Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[O:29][CH3:30])=[CH:17][CH:16]=2)[CH:8]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(N(C(C)C)CC)(C)C.[C:51](Cl)(=[O:53])[CH3:52]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:51](=[O:53])[CH3:52])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[O:29][CH3:30])=[CH:19][CH:20]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C(C)=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial containing [3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamino]-acetic acid ethyl ester (47 mg, 0.11 mmol) dissolved in dimethylformide (1 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 0.13 mL, 0.13 mmol), diisopropylethyl amine (0.238 mL, 1.3 mmol) and acetyl chloride. The reaction was stirred at room temperature overnight. Reaction was filtered and purified by HPLC with increasing concentration of acetonitrile in water with 0.1% trifluoroacetic acid to yield {acetyl-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-amino}-acetic acid ethyl ester as a clear film (10 mg, 21%). LC-MS (ES) calculated for C26H25F2NO5, 469.17; found m/z 470 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([CH:11]=O)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([CH2:11][N:27]2[CH2:26][CH2:25][N:24]([C:22]([NH:21][C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)=[O:23])[CH2:29][CH2:28]2)[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)N1CCOC(C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)N1CCOC(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 8 h
Yield: 19.4 %

Procedure:
A solution of 4-tert-butylmorpholine-2-carbaldehyde (154 mg) and N-(3,4-dichlorophenyl)piperazine-1-carboxamide (247 mg) in dichloromethane (20 mL) was stirred at room temperature under argon. Sodium triacetoxyborohydride (381 mg) was added and the mixture was stirred overnight. The reaction was quenched with water and partitioned between water and dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then brine, dried (Na2SO4), filtered and concentrated. The residue was purified on the Isco™ Companion (12 g column: 0-11% MeOH in DCM) to give the title compound as a white solid (75 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)=[S:27])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2nc3ccccc3s2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4s3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenylthio)benzothiazole (10.0 mmoles, 2.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate 10.0 mmoles, 2.4 g) were reacted according to procedure C to yield of the title compound, 1.5 g, 30%. Mass Spec (FD) 495. Calculated for C21H13ClF3 N3S3 : C, 50.85H, 2.64N, 8.47. Found: C, 51.02; H, 2.71; N, 8.31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][C:24]=1[CH3:25])=[CH:16][CH:15]=3.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[C:24]([CH3:25])=[CH:23][N:22]([C:34](=[O:35])[CH2:33][O:32][CH3:31])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: COCC(=O)Cl
Product: COCC(=O)n1cc(C)c(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 70 above, with the compound from Example 53 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(4-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and methoxyacetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[NH:4][C@@H:5]1[C@@H:9]([N:10]2[CH2:15][C:14]([F:17])([F:16])[CH2:13][CH2:12][C:11]2=[O:18])[CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1>[OH-].[OH-].[Pd+2].C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:26])[NH:4][C@@H:5]1[C@@H:9]([N:10]2[CH2:15][C:14]([F:17])([F:16])[CH2:13][CH2:12][C:11]2=[O:18])[CH2:8][NH:7][CH2:6]1
Reactant: COC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CC(F)(F)CCC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)N[C@H]1CNC[C@@H]1N1CC(F)(F)CCC1=O
Temperature: 50 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
To a solution of the product from Step 5 in a 2:1 mixture of ethanol/acetic acid (30 mL) was added palladium hydroxide on carbon powder (0.13 g, 10 wt. %). The mixture was degassed and shaken under an atmosphere of hydrogen (75 psi) at 50° C. for 12 hours. The mixture was cooled to room temperature, filtered through diatomaceous earth and the solids washed with ethanol. The filtrate was concentrated and the residue was dissolved in saturated sodium carbonate solution and extracted with chloroform (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated to afford 0.98 g (86.6%) of the product as a foam. 1H NMR (400 MHz, Methanol-d4) δ 4.49 (q, 1H), 4.20 (q, 1H), 3.86-3.67 (m, 2H), 3.61 (s, 3H), 3.28-3.21 (m, 1H), 3.19-3.09 (m, 1H), 2.96-2.87 (m, 1H), 2.74-2.64 (m, 1H), 2.63-2.47 (m, 2H), 2.38-2.23 (m, 2H). MS 278.3 (AP+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[C:12]([S:17](Cl)(=[O:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:17]([C:12]2[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:19])=[O:18])=[CH:5][CH:4]=1
Reactant: Cc1cccnc1S(=O)(=O)Cl
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NS(=O)(=O)c2ncccc2C)cn1

