Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][NH2:11])=[CH:5][C:4]=1[CH3:12].[OH-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][NH:11][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:5][C:4]=1[CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(CN)c(C)cc1CN
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CNCc2ccccc2)c(C)cc1CNCc1ccccc1

Procedure:
Separately, 32.8 parts of 1,4-diaminomethyl-2,5-dimethylbenzene and 100 parts of 20% caustic soda were heated at 80C. and reacted by adding 50.4 parts of benzyl chloride with stirring to obtain 50 parts of 1,4-bis(benzylaminomethyl)-2,5-dimethylbenzene, to which was then admixed 30 parts of octylphenoxyhexadecylethenoxyethylsulfate soda, 10 parts of a sperm oil alcohol-ethylene oxide adduct and 10 parts of isopropanol with stirring to obtain 100 parts of an emulsifier-incorporated composition.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([B:23]2[O:27][C:26]([CH3:29])(C)C(C)(C)[O:24]2)=[C:17]([CH:20]=[CH:21][CH:22]=1)C=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:32](C)([O-:34])=[O:33]>O.C1COCC1>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]2[B:23]([OH:24])[O:27][CH:26]([CH2:29][N+:32]([O-:34])=[O:33])[C:17]=2[CH:20]=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2c(C=O)cccc2OCCCOCc2ccccc2)OC1(C)C
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To an ice cold solution of NaOH (0.68 g, 0.017 mol) in 10 ml of water was added a solution of compound D (6.8 g, 0.017 mol) dissolved in 5 ml of THF. After 15 minutes, nitromethane (0.93 ml, 0.017 mol) was added drop by drop and the content stirred at RT overnight. The THF was evaporated under reduced pressure and the contents acidified to pH-3 with 2N HCl. The aqueous layer was extracted with EtOAc several times, and the combined ethyl acetate layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of 10% EtOAc/hexane to 30% EtOAc/hexane) provided 3.7 g (55% yield) of E [7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol] 3.7 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](/[F:15])\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]1[C:16]([OH:18])=[O:17].[C:20]([C@@H:22](O)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1)#[N:21]>>[CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](/[F:15])\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[C@H:3]1[C:16]([O:18][C@H:22]([C:20]#[N:21])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1)=[O:17]
Reactant: N#C[C@@H](O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C(/F)C(=O)OCC(F)(F)F
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C(/F)C(=O)OCC(F)(F)F

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxy-4-fluoro-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-4-fluoro-benzyl (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropanecarboxylate melting at 85° C. and having a specific rotation of [α]D20 =+43°±2.5° (c=0.65% in chloroform).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([O:8]S(C)(=O)=O)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH2:20]([C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[C:34](O)[CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:29][N:30]=[C:24]2[CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[C:34]([O:8][C@@H:7]5[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]5[F:1])[CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:29][N:30]=[C:24]2[CH:23]=1)[CH3:21]
Reactant: CCc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Product: CCc1ccn2c(-c3ccc4cccc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1

Procedure:
Prepared according to the procedure for Example 16, using (cis)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate in place of tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate and 2-(7-ethylimidazo[1,2-a]pyridin-3-yl)quinolin-8-ol in place of 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol. MS APCI (+) m/z 391.2 (M+1) detected.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[N:20]1[C:21]([C:29](O)=[O:30])=[CH:22][N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(N(CC)CC)C.CN(C)C=O>[O:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([O:3][C:2]([F:18])([F:1])[F:19])[CH:5]=2)[C:29]([C:21]2[N:20]=[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]3[CH:22]=2)=[O:30])[CH2:10][CH2:11]1
Reactant: O=C(O)c1cn2ccccc2n1
Reactant: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cn2ccccc2n1)N(Cc1cccc(OC(F)(F)F)c1)C1CCOCC1
Yield: 77.6 %

