Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([O:8][Si](C)(C)C)([CH3:7])[C:5]#[N:6])[CH2:3][CH2:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:13]([O:8][C:4]([CH3:7])([CH:1]1[CH2:3][CH2:2]1)[C:5]#[N:6])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C#N)(O[Si](C)(C)C)C1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: CC(=O)OC(C)(C#N)C1CC1
Yield: 87.5 %

Procedure:
To a well stirred and ice-cooled solution of 2-cyclopropyl-2-trimethylsilanyloxy-propionitrile (188.5 g, 1.03 mol) in acetonitrile (1000 mL) was added acetic anhydride (194 mL, 2.06 mol) and scandium trifluoromethanesulfonate (5 g, 10.3 mmol). The temperature rose to ˜10° C. and stirring was continued for 15′ at room temperature. The solvent was evaporated in vacuo and the residue was distilled to yield 138 g of the title compound as colorless liquid, bp: 84-86° C./6 mbar.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)(=[O:36])=[O:35].N1CCCCC1>CO>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](/[CH:46]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:38]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1cn(S(=O)(=O)c2c(Cl)cccc2Cl)c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4c(Cl)cccc4Cl)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 1-(2,6-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.0918 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(2,6-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.137 g, 69%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:6]1[C:27]([CH3:28])=[CH:26][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[C:18](=[CH:23]\[O:24][CH3:25])/[C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:29])[CH:7]=1)\[CH2:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36](Br)[CH2:37][CH3:38]>C(#N)C.O>[CH3:29][C:8]1[CH:7]=[C:6](/[C:3](=[N:2]/[O:1][CH2:36][CH2:37][CH3:38])/[CH2:4][CH3:5])[C:27]([CH3:28])=[CH:26][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[C:18](=[CH:23]\[O:24][CH3:25])/[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC/C(=N\O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCCO/N=C(\CC)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of 0.12 g (0.3 mmol) of (E)-methyl 2-(2-((4-((E)-1-(hydroxyimino)propyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 4 and 0.2 g (0.61 mmol) of cesium carbonate in 10 mL of acetonitrile (CH3CN) was added propyl bromide (0.05 mL, 0.55 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue thus obtained was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum and the concentrate was purified by silica gel chromatography to afford 0.1 g of (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)propyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate as a white oil (yield: 77%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1S(Cl)(=O)=O.[S:17](Cl)(Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:17]([O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:19])=[O:18])=[CH:9][CH:8]=1
Reactant: COCCO
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: c1ccncc1
Product: COCCOS(=O)(=O)c1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Into a 125 mL erlenmyer flask immersed in an ice/water bath at 5° C. was added 14.2 mL (0.18 Mol) of 2-methoxyethanol and 40 mL of anhydrous pyridine. To the stirred solution was added 51 grams (0.20 Mol) of bromobenzenesulfonyl chloride in portions while keeping the temperature of the reaction below 7° C. After total addition the sulfonyl chloride, the reaction was stirred for one hour and allowed to warm to 10° C. Then the product mixture was poured into 200 mL of ice water and stirred rapidly for 30 min. The mother liquors were decanted and the remaining oily product was treated again with 200 mL of water and rapidly stirred for 30 min. To this mixture was added 400 mL of diethyl ether, and after brief stirring the organic layer was separated from the aqueous layer. The aqueous layer was extracted with 200 mL of diethyl ether and the combined organic layers were dried over magnesium sulfate overnight in the refrigerator at 5° C. The magnesium sulfate was removed by gravity filtration and the ether was removed in vacuo to afford 48 grams (0.16 Mol, 88% yield) of the desired product as a thick oil. This material was noted to crystallize when stored in the refrigerator for extended periods of time.
Reaction SMILES: [C-:1]#[N:2].[K+].BrC[C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:21]O>>[C:15]1([C:12]2([CH2:21][C:1]#[N:2])[CH2:11][CH:10]=[C:9]3[CH:8]=[CH:7][CH:6]=[C:14]3[O:13]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [C-]#N
Reactant: BrCc1cccc2cc(-c3ccccc3)oc12
Reactant: CO
Agent: [K+]
Product: N#CCC1(c2ccccc2)CC=C2C=CC=C2O1

