Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:8]C)(=O)[CH2:3][C:4]([CH3:6])=[O:5].[F:10][C:11]([F:22])([F:21])[C:12]([CH3:20])=[CH:13]C(OC(C)C)=O>C(O)C>[CH3:13][C:12]1([C:11]([F:22])([F:21])[F:10])[CH2:20][C:2](=[O:8])[CH2:3][C:4](=[O:5])[CH2:6]1
Reactant: CC(=CC(=O)OC(C)C)C(F)(F)F
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CC1(C(F)(F)F)CC(=O)CC(=O)C1

Procedure:
0.64 g of sodium were introduced into 40 ml of ethanol, and 3.23 ml of methyl acetoacetate and 4.9 g of isopropyl 4,4,4-trifluoro-3-methylbut-2-enoate were introduced, and the mixture was heated at the boil for 18 hours. After the mixture has been partitioned between dilute hydrochloric acid and ethyl acetate, the mixture is evaporated. The remaining unpurified methyl 2-methyl-4,6-dioxo-2-trifluoromethylcyclohexanecarboxylate is hydrolysed in a mixture of methanol and water at boiling point in the presence of 9.1 g of sodium hydroxide. The mixture is subsequently acidified with hydrochloric acid and extracted with fresh ethyl acetate. After recrystallization (ethyl acetate), pure 5-methyl-5-trifluoromethylcyclohexane-1,3-dione of melting point 150-152° C. is obtained.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[CH:15][C:14]=12.C(N(CC)CC)C>CN1CCCC1=O>[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:23]=[CH:24][C:25]([CH:28]4[CH2:33][CH2:32][N:31]([C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)=[CH:15][C:14]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Reactant: O=C(Cl)N1CCCCC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCN(C(=O)N3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of piperidine-1-carbonyl chloride (0.033 g, 0.224 mmol) in N-methyl-2-pyrrolidinone (1 mL) was treated with N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)-benzamide (0.05 g, 0.150 mmol) and triethylamine (0.042 ml, 0.299 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was purified by reverse-phase HPLC to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (t, J=5.9 Hz, 1H), 8.84 (d, J=7.0 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.91-7.84 (m, 2H), 7.76 (s, 1H), 7.50-7.44 (m, 1H), 7.42-7.36 (m, 2H), 4.67 (d, J=5.8 Hz, 2H), 3.71-3.62 (m, 2H), 3.16-3.10 (m, 4H), 2.89-2.68 (m, 3H), 1.81-1.72 (m, 2H), 1.68-1.44 (m, 8H); MS (ESI(+)) m/e 446 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[CH:15]=[CH:16][C:17]([N+:31]([O-])=O)=[C:18]([CH:20]=[C:21]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]#[N:23])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1.[NH4+].[Cl-].CO>[Zn].C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[CH:19]=[C:18]3[C:17](=[CH:16][CH:15]=2)[N:31]=[C:22]([NH2:23])[C:21]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:20]3)[CH:10]=[CH:11][CH:12]=1
Reactant: N#CC(=Cc1cc(Sc2cccc(C3OCCCO3)c2)ccc1[N+](=O)[O-])CC1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc2ccc(Sc3cccc(C4OCCCO4)c3)cc2cc1CC1CCOCC1

Procedure:
In four μwave tubes, 3-[5-(3-[1,3]dioxan-2-yl-phenylsulfanyl)-2-nitro-phenyl]-2-(tetrahydro-pyran-4-ylmethyl)-acrylonitrile (0.175 g, 0.375 mmol, each tube), Zn (2.5 g, 0.038 mol, each tube), NH4Cl (0.8 g, 0.015 mol, each tube), CH3OH (3 mL, in each tube) and THF (3 mL, in each tube) was reacted via μwave at 300W, 150° C. for 11 min. The resulting mixtures were combined and then filtered through Celite®. The solvent was removed to yield a residue which was purified by reverse phase column chromatography (10-90% CH3CN/H2O/0.1% TFA) to yield a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-carboxylate (5.8 g, 15.54 mmol), 4-(trifluoromethoxy)phenylboronic acid (8.2 g, 38.85 mmol), potassium carbonate (5.4 g, 38.85 mmol), [1′1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with methylene (1:1) (4.41 g, 5.44 mmol) in dioxane-water (10:1, 154 mL) was stirred at 70° C. for two days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and brine, and then concentrated to an oil. This residue was crystallized from ethyl ether to afford the title compound as an off-white solid, m.p. 77-78° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.78 (d, 2H, J=8.70 Hz), 7.67 (d, 1H, J=8.85 Hz), 7.61 (dd, 1H, J=8.70 and 1.68 Hz), 7.44 (s, 1H), 7.42-7.41 (m, 3H), 7.06 (d, 2H, J=7.94 Hz), 6.94 (d, 2H, J=8.09 Hz), 5.83 (s, 2H), 4.29 (q, 2H), 2.21 (s, 3H), and 1.30 ppm (t, 3H).