Procedure:
N-[3-(Trifluoromethoxy)benzyl]tetrahydro-2H-pyran-4-amine (242 mg), imidazo[1,2-a]pyridine-2-carboxylic acid (194 mg), EDC.HCl (199 mg), HOBt (138 mg), dimethylformamide (5 mL) and triethylamine (0.33 mL) was stirred overnight at room temperature. The solvents were distilled off under reduced pressure and following extraction with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and, thereafter, the solvents were concentrated. The residue was purified by column chromatography (NH silica gel cartridge; ethyl acetate) to give the titled compound (286 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]=4)=[O:22])=[CH:16][CH:15]=3)[CH:9]=[C:10]([C:11](O)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[N:25]=4)=[O:22])=[CH:18][CH:19]=3)[CH:9]=[C:10]([C:11]([NH:37][CH2:36][C:35]([F:39])([F:38])[F:34])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: NCC(F)(F)F
Reactant: Nc1ncnn2c(C(=O)O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ncnn2c(C(=O)NCC(F)(F)F)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of 4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (30.0 mg, 0.066 mmol), 2,2,2-trifluoroethylamine (32.5 mg, 0.33 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (58.0 mg, 0.13 mmol), and 4-methylmorpholine (13.3 mg, 0.13 mmol) in DMF (2 mL) was stirred at rt overnight. The crude reaction mixture was purified directly by HPLC using a gradient of 30-90% MeCN in water to afford 16.4 mg (36%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.88 (s, 1 H), 9.73 (s, 1 H), 9.40 (t, J=6.6 Hz, 1 H), 8.34 (bs, 1 H), 8.18 (s, 1 H), 8.05 to 7.98 (m, 2 H), 7.58 (d, J=8.6. Hz, 2 H), 7.51-7.49 (m, 1 H), 7.44 (d, J=8.7 Hz, 2 H), 7.24 (s, 1H), 5.94 (bs, 1 H), 4.33-4.24 (m, 2 H); MS [M+H]+=539.0; LCMS RT=3.24 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:12][C:5]1[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: c1cncc(CN2CCNCC2)c1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.030 g, 0.14 mmol) and isopropanol (3.0 ml) was added 1-[(3-pyridyl)-methyl)-piperazine (0.028 g, 0.16 mmol) followed by diisopropylethylamine (0.03 ml, 0.18 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature, and diluted with isopropanol (2.5 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.036 g, 75%); 1H-NMR (500 MHz, DMSO-d6) 3.06 (br t, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2pyridyl), 6.95 (s, 2H, NH2), 7.36 (dd, J=7.8, 5.4 Hz, 1H, pyridine 5-H), 7.73 (dt, J=7.8, 1.8 Hz, 1H, pyridine 4-H), 8.07 (s, 1H, 6-H), 8.47 (dd, J=4.8, 1.6 Hz, 1H, pyridine 6-H), 8.51 (d, J=1.7 Hz, 1H, pyridine 2-H);
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:50])[N:29]([C@H:31]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][N:40]([CH3:42])[CH3:41])=[O:33])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH2:43]([C@@H:31]([N:29]([CH3:30])[C:28](=[O:50])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][N:40]([CH3:41])[CH3:42])=[O:33])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN(C)C[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1CN(C)C
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
At 0° C., trifluoroacetic acid (10 ml) was added to a solution of N-((1R)-1-{N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester.(1.37 g, 2.28 mmol) in dichloromethane (10 ml). The reaction mixture was stirred for 75 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (70 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 692 mg of (2R)-N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(F)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cncc(F)c3)n2)CN1

Procedure:
75 mg (0.17 mmol) of the compound of Example 44A is reacted analogously to the synthesis of the compound of Example 1 with 23 mg (0.19 mmol) of 4-imidazolinone-hydrochloride. 71 mg (82% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:10]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[O:13].C1(P(C2C=CC=CC=2)[C@@H]([C@H](P(C2C=CC=CC=2)C2C=CC=CC=2)C)C)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Rh].[Rh].[Rh].[Rh]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:10][CH:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[O:13]
Reactant: COCCCOc1cc(C=C(C=O)C(C)C)ccc1OC
Agent: [Rh]
Agent: C[C@H]([C@@H](C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [C-]#[O+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCCCOc1cc(CC(C=O)C(C)C)ccc1OC

Procedure:
A solution of 2-(3-(methoxypropoxy)-4-methoxybenzylidene) -3-methylbutanal (7.0 mmol, 74% E and 26% Z), tetrarhodium dodecacabonyl (0.14 mmol), (2R,3R)-(+)-2,3-Bis-(Diphenylphosphino)butane (R, R-Chiraphos, 0.63 mmol) and 300 ul triethylamine in toluene (75 ml) was transferred into an autoclave. The mixture was hydrogenated at 70-80° C. and 20 bar H2. After 42 hr additional tetrarhodium dodecacarbonyl (0.14 mmol) was added to complete the reaction in 62 hr. The mixture was concentrated to 3.5 g black oil and purified by flash chromatography (heptane/ethyl acetate=2/1). Yield=1.6 g yellow oil (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH:16]3[CH2:18][O:17]3)[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][S-:27].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH:16]([OH:17])[CH2:18][S:27][CH3:26])[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(C2CO2)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCC(O)C1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
To a solution of a mixture (420 mg) of tert-butyl (6RS,7RS)-6-(3,4-dichlorophenyl)-7-[(2RS)-oxiran-2-yl]-1,4-oxazepane-4-carboxylate and tert-butyl (6SR,7SR)-6-(3,4-dichlorophenyl)-7-[(2RS)-oxiran-2-yl]-1,4-oxazepane-4-carboxylate in DMF (2 mL) was added sodium thiomethoxide (114 mg), and the mixture was stirred at room temperature for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous potassium carbonate and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (130 mg) in a less polar fraction as colorless crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:12]=1.C1COCC1.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1(C)C=CC=CC=1>[CH:14]([O:13][C:11]1[CH:12]=[C:7]([B:26]([OH:27])[OH:25])[CH:8]=[N:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Oc1cncc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred, −78° C. solution of 2.5 M n-butyllithium (44.0 mL, 110 mmol) in toluene (120 mL) was slowly added a solution of 3-bromo-5-isopropoxypyridine (21.6 g, 100 mmol) in toluene (40 mL) while maintaining the temperature below −50° C. After the addition was complete, the reaction was stirred at −78° C. for 30 min. Distilled THF (40 mL) was added, and the reaction stirred for 15 min at −78° C., followed by the addition of triisopropylborate (27.7 mL, 120 mmol) in one portion. After warming to −15° C., the reaction was quenched with 1M HCl (260 mL), and stirred for one hour. The mixture was then neutralized (to pH 7) with 5 M NaOH and extracted with THF (4×100 mL). The combined extracts were dried (Na2SO4), filtered and concentrated. The residue was dissolved in 1:1 THF/MeOH, filtered, concentrated, and dissolved in warm acetonitrile. Upon cooling, the acetonitrile solution deposited a light brown powder, which was collected by filtration and vacuum dried (8.94 g, 49%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])=[CH:21][CH:20]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:5]=3[C:6](=[O:12])[NH:7]4)=[CH:24][CH:23]=2)=[O:38])=[C:28]([C:34]([F:35])([F:36])[F:37])[CH:29]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2cccc(O)c12
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4c(O)cccc4c23)cc1)c1ccc(F)cc1C(F)(F)F