Procedure:
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 3-methyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [F:1]/[CH:2]=[C:3](/[CH2:13]O)\[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:27].[Li+]>CC(C)=O>[Br:27][CH2:13]/[C:3](=[CH:2]/[F:1])/[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)NC/C(=C\F)CO
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC/C(=C\F)CBr
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a stirring solution of (E)-tert-butyl 3-fluoro-2-(hydroxymethyl)-allylcarbamate (1.20 g, 5.85 mmol) in acetone (20 mL) at 0° C. under N2 was added sequentially triethylamine (1.22 mL, 8.77 mmol) and methanesulfonyl chloride (0.54 mL, 7.02 mmol). The resulting mixture was stirred at this temperature for 30 min. The reaction mixture was filtered to remove the precipitated salts and the filter cake was washed with further acetone (10 mL). The filtrate was charged with lithium bromide (2.54 g, 29.24 mmol) and the resulting suspension was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (25 mL) and ethyl acetate (25 mL) and the aqueous layer was extracted with further ethyl acetate (25 mL). The combined organics were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo to give (E)-tert-butyl 2-(bromomethyl)-3-fluoroallylcarbamate as a pale yellow oil (1.46 g, 93%). 1H-NMR (300 MHz; CDCl3) δ ppm: 1.47 (9H, s), 3.97 (2H, dd, J 3.5, 0.7 Hz), 4.02 (2H, br d, J 6.1 Hz), 4.78 (1H, br s), 6.79 (1H, d, J 81.1 Hz).
Reaction SMILES: [O:1]=[C:2]([N:8]([CH3:16])[CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:3]([O:5]CC)=O.Cl[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]=[CH:24][C:23]1=[O:28].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[N:15]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[CH:9]1[N:8]([CH3:16])[C:2](=[O:1])[C:3]([OH:5])=[C:24]2[CH:25]1[CH2:26][CH2:27][N:22]([CH2:21][C:20]1[CH:19]=[CH:18][C:31]([F:32])=[CH:30][CH:29]=1)[C:23]2=[O:28]
Reactant: CCOC(=O)C(=O)N(C)Cc1ncccn1
Reactant: O=C1C=CCCN1Cc1ccc(F)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1c1ncccn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of ethyl 2-oxo-2-[N-methyl-N-(pyrimidin-2-yl)methylamino]acetate from the previous step (1.43 g, 5.85 mmol) and 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (1 g, 5 mmol) in anhydrous THF (10 mL) was added LiHMDS (1 M in THF) (1.02 g, 6.09 mmol) dropwise. The reaction mixture was stirred for 10 min at −78° C., warmed to room temperature for 2.5 hours, then heated to 40° C. for 48 hours. The mixture was cooled to ambient temperature and the solvent was removed under vacuum. The residual material was purified using reverse phase HPLC on a C18 stationary phase eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to give the title compound as a mixture of enantiomers. The hydrogens at positions 4a and 5 were found to have a trans relationship to one another. The enantiomers were separated on a ChiralPak AD column with 1:1 EtOH:MeOH as the mobile phase. The first eluting enantiomer had a positive sign of rotation and the following properties: 1H NMR (400 MHz, CD3OD), δ8.76 (d, J=4.8 Hz, 2H), 7.41 (t, J=4.8 Hz, 1H), 7.23 (dd, J=8.5, 5.5 Hz, 2H), 7.01 (t, J=Hz, 2H), 4.81 (d, J=6.7 Hz, 1H), 4.57 (d, J=15 Hz, 1H), 4.47 (d, J=15 Hz, 1H), 3.63 (m, 1H), 3.2-3.4 (m, 2H), 2.91 (s, 3H), 2.11 (m, 1H), 0.96 (dq, Jd=4.5 Hz, Jq=13 Hz, 1H). ES MS M+1=383. The second eluting enantiomer had a negative sign of rotation and 1H NMR and MS properties identical to that of the first eluting enantiomer.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.B(F)(F)F.CCOCC>>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]([OH:9])[CH:7]=[CH:6][C:5]=1[C:18](=[O:19])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cc1c(O)cccc1O
Agent: FB(F)F
Solvent: CCOCC
Product: Cc1c(O)ccc(C(=O)Cc2ccc(O)cc2)c1O
Temperature: 110 °C