Reaction SMILES: CN(CCN(C)C)C.[Li]CCCC.[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:22]=[N:23][C:24]([Cl:27])=[CH:25][CH:26]=1)([CH3:17])([CH3:16])[CH3:15].[I:29]I>CCOCC>[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:22]=[N:23][C:24]([Cl:27])=[CH:25][C:26]=1[I:29])([CH3:17])([CH3:15])[CH3:16]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of TMEDA (1.45 g, 12.5 mmol) in dry Et2O (30 mL) was added dropwise n-BuLi (5.0 mL, 12.5 mmol) at −78° C. The mixture was stirred for 0.5 h at −78° C. A solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (1.14 g, 5.0 mmol) in dry Et2O (10 mL) was added dropwise to the reaction mixture at −78° C. and the resultant mixture was continued to stir for 1 h at −78° C. A solution of I2 (1.52 g, 6.0 mmol) in dry Et2O (10 mL) was added dropwised at −78° C. The mixture was continued to stir for 1 h at this temperature. The reaction was quenched with saturated aqueous NH4Cl. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a residue, which was purified by column (petroleum ether/ethyl acetate=10/1) to obtain (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (1.75 g, 30%). 1H NMR (400 MHz, CDCl3) δ 8.95 (br s, 1H), 7.73 (s, 1H), 6.64 (br s, 1H), 1.54 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(CC(=O)O)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 100 °C
Yield: 55.3 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.6 g, Example 33), 4-bromophenylacetic acid (0.624 g), 2M aqueous sodium carbonate (2.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.5 g) in ethanol (15 ml). The reaction mixture was heated at 100° C. for 3 hours. After cooling, the solution was concentrated under reduced pressure. Water was added to the residue then washed with diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid and washed with diethyl ether. The aqueous layer was neutralised to pH 7.11 and the solid filtered off washing with diethyl ether to give the title compound as a solid (0.431 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[CH:24]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:27]([C:26]4[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][C:25]=4[N:32]4[N:36]=[CH:35][CH:34]=[N:33]4)=[O:28])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Reactant: COc1ccc(C(=O)O)c(-n2nccn2)c1
Product: COc1ccc(C(=O)N2CC3CN(c4cnc5cc(F)c(F)cc5n4)CC3C2)c(-n2nccn2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and Intermediate 54 in the last step MS (ESI): mass calculated for C24H21F2N7O2, 477.17; m/z found 478.1 [M+H]+. 1H NMR (500 MHz, CDCl3) 8.26 (d, J=14.7, 1H), 7.71 (s, 2H), 7.63 (dd, J=10.6, 8.5, 1H), 7.49 (t, J=7.1, 1H), 7.41 (dd, J=11.4, 8.0, 1H), 7.33 (t, J=6.7, 1H), 6.95 (dt, J=8.4, 4.2, 1H), 3.99-3.85 (m, 5H), 3.83-3.69 (m, 2H), 3.70-3.57 (m, 1H), 3.52 (dd, J=11.0, 3.5, 1H), 3.44 (s, 1H), 3.19-3.09 (m, 1H), 3.09-2.97 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.CS(O)(=O)=O.[N-:17]=[N+]=[N-].[Na+].[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:17][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(F)ccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
To 25.0 g (166.15 mmol) 5-fluoroindanone in a 3 L flask equipped with a mechanical stirrer was added 280 ml dichloromethane and 200 ml methanesulfonic acid. The mixture was cooled to 0° C. and 15.15 g (233.1 mmol) sodium azide was added in portions over 20 minutes. The mixture was stirred at 0° C. for 2 h, then 490 ml 20% aqueous sodium hydroxide was added dropwise over 30 minutes. The layers were separated and the organic phase dried over MgSO4 and concentrated. Purification by column chromatography eluting with ethyl acetate/hexanes provided 16.76 g (61%) of the desired 6-fluoro-3,4-dihydroisoquinolinone isomer.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O[C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][C@H:29]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:26]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 25.2 %

Procedure:
To a solution of 4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol (640 mg, 1.76 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (513 mg, 2.64 mmol) and triphenylphosphine (692 mg, 2.64 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (666 mg, 2.64 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 240 mg (yield: 25.2%)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>O>[NH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCCCN
Reactant: CN(C)c1ccc(-c2cc3ncccc3c(Cl)n2)cc1
Solvent: O
Product: CN(C)c1ccc(-c2cc3ncccc3c(NCCCN)n2)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 5-chloro-7-(4-dimethylaminophenyl)-[1,6]naphthyridine (Example 2) (10 mg, 0.035 mmol) and 1,3-diaminopropane (200 microL, 2.4 mmol) was stirred at 100 ° C. for 5 hours. After cooling to room temperature, water was added and the resulting mixture was extracted with dichloromethane (2×3 mL). Purification by preparative thin layer chromatography afforded the title compound as a yellow film (8.5 mg). 1H NMR (CDCl3, 400 MHz) δ 8.85 (dd, 1H), 8.10 (d, 2H), 8.07 (d, 1H), 7.50 (s, 1H), 7.21 (dd, 1H), 6.81 (d, 2H), 3.87 (t, 2H), 3.02 (s, 6H), 2.97 (t, 2H), 1.90 (quint, 2H); MS (m/e) calculated for C19H23N5 321.2, found 322.4 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[CH:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1.[Cl-].[NH4+]>[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[C:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(C)C2C
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(C)C2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of diisopropylamine (3.0 mL, 22 mmol) in THF (34 mL) at 0° C. under nitrogen was added n-BuLi (8.8 mL, 22 mmol, 2.5 M in hexane). A solution of ethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6-carboxylate (4.8 g, 20 mmol) in THF (46 mL) was added to the mixture and the reaction was stirred at 0° C. for 1 hour. Ethyl chloroformate (2.3 mL, 24 mmol) in THF (3 mL) was then added and the mixture was stirred for 15 minutes. The reaction mixture was diluted with saturated ammonium chloride and partitioned between water and ether. The aqueous layer was extracted with ether (2×) and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ether/hexane (15/85) to afford 3.9 g (63%) of diethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([Cl:18])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(Trifluoromethyl)phenyl]acetic acid (4.1 g, 20.1 mmol) was dissolved in tetrahydrofuran (20 mL), and oxalyl chloride (2.1 mL, 24.5 mmol) and N,N-dimethylformamide (5 μL) were added. The reaction mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to give [3-(trifluoromethyl)phenyl]acetyl chloride. To a solution of 3-amino-4-fluorophenol (2.43 g, 19.1 mmol) in tetrahydrofuran (20 mL) was added a suspension of sodium hydrogen carbonate (2.41 g, 28.6 mmol) in water (30 mL), and the mixture was vigorously stirred at room temperature. A solution of [3-(trifluoromethyl)phenyl]acetyl chloride produced above in tetrahydrofuran (10 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 min. Ethyl acetate (100 mL) was added to the reaction mixture to separate the aqueous layer. The organic layer was washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the obtained solution was purified by silica gel chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (5.84 g, 98%) as a pale-brown solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[H-].[Na+].CI.[C:36](OCC)(=O)C>C1COCC1>[CH3:36][N:23]([C@@H:4]([CH2:3][CH:2]([CH3:31])[CH3:1])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (200 mg, 0.470 mmol) (Preparation description in Example 2, Part D) in THF (4 mL) at 0° C. was added NaH (37.6 mg, 0.940 mmol). The reaction was stirred at 0° C. for 30 min then MeI (0.044 mL, 0.705 mmol) was added. The reaction mixture was then stirred at 0° C. for 16 h. The reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers and washed with brine (1×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether: ethyl acetate mobile phase to afford (S)-tert-butyl methyl(4-methyl-1-(6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)pentan-2-yl)carbamate (180 mg, 0.409 mmol, 87% yield) as a yellow solid. LC/MS (ESI) m/e 440.4, [(M+H)+, calcd for C25H34N3O4, 440.3]; LC/MS retention time (method I): tR=2.4 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:17])[C:6]([C:18]([O:20]C(C3C(=O)C4C(=C(OC)C(F)=CC=4)N(C4CC4)C=3)=O)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.B(O)(O)O.[NH:44]1[CH2:47][CH:46]([NH:48][CH2:49][C@H:50]2[O:54][C:53](=[O:55])[N:52]([C:56]3[CH:57]=[CH:58][C:59]4[S:64][CH2:63][C:62](=[O:65])[NH:61][C:60]=4[CH:66]=3)[CH2:51]2)[CH2:45]1>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N:44]4[CH2:47][CH:46]([NH:48][CH2:49][C@H:50]5[O:54][C:53](=[O:55])[N:52]([C:56]6[CH:57]=[CH:58][C:59]7[S:64][CH2:63][C:62](=[O:65])[NH:61][C:60]=7[CH:66]=6)[CH2:51]5)[CH2:45]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C1CSc2ccc(N3C[C@@H](CNC4CNC4)OC3=O)cc2N1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)OC(=O)c3cn(C4CC4)c4c(OC)c(F)ccc4c3=O)cn(C3CC3)c12
Agent: OB(O)O
Solvent: CC(=O)O
Product: COc1c(N2CC(NC[C@@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)C2)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
The title compound was prepared in analogy to Example 2, starting from 1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid anhydride with boric acid (1:1) and with acetic acid (1:2) (101 mg; prepared according to WO 2010/056633) and 6-[(5R)-5-[(3-azetidinylamino)-methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one (prepared according to WO 2008/126034; 167 mg). At the end of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was taken up in MeOH and treated with 1N HCl in MeOH (3 ml) for 15 min. The reaction mixture was diluted with water (2 ml) and the solid was filtered off. The org. phase was concentrated under reduced pressure and purified by CC (DCM/MeOH 9:1 followed by DCM/MeOH 9:1+1% AcOH), affording after evaporation and stirring of the residue with MeOH/TBME a beige solid.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:17])[N:5]([CH3:16])[C:6](=[O:15])[N:7]([CH3:14])[C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].[CH3:18]N>CO>[CH3:18][NH:2][C:1]1[N:11]=[CH:10][N:9]=[C:8]2[N:7]([CH3:14])[C:6](=[O:15])[N:5]([CH3:16])[C:4](=[O:17])[C:3]=12
Reactant: CN
Reactant: CN(C)C=Nc1c(C#N)c(=O)n(C)c(=O)n1C
Solvent: CO
Product: CNc1ncnc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
0.47 g of the above compound 15 was dissolved in 11 ml of methanol and then 1 ml of methylamine (30% methanol solution) was added dropwise thereto. After stirring overnight at room temperature, the crystalline precipitate was filtered off and recrystallized from ligroin to give 0.38 g of 5-methylamino-1,3-dimethylpyrimido[4,5-d]pyrimidine-2,4-dione (compound 16) in a 85% yield.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:22][CH:23]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cnn(C)c1
Reactant: Nc1ccc(F)cn1
Product: Cc1ccc(Nc2cnn(C)c2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 6-Methyl-3-(1-methyl-1H-pyrazol-4-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-fluoropyridine in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=327.1 (M+H+).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:18]>CO>[NH2:18][C@H:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C[C@H](N)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Ru(OAc)2((R)-dm-binap) (13.4 mg, 0.0140 mmol), methyl benzoylacetate (500 mg, 2.806 mmol), ammonium acetate (216 mg, 2.806 mmol) and methanol (2.5 mL) were placed in a 100 mL stainless steel autoclave under nitrogen atmosphere, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled down to room temperature and further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate/triethylamine=50/50/5-0/95/5) to give methyl (3S)-3-amino-3-phenylpropionate (201 mg) as a colorless oil in 40.0% yield. The enantiomeric excess of the product was determined to be 96.7% ee by HPLC analysis using a SUMICHIRAL OA-4100R column (available from SUMIKA CHEMICAL ANALYSIS SERVICE LTD.) after conversion into methyl (3S)-3-(4-nitrobenzoylamino)-3-phenylpropionate.