Procedure:
The intermediate ethyl ester was synthesized according to the procedure described for the preparation of Example 378, method 2 using 1-chloro-7-hydroxy-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-amino-phenyl)-4-fluoro-2-trifluoromethyl-benzamide to provide 445. LC-MS (M+H=509, obsd.=509). 1H NMR (400 MHz, DMSO-d6): δ, 6.95 (m, 2H), 7.18 (m, 2H), 7.67 (m, 4H), 7.81 (m, 3H), 8.11 (d, 1H), 8.24 (s, 1H), 8.79 (d, 1H), 10.53 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[O:31]([C:33]([C:35]1[S:36][CH:37]=[CH:38][C:39]=1[S:40](Cl)(=[O:42])=[O:41])=[O:34])[CH3:32]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:40]([C:39]3[CH:38]=[CH:37][S:36][C:35]=3[C:33]([O:31][CH3:32])=[O:34])(=[O:41])=[O:42])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 2-(methoxylcarbonyl)thiophene-3-sulfonyl chloride (0.014 g, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 1001C for 30 minutes. The reaction was cooled to 25° C., diluted with ethyl acetate (40 mL), washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99:1 dichloromethane/methanol to give the title compound (15 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.69 (m, 1 H) 3.89 (s, 3 H) 4.46 (m, 2 H) 7.50 (m, 4 H) 7.65 (d, J=8.82 Hz, 1 H) 8.01 (d, J=5.15 Hz, 1 H) 8.54 (dd, J=7.91, 1.65 Hz, 1 H) 8.88 (dd, J=4.60, 1.65 Hz, 1 H) 10.74 (s, 1 H) 14.06 (s, 1 H). MS (ESI−) m/z 630 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[C:22]1[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[N:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Cl)c1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)c1cncc(Cl)n1

Procedure:
A solution of (3-chloro-benzyl)-carbamic acid tert-butyl ester (458 mg, 1.9 mmol) in DMF (20 mL) was treated with 60% NaH in mineral oil (152 mg, 3.79 mmol). The resulting mixture was stirred at room, temperature until the gas evolution ceased and 2,6-dichloro-pyrazine (282 mg, 1.89 mmol) was added. The reaction mixture was stirred at 80° C. until the LC/MS indicated the reaction was complete. The reaction mixture was cooled and poured into Ethyl Acetate and washed with H2O and brine. The organic layers were combined, dried (Na2SO4), and concentrated to yield the title compound I-4e (199 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:30].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:30])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example #71, Step B, 0.50 g, 1.249 mmol) in DCM (5 mL) and MeOH (5 mL) was added tetrabutylammonium tribromide (0.662 g, 1.373 mmol) in portions and the mixture was stirred for 30 min at ambient temperature. The reaction was quenched by addition of saturated aqueous Na2S2O3 solution (5 mL) and the pH was adjusted to 7 with saturated aqueous NaHCO3 solution. The mixture was extracted with DCM (3×20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.34 g, 57%). LC/MS (Table 1, Method 2) Rt=1.289 min.; MS m/z: 479/481 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:26]([CH:29]([CH3:31])C)=[C:27]=[O:28]>C(N(CC)CC)C>[C:27]([N:26]1[CH2:29][CH2:31][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:2]=3[Cl:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:28])[CH2:8][CH2:7][CH3:16]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccc(Cl)cc3Cl)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2,4-dichloro-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.87 (s, 1H), 8.70 (dd, 1H), 8.34 (dd, 1H), 8.21 (d, 1H), 8.13 (d, 1H), 8.01 (d, 1H), 7.82 (m, 2H), 7.73 (m, 1H), 7.63 (d, 1H), 4.00 (d, 1H), 3.6 (d, 1H), 3.24 (m, 1H), 2.92 (t, 1H), 2.59 (m, 1H), 2.17 (t, 2H), 1.47 (m, 2H), 1.43 (m, 2H), 1.18 (m, 2H), 0.82 (t, 3H). LC/MS m/z 548 (M−H)—, 560 (M+H)+