Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C:23]4([F:36])[F:35])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[ClH:37].O1CCOCC1.CCOCC>CO>[ClH:37].[ClH:37].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]4([F:36])[F:35])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)C(F)(F)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: Fc1cc(OC2CCNCC2(F)F)c2nc(-c3nnc4ccccn34)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-3,3-difluoropiperidine-1-carboxylate (0.072 g, 0.144 mmol) was dissolved in MeOH (0.72 mL) and treated with 4.0 M HCl in dioxane (0.360 mL, 1.44 mmol), then stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in MeOH and concentrated three times. The residue was chromatographed on SiO2 eluting with a gradient of 2% NH4OH in isopropanol/methylene chloride. The desired product was dissolved in MeOH (2 mL), treated with 2.0 M HCl in ether (0.809 mL, 1.62 mmol) and concentrated in vacuo. The residue was again dissolve in MeOH and concentrated in vacuo several times, then placed under vacuum to give the desired product as a white solid (27.8 mg). MS APCI (+) m/z 400.3 (M+1) detected.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=3)[CH2:11][C@H:10]2[CH3:24])[CH:5]=[CH:4][C:3]=1[N:25]1[C@@H:29]([CH2:30][C:31]([O:33]C)=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:39])([F:38])[F:37])=[N:26]1.[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=3)[CH2:11][C@H:10]2[CH3:24])[CH:5]=[CH:4][C:3]=1[N:25]1[C@@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:37])([F:39])[F:38])=[N:26]1
Reactant: COC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(O[C@@H]2CCN(c3cc(OC)ncc3Cl)C[C@H]2C)cc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)O)c(Br)c3)[C@H](C)C2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of methyl 2-((4S,5S)-1-(2-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (6.5 mg, 10.25 μmol) in THF (0.5 mL) and water (0.04 mL) at rt was added 1.0M aqueous lithium hydroxide (0.04 mL, 0.040 mmol). The mixture was stirred at rt for 13.5 h and then partially evaporated to remove most of the THF. The remaining solution was partitioned between water (40 mL) and Hex (15 mL). The aqueous layer was acidified to pH 2 by dropwise addition of 1M HCl, and then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was dried under vacuum to afford 2-((4S,5S)-1-(2-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (6 mg, 89% yield) as a white solid: LC-MS [M+H] 619, 621. 1H NMR (400 MHz, CD2Cl2) δ 7.96 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.91 (dd, J=8.8, 2.8 Hz, 1H), 6.29 (s, 1H), 4.63 (m, 1H), 3.99 (dt, J=4.1, 8.8 Hz, 1H), 3.86 (s, 3H), 3.52 (m, 2H), 3.27 (m, 1H), 2.89 (m, 1H), 2.66 (dd, J=12.2, 9.3 Hz, 1H), 2.41 (m, 2H), 2.18 (m, 2H), 1.79 (m, 1H), 1.41 (d, J=7.1 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H). Analytical HPLC (Zorbax method, 0% Solvent B start): RT=8.69 min, HI: 97%. hGPR40 EC50=844 nM.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:2]([NH:9][C:8]1[CH:10]=[CH:11][C:5]([F:4])=[CH:6][CH:7]=1)[CH3:3]
Reactant: Nc1ccc(F)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1ccc(F)cc1
Reaction time: 18.5 h

Procedure:
Iodoethane (3.6 ml) was added to a mixture of 4-fluoroaniline (4.26 ml) and potassium carbonate (6.9 g) in dry DMF (100 ml). After 18.5 h at 23°, the resulting suspension was poured into water (400 ml) and extracted with EA (400 ml). The organic extract was washed with water (200 ml) then saturated brine (200 ml), dried and evaporated. The residual oil was chromatographed with 2 to 3 to 4% EA in hexane as eluent to give the title compound (3.667 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:32])[CH2:9][CH2:10][CH:11]2[C:14](=[O:15])[N:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:12]2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([N:13]2[CH:12]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:11]([CH2:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[OH:32])[C:14]2=[O:15])=[CH:17][CH:18]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Temperature: 60 °C

