Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1cccc(Cl)c1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1O
Reaction time: 24 h
Yield: 43.3 %

Procedure:
2,3-dichlorophenol (3.26 g, 20 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.88 g, 22 mmol). The addition of sulfuric acid (20 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.8 g, 44%). 1H NMR (CD3COCD3): δ 8.04 (d,1H), 7.15 (d, 1H).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:23][O:24][C:25]1[CH:30]=[CH:29]C(CO)=[CH:27][CH:26]=1>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][C:7]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Reactant: COc1ccc(CO)cc1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1ccc(COC(=O)C(=O)c2ccc3c(c2)C2(C)CCN(C)C2N3C)cc1

Procedure:
To a chilled (0° C.) solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (2.07 g) in anhydrous 4-methoxyphenylmethyl alcohol (40 ml) was added titanium (IV) ethoxide (0.54 ml) with stirring under nitrogen atmosphere. The reaction mixture was heated without refluxing for 8 hours. The 4-methoxyphenylmethyl alcohol was removed by distillation under high vacuum and the residue was dissolved in dichloromethane (200 ml). The residue was washed successively with two 100 ml portions of saturated aqueous NH4Cl solution, two 100 ml portions of saturated aqueous NaHCO3 solution and with brine, dried (Na2SO4), filtered and evaporated to yield an oil. The oil was purified by preparative HPLC (silica gel, 3% methanol in ethyl acetate as the loading solvent and eluent). A second preparative HPLC purification using 3% methanol in dichloromethane, yielded 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, 4-methoxyphenylmethyl ester (0.84 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([F:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(F)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the commercially available 3-chloro-4-fluorobenzenesulfonyl chloride (7 g, 30 mmol) in CH3CN (40 mL) was added KF (7 g, 120 mmol) and 18-crown-6 (0.5 g), then the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous water and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the crude product which was purified by column to give the reagent R-12a (4.2 g, 95.5%) as a pale yellow solid. ESI-MS (M+1): 213.2 calc. for C6H3CIF2O2S
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:20]O.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[C:1]([N:11]1[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([O:15][CH3:20])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.5 g (0.024 mole) of N-carbobenzyloxy-cis-4-hydroxy-L-proline (J.A.C.S., 79, 189 (1957)] is dissolved in 65 ml. of methanol, stirred, and treated with 0.65 ml. of concentrated sulfuric acid. After stirring at room temperature for one-half hour, the solution is allowed to stand overnight. The bulk of solvent is removed on a rotary evaporator and the oily residue (13 g.) is taken up in 70 ml. of ether and washed with 35 ml. of 10% sodium bicarbonate solution. The wash is back extracted with 35 ml. of ether. The combined organic layers are dried (MgSO4), and the ether is evaporated to give 6.5 g. (96%) of product as a pale yellow viscous oil. [α]D25 -24° (c, 1% in chloroform).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=2[C:26](O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>C(#N)C>[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][C:25]=2[C:26]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:17]=[N:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH2:7][CH2:6]2)=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3cnc4ccccc4n3)CC2)c1

Procedure:
Prepared in analogy to example 1.1(b) from 2-piperazin-1-yl-quinoxaline hydrochloride and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[ClH:20].[Cl:21][CH2:22][CH2:23][N:24]1[CH2:30][CH:29]2[CH2:31][CH2:32][CH:26]([CH2:27][CH2:28]2)[CH2:25]1>>[ClH:21].[ClH:20].[CH:29]12[CH2:31][CH2:32][CH:26]([CH2:27][CH2:28]1)[CH2:25][N:24]([CH2:23][CH2:22][N:14]1[CH2:15][CH2:16][C:11]3[C:8]4[CH:9]=[CH:10][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][C:7]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]1)[CH2:30]2
Reactant: CC(C)(C)c1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Product: CC(C)(C)c1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC(CC2)C1)CC3
Yield: 48 %

Procedure:
Prepared by the method described for Example 1 from 8-(1,1-dimethylethyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]-pyridin-5-one (4 g, 0.016 moles) and 3-(2-chloroethyl)-3-azabicyclo(3.2.2)nonane hydrochloride (3.6 g, 0.016 moles). Recrystallization from methanol gave the product (3.7 g), mp 312°-315° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=2[F:20])=O)[CH:7]=1.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=2[F:20])[CH:7]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)c(F)c1F
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.8 %

