Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:18][C:19](=[O:22])[CH2:20][Cl:21])[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.[I-].[Na+].[CH3:27][NH2:28].Cl>C1COCC1.C(OCC)(=O)C.C(#N)C.CCOCC.O>[ClH:21].[O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:18][C:19](=[O:22])[CH2:20][NH:28][CH3:27])[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1
Reactant: CN
Reactant: O=C1CCC(N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)C(=O)N1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCOCC
Product: CNCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
To a suspension of N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-2-chloroacetamide (0.95 g, 2.72 mmol) in THF (30 ml) was added sodium iodide (0.41 g, 2.72 mmol) and 2M methyl amine in THF (4.08 ml, 8.15 mmol). The mixture was stirred at room temperature for 5 hours. The solvent was evaporated in vacuo leaving a white solid. The solid was slurried in ethyl acetate (200 ml) for 2 h. The suspension was then washed with water (3×100 ml), brine (100 ml), and dried (MgSO4). The solvent was evaporated in vacuo leaving an off-white solid. The solid was dissolved in acetonitrile (20 ml) and to this solution was added 2M HCl in ether (2 ml). The mixture was stirred for 1 h and the solvent evaporated in vacuo. The residue was slurried in ethyl acetate for 3 h and filtered to give an off-white solid. The solid was dissolved in water (40 ml) and washed with ethyl acetate 2×50 ml). The pH of the aqueous portion was adjusted to 11-12 by dropwise addition of saturated aqueous sodium carbonate. The aqueous mixture was washed with ethyl acetate (3×100 ml). The combined ethyl acetate extracts were washed with brine (100 ml), and dried (MgSO4). The solvent was evaporated in vacuo leaving a white solid. The solid was dissolved in acetonitrile (15 ml) and 2M HCl in ether (2 ml) was added to the solution. The mixture was stirred for 1 h and the solvent was evaporated in vacuo leaving a white solid. The solid was slurried in diethyl ether (20 ml) and filtered to give 0.18 g (17%) of product as a white solid: mp 228-230° C.; 1H NMR (DMSO-d6) d 11.13 (s, 1H), 10.50 (s, 1H), 9.35 (bs, 2H), 8.28-8.21 (m, 1H), 7.93-7.63 (m, 2H), 5.15 (dd, J=5.1 and 12.6 Hz, 1H), 4.09 (s, 2H), 3.03-2.85 (m, 1H), 2.63-2.47 (m, 5H), 2.10-2.05 (m, 1H); 13C NMR (DMSO-d6) d 171.99, 169.03, 166.35, 166.07, 164.75, 135.63, 134.46, 131.56, 127.45, 119.14, 118.85, 49.56, 48.82, 32.49, 30.59, 21.69; Anal. Calcd. For C16H17ClN4O5: C, 48.99; H, 4.70; N, 14.28. Found: C, 48.82; H, 4.72; N, 14.02+0.64H2O.
Reaction SMILES: [C:1]([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].Br[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][C:39]([F:42])([F:41])[F:40])[CH:32]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][C:39]([F:41])([F:42])[F:40])[CH:32]=3)[CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)C1CCNCC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)C1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A cloudy solution of (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (32 mg, 0.078 mmol), 4-bromo-1-chloro-2-(trifluoromethyoxy)benzene (26 mg, 0.094 mmol), Pd(OAc)2 (2 mg, 8 umol), BINAP (5 mg, 8 umol), and Cs2CO3 (51 mg, 0.156 mmol) in 6 mL toluene was heated at 90° C. for 3 days. The mixture was cooled to room temperature, and filtered through Celite. The celite cake was rinsed with 5 mL EtOAc. The filtrate was poured into 5 mL water. Organic layer was separated, and the aqueous was further extracted with EtOAc (5 mL). The organic extracts were combined and concentrated by rotary evaporation. The crude was dissolved in a mixture of MeOH (1 mL) and DMSO (1 mL) and purified by reverse phase HPLC. Selected fractions were collected and concentrated by rotary evaporation to afford the title product as a colorless oil (34 mg). (400 MHz, CD2Cl2) b 8.19 (d, J=2.95 Hz, 1H), 7.31 (d, J=8.85 Hz, 1H), 6.87-6.80 (m, 2H), 5.05 (br s, 1H), 4.73-4.63 (m, 1H), 4.56-4.44 (m, 2H), 4.25-4.13 (m, 1H), 4.01-3.88 (m, 1H), 3.79-3.69 (m, 2H), 2.82-2.69 (m, 2H), 2.00-1.79 (m, 2H), 1.68-1.56 (m, 1H), 1.54-1.36 (m, 2H), 1.23 (d, J=6.87 Hz, 3H), 1.15 (s, 9H), 1.09 (d, J=6.44 Hz, 3H), HRMS(C) tR=5.61 min; MS m/z 604.2328 (M+H)+
Reaction SMILES: [CH2:1]([N:8]([CH:33]([CH3:35])[CH3:34])[C:9](=[O:32])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1>>[CH2:1]([N:8]([CH:33]([CH3:35])[CH3:34])[C:9](=[O:32])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:36][CH:37]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Reactant: O=Cc1c[nH]c2ccccc12
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 104.7 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-benzyl-N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 10) (13.9 g, 29.8 mmol) was condensed with 1H-indole-3-carbaldehyde (5.2 g, 35.8 mmol) for 48 hours. The volatiles were concentrated in vacuo to provide 18.5 g of N-benzyl-2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 8.01 (d, 1H), 7.67-7.50 (m, 4H), 7.43-7.11 (m, 12H), 6.99 (m, 1H), 6.99 (m, 1H), 6.80 (m, 1H), 4.96 (m, 1H), 4.71-4.49 (m, 4H), 4.23 (m, 1H), 1.20 (m, 6H); MS 593.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([CH:32]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33]1)=[CH2:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(=O)([O-])[O-].[Ag+2].C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[CH:31]=[CH:30][CH:32]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(I)c1)CCC2
Reactant: C=CC1CCC(=O)C1
Agent: [Ag+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=CC3CCC(=O)C3)c1)CCC2

Procedure:
4-(4-benzyloxy-3-iodo-phenoxy)-5-methyl-7-nitroindane (571 mg), 3-vinylcyclopentanone (197 μL), palladium acetate (II)(13 mg), triphenylphosphine (30 mg), and silver carbonate (189 mg) were stirred at 80° C. for 21 hours. To the reaction mixture were added water and ethyl acetate. The insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1−5/1) to give the title compound (155 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([NH2:27])=[O:26]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC(=O)CBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 33.1 %

Procedure:
The mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (6.77 g, 30.7 mmol), K2CO3 (5 g, 36.2 mmol) and 2-bromoacetamide (4.46 g, 32.3 mmol) in acetonitrile (250 ml) was heated to reflux for 4 hours. The insolubles were filtered and rinsed with dichloromethane (DCM). The solvents were removed. The residual solid was dissolved in DCM and upon concentration of this solution, 2.3 g of product crystallized out and was collected when the volume was reduced to about 50 ml. The rest of the product in DCM was purified by flash chromatography over a silica gel column (80 gm, SiO2 ; eluted with DCM and 1% CH3OH in DCM). The total product (4.2 g) thus purified was recrystallized from ethanol to yield 2.82 g of white crystals, m.p. 170-172° C. dec.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:20]O)[CH:8]=2)[NH:3]1.[Se](=O)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:8]=2)[NH:3]1
Reactant: O=C1Nc2ccc(-c3cccc(C=NO)c3)cc2C12CCCCC2
Agent: O=[Se]=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=O)N3)c1
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A solution of 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde oxime (0.48 g, 1.49 mmol) in chloroform (10 cm3) was treated with selenium dioxide (0.38 g, 3.50 mmol) and heated under reflux. After 16 h, the mixture was concentrated and the residue purified by column chromatography (SiO2, EtOAc:hexane 1:4) and the product re-crystallized from EtOAc-hexane to afford the title compound (0.161 g, 0.53 mmol, 35%) as a white solid: mp. 190-191° C.; 1H NMR (CDCl3) δ 1.59-1.87 (m, 6H), 1.88-2.09 (m, 4H), 7.03 (d, 1H, J=8 Hz), 7.42 (dd, 1H, J=8, 2 Hz), 7.54 (t, 1H, J=8 Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H, J=7, 2 Hz), 7.83 (m, 1H), 8.26 (s, 1H, br); MS ((+) ESI) m/z 303 (M+H)+.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]([NH2:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[Br:19][CH:20]([CH2:24][CH3:25])[C:21](Br)=[O:22].O>ClCCl>[Br:19][CH:20]([CH2:24][CH3:25])[C:21]([NH:11][C:8]([CH3:10])([CH3:9])[C:7]#[C:6][CH2:5][CH2:4][CH2:3][Cl:2])=[O:22]
Reactant: CC(C)(N)C#CCCCCl
Reactant: CCC(Br)C(=O)Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(Br)C(=O)NC(C)(C)C#CCCCCl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
The product from Step 2 (12.2 g) was suspended in dry dichloromethane (300 ml), cooled to 5° C. with stirring and dry triethylamine (18.1 ml) was added. The mixture was stirred for 0.25 hours and 2-bromobutyryl bromide (14.3 g) in dichloromethane (25 ml) was added dropwise over 0.5 hours at 10–18° C. The mixture was stirred for a further 0.5 hours then allowed to warm to ambient temperature for 2 hours and stored for 18 hours. Water was added and the organic phase was separated, washed with water (three times), dried over magnesium sulphate then evaporated under reduced pressure to give the required product as a dark yellow oil, 17.4 g, 1H NMR (CDCl3) δ: 1.04(3H, t); 1.62(6H, s); 1.96(2H, m); 2.10(2H, m); 2.38(2H, m); 3.66(2H, t); 4.12(1H, t); 6.44(1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.C(N(CC)CC)C.[S:37]([O:44]S(C(F)(F)F)(=O)=O)([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38].O>C(Cl)Cl.C(OCC)C>[F:41][C:40]([S:37]([OH:44])(=[O:39])=[O:38])([F:43])[F:42].[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4ccccc4O)c3c2)c1=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[3-(o-hydroxyphenyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.67 g, 8.75 mmol) and triethylamine (0.970 g, 9.63 mmol) in methylene chloride is cooled with an ice-water bath, treated with triflic anhydride (2.72 g, 9.63 mmol), stirred at room temperature overnight, and poured into water. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and a 3% diethyl ether in methylene chloride solution gives the title product as a white foam which is identified by NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].Cl.[NH2:13][C@@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[C:4]([C:3]1[C:2]([F:1])=[CH:9][C:8]([NH:13][C@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:19]([NH2:21])=[O:20])=[CH:7][C:6]=1[F:11])#[N:5]
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)C[C@@H](Nc1cc(F)c(C#N)c(F)c1)C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.1 %

Procedure:
To a solution of 2,4,6-trifluorobenzonitrile (208 mg, 1.32 mmol) in DMSO (2 mL), a solution of D-leucine amide hydrochloride (220 mg, 1.32 mmol) and DIEA (0.688 mL, 3.96 mmol) in DMSO (5 mL) was added. After being stirred at room temperature for 18 h, water and EtOAc were added. The organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with 20-80% EtOAc in hexane to give (R)-2-(4-cyano-3,5-difluorophenylamino)-4-methylpentanamide (92 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]([NH2:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH2:25]([NH:27][C:18]([C:17]1[CH:21]=[CH:22][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[C:15]([CH3:23])[CH:16]=1)=[O:20])[CH3:26]
Reactant: Cc1cc(C(=O)O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylbenzoic acid (0.866 g, 2.70 mmol), ethanamine hydrochloride (0.264 g, 3.24 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.777 g, 4.05 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.621 g, 4.05 mmol) were suspended in DMF (Volume: 3.68 ml) and 4-methylmorpholine (1.486 ml, 13.52 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h. It was diluted with water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with 1N HCl (aq., 25 mL), NaHCO3 (sat. aq., 25 mL), water (25 mL), brine (25 mL), dried (MgSO4), concentrated in vacuo and dried under vacuum to afford tert-butyl 4-(4-(ethylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (0.9327 g, 2.68 mmol, 99% yield) as a white solid. 1H NMR (DMSO-d6,400 MHz): δ=8.24 (t, J=5.4 Hz, 1 H), 7.66 (d, J=1.8 Hz, 2 H), 7.03 (d, J=8.3 Hz, 1 H), 3.42-3.52 (m, 4 H), 3.20-3.27 (m, 2 H), 2.78-2.87 (m, 4 H), 2.28 (s, 3 H), 1.43 (s, 9 H), 1.10 ppm (t, J=7.2 Hz, 3 H). ESI-MS: m/z 348.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[N+](C1C=CC=C([N+]([O-])=O)C=1C(O)=O)([O-])=O.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: NCC(=O)O
Agent: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]

Procedure:
As shown in scheme G, 2,6-dinitrobenzoyl chloride prepared from 2,6-dinitrobenzoic acid is treated with glycine in the presence of sodium carbonate to yield 2-(2,6-dinitrobenzamido)acetic acid (intermediate 10). Treatment of intermediate 10 either with K18F or K19F gave 2-(2-fluoro-6-nitrobenzamido)acetic acid, which on reduction with indium powder in the presence of either acetic acid or acetic anhydride-acetic acid gave the corresponding 2-(2-amino-6-fluorobenzamido)acetic acid (compound 8) or 2-(2-acetamido-6-fluorobenzamido)acetic acid (compound 9) respectively.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:37]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1)[CH3:38]
Reactant: CCBr
Reactant: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.6 %

Procedure:
A mixture of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide (32) (74 mg, 0.15 mmol), bromoethane (12 μL, 0.16 mmol) and potassium carbonate (63 mg, 0.46 mmol) in DMF (5 mL) was stirred for 48 h at room temperature under an inert atmosphere. The volatiles were removed under reduced pressure and the residue partitioned between ethyl acetate (20 mL) and saturated sodium hydrogen carbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organics were washed with brine then dried (MgSO4). The solvent was removed under reduced pressure and the resulting solid was chromatographed (Biotage Isolera: C-18 reverse phase column, 0-100% MeCN in H2O) to give the title compound (38) (22 mg, 28%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.65 (s, 1H), 8.37 (dd, J=4.8, 1.7 Hz, 1H), 7.65-7.57 (m, 3H), 7.55 (s, 1H), 7.26-7.13 (m, 3H), 7.02 (s, 1H), 3.54 (s, 2H), 3.25 (s, 4H), 2.98 (d, J=11.3 Hz, 2H), 2.48-2.30 (m, 3H), 1.95 (q, J=11.7, 11.3 Hz, 2H), 1.73 (d, J=10.5 Hz, 2H), 1.63 (qd, J=12.4, 3.6 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). LCMS Method C: rt 4.16 min; m/z 513 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[CH:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21](Br)[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:34]1.C([O-])(=O)C.[K+].OO.O.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[CH:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21]([OH:34])[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(Br)cc3c2ccn3-c2ccc(F)cc2)cc1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(O)cc3c2ccn3-c2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromo-1-(4-fluorophenyl)-1H-indole-4-carboxylic acid 4-methylsulfamoyl-benzylamide (0.1 g, 0.2 mmol), bis(pinacolato)diboron (0.1 g, 0.4 mmol), PdCl2(dppf) (0.04 g, 0.05 mmol), potassium acetate (0.05 g, 0.5 mmol) is charged in a sealed tube with anhydrous THF (7 mL). The solution is warmed at 80° C. for 16 hours. The reaction mixture is cooled to room temperature and quenched with water (15 mL) and diluted with CH2Cl2 (20 mL). The organic layer is separated and washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in THF (10 mL), and a solution of 30% H2O2 in water (0.15 mL, 0.5 mmol) and NaOH (0.01 g, 0.3 mmol) is added. The mixture is stirred at 10° C. for 3 hours and is then quenched with water (10 mL) and diluted with CH2Cl2 (20 mL). The organic layer is washed with brine (10 mL) and dried over sodium sulfate and concentrated in vacuo. The residue is purified by reversed-phase HPLC eluting with a gradient of 5-100% CH3CN in water. The desired fractions are combined and diluted with saturated aqueous NaHCO3 (20 mL) and EtOAc (20 mL). The organic layer is separated, dried over sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([Cl:10])[CH:3]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(Br)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 129 %

Procedure:
To a stirred solution of (4-bromo-2-chlorophenyl)methanol (4.34 g, 19.6 mmol) in dichloromethane (98 mL) at 0° C. is added carbon tetrabromide (6.5 g, 19.6 mmol) and triphenylphosphine (5.14 g, 19.6 mmol). The reaction mixture is stirred 16 h at room temperature. Then, the solvent is removed and the crude solid suspended in hexanes/EtOAc 9:1 (100 mL) and filtered on a silica gel pad. The pad is rinsed with hexanes/EtOAc 9:1 (100 mL) and the filtrate is concentrated in vacuo to provide the expected product 4-bromo-1-(bromomethyl)-2-chlorobenzene (7.19 g, 129%) contaminated with bromoform. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.57 (1H, d, J=2.0 Hz), 7.39 (1H, dd, J=8.2, 2.0 Hz), 7.30 (1H, d, J=8.2 Hz), 4.53 (2H, s).