Procedure:
1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile are dissolved in 90 ml of ethanol, 10 ml of conc. ammonia solution and an excess of Raney nickel are added and the mixture is stirred at 60° C. and a hydrogen pressure of 10 bar for 8 h. Overnight, the reaction mixture cools to room temperature. The next day, the catalyst is separated off, the filtrate is concentrated under reduced pressure and the residue is purified chromatographically on silica gel using dichloromethane/methanol/ammonia solution 10/1/0.1. This gives 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one of molecular weight 434.51 (C26H27FN2O3); MS (ESI): 418.2 (MH+-NH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:18]>CN(C)C=O>[Br:1][C:2]1[C:7](=[O:18])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(F)cc(Br)c[n+]1[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(=O)c(Br)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 5-bromo-3-fluoro-1-oxido-pyridin-1-ium-2-carboxylate (3, 0.85 g, 3.21 mmol) in dimethylformamide (15 mL) was added trifluoroacetic anhydride (1.35 g, 6.42 mmol) at 0° C. The reaction mixture was warmed to 50° C. and stirred for 1 h, quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2×100 mL). The organic layers were separated, dried with magnesium sulfate, filtered and concentrated to dryness under vacuum to afford ethyl 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate (4) as a yellow solid. Yield: 0.8 g, 94%; MS (ESI) m/z 264 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (m, 1H), 4.47 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:20][C:21]([CH2:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[CH2:22]>C1COCC1>[Si:1]([N:8]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:10]([CH2:22][C:21]([CH2:23][O:24][C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[CH2:20])[C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1c1ccccc1
Reactant: C=C(CBr)COC(=O)c1ccc(OC)cc1
Solvent: C1CCOC1
Product: C=C(COC(=O)c1ccc(OC)cc1)C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 112.4 %

Procedure:
Under an atmosphere of N2, a 1.5M solution of LiN(Pri)2THF in c-C6H6 (Aldrich; 43.9 ml, 65.9 mmol) was added dropwise to a stirred solution of 1-tert-butyldimethylsilyl-4-phenyl-2-azetidinone (13.24 g, 50.64 mmol) in dry THF (230 ml) at an inner temperature between -78 and -73 C. After stirring at -78 C for 30 minutes, the reaction mixture became a white slurry. A solution of 3-bromo-2-[(4-methoxybenzoyloxy)methyl]propene (14.69 g, 54.18 mmol) in dry THF (30.0 ml) was added dropwise at an inner temperature between -78 and -71 C. After the addition was complete, the dropping funnel used was rinsed with dry THF (5 ml×2). The resultant homogeneous reaction mixture was stirred at -78 C. for an hour, and then at -10 C. for 50 minutes. The reaction was quenched by adding sat. NH4Cl aq. solution (30.0 ml) below 0 C. The mixture was taken up in AcOEt (500 ml). The AcOEt solution separated was washed with sat. NaCl aq. solution (100 ml×2), dried (MgSO4), and concentrated in vacuo to give a heterogeneous yellow oil (26.51 g). This was, then, diluted with Et2O (250 ml), washed with H2O (×2), and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a homogeneous yellow oil (24.91 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 250 g). Elution with n-hexane-AcOEt (40:1/30:1/20:1/10:1) gave title compound (19.73 g, 86.3%) as a viscous pale yellow oil. IRmax (film): 1745(s), 1645(m), 1610(m), 1510(m), 990(shoulder, m), 910(m), 775(m), 745(w), 700(m), 680(m) cm-1 ; 1H-NMR δ: 7.40-7.25(m, 5H), 7.20(d, J=8.8 Hz, 2H), 6.85(d, J=8.8 Hz, 2H), 5.05(s, 1H), 4.84(s, 1H), 4.35(s, 2H), 4.20(d, J=2.6 Hz, 1H), 3.86(s, 2H), 3.80(s, 3H), 3.25(ddd, J=10.5, 5.1, 2.6 Hz, 1H), 2.70(dd, J=15.7, 5.1 Hz, lH), 2.48(dd, J=15.7, 10.7 Hz, 1H), 0.92(s, 9H), 0.21(s, 3H), -0.21(s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>C(Cl)Cl.O>[CH3:21][CH:20]([CH3:22])[CH2:19][O:18][C:16](=[O:17])[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)COC(=O)Nc1cccc(F)c1
Reaction time: 2.5 h