Procedure:
To a solution of (5-bromo-2-chloro-phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanone 23d (17.6 g, 46.8 mmol) in acetonitrile (100 mL) was added triethyl silicane (18.7 mL, 117.1 mmol) at 15° C., and then boron trifluoride diethyl ether (28.9 mL, 234.1 mmol) was added. The mixture was warmed up to room temperature and stirred for 15 hours. The reaction mixture was adjusted with saturated aqueous sodium bicarbonate to pH 7 and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE to give the title compound 23e as a white solid (9.45 g, 63%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.34-7.30 (m, 1H), 7.29-7.26 (m, 2H), 6.79-6.75 (m, 1H), 6.71-6.66 (m, 1H), 4.12 (q, 2H), 4.04 (s, 2H), 1.47 (t, 3H).
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:22]([F:23])=[CH:21][C:20]([N:24]4[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]4=[O:34])=[CH:19][C:18]=3[F:35])[CH2:13][CH2:12]2)=O)C=CC=CC=1.FC(F)(F)C(O)=O>>[O:34]=[C:25]1[N:24]([C:20]2[CH:19]=[C:18]([F:35])[C:17]([CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[C:22]([F:23])[CH:21]=2)[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-(−)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester ((EXAMPLE 35, Step 7, 847 mg) and trifluoroacetic acid (12 mL) maintained at 0° C. under N2 is stirred for two hours and then concentrated under reduced pressure to remove excess trifluoroacetic acid. The residue is diluted with saturated aqueous potassium carbonate (70 mL) and methylene chloride (50 mL), and the layers are separated. The aqueous phase is extracted with methylene chloride (2×50 mL), and the combined organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, triturated with diethyl ether and recrystallized from ethyl acetate to give the title compound, NMR (CDCl3, 400 MHz) 7.08, 6.10, 4.78, 4.00, 3.74, 3.64, 3.19, 3.07, 2.72, 2.03, 1.99, 1.68δ.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(O[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])C.CC[O-].[Na+]>>[CH2:15]([O:14][C:12](=[O:13])[C:11]([CH:4]1[CH2:5][CH2:6][CH:2]([CH3:1])[C:3]1=[O:7])=[O:17])[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC1CCCC1=O
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C1CCC(C)C1=O
Temperature: 25 °C
Yield: 27.9 %

Procedure:
2-methylcyclopentanone (1.0058 g, 10.2 mmol) and diethyloxalate (1.38 mL, 10.2 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 3.4 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 4. The crude material was purified with 98:2 to 96:4 Hexanes: EtOAc to obtain 0.5635 g (27.7%) of 4. 1H (CDCl3, 400 MHz): δ 4.29 (2H, q, J=7.1 Hz), 2.96 (1H, ddd, J=17.6, 8.1, 1.5 Hz), 2.69 (1H, ddd, J=17.6, 9.5, 8.1 Hz), 2.57-2.47 (1H, m), 2.24 (1H, dtd, J=12.5, 8.3, 2.4 Hz), 1.49 (1H, dtd, J=12.5, 10.3, 8.4 Hz), 1.34 (3H, t, J=7.1 Hz), 1.13 (3H, d, J=7.0 Hz) ppm. 13C (CDCl3, 100 MHz): δ 164.09, 153.19, 117.67, 62.92, 44.76, 30.60, 30.36, 26.55, 14.63, 14.37 ppm.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[O:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccccc1Oc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Thionyl chloride (1.92 ml) was added in one portion to a solution of 2-phenoxybenzyl alcohol (4.80 g) in dry dichloromethane (50 ml). The resulting mixture was stirred at room temperature for 2 hours, then washed with water (×2), aqueous sodium bicarbonate (×2) and aqueous sodium chloride, dried and concentrated under reduced pressure to give 2-phenoxybenzyl chloride (4.87 g, 93%) as a colourless oil.
Reaction SMILES: [I:1]Cl.Cl.Cl.[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=[CH:9][C:8]=1[OH:17].[OH-].[NH4+]>Cl.O>[I:1][C:9]1[C:8]([OH:17])=[C:7]([CH2:6][NH2:5])[CH:12]=[C:11]([C:13]([CH3:14])([CH3:16])[CH3:15])[N:10]=1
Reactant: CC(C)(C)c1cc(CN)c(O)cn1
Reactant: ClI
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(CN)c(O)c(I)n1
Reaction time: 18 h
Yield: 78.4 %

