Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1
Reactant: CCC(C)n1cc(C)c2c(C(=O)O)cc(Br)cc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: CCC(C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Added sequentially to a reaction flask were 6-bromo-1-(sec-butyl)-3-methyl-1H-indole-4-carboxylic acid (1.33 g, 4.29 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (1.213 g, 6.43 mmol), 1-hydroxy-7-azabenzotriazole (0.875 g, 6.43 mmol), EDC (1.233 g, 6.43 mmol), followed by DMSO (30 mL, via syringe) and then N-methylmorpholine (1.886 mL, 17.15 mmol, via syringe). The contents were sealed and stirred at room temperature and the solids gradually dissolved. The contents were stirred at room temperature for 32 h, and then slowly diluted into 220 mL of ice-water with stirring. The contents were stirred for 10 min, and then allowed to stand for an additional 10 min. The contents were filtered and the filtered solid was washed with additional water (50 mL). The solid was then air dried for 10 min, and then in a vacuum oven at 50° C. for 23 h total. The product was collected as 1.75 g (87%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H), 1.36 (d, J=6.57 Hz, 3H), 1.77 (dq, J=10.29, 7.09 Hz, 2H), 2.12 (d, J=9.09 Hz, 6H), 2.21 (s, 3H), 4.30 (d, J=5.05 Hz, 2H), 4.43-4.56 (m, 1H), 5.86 (s, 1H), 6.99 (d, J=1.52 Hz, 1H), 7.30 (s, 1H), 7.77 (d, J=1.77 Hz, 1H), 8.25 (t, J=4.93 Hz, 1H), 11.49 (br. s., 1H); LCMS=444.1 (MH+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:36])([F:35])[C:10]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:11]=1[NH:12][C:13](=[O:28])[C:14]1[C:15](=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[C:19]([C:22]#[N:23])[C:20]=1[CH3:21])[OH:16].C(NC1C=CC=CC=1)(=O)C1C(=CC=CC=1)O.Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]([O:16][C:15]1[C:14](=[C:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][C:17]=1[C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]([NH:12][C:11]1[CH:29]=[CH:30][C:31]([C:33]#[N:34])=[CH:32][C:10]=1[C:9]([F:35])([F:36])[F:8])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C#N)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1C(F)(F)F
Agent: Cl
Agent: O=C(Nc1ccccc1)c1ccccc1O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1c(C(C)(C)C)cc(C#N)c(C)c1C(=O)Nc1ccc(C#N)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of acetic anhydride (0.1 ml.) in dry pyridine (1 ml.) is added dropwise to a stirred solution of 2'-trifluoromethyl-4',5-dicyano-3-t-butyl-6-methylsalicylanilide (0.38 g.) in dry pyridine (4 ml.) at 0°-5° C. The mixture is stirred at 0°-5° C. for 1 hour and then at room temperature until no starting salicylanilide is left, as shown by the absence of the characteristic ferric chloride positive spot, on TLC analysis on silica using chloroform as eluant. The mixture is then poured onto a mixture of ice (30 g.) and 2N hydrochloric acid solution (20 ml.). The solid which is formed is collected and washed with water. After drying, the solid is recrystallised from a mixture containing equal parts of ether and cyclohexane to give 2-O-acetyl-2'-trifluoromethyl-4',5-dicyano-3-t-butyl-6-methylsalicylanilide, m.p. 171°-172° C., having spectroscopic properties consistent with those of an O-acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].C(O[I:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)OC(=O)C)(=O)C.[F:29][C:30]([F:36])([F:35])[S:31]([OH:34])(=[O:33])=[O:32]>ClCCl>[F:29][C:30]([F:36])([F:35])[S:31]([O-:34])(=[O:33])=[O:32].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([I+:18][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1[I+]c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-bromo-4-hydroxyquinolin-2(1H)-one (11.0 g, 45.8 mmol, Intermediate 8, step a) and (diacetoxyiodo)benzene (13.4 g, 41.7 mmol) in dichloromethane (180 mL) at 0° C. was added trifluoromethanesulfonic acid (4.06 mL, 45.8 mmol) dropwise. The resulting mixture was stirred in an ice-water bath for 1 hour and at room temperature for 2 hours to receive a suspension which was filtered. The solid product was washed with dichloromethane and dried under vacuum at 50° C. for 12 hours to yield the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][CH:7]([N:21]([C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH3:22])[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.CO>[F:31][C:30]([F:32])([F:33])[C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:34]([F:36])([F:35])[F:37])[CH:27]=1)[C:23]([N:21]([CH:7]([CH:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][C:5]([OH:39])=[O:4])[CH3:22])=[O:38]
Reactant: COC(=O)CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)C(c1ccccc1)c1ccccc1

