Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([N:14]([CH2:22][CH3:23])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH3:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([N:14]([CH2:22][CH3:23])[CH2:12][CH3:13])=[CH:20][CH:19]=2)[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CCN(CC)c1ccc(N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2,6-dichloronicotinamide (1 g, 5.24 mmol) and N1,N1-diethylbenzene-1,4-diamine (2.150 g, 13.09 mmol) in THF (50 mL) was added lithium bis(trimethylsilyl)amide (26.2 mL, 26.2 mmol) drop-wise at first then portion-wise at −78° C. The reaction mixture was stirred at rt for 30 min. The ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water, extracted twice with ethyl acetate, and the combined organic layers were washed with water and concentrated. The residue was purified by MPLC (ISCO, hexane/ethyl acetate, 120 g silica gel column) to give 6-chloro-2-(4-(diethylamino)phenylamino)nicotinamide. LCMS: (M+H)+=319.10. 1H NMR (400 MHz, CDCl3) δ ppm 10.44 (1H, s), 7.56 (1H, d, J=7.91 Hz), 7.47 (2H, d, J=9.23 Hz), 6.69 (2H, d, J=9.23 Hz), 6.55 (1H, d, J=7.91 Hz), 5.73 (2H, br. s.), 3.33 (4H, q, J=7.03 Hz), 1.15 (6H, t, J=7.03 Hz).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][OH:15])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: OCCCBr
Reactant: CS(=O)(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(CCCO)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A suspension of 1-(methylsulfonyl)piperazine (3 g, 18.3 mmol), 3-bromopropan-1-ol (3.3 g, 23.8 mmol) and potassium carbonate (3.28 g, 23.8 mmol) in acetonitrile (20 ml) was stirred at 70° C. for 4 hours. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of methanol and methylene chloride to give 3-(4-methylsulphonylpiperazin-1-yl)propan-1-ol (2.93 g, 72%).
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[N+:7]([C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=1[CH3:19])([O-])=O>>[CH3:5][O:4][C:1]([NH:7][C:10]1[CH:15]=[C:14]([NH:16][C:1]([O:4][CH3:5])=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:19])=[O:6]
Reactant: COC(=O)OC
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: COC(=O)Nc1ccc(C)c(NC(=O)OC)c1
Reaction time: 23 h
Yield: 63 %

Procedure:
In a 5 ml reinforced glass flask capable of pressure sealing dimethyl carbonate (2 ml), 2,4-dinitrotoluene (150 mg), the Au/CeO2 catalyst (100 mg, 1 wt % gold relative to cerium) are placed, and the reactor is closed. After purging with N2 for 5 minutes, the reactor is loaded with hydrogen gas at a pressure of 15 bars. The reactor is immersed in a silicone bath preheated at 150° C. and the mixture is magnetically stirred for 23 hrs. After this time, the reactor is brought to atmospheric pressure and opened. The catalyst is filtered and the liquid phase is analyzed by gas chromatography. The disappearance of 2,4-dinitrotoluene and the formation of 2,4-bis(methoxycarbonylamino) toluene in a 63% yield is observed. Smaller amounts (20%) of ortho and para mixtures of the mono carbamoylate 2,4-diaminotoluene derivative are detected.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl.Cl[C:32]([O:34][CH3:35])=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([C:32]([O:34][CH3:35])=[O:33])[CH3:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CNC)c2ccccc2n1Cc1cccc2ccc(F)cc12
Reactant: COC(=O)Cl
Agent: Cl
Product: CCOC(=O)c1c(CN(C)C(=O)OC)c2ccccc2n1Cc1cccc2ccc(F)cc12

Procedure:
1-(7-Fluoro-naphthalen-1-ylmethyl)-3-methylaminomethyl-1H-indole-2-carboxylic acid ethyl ester; salt with HCl was reacted with methyl chloroformate as described in Example 77.1. to give 1-(7-fluoro-naphthalen-1-ylmethyl)-3-[(methoxycarbonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 1-(7-fluoro-naphthalen-1-ylmethyl)-3-[(methoxycarbonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid as a white solid. MS: 419.5 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=CN(C)C)[C:5]#[N:6].I([O-])(=O)(=O)=[O:16].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:16])[C:5]#[N:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1ccc(C#N)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude 3-chloro-4-[2-(dimethylamino)vinyl]benzonitrile obtained in this way is taken up in 500 ml of THF/water (1:1), and 77.6 g (362.9 mmol) of sodium periodate are added. The mixture is stirred at room temperature for 18 h, and then the precipitate which has separated out is removed by filtration. The filtrate is mixed with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The crude product is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 7:3). 3.0 g (15% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[N:3]=1.[CH3:13][O-:14].[Na+].CO>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:14][CH3:13])[N:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(Cl)nc1F
