyl-cyclohexyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (227 mg, 50%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.[CH3:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=3[CH:17]=2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: O=C1Nc2ccc(OCCCCCl)cc2CO1
Reactant: Cc1ccc(S)cc1C
Product: Cc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4H-3,1-benzoxazin-2-one and 3,4-dimethyl-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[C:19]([NH2:28])[CH:18]=2)[CH:5]=[C:6]([CH2:8][O:9][C:10]([CH3:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[C:19]([NH:28][C:35]([C@H:32]3[CH2:31][C:30](=[O:29])[NH:34][CH2:33]3)=[O:36])[CH:18]=2)[CH:5]=[C:6]([CH2:8][O:9][C:10]([CH3:15])([CH3:16])[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: CC(C)(OCc1cc(Cl)cc(-c2cc(N)nn2-c2ccccc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(OCc1cc(Cl)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2)c1)C(F)(F)F
Reaction time: 1 h
Yield: 44.4 %

Procedure:
Under argon atmosphere, to a solution of 5-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine (62 mg) in N,N-dimethylacetamide (1 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (26 mg) prepared according to the same procedures as Preparation 14, WSC.HCl (40 mg) at room temperature, and the mixture was stirred for 1 hour. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (35 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[C:11]([OH:29])[C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([CH2:38][CH2:39]O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[C:11]([O:29][CH2:39][CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:10]=1[CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccccc1
Reactant: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Product: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1OCCc1ccccc1

Procedure:
4-(4-benzyloxy-3-ethyl-2-phenethyloxyphenoxy)-5-methyl-7-nitroindane was prepared in a similar manner to those described in Example 2 using 3-benzyloxy-2-ethyl-6-(5-methyl-7-nitroindan-4-yloxy)phenol instead of ethyl N-[7-(3-ethyl-2-hydroxy-4-trifluoromethanesulfonyloxyphenoxy)-6-methylindan-4-yl]malonamate and using 2-phenylethanol instead of 4-fluorobenzylalcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:22][NH2:23])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Solvent: CCO
Product: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1

Procedure:
A mixture of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (4.8 g, 0.015 mol) in hydrazine (20 ml, 0.41 mol) is refluxed for 90 minutes. The reaction is poured into ethanol (300 ml) with efficient stirring. The resulting precipitate is filtered with suction to yield the title compound, m.p. 201–203° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[C:5]2[C:17]([NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:18].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:7]1[CH:6]=[C:5]([C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:3]=2)[N:8]=1
Reactant: Nc1ccccn1
Reactant: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(Br)cc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(Nc3ccccn3)cc12
Temperature: 90 °C
Yield: 18.1 %

Procedure:
6-bromo-2-(furan-2-yl)-N-(pyridin-3-yl)quinoline-4-carboxamide (prepared as described above, 0.080 g) was added to a sealed tube and dissolved in toluene (5 ml). The vessel was purged with argon for 5 minutes, and 2-aminopyridine (0.029 g, 1.50 eq.) was then added. The vessel was purged with argon for an additional 5 minutes, cesium carbonate (0.200 g) was added, and the tube was purged with argon for an additional 15 minutes. DavePhos (2-(2-dicyclohexylphosphanylphenyl)-N,N-dimethylaniline, 0.012 g) and Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0), 0.014 g) were added, the tube was flushed with argon and sealed. The reaction mixture was heated to 90° C. for 16 hours, and completion of the reaction was monitored by TLC using ethyl acetate:hexanes (5:5) as a mobile phase. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 ml), filtered through celite bed, which was washed with ethyl acetate (3*10 ml). The ethyl acetate was removed by distillation and the crude product was subjected to silica gel column chromatography purification. Elution of the compound with 20% ethyl acetate in hexanes provided 2-(furan-2-yl)-6-(pyridin-2-ylamino)-N-(pyridin-3-yl)quinoline-4-carboxamide (0.015 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (s, 1H), 9.62 (s, 1H), 8.99 (m, 1H), 8.57 (m, 1H), 8.41 (m, 1H), 8.27 (m, 2H), 8.05 (m, 2H), 8.00 (m, 1H), 7.95 (m, 1H), 7.61 (m, 1H), 7.50 (m, 1H), 7.38 (m, 1H), 6.92 (m, 1H), 6.81 (m, 1H), 6.74 (m, 1H); m/z 408.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].C(Cl)Cl.N1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Reaction time: 0.33 h