Procedure:
25 ml of 1N sodium hydroxide are added to a solution of 7.8 g (15 mmol) of 3-[N-(3,5-bis-trifluoromethyl-benzoyl)-N-methyl-amino]-4,4-diphenyl-butanoic acid methyl ester in 100 ml of tetrahydrofuran/methanol (2:1). After 5 hours the reaction mixture is concentrated by evaporation, diluted with water and rendered acidic with cold 2N hydrochloric acid. The white precipitate is filtered off, then washed with water and dried under a high vacuum at 50° C. The title compound is obtained in the form of a white solid. TLC: methylene chloride/methanol (95:5) Rf =0.14; Rt (HPLC)=19.2 min; 1H-NMR (400 MHz, d6 -DMSO, 150° C.) d 7.96 (br, 1H), 7.42-7.19 (m, 12H), 5.42 (br, 1H), 4.45 (d, 1H), 2.79 (dd, 1H), 2.72 (s, 3H), 2.37 (dd, 1H); FAB-MS (M+H)+ =510.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].C(C1C=CC([N+]([O-])=O)=C(C)C=1[N+]([O-])=O)(C)(C)C.C[C:36]([N:38]([CH3:40])[CH3:39])=O>CN(C=O)C>[C:1]([C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9](/[CH:11]=[CH:36]/[N:38]([CH3:40])[CH3:39])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(C)(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(=O)N(C)C
Agent: Cc1c([N+](=O)[O-])ccc(C(C)(C)C)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(C(C)(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 1-tert-butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-3-methyl-2,4-dinitrobenzene (9.0 g, 38 mmol, 2:1 by NMR) and DMA (5.4 g, 45 mmol) in DMF (50 mL) was heated at reflux for 2 h before being cooled to room temperature. The reaction mixture was poured into water-ice and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, before being evaporated to give a brown oil, which was purified by column to give (E)-2-(5-tert-butyl-2,4-dinitrophenyl)-N,N-dimethylethen-amine (5.0 g, 68%).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1CCN(CCC(O)=O)CC1)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O:56][C:57]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][NH2:65])=O)(C)(C)C.[CH3:66][CH2:67][N:68]([CH:72]([CH3:74])C)[CH:69]([CH3:71])C>C(Cl)Cl>[NH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][NH:59][C:57]([CH2:74][CH2:72][N:68]1[CH2:67][CH2:66][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:71][CH2:69]1)=[O:56]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: NCCCCCNC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.2 %

Procedure:
A mixture of 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (3 g, 8.15 mmol; prepared as described in Preparation 3), HATU (4.65 g, 12.2 mmol), N-tert-butoxycarbonyl-1,5-diaminopentane (2.47 g, 12.2 mmol) and DIPEA (4.25 mL, 24.52 mmol) in 100 mL of DCM was stirred at room temperature for 1 hour. The reaction mixture was washed with a 1:1 solution of brine and 1N HCl (100 mL), water (100 mL), dried over magnesium sulfate, filtered and concentrated. The residue was treated with 20% TFA in DCM (100 mL) at room temperature for 2 hours. The solvent and TFA were removed under reduced pressure. The residue was taken up in 100 mL of DCM and washed with 1N NaOH (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to give 4.36 g of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:38][CH2:37][CH2:36][CH2:35][N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)N1CCN(CCCN)CC1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN(CCCNc2ccnc(Nc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (0.2 g, 0.837 mmol) in THF (10 mL) is added DIPEA (0.29 mL, 1.67 mmol) followed by 3-(4-(methylsulfonyl)piperazin-1-yl)propan-1-amine, 25, (0.0.369 g, 1.67 mmol). The resulting mixture is refluxed for 12 hours after which the reaction mixture is cooled to room temperature and the solvent removed in vacuo. To the resulting residue is added water (50 mL) and the solution is washed with EtOAc (3×100 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue which is obtained is purified over silica (10% MeOH in CH2Cl2) to afford 0.129 g (50% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz) δ1.71 (m, 2H), 2.39-2.45 (m, 6H), 2.84 (s, 3H), 3.08 (m, 4H), 3.38 (m, 2H), 5.96 (d, J=5.7 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 7.18-7.27 (m, 2H), 7.58 (d, J=7.5 Hz, 1H), 7.81 (bs, 1H), 8.12 (bs, 1H), 9.18 (s, 1H). MS (ESI, pos. ion) m/z: 425 (M+1). HRMS calcd for C18H25ClN6O2S, 425.1526 m/z (M+H)+; observed 425.1512 m/z.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[F:36][C:37]1[CH:38]=[C:39]([NH:44][C:45]2[CH:50]=[N:49][CH:48]=[CH:47][N:46]=2)[C:40]([NH2:43])=[CH:41][CH:42]=1>C(Cl)Cl.CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[NH:43][C:40]1[CH:41]=[CH:42][C:37]([F:36])=[CH:38][C:39]=1[NH:44][C:45]1[CH:50]=[N:49][CH:48]=[CH:47][N:46]=1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cnccn1
Reaction time: 3 h
Yield: 48.7 %

