Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23](=[O:57])[N:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[N:34]=[CH:35][N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:37]=3)=[CH:28][N:27]=2)[CH:25]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH2:17][N:34]2[C:33]([CH2:32][C:29]3[CH:30]=[CH:31][C:26]([N:24]4[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]4=[O:57])=[N:27][CH:28]=3)=[CH:37][N:36]=[CH:35]2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CO)cc1OCc1ccccc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 2-benzyloxy-4-hydroxymethyl-benzonitrile from step 2 (100 mg, 0.42 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (221 mg, 0.42 mmol) in CH2Cl2 (2.1 ml) was added DIEA (325 μl, 0.92 mmol) followed immediately by the addition of Tf2O (160 μl, 0.63 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH and heated to 60° C. for several hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][CH2:6][C:5]([N+:13]([O-])=O)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][O:3]1.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C(O)(=O)C.[Zn]>[CH2:30]([O:29][C:27]([NH:13][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][O:7][C:2]([CH3:16])([CH3:1])[O:3][CH2:4]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)C1([N+](=O)[O-])COC(C)(C)OC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)COC(C)(C)OC1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a solution of 5.0 g of ethyl 2,2-dimethyl-5-nitro-1,3-dioxane-5-carboxylate in 50 ml of acetic acid was added 7 g of zinc powder in four divided portions at room temperature, followed by stirring at 45° C. for 4 hours. The insoluble materials of the reaction mixture were separated by filtration and washed with chloroform. The filtrate was concentrated under reduced pressure and neutralized by the addition of a saturated aqueous sodium hydrogen carbonate solution. To a mixture formed by adding 100 ml of chloroform thereto were added 2.7 g of sodium hydrogen carbonate and 3.7 ml of benzyl chloroformate at 0° C., followed by stirring at room temperature for 2 hours. The obtained organic layer was dried over anhydrous sodium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6.6 g of ethyl 5-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-1,3-dioxane-5-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C=O)C>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=[C:2]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CCOCC3)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (100 mg, 0.164 mmol, Intermediate 65), morpholine (144 mg, 1.64 mmol) and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 48 hours. The vessel was then cooled to room temperature and the solvent was removed by a stream of nitrogen. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C34H29ClF3N7O2, 659.2. m/z found, 660.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.80 (d, J=1.9 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.88-7.83 (m, 3H), 7.63 (d, J=1.4 Hz, 1H), 7.60-7.52 (m, 3H), 7.25 (s, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.10 (s, 1H), 6.42 (dd, J=2.4, 1.9 Hz, 1H), 6.21 (d, J=0.9 Hz, 1H), 4.38 (s, 2H), 3.83-3.75 (m, 4H), 3.30 (s, 3H), 3.25-3.16 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[N:17][C:10]=3[N:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:20]=[CH:19][C:18]([CH:21]=[N:24][OH:25])=[N:17][C:10]=3[N:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C=NO)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
4-(3-Chlorophenyl)-1-ethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-7-carbaldehyde (900 mg, 2.9 mmol) was dissolved in 10 ml of methanol, 420 mg (6.0 mmol) of hydroxylamine hydrochloride and 550 mg (6.7 mmol) of sodium acetate were added thereto, followed by stirring overnight at room temperature. The insoluble matter was washed with water and chloroform and recrystallized from dimethylformamide-acetonitrile to give 171 mg (18%) of 4-(3-chlorophenyl)-1-ethyl-7-hydroxyiminomethylpyrido[2,3-d]pyrimidin-2(1H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1CO
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)4-(2,4-difluorophenoxy)pyrrolidine-2-carboxylic acid (2.55 g, 7.43 mmol) in THF (50 ml) was added BH3.DMS (452 ul, 7.43 mmol). The mixture was heated at reflux overnight. After cooling to room temperature, the mixture was concentrated in vacuo and quenced by the addition of H2O (100 ml). The mixture was extracted with CHCl3 (2×200 ml), dried over MgSO4, and evaporated. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethanol (1.76 g, 72%) as a colorless oil. 1H-NMR (CDCl3) δ 1.45 (s, 9 H), 2.28–2.36 (m, 2 H), 3.58–4.99 (series of m, 8 H), 6.74–6.90 (m, 3 H).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[N+:5]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[CH:16]=[C:15]([OH:18])[CH:14]=[CH:13]2)([O-:7])=[O:6].FC(F)(F)S(O)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:2]([O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][CH:9]=[C:8]2[N+:5]([O-:7])=[O:6])=[CH:13][CH:14]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: O=[N+]([O-])c1cccc2ccc(O)cc12
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Oc1ccc2cccc([N+](=O)[O-])c2c1
Temperature: -20 °C