Procedure:
A mixture of 570 mg. of l-ethyl 6,7-dimethoxy-3-aminomethylene-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate, 1.78 ml. of 1N sodium hydroxide and 3 ml. of ethanol was heated under reflux for 24 hours and then stored at 25° C. for 3 days. The solvent was removed by evaporation in vacuo, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and then it was concentrated to give 540 mg. of an oil. The oil was chromatographed using 30 g. of silica gel, and using 6:4 benzene-ethyl acetate as solvent, giving 6 fractions. Fractions 1 and 2 were combined and recrystallized from ethyl acetate-hexane to give 49 mg. of the title product, m.p. 92°-93° C. Fractions 3-6 were combined to give 152 mg. of 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline. This latter material was dissolved in 3 ml. of methylene chloride, and 3 ml. of pyridine followed by 0.5 ml. of ethyl chloroformate was added. After 20 minutes, the reaction mixture was diluted with an excess of methylene chloride and water. The organic phase was separated and washed successively with dilute hydrochloric acid, saturated sodium bicarbonate and brine. The methylene chloride solution was then dried, and evaporated in vacuo to give an oil. The oil was recrystallized from ethyl acetate-hexane to give 95 mg. of the title compound, m.p. 92°-93° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[CH3:8])(=[O:3])[CH3:2]>O1CCCC1.O>[C:1]([NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1)[CH3:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)CCNC(C)=O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCC(C)c1ccc(C(=O)O)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
Methyl 4-(4-acetamidobutan-2-yl)benzoate (0.23 g, 0.9 mmol) was dissolved in a mixture of in tetrahydrofuran (10 mL) and water (50 mL), then stirred at 45° C. for 12 hours, after the completion of the reaction, the organic phase was removed under reduced pressure, to the residue was added 1 N hydrochloride to adjust the pH 3-4, then the mixture was extracted with ethyl acetate (10 mL×3), collected the organic phase and dried over Sodium sulfate anhydrous, removed the solvent to afford 4-(4-acetamidobutan-2-yl)benzoic acid (0.21 g, 100%) as a pale yellow oil and directly used in next step. LRMS (M+H+) m/z: calcd for 235.28. found 235.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)=[C:9]([C:18]#[N:19])[C:8]2=[O:20])=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25]>O>[Cl:25][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[C:8](=[O:20])[C:9]=1[C:18]#[N:19]
Reactant: N#Cc1c(O)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 100 °C

Procedure:
To 1-(4-Fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1 eq, 0.250 g, 0.85 mmole) was added POCl3 neat. The resulting solution was heated to 100° C. for 8 hours, Reaction mixture was added dropwise to water (20 mL) which had been heated to 80° C. then cooled to RT and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-Chloro-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.156 g, 59%. LCMS calc M+H 313, obs M+H 313).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:12]([O:14][C:15](=[O:21])[CH2:16][N:17]([C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[CH:18]([CH3:20])[CH3:19])[CH3:13]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CNC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Yield: 72 %

Procedure:
2,4-Dichloro-5-nitro-pyrimidine (40 g; 0.207 mol) was added to a cooled (0-10° C.) solution of isopropylamino-acetic acid ethyl ester (30 g; 0.207 mol) in 300 ml of acetone. A solution of potassium carbonate (28.5 g; 0.207 mol) in water was then added to the cooled reaction mixture. The reaction mixture was allowed to reach room temperature and was maintained at that temperature until complete conversion of the starting material into the desired product.