Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].C[O-].[Na+].Cl>COC(C)(C)C.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13](=[O:15])[CH2:14][C:18](=[O:19])[C:17]([F:24])([F:23])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1
Reactant: CC(=O)c1ccc(-c2ncco2)c(Cl)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: O
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2ncco2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.1 %

Procedure:
To a solution of 1-[3-chloro-4-(1,3-oxazol-2-yl)phenyl]-1-ethanone (1.89 g, 8.572 mmol) in t-butyl methyl ether (100 mL) were added ethyl trifluoroacetate (1.1 mL, 9.38 mmol) and 28%wt sodium methoxide in MeOH (2.6 ml) at 0° C. and stirred at room temperature for 4 hours. Water (100 mL) was added to the mixture, the mixture was neutralized with 2N HCl, extracted with ethyl acetate (100 mL×2) and dried over MgSO4. Removal of the solvent, gave a title compound (3.08 g).
Reaction SMILES: [CH3:1][CH:2]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3][NH:4][C@H:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([N:14]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH2:10]1)=[O:7].[CH3:42]I>>[CH3:1][CH:2]([N:34]([CH3:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3][NH:4][C@H:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([N:14]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15](=[O:19])[CH:16]([CH3:17])[CH3:18])[CH2:10]1)=[O:7]
Reactant: CC(CN[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC[C@H](N(C(=O)C(C)C)C2CCCCC2)C1)NC(=O)OC(C)(C)C
Reactant: CI
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NCC(C)N(C)C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Example 128 using (2R)-2-{methyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in the above Step A and methyliodide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[O:36][N:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[O:36][N:35]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)on3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionic acid tert.-butyl ester (Example K15) according to the general procedure M. Obtained as a yellow foam (232 mg).
Reaction SMILES: [CH2:1]([C:16]([OH:18])=O)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[CH2:19]([NH2:34])[CH:20]=[C:21]([CH2:23][CH2:24][CH:25]=[C:26]([CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Na+].[Cl-]>CN(C)C=O.O.C(N(CC)CC)C>[CH2:19]([NH:34][C:16]([CH2:1][CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH3:9])[CH3:4])=[O:18])[CH:20]=[C:21]([CH2:23][CH2:24][CH:25]=[C:26]([CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC(=O)O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCN
Agent: [Cl-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)=CCCC(C)=CCNC(=O)CC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a mixture of farnesyl carboxylic acid (7.15 g) and farnesylamine (6.95 g) in 20 ml of dimethylformamide was added at 0° C. to a solution of diphenylphosphorylazide (7.62 g) in 7 ml of dimethylformamide. Next, to this mixture was added a solution of triethylamine (3.20 g) in dimethylformamide (3 ml). The reaction mixture was kept at room temperature overnight and poured into water (900 ml). After adding table salt, this mixture was extracted with ethyl acetate. The organic phase was worked up as usual manner and gave pale yellow oil. This material was purified by silica gel chromatography by using a mixture of methanol:benzene (2:1) as the eluent and gave 11.20 g of the titled compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[C@@H:3]1[CH2:14][OH:15].[ClH:16].C[C@H]1CCN[C@@H]1CO>>[ClH:16].[OH:15][CH2:14][C@@H:3]1[C@@H:2]([OH:1])[CH2:6][CH2:5][NH:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Agent: C[C@H]1CCN[C@@H]1CO
Agent: Cl
Product: OC[C@H]1NCC[C@@H]1O

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate using the methods used to prepare [(2S,3S)-3-methyl-2-pyrrolidinyl]methanol hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 1 H) 2.0 (m, 1H) 2.5 (m, 2 H) 3.2 (m, 2 H) 3.3 (m, 1 H) 3.5 (m, 1 H) 3.6 (m, 1 H) 4.1 (m, 1 H) 8.7 (s, 1 H) 9.5 (m, 1 H). ES+=117.97.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][C:14]([C:18]([CH3:23])([CH3:22])C(O)=O)([OH:17])[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:31])C=CC=CC=1.C([N:43]([CH2:46]C)CC)C.C1(C)C=CC=CC=1>ClCCl>[CH3:23][C:18]1([CH3:22])[C:14]2([CH2:13][CH2:12][N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH2:16][CH2:15]2)[O:17][C:46](=[O:31])[NH:43]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC(C)(C(=O)O)C1(O)CCN(C(=O)OCc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1(C)NC(=O)OC12CCN(C(=O)OCc1ccccc1)CC2