Procedure:
To a mixture of 3-fluoroaniline (I, 29.058 g, 261.5 mmol) in methylene chloride (116 ml) is added a mixture of potassium carbonate (27.26 g, 197.3 mmol, 0.75 eq) in water (116 ml) at 20-25°. The mixture is warmed to 32°, and isobutyl chloroformate (38.5 g, 282 mmol, 1.08 eq) is added over 13 min while maintaining 30-35° with mild cooling. The mixture is stirred at 30-35° for 2.5 hr until the reaction is complete to give 2-methylpropyl-(3-fluorophenyl)carbamate as determined by GC [GC method A, <0.1 area % 3-fluoroaniline; RT (3-fluoroaniline)=3.97 min, RT=14.2 min]. Aqueous ammonia (29.3 wt %, 4.20 ml, 65.0 mmol, 0.25 eq) is added and the mixture stirred at 30-35° for 15 min. The mixture is cooled to 20-25° and the pH adjusted from 8.7 to 1.9 with hydrochloric acid (37 wt %, 6.36 g, 64.5 mmol, 0.25 eq). The phases are separated and the aqueous washed with methylene chloride (58 ml). The combined organics are washed with water (118 ml) and the water wash back extracted with methylene chloride (58 ml). [In a prior experiment crystallization at this point from heptane at −30° gave 2-methylpropyl-(3-fluorophenyl)carbamate analytically pure in 98.1% yield.]. Dibromantin (57.37 g;, 200.6 mmol, 0.767 eq) and water (174 ml) are added to the combined organics and the mixture stirred at 40° for 12 hr until complete as measured by HPLC (<0.1 2-methylpropyl-(3-fluorophenyl)carbamate). The mixture is cooled to 20-25° and clarified on a “C” frit by vacuum filtration. The phases are separated and the organic (lower) phase added to a mixture of sodium sulfite (33.06 g, 262.3 mmol, 1.00 eq) in water (220 ml) with good agitation. The phases are separated and the organic phase washed with water (150 ml). Serial back-extracted the clarified solids and all aqueous with a single portion of methylene chloride (150 ml). Added heptane (520 ml) to the combined organic phases and concentrated under reduced pressure. Heptane (240 ml) is added, the mixture cooled to −30°, the precipitate is collected by vacuum filtration, washed with cold heptane (150 ml) and dried in a nitrogen stream to give the title compound; mp=79-82°; TLC Rf=0.41 (ethyl acetate/hexanes, 5/95); HPLC (method A) rt=6.75 min; NMR (CDCl3, 400 MHz) d 7.41, 6.96, 6.87, 3.96, 1.97 and 0.96; CMR (CDCl3, 75 MHz) d 159.2, 153.4, 139.0, 133.3, 115.1, 107.1, 102.0, 71.8, 27.9 and 19.0; MS (CI, NH3) m/Z (relative intensity) 310 (9.3), 309 (100), 308 (6.1), 307 (100), 292 (11), 291 (18), 290 (7.5) and 289 (19)
Reaction SMILES: [H-].[Na+].C1(S([CH2:12][C:13]2[N:17]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[NH:15][N:14]=2)(=O)=O)C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]#[N:33])=[CH:26][CH:25]=1.CO>O1CCCC1>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:31]=[C:32]([NH2:33])[N:14]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:13]3[CH:12]=2)=[CH:28][CH:29]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(-c2ccc(Cl)cc2)cc2nc(-c3ccco3)nn12
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
0.7 g (0.015 mol) sodiumhydride (55%) were added to a solution of 1.50 g (0.005 mol) 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole in 50 ml tetrahydrofuran. The mixture was refluxed and 0.85 g (0.005 mol) 3-(4-chlorophenyl)-2-propenenitrile in 30 ml tetrahydrofuran were added during, aperiod of 5.5 hours. Boiling was continued for 30 minutes and then 20 ml methanol were added at room temperature. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 99/1 gave 0.57 g (35%) 7-(4-chloro-phenyl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine as pale crystals. MS m/e (%): 311 (M+H+, 100).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH:39]([C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])=[CH:34][CH:35]=1)([CH3:41])[CH3:40]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CC(C)c1ccc([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(C(C)C)cc1