Procedure:
2-Methylresorcinol (4.00 g, 1 equivalent) and 4-Hydroxyphenylacetic acid (5.00 g, 1 equivalent) were added to a round bottom flask. The round bottom flask was attached to a condenser and placed in an oil bath, the whole system was kept under nitrogen. Distilled BF3.OEt2 (20 ml, 5 equiv.) was added to the mixture while stirring. The mixture was refluxed (110° C.). A yellow solid formed at 20 minutes indicating that the reaction had gone to completion. The reaction was left on heat for a further 10 minutes and then cooled to room temperature. The yellow solid was collected by suction filtration and washed with distilled water (200 ml) to remove any excess BF3.OEt2 present. 1H NMR in d-DMSO indicated the yellow solid was 1-(2,4-Dihydroxy-3-methyl-phenyl)-2-(4-hydroxy-phenyl)-ethanone in >95% purity. The solid was dried on a freeze dryer for 24 hours (8.93 g, 99%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1>C1C=CC=CC=1>[SH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[O:18][CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: OCc1cccnc1
Reactant: O=C=Nc1ccc(S)cc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(S)cc1)OCc1cccnc1
Yield: 78 %

Procedure:
p-Mercaptophenyl isocyanate (0.9g., 0.00595 mole) was added to a solution of 3-pyridyl carbinol (0.65g., 0.00595 mole) in 50 ml. of benzene and the reaction mixture was allowed to stand over the weekend. It was then heated to reflux to assure completion of the reaction and then cooled to give a white solid. This was isolated as 1.2g. and was a 78% yield of 3-pyridylmethyl N-(4'-mercaptophenyl)carbamate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[CH:27][CH:26]=[C:25]([OH:24])[CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1cccc(O)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 3-hydroxyphenylboronic acid (Aldrich, Buchs, Switzerland, 17 mg, 0.123 mmol) to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=386 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.58 (s, 1H), 8.95 (s, 1H), 8.20-8.11 (m, 1H), 8.10-8.01 (m, 1H), 7.88-7.77 (m, 1H), 7.57-7.47 (m, 1H), 7.31-7.20 (m, 1H), 6.93-6.83 (m, 2H), 6.82-6.73 (m, 1H), 3.95 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3F)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:25]>>[NH2:1][C@@H:2]([CH3:5])[CH2:3][O:4][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:8]([OH:25])=[C:7]([Cl:6])[CH:12]=1)=[N:15][CH:16]=[N:17]2
Reactant: C[C@H](N)CO
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Product: C[C@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 54 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (2S)-2-aminopropan-1-ol and 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) to give 4-[(5-{[(2S)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol in 54% yield; NMR spectrum (DMSO-d6); 1.30 (d, 3H), 3.30 (bs, 2H), 3.80 (m, 1H), 4.40 (m, 2H), 7.00 (d, 1H), 7.20 (d, 1H), 7.30 (d, 1H), 7.50 (dd, 1H), 7.70 (t, 1H), 8.00 (d, 1H), 8.45 (s, 1H); Mass spectrum MH+ 345.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[S:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[S:10](=[O:34])[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])=[CH:24][CH:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)c2sc3ccccc3c2-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccccc3S2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 1 (8.2 g,; 0.0238 mole) dissolved in chloroform was cooled in an ice-ethanol bath, and 4.5 g. (0.026 mole) of m-chloroperbenzoic acid in chloroform were added dropwise. The mixture was stirred at room temperature overnight. The resulting mixture then was washed successively with aqueous sodium bicarbonate solution, aqueous sodium chloride solution, and water. The mixture then was dried over magnesium sulfate. The mixture was concentrated, and ethanol was added to the residue. The product crystallized upon scratching of the vessel wall. The solid was filtered and washed with a mixture of ethanol and ether. The solid was air dried to obtain 7.2 g. of product, m.p. 118°-120° C. Thin layer chromatography (TLC) showed the presence of a trace of starting material.
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)[CH:2]=1.[NH2:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CN>C1COCC1>[NH2:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([NH:3][CH3:2])=[O:17]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)cc1N
Reaction time: 3 h
Yield: 55.3 %

Procedure:
Carbonyl-1,1′-diimidazole (1.26 g) was added to 2-amino-4-fluorobenzoic acid (1.0 g) in THF (16.3 mL). After stirring overnight a solution of methylamine in THF (2M, 4.9 mL) was added and the reaction stirred for 3 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The phases were separated and the organics were washed with water (2×100 mL) and then saturated aqueous brine (30 mL). The organics were dried (MgSO4, 15 g), filtered and concentrated in vacuo to give crude product (0.9 g). This material was purified by column chromatography (SiO2, 40 g, eluent 3% MeOH in DCM) to give 2-amino-4-fluoro-N-methylbenzamide (0.6 g). 1H NMR spectrum (270 MHz, DMSO): 2.69 (d, 3H), 6.28 (ddd, 1H), 6.42 (dd, 1H), 6.74 (bs, 2H), 7.48 (dd, 1H), 8.16 (q, 1H); Mass spectrum: ESI+ MH+ 169.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([CH3:3])=[CH2:2].[H][H]>CO.CCOC(C)=O.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)c1cc(O)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cc(O)cc(C(F)(F)F)c1
Yield: 99 %