Procedure:
A mixture of 2-(1-carbobenzyloxy-4-hydroxypiperidin-4-yl)-2-methylpropionic acid, 1.29 g diphenylphosphoryl azide, 0.47 g of triethylamine, and 50 ml toluene is heated at reflux for 18 hours. Evaporation of solvent gives a residue which is taken up in 125 ml dichloromethane and is washed with 50 ml 1 N hydrochloric acid and 50 ml, 5% sodium bicarbonate. Evaporation of the solvent followed by trituration with diethyl ether affords 1.86 g 4,4-dimethyl-8-carbobenzyloxy-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 208°-209°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2)=[CH2:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[O:13]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C=Cc1ccc2c(=O)[nH]ncc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(=O)n(CC(=O)OCC)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a stirred solution of 6-vinylphthalazine-1(2H)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs2CO3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min Ethyl bromoacetate (0.48 g, 2.90 mmol) was added to the reaction mixture at RT and the reaction was stirred for 8 h at RT. The reaction mixture was diluted and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine solution (2×). The separated ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.34 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.56 (d, J=10.8 Hz, 1H), 4.92 (s, 2H), 4.19 (m, 2H), 1.23 (m, 3H). ESIMS m/z 259.10 ([M+H]+); IR (thin film) 1750, 1660 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:22])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc2c(cc1NC(=S)Oc1ccccc1)CCCC2
Product: COc1nc2c(cc1NC(=S)N1CCN(c3cc(C)cc(C)c3)CC1)CCCC2
Yield: 54 %

Procedure:
Phenyl N-(2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]3[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=3)[CH:5]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1ccnn1C
Yield: 81.1 %

Procedure:
4-Methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.291 g, 1.43 mmol) was treated with 4-chlorophenyl isocyanate (0.247 g, 1.57 mmol, 1.1 equiv.) in CH2Cl2 (5 mL), in a similar manner as described in Example 1.2 to afford Compound 75 (0.415 g, 1.16 mmol, 81%) as a white solid. LCMS m/z (%)=357 (M+H). 1H NMR (400 MHz, acetone-d6) δ: 8.21 (s, 1H), 8.07 (s, 1H), 7.58 (dd, J=2.8, 8.9 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.44 (d, J=2.7 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.9 Hz, 1H), 6.20 (d, J=1.8Hz, 1H), 3.81 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>C1COCC1>[C:12]1([C:11]2[O:5][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[N:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino benzoic acid (10 mmol) in THF was added benzoyl chloride (2.8 g, 20 mmol) followed by pyridine (1.58 g, 20 mmol). The mixture was stirred for 1 h at room temperature. The 2-phenyl-benzo[d][1,3]oxazin-4-one formed was filtered and the residue was washed with water and dried in vaccuum desiccator.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(CC)CC)C.[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>CCCCCC.CCOC(C)=O>[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][N:44]([C:11]([NH:5][CH2:4][C:3]4[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=4[Cl:1])=[O:12])[CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: NCc1ccccc1Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Cl)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
2-Chlorobenzylamine (60 μL, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol), triethylamine (238 μL, 1.7 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (124 mg, 0.5 mmol) are treated according to method D delivering 147 mg of the product as a pale yellow solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:40](Cl)(=[O:43])[CH2:41][CH3:42].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:40](=[O:43])[CH2:41][CH3:42])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 56.5 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (70.8 mg, 0.12 mmol) in dichloromethane (1 mL) was added propanoyl chloride (11.5 mg, 0.12 mmol). Triethylamine (50 mg, 0.50 mmol) was added and the resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 42.4 mg (56%) of the title compound as off white solid. MS (ES) m/e 625.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:19]1([C:26](=[O:28])[CH3:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([N:22]2[CH2:23][CH2:24][CH2:25][N:19]([C:26](=[O:28])[CH3:27])[CH2:20][CH2:21]2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: CC(=O)N1CCCNCC1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCCN(c2cnc(N)c(-c3nc4ccc(C)cc4[nH]3)n2)CC1
Temperature: 190 °C
Yield: 56.3 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (100 mg, 0.3288 mmol) and 1-(1,4-diazepan-1-yl)ethanone (701 mg, 4.932 mmol) in NMP (200.0 μL) was heated at 190° C. in the microwave for 2 hours. The reaction mixture was partitioned between DCM and water and the organics separated and concentrated to dryness. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound (67.7 mg, 54% Yield). 1H NMR (400.0 MHz, DMSO) d 1.80-1.94 (2H, m), 1.78 (3H, s), 2.43-2.46 (3H, s), 3.40 (2H, m), 3.63-3.83 (5H, m), 3.92 (1H, m), 7.04-7.11 (3H, m), 7.38-7.59 (2H, m), 7.90 (1H, m), 12.37 (1H, m) ppm; MS (ES+) 366
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O)[CH3:4].[BH4-].[Na+]>>[CH2:3]([O:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][CH2:1][NH2:2])[CH3:4]
Reactant: CN
Reactant: CCOc1c(C=O)cccc1C(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1c(CCN)cccc1C(C)C
Reaction time: 72 h
Yield: 94 %