Procedure:
N-(tert-Butoxycarbonyl)-L-alanine (150 mg, 0.78 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) and HOAt (106 mg, 0.78 mmol) were added to 4-fluoro-N2-pyrazin-2-yl-benzene-1,2-diamine (160 mg, 0.78 mmol) in DCM (10.0 ml) and DMF (1.00 ml) at 0° C. The reaction was stirred for 3 h then poured into water and the aqueous layer extracted with DCM (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% methanol/DCM) to yield the title compound (144 mg, 0.38 mmol, 50%). LCMS: RT 3.02 min [M+H]+ 376.2. 1H NMR (CDCl3, 400 MHz): δ 8.36 (1H, s), 8.12 (1H, dd, J2.8, 1.5 Hz), 8.03 (1H, br s), 8.02 (1H, d, J=2.7 Hz), 7.92 (1H, br s), 7.62 (1H, br s), 7.28 (1H, m), 6.77 (1H, td, J 8.4, 2.9 Hz), 4.97 (1H, br s), 4.20 (1H, m), 1.49 (3H, d, J 7.2 Hz), 1.45 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][S:39]([CH3:38])(=[O:41])=[O:40])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
Compound 29a (0.035 gram, 0.076 mmol) was dissolved in dichloromethane (4.3 ml) and triethylamine (0.032 gram, 3.82 mmol) was added to the resulting solution. Methanesulfonyl chloride (MsCl, 0.025 gram, 0.022 mmol) was then added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was thereafter extracted twice with CH2Cl2, washed with brine and dried over sodium sulfate. The crude residue was purified by silica gel column chromatography, using a mixture of 2% methanol in dichloromethane as eluent, to give Compound 32a (0.012 gram, 29% yield).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Br-:1].[C:9]([C:7]1[CH:6]=[CH:5][C:4]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[C:3]([CH2:2][P+:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=1)#[N:10]
Reactant: N#Cc1ccc(NC(=O)C(F)(F)F)c(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NC(=O)C(F)(F)F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 85 °C
Yield: 58.4 %

Procedure:
In a 250 mL round-bottomed flask N-[2-(bromomethyl)-4-cyanophenyl]-2,2,2-trifluoroacetamide (Intermediate 6, 6 g, 19.54 mmol) was dissolved in toluene (100 mL). Triphenylphosphine (5.12 g, 19.54 mmol) was added and the reaction mixture heated to 85° C. under argon for 5 hrs. The reaction mixture was allowed to cool to room temperature and the resulting yellow solid was collected, washed well with toluene, to give the title compound as a yellow solid (6.5 g);
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[C:16]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:15]2=[N:14][C:13]=3[NH2:24])=[C:5]([CH3:27])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:24][C:13]1[C:12]2[N:11]=[CH:10][C:9]([CH2:8][CH2:7][C:6]3[CH:25]=[CH:26][C:3]([OH:2])=[CH:4][C:5]=3[CH3:27])=[CH:18][C:17]=2[C:16]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:15]=2[N:14]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12

Procedure:
To a stirred solution of 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) in methylene chloride (0.2 M) in an ice-water bath was added 1 N solution of BBr3 (2 eq) in CH2Cl2 in a drop-wise fashion. In 30 minutes the reaction was quenched with methanol and was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% methanol in dichloromethane to give 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (B-4) as a white solid. 1H NMR (DMSO-d6): δ 8.99 (s, 1H), 8.75 (d, 1H), 8.60 (d, 1H), 8.27 (d, 1H), 7.28 (s, 1H), 7.09 (dd, 1H), 6.99 (bs, 2H), 6.88 (d, 1H), 6.49 (d, 1H), 6.42 (dd, 1H), 3.02-2.96 (dd, 2H), 2.86-2.81 (dd, 2H), 2.38 (s, 3H), 2.13 (s, 3H). LRMS [M+H]=344.2.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=O.[H][H]>C(O)(C)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([OH:18])=[O:17]
Reactant: [H][H]
Reactant: CC(=O)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Pd]
Solvent: CC(C)O
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Yield: 98.1 %

Procedure:
2,3,4-Trifluoronitrobenzene (5.03 g) and pyruvic acid (2.75 g) were dissolved in isopropanol (IPA; 40 ml). After adding 10% Pd-C (0.21 g), the mixture was stirred at 40° C. under atmospheric pressure in a hydrogen atmosphere for 3 hours. After filtering off Pd-C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (6.11 g) was obtained as colorless crystals. Various spectral data of this product was identical with those of a specimen synthesized separately.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[OH-:12].[Na+].[O-:14][Mn](=O)(=O)=O.[K+]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([OH:14])=[O:12]
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 95 °C
Yield: 42 %

