Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[O-].[Na+].C(O)C.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>ClCCl>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CS
Reactant: Cc1ccc(CBr)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CSCc1ccc(C)cc1

Procedure:
Ethyl 2-mercaptoacetate (8.5 cc) is added in the course of 15 minutes at a temperature in the region of 20° C. to a stirred solution, through which a stream of nitrogen is passed, of a 2M ethanolic solution of sodium ethylate (37.5 cc) and ethanol (50 cc). The mixture is left with stirring for 15 minutes at the same temperature, and α-bromo-p-xylene (13.9 g) is then added in the course of 20 minutes at a temperature in the region of 20° C. Stirring is maintained for 60 minutes at this temperature, and the reaction mixture is then evaporated to dryness at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is dissolved in dichloromethane (100 cc), and the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Ethyl (4-methylbenzylthio)acetate (15.6 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.O.[NH2:13][NH2:14]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:13][NH:14]2)=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1cc(F)c(Cl)cc1F
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Fc1cc2cn[nH]c2cc1Cl
Temperature: 140 °C
Reaction time: 72 h
Yield: 15.7 %

Procedure:
A mixture of 4-chloro-2,5-difluorobenzaldehyde (20.6 g, 105.0 mmol) and hydrazine hydrate (77.2 mL, 1575.2 mmol, 15 eq) in n-butanol (35 mL) was stirred at 140° C. for 3 days. The mixture was cooled to room temperature and poured into ice water (750 mL). The mixture was stirred vigorously for 2 h, and the orange solid was filtered. The filtrate was extracted with EtOAc (3×250 mL), and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was combined with the orange solid and then purified by MPLC (Biotage®, gradient elution 25% EtOAc/hexane) to give 2.81 g (16%) of a white solid. 1H-NMR (300 MHz, DMSO-d6) 13.3 (broad s, 1H), 8.09 (s, 1H), 7.80 to 7.76 (m, 2H); ES-MS m/z 171.2/173.2 [M+H]+, RT (min) 3.02.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(=O)C.[N+:14]([O-])([OH:16])=[O:15]>O>[CH3:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cc1C
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(O)c([N+](=O)[O-])c1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 20 a) except for using 15.7 g (129 mmol) of 3,4-dimethylphenol, 130 ml of acetic acid, 8 ml of water and 12.2 g (135 mmol) of 70% nitric acid. 3,4-Dimethyl-2-nitrophenol was thus obtained in the yield of 7.01 g (26.0%).
Reaction SMILES: [OH-].[Na+].O.C[O:5][C:6](=[O:42])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])=[CH:10][C:9]=1[Cl:41].Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:42])=[O:5])=[C:9]([Cl:41])[CH:10]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(Cl)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(Cl)c2)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 9.8 %

Procedure:
A mixed solution of a 6 N sodium hydroxide aqueous solution (0.009 mL) with water (0.027 mL) was added to a solution of (4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-chloro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 61-(2); 2.3 mg, 0.042 mmol) in methanol (0.08 mL) at room temperature, and the mixture was stirred at room temperature for six hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (2.2 mg, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[C:3]1=[O:31].[C:32]([O:35][CH2:36][C:37]1[C:42]([N:43]2[CH2:54][CH2:53][N:52]3[C:45](=[CH:46][C:47]4[CH2:48][C:49]([CH3:56])([CH3:55])[CH2:50][C:51]=43)[C:44]2=[O:57])=[CH:41][CH:40]=[CH:39][C:38]=1Br)(=[O:34])[CH3:33]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:35][CH2:36][C:37]1[C:38]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:20][N:19]=3)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=2)=[CH:39][CH:40]=[CH:41][C:42]=1[N:43]1[CH2:54][CH2:53][N:52]2[C:45](=[CH:46][C:47]3[CH2:48][C:49]([CH3:56])([CH3:55])[CH2:50][C:51]=32)[C:44]1=[O:57])(=[O:34])[CH3:33]
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 23.3 %

Procedure:
In a 10-mL glass vessel equipped with a magnetic stirring bar were placed 1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one 197e (210 mg, 0.49 mmol), 10-[2-(acetoxymethyl)-3-bromophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one 167f (143 mg, 0.33 mmol), Pd(PPh3)4 (30 mg, 0.0.26 mmol) in 2 N Na2CO3 (2 mL) and 1,2-dimethoxyethane (5 mL). The vessel was sealed with a septum and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 26% (50 mg) of 173a as a solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:22][N:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(OCc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
A mixture of 110.6 g of the product of Example 32, 49.8 g of anhydrous potassium carbonate, 55.8 g of methyliodide and 500 ml of acetone was stirred at ambient temperature for 20 hours. The solvent was evaporated and the residue partitioned between methylene chloride and water. Concentration of the organic extract afforded 88.9 g of N-methyl-N-(phenylmethoxy)-2-nitrobenzenesulfonamide as a yellow oil. [NMR:δ 2.8(s, 3H, NCH3)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[OH:28][C:29]1[CH:39]=[CH:38][C:32]2[C:33](=[O:37])[CH2:34][CH2:35][O:36][C:31]=2[C:30]=1[CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:28][C:29]1[CH:39]=[CH:38][C:32]2[C:33](=[O:37])[CH2:34][CH2:35][O:36][C:31]=2[C:30]=1[CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COC(=O)CCCOc1cccc(CCCCCCI)c1CCC(=O)OC
Reactant: O=C1CCOc2c1ccc(O)c2CCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCCOc1cccc(CCCCCCOc2ccc3c(c2CCCc2ccccc2)OCCC3=O)c1CCC(=O)OC
Yield: 102.4 %

Procedure:
A mixture of 12.25 g (25 mmol) of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (preceding example), 7.1 g (25.2 mmol) of 2,3-dihydro-7-hydroxy-8-(3-phenylpropyl)-4H-1-benzopyran-4-one (example 9), 8.3 g (60 mmol) of anhydrous potassium carbonate, and 60 mL of dry acetonitrile was stirred and refluxed for 22 hr. After being cooled, the mixture was diluted with ether and filtered with suction. The solids were washed well with ether. The filtrate and washes were combined and concentrated in vacuo giving 16.5 g of a yellow oil. This material was chromatographed on silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 13.75 g (85.4%) of pure title dimethyl ester, as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([CH3:26])[CH:18]=1>>[CH:11]1([NH:10][C:6]2[C:7]([CH:8]=[O:9])=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=3[CH3:26])[N:3]=[C:4]([S:14][CH3:15])[N:5]=2)[CH2:13][CH2:12]1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CSc1nc(Cl)c(C=O)c(NC2CC2)n1
Product: CSc1nc(NC2CC2)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.69 (m, 2H), 0.94 (m, 2H), 2.23 (s, 3H), 2.62 (s, 3H), 3.14 (m, 1H), 6.98 (m, 2H), 7.20 (m, 1H), 9.09(br s, 1H), 9.49 (s, 1H). LC MS (m/e)=318 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N:21]=[C:22]=[O:23].S([O-])(O)(=O)=O.[K+]>ClCCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[NH:21][C:22]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)=[O:23]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1cccc(C=O)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCCl
Product: O=Cc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Yield: 57 %

Procedure:
A mixture of 484 mg of 3-aminobenzaldehyde (4 mmol) (polymerized form) and 290 μl of 2-fluoro-5-trifluoromethylphenyl isocyanate in 4 ml of DCE is treated in a CEM Discover microwave oven at 100° C. for 10 minutes (power 90). After cooling, the mixture is poured into 100 ml of saturated potassium hydrogen sulfate solution and extracted with twice 50 ml of ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. 740 mg of the expected aldehyde (yield=57%) are obtained in an LC/MS purity of 82%. The crude product is used directly for the following steps. ([M+H]+): 327. RT=4.28 min (acetonitrile/water gradient from 30% to 90%—Method B).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[Br:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:44])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH:30]=[CH:31][CH:32]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH:44][C:8](=[O:10])[C:7]#[C:6][CH2:5][O:4][CH2:3][O:2][CH3:1])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: COCOCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCOCC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.66 g of 4-methoxymethoxy-but-2-ynoic acid and 0.60 mL of isobutyl chloroformate in 16 mL of tetrahydrofuran at 0° C. was added 0.5 mL of N-methylmorpholine followed by 1.2 g of solid N-(3-bromophenyl)-4,6-quinazolindiamine. Stirring was continued for 1 hr at 0° C. and 30 min at room temperature. Another equal amount of mixed anhydride as prepared above was added. The mixture was stirred an addition 30 min and stored at −10° C. over night. The mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate and choroform solvent mixtures to give 0.35 g of 4-Methoxymethoxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as a tan solid: mass spectrum (m/e): M+H 441.0.
Reaction SMILES: [CH:1]([NH:4][NH2:5])([CH3:3])[CH3:2].[F:6][C:7]([F:18])([F:17])[C:8](=O)[CH:9]([CH3:15])[C:10]([O:12]CC)=O.Cl>C(O)C>[OH:12][C:10]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:8]([C:7]([F:6])([F:17])[F:18])[C:9]=1[CH3:15]
Reactant: CC(C)NN
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1c(C(F)(F)F)nn(C(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 7.4 g (100.0 mmol) of isopropylhydrazine in 100 ml of ethanol was added dropwise under stirring 23.3 g (purity: 85.0%, 100.0 mmol) of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate under ice-cooling so that the temperature in the reaction system did not exceed 10° C. After the dropwise addition, the whole was stirred at room temperature for 30 minutes. Then, 1 ml of concentrated hydrochloric acid was added into the reaction solution, followed by 2 days of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was washed with n-hexane to obtain 18.1 g (yield: 87.0%) of 5-hydroxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole as white crystals (melting point: 150 to 153° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:63]1([SH:69])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C(N(C(C)C)C(C)C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:20][C:19]1[CH:18]=[CH:17][C:4]([C:5]([NH:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH3:9])=[O:6])=[CH:3][C:2]=1[S:69][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: C[C@@H](NC(=O)c1ccc(Cl)c(Br)c1)c1cccc(Cl)c1
Reactant: Sc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1ccc(Cl)c(Sc2ccccc2)c1)c1cccc(Cl)c1
Reaction time: 18 h
Yield: 92.3 %

Procedure:
To a mixture of (R)-3-bromo-4-chloro-N-(1-(3-chlorophenyl)ethyl)benzamide 32 (0.634 g, 1.7 mmol), Pd2(dba)3 (0.100 g, 0.11 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.125 g, 0.22 mmol) was added benzenethiol (0.173 mL, 1.7 mmol), dioxane (4.5 mL) and N-ethyl-N-isopropylpropan-2-amine (0.590 mL, 3.4 mmol). The reaction mixture was degassed and heated to reflux. After 18 h, the reaction mixture was diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 5% to 30% EtOAc in hexanes) gave (R)-4-chloro-N-(1-(3-chlorophenyl)ethyl)-3-(phenylthio)benzamide 33 (0.631 g, 92% yield) as a white solid. Mass spectrum: calculated for C21H17Cl2NOS 401.0. found 402.1 (M++1).
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[C:32]([F:35])([F:34])[F:33]>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:20]2[CH2:21][CH2:22][C:5]3([O:4][C:3](=[O:2])[N:7]([C:8]4[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=4)[CH2:6]3)[CH2:18][CH2:19]2)=[CH:26][C:25]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(Cl)c(C(F)(F)F)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 4-chloro-3-trifluoromethylbenzaldehyde (38.3 mg, 0.184 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow solid (73 mg) that was used without any further purification.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([O:24][CH3:25])[N:18]=1)=[O:15])(=[O:12])=[O:11].O1CCOCC1.[F:33][C:34]([F:38])([F:37])[CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>O>[F:26][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:16][C:17]1[N:18]=[C:19]([O:24][CH3:25])[N:20]=[C:21]([O:36][CH2:35][C:34]([F:38])([F:37])[F:33])[N:22]=1)=[O:15])(=[O:12])=[O:11]
Reactant: OCC(F)(F)F
Reactant: COc1nc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(OCC(F)(F)F)n1
Reaction time: 12 h

Procedure:
A mixture of 8.2 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-chloro-6-methoxy-1,3,5-triazin-2-yl)-urea, 60 ml of dioxane, 20 ml of 2,2,2-trifluoroethanol and 5.5 g of potassium carbonate is stirred at 55°-60° for 12 hours and then taken up in 300 ml of water and filtered over active charcoal. After the mixture has been acidified with 2N hydrochloric acid, the product precipitates and is separated off by filtration. Yield: 7.7 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-[4-methoxy-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]-urea of melting point 155°-157°.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([OH:9])[CH:8]=1.CC(C)([O-])C.[K+].Br[C:20]1[O:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1.Cl>C1COCC1.O>[CH3:10][C:6]1[CH:5]=[CH:4][C:3]([Si:2]([CH3:11])([CH3:12])[CH3:1])=[CH:8][C:7]=1[O:9][C:20]1[O:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(Br)o1
Reactant: Cc1ccc([Si](C)(C)C)cc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Oc2cc([Si](C)(C)C)ccc2C)o1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a solution of 5-trimethylsilyl-2-methylphenol (Intermediate 3; 653 mg, 3.6 mmol) in THF was added potassium tert-butoxide (407 mg, 3.6 mmol) and the reaction heated at reflux for 1.5 hours. The resulting solution was allowed to cool to room temperature and concentrated under reduced pressure. The residue was taken up in dimethyl sulphoxide (10 mL), treated with methyl 5-bromo-2-furoate (632 mg, 3.1 mmol) and heated at 85° C. for 18 hours. The dark brown mixture was allowed to cool to room temperature, diluted with water (10 mL) and then acidified by the addition of hydrochloric acid (1 M). The mixture was extracted with diethyl ether (3×30 mL) and the combined organic extracts were dried (magnesium sulphate), concentrated under reduced pressure and purified by column chromatography (SiO2; light petroleum to 95:5 light petroleum-diethyl ether) to give the title compound as a colourless oil (534 mg, 57%). Rf=0.21 (9:1 light petroleum-diethyl ether). LCMS Rt=4.9 mins, m/z=305 (MH+).
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=O.[Na+].[BrH:14]>>[Br:14][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)C[C@@H](Br)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of D-leucine (50 g, 0.381 mol) in 570 mL of 3N HBr (aq) at 0° C. was added sodium nitrite (42 g, 1.6 eq) portion-wise over 1 hour and 15 minutes. The reaction was further stirred for 3 hrs at 0° C. then it was extracted with ether (1000 mL). After washing the ether layer with water (2×500 mL) it was dried over MgSO4 and concentrated. The red syrup was then co-evaporated with chloroform (3×200 mL) to remove the color and then it was pumped to give (2R)-2-bromo-4-methylpentanoic acid, as a colorless oil with a constant weight of 71.3 g.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([C:27]1[CH:51]=[CH:50][C:30]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:40][CH:39]=3)[C:33]2=O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC=CC=1>O>[C:23]([C:27]1[CH:51]=[CH:50][C:30]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:40][CH:39]=3)[C:33]2=[S:10])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=O)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=S)cc1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetan-2,4-disulfide) (640 mg, 1.58 mmol) was added to a solution of N-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}methanesulfonamide (4) (1008 mg, 2.63 mmol) in abs. toluene (30 mL). The reaction mixture was heated to the boil over a period of 5 h. The reaction mixture was then stirred overnight. Water (40 mL) was added and the mixture was extracted with chloroform (3×30 mL). The combined organic phases were washed with H2O (2×20 mL), dried over Na2SO4, and the solvent was removed in vacuo. Following purification of the residue by means of column chromatography (SiO2 (150 g); 1000 mL cyclohexane/EtOAc 4:1), the desired product N-{4-[3-(4-tert-butylbenzyl)-2-thioxoimidazolidinylmethyl]phenyl}methanesulfonamide (1) (545 mg, 52% of theory) was obtained.