Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([F:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>O1CCCC1>[F:18][C:17]1[C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(C(F)(F)F)cc2F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cnn1-c1ncc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.17 g) in tetrahydrofuran (10 ml) was added 1 N aqueous solution of sodium hydroxide (10 ml), and stirred at room temperature overnight. After completion of the reaction, the organic solvent was evaporated in vacuo, then water and diethyl ether were added thereto, and the aqueous layer was separated. To the aqueous layer was added 1 N hydrochloric acid aqueous solution under ice-cooling to adjust the layer to pH 5, the precipitated solid was collected by filtration, and dried at 60° C. under air blow to give the titled compound (1.7 g) as a white solid. MS (ESI) m/z: 290 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[N:4]=1)[NH2:2].[C:13]([CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17](OCC)=[O:18])(=O)[CH3:14].C(#N)C.O>C(O)(=O)C>[CH3:14][C:13]1[C:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:17]([OH:18])[N:1]([C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=3[N:4]=2)[N:2]=1
Reactant: Cc1ccc2[nH]c(NN)nc2c1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2[nH]c(-n3nc(C)c(Cc4ccccc4)c3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-hydrazino-5-methyl-1H-benzimidazole (4) (1.0 g) and ethyl 2-acetyl-3-phenylpropanoate (1.4 mL) in acetic acid (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was added to a mixture of acetonitrile (100 mL) and water (100 mL). After stirring at room temperature, the resulting precipitate was collected by filtration, and washed with a mixture of acetonitrile and water (1:1). The precipitate was recrystallized from ethanol (95 mL) to give 3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-4-(phenylmethyl)-1H-pyrazol-5-ol (5) (0.64 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[CH:7](O)[CH2:8][CH2:9][CH2:10][CH3:11].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:7]([C:6]1[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:3][C:2]=1[CH3:1])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCCCC(O)c1cc(-c2ccccc2)oc1C
Solvent: Cc1ccccc1
Product: CCCCC(Cl)c1cc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-(2-methyl-5-phenylfuran-3-yl)pentan-1-ol (1.6 g) in toluene (20 mL) was added thionyl chloride (1.0 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.7 g, 100%) as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([N:57]1[CH:61]=[C:60]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)[CH:59]=[N:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH2:50]([N:57]1[CH:61]=[C:60]([C:62]2[CH:63]=[C:64]([NH:68][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:65]=[CH:66][CH:67]=2)[CH:59]=[N:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cnn(Cc5ccccc5)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 61.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-benzyl-1H-pyrazol-4-yl)-phenylamine (0.016 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 62% yield: LCMS (ESI) m/z 452 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([O:22][C:4]2[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: N#Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C#N)C1
Reaction time: 18 h
Yield: 79.3 %

Procedure:
To a solution of 4-bromo-2-fluoro-benzonitrile (1.0 g, 5.0 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (0.95 g, 5.5 mmol) in DMF (15 mL) at 0° C., was added NaH (60% in mineral oil, 130 mg, 5.5 mmol). After 18 h, H2O and EtOAc were added and the organic portion washed with brine (3×) and dried to provide the title compound (1.4 g, 79%). MS (ESI): mass calcd. for C15H17BrN2O3, 352.0. m/z found, 377.1 [M+Na]+. 1H NMR (CDCl3): 7.48 (d, J=8.2 Hz, 1H), 7.25 (dd, J=8.2, 1.7 Hz, 1H), 6.79 (d, J=1.6 Hz, 1H), 5.00-4.92 (m, 1H), 4.38 (ddd, J=9.9, 6.4, 1.1 Hz, 2H), 4.11 (dd, J=10.0, 3.8 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[O:3]1.[Si](C=[N+]=[N-])(C)(C)[CH3:17].C(O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:17])=[O:13])[CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CCc2cccc(C(=O)O)c2O1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1OC(C)(C)CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2,2-dimethyl-3,4-dihydro-2H-chromene-8-carboxylic acid (300 mg, 1.45 mmol) in methanol (2.10 mL) and toluene (5.20 mL) cooled to 0° C. was added TMS-diazomethane (1.82 mL, 3.64 mmol) dropwise via a syringe. The reaction mixture was warmed to room temperature and stirred for 45 minutes. It was then cooled to 0° C., and acetic acid (2.00 mL) was added carefully. The solvent was evaporated under vacuum and the residue was re-dissolved in EtOAc (80.0 mL), washed with a saturated NaHCO3 solution (20.0 mL, dried over Na2SO4, filtered and concentrated under vacuum. The crude product was used directly to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc(I)cc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1c(Cl)cc(-c2ccccc2)cc1Cl
Temperature: 25 °C