Procedure:
Isobutylene (150 mL) was condensed into a stirred mixture of 8-nitro-2-naphthol, as described above in Step C, (4.35 g, 23.0 mmol) in CH2Cl2 (200 mL) at −78° C. Trifluoromethanesulfonic acid (0.203 mL, 2.30 mmol) was added and the mixture was allowed to slowly warm to −20° C. over about 4 hours. Triethylamine (2.56 mL, 18.4 mmol) was added and the mixture was allowed to warm to ambient temperature, then concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica, eluting with hexane—5% EtOAc to yield the titled product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(F)c(F)c2)cn1
Yield: 15 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluoro-phenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3,4-difluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (16 mg, 15%) which was obtained as an off-white solid. MS: m/e=356.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[Br:13]Br>C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]2[C:11](=[O:12])[CH:10]([Br:13])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Nc1nc2c(s1)C(=O)CCCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1nc2c(s1)C(=O)C(Br)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 26z (1.96 g, 7.45 mmol; HBr salt form) in glacial acetic acid (70 mL) was treated dropwise with Br2 (421 uL, 8.2 mmol). The reaction mixture was stirred at room temperature for 30 min. The crude product was collected by filtration, washed with cold acetone, and dried to yield 27z which was used in the next step without purification (1.98 g, 78%). 1H NMR (600 MHz, 2 DMSO-d6): δ 8.71 (br s, 2H), 5.11 (dd, J=6.9 Hz, 3.3 Hz, 1H), 3.08-2.90 (m, 2H), 2.473 2.39 (m, 1H), 2.28-2.20 (m, 1H), 2.14 (dd, J=10.1 Hz, 2.3 Hz, 1H), 1.98-1.90 (m, 1H). MS (ESI) m/z [M+H]+ 260.92; [(M+2)+H]+ 262.88. 5 6
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[C:9]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][N:21]2[CH2:22][CH2:23][CH:18]([NH:17][C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:19][CH2:20]2)=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NC1CCN(CCc2ccncc2)CC1)c1ccccc1

Procedure:
A mixture of 4-vinylpyridine (578 mg.), 4-benzamidopiperidine (1.02 g.), acetic acid (330 mg.) and methanol (5 ml.) was refluxed for 8 hours, cooled, and evaporated. The residue in water was basified with potassium carbonate and the resulting solid was collected. Recrystallisation from aqueous ethanol gave the product (1.24 g.) m.p. 193°-5° C. (Found: C, 73.3; H, 7.4; N, 13.3. C19H23N3O requires C, 73.75; H, 7.4; N, 13.3%).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br[CH2:23][C:24]([C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)=O>>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([C:24]2[N:4]=[C:1]([CH2:2][CH3:3])[N:5]([C:6]3[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=3)[CH:23]=2)=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Product: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 4-(bromoacetyl)benzonitrile: MS (ESI) m/z 417 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][CH:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6](=[O:14])[CH2:5]3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C1CC(CCBr)c2ccccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc2N1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
A suspension of 4-(2-bromoethyl)-3,4-dihydro-2(1H)-quinolinone (II'-1) (500 mg, 1.97 mmol),3-(4-piperidinyl)-1H-indole (394.5 mg, 1.97 mmol) and sodium hydrogencarbonate (248.7 mg, 2.96 mmol) in dry dimethylformamide (5 ml) was allowed to react at 90 ° C. for 4 hours. Ice-water (50 ml) was poured into the reaction mixture and then the separated solid was filtered by aspiration. The residue was washed with water and dissolved in chloroform (50 ml). The solution was dried (anhydrous magnesium sulfate) and the solvent was distilled off. The residue was dissolved in developing solvent (chloroform: methanol=85:15) and purified by silica gel column chromatography (chloroform: methanol=85:15). After removing the first eluted impurity , a colorless solution was collected and the solvent distilled off to give the desired product (IV-1) (540 mg) as a pale yellow solid (yield 73.4%, mp 115°-117 ° C. (methanol/tetrahydrofuran/water).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH3:10])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH3:10])[C:5]([CH2:8][O:9][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[N:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1c(Br)cnc(CO)c1C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cnc(CO[Si](C)(C)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
The above (5-bromo-4-methoxy-3-methylpyridin-2-yl)methanol (500 mg) was dissolved in dichloromethane (10 ml), and t-butyldimethylsilyl chloride (487 mg), triethylamine (0.48 ml), and dimethylaminopyridine (30 mg) were then added to the solution under cooling in an ice bath. The resulting mixture was stirred at room temperature overnight. Thereafter, the reaction solution was diluted with dichloromethane, and was then washed with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain the title compound (743 mg) as an oily substance.
Reaction SMILES: [F:1][C:2]1[C:3]([F:12])=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([F:1])[C:3]=2[F:12])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Fc1cc2ccoc2c(Br)c1F
Product: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)c(F)cc2ccoc12
Yield: 38.7 %

Procedure:
Beginning with 0.22 gm (0.94 mMol) 5,6-difluoro-7-bromobenzofuran and 0.21 gm (1.04 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 0.13 gm (38%) of the desired compound were prepared essentially as described in EXAMPLE 19.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=[O:24]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1C(=O)c1nccs1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2nccs2)cc1