Procedure:
11 g of potassium cyanide were added to 110 ml of methanol and then 23.5 g of 7-(bromomethyl)-2-phenyl benzofuran (Helvetica Chimica Acta, Vol. 57, 5, 1974, p. 1381) in 250 ml of methanol were added. The mixture was refluxed for 5 hours, then separated, filtered and concentrated. The crystals were crystallized from flugene-1,1,3 at reflux to obtain 5.78 g of the desired product melting at 65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(N(CC)C(C)C)(C)C.[C:35]1([C:41]2[O:45][N:44]=[C:43]([NH:46][C:47](=O)[O:48]C3C=CC=CC=3)[CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:47]([NH:46][C:43]2[CH:42]=[C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:45][N:44]=2)=[O:48])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1cc(-c2ccccc2)on1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(-c5ccccc5)on4)c3)c2cc1OC
Temperature: 50 °C
Yield: 69.5 %

Procedure:
According to the procedure described in Example 113C, 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.3 mmol) in THF (1.5 mL) was treated with N,N-diisopropylethylamine (68 μl, 0.39 mmol), 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) and phenyl 5-phenylisoxazol-3-ylcarbamate from Example 113B (109 mg, 0.39 mmol). The reaction mixture was heated to 50° C. for 4h. After cooling to room temperature, the mixture was partitioned between chloroform and a saturated solution of sodium bicarbonate. The water phase was back extracted three times with chloroform and the organics combined and dried (MgSO4). Concentration under reduced pressure gave a residue which was purified by preparative HPLC (phenylhexyl reverse phase column). The obtained solid was triturated with anhydrous diethyl ether to afford 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea as a white solid (110 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.06 (s, 1H), 8.57 (s, 1H), 7.86 (d, 2H), 7.62-7.53 (m, 5H), 7.51 (t, 2H), 7.28 (m, 2H), 6.99 (d, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.77 (bs, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][CH:22]([CH2:24][CH2:25][CH:26](Br)[CH3:27])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:26]([CH3:27])[CH2:25][CH2:24][CH:22]([Br:21])[CH3:23])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Br)CCC(C)Br
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(Br)CCC(C)Oc1ccc2[nH]cc(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
To a solution of 3-[2-(t-butyloxycarbonylamino)ethyl]-5-hydroxy-1H-indole (1.34 g, 4.86 mmol) in acetonitrile (50 mL) were added 2,5-dibromohexane (2.4 g, 9.72 mmol) and potassium carbonate (1.3 g, 9.72 mmol) and the resulting mixture was stirred at reflux for 60 hours. After cooling to room temperature, the solution was poured into ethyl acetate (40 mL), washed with water (40 mL), dried over sodium sulfate and evaporated to dryness. Column chromatography on silica gel using hexane/ethyl acetate (4:1, 2:1 and 1:1) provided the title compound as a syrup (0.65 g, 30%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:10]=[C:11]=O>C(O)(=O)C>[C:1]1([NH:7][C:8](=[O:9])[NH:10][C:11]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:11]
Reactant: [N-]=C=O
Reactant: O=C=Nc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1

Procedure:
1.19 g phenyl isocyanate and 0.6 g acetic acid were reacted in a 1:1 isocyanate:acetic acid molar ratio. The reaction, product isolation and analysis were conducted as in Example 1. 0.45 g diphenyl urea and 0.9 g acetanilide were obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1>>[C:1]1([CH2:7][C:8]([CH:13]2[C:14](=[O:17])[CH2:15][CH2:16][S:11][CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCSCC1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C1CCSCC1C(=O)Cc1ccccc1
Yield: 83 %

Procedure:
3-(2-Phenylacetyl)dihydro-2H-thiopyran-4(3H)-one (291 mg, 83%) was synthesised from 2-phenylacetyl chloride and dihydro-2H-thiopyran-4(3H)-one according to the general procedure for the preparation of diketones. MS (ES−) m/z 233 (M−H)−
Reaction SMILES: [OH:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.C(N(CC)CC)C.[Si:26](OS(C(F)(F)F)(=O)=O)([CH3:29])([CH3:28])[CH3:27].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[CH3:17][CH:15]1[CH2:16][C:2]2([O:1][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:13](=[O:18])[CH2:14]1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1CC(=O)C2CCCCCCCCCC2(O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CC(=O)C2CCCCCCCCCC2(O[Si](C)(C)C)C1
Yield: 98.6 %