Procedure:
2,6-Dichloro-4-iodoaniline (10.4 g, 36.0 mmol) is dissolved in toluene (100 mL) and treated with 1.5 equivalents of phenylboronic acid (6.6 g, 54 mmol), and a catalytic amount of tetrakistriphenylphosphine palladium(0) (3.0 g, 2.6 mmol) as a solution in ethanol (20 mL). Sodium carbonate (40 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to reflux temperature for 24 hours. After cooling to room temperature, the mixture is partitioned between Et2O (300 mL) and water (150 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,6-dichloro-4-phenylaniline (m.p. 112–113° C.).
Reaction SMILES: C([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])(C)(C)C>CO.[Pd]>[CH2:18]([O:17][C:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:29])=[O:5])=[O:28])[CH:25]([CH3:27])[CH3:26])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 69.7 %

Procedure:
A solution of N-benzyloxycarbonyl-L-valyl-L-proline tert-butyl ester (20 g) in methanol (300 ml) was hydrogenated at 50 psi over 10% palladium on carbon catalyst (2 g) for 12 hours. The reaction mixture was then filtered through diatomaceous earth and the filter cake washed with methanol. The filtrate was evaporated to give L-valyl-L-proline tert-butyl ester (A) (12 g) as an oil; NMR (300 MHz, d6 -DMSO): 0.80(d,3H), 0.92(d,3H), 1.74(s,9H), 1.79-2.15(m,5H), 3.22(d,1H), 3.30(bs,2H), 3.40(m,1H), 3.62(m,1H), 4.16(dd,1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:4]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:5]=1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.N1C=CC=CC=1.[C:49](Cl)(=[O:51])[CH3:50]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1)[CH2:14][N:7]([CH2:6][C:5]1[CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:4]=1[CH:3]([O:2][CH3:1])[CH:37]1[CH2:38][CH2:39][N:40]([C:49](=[O:51])[CH3:50])[CH2:41][CH2:42]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CC(=O)Cl
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a solution of N-(2-(methoxy piperidin-4-ylmethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (20.5 mg, 0.034 mmol) in methylene chloride (0.5 mL) at room temperature was added pyridine (10 μL, 0.1 mmol) followed by acetyl chloride (5 μL, 0.07 mmol). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 10-100% ethyl acetate in hexanes) to afford the title compound (14 mg, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 1.17-1.34 (m, 3H) 1.69-1.78 (m, 1H) 1.87 (t, J=12.65 Hz, 1H) 2.04 (s, 1.5H) 2.06 (s, 1.5H) 2.27-2.41 (m, 1H) 2.82-2.93 (m, 1H) 3.04 (s, 3H) 3.72 (d, J=15.77 Hz, 0.5H) 3.81 (d, J=12.45 Hz, 0.5H) 4.18 (d, J=6.64 Hz, 1H) 4.21 (s, 3H) 4.54-4.65 (m, 1H) 4.65-4.73 (m, 3H) 4.87 (d, J=16.60 Hz, 1H) 7.37 (s, 1H) 7.50 (d, J=7.88 Hz, 1H) 7.59 (d, J=7.88 Hz, 1H) 7.64 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 652.2, Found: 653.5 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cccc(-c2ccccc2)c1
Reaction time: 4 h
Yield: 94.6 %

Procedure:
A mixture of 3-nitrobiphenyl (20 g, 100 mmol) and 10% Pd/C (2 g) in MeOH/CHCl3 (300 mL, 1:1) is hydrogenated at 40 psi for 4 hours. The mixture is suction filtered through a layer of diatomaceous earth and washed with MeOH. The filtrate is evaporated to dryness and the solid is further dried under vacuum to give 16 g (95%) of 3-aminobiphenyl.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH2:26]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:26][CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([CH3:20])[CH:29]=[CH:28][CH:27]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: Cc1cccc(CCN)c1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Product: Cc1cccc(CCNCc2ccc(Oc3ccc(C(N)=O)nc3)c(F)c2)c1
Yield: 52.4 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 405, Part B) (0.040 g, 0.154 mmol) and 3-methylphenethylamine (0.021 g, 0.154 mmol) gives the title compound (0.0306 g, 52.5%): TOF MS ES+ 380.2 (M+H)+, HRMS calcd for C21H23N3O2F 380.1774 (M+H)+, found 380.1757, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 m, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=8.4 min, 100% purity.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([SH:12])[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1)=[O:5])C>[OH-].[K+].O>[C:4]([C:6]1[CH:11]=[C:10]([SH:12])[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(S)n2ncnc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(S)n2ncnc2n1
Temperature: 80 °C
Yield: 91.4 %