Procedure:
A 3L 3-necked flask equipped with a magnetic stirrer was charged with 25.00 g of 2-fluoro-4-nitrotoluene (Aldrich Chemical Co., Milwaukee, Wis., 53233), 1.65 L of 1 N NaOH, and 25.00 g of KMnO4. The resulting mixture was heated to 95° C. with stirring. Additional 25.00 g portions of KMnO4 were added after 1 h and 2 h. After stirring at 95° C. for an additional hour the reaction mixture was cooled to RT and filtered through celite to remove MnO2. The filtrate was concentrated in vacuo to 500 mL and acidified to pH 2 by addition of concentrated H2SO4. A yellow-orange precipitate formed which was collected by vacuum filtration. The crude solid was dissolved in 300 mL of 1 N aqueous NaOH, acidified to pH 2 and the mixture extracted with CH2Cl2 (4×150 mL). The combined CH2Cl2 extracts were washed with 0.1 N aqueous HCl (2×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 12.44 g (42%) of 2-fluoro-4-nitrobenzoic acid as a yellow crystalline solid, m.p. 165-167° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].OC(C(F)(F)F)=O.[NH2:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35].C[O-].[Na+]>CCO>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 62.3 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol), 3-Amino-2,2-dimethyl-propionic acid TFA salt (120 mg, 0.52 mmol) and NaOMe (56 mg, 1.03 mmol) in EtOH (2 mL) was heated at 150° C. for 6 h in a CEM microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as a yellow solid. MS: (+) m/z 396.15 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([NH:15][NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[CH3:25])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:43][C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=3[CH3:25])=[N:16][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: Cc1cc(Br)ccc1C(=O)NNC(=O)c1ccc(OC(C)C)c(C#N)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(Br)ccc1-c1nnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 125 °C

Procedure:
In an oven-dried high-pressure tube, 240 mg (0.58 mmol) of N′-(3-cyano-4-isopropyloxyphenylcarbonyl)-4-bromo-2-methylbenzhydrazide (from Step A) was combined with 40 mL of anhydrous toluene, 300 mg of Lawesson's Reagent (0.74 mmol), and 100 μL of pyridine. The tube was sealed with a plastic/teflon cap and the reaction mixture was heated to 125° C. for 2 h. The resulting mixture was cooled down to rt, solvents were removed under reduced pressure and residual solids were dissolved in 10 mL of pyridine. To this mixture, 0.5 g of phosphorous pentasulfide was added and the mixture heated to 110° C. The reaction mixture was combined with ice-water and extracted 2×100 mL of EtOAc. Combined organic layers were dried over sodium sulfate, and solvents removed under reduced pressure. Pure title compound was isolated by flash chromatography using Biotage 40S (eluant: hexanes/EtOAc-4/1) to yield 239 mg: 1H NMR (500 MHZ, CDCl3) δ 1.49 (d, J=6.5, 6H), 2.65 (s, 3H), 4.79 (sep, J=6.5, 1H), 7.13 (dd, J=9.0, 2.0, 1H), 7.50 (dd, J=9.0, 2.0, 1H), 7.56 (d, J=2.0, 1H), 7.63 (d, J=8.0, 1H), 8.17 (d, J=2.0, 1H), 8.24 (dd, J=8.0, 2.0, 1H).
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:20])[C:11]2=[CH:21][S:22][CH:23]=[C:10]12)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[H][H].[CH3:28]O>>[CH3:28][N:5]1[CH2:4][CH2:3][C:2]([C:1]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[C:11]3=[CH:21][S:22][CH:23]=[C:10]23)=[O:8])=[CH:7][CH2:6]1
Reactant: O=C1Nc2ccccc2N(C(=O)c2ccncc2)c2cscc21
Reactant: [H][H]
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CN1CC=C(C(=O)N2c3ccccc3NC(=O)c3cscc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
4,9-Dihydro-4-isonicotinoyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one methoiodide in an amount of 3.4 gm (0.0073 mol) was suspended in 40 ml of methanol, and at 0° C. 0.5 gm (0.014 mol) of sodium borohydride were added in portions. After the development of hydrogen ceased, the mixture was stirred for a further two hours in an ice bath. Then, 100 ml of ice-water was added, the mixture was filtered, and the filtrate was extracted with methylene chloride. The extraction residue was recrystallized from acetonitrile. 4,9-Dihydro-4-[(1-methyl-1,2,5,6-tetrahydro-4-pyridinyl)carbonyl]-10H-thieno[3,4-b][1,5]benzodiazepin-10-one was obtained, m.p.: 210°-212° C., in a yield of 35% of theory.