Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29]>C1COCC1>[O:29]=[C:24]1[CH2:25][CH2:26][CH2:27][CH2:28][N:23]1[CH2:22][O:19][C:18]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20]
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: O=C1CCCCN1CCl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCN1CCCCC1=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
Heat at 50° C. a suspension of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (1.6 g, 5.49 mmol) in anhydrous THF (30 mL) in an oil bath for 20 min. Add a solution of N-(chloromethyl)-2-piperidone (850 mg, 5.76 mmol) in anhydrous THF (5 mL) dropwise. After 30 min, cool the reaction to ambient temperature. Add water (100 mL), and extract with ethyl acetate (3×100 mL). Combine the organic layers, wash with NaHCO3 (sat), water, brine, dry with MgSO4 and then concentrate. Purify the residue on an ISCO RediSep 35 gram silicagel cartridge, eluting with 5% methanol in ethyl acetate then 20% methanol in ethyl acetate. Combined product containing fractions and, concentrate to give the title compound as a white solid (520 mg, 26%): MS 365 (M+H), TLC (silica gel, MeOH/EtOAc 25:75) Rf=0.18, 1H NMR (DMSO-d6) δ 11.77 (1H, s), 8.46 (1H, s), 8.08 (2H, d, J=5.7 Hz), 7.50 (3H, m), 7.09 (1H, m), 6.58 (2H, d, J=6 Hz), 5.54 (2H, s), 3.27 (2H, br2), 2.23 (2H, brs), 1.66 (4H, brs). 13C NMR (DMSO-d6) δ 170.00, 160.43, 152.25, 149.44, 135.54, 125.60, 122.96, 121.84, 120.22, 119.87, 118.99, 113.00, 108.59, 70.99, 47.00, 31.99, 22.39, 20.60.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](O)=O)=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[N:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccc(Br)cn1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Br)cn2)o1
Yield: 39 %

Procedure:
As described for example 137a, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (4.14 g, 19.0 mmol) using 5-bromo-2-carboxy pyridine instead of 6-chloronicotinic acid was converted to the title compound (2.83 g, 39%) which was obtained as a brown solid. MS: m/e=385.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[NH:13][CH3:14].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C)C=O>[Cl:19][CH2:18][CH2:17][CH2:16][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[NH:13][CH3:14]
Reactant: CNc1cc(C(C)=O)ccc1O
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(C(C)=O)ccc1OCCCCl
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 134.5 %

Procedure:
To a stirred suspension of sodium hydride (0.87 g, 18.2 mmol of a 50% oil dispersion) in dimethylformamide (25 ml) under nitrogen and cooled to 0° in an ice-salt bath was added, dropwise, a solution of 1-(4-hydroxy-3-methylamino-phenyl)ethanone (3.0 g, 18.2 mmol) dissolved in dimethylformamide (55 ml) so that the temperature did not rise above 3° C. After the addition was complete, the reaction was stirred for 80 minutes at ambient temperature. The reaction was cooled to 5° C. and a solution of 1-bromo-3-chloropropane (3.1 g, 0.0120 mol) in dimethylformamide (20 ml) was added dropwise. After this addition was complete, the ice bath was removed and the reaction was stirred at ambient temperature for 2.5 hours. Water (75 ml) was carefully added and after stirring vigorously for 5 minutes, the reaction was left to stand overnight. The aqueous mixture was extracted with ethyl acetate and the ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 3.9 g of a dark solid. The compound was purified by preparative HPLC to afford 2.4 g of a beige solid. This was combined with an additional sample (3.8 g total) and two consecutive recrystallizations from ethanol gave 2.1 g (31%) of 1-[4-(3-chloropropoxy)-3-methyl-aminophenyl]ethanone as a fluffy, beige solid, m.p.=115°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.C1C(=O)N([I:19])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][CH:10]=[C:11]([I:19])[C:3]=12
Reactant: Cc1cc(Cl)c2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1cc(Cl)c2c(I)c[nH]c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a stirred solution of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (4.06 g, 24.37 mmol) in DCM (80 mL) at 0° C., was added NIS (6.22 g, 27.6 mmol). The reaction mixture was then warmed to RT and stirred for 18 hours. The reaction mixture was then filtered (washed with excess DCM) to give the title compound (4.01 g). LCMS (A): m/z (M+H)+ 293, C8H6ClIN2 requires 292 (acidic).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([Cl:18])=[CH:4][CH:3]=1.[O:19]1CCC[CH2:20]1.C[O-].[Na+]>CO>[CH3:20][O:19][C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([Cl:18])=[CH:4][CH:3]=1
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1Cl
Reactant: C1CCOC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCN(Cc1cnc(Cl)s1)c1nc(OC)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.5 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-chloropyridine-2-amine, prepared according to the example 11, and 20 mL of tetrahydrofuran were added in a 150 mL single neck flask equipped with a magnetic stirrer, after stirred at room temperature for 10 to 30 minutes, 0.25 g of sodium methoxide in 2.0 mL of methanol were added dropwise. The reaction mixture was stirred at the same temperature overnight, and then extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 1.20 g of crude product which was purified by a silica gel column chromatography using a petroleum ether/ethyl acetate (15/1) as an eluent to obtain 0.42 g of 6-methoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-chloropyridin-2-amine, having the content of 95.0% as a yellow viscous liquid, GC-MS (M+) (EI: 70 eV, m/z) calc: 317. found: 317. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.202 (t, J=7.2 Hz, 3H, CH3), 3.418 (q, J=7.2 Hz, 2H, CH2), 4.033 (s, 3H, CH3), 4.530 (d, J=0.6 Hz, 2H, CH2), 6.726 (d, J=8.1 Hz, 1H, Py H), 7.034 (s, 1H, Thiazole-H), 7.454 (d, J=8.1 Hz, 1H, Py H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].CON(C)[C:16](=[O:33])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([S:31][CH3:32])[CH:26]=2)=[CH:21][CH:20]=1>>[F:5][C:3]([F:6])([C:2]([F:8])([F:7])[F:1])[C:16](=[O:33])[CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([S:31][CH3:32])[CH:26]=2)=[CH:23][CH:24]=1
Reactant: CON(C)C(=O)C=Cc1ccc(-c2cccc(SC)c2)cc1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: CSc1cccc(-c2ccc(C=CC(=O)C(F)(F)C(F)(F)F)cc2)c1
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (203.5 mL, 162.8 mmol), was slowly added methyllithium/lithium bromide (1.5 M, in diethyl ether) (108.6 mL, 162.8 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of N-methoxy-N-methyl-3-(3′-methylsulfanyl-biphenyl-4-yl)-acrylamide (17.0 g, 54.3 mmol, in tetrahydrofuran 20.0 mL) prepared in Step 1 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with diethyl ether three times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to give 15.4 g of the titled compound as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.Cl.O.[CH3:12]O>>[CH3:12][O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1csc(Br)c1
Reactant: CO
Agent: Cl
Solvent: O
Product: COC(=O)c1csc(Br)c1
Temperature: 25 °C

Procedure:
Prepare a solution of 5-bromothiophene-3-carboxylic acid (500 mg, 2.41 mmol) in methanol (5 mL). Add concentrated hydrochloric acid (0.1 mL). Reflux the mixture for 3 hours, cool to room temperature, pour into water, and extract with diethyl ether (3×10 mL). Wash the combined organic phases with water (10 mL), then saturated aqueous sodium hydrogencarbonate (10 mL). Dry (magnesium sulfate), filter and concentrate. Perform flash chromatography on silica gel eluting with 5:1 hexane/ethyl acetate to afford 409 mg of 5-bromothiophene-3-carboxylic acid methyl ester as a white solid. 1H NMR (CDCl3) δ 8.10 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13]I.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: FC(F)(F)CCI
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)C1CCN(CCC(F)(F)F)CC1
Yield: 23.4 %

Procedure:
Prepared from isonipecotamide (2.85 g, 22.3 mmol), 3,3,3-trifluoropropyl iodide (5 g, 22.3 mmol) and potassium carbonate (3.08 g, 22.3 mmol) of according to the procedure used for Example 8 (Step A) to give 1.17 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](Br)[CH2:35][CH:36]([CH3:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCN([C@@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl [(3R,4R)-1-benzyl-4-{[(4-nitrophenyl)sulfonyl]amino}pyrrolidin-3-yl]carbamate (4.76 g, 10 mmol), isoamyl bromide (1.2 eq), and K2CO3 (2.76 g, 20 mmol) in 50 mL of DMF was stirred overnight at 50° C. The mixture was diluted with H2O, extracted with EtOAc, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5→20% EtOAc in hexane to give the title product.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[F:7][C:8]([F:31])([C:13]1[N:14]=[CH:15][C:16]([N:19]2[C:26]3[C@@H:25]4[CH2:27][C@@H:24]4[CH2:23][C:22]=3[C:21]([C:28](O)=[O:29])=[N:20]2)=[N:17][CH:18]=1)[C:9]([F:12])([F:11])[F:10]>>[OH:4][CH2:3][C:2]([NH:1][C:28]([C:21]1[C:22]2[CH2:23][C@H:24]3[CH2:27][C@H:25]3[C:26]=2[N:19]([C:16]2[CH:15]=[N:14][C:13]([C:8]([F:7])([F:31])[C:9]([F:12])([F:10])[F:11])=[CH:18][N:17]=2)[N:20]=1)=[O:29])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1nn(-c2cnc(C(F)(F)C(F)(F)F)cn2)c2c1C[C@H]1C[C@@H]21
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(C(F)(F)C(F)(F)F)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using 2-amino-2-methylpropan-1-ol and (1aR,5aR)-2-(5-(perfluoroethyl)pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid. LCMS m/z=432.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.7, 3.3 Hz, 1H), 1.29 (td, J=8.0, 4.9 Hz, 1H), 1.42 (s, 6H), 2.30-2.37 (m, 1H), 2.75-2.79 (m, 1H), 2.93 (d, J=16.9 Hz, 1H), 3.02 (dd, J=16.7, 6.3 Hz, 1H), 3.71 (d, J=6.1 Hz, 2H), 4.40 (d, J=6.1 Hz, 1H), 6.93 (s, 1H), 8.78 (d, J=1.3 Hz, 1H), 9.35 (d, J=1.0 Hz, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:34]([CH3:36])[CH3:35])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3C(C)C)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a light brown foam (42%).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Reactant: C1CNCCN1
Solvent: ClC(Cl)Cl
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)N2CCNCC2)CC1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A solution of 3.45 g of 2-tert-butyl-6-isothiocyanato-5-(4-methylpiperidin-1-yl)benzothiazole, described in Example 1, and 8.6 g of anhydrous piperazine in 30 ml of chloroform is stirred for 3 hours, washed with water, dried over anhydrous sodium sulphate and evaporated to get a sticky residue which is triturated with isopropanol and filtered to obtain 3 g of 2-tert-butyl-5-(4-methyl-piperidin-1-yl)-6-[(piperazin-1-yl)thiocarbonylamino]benzothiazole, melting at 278°-281°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.77 (br s, 1H, NH), 8.44 (dm, 1H, J=2.2 Hz), 7.87 (d, 2H, J=8.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.60 (dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.36 (d, 1H, J=2.2), 7.26 (d, 1H, J=8.0 Hz), 3.00 (s, 3H), 2.66 (s, 3H). MS: m/z 465 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Prepared according to procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.94 g, 7.8 mmol) (described herein), 2-(tributylstannyl)pyridine (2.9 mL, 7.8 mmol), and tetrakis(triphenylphosphine)palladium(o) (0.69 g, 0.59 mmol) in toluene. The reaction was stirred at 100° C. for 18 h, then cooled to rt, concentrated, and the resulting residue triturated with hexanes. Column chromatography afforded 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinoline as a white solid. Mass Spectrum (ESI) m/e=291 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[C:31]([S:34][CH2:35][CH:36]([CH3:40])[C:37](Cl)=[O:38])(=[O:33])[CH3:32]>ClCCl>[C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:37](=[O:38])[CH:36]([CH3:40])[CH2:35][S:34][C:31](=[O:33])[CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred solution of L-prolyl-L-phenylalanine tert-butyl ester (1.0 g) [prepared by the method described in Ann. Chem. 680, 132-141 (1964)] in dichloromethane at about -30° C. were added N-methylmorpholine (0.32 g) and then dropwise 3-acetylthio-2-methylpropanoyl chloride (0.57 g). The mixture was stirred at the same temperature for 30 minutes and then at room temperature for one hour. The reaction mixture was washed successively with 4% sodium bicarbonate, water, 10% citric acid, and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel with chloroform to give 1-(3-acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([NH2:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:22]>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([N:19]=[C:21]=[S:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(F)(F)F)c(N)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(F)(F)F)c(N=C=S)c1
Yield: 86 %

Procedure:
The sub-title compound was prepared from tert.-butyl-N-(3-amino-4-trifluoromethyl-benzyl)carbamate with 1,1′-thiocarbonyldi-2-pyridone in analogy to example 1d.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([CH2:9][OH:10])[O:8][C:4]=2[C:3]=1[Cl:13].S(=O)(=O)(O)[OH:15].O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:7]([C:9]([OH:15])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:13]
Reactant: OCC1Cc2ccc(Cl)c(Cl)c2O1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6,7-dichloro-2,3-dihydro-2-hydroxymethylbenzofuran (10.4 gm.) in acetone (200 ml.) cooled to 20° C. is added an oxidizing solution prepared from chromium trioxide (6.0 g.), concentrated sulfuric acid (5.3 ml.) and water (43 ml.) over a one-half hour period. The reaction mixture is stirred at 25° C. for 18 hours. The acetone layer is separated from the precipitated chromium salts, added to water (600 ml.) and extracted with ether (2×150 ml.). The ether extract is washed with water then extracted with aqueous sodium bicarbonate. Acidification of the basic solution gives 3.4 g. of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid which is purified by reprecipitation from aqueous sodium hydroxide with aqueous hydrochloric acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[N+:8]([C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][OH:11])=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: OCc1ccc(B(O)O)cc1
Product: O=[N+]([O-])c1cccc(-c2ccc(CO)cc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using 1-bromo-3-nitrobenzene instead of tert-butyl N-(4-bromobenzyl) carbamate and 4-hydroxymethylphenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([O:43][CH3:44])[CH:37]=1>>[OH:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][NH:33][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:15]([CH3:18])(=[O:16])=[O:17])[CH:31]=[CH:30][N:29]=2)=[CH:37][C:38]=1[O:43][CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Reactant: COc1cc(CCN)ccc1O
Product: COc1cc(CCNc2nccc(-c3cccc(CN(C4CCNCC4)S(C)(=O)=O)c3)n2)ccc1O

Procedure:
Intermediate 30 was coupled with 4-(2-amino-ethyl)-2-methoxy-phenol following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 512. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.0 (d, 2H) 7.6 (m, 2H), 7.5 (t, 1H), 7.2 (d, 1H), 6.8 (d, 1H), δ 6.7 (s, 1H), 4.5 (d, 2H), δ 3.8 (s, 3H), 3.3 (t, 2H), δ 3.0 (s, 3H), 2.9 (m, 5H), δ 2.8 (t, 2H), δ 2.0 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[OH-].[Na+]>O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[O:10])[CH3:9])[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccccc1N1CCN(C)CC1

Procedure:
A mixture of 55.2 g. of o-fluoroacetophenone and 100 ml. of N-methyl-piperazine is heated at 95°-100° for 19 hours, then cooled and poured into 1600 ml. of water containing 22 ml. of 50% aqueous sodium hydroxide. The mixture is extracted with three 300 ml. portions of ether. The combined ether extract is washed thoroughly with water, then with saturated aqueous sodium chloride, dried and evaporated to give o-(4-methyl-1-piperazinyl)acetophenone as a viscous oil, suitable for use without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].S(Cl)([Cl:15])=O>>[Cl:15][C:4]1[C:3]([C:9]([F:10])([F:11])[F:12])=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: Oc1ccc(F)c(C(F)(F)F)c1Cl

Procedure:
4-Fluoro-3-(trifluoromethyl)phenol was chlorinated with thionyl chloride to afford 2-chloro-4-fluoro-3-(trifluoromethyl)phenol.