Procedure:
The title compound was prepared by the reaction of 4-t-butylbenzenesulfonyl chloride with (2-Amino-5-chloro-phenyl)-thiazol-2-yl-methanone following the general procedure. MS: m/z 435.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:17][C:18]([C:20]1[N:21]=[C:22]([CH2:25]Br)[S:23][CH:24]=1)=[O:19])C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][C:22]3[S:23][CH:24]=[C:20]([C:18]([OH:19])=[O:17])[N:21]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Product: Cc1ccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)cc1

Procedure:
2-(4′-Methyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 4′-methyl-biphenyl-4-ol (purchased from Maybridge plc, Tintagel, Cornwall, UK or from Intermediate 5) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (intermediate 3). Yield: 70 mg. Mass spectrum (ES) MH+=326.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Cl)=[C:7]([N+:16]([O-:18])=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[CH3:20][NH2:21]>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:21][CH3:20])=[C:7]([N+:16]([O-:18])=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c([N+](=O)[O-])c(Cl)c2ccccc21
Reactant: CN
Solvent: C1CCOC1
Product: CCCCn1c(=O)c([N+](=O)[O-])c(NC)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
11 g (0.039 mole) of Compound d obtained in Reference Example 4 was dissolved in 100 ml of tetrahydrofuran, and 30 ml (0.39 mole) of 40% methylamine was added with ice cooling, followed by stirring at room temperature for one hour. Then, the solvent was evaporated under reduced pressure, and water was added to the residues. The precipitate was collected by filtration and dried, to afford 9.2 g of Compound w (yield: 87%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.ON1C2C=CC=CC=2N=N1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:26]([CH:29]=1)[C:27]#[N:28]>C(O)C>[C:27]([C:26]1[CH:29]=[C:22]([NH:21][C:8]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])=[O:10])[CH:23]=[CH:24][C:25]=1[O:30][CH2:31][CH:32]([CH3:33])[CH3:34])#[N:28]
Reactant: Cc1c(C(=O)O)cnn1C
Reactant: CC(C)COc1ccc(N)cc1C#N
Agent: On1nnc2ccccc21
Solvent: CCO
Product: Cc1c(C(=O)Nc2ccc(OCC(C)C)c(C#N)c2)cnn1C
Temperature: 78 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
1-Hydroxybenzotriazole 1,5-dimethylpyrazole-4-carboxylate (2 g) and 5-amino-2-isobutoxybenzonitrile (1.9 g) were added to ethanol (25 ml) and the mixture was stirred at 78° C. for 3 h. After evaporation of the solvent, the residue was purified by silica gel column chromatography (mobile phase:chloroform:methanol=50:1) to give the title compound (0.8 g), melting point: 160–162° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 62.3 %

Procedure:
3-chloro-2-fluoroaniline (0.179 mL, 1.63 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (200 mg, 0.41 mmol, as described in Example 3.03) using a procedure similar to the one described in Example 3.00 to give 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (121 mg, 62.6%) as a white solid. Mass Spectrum: M+H+ 474. NMR Spectrum: (DMSOd6) 1.58 (d, 3H), 2.70 (s, 3H), 2.94 (s, 3H), 3.50-3.64 (m, 4H), 3.70-3.80 (m, 4H), 5.05-5.15 (m, 1H), 5.60 (m, 1H), 6.37 (dd, 1H), 6.44 (d, 1H), 6.65 (ddd, 1H), 6.83 (dd, 1H), 7.60 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1B(O)O>CN(C=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: Cc1ccc(F)c(B(O)O)c1
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-fluoro-5-methylphenylboronic acid (CAS RN 166328-16-1) and using DMF as reaction solvent. Pale yellow solid (26%). MS (ESI): m/z=457.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][CH2:10][C:11]([O:13][C:14]1[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[CH3:23])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:22][C:21]1[CH:20]=[C:17]([CH2:18][OH:19])[CH:16]=[C:15]([CH3:23])[C:14]=1[O:13][C:11](=[O:12])[CH2:10][NH:9][CH2:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7]
Reactant: Cc1cc(C=O)cc(C)c1OC(=O)CNCC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(C)c1OC(=O)CNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of 2.88 g of 4-(tert-butoxycarbonylmethylamino)acetoxy-3,5-dimethylbenzaldehyde and 0.34 g of sodium borohydride in 25 ml of tetrahydrofuran was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and was washed with 0.25N HCl. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain (tert-butoxycarbonylmethylamino)acetic acid 2,6-dimethyl-4-hydroxymethylphenyl ester (2.9 g) as a colourless syrup. To a solution of 2.8 g of (tert-butoxycarbonylmethylamino)acetic acid 2,6-dimethyl-4-hydroxymethylphenyl ester and 2.73 g of triphenylphosphine in 30 ml of dichloromethane, 3.44 g of carbon tetrabromide was added and the mixture was stirred for 1 h at room temperature. The mixture was concentrated and the residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2)to obtain (tert-butoxycarbonylmethylamino)acetic acid 4-bromomethyl-2,6-dimethylphenyl ester (2.97 g, 89% ) as a colourless oil.