Procedure:
A solution of iodine monochloride (2.68 g., 0.02 mole) in 4N hydrochloric acid (15 ml.) is added to a solution of 4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol . dihydrochloride (5.06 g., 0.02 mole) in water (30 ml.). The resulting solution is kept at 20°-25° C. for 18 hours, diluted with water to a volume of 100 ml. and basicified with concentrated ammonium hydroxide (12 ml.) whereupon a solid is deposited. The solid is collected, washed with water and air-dried to give 2-iodo-4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol (4.8g., 78%), m.p. 162°-165° C. Recrystallization of the latter from 50% ethanol provides an analytical sample of 2-iodo-4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol as pale beige crystals, m.p. 170°-171° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@@H:21]([CH3:25])[NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.[H-].[Na+]>>[CH:28]1([CH2:27][N:22]2[C@H:21]([CH3:25])[CH2:20][N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])[CH2:30][CH2:29]1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@@H](C)NC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@@H](C)N(CC3CC3)C2=O)CC1

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 14), 1-(bromomethyl)cyclopropane and sodium hydride, to give the compound as a colorless oil (77%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:21][OH:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl>CO.[Pd]>[NH2:15][CH2:14][C:13]1[C:12]([NH:19][C@H:20]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:21][OH:22])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Reaction time: 6 h
Yield: 57 %

Procedure:
The mixture of (R)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile (Example 6; 0.13 g, 0.33 mmol), conc. HCl (0.1 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.12 g) in MeOH (5 ml) was flushed with N2, evacuated, and then placed under H2 (40 psi) for 6 hrs. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated. The resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml), and a saturated aqueous solution of Na2CO3 (100 ml) was added. The mixture was shaken vigorously for 30 min and allowed to separate. The aqueous layer was extracted with DCM (3×100 ml). The combined organic layer was dried, filtered and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.074, 57%). 1H NMR (400 MHz, CD3OD) δ 7.45-7.42 (m, 2H), 7.17 (d, J=11.1 Hz, 1H), 7.04-7.00 (m, 2H), 5.72 (br s, 1H), 5.18-5.08 (m, 1H), 3.89-3.72 (m, 4H), 1.87-1.83 (m, 1H), 0.94-0.92 (m, 2H), 0.69-0.65 (m, 2H). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10](=[O:18])[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]1)=[O:6])([CH3:3])[CH3:2].[CH2:24]([Mg]Br)[CH3:25].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10](=[O:18])[CH:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]1[CH2:24][CH3:25])=[O:6])([CH3:2])[CH3:3]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1cn(C(=O)OC(C)C)c2nc(C)ccc2c1=O
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2ccc(C)nc2N(C(=O)OC(C)C)C1CC
Temperature: -78 °C
Yield: 54 %

