Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][Si](C)(C)C)=[N:4][C:5]([O:8][Si](C)(C)C)=[N:6][CH:7]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].II.[OH-].[Na+]>ClCCCl.O>[Cl:22][CH2:21][CH2:20][CH2:19][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:13])[NH:4][C:5]1=[O:8]
Reactant: ClCCCBr
Reactant: C[Si](C)(C)Oc1ncc(F)c(O[Si](C)(C)C)n1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCl)cc1F

Procedure:
A mixture of 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine (1 g, commercially available from Lancaster), 1-bromo-3-chloropropane (0.44 mL) and I2 (10 mg) in 1,2-dichloroethane (10 mL) was heated to reflux for 30 h. Then the reaction mixture was treated with water and the pH was brought to 7 using aqueous 6N NaOH solution, the mixture was extracted twice with DCM, the organic phase dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with DCM/MeOH 95/5 to give 35 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[ClH:25].Cl.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][C@@H:36]([N:38]2[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]2)[CH3:37])[CH2:31][CH2:30]1>>[ClH:25].[ClH:25].[OH:44][CH:41]1[CH2:40][CH2:39][N:38]([C@@H:36]([CH3:37])[CH2:35][N:32]2[CH2:31][CH2:30][CH:29]([NH:28][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:34][CH2:33]2)[CH2:43][CH2:42]1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5cc(F)ccc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 50 analogously to the method described in example 1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N+:30]([C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:37][CH:38]=1)([O-])=O>>[NH2:30][C:33]1[CH:34]=[CH:35][C:36]([N:39]([CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[N:24]=[CH:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:21][CH2:22]2)[C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Product: CC(C)(C)OC(=O)N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(N)cn1

Procedure:
The title compound was synthesized by procedure analogous to Step 2 and 3 of Example 28 from 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from Step 1 of Example 5 and tert-butyl (5-nitropyridin-2-yl)carbamate from Step 1 of this example.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O.CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:34][O:33][CH2:32][C@H:31]([CH3:35])[O:30][C:15]1[CH:14]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:1][CH2:2][CH2:3][CH2:4][N:5]=3)=[CH:12][CH:11]=2)[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:16]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCO)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCCO3)[nH]2)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
N-(3-Hydroxypropyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (216 mg, 0.430 mmol) synthesized in Example (37a) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (115 mg, 0.660 mmol) and triethylamine (0.18 mL, 1.29 mmol) were added, followed by stirring at room temperature for 4 days, further at 80° C. for 17 hours, under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired product (150 mg, yield 72%) as a pale brownish solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[P:21]([O-])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C>[O:20]=[C:17]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[O:13][C:14]4[CH:15]=[CH:16][C:3]([CH2:2][O:1][P:21](=[O:22])([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:4][C:5]=4[C:6]([C:7]=23)=[N:19][NH:18]1
Reactant: O=c1[nH]nc2c3c(cccc13)Oc1ccc(CO)cc1-2
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1[nH]nc2c3c(cccc13)Oc1ccc(COP(=O)(OCc3ccccc3)OCc3ccccc3)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of compound 57 (0.25 mmol) in anhydrous DMF was added dibenzyl phosphate (0.80 mmol) and triphenylphosphine (0.80 mmol). The reaction mixture was stirred while diisopropyl azodicarboxylate was added slowly. The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed in vacuo. To the residue, 100 mL of ethyl acetate was added. The organic layer was washed with water and brine, then dried with MgSO4. The Solvents were removed to afford a yellow oil. The oil was re-crystallized in EtOAc/Hexanes to afford an off-white solid 60 in 40% yield. MS (ES+): 527; Mp: 223-225° C.; 1H-NMR (CDCl3, 400 MHz): 9.91 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.11 (dd, J=8.0 and 1.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.59 (dd, J=8.0 and 1.0 Hz, 1H), 7.45 (dd, J=8.5 and 1.0 Hz, 1H), 7.36-7.26 (m, 11H), 5.08 (m, 6H). Anal. Calcd. for C29H23N2O6P.(0.15hydrazine): C, 65.56; H, 4.48; N, 6.06. Found: C, 65.55; H, 4.33; N, 6.09.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[SH:9].Br[C:11]1[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][C:11]1[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1
Reactant: Cc1ccc(F)cc1S
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1Sc1cc(C(=O)O)co1

Procedure:
In an open flask cuprous oxide (500 mg., 3.5 mmoles) and 2-methyl-5-fluorothiophenol (1.0 g., 7 mmoles) were combined in 35 ml. of dimethylformamide and heated in an oil bath at 135°-140° C. for 2.5 hours. The mixture was cooled slightly, 5-bromofuran-3-carboxylic acid (668 mg., 3.5 mmoles) was added and the mixture refluxed for approximately 16 hours. Crude product was isolated according to Example 16. The resulting oil was crystallized by trituration with water (170 mg.). Recrystallization from methanol/water gave purified 5-(2-methyl-5-fluorophenylthio)furan-3-carboxylic acid (125 mg., m.p. 150°-152° C., m/e 252).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccncc1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Product: O=C(Nc1ccncc1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-aminopyridine (Aldrich), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. 1H NMR (300MHz, DMSO-d6) δ [ppm] 10.82 (1H, s), 8.56 (1H, s), 8.47 (2H, d, J=5.0 Hz), 7.89 (2H, d, J=5.0 Hz), 7.84 (1H, d, J=9.0 Hz), 7.16 (1H, s), 3.88 (1H, m), 1.91-1.57 (5H, m), 1.39-1.16 (5H, m). MS (ESI): 298.0. HPLC (Condition A): Rt 2.12 min (HPLC purity 99.4%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17].CC1C(/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=C(OC)C(OC)=C(OC)C=1OC>>[CH3:1][C:2]1[C:7](/[CH:8]=[C:26](\[CH3:25])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: CCOC(=O)/C=C/c1c(C)c(OC)c(OC)c(OC)c1OC
Product: CCOC(=O)/C(C)=C/c1c(C)c(OC)c(OC)c(OC)c1OC

Procedure:
Compound 8b was prepared from 7 (0.569 g, 2.37 mmol) as described above for 8a to give 0.674 g (2.08 mmol, 88%) of the product as a yellow oil following flash chromatography (1:3 EtOAc:hexanes).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].CCN(CC)CC.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ClCCNCCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a suspension of bis(2-chloroethyl)amine hydrochloride (4.68 g, 26.2 mmol) in dry THF (50 mL) was added Et3N (18.3 mL, 131 mmol) at 0° C. and the mixture was stirred for 15 min. p-Toluenesulfonyl chloride (5.00 g, 26.25 mmol) and DMAP (a spatula pinch) were added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. When TLC analysis showed complete conversion, the mixture was filtered to remove the Et3N.HCl and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography to afford N,N-bis(2′-chloroethyl)-4-methylbenzenesulfonamide (6.22 g, 80% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[NH:9][N:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:11]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:8][N:9]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccn3)n[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.3 %

Procedure:
tert-Butyl 4-(3-pyridin-2-yl-1H-pyrazol-5-yl)piperidine-1-carboxylate (1.46 g, 4.45 mmol) was dissolved in 15 ml DCM. Trifluoroacetic acid (5 ml) was added gradually and the resulting solution was stirred at ambient temperature for 3 h and was then concentrated in vacuo. The residue was dissolved in 4:1 MeOH/water and treated with MP-carbonate resin (5 g, 2.55 mmol/g). After stirring overnight the reaction was filtered and the filtrate was concentrated in vacuo to provide 1.1 g of 2-(3-piperidin-4-yl-1H-pyrazol-5-yl)pyridine (1-4) as a tan solid. δ 8.56 (d, J=3.9 Hz, 1H), 7.84 (m, 2H), 7.21 (m, 1H), 6.65 (s, 1H), 3.22 (m, 3H), 2.87 (m, 2H), 2.03 (d, J=12.8 Hz, 2H), 1.71 (d, J=10.3 Hz, 2H). m/z (m+1): 229.3,
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:25][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(c2ccccc2)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Bromodiphenylmethane (3.5 g) and 3-fluoro-4-nitrophenol were dissolved in N,N-dimethylformamide (30 mL), and then K2CO3 (4.2 g) was added and the reaction stirred at room temperature for 60 hours. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with 2.11 aqueous Na2CO3 and brine, then dried over Na2SO4. After filtration and concentration, the crude material was purified by column chromatography using 1.5-2.0% ethyl acetate in hexanes.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[C:23]4[C:29]([C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:28][N:27](COCC[Si](C)(C)C)[C:24]4=[N:25][CH:26]=3)=[CH:16][CH:15]=2)[C:11]#[N:12])=[O:9])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10](=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:22]=[C:23]4[C:29]([C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:28][NH:27][C:24]4=[N:25][CH:26]=3)=[CH:18][CH:19]=2)[C:11]#[N:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)C(C#N)=Cc2ccc(Nc3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)C(C#N)=Cc2ccc(Nc3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)cc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
To a 35 ml vial, 2-(4-methylpiperazine-1-carbonyl)-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile (0.100 g, 0.0001 mole) was taken in CH2Cl2 (8 ml) and cooled to 0° C. under N2 atm. TFA (2 ml, 0.0238 mole) was added drop wise at 0° C. and stirred for 16 h at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure from the reaction mixture and saturated NaHCO3 solution was added dropwise to make pH basic. The solid which precipitated out was filtered and washed with water and pentane. The solid (0.050 g) was taken in ethanol (20 ml), NaOAc.3H2O (0.226 g, 0.0016 mole) was added and the reaction mixture and stirred at room temperature for 32 hr. Ethanol was evaporated under reduced pressure from the reaction mixture and obtained solid material was washed with water and pentane. The crude compound was purified by triturating with pentane to yield 0.017 g of 2-(4-methylpiperazine-1-carbonyl)-3-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:23][C@H:20]1[CH2:19][CH2:18][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccncc4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccncc4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-(cyclopropanecarbonyl)-6-(pyridin-4-yl)quinolin-4-ylamino]cyclohexylcarbamate (50 mg, 0.100 mmol) was reacted with TFA (2 mL) to afford the desired product (14.9 mg, 39%) as a yellow solid: NMR (500 MHz, CD3OD) δ 9.26 (s, 1H), 8.70 (dd, J=4.6, 1.6 Hz, 2H), 8.65 (s, 1H), 8.30 (dd, J=8.7, 1.7 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.87 (dd, J=4.6, 1.7 Hz, 2H), 4.31 (br s, 1H), 3.28-3.22 (m, 1H), 2.91-2.82 (m, 1H), 2.41 (d, J=13.2 Hz, 2H), 2.20 (d, J=11.3 Hz, 2H), 1.82-1.69 (m, 2H), 1.67-1.55 (m, 2H), 1.28-1.23 (m, 2H), 1.20-1.16 (m, 2H); ESI MS m/z 387 [C24H26N4O+H]+; HPLC 95.0% (AUC), tR=8.34 min.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:23]=[CH:22][C:13]2[S:14][C:15]([S:18](Cl)(=[O:20])=[O:19])=[C:16]([CH3:17])[C:12]=2[CH:11]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:18]([C:15]1[S:14][C:13]2[CH:22]=[CH:23][C:10]([Cl:9])=[CH:11][C:12]=2[C:16]=1[CH3:17])(=[O:20])=[O:19]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1Br
Yield: 18 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-chloro-3-methylbenzo[b]thiophene-2-sulphonyl chloride in 18% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 153°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH2:37]([NH2:47])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1>>[O:43]1[C:44]2[CH:45]=[CH:46][C:38]([CH2:37][NH:47][C:23](=[O:24])[CH:22]([N:8]3[CH2:9][CH2:10][CH2:11][C:12]4[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=4[CH:7]3[CH2:6][C:5]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:39][C:40]=2[O:41][CH2:42]1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1ccc2c(c1)OCO2
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccc3c(c2)OCO3)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with piperonylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[C:14]([F:20])=[C:15]([O:18]C)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[C:14]([F:20])=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2cc(Cl)cnc2ccc2ccc(O)c(F)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-chloro-6-fluoro-7-methoxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (2.0 g, 6.9 mmol) in CH2Cl2 (100 mL) was added BBr3 (1 M in CH2Cl2, 27.6 mL, 27.6 mmol) at −78° C. The mixture was allowed to warm to room temperature as the bath did. After 6 h at room temperature, the mixture was cooled to 0° C. and treated with aqueous NaHCO3 solution. The yellow precipitate was filtered, washed with CH2Cl2, and dried under high-vacuum overnight to afford the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 8.93 (d, 1H); 8.28 (d, 1H); 7.46 (d, 1H); 7.37 (d, 1H); 7.33 (t, 1H); 7.08 (d, 1H). LRMS (ESI) calc'd for (C14H7ClFNO2) [M+H]+, 276.0; found 276.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:44]=[CH:45][CH:46]=1)[C:38]([NH:40][CH:41]1[CH2:43][CH2:42]1)=[O:39].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:45]2[CH:46]=[CH:35][CH:36]=[C:37]([C:38](=[O:39])[NH:40][CH:41]3[CH2:43][CH2:42]3)[CH:44]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC1)c1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NC1CC1)c1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (93.7 mg, 0.21 mmol), 3-bromo-N-cyclopropyl-benzamide (50.0 mg, 0.21 mmol), and Pd[P(Ph)3]4 (12.8 mg, 5.3 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.1 mg. MS: 484.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.54-0.78 (m, 4H), 1.77-2.05 (m, 3H), 2.14-2.37 (m, 1H), 2.80-2.94 (m, 1H), 3.40-3.58 (m, 2H), 4.30-4.44 (m, 1H), 4.38-5.14 (m, 2H), 7.00-8.07 (m, 13H), 8.49-8.59 (m, 1H), 10.10-10.09 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[C:10]([OH:12])=[O:11].[OH-].[Na+].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O.O1CCOCC1>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C@@H:2]2[C:10]([OH:12])=[O:11])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)[C@H]1Cc2ccccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of (R)-2,3-dihydro-1H-indole-2-carboxylic acid (2.89 g, 14.5 mmol) and 1N sodium hydroxide (37.7 mL, 37.7 mmol) in water (79 mL) stirring at room temperature is added dropwise a solution of 4-benzyloxybenzenesulfonyl chloride (4.1 g, 14.5 mmol) in dioxane (104 mL). Upon completion of the addition, the pH of the reaction mixture is monitored and maintained between 7–8 by slow addition of 1N aqueous sodium hydroxide over the next 2 hours. The reaction mixture is stirred overnight at room temperature. The solution is poured into crushed ice and the resulting mixture is acidified to pH 2–3 with 1N aqueous hydrochloric acid (15 mL). The product is extracted into dichloromethane (2×150 mL). The extract is washed with water (150 mL), brine (150 mL), dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated to give 5.5 g of (R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid as an oil: [M+1]+=410.32, [M−1]−=408.24.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:29](=[O:30])[CH2:28][Cl:27])[CH:9]=2)=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: CNc1ccc(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNc1ccc(Oc2ccnc(NC(=O)CCl)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-amine (1 eq) and triethylamine (2 eq) in tetrahydrofuran was treated with 2-chloroacetyl chloride and stirred for 15 minutes at room temperature. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuum to give crude product. Purification on silica gel with 2% methanol in methylene chloride gave N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide as a bright orange solid. HPLC=3.82 min; MS: MH+=337.