Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>C(O)(=O)C>[Br:1][CH2:14][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:3]=[CH:4][CH:5]=[CH:6]2)=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1ccc2ncccc2c1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Bromine (6.69 g, 132 mmol) was added to a warm (100° C.) solution of 1-quinolin-6-yl-ethanone (Stage 1.4, 18.8 g, 110 mmol) in acetic acid (50 mL). The mixture was stirred at 100° C. for 45 min then cooled to rt. A precipitate was formed which was filtered off and washed with Et2O. Drying under HV at 50° C. afforded the title compound as a brown solid (tR 1.3 min (conditions 1), MH+=251.8).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9]Br>C(Cl)(Cl)Cl>[Br:9][C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: COc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1
Yield: 80 %

Procedure:
The bromination of anisole with one equivalent of bromine is chloroform, at room temperature, is reported to give an 80% yield of monobromoanisole. Grignard, Bellet and Courtot, Ann. Chim. 4, 28 (1915). The preparation of dibromoanisole from anisole, and of tribromoanisole from dibromoanisole, in carbon tetrachloride, is also reported. Kohn and Sussman, Monatsh. Chem. 46, 575 (1925). "Several days" reaction time is reported for the preparation of several tribromophenyl alkyl ethers. Yields are not reported. Baiford and Birosel, J. Am. Chem. Soc., 51, 1776 (1929). The bromination of anisole with three equivalents of bromine yields 1.5% tribromoanisole. Similarly, the bromination of monobromoanisole with two equivalents of bromine in chloroform is reported to give only small quantities of tribromoanisole, and tribromoanisole is reported not to brominate further. D. M. Birosel, Univ. Phillipines Natural Applied Sci. Bull. 1, 145 (1931).
Reaction SMILES: [Cl:1]C1C=C(Cl)C(Cl)=CC=1[O:10][C:11](=O)[CH2:12][NH:13]C(OC(C)(C)C)=O.[CH2:22]([O:29][C:30](=[O:34])[C@H:31]([CH3:33])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[ClH:1].[CH2:22]([O:29][C:30](=[O:34])[C@H:31]([CH3:33])[NH:32][C:11](=[O:10])[CH2:12][NH2:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Product: C[C@H](NC(=O)CN)C(=O)OCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution containing 19.5 parts N-t-butoxycarbonylglycine 2,4,5-trichlorophenyl ester and 13.8 parts L-alanine benzyl ester in 200 parts methylene chloride is stirred overnight at room temperature. The solvent is then removed by evaporation under reduced pressure and the residue subjected to low pressure column chromatography. The resulting pure N-t-butoxycarbonylglycyl-L-alanine benzyl ester is dissolved in 60 parts dioxane and treated with a ten-fold excess of 2 N HCl in dioxane, with stirring, for 15 minutes. The solvent is again removed by evaporation under reduced pressure and the residue triturated with ethyl ether to afford glycyl-L-alanine benzyl ester hydrochloride. This compound is represented by the following formula
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16](NC(NC(CO)CO)=O)[CH:17]=[CH:18][CH:19]=1.[N:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:30]=[O:31].C(#[N:40])C>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:40][C:30](=[O:31])[NH:29][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)NC(CO)CO)c2)C1
Reactant: CC#N
Reactant: CCOC(=O)CN=C=O
Product: CCOC(=O)CNC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Product: Cl
Reaction time: 4 h

Procedure:
4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (95 mg, example 1, intermediate 6) was dissolved in acetonitrile (2 ml) and ethyl isocyanatoacetate (30 mg) was added dropwise with stirring. After four hours, the solution was concentrated and the residue purified by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with ethyl acetate. Drying over magnesium sulfate was followed by drying. The residue was taken up with aqueous hydrochloric acid and freeze-dried. 107 mg of the desired compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:43]=[CH:42][C:5]([O:6][CH2:7][C:8]([NH:10][CH2:11][C@H:12]([OH:41])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:15]([N:28]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:14]=2)=O)=[CH:4][CH:3]=1.N(CCO)(CCO)CCO.O>O1CCCC1>[Br:1][C:2]1[CH:43]=[CH:42][C:5]([O:6][CH2:7][CH2:8][NH:10][CH2:11][C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:15]([N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[S:37]([CH3:40])(=[O:39])=[O:38])[CH:14]=2)[OH:41])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CNC(=O)COc2ccc(Br)cc2)cc1N(COCC[Si](C)(C)C)S(C)(=O)=O
Solvent: OCCN(CCO)CCO
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CNCCOc2ccc(Br)cc2)cc1N(COCC[Si](C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
A 2 mol/L solution of borane dimethylsulfide complex in tetrahydrofuran (1.96 mL) was added dropwise to a solution of 2-(4-bromophenoxy)-N—((R)-2-hydroxy-2-{3-[methanesulfonyl-(2-trimethylsilylethoxymethyl)amino]-4-(2-trimethylsilylethoxymethoxy)phenyl}ethyl)acetamide (1.35 g) in tetrahydrofuran (10 mL) at room temperature under an atmosphere of argon. The mixture was stirred under ref lux for 1.5 hrs, and then cooled to room temperature. A solution of triethanolamine (0.88 g) in tetrahydrofuran (5 mL) was added dropwise to the reaction mixture. After being stirred under reflux for 5 hrs, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: ethyl acetate/ethanol=15/1) to afford the title compound (1.13 g).
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:29]([C:40]([O:42][CH2:43][CH3:44])=[O:41])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.Cl.O>CO>[OH:1][CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CCC1(CCO)CCCCC1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
To a solution of triethyl 3-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]-1,1,1-propanetricarboxylate (470 mg) in methanol (10 mL)/tetrahydrofuran (5 mL) was added 3N hydrochloric acid (2.5 mL) at room temperature. After stirring the solution at room temperature for 4 hours, water was added to the solution, and it was concentrated under reduced pressure. The solution was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1) to give the title compound (230 mg).
Reaction SMILES: COC[O:4][C:5]1[C:6](C#N)=[N:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][CH:10]=1.C[Mg]Cl.[CH3:21][CH2:22][O:23][C:24](C)=[O:25].[CH3:27]CCCCC>C1COCC1>[CH3:27][O:25][CH2:24][O:23][C:22]1[C:6]([C:5](=[O:4])[CH3:10])=[N:7][C:8]([CH2:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:9][CH:21]=1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Reactant: COCOc1ccc(CC(C)(C)C)nc1C#N
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: COCOc1ccc(CC(C)(C)C)nc1C(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
3-(Methoxymethoxy)-6-neopentylpicolinonitrile (8.3 g, 35 mmol) was dissolved in THF (125 mL). The solution was cooled to 0° C. and methylmagnesium chloride (24 ml, 71 mmol) (3.0 M in Et2O) was added. The reaction mixture stirred for 2 h at rt under N2 then quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over MgSO4 and evaporated to give the crude product as a yellow oil. Purification of the crude residue by ISCO (40 g SiO2, O-40% EtOAc/Hexane) gave 1-(3-(methoxymethoxy)-6-neopentylpyridin-2-yl)ethanone (3.8 g, 43% yield) as a clear, light orange oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C@@H:13]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@H:35]3[CH3:40])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:42]>CCO>[NH2:42][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C@@H:13]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]3[CH3:40])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 140 °C

Procedure:
The crude chloropyridine derivative was dissolved in 2 mL of EtOH and 2 mL of 30% aqueous ammonium hydroxide. This solution was heated to 140° C. for 60 min. The mixture was concentrated in vacuo and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (23 mg) as a foamy solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:25]=1[C:26](O)=[O:27].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH:18][C:26]([C:25]3[N:24]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[CH:23]=[N:22][C:21]=3[Cl:20])=[O:27])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (667 mg, 1.828 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (506 mg, 1.828 mmol) and diisopropylethyl amine (0.669 mL, 3.83 mmol) in DMF (20 ml) was added HATU (695 mg, 1.828 mmol) and the mixture was stirred for 30 minutes. The mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (589 mg, 0.944 mmol, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 7.95 (s, 1H), 7.40-7.51 (m, 2H), 7.37 (t, 1H), 7.09 (t, 1H), 7.01 (t, 1H), 5.46 (s, 2H), 4.46 (d, 2H), 3.35 (t, 2H), 0.72 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 68a (7.5 g, 0.032 mol) in THF (100 mL), 1 M THF solution of NaHMDS (36 mL, 0.036 mol) was added dropwise at 0 C. The resulting solution was allowed to warm to room temperature and stirred for 1 h before cooling back down to 0° C. The cooled reaction mixture was treated dropwise with iodomethane (5.1 g, 0.035 mol). The ice-water bath was removed and stirring was continued for an additional hour at room temperature. The reaction was then quenched by the addition of water (50 mL). The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 68b as a yellow oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C10H11BrO2: 242.0 (M). found: 242.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][SH:8])=[N:3][CH:2]=1.Cl[CH2:10][CH2:11][OH:12].BrCCO>>[OH:12][CH2:11][CH2:10][S:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: SCc1ccncn1
Reactant: OCCCl
Agent: OCCBr
Product: OCCSCc1ccncn1

Procedure:
According to the methodology of Examples 11 to 15, 4-pyrimidylmethyl mercaptan is reacted with 2-chloroethanol or 2-bromoethanol to yield 4-(2-hydroxyethylthiomethyl)pyrimidine, with chloroacetone to yield 4-pyrimidylmethylthioacetone, with alphabromoacetophenone to yield alpha-(4-pyrimidylmethylthio)acetophenone, with alpha-bromo-p-methoxyacetophenone to yield alpha-(4-pyrimidylmethylthio)-p-methoxyacetophenone, with alpha-bromo-p-nitroacetophenone to yield alpha-(4-pyrimidylmethylthio)-p-nitroacetophenone, with alpha-bromopropiophenone to yield alpha-(4-pyrimidylmethylthio)propiophenone, with ethyl 2-bromoacetate to yield 2-(4-pyrimidylmethylthio)acetate, with ethyl 2-chloropropionate to yield 2-(4-pyrimidylmethylthio)propionate and with ethyl 2-phenyl-2-bromoacetate to yield 2-phenyl-2-(4-pyrimidylmethylthio)acetate (when ethyl esters are prepared, it is preferable to substitute an equivalent of sodium ethoxide for sodium methoxide; when the corresponding methyl esters are prepared, it is preferable to substitute methanol for ethanol).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[CH3:20][N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4]
Reactant: CNCCc1ccccn1
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(CCc1ccccn1)CC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 55.9 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), 2-(2-methylaminoethyl)pyridine (0.078 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided N2-methyl-N2-(2-pyridin-2-ylethyl)-N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylglycinamide (0.095 g) as its trifluroacetic acid salt after reverse-phase HPLC purification.MS (ESI) m/z 378 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH:29]([NH2:30])[S:40]([CH3:39])(=[O:42])=[O:41])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1nc(OCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(OCC(N)S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 131 (100 mg, 0.23 mmol) in CH2Cl2 (4 mL) was stirred under Ar at 23°. Triethylamine (0.1 mL) was added followed by the addition of a solution of methanesulfonyl chloride (29 mg, 0.25 mmol) in CH2Cl2 (1 mL). The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-10% EtOAc/CH2Cl2 gave the title compound as a white-amorphous solid. mp 95-99°, LC MS m/z=505 (MH+) Retention time=2.02 min.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:12]([N:14]1[CH2:15][C:16](=[O:17])[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]1=[S:11])[CH3:13]
Reactant: S=C=NCCc1ccccc1
