Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C:23]1[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:22]=1[F:21])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
To an oven-dried flask was added potassium ethyl malonate (3.66 g, 21.5 mmol) and freshly distilled acetonitrile (70 mL). The mixture was cooled to 10° C. to 15° C. and stirred under an atmosphere of nitrogen and to it added anhydrous magnesium chloride (2.44 g, 25.7 mmol) and triethylamine (2.05 g, 20.3 mmol). The mixture was then stirred at room temperature under nitrogen for 2.5 hours. The resultant white slurry was recooled to 0° C. and 2,4,5-trifluorobenzoyl chloride was added over a period of 15 minutes, followed by more triethylamine (0.23 g, 2.3 mmol). The mixture was then stirred at room temperature overnight under nitrogen. Acetonitrile was then removed in vacuo and toluene (30 mL) was added. The mixture was reconcentrated and more toluene (60 mL) then added. Hydrochloric acid (1.5 M, 40 mL) was cautiously added, ensuring that the temperature did not exceed 25° C., and the aqueous layer separated. The organic fraction was washed with 1.5 M HCl (2×25 mL) and water (2×25 mL), dried over MgSO4, and solvent removed in vacuo to afford 3-oxo-3-(2,4,5-trifluoro-phenyl)-propionic acid ethyl ester as a pale orange solid (2.35 g, 9.55 mmol, 94%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[OH:11])[CH:7]=[CH:8][CH:9]=1>ClCCl>[CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(OC)c1cccc(C(O)c2cccnc2)c1
Solvent: ClCCl
Product: COC(OC)c1cccc(C(=O)c2cccnc2)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 19 parts of α-[3-(dimethoxymethyl)phenyl]-3-pyridinemethanol, 36 parts of activated mangenese (IV) oxide and 280 parts of dichloromethane was stirred over weekend at room temperature. The reaction mixture was filtered over silica gel and the filtrate was filtered again over diatomaceous earth and silica gel. The filtrate was evaporated and the residue was distilled in vacuo. The desired fraction was collected, yielding 15.7 parts (82% of [3-(dimethoxymethyl)phenyl] (3-pyridinyl)methanone (intermediate 6).
Reaction SMILES: [CH2:1]([CH:8]([C:14]([NH:16][C@H:17]([C:28]1[S:29][CH:30]=[C:31]([CH2:33][CH3:34])[N:32]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:15])[C:9]([O:11]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:41](=[N:44]O)([NH2:43])[CH3:42]>C1(C)C=CC=CC=1>[CH2:33]([C:31]1[N:32]=[C:28]([C@@H:17]([NH:16][C:14](=[O:15])[CH:8]([C:9]2[O:11][N:44]=[C:41]([CH3:42])[N:43]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[S:29][CH:30]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1nc(CC)cs1
Reactant: CC(N)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)C(Cc2ccccc2)c2nc(C)no2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
Ethyl 2-benzyl-3-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoate is dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate (80 mg) and acetamide oxime (43 mg) are added and treated with 80 mg potassium carbonate and 43 mg acetamide oxime at reflux. The reaction mixture is cooled to room temperature, filtered and concentrated. The residue is chromatographed over silica to afford 0.221 g (94%) of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[N:16]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:28][CH2:27]1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: C1CCN(CCN2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCN(CCN2CCCC2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 1-(2-(1-Pyrrolidinyl)-ethyl)-piperazine (39.4 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H28N4O2: 368.2212, found 368.2217.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][C:17]([OH:19])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:6]=1[CH3:7]
Reactant: C1COCCN1
Reactant: Cc1c(Br)cnn1CC1(OCC(=O)O)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(Br)cnn1CC1(OCC(=O)N2CCOCC2)CCCCC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 174B (331 mg) in dichloromethane (10 mL) was added morpholine (174 mg), 4-dimethylaminopyridine (122 mg) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (287 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Reactant: CN1CCN(CCCCCN)CC1
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(NCCCCCN3CCN(C)CC3)nc21
Yield: 31 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1365 g (0.745 mmol) of 5-(4-methyl-piperazin-1-yl)-pentylamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v), to give 0.041 g (31%) of the title compound:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:24][N:25]=[C:26]=[O:27]>>[CH3:24][NH:25][C:26]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[C:2]([NH2:1])[N:3]=2)[CH2:23][CH2:22]1)=[O:27]
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Reactant: CN=C=O
Product: CNC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (Example 9) and methyl isocyanate (Aldrich 98%) using the procedure described in Example 12. HRMS, observed: 371.1756, calcd for M+: 371.1758.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@@H:6]([N:10]1[C:14]2=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=[C:13]2[NH:12][C:11]1=[O:20])[CH2:7][CH2:8][CH3:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:29][N:30]1[C:38]2[C:33](=[C:34]([CH3:39])[CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:40][N+](C)(C)C)=[CH:31]1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@@H:6]([N:10]1[C:14]2=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=[C:13]2[N:12]([CH2:40][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[N:30]([CH3:29])[CH:31]=2)[C:11]1=[O:20])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccc(C)nc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C)nc21
Temperature: 60 °C
Yield: 44.6 %

