Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[F:20][C:21]([F:40])([F:39])[C:22]([NH:24][CH2:25][C:26]1[C:27]([F:38])=[CH:28][C:29]([Cl:37])=[C:30]([CH:36]=1)[C:31]([N:33]=[C:34]=[O:35])=O)=[O:23].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:37][C:29]1[C:30]([C:31]2[NH:33][C:34](=[O:35])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=3)[N:10]=2)=[CH:36][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:21]([F:40])([F:39])[F:20])=[C:27]([F:38])[CH:28]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 6.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 0.300 g), 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.300 g), DCM (20 mL), trifluoro acetic acid (5.0 mL) to afford 0.030 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 4.49 (m, 2H), 7.74-7.77 (m, 1H), 7.78-7.80 (m, 1H), 7.87 (d, J=5.1 Hz, 2H), 8.19 (d, J=4.2 Hz, 2H), 10.06 (m, 1H), 12.76 (s, 1H); MS (m/z): 467.15 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]([C@@H:11]2[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH2:8][C:9]#[N:10])#[N:2].C(O)C.[SH2:44]>C(N(CC)CC)C>[NH2:10][C:9]1[NH:2][C:1](=[S:44])[C:3]2[N:4]=[CH:5][N:6]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1
Reactant: S
Reactant: N#CCc1c(C#N)ncn1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc2c(ncn2[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=S)[nH]1

Procedure:
A mixture of 8 g of 4-cyano-5-cyanomethyl-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)imidazole, 250 ml of ethanol saturated at 0° C. with hydrogen sulfide, and 2.5 g of triethylamine is kept in a steel bomb for 48 hours at ambient temperature. The reaction solution is evaporated in vacuo to a yellow foam which is coevaporated with ethanol several times to provide 6-amino-1,5-dihydro-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-4H-imidazo[4,5-c]pyridine-4-thione.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17](Cl)=[N:16][C:15]=3[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][N:33]=1>>[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35]([C:17]2[N:18]=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:20]3[S:21][C:13]([CH2:12][N:9]4[CH2:10][CH2:11][N:6]([S:3]([N:2]([CH3:29])[CH3:1])(=[O:5])=[O:4])[CH2:7][CH2:8]4)=[CH:14][C:15]=3[N:16]=2)=[CH:34][N:33]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)N(C)C)CC4)cc3n2)c(OC)n1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-sulfonic acid dimethylamide (Example 28) was reacted with 2,4-dimethoxypyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 113. