Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]([OH:14])=O)[CH:10]=1)=[O:5])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH2:37]>ClCCl.O>[C:41]([O:40][C:38]([NH:36][NH:37][C:12](=[O:14])[CH2:11][N:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOC(=O)c1cnn(CC(=O)O)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(CC(=O)NNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A solution of the compound (9.4 g) obtained in Example 115b, N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (18.1 g) and 1-hydroxybenzotriazole (6.5 g) in dichloromethane (100 mL) was cooled to −20° C., and a solution of tert-butyl hydrazinecarboxylate (9.5 g) in dichloromethane (20 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether/ethyl acetate/triethylamine=10/1/0.001) to give ethyl 1-{2-[2-(tert-butoxycarbonyl)hydrazino]-2-oxoethyl}-1H-pyrazole-4-carboxylate (9.2 g) as a colorless solid. The solid was dissolved in ethyl acetate (50 mL), and hydrogen chloride-ethyl acetate (50 mL) was added. The mixture was stirred at room temperature for 1 hr, and the precipitate was collected by filtration to give the title compound (6.0 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[NH:40][C:41]([C:43]1[C:51]2[NH:50][C:49]([NH2:52])=[N:48][C:47]=2[CH:46]=[CH:45][CH:44]=1)=[O:42]>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:37]1[CH:38]=[CH:39][N:35]=[C:36]1[NH:40][C:41]([C:43]1[C:51]2[N:50]=[C:49]([NH:52][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:48][C:47]=2[CH:46]=[CH:45][CH:44]=1)=[O:42]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc(Cl)cc1
Yield: 19.7 %

Procedure:
70 mg (0.45 mmol) of 4-chloro-benzoic acid 170 mg (0.45 mmol) of HBTU in a mixture of 3 ml of DMF and 1 mL of DIEA was reacted with 100 mg (0.4 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide synthesized above as described in general procedure A and 2-(4-chloro-benzoylamino)-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (30 mg, 17.24%) was isolated. LCMS: 382 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 11.99 (d, 1H), 8.16 (d, 2H), 7.94 (d, 1H), 7.70 (dd, 3H), 7.30 (t, 1H), 6.81 (d, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([C:18](=[O:19])[CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:10]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Brc1ccc2sccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1csc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 5-bromobenzothiophene (1 g) and phenylacetyl chloride (1.1 g) in dichloromethane (50 mL) was added aluminum chloride (1.9 g) at 0° C. and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into an ice-cooled hydrochloric acid aqueous solution (2 mol/L) and the mixture was extracted with diethyl ether. The organic layer washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1). After the solvent was removed, the residual solid washed with hexane to give the title compound (1.1 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: CC1(c2ccccn2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccccn2)CN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.7 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) was dissolved in 20 mL DMF and stirred for 10 min at RT. Sodium hydride (180 mg, 7.5 mmol) was added portionwise at RT and the mixture stirred for 10 min. 2-(2-Methyl-oxiranyl)-pyridine (472 mg, 3.5 mmol) was added dropwise at the same temperature and stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated and the residue was crystallized in hexane to obtain 115 mg of 1-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-2-yl-propan-2-ol. 1HNMR (CDCl3, freebase) δ (ppm): 8.51 (d,1H), 7.65 (t,1H), 7.29 (d, 1H), 7.22 (d,1H), 7.20 (s,1H), 6.95 (d,1H), 6.85 (d, 1H), 4.9 (bs,1H), 4.18 (s, 2H), 3.21 (dd, 2H), 2.77 (m, 2H), 2.69 (m, 2H), 2.42 (d, 6H), 1.63 (s, 3H). Separation by chiral HPLC provided enantiomers 16a and 16b. Optical rotations: Compound 16a, (−)5.77(c 0.52, Chloroform, 98.11% HPLC purity); Compound 16b, (+)5.85 (c 0.51, Chloroform, 98.06% HPLC purity).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:18][CH:15]1[CH2:17][CH2:16]1)=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2 g (9.11 mmol) of 2-chloro-4-fluoro-5-nitrobenzoic acid were dissolved in 91 g of dichloroethane, 22.66 g of thionyl chloride were added and the mixture was boiled until the evolution of gas had ended. The volatile constituents were distilled off and the acid chloride thus obtained was used directly in the next step. 2.166 g (9.1 mmol) of 2-chloro-4-fluoro-5-nitrobenzoyl chloride were dissolved in 100 ml of dichloromethane, this solution was cooled to 0° C., and 0.52 g (9.1 mmol) of cyclopropylamine and 1.38 g (13.65 mmol) of triethylamine were added together, predissolved in 5 ml of dichloromethane. After stirring at room temperature for two hours, the volatile constituents were distilled off, the resulting residue was slurried with a little diethyl ether, the diethyl ether phase was decanted off and the residue was stirred with water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2O[C:10](=[O:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1.[NH2:21][CH2:22][C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:21]([CH2:22][C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:10](=[O:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NC(=O)CN
Reactant: COc1ccc2cc(-c3cccc(Cl)c3)oc(=O)c2c1
Solvent: CCO
Product: COc1ccc2cc(-c3cccc(Cl)c3)n(CC(=O)NC(C)C)c(=O)c2c1
Temperature: 120 °C
Yield: 73.4 %

Procedure:
In an open, 50 mL two-necked round bottom flask, a neat mixture of compound 3-(3-chlorophenyl)-7-methoxyisochromen-1-one (1.00 g, 3.49 mmol) and 2-amino-N-isopropylacetamide (INTERMEDIATE I.1) (2.02 g, 17.4 mmol, 5 eq) was heated to 120° C. under argon for 3 days, adding absolute EtOH in aliquots (2 mL) daily to loosen up the reaction mixture. The residue was purified by chromatography on silica gel with ethyl acetate:hexane (1:3, v/v) as eluent to give 2-[3-(3-chlorophenyl)-7-methoxy-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (0.985 g, 2.56 mmol, 73%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:24]=1)([CH3:3])[CH3:2].O.[Li+].[OH-].Cl>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:24]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(Nc2ncnc3nc(C(C)C)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cccc(C(=O)O)c3)ncnc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 149.2 %

Procedure:
The product from Example 7A (1.0 g, 3.26 mmol) was dissolved in THF (12.0 mL) and water (12.0 mL) and LiOH (390 mg, 16.29 mmol) was added and the reaction was stirred at room temperature overnight. Reaction was neutralised with 1 N HCl and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated to give the title compound (1.5 g).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]2.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42])[C:34](Cl)=[O:35]>ClCCl>[Cl:30][C:31]1[CH:32]=[C:33]([C:34]([O:1][NH:2][C:3](=[NH:22])[C:4]2[C:5]([CH3:21])=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:8][CH2:7]3)=[O:35])[CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42]
Reactant: Cc1c(C(=N)NO)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=N)NOC(=O)c2ccc(OC(C)C)c(Cl)c2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of 1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 17; 435 mg; 1.42 mmol) in dichloromethane (10 ml) was added triethylamine (0.30 ml; 2.14 mmol) followed by 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (Preparation 8; 365 mg; 1.57 mmol) in dichloromethane (5 ml). After 30 min, the reaction was concentrated, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with a gradient of 10-50% ethyl acetate in cyclohexane gave the title compound as a white foam (413 mg).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:3]=1[CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[CH2:15]=O>Cl.O>[Br:1][C:2]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:3]=1[CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[NH:6][CH2:15]2
Reactant: N[C@H](Cc1cc(O)ccc1Br)C(=O)O
Reactant: C=O
Agent: Cl
Solvent: O
Product: O=C(O)[C@H]1Cc2c(Br)ccc(O)c2CN1
Temperature: 90 °C
Yield: 75 %

Procedure:
Slurry 2-bromo-5-hydroxy-(D)-phenylalanine (1.87 g, 0.00719 mol) in 0.05 M hydrochloric acid (10.7 mL) and add 37% formaldehyde solution in water (1.02 mL). Heat at 90° C. for one hour. Cool to room temperature, filter, and wash with water (2×) and acetone (2×) and dry in a vacuum oven to give the desired product (1.53 g, 75%) as a light pink solid.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][CH2:30][N:29]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCNC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCN(S(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(3-piperidinyl)-1,3-propanediamine (155 mg, 0.28 mmol) and DIPEA (1 mL) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (0.5 mL) at 0° C. The resulting mixture was stirred for 16 hrs at room temperature. After dilution with water, the organic layer was separated, and the aqueous layer was further extracted with CH2Cl2 (3×15 mL). The combined organic fractions were dried over Na2SO4, and the solvent removed under vacuum. The residue was chromatographed on alumina eluting with CH2Cl2/MeOH (97:3) to give partially pure material, which was further purified by chromatography on silica eluting with CH2Cl2/MeOH (97:3) to give N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-[1-(methylsulfonyl)-3-piperidinyl]-1,3-propanediamine (125 mg, 72% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH2:5]2.[Br:14]C1C=CC2C(=CC=CC=2)C=1Br.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:14][CH:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6]1
Reactant: CC1(C)CCCc2cc(Br)ccc21
Reactant: Brc1ccc2ccccc2c1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Product: CC1(C)CCC(Br)c2cc(Br)ccc21

Procedure:
Employing the above-described procedure for the conversion of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) to the dibromonaphthalene derivative (Compond I), 3.5 g (14.6 mmol) of (Compound F), 2.86 g (16.1 mmol) of N-bromosuccinimide and 150 mg (0.62 mmol) of benzoylperoxide gave crude 4,6-dibromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound I). To a solution of this crude dibromonaphthalene derivative (Compound I) in 50 ml of THF was added 5.38 g (47.1 mmol) of potassium thioacetate. The mixture was refluxed for 6 hours under argon atmosphere, filtered through celite and concentrated in vacuo. Purification by chromatography (silica, 10% EtOAc-hexane) yielded the title compound as red oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[C:35]([N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1)(=[O:37])[CH3:36]>C1COCC1>[C:35]([N:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:2]2[N:7]=[C:6]([C:8]3[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[F:33])(=[O:24])=[O:25])[CH:21]=3)[CH:5]=[CH:4][N:3]=2)[CH2:40][CH2:39]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Nc2nccc(-c3sc(C(C)C)nc3-c3ccc(F)c(NS(=O)(=O)c4cc(F)ccc4F)c3)n2)CC1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) and 1-acetyl-4-piperidinamine (0.27 g, 1.9 mmol) in THF (1 mL) the title compound was obtained as an off-white solid (0.075 g, 0.12 mmol, 62% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 8.12 (d, J=5.0 Hz, 1H), 7.68-7.43 (m, 3H), 7.44-7.17 (m, 5H), 4.33-4.18 (m, 1H), 3.83-3.73 (m, 1H), 3.44-3.20 (m, 2H), 2.66-2.32 (m, 4H), 1.99 (s, 3H), 1.36 (d, J=6.8 Hz, 6H), 1.35-1.10 (m, 2H). MS (ESI): 631 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8](=[O:20])[N:7]([CH3:21])[C:6]=2[S:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:2][C:3]2[C:11]3[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8](=[O:20])[N:7]([CH3:21])[C:6]=3[S:5][C:4]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCn1c(=O)c2c(CBr)c(-c3cccc(OC(F)(F)F)c3)sc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCn1c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)sc2n(C)c1=O
Temperature: 100 °C
Yield: 48.1 %

Procedure:
To a solution of ethyl 3-(5-(bromomethyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (100 mg, 0.187 mmol) in toluene (5 mL) was added (4-chlorophenyl)boronic acid (32.1 mg, 0.205 mmol) and aq. Cs2CO3 (1 M, 0.28 mL). The reaction was degassed under nitrogen gas (3×) then Pd(PPh3)4 (10 mg) was added. The reaction was heated at 100° C. for 18 h, cooled to RT then diluted with EA (10 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (4:1 to 2:1) to give ethyl 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (51 mg, 48.1% yield) as a yellow solid. LCMS: MH+ 567 and TR=1.710 min.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:16][C:15]=2[Cl:26])[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:46]N1C(=O)CCC1=O>C(Cl)Cl>[Br:46][CH2:2][C:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:16][C:15]=2[Cl:26])[O:5][N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(C2=NCCO2)cc(Cl)c1OCCCCCc1cc(CBr)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
3-(Hydroxymethyl)-5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole (540 mg, 1.25 μmnol) in DCM (5 ml), prepared according to a literature procedure J. Med. Chem. (1990) 33, 1306-1311, was added rapidly to triphenylphosphine (410 mg, 1.56 mmol) and N-bromosuccinimide (278 mg, 1.56 mmol) in DCM (15 ml) at 0° C. The reaction was allowed to warm to room temperature, then after 3 hours the product was adsorbed onto silica gel and chromatographed on silica gel, eluent 1:1 ethyl acetate/hexane to give the brominated compound, 3-(bromomethyl)-5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole as an off white solid (408 mg, 0.88 mmol) in 70% yield, Rf=0.25. 1H mm (D6 acetone): δ=8.01 (s, 2H); 6.46 (s, 1H); 4.69 (s, 2H); 4.61 (t, 2H); 4.26 (t, 2H); 4.16 (t, 2H); 3.00 (m, 2H); 2.2-1.7 ppm (m, 6H). MS (ES):(M+H)+ 461,463,465. Neat 3,6,9-trioxa-11-azidoundecanol (237 mg, 1.08 mmol) prepared according to a literature procedure J Org. Chem. (1991) 56 4326, was added to a solution of sodium hydride (1.6 mmol) in DMF (3 ml) and stirred for 3 hours under argon. Tetrabutylammonium iodide (40 mg, 0.11 mmol) and a solution of the brominated compound (500 mg, 1.08 mmol) in DMF (3 ml) was added to the reaction. After 3 hours the reaction was quenched with water (1 ml) then partitioned between ethyl acetate (150 ml) and water (30 ml). The organic phase was washed with brine (30 ml), dried (Na2SO4) and concentrated to give a yellow brown oil. Chromatography of the crude residue twice on silica gel (50 g), eluent 2:1-3:1 ethyl acetate/hexane then 1:1 DCM/hexane gave 3-(1-azido-3,6,9,12-tetraoxamidecyl)-5-[5-[2,6-dichloro-4(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole (Compound 1) (400 mg, 0.67 mmol) in 62% yield. 1H nmr (D6 acetone): δ=8.01 (s, 2H); 6.34 (s, 1H); 4.70 (s, 2H); 4.61 (t, 2H); 4.26 (t, 2H); 4.16 (t, 2H); 3.8 (m, 14H); 3.52 (t, 2H); 2.95 (m, 2H); 2.2-1.7 ppm (m, 6H). MS (ES): (M+H)+ 600.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.O.NN>ClCCl.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CN1C(=O)C(=O)c2ccc(Br)cc21
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)Cc2ccc(Br)cc21
Temperature: 130 °C
Reaction time: 1.33 h

Procedure:
To a solution of 6-bromoisatin (CAS#6326-79-0, 4.52 g, 20.0 mmol) in acetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol) followed by iodomethane (2.75 mL, 44.0 mind). The reaction was then placed at 60° C. and stirred for 40 minutes. The reaction was then cooled to room temperature, filtered and concentrated to 10% of the original volume. The reaction was then diluted with dichloromethane, water, and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate filtered and concentrated to provide 6-bromo-1-methyl-1H-indole-2,3-dione as an orange solid without the need for further purification. The 6-bromo-1-methyl-1H-indole-2,3-dione (1.0 g, 4.2 mmol) was then treated with hydrazine hydrate (7.0 mL, 225 mmol). The reaction was heated to 130° C. and stirred for 80 minutes, at which time the reaction was placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford 6-bromo-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 225.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([OH:11])[CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][C:23]([NH2:25])=[O:24]>>[C:23]([CH2:22][O:11][C:9]1[CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=1[N+:12]([O-:14])=[O:13])(=[O:24])[NH2:25]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCC(N)=O)c1

Procedure:
Reaction of 1.08 g of 5-methoxycarbonyl-2-nitrophenol, 1.82 g of potassium carbonate and 2.02 g of iodoacetamide gives 2-carbamoylmethoxy-4-(methoxycarbonyl)nitrobenzene of mp 138°-9° C.; Rf (O)=0.63; FAB-MS: (M+H)+ 255; anal. calc. for C10H10N2O6 : C47.25%, H3.97%, N11.02%; found C47.08%, H4.04%, N10.79%. Starting from 1.16 g of 2-carbamoylmethoxy-4-(methoxycarbonyl)nitrobenzene, 2-carbamoylmethoxy-4-(methoxycarbonyl)aniline of mp 178°-80° C.; Rf (O)=0.37; MS: M+ =224; anal, calc. for C10H12 N2O4 : C53.57%, H5.39%, N12.49%; found C53.41%. H5.32%, N12.53%.