Procedure:
A mixture of 25 mg (0.1 mmol) of (16) and 17 μl (0.12 mmol) triethyl amine in 0.5 ml THF was treated at 0° C. with 21 μl (0.11 mmol) TMSOTf. After 30 min 8 μl (0.06 mmol) triethyl amine and 10 μl (0.055 mmol) TMSOTf were added. After 10 min the mixture was diluted with diethyl ether and was poured into 2 ml of a saturated NH4Cl solution. The organic phase was separated, diluted with 3 ml of dichloro methane and the solvent was evaporated at room temperature under vacuum to afford 32 mg (19) (yield: 99%).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=1.[Cl:16]N1C(=O)CCC1=O.[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[C:5]([Cl:16])=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCNc1cc(N(C)C)nc(N)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCNc1c(Cl)c(N(C)C)nc(N)[n+]1[O-]
Reaction time: 4 h
Yield: 60.2 %

Procedure:
1 g of 2-amino-4-propylamino-6-dimethylamino-pyrimidine 3-oxide of Example 1 is dissolved in 15 ml of ethanol. 0.75 g of N-chlorosuccinimide are added as solution in 35 ml of ethanol, dropwise at room temperature. After 4 hours' stirring the reaction mixture is evaporated to dryness. The oil obtained is taken up in 10 ml of water. The pH is adjusted to 8 by adding sodium hydroxide and the mixture is then extracted with 3×20 ml of butanol. The butanol phase is evaporated to dryness. The residue is recrystallized from 5 ml of acetonitrile. 0.7 g of 2-amino-4-propylamino-5-chloro-6-dimethylaminopyrimidine 3-oxide are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][CH:23]([OH:25])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:12][CH2:13][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][CH:23]([O:25][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:22]3)(=[O:19])=[O:20])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(S(=O)(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a stirred solution of 1-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexylmethanesulfonyl]-azetidin-3-ol (Example 30) (180 mg, 0.35 mmol) in dichloromethane (10 mL) at 0° C. was added triethylamine (0.08 mL, 0.58 mmol) and methanesulfonyl chloride (0.035 mL, 0.45 mmol) and the mixture stirred 2 hours at 0° C. Ethyl acetate (20 mL) was added and the mixture washed with 2N aqueous hydrochloric acid (20 μL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with ethyl acetate:iso-hexane (1:1), to afford the desired product (162 mg).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]([O:28][CH3:29])=[CH:20][C:21]=3[O:26][CH3:27])[N:16]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)=[N+]=[N-].[C:30]([OH:33])(=S)[CH3:31]>>[CH3:27][O:26][C:21]1[CH:20]=[C:19]([O:28][CH3:29])[CH:18]=[C:17]2[C:22]=1[C:23](=[O:25])[NH:24][C:15]([C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1)[O:6][CH2:5][CH2:4][NH:1][C:30](=[O:33])[CH3:31])=[N:16]2
Reactant: COc1cc(OCCN=[N+]=[N-])cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Reactant: CC(O)=S
Product: COc1cc(OCCNC(C)=O)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[3-(2-Azido-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (90 mg, 0.22 mmol) was taken in thioacetic acid (2 mL) and the reaction mixture was stirred at room temperature for 2 hours. Thioacetic acid was removed under reduced pressure, and the residue was purified by column chromatography (silica gel 230-400 mesh; 3.5% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 45 mg (49%). MP 264-265° C. 1H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.13 (t, J=5.86 Hz, 1H), 7.39 (d, J=1.56 Hz, 2H), 6.76 (d, J=2.34 Hz, 1H), 6.69 (t, J=2.15 Hz, 1H), 6.55 (d, J=2.34 Hz, 1H), 4.07 (t, J=5.67 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.43 (q, J=5.47 Hz, 2H), 1.84 (s, 3H). MS (ES+) m/z: 414.11 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH:16]([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[C@H:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC2CC2)cc1Cl
Product: C[C@@H](C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 1B using 2-chloro-4-[(cyclopropylmethyl)amino]benzonitrile and 1,1-dimethylethyl 2-bromopropanoate: MS (ES) m/z335 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[CH3:12])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25]>>[CH3:25][O:24][N:23]([CH3:22])[C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:13][CH3:14])[C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1C
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: COc1cc(C(=O)N(C)OC)cc(OC)c1C