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 6-chloro-2-fluoronicotinate (Example 454, Step 1) (76 mg, 0.40 mmol) was taken up in a 0.5 M solution of sodium methoxide in methanol (0.80 ml, 0.40 mmol) and stirred at room temperature for 3 hours. The mixture was quenched with saturated aqueous ammonium chloride and extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via flash chromatography (silica, 0-17% ethyl acetate/hexanes) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH:10]([O:19][CH3:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].Cl.CN(C)CCCN=C=NCC.O.[OH:35][N:36]1C2C=CC=CC=2N=N1.NOC1CCCCO1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C=O)C>[OH:35][NH:36][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:21])([CH3:1])[CH:10]([O:19][CH3:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OC)C(C)(C)CCCCC(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(OC)C(C)(C)CCCCC(=O)NO)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 199.2 %

Procedure:
To a solution of the carboxylic acid from step 1 (100 mg, 0.344 mmol), in DMF (10 mL) at room temperature were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 79 mg, 0.414 mmol) and 1-hydroxybenzotriazole hydrate (HOBt, 70 mg, 0.516 mmol). The mixture was stirred for 20 min. at room temperature, and then NH2OTHP (60 mg, 0.516 mmol) was added. The resulting mixture was heated overnight at 50° C., and then concentrated. The crude material was dissolved in CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted several times with CH2Cl2 and the combined organic extracts were dried over anhydrous MgSO4 and concentrated. The crude material was purified by flash chromatography using hexane/acetone (7:3) as the solvent mixture. The pure protected hydroxamate was then dissolved in MeOH (10 mL), and 10-camphorsulfonic acid (CSA, 40 mg, 0.172 mmol) was added. The mixture was stirred for 2 h at room temperature, and then the solvents were evaporated under reduced pressure at room temperature to avoid thermal decomposition. The crude mixture was purified by flash chromatography using CH2Cl2/MeOH (9:1) as the solvent mixture, giving compound 28 as colorless oil (212 mg, 68%): 1H NMR: (300 MHz, d6-acetone) δ 7.18 (d, J=8 Hz, 2H), 6.89 (d, J=8 Hz, 2H), 3.85 (s, 1H), 3.79 (s, 3H), 3.11 (s, 3H), 2.11-2.05 (m, 2H), 1.45 (br. s, 2H), 1.34 (br. s, 4H), 0.83 (s, 3H), 0.76 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1.[CH2:26](I)[CH3:27]>C1COCC1.C([Li])(C)(C)C>[CH2:26]([C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1)[CH3:27]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)ccc(OC)c21
Reactant: CCI
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1ccc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of 150 mg (0.223 mmol) 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 8 ml THF, 0.289 ml tert-butyllithium (1.7M in pentane) is slowly added at −78° C. This mixture is stirred for 1 h at −78° C. then 54 μl (0.669 mmol) ethyl iodide is added. The reaction mixture is warmed to room temperature and stirring is continued for 12 h. The reaction mixture is cooled to room temperature, poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 25 mg of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:7])=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=3)[CH2:14][CH2:15]2)=[O:7])=[CH:16][CH:17]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: O=C(NCC1CCNCC1)c1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CN2CCC(CNC(=O)c3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-hydroxy-N-piperidin-4-ylmethyl-benzamide (EXAMPLE 154, Step 1) (50 mg, 0.21 mmol) in MeOH (3 mL) was added 4-methylbenzaldehyde (25 mg, 0.21 mmol) and sodium cyanoborohydride (40 mg, 0.64 mmol). The reaction mixture was stirred at rt for 15 h, concentrated and purified by reverse-phase HPLC. (M+H)+=339.2
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)([OH:12])[CH3:11].O>C(Cl)Cl>[OH:12][C:10]([C:13]1[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=1)([CH3:11])[CH2:9][NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(O)(CN)c1ccc(I)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(I)cc1
Temperature: 0 °C
Yield: 19.4 %

Procedure:
Into a 250 mL 3 necked flask fitted with a stirrer and thermometer, was added dropwise 2-propanesulfonyl chloride (1.60 g, 0.011 mol) to 1-amino-2-(4-iodophenyl)propan-2-ol (2.77 gm, 0.01 mol) in 125 mL CH2Cl2 while stirring at 0° C. under nitrogen. The reaction was then allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the mixture was poured into H2O and the layers were separated. The organic layer was washed once with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was purified via silica gel chromatography employing the Prep. LC-2000 and eluting with a solvent of Hexane/EtOAc 3:1 to provide the intermediate title compound (744 mg, 19%) as a solid material. FDMS 382 (M*).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>C1COCC1.CO>[F:30][C:28]([F:29])([F:31])[O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:32])=[O:3])=[CH:10][CH:11]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1ccc2ccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of {6-[5-(4-trifluoromethoxy-phenyl)-pent-4-ynyloxy]-indol-1-yl}-acetic acid ethyl ester (30 mg, 67 μmol) in THF/methanol 2/1 (1.5 ml) was added 1 N aqueous LiOH solution (400 μl). The reaction mixture was stirred for 14 h at ambient temperature and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (28 mg, 67 μmol, quant.) as brown crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.CN1CCOCC1.[CH2:37]([O:41][C:42](Cl)=[O:43])[CH:38]([CH3:40])[CH3:39]>C1COCC1>[F:29][C:7]1[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:42]([O:41][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:43])[N:6]=1
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)COC(=O)NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
4-(3-Aminopropyl)-2-fluoro-1-triphenylmethylimidazole was dissolved in THF and treated with N-methylmorpholine and isobutylchloroformate. Extractive work-up followed by chromatography gave 2-fluoro-4-(3-isobutoxycarbonylaminopropyl)-1-triphenylmethylimidazole.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:14])[CH:8]=[C:9]2[S:13][CH:12]=[N:11][C:10]=12)=[O:4].[OH-].[Li+]>O1CCCC1>[F:14][C:7]1[CH:8]=[C:9]2[S:13][CH:12]=[N:11][C:10]2=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cc(F)cc2scnc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)cc2scnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a solution of 6-fluoro-benzothiazole-4-carboxylic acid methyl ester (1.97 g, 9.33 mmol) in tetrahydrofuran (30 mL) was added aqueous lithium hydroxide solution (2M, 14.0 mL, 28 mmol, 3 eq.) and then stirred, at room temperature, for 4 hr. The reaction mixture was quenched with aqueous hydrochloric acid (2M, 30 mL) and stirred for 15 min. The resulting suspension was filtered and the solid produced was washed with water and air dried to give the title compound as a grey solid (1.51 g, 82%).
Reaction SMILES: [Br:1]Br.C(OCC)(=O)C.O.[CH3:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N+:18]([O-])=O>[Fe]>[Br:1][C:14]1[CH:15]=[C:16]([CH3:17])[C:11]([CH3:10])=[C:12]([CH:13]=1)[NH2:18]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: BrBr
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)cc(N)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
In 45.3 g of 2,3-dimethylnitrobenzene was uspended 0.6 g of iron powder, followed by adding dropwise thereto 57.5 g of bromine on an oil bath at 75° C., and the resulting mixture was stirred at the same temperature for 3.5 hours. The reaction mixture was cooled to room temperature and then added to a mixed solvent of 200 ml of ethyl acetate and 200 ml of water, and the organic layer was separated. The organic layer obtained was washed with an aqueous sodium thiosulfate solution and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in 200 ml of methanol and 200 ml of concentrated hydrochloric acid, followed by adding thereto 50.0 g of iron powder by portions, and the resulting mixture was stirred at 70° C. for 30 minutes. The reaction mixture was cooled to room temperature and then added to a mixed solvent of 300 ml of ethyl acetate and 300 ml of water, and the pH was adjusted to 10 with potassium carbonate, after which the organic layer was separated. The organic layer obtained was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain 22.6 g of 5-bromo-2,3-dimethylaniline as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[NH2:32][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](NC(=O)C(C)C)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(=O)N[C@H]1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of N-[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]-2-methylpropanamide (0.031 g, 0.086 mmol) and ammonium acetate (0.066 g, 0.86 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.21 mL, 0.21 mmol). The reaction was heated at 65° C. overnight and then cooled to room temperature. The mixture was quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H26ClN4O (M+H)+: m/z=361.2; Found: 361.2.
Reaction SMILES: C(S([C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]2[CH2:16][CH2:17][F:18])=[CH:8][C:7]=1[F:25])(=O)=O)C.[C:26]([N:29]([CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:30])(=[O:28])[CH3:27].C(N(CC)CC)C>C(O)C>[C:26]([N:29]([CH:31]1[CH2:35][CH2:34][N:33]([C:6]2[N:15]=[C:14]3[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]3[CH2:16][CH2:17][F:18])=[CH:8][C:7]=2[F:25])[CH2:32]1)[CH3:30])(=[O:28])[CH3:27]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: CCOC(=O)c1cn(CCF)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cn(CCF)c2nc(N3CCC(N(C)C(C)=O)C3)c(F)cc2c1=O
Yield: 82.3 %

Procedure:
A mixture of ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (26.7 g) obtained according to the Reference Example 2, 3-(N-acetyl-N-methylamino)pyrrolidine (15.5 g), triethylamine (10.0 ml), and ethanol (300 ml) was heated under reflux for one hour. The reaction mixture was concentrated to a half volume under reduced pressure. To the mixture was added water (200 ml), and the resulting crystals were collected by filtration, and recrystallized from chloroform-ethanol to give 24.8 g of ethyl 7-[3-(N-acetyl-N-methylamino)-1-pyrrolidinyl]-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate melting at 227°-229° C. A solution of the above ester (20.0 g) in 20% hydrochloric acid (120 ml) was heated under reflux for 3 hours. After the reaction was completed, water (60 ml) and ethanol (120 ml) were added to the reaction mixture, and the resulting crystals were collected by filtration. The crystals were dissolved in hot water (800 ml) and the solution was treated with charcoal. The filtrate was adjusted to pH 8.5-9.0 by addition of 27% aqueous ammonia. The crystals were collected by filtration, washed with water, and dried to give 11.0 g of the compound 4, m.p. 243°-245° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]2=[O:19])(=O)=O.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>CCN(CC)CC.CN(C=O)C.O.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>[CH3:17][C:12]1([CH3:18])[CH:11]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[C:10](=[O:19])[C:9]2[C:14](=[CH:15][CH:16]=[CH:7][CH:8]=2)[S:13]1
Reactant: CC1(C)CC(=O)c2cc(OS(=O)(=O)C(F)(F)F)ccc2S1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)Sc2ccccc2C(=O)C1C#C[Si](C)(C)C
Temperature: 95 °C
Yield: 90.9 %

Procedure:
A solution of 2,2-dimethyl-4-oxo-thiochroman-6-yl trifluoromethanesulfonate (2.88 g. 8.50 mmol) in 10 mL Et3N and 20.0 mL DMF was sparged with argon for 10 minutes. To this solution was added trimethylsilylacetylene (4.15 g. 42.0 mmol) and bis(triphenylphosphine)-palladium(II) chloride (298.0 mg. 0.425 mmol). The solution was heated to 95° C. for 5 h, cooled to room temperature, and diluted with H2O. Extraction with EtOAc was followed by washing the combined organic layers, with H2O and saturated aqueous NaCl and drying over MgSO4. Concentration of the dry solution under reduced pressure and isolation of the product by column chromatography (3% EtOAc/hexanes) afforded 2.23 g (91%) of 2,2-dimethyl-trimethylsilanylethynyl-thiochroman-4-one as an orange oil. 1H NMR (300 MHz, CDCl3) δ: 8.18 (1H, d, J=1.9 Hz), 7.34 (1H, dd, J=1.9, 8.2 Hz), 7.15 (1H, d, J=8.1 Hz), 2.85 (2H, s), 1.45 (6H, s), 0.23 (9H0, s).
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:14]([F:16])([F:15])[F:17])[N:3]=1
Reactant: COC(=O)/C=C/c1ccc(C(F)(F)F)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (E)-methyl 3-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acrylate (Gray, M.; Andrews, I. P.; Hook, D. F.; Kitteringham, J.; Voyle, M. Tet. Lett. 2001, 41, 6237-6240.) (150 mg, 0.61 mmol) in MeOH (2.0 mL) was added 1M NaOH (aq.) (1.8 mL). The reaction mixture was stirred for 2 h at 40° C. The volatiles were then evaporated and the remaining water phase neutralized with 1M HCl (aq). The title compound (141 mg, 0.61 mmol, quant.), which precipitated as a white solid, was filtered off and dried under vacuum at 45° C. This material was used directly in the next step without further purification.