Procedure:
Compound 39 was prepared following general synthesis scheme 8 wherein a mixture of 4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and 4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H) was reacted with N—[(S)-2-Amino-2-(4-isopropyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride. The title compound was isolated as the major product (white solid). LC/MS [365 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.47 (d, J=8.6 Hz, 1H), 9.03 (d, J=4.3 Hz, 1H), 8.63 (s, 1H), 8.41 (d, J=4.3 Hz, 1H), 8.22 (s, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 5.92-5.76 (m, 1H), 3.89-3.65 (m, 1H), 3.39 (d, J=12.6 Hz, 1H), 2.94-2.81 (m, 1H), 2.61 (s, 3H), 1.16 (d, J=6.8 Hz, 6H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1>CN(C=O)C.O>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:64]1[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]2[CH:48]=[CH:49][C:50]([O:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:51][CH:52]=2)[CH2:62][CH2:63]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2F)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
DIPEA (0.106 mL, 0.62 mmol) was added drop wise to 2-fluorobenzoic acid (34 mg, 0.25 mmol) in DMF (5 mL). EDCI (98 mg, 0.51 mmol) and HOBT (33 mg, 0.25 mmol) were added consecutively and, after 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (77 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded N-{2-[4-(2-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 42% yield. LC-MS purity: 97%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.5 (m, 4H), 7.3 (m, 2H), 7.2 (t, 1H), 7.1 (m, 4H), 4.2 (dd, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: Br[CH:2]1[CH2:5][C:4]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:3]1.[I:10][C:11]1[CH:12]=[N:13][NH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C>[CH2:3]1[C:4]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:5][CH:2]1[N:13]1[CH:12]=[C:11]([I:10])[CH:15]=[N:14]1
Reactant: BrC1CC2(C1)OCCO2
Reactant: Ic1cn[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1cnn(C2CC3(C2)OCCO3)c1
Temperature: 87.5 °C
Reaction time: 48 h
Yield: 28.7 %

Procedure:
To a solution of 2-bromo-5,8-dioxa-spiro[3.4]octane (Compound 100F, 19 g, 100 mmol) and 4-iodopyrazole (38.6 g, 200 mmol) in DMF (100 mL) was added powdered K2CO3 (41.4 g, 300 mmol) and 18-crown-6 ether (5.3 g, 20 mmol). The reaction mixture was stirred at 85-90° C. for 2 days. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water (4×100 mL). The combined organic layers were washed with brine and concentrated, the residue was purified by column chromatography (ethyl acetate/DCM: 5:95) to give 8.8 g (29%) of 1-(5,8-dioxa-spiro[3.4]oct-2-yl)-4-iodo-1H-pyrazole. 1H NMR (CDCl3, 300 MHz): δ=2.87-2.89 (m, 4 H), 3.92-3.96 (m, 4 H), 4.64-4.68 (m, 1 H), 7.53 (s, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[C:13]([N:20]1[CH:24]=[CH:23]N=C1)(N1C=CN=C1)=[O:14].[CH3:25][O:26][C:27](=[O:37])[C:28]1C=C(N)[CH:31]=[CH:30][C:29]=1[O:35][CH3:36]>CN(C=O)C.C(OCC)(=O)C>[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:23]=[C:24]([NH:20][C:13]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[N:5]=[C:4]([CH3:12])[CH:3]=2)=[O:14])[CH:31]=[CH:30][C:29]=1[O:35][CH3:36]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: Cc1cc(N)c2ncccc2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)Nc2cc(C)nc3cccnc23)ccc1OC
Temperature: 100 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
D2 (0.51 g) was added in portions over 10 min to a solution of 1,1′-carbonyl diimidazole (0.536 g) and 4-N,N-dimethylaminopyridine (0.004 g) in DMF (10 ml). The resulting solution was stirred for 16 h, 5-amino-2-methoxybenzoic acid methyl ester (0.577 g) added in DMF (2 ml) and the mixture heated at 100° C. for 2 h. The mixture was diluted with ethyl acetate and washed with water (×2) and brine, dried (Na2SO4) and solvent removed at reduced pressure. The pale pink solid was triturated with DCM to give the title compound (0.58 g). 1H NMR δ: 2.64 (3H, s), 3.34 (3H, s), 3.81 (3H, s), 7.15 (1H, d), 7.59 (1H, dd), 7.80 (1H, dd), 7.94 (1H, d), 8.29 (1H, dd), 8.34 (1H, s), 8.89 (1H, m), 9.85 (1H, s), 10.05 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[N:8]=[C:9]([NH:12][C:13]3([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43])(=[O:35])=[O:34].C(=O)(O)[O-].[Na+]>COCCOC>[CH3:32][S:33]([C:36]1[CH:37]=[C:38]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[C:7]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[N:8]=[C:9]([NH:12][C:13]4([C:16]([F:18])([F:19])[F:17])[CH2:15][CH2:14]4)[C:10]=3[N:11]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43])(=[O:34])=[O:35]
Reactant: NS(=O)(=O)c1ccc(CNc2nc(NC3(C(F)(F)F)CC3)c3nc(Cl)ccc3n2)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc3nc(NCc4ccc(S(N)(=O)=O)cc4)nc(NC4(C(F)(F)F)CC4)c3n2)cc1S(C)(=O)=O
Temperature: 65 °C
Yield: 39.1 %

Procedure:
4-{[6-Chloro-4-(1-trifluoromethyl-cyclopropylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}benzenesulfonamide (0.100 g, 0.23 mmol) was combined with 2-(3-methanesulfonyl-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.091 g, 0.34 mmol, see Scheme 7), palladium tetrakistriphenylphosphine (0.013 g, 0.011 mmol) and sodium bicarbonate (1.5 mL of a saturated aqueous solution). The mixture was suspended in DME (3 mL) and heated to 65° C. for 1 h. Crude product was precipitated by the addition of water (5 mL). The precipitate was filtered and purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) to give 0.056 g (40% yield) of the title compound, and was characterized by its NMR and mass spectrum as follows: 1H NMR (d6-DMSO): d 1.38-1.26 (m, 4H), 3.31 (s, 3H), 4.06 (s, 3H), 4.79 (m, 2H), 7.34 (s, 2H), 7.46 (d, J=8.7 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 8.01 (d, J=9.0 Hz, 1H), 8.45-8.41 (m, 2H), 8.90 (d, J=11.4 Hz, 1H), 9.08 (bs, 1H), 10.15 (bs, 1H): MS (m/z): 623.2 ([M+H]+, 100).
Reaction SMILES: C(O)(=O)C.C(OCC)(=O)C.[Cl:11][C:12]1[C:17]2[C:18]([N+:22]([O-])=[O:23])=[C:19]([CH3:21])[O:20][C:16]=2[C:15]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:14][CH:13]=1>[Fe].O>[Cl:11][C:12]1[C:17]2[C:18]([NH:22][OH:23])=[C:19]([CH3:21])[O:20][C:16]=2[C:15]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:14][CH:13]=1
Reactant: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2c1NO
Reaction time: 2 h
Yield: 54 %

Procedure:
5 ml of acetic acid, 200 ml of ethyl acetate and 100 ml of water were added to 2.3 g (5.7 mmol) of 3-(4-chloro-2-methyl-3-nitrobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 1.6 g (28 mmol) of iron powder, followed by stirring for 2 hours under heating and refluxing. After completion of the reaction, insoluble matters were filtered off. The organic layer was washed sequentially with water and a sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.2 g (yield: 54%) of the desired product as pale yellow crystals. Melting point: 134-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9](=[CH:12]N(C)C)[C:10](=O)[C:4]=2[CH:3]=1.[NH:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:20]([NH2:22])=[NH:21]>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9]3[CH:12]=[N:22][C:20]([NH:19][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:10]=3[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Product: O=C1Cc2cnc(Nc3ccc(C(=O)O)cc3)nc2-c2cc(Br)ccc2N1

Procedure:
In a manner similar to method I, 7-bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-k) and 4-guanidinobenzoic acid were converted to I-25 (22%): HRMS Calcd. for C19H13BrN4O3: 425.0249, Found 425.0269.