Procedure:
The product obtained in Step 2 (2.0 g) was dissolved in a solution of 1.0 g potassium hydroxide in 80 ml of water, the mixture was heated at 80° C. for 30 minutes. After cooling the resulting orange solution to room temperature, it was washed with 50 ml of ethyl acetate, the pH of the aqueous layer was lowered to 1.0 with 6N hydrochloric acid, and the crystals thus formed were collected by filtration, washed with 50 ml of acetone, giving 1.6 g of the objective compound as orange crystals.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=4[CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[F:31][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[CH3:30])[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: COc1ccc(C)c(-c2cc(F)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Product: CNCC1Cc2cc(F)cc(-c3cc(OC)ccc3C)c2O1

Procedure:
The title compound was prepared (0.73 g, 50%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.40 mmol) and methylamine (0.124 g, 4.0 mmol). mp 173-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([OH:39])=[CH:34][C:33]=3[CH3:40])[C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].[O:48]1[C:50]2([CH2:55][CH2:54][S:53][CH2:52][CH2:51]2)[CH2:49]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([O:39][CH2:49][C:50]4([OH:48])[CH2:55][CH2:54][S:53][CH2:52][CH2:51]4)=[CH:34][C:33]=3[CH3:40])[C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CCOC(=O)CCc1ccc(N(Cc2ccc(OC(C)C)c(-c3c(C)cc(O)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: C1CC2(CCS1)CO2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(N(Cc2ccc(OC(C)C)c(-c3c(C)cc(OCC4(O)CCSCC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[(4′-hydroxy-6-isopropoxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (993 mg, 1.49 mmol) and 1-oxa-6-thiaspiro[2.5]octane (779 mg, 5.98 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (827 mg, 5.98 mmol), and the mixture was stirred overnight at 80° C. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/1) to give the title compound (605 mg, yield 51%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reactant: COC(=O)c1ccc(OCC2CCCN2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Br)c(OC)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.3 %

Procedure:
To a stirred mixture of methyl 5-(2-pyrrolidinyl)methoxypyridine-2-carboxylate (370 mg, 1.57 mmol), 4-[N′-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (595 mg, 1.57 mmol), 4-DMAP (230 mg, 1.88 mmol) in DMF (10 ml) was added EDC.HCl (360 mg, 1.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hr. The mixture was pored into ice-water. The solid was collected, washed with water and air-dried. The crude solid was purified by silica-gel (30 ml) column chromatography with CHCl3—EtOH (98:2, v/v) as eluent and crystallized with Et2O to give methyl 5-[1-[4-[N′-(2-bromophenyl)ureido]-3-methoxypheny lacetyl]-2-pyrrolidinylmethoxy]pyridine-2-carboxylate (650 mg, 69%) as an amorphous solid. IR (KBr) n 3323, 1720, 1624, 1601, 1527 cm−1; 1H-NMR (CDCl3) δ1.22 and 2.00 (each m, 4 H), 3.48-4.55 (series of s and m, 13 H which contains amide-isomers), 6.93-8.82 (series of s and m, 12H which contains amide-isomers); MS (FAB) m/z 597 (M+−1) and 599 (M++1); Anal. Calcd. for C28H30BrN4O6.1.0×H2O: C, 54.55; H, 5.23; N, 9.09. Found: C, 54.13; H, 5.03; N, 9.33.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:13][C:14]1[CH:24]=[CH:23][C:17]2[CH:18]=[C:19]([CH2:21]O)[S:20][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[CH2:6]([O:13][C:14]1[CH:24]=[CH:23][C:17]2[CH:18]=[C:19]([CH2:21][Cl:4])[S:20][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1cc2ccc(OCc3ccccc3)cc2s1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: ClCc1cc2ccc(OCc3ccccc3)cc2s1
Temperature: 25 °C

