Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[N-:16]=[N+:17]=[N-:18].[Na+]>O1CCOCC1.O>[N:16]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CN=[N+]=[N-])CC1
Yield: 94.7 %

Procedure:
To a solution of the compound prepared in Example 255 (0.500 g) in dioxane (31 mL) and water (3 mL) was treated with sodium azide (0.143 g) at room temperature. The mixture was refluxed overnight. The solvent was evaporated in vacuo and the residue was distributed between ethyl acetate and water. The aqueous layer was extracted with more ethyl acetate, dried and evaporated in vacuo to obtain the title compound (0.534 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:42][C@@H:43]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C@@H:44]([OH:62])[CH2:45][C@@H:46]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH2:63]([C@H:43]([NH:42][C:7]([C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[C@@H:44]([OH:62])[CH2:45][C@@H:46]([NH:54][C:55]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:61])[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A solution of the product from Example 1F (7.0 g, 37.0 mmol), EDAC (8.5 g, 44.3 mmol), HOBT (6.0 g, 44.4 mmol), and NMM (8.0 mL, 72.8 mmol) in DMF (30 mL) was stirred at 25° C. for 1 hour, treated with a solution of the product from Example 6A (14.15 g, 36.8 mmol) in DMF (30 mL), stirred at 25° C. for 16 hours, concentrated, and partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaHCO3 and brine, and concentrated. The solution of the residue in hot methanol (20 mL) and water (10 mL) was allowed to cool and stand for 16 hours. The solids were collected by filtration and rinsed several times with hexanes, followed by drying under vacuum to give the title compound (16.97 g, 77% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[N:15]=[C:16]([C:19]([OH:21])=O)[S:17][CH:18]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[N:15]=[C:16]([C:19]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:21])[S:17][CH:18]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1cnc2[nH]cc(-c3csc(C(=O)O)n3)c2c1
Reactant: C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Cc1cnc2[nH]cc(-c3csc(C(=O)N4CCCCC4)n3)c2c1
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred solution of 82 (60 mg, 0.20 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (50 mg, 0.39 mmol), piperidine (40 mg, 0.47 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP; 180 mg, 0.35 mmol). After stirring for 1 h, the reaction mixture was filtered and purified by preparative LCMS (column LUNA 10 g C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 83 as a white solid (42 mg, 0.11 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ 0.89 (d, J=6.6 Hz, 2H), 1.63-1.76 (m, 6H), 1.86 (nonet, J=6.6 Hz, 1H), 2.56 (d, J=7.2 Hz, 2H), 3.69-3.75 (m, 2H), 4.32-4.39 (m, 2H), 7.45 (s, 1H), 7.70 (d, J=2.6 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 9.26 (s, 1H). MS (CI) m/z 369 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:36]/[O:37][CH3:38])/[C:17]([NH:19][CH:20]2[C:34](=[O:35])[N:22]3[C:23]([C:31]([OH:33])=[O:32])=[C:24](/[CH:27]=[CH:28]\[CH2:29][CH3:30])[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:36]/[O:37][CH3:38])/[C:17]([NH:19][CH:20]2[C:34](=[O:35])[N:22]3[C:23]([C:31]([O:33][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:32])=[C:24](/[CH:27]=[CH:28]\[CH2:29][CH3:30])[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC/C=C\C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h

Procedure:
Pivaloyloxymethyl iodide (162 mg, 0.67 mmole) was added at 0° C. to a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (197 mg, 0.45 mmole) and K2CO3 (93 mg, 0.67 mmole) in DMF (4 ml). The mixture was stirred at 0°-5° C. for 1 hour and diluted with ethyl acetate (30 ml). The dilute was washed with water and a saturated NaCl solution, dried over anhydrous MgSO4 and evaporated in vacuo. The residue was chromatographed on a silica gel column (5 g) with 1% methanol in CHCl3. The desired fractions were combined and concentrated in vacuo. The residue was dissolved in dioxane and lyophilized to afford 242 mg (97%) of the dioxane solvate of the title compound. Silica gel TLC: Rf 0.25 (1:1 CHCl3 -ethyl acetate). Estimated purity 85% (by HPLC). Mp. 90°-95° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>N1CCCCC1>[CH2:12]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCc1ccc(C=O)cc1
Solvent: C1CCNCC1
Product: CCCCCCCCc1ccc(C=C(C(=O)OCC)C(=O)OCC)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Diethyl malonate (1.76g, 0.011 moles), paraoctylbenzaldehyde (2.4g, 0.011 moles) and piperidine (5 drops) were heated to 98° C. for 2.5 hrs. and 45° C. for 16 hrs. The solution was heated to 100° C. for 64 hrs. The title compound was purified by silica gel chromatography. The structure assignment was supported by NMR, infrared and uv spectra and elemental analysis (360.5).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:2]1.B.[O:20]1CCCC1>>[N:13]1([CH2:12][CH2:11][CH2:10][CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1][CH:2]2[OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C1=C(CCCN2CCCCC2)c2ccccc2C1
Reactant: C1CCOC1
Agent: B
Product: OC1Cc2ccccc2C1CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[3-(3-Indenyl)propyl]piperidine (48.2 g, 0.2 M) is dissolved in 400 ml tetrahydrofuran and stirred in a nitrogen atmosphere while 400 ml 1M borane in tetrahydrofuran is added dropwise over a period of 1 hour. The mixture is left stirring overnight at room temperature. Most of the solvent is then removed in vacuo. The viscous residue is dissolved in 500 ml 95% ethanol, treated with 20 g NaOH and then 65 ml of 30% H2O2 is added dropwise over a period of 30 minutes. The mixture is stirred at room temperature for 2 hours and then heated under reflux for 21/2 hours. The mixture is then taken to near dryness in vacuo. The residue is then extracted three times with benzene. The benzene extracts are dried, filtered and the solvent is removed in vacuo leaving 57 g of oil. The VPC of this material indicates ~ 97% of purity.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])([O-:20])=[O:19].CO.C([O-])(O)=O.[Na+]>COCCO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Solvent: CO
Product: COc1cc2ncc(C#N)c(Nc3cccc([N+](=O)[O-])c3)c2cc1OC
Yield: 68.5 %

Procedure:
A solution of 0.500 g (2.00 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile and 0.332 g (2.41 mmol) of 3-nitroaniline in 6 mL of methyl cellosolve was refluxed under N2 for 8 hr. Methanol was added, followed by satd NaHCO3 (pH 8) and volatile material was removed. The residue was slurried with water, collected by filtration and dried. Recrystallization from ethanol gave 0.480 g of 6,7-dimethoxy-4-(3-nitrophenylamino)quinoline-3-carbonitrile as yellow crystals: mass spectrum (electrospray, m/e): M+H 351.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C(C3C(C)=NC(C)=CC=3)O)[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C([Li])CCC.[CH3:40][C:41]1[S:42][C:43]([C:47]([C:49]2[N:53]([CH3:54])[N:52]=[N:51][CH:50]=2)=[O:48])=[C:44]([CH3:46])[N:45]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:47]([C:43]3[S:42][C:41]([CH3:40])=[N:45][C:44]=3[CH3:46])([C:49]3[N:53]([CH3:54])[N:52]=[N:51][CH:50]=3)[OH:48])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=1
Reactant: Cc1nc(C)c(C(=O)c2cnnn2C)s1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3sc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.02 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (500 mg, 116 mmol, Intermediate 47: step d) was added THF (15 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-butyllithium (2.5 M in hexanes, 0.45 mL, 1.13 mmol) was added drop wise. The color of the solution became a dark brown. After 1 minute, (2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (275 mg, 1.24 mmol in 2 mL THF, Intermediate 48: step b) was introduced and the color of the mixture went from dark brown to greenish to light orange color all within 1 minute. The mixture was allowed to warm to 0° C. over 45 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The mixture was diluted further with water and extracted with EtOAc, 3×45 mL. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a light orange foam. The crude was chromatographed on silica gel (initially using 10% CH3CN-toluene then changing to 80% CH3CN-DCM) to afford the title compound as an off white solid. MS m/e 574.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 8.14 (d, J=2.1 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.56-7.48 (m, 3H), 7.39 (d, J=8.1 Hz, 2H), 7.21-7.13 (m, 1H), 4.44-4.64 (m, 1H), 4.34 (s, 2H), 4.09 (s, 3H), 3.91 (s, 3H), 2.57 (s, 3H), 2.36 (s, 3H), 2.13 (s, 3H). Example 79A was separated into its individual enantiomers using the following conditions: Chiralpack OD, 80% heptanes: 20% ethanol; wavelength=242 nM to provide the two enantiomers. The first eluting enantiomer was Example 79B and the second eluting enantiomer was Example 79C.
Reaction SMILES: CC(C)=O.[F:5][C:6]1[CH:13]=[CH:12][C:9]([NH:10][CH3:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)=[O:22]>O>[F:5][C:6]1[CH:13]=[CH:12][C:9]([N:10]([CH3:11])[C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=2)=[CH:8][CH:7]=1
Reactant: CNc1ccc(F)cc1
Reactant: CC(C)(C)c1cc(OC(=O)Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C(=O)Oc1ccc(Cl)c(C(C)(C)C)c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To 20 ml of acetone were added 1.25 g of 4-fluoro-N-methylaniline and 1.38 g of anhydrous potassium carbonate, and a solution obtained by dissolving 2.5 g of 3-tert-butyl-4-chlorophenyl chloroformate into 20 ml of acetone was added thereto with stirring at room temperature. After stirring for 30 minutes as it is, the mixture was refluxed with heating for 2 hours. After cooled down to room temperature, the reaction mixture was poured into cold water and the resultant product was extracted with benzene. The benzene solution was washed with water and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, and thereafter benzene was distilled off under reduced pressure. The residue was purified through a column chromatography (employing silica gel as carrier and benzene as developing solvent) and further recrystallized from ethanol to give 2.7 g of 3-tert-butyl-4-chlorophenyl N-(4-fluorophenyl)-N-methylcarbamate having melting point of 92°-94° C.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)=O>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][CH2:20][C:22]4[NH:23][CH:24]=[CH:25][N:26]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Product: c1c[nH]c(CNc2ccc3c(c2)COC(NC2CCCCCC2)=N3)n1
Yield: 73.7 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (150 mg, 0.58 mmol) and 2-formylimidazole (67 mg, 0.70 mmol) according to the procedure described for example 88. Obtained the title compound as an off-white foam (145 mg, 74%), MS (ISP) m/e=338.5 [(M−H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1>C1COCC1.CO.[Ni]>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:20][CH:21]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2
Reactant: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Cl)cc23)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Cl)cc23)cc1

Procedure:
2-(4-(6-Chloro-3-nitroquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation F, 5 g, 13.6 mmol) and Raney-Ni (2 g) were shaken in 100 mL of THF-MeOH (1:1) under 25 psi of H2 for 3 hours at RT. After completion of reaction, the catalyst was filtered-off and the filtrate was evaporated to dryness to obtain the title compound. Yield: 3.5 g (66%); 1H NMR (DMSO-d6, 300 MHz): δ 8.599 (s, 1H), 7.892 (s, 1H), 7.816-7.846 (d, 1H, J=9 Hz), 7.655-7.663 (d, 1H, J=2.4), 7.312-7349 (dd, 1H, J=8.7 Hz, 2.4 Hz), 7.233-7.262 (d, 2H, J=8.7 Hz), 6.510-6.538 (d, 2H, J=8.4 Hz), 5.457 (s, 2H), 1.598 (s, 6H); MS: m/z 337 (M+).
Reaction SMILES: [CH:1]1([C:5]([O:7]CC)=O)[CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]([CH3:13])=[O:12]>CCOCC>[CH:1]1([C:5](=[O:7])[CH2:10][C:11](=[O:12])[CH3:13])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)=O
Reactant: CCOC(=O)C1CCC1
Solvent: CCOCC
Product: CC(=O)CC(=O)C1CCC1
Reaction time: 4 h
Yield: 46.1 %

Procedure:
To a solution of NaNH2 (11.7 g, 91 mmol) in anhydrous ether (150 mL) under N2 at 30° C. was added dropwise a mixture of ethyl cyclobutanecarboxylate (19.2 g, 150 mmol) and acetone (21.75 g, 375 mmol). After addition, the reaction mixture was stirred for 4 h, then poured onto ice water with stirring. Ether was added and the unreached components were extracted into the organic phase. The clear aqueous extract was acidified to pH 5.0 with 2 N HCl, and then to pH 7.5 with Na2CO3. The solution was extracted with ether. The combined organic layers were dried (Na2SO4), filtered, and concentrated to give the crude product of 1-cyclobutyl-1,3-butanedione (9.7 g, 76%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3-d3) δ 5.42 (s, 1H), 3.66 (s, 1H), 2.11-2.23 (m, 4H), 2.02 (s, 3H), 1.93-1.99 (m, 2H).
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC(OCC)=O.C(N(CC)CC)C.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[Cl-].[Na+]>>[CH:25]1([NH:28][C:9](=[O:11])/[CH:8]=[CH:7]/[CH:1]2[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=C(O)/C=C/C1CC=CCC1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=C(/C=C/C1CC=CCC1)NC1CC1
Yield: 69 %

Procedure:
3-(3-Cyclohexenyl)-2E-propenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.5 eq, cyclopropylamine 1.6 eq, quench with 10% sodium chloride solution, yield=69%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[CH3:23][N:24]1[CH2:31][C:30]2[CH2:29][NH:28][CH2:27][C:26]=2[CH2:25]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][C:30]5[CH2:31][N:24]([CH3:23])[CH2:25][C:26]=5[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN1CC2=C(CNC2)C1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CN1CC2=C(C1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Reaction time: 8 h
Yield: 62.7 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.42 g), 3-methyl-3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide (0.47 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.63 g) were dissolved in acetonitrile (20 ml) and refluxed for 7 hours. The reaction mixture was kept at room temperature overnight and then the produced precipitate was filtered, washed with acetonitrile and methanol to give the title compound 0.36 g (yield 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:13][C:4]1[C:5]([Cl:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(Br)cc(N)c1Cl
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To stirred solution of methyl 5-bromo-2-chloro-3-nitrobenzoate (3.4 g, 11.6 mmol) in ethanol (19 mL) was added ammonium chloride (3.4 g, 57.8 mmol) dissolved in water (30 mL) and iron powder (5.16 g, 92.5 mmol). The reaction mixture was heated at 80° C. for 1 h. On completion, the reaction mixture was filtered through celite washing with ethanol and ethylacetate. The filtrate was extracted with ethyl acetate and the combined organic layers were washed with water, dried and concentrated under reduced pressure to give methyl 3-amino-5-bromo-2-chlorobenzoate (2.8 g, 92.1%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[N:22]([CH:24]([C:29]([NH:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH:1]1([NH:4][CH2:5][C:7]2[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:33])[N:22]([CH:24]([C:29]([NH:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(CNC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
Cyclopropylamine (0.15 g) and acetic acid (0.16 g) were added to a chloroform (20 mL) solution of 1-formyl-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (1.0 g) as obtained in Example 10-(5), and the mixture was stirred for 2.5 hours at room temperature. Then, sodium triacetoxyborohydride (0.89 g) was added, and the mixture was stirred for 15 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the mixture was extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=34/66→1/100) to obtain 1-[(cyclopropylamino)methyl]-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (colorless foam) (0.84 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[Cl:20]C1C=C(CC(=O)C)C=CN=1>>[Cl:20][C:11]1[CH:12]=[C:7]([C:6]2[S:5][C:4]([NH:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:3][C:2]=2[CH3:1])[CH:8]=[CH:9][N:10]=1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1ccncc1
Reactant: CC(=O)Cc1ccnc(Cl)c1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccnc(Cl)c1

Procedure:
The titled compound is prepared by an analogous procedure to (4-Methyl-5-pyridin-4-yl-thiazol-2-yl)-pyrazin-2-yl-amine (Example 1) by replacing 1-pyridin-4-yl-propan-2-one (1b) in this procedure with 1-(2-chloro-pyridin-4-yl)-propan-2-one.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:24]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[CH2:30][NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:23][C:7]2[C:8]3[C:9](=[O:22])[C:10]([C:17]([O:19]CC)=[O:18])=[CH:11][N:12]([CH3:16])[C:13]=3[CH:14]=[N:15][C:6]=2[CH:5]=1.Cl>C(O)C.O>[F:3][C:4]1[C:24]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[CH2:30][NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:23][C:7]2[C:8]3[C:9](=[O:22])[C:10]([C:17]([OH:19])=[O:18])=[CH:11][N:12]([CH3:16])[C:13]=3[CH:14]=[N:15][C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(N4CCC[C@H]4CNc4ccccc4)cc3c2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(=O)c2c3cc(N4CCC[C@H]4CNc4ccccc4)c(F)cc3ncc21
Temperature: 100 °C
Yield: 161 %

Procedure:
3.4 cm3 of 1 N aqueous potassium hydroxide was added, with stirring, to a suspension of 0.66 g of ethyl (S)-8-fluoro-4-methyl-1-oxo-9-(2-phenylaminomethylpyrrolidin-1-yl)-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in 15 cm3 of ethanol and 10 cm3 of water. The mixture was heated at about 100° C. for 24 hours. The suspension obtained was acidified by addition of 3.4 cm3 of 1 N aqueous hydrochloric acid. After cooling, the solid was dewatered and washed three times with 50 cm3 of water and dried at about 100° C. for 4 hours at a pressure of 1 kPa. 1 g of (S)-8-fluoro-4-methyl-1-oxo-9-(2-phenylaminomethylpyrrolidin-1-yl)-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of an orange-colored solid, which melted at around 250° C.