Procedure:
Mix 7-methyl-4-oxo-4H-[1,8]naphthyridine-1,3-dicarboxylic acid 3-ethyl ester 1-isopropyl ester (1.21 g, 3.80 mmol) and copper(I) iodide (1.59 g, 8.36 mmol) in THF (75 ml). Cool the mixture to −78° C. Inject ethyl magnesium bromide (3.0 M in diethyl ether, 7.60 ml) and stir for 2 h. Warm up to −20° C. and keep the reaction at that temperature for 3 h. Pour the reaction mixture into saturated ammonium chloride solution (100 ml). Extract with ethyl acetate (3×100 ml). Combine the organic layers, dry over sodium sulfate, filter and concentrate. Purify using silica gel column chromatography (gradient eluent, 0-60% ethyl acetate in hexane) to provide 2-ethyl-7-methyl-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1,3-dicarboxylic acid 3-ethyl ester 1-isopropyl ester (0.715 g, 54%). MS (ES+): 349 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH:7](Cl)CC.[H-].[Na+].CN(C=[O:26])C>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]2([C:3]([OH:2])=[O:19])[CH2:5][CH2:6][CH2:7][O:26]2)=[CH:12][CH:13]=1
Reactant: CCC(Cl)CCC(C(=O)OC)c1ccc(OC)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C2(C(=O)O)CCCO2)cc1
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-(4-methoxyphenyl)-heptanoic acid methyl ester (0.26 g, 0.96 mmol) in 5 ml of DMF at 0° C. was added sodium hydride (0.6 g, 1.4 mmol). The reaction was stirred for 1 h at this temperature then quenched with 10 ml of water. The product was extracted into ethyl acetate (3×15 ml), washed with brine (20 ml), dried with magnesium sulfate and concentrated in vacuo to give a yellow oil. Silica gel chromatography eluting with hexane/ethyl acetate (4:1) gave 0.063 g of the title compound as a colorless oil.
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:26])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.[CH:27]([N-:30][CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28].[Li+].C1C(=O)N(Br)C(=O)C1.O>O1CCCC1>[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]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH2:26][N:30]([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Reactant: CC(C)[N-]C(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3CN(C(C)C)C(C)C)c2cc1OC
Reaction time: 0.17 h
Yield: 16 %

Procedure:
6,7-Dimethoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 276) (108 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution. A lithiumdiisopropylamide/1.8 M heptane-tetrahydrofuran-ethylbenzene solution (0.3 ml) was added to the solution at −78° C., and the mixture was stirred for 10 min. N-Bromosuccimide (180 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (23 mg, yield 16%).
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][C:15]([NH:18]C(=O)OCC1C=CC=CC=1)([CH3:17])[CH3:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[OH-].[OH-].[Pd+2].CO>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16])=[O:7]
Reactant: [H][H]
Reactant: CC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(N)COP(=O)(OC(C)(C)C)OC(C)(C)C
Yield: 94.8 %

Procedure:
The product of Example 95B (0.40 g, 0.96 mmol) and 20% palladium hydroxide on carbon (0.21 g) in a ethyl acetate (10 mL) and methanol (1 mL) was stirred under a an atmosphere of hydrogen for 0.5 hours. The reaction was filtered through a bed of celite and concentrate to give the title product (0.256 g).
Reaction SMILES: [C:1]([C:3](=[C:8](SC)[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:13]([NH2:16])[CH:14]=[CH2:15]>C(COC)OC>[C:1]([C:3](=[C:8]([S:9][CH3:10])[NH:16][CH2:13][CH:14]=[CH2:15])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: C=CCN
Reactant: COC(=O)C(C#N)=C(SC)SC
Solvent: COCCOC
Product: C=CCNC(SC)=C(C#N)C(=O)OC
Yield: 101.5 %

Procedure:
To a suspension of 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester (8.12 g) in dimethoxyethane (13 mL) was added (2-propenyl)amine (2.51 g). The mixture dissolved. After about 15 min the solvent was evaporated under nitrogen and the solid residue was filtered with diethyl ether to give 2-cyano-3-methylthio-3-(2-propenyl)amino-2-propenoic acid, methyl ester (8.61 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(Cl)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-chlorophenylmagnesium bromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=O)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:10].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:28]=[C:27]([N:29]=[C:30]=[S:31])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[C:12]([CH3:18])([CH3:17])[C:13](=[O:15])[N:29]([C:27]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:20]([F:33])([F:19])[F:32])[CH:28]=3)[C:30]2=[S:31])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:10]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: COCc1ccc(NC(C)(C)C(=O)OC)cc1F
Solvent: CS(C)=O
Solvent: O
Product: COCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F
Yield: 4.6 %

Procedure:
The title compound was prepared according to General Method 1. A solution of methyl 2-(3-fluoro-4-(methoxymethyl)phenylamino)-2-methylpropanoate (60 mg, 0.24 mmol) and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (120 mg, 0.52 mmol) in DMSO (1 mL) was heated at 82° C. for 12 h. The reaction mixture was poured in water (10 mL) and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography (100-200 mesh) to obtain 5 mg of final product, HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 13.316 min, M+1, 452.