Procedure:
Sulfonyl chloride (20 ml) is added to a solution of (6-benzyloxy-benzothien-2-yl) methanol (4.20 g, 15.50 mmol) in dichloromethane (40 ml). The mixture was maintained at reflux for 2 h, cooled at room temperature then concentrated under vacuum to give 4.20 g as an oil.
Reaction SMILES: [BrH:1].[CH:2]1([N:5]([C:13]2[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=[C:15]([C:24]3[CH:28]=[C:27]([CH2:29]O)[S:26][CH:25]=3)[CH:14]=2)C(=O)OC(C)(C)C)[CH2:4][CH2:3]1>ClCCl>[Br:1][CH2:29][C:27]1[S:26][CH:25]=[C:24]([C:15]2[CH:14]=[C:13]([NH:5][CH:2]3[CH2:4][CH2:3]3)[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2csc(CO)c2)nc2c(C=O)cnn12)C1CC1
Reactant: Br
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)cc(-c3csc(CBr)c3)nc12
Temperature: 40 °C
Yield: 20 %

Procedure:
Hydrogen bromide (48% in water, 2.5 mL) was added dropwise to tert-butyl cyclopropyl(3-formyl-5-(5-(hydroxymethyl)thiophen-3-yl)pyrazolo[1,5-a]pyrimidine-7-yl)carbamate (561 mg, 1.35 mmol) suspended in dichloromethane (3.5 mL). The solution immediately became dark brown and homogeneous upon addition. The reaction was heated to 40° C. for 3 h, then diluted with dichloromethane (10 mL). The liquid was decanted and the gummy residue was washed with dichloromethane (3×10 mL). The combined liquids were washed successively with sat. NaHCO3 (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexanes and then purified via flash column chromatography (15-40% EtOAc/hexanes) to provide 5-(5-(bromomethyl)thiophen-3-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (105 mg, 20%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ: 10.26 (s, 1H), 8.44 (s, 1H), 8.12 (d, 1H, J=1.6 Hz), 7.80 (s, 1H), 6.73 (s, 1H), 6.65 (bs, 1H), 4.80 (s, 2H), 2.81 (m, 1H), 1.03-1.09 (m, 2H), 0.84-0.89 (m, 2H). LCMS (ES): >95% pure, m/z 378 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:32][C:33]1([CH2:37][CH3:38])[CH2:36][NH:35][CH2:34]1>>[NH2:32][C:33]1([CH2:37][CH3:38])[CH2:36][N:35]([C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:34]1
Reactant: CCC1(N)CNC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Agent: CS(=O)(=O)O
Product: CCC1(N)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)C1
Yield: 68.9 %

Procedure:
8-(3-Amino-3-ethyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3carboxylic acid was prepared under the conditions of Example 15, but starting with 1.66 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 3.1 g of 3-amino-3-ethylazetidine dimethane-sulphonate. 1.46 g of 8-(3-amino-3-ethyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 294° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Cc1ccc(Br)cc1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Br)cc1Oc1ccccc1
Reaction time: 96 h

Procedure:
A mixture of 5-bromo-2-methylphenol (1.0 g), phenylboronic acid (1.30 g), Cu(OAc)2 (0.97 g), and triethylamine (2.98 mL) in dichloromethane (50 mL) was stirred for 4 days. The mixture was diluted with ethyl acetate, washed four times with 1M aqueous NaOH solution and once with brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed on silica gel using 2% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=1F)=[O:4].[N-:26]=[N+]=[N-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=1[NH2:26])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1c(F)ccc2nc3ccc4c(OC)cccc4c3nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(N)ccc2nc3ccc4c(OC)cccc4c3nc12
Temperature: 90 °C
Yield: 52.4 %

Procedure:
A mixture of 10-fluoro-4-methoxy-benzo[a]phenazine-11-carboxylic acid methyl ester (IV.5) (466 mg) and sodium azide (900 mg) in N,N-dimethylformamide (10 mL) was heated at 90° C. for 18 hours. The reaction mixture was then cooled, diluted with water, and then sodium hydroxide solution was added resulting in a brown precipitate. This was collected by filtration and washed with water and ether to yield the desired title compound as a yellow solid (242 mg).