Procedure:
A mixture of 3-isopropenyl-5-trifluoromethyl-phenol and 10% Pd/C (40 mg) in methanol (10 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 3-isopropyl-5-trifluoromethyl-phenol (120 mg, 99%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5](F)[CH:4]=[C:3]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)=[S:12])[CH:2]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:5]1[CH:4]=[C:3]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)=[S:12])[CH:2]=[CH:1][CH:6]=1
Reactant: Fc1cccc(CCNC(=S)Nc2ccc(Br)cn2)c1
Reactant: CO
Product: COc1cccc(CCNC(=S)Nc2ccc(Br)cn2)c1

Procedure:
N-[2-(3-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (II-5) yield: 73%; mp 171-172° C.; UV (MeOH) λmax: 202, 208, 258, 275 and 306 nm; IR(KBr) ν 3213, 3155, 3084, 3028, 2866, 1595, 1533, 1477, 1336, 1308, 1229, 1211, 1173, 1136, 1092, 1026, 935, 870, 827, 791, 740 cm−1; 1H NMR (CDCl3)δ 811.3 3 (br s, 1H), 9.46 (br s, 1H), 8.05-8.04 (d, 1H), 7.73-7.69 (dd, 1H), 7.31-7.26 (m, 1H), 7.08-6.97 (m, 3H), 6.87-6.83 (d, 1H), 4.06-3.99 (q, 2H), 3.05-3.00 (t, 2H); 13C NMR (CDCl3) δ 179.1, 163.1, 151.7, 146.2, 141.2, 130.1, 129.9, 124.5, 115.9, 115.6, 113.7, 113.5, 113.4, 112.8, 46.7 and 34.6; 19F NMR(CDCl3) δ −37.30 & −37.33 (d); Maldi Tof found: 354.0 (M+), calculated: 354.0; Anal. (C14H13BrFN3S) C, H, N, S.
Reaction SMILES: [CH:1]([S:4]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([NH:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CC(C)S(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
A mixture of 250 mg of 4-isopropanesulfonamidobenzoylchloride 1, 181 mg of 4-bromoaniline 2, 106 mg of triethylamine, and 5 ml of methylene chloride is stirred at room temperature for 5 minutes. The reaction mixture is neutralized with a sodium bicarbonate solution, and extracted with methylene chloride. The organic layer is concentrated under reduced pressure, and the residue is chromatographed on a column of silica-gel. The eluate with 3% methanolmethylene chloride is concentrated, and the residue is crystallized from ethyl acetate-isopropyl ether. The crude resulting crystals are recrystallized from ethyl acetateisopropyl ether to give 200 mg of 4'-bromo-4-isopropanesulfonamidobenzanilide 3 as pure specimen, m.p. 213°-214° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>CCCCCC>[CH3:8][C:6]1[CH:7]=[C:2]([B:15]([OH:20])[OH:16])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-m-xylene (1.5 g in 15 mL of dry tetrahydrofuran) at -78° C. was added 6.4 mL of a 1.4M solution of butyllithium in hexane and the mixture stirred for 20 minutes. At this time triisopropyl borate (2.8 mL) was added and the mixture allowed to warm to room temperature. After 1.5 hours the reaction was concentrated in vacuo to 1/3 volume then cooled to 0° C. and treated with 2N hydrochloric acid (9 mL) followed by warming to room temperature. After 4 hours the mixture was made basic by the addition of 2.5M sodium hydroxide and partitioned between ethyl ether (75 mL) and 1.25M sodium hydroxide. The organic layer was extracted with 1.25M sodium hydroxide (2×) and the aqueous portion then cooled to 0° C. and acidified to pH 3 by the dropwise addition of conc. hydrochloric acid. The white slurry was dissolved in methylene chloride, the organic portion dried over magnesium sulfate and concentrated in vacuo to provide the title compound (960 mg).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: COc1ccccc1B(O)O
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: [K+]
Product: COc1ccccc1-c1nc(C)c2c(C)nc3ccc(F)cc3n12
Yield: 89.6 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 2-methoxyphenylboronic acid (46 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (72 mg, 90% yield). EIMS 322.1 [M+H]+.