Procedure:
A solution of methylamine (30 mL of a 2.0 M solution, 60 mmol) was added to 2-ethoxy-3-isopropylbenzaldehyde (1.49 g, 7.75 mmol) and the mixture was stirred for 72 h. The solution was concentrated under reduced pressure. The residue was dissolved in EtOH (30 mL) and treated with NaBH4 (0.293 g, 7.75 mmol). After stirring for 18 h, the reaction mixture was concentrated under reduced pressure and then dissolved in 1 N NaOH (30 mL). The mixture was extracted with Et2O (3×50 mL). The combined organics were collected, washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (1.51 g, 94%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.21-7.13 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 3.79 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 3.28-3.23 (m, 1H), 2.29 (s, 3H), 1.93 (br s, 1H), 1.35 (t, J=3.8 Hz, 3H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([CH:4]1[O:21][C:20]2[C:15](=[C:16]([O:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[C:14]2[C:5]1=[C:6]1[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[NH:7]1)[CH:2]=[CH2:3].[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>CC#N.O>[CH2:1]([CH:4]1[O:21][C:20]2[C:15](=[C:16]([O:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[C:14]2[C:5]1=[C:6]1[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]1[CH3:27])[CH:2]=[CH2:3]
Reactant: C=CCC1Oc2cccc(OC)c2-c2ccc3c(c21)NC(=O)C(C)(C)N3
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: C=CCC1Oc2cccc(OC)c2-c2ccc3c(c21)N(C)C(=O)C(C)(C)N3
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
To a solution of xiii (10 mg, 0.029 mmol) in CH3CN (1 mL) was added cesium carbonate (14 mg, 0.043 mmol) and methyl iodide (3.5 mL, 0.57 mmol) and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The organic extracts were combined, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography to provide compounds xv (6.2 mg, 60%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[C:33]([CH2:37][CH2:38][C:39](Cl)=[O:40])([O:35][CH3:36])=[O:34].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:39]([CH2:38][CH2:37][C:33]([O:35][CH3:36])=[O:34])=[O:40])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Oc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 3-carbomethoxypropionyl chloride (14 mg) and N,N-diisopropylethylamine (40 μl) in tetrahydrofuran (2 ml) was performed according to the method described in example 6.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:29])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:24]([CH2:25]O)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.[CH2:30]([N:32](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:29])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:24]([CH2:25][C:30]#[N:32])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCN(CC)CC
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ncccc2CO)cc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ncccc2CC#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a mixture of [2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]-3-pyridyl]methanol (2.12 g), triethylamine (1.09 g) and ethyl acetate (150 mL) was dropwise added methanesulfonyl chloride (1.24 g) under ice-cooling and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (30 mL) was added an aqueous solution (3 mL) of sodium cyanide (0.66 g) at room temperature and the mixture was stirred at room temperature for 3 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.63 g, 75%) of 2-[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13](=[O:27])[C:14]([C:24]([OH:26])=[O:25])=[CH:15][N:16]2[C@@H:20]2[CH2:22][C@@H:21]2[F:23])=[CH:11][CH:10]=1.C(OC([NH:35][C@:36]12[CH2:44][NH:43][CH2:42][C@@H:41]1[CH2:40][CH2:39][CH2:38][CH2:37]2)=O)(C)(C)C>CS(C)=O.C(OCC)(=O)C.Cl>[NH2:35][C@:36]12[CH2:44][N:43]([C:9]3[C:18]([CH3:19])=[C:17]4[C:12]([C:13](=[O:27])[C:14]([C:24]([OH:26])=[O:25])=[CH:15][N:16]4[C@@H:20]4[CH2:22][C@@H:21]4[F:23])=[CH:11][CH:10]=3)[CH2:42][C@@H:41]1[CH2:40][CH2:39][CH2:38][CH2:37]2
Reactant: CC(C)(C)OC(=O)N[C@@]12CCCC[C@H]1CNC2
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(N2C[C@@H]3CCCC[C@@]3(N)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 75 °C
Reaction time: 288 h
Yield: 33.5 %

Procedure:
Triethylamine (0.277 mL, 1.98 mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (185 mg, 0.663 mmol) were added to a solution of (1S,6S)-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (175 mg, 0.728 mmol) in dimethyl sulfoxide (1.33 mL) in a nitrogen atmosphere, and the mixture was stirred at 75° C. for 12 days. The reaction solution was diluted with ethyl acetate (45 mL) and then washed with a 10% citric acid solution (40 mL), water (40 mL), and a saturated sodium hydroxide solution (40 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). 260 mg (0.578 mmol) of the resulting residue was dissolved in concentrated hydrochloric acid (2.5 mL) under ice-cooling, and the solution was stirred at room temperature for 10 minutes. After washing with chloroform (50 mL×2), the aqueous layer was adjusted to pH 12 with a saturated sodium hydroxide solution. The basic solution was adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100 mL×2) and chloroform/methanol=10/1 (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by PTLC (developed with the lower layer of chloroform/methanol/water=7/3/1). After the fluorescent part was collected, the lower layer of chloroform/methanol/water=7/3/1 (70 mL) was added. After ultrasonic treatment, the silica gel was filtered off. The filtrate was concentrated under reduced pressure and then vacuum dried. Ethanol (1 mL), diethyl ether, and 2-propanol were added to the residue. Diethyl ether was added. After repeating ultrasonic treatment and ice-cooling several times, the mixture was stirred at 40° C. for 30 minutes. After stirring at room temperature for two hours, the crystals were collected by filtration and dried under reduced pressure to give 88.7 mg of the title compound as pale yellow crystals.