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(CCc2ccccc2)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 16 using 16.3 g of phenethyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 m/L of chloroform. Purification was achieved by flash chromatography on silica gel (20% ethyl acetate in hexane) The title compound (15.0 g) was obtained as an off-white solid, m.p. 66°-68° C. Anal. Calcd. for. C13H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 63.03; H, 6.49; N, 11.32. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:21]([OH:23])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=NC=C(F)C=3)=CC(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:21]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2cncc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cncc(F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cncc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
100 mg (0.28 mmol) of the compound of Example 61A is reacted analogously to the synthesis of the compound of Example 98 with 38 mg (0.31 mmol) of 4-imidazolinone-hydrochloride. 62 mg (52% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[C:26]([O:30][C:31](=[O:34])[CH2:32]Br)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>O>[C:26]([O:30][C:31](=[O:34])[CH2:32][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidine (200 mg, 0.658 mmol) was taken into DMF (2 mL), and t-butylbromoacetate (141 mg, 0.724 mmol) was added, followed by potassium carbonate (182 mg, 1.317 mmol). The mixture was heated to 60° C. and left to react overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, and concentrated to dryness. The compound was then purified by flash chromatography (eluted with 0.5% methanol in dichloromethane with a 40:1 silica ratio) to obtain the title product (161 mg, 0.423 mmol, 64% yield); LCMS; m/z 381.52. found 381 (M). 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.66-1.73 (m, 2H), 1.79-1.85 (m, 2H), 1.99-2.06 (m, 1H), 2.63-2.69 (m, 1H), 3.18-3.22 (m, 2H), 3.40 (d, J=17.2, 1H), 3.59 (d, J=16.8, 1H), 3.79-3.83 (m, 1H), 3.91-3.95 (m, 2H), 6.82 (d, J=8.88, 2H), 7.08 (d, J=8.8, 2H), 7.15-7.27 (m, 5H).
Reaction SMILES: Br[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)CN[C:3]1=[O:12].[N:13]1([C:19](OC(C)(C)C)=O)CCNCC1.BrNC1C=CC=CC=1.ClC(Cl)(Cl)C(O)[OH:37].Cl.NO>>[CH:8]1[CH:9]=[CH:10][C:11]([NH:2][C:3](/[CH:19]=[N:13]/[OH:37])=[O:12])=[CH:6][CH:7]=1
Reactant: O=C1NCc2ccccc2N1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: BrNc1ccccc1
Agent: Cl
Agent: NO
Product: O=C(/C=N/O)Nc1ccccc1

Procedure:
Referring to FIG. 1, the synthesis of piperazinyl compounds 5a-5f required the key intermediate 16, which was envisioned to be synthesized by Buchwald-Hartwig reaction of bromo-3,4-dihydroquinazolin-2(1H)-one 13 with tert-butyl piperazine-1-carboxylate. Therefore, preparation of 13 was commenced with the reaction of bromoaniline 7 with chloral hydrate and hydroxylamine hydrochloride to afford the corresponding isonitrosoacetanilide 8, which, in turn, was heated in concentrated sulfuric acid to afford (after regioisomers separations) isatin 9. Condensation of intermediate 9 with hydroxylamine hydrochloride smoothly furnished oxime 10. Intermediate 10 was treated with trifluorosulfonic anhydride, followed by exposure of the resultant trifluorate to DBU to afford nitrile 11 in 82% yield. Reduction of intermediate 11 with borane at room temperature generated diamine 12 in good yield 85%. Reaction of diamine 12 with carbonyldiimidazole CDI in THF at 80° C. finally furnished intermediate 13 in 74% yield. However, unexpectedly, the Buchwald-Hartwig coupling of bromide 13 with tert-butyl piperazine-1-carboxylate under different reaction conditions, such as PdCl2 dppf, KOAc, DMF, 80° C.; and Pd(PPh3)4, toluene, ethanol, Na2CO3, reflux, were unsuccessful. The desired intermediate 16 was not observed in any case. Rather, the starting intermediate 13 was recovered instead (scheme 1). Therefore, bromide 13 was protected with di-tert-butyl dicarbonate to furnish 14, whereas diamine 12 was acetylated with acetic anhydride in pyridine to render intermediate 15. Buchwald-Hartwig reaction of intermediates 14 or 15 with tert-butyl piperazine-1-carboxylate under different reaction conditions, as was attempted in the case of intermediate 13, also failed. The desired coupled products were not detected in any case. Rather, the starting 13 (when 14 was used as coupling partner) and 15 were recovered from the reactions instead (see FIG. 1).