Procedure:
3,5-Dimethoxy-4-methylbenzoic acid was allowed to react with oxalyl chloride, and the resulting acid chloride was allowed to react with N,O-dimethylhydroxyamine hydrochloride to obtain N,3,5-trimethoxy-N,4-dimethylbenzamide. The resulting compound was allowed to react with 4-phenylbutylmagnesium chloride to obtain 1-(3,5-dimethoxy-4-methylphenyl)-5-phenylpentan-1-one. The resulting compound was allowed to react with lithium diisopropylaminez and methyl[4-(bromomethyl)phenyl]acetate in the presence of N,N,N′,N″,N″-pentamethyldiethylenetriamine to obtain methyl{4-[2-(3,5-dimethoxy-4-methylbenzolyl)-5-phenylpentyl]phenyl}acetate. Using the obtained compound, the procedure similar to Example 2 were carried out to give the title compound having the following physical properties.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 509.0 [M+H]+; tR=3.07 min (System 1); Rf=0.10 (CH2Cl2/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH3:11][C:5]1[CH:4]=[C:3]([C:12]2[N:13]([CH3:20])[CH:14]=[CH:15][N:16]=2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: CI
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1-c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nccn2C)c(C)cc1N
Reaction time: 0.25 h

Procedure:
To a solution of 2-(2,5-dimethyl-4-nitrophenyl)-1H-imidazole (50 mg, 0.23 mmol) in DMF (2 mL) was added NaH (11 mg, 0.46 mmol) at 0° C. After stirring for 15 min, iodomethane (65 mg, 0.46 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hr, and quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (3×15 mL). The organic layer was washed with brine and dried over sodium sulfate. After concentration, the residue was dissolved in methanol (10 mL). To the solution was added Pd/C (10%). The reaction mixture was degassed and purged with H2 for several times and stirred under 1 atm. hydrogen gas overnight. The mixture was filtered and concentrated to afford 2,5-dimethyl-4-(1-methyl-1H-imidazol-2-yl)aniline. ESMS m/z 202 (M+H+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[C:21]([C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1)#[N:22].C([N:32]([CH2:35][CH3:36])CC)C>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17][O:29][C:25]1[CH:24]=[CH:23][CH:21]=[C:36]([C:35]#[N:32])[CH:26]=1)([O:15][O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:21]#[N:22])[CH:24]=1)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CCN(CC)CC
Reactant: N#Cc1cccc(O)c1
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(OOc1cccc(C#N)c1)OOc1cccc(C#N)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (4.95 g, 0.015 mole) in ether (100 ml.) was added dropwise with good agitation to a solution of m-cyanophenol (3.57 g, 0.03 mole) and triethylamine (3.03 g, 0.03 mole) in dry ether (50 ml.). The reaction mixture was stirred at room temperature for several hours, then filtered. The filtrate was washed with a 5% solution sodium hydroxide, dried over magnesium sulfate, and concentrated in vacuo to afford ethyl N-trifluoroacetyl-N-(bis(m-cyanophenoxy)phosphonomethyl)glycinate (3.4 g.) as a yellow gum, ND22 =1.5185.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:16])[NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)C(O)=O)([CH3:3])[CH3:2].NC1C=C(C=CN=1)[C:21]([O:23]CC)=[O:22].NC1C=CC(C(OC)=O)=CN=1>>[CH:1]([NH:4][C:5](=[O:16])[NH:6][C:7]1[CH:8]=[CH:9][C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]=1)([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)Nc1cc(C(=O)O)ccn1
Reactant: CCOC(=O)c1ccnc(N)c1
Agent: COC(=O)c1ccc(N)nc1
Product: CC(C)NC(=O)Nc1ccc(C(=O)O)cn1

Procedure:
This compound is prepared analogously to Intermediate Y by replacing ethyl 2-aminoisonicotinate in step 1 with methyl 6-aminonicotinate; [M+H]+ 224.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]2[CH2:13][C@@H:14]3[C:19]([CH3:21])([CH3:20])[C@:18]([CH3:22])([C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:17][CH2:16][N:15]3[C:23]([C:25]1[CH:29]=[CH:28][O:27][C:26]=1[CH3:30])=[O:24].O>ClCCl>[OH:6][C:7]1[C:12]2[CH2:13][C@@H:14]3[C:19]([CH3:21])([CH3:20])[C@:18]([CH3:22])([C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:17][CH2:16][N:15]3[C:23]([C:25]1[CH:29]=[CH:28][O:27][C:26]=1[CH3:30])=[O:24]
Reactant: COc1cccc2c1C[C@H]1N(C(=O)c3ccoc3C)CC[C@]2(C)C1(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1occc1C(=O)N1CC[C@@]2(C)c3cccc(O)c3C[C@@H]1C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (2 mL) is added to a solution of [(2R,6S)-10-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-methyl-furan-3-yl)-methanone (0.22 g) in dichloromethane (10 mL). The resulting solution is stirred at ambient temperature for 2 h. Then, water is added and the mixture is stirred for another 10 min. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine and dried (Na2SO4). The solvent is evaporated to give the title compound.