Procedure:
To a solution of (S)-3-(5-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-hexanoic acid ethyl ester (247 mg, 0.85 mmol) in DMF (5 mL) were added K2CO3 (234 mg, 1.7 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (438 mg, 1.27 mmol). The reaction mixture was heated to 60° C. for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 170 mg (45%) of the title compound. LCMS, M++1, m/z: 449.47.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.C(N(CC)CC)C.[CH3:54][Si:55]([C:58]#[CH:59])([CH3:57])[CH3:56]>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:59]#[C:58][Si:55]([CH3:57])([CH3:56])[CH3:54])[CH:33]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH3:13])=[N:7]2
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#C[Si](C)(C)C)c3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was purged with nitrogen and charged with compound 138 (220 mg, 0.33 mmol), dichlorobis(triphenylphosphine) palladium(II) (27.1 mg, 0.039 mmol), and anhydrous DMF (1 mL). Triethylamine (146 mg, 1.44 mmol) and (trimethylsilyl) acetylene (102 mg, 1.04 mmol) were added, and the reaction mixture was stirred for 10 h at 90° C. and an additional 8 h at 100° C. Evaporation of the reaction mixture to dryness followed by column chromatography purification afforded 63% yield of compound 139 as an off-white solid. 1H NMR (CD3OΔ) δ (ppm) 7.43-8.33 (m, 8H), 7.30 (d, 1H, J=6.6 Hz), 5.64 (s, 2H), 5.14 (bs, 1H), 3.68 (t, 2H, J=8.0 Hz), 2.81 (s, 3H), 1.59-1.64 (m, 3H), 0.94 (m, 2H), 0.32 (s, 9H), −0.09 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:30])[CH3:29])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=O)[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:30])[CH3:29])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[N:32][OH:33])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=NO)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Temperature: 25 °C
Yield: 50 %

Procedure:
100 mg of 4-stigmasta-ene-3-one (0.24 mmol) is solubilized in 10 ml of pyridine in a 50 ml flask, then 100 mg of hydroxylamine hydrochloride is added. Stirring is maintained for 24 hours at ambient temperature, and the solvent is evaporated off under reduced pressure. Water then ethyl acetate is added in order to carry out an extraction. Then the organic phase is washed with an acidified aqueous solution (HCl 1%). The ethyl acetate is evaporated off under reduced pressure. A white powder is obtained with a yield greater than 50%.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.[CH3:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:28][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][N:22]3[CH3:21])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Reactant: CN1CCCCC1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCCC1COc1ccc2nc(C#N)nc(NCC(C)(C)C)c2c1

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.3 1 mmol), 1-methyl-2-chloromethyl-piperidine hydrochloride (0.41 mmol) and potassium carbonate (7.2 mmol) are stirred in DMF (3 ml) at 80° C. for 8 hours. The solvent is evaporated, the residue is dissolved in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=9:1) as mobile phase. The product containing fractions are combined and evaporated. A pale oil with Rf=0.54 (CH2Cl2/MeOH=10:1) is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:1].[ClH:49].[CH3:24][N:23]([CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)[CH3:25]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](CN(C)C)CC4)c3n2)cc1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (72 g, 0.20 mmol) was reacted with (4-methoxyphenyl)boronic acid (45 g, 0.30 mmol) followed by formation of the dihydrochloride salt to afford the desired product (80 mg, 79%) as an orange solid: 1H NMR (300 MHz, CD3OD) δ 9.13 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.15-8.03 (m, 2H), 7.24-7.12 (m, 2H), 5.73-5.59 (m, 1H), 3.91 (s, 3H), 3.13 (d, J=6.7 Hz, 2H), 2.94 (s, 6H), 2.75 (s, 3H), 2.50-2.42 (m, 2H), 2.09-1.96 (m, 3H), 1.77-1.60 (m, 2H), 1.45-1.25 (m, 2H); ESI MS m/z 433 [M+H]+; HPLC>99% (AUC), tR=9.83 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Cc1cccc(N)c1C(=O)O
Product: Cc1cccc(N)c1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 77 %

Procedure:
Starting from 2-amino-6-methylbenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (180 mg; 77% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=O)[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(O)C.[Pt]=O>[CH3:15][CH:14]([NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCCCOCCc1ccccc1
Reactant: NCc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(CCCCOCCc1ccccc1)NCc1ccccc1
Yield: 97.4 %

Procedure:
The product of step (i) (4.16 g) and benzylamine (2.03 g) in toluene (50 ml) was refluxed using a Dean-Stark apparatus for 1 h. The toluene solution in ethanol (100 ml) was hydrogenated over pre-reduced 5% platinum oxide on charcoal (0.40 g). The reaction mixture was filtered (hyflo) and evaporated to give an oil (5.73 g) which was purified by FCC eluting with EA-CX (1:4)+1% TE to give the title compound as a yellow oil (4.51 g). T.l.c. (EA-CX 1:4+few drops TE) Rf 0.11.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2F)C1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
To 200 mg of N,N-dimethylformamide were added 65 mg 1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 45 mg of 3-methylaminoazetidine dihydrochloride, and 100 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 30 minutes. After adding 0.2 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 52 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20])=O.[OH-].[K+]>CO>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[C:11]1[CH:10]=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)c1c(F)cccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Fc1cccc(F)c1-c1ccc2cccnc2n1
Yield: 78.4 %

Procedure:
2-Aminonicotinaldehyde (2.44 g, 20 mmol) and 2,6-difluoroacetophenone (3.28 g, 21 mmol) are dissolved in 20 ml of MeOH. The mixture is treated dropwise with 3 ml of 40% KOH and, after the exothermic reaction has subsided, it is poured onto water and the residue which is deposited is filtered off with suction. 3.8 g (79% yield) of the desired product are obtained. M.p. 100°-103° C.
Reaction SMILES: [Cl-].CC(C)([O-])C.[K+].[CH:8]([CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[CH2:9].O.C1[CH2:29][O:28][CH2:27]C1>>[CH3:27][O:28][CH:29]=[CH:22][CH:19]1[CH2:18][CH2:17][CH:16]([CH:13]2[CH2:12][CH2:11][CH:10]([CH:8]=[CH2:9])[CH2:15][CH2:14]2)[CH2:21][CH2:20]1
Reactant: C=CC1CCC(C2CCC(C=O)CC2)CC1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: C=CC1CCC(C2CCC(C=COC)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methoxymethyltryphenylphosphonium chloride (17.9 g) was suspended in THF (150 mL), to which THF solution (150 mL) of potassium tert-butoxide was then added dropwise at −20° C., followed by stirring at that temperature for 0.5 hour. To the resulting mixture, THF solution (100 mL) of 4′-Vinyl-bicyclohexyl-4-carbaldehyde (9.0 g) was added dropwise at −20° C., followed by stirring at that temperature for further 1 hour, and then the temperature of the system was gradually increased to room temperature. To the resulting solution, water (300 mL) was added, followed by extracting with toluene. The organic layer was washed with water and concentrated in about 300 mL under reduced pressure, and then the resulting solution was poured into 1000 mL of n-heptane with vigorous stirring. The resulting suspension was filtered under reduced pressure, and then the filtrate was concentrated under reduced pressure. The resulting colorless yellow residue was purified by silica gel column chromatography to obtain 4-(2-methoxy-vinyl)-4′-vinylbicyclohexyl (8.9 g) in a colorless yellow oily form.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH2:13]([C:15]1[CH:16]=[C:17]([CH3:27])[C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:19][CH:20]=1)[CH3:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH2:13][CH3:14])=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Yield: 90.4 %

Procedure:
Using 4-bromo-2-cyanobenzoic acid (4.55 g) described in Preparation Example 76 and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (4.13 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (7.52 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([OH:12])[C:10]#[N:11].[CH3:13][OH:14].Cl>C(OCC)C.O1CCOCC1>[ClH:8].[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH:9]([OH:12])[C:10](=[NH:11])[O:14][CH3:13])[CH:4]=1
Reactant: CO
Reactant: N#CC(O)c1cc(Cl)ccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=N)C(O)c1cc(Cl)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 121A (640 mg, 3.48 mmol) in anhydrous diethyl ether (115 mL) at 0° C. was added MeOH (1.4 mL) and 4.0 N HCl in dioxane (3.5 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 4 h. The solvent was removed to give methyl 2-(5-chloro-2-fluorophenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (10 mL) was added H2O (10 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 121B (610 mg, 80% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.55 (d, J=4.83 Hz, 1H) 3.80 (s, 3H) 5.38 (d, J=4.83 Hz, 1H) 7.03 (t, J=9.23 Hz, 1H) 7.27-7.31 (m, 1H) 7.39 (dd, J=6.15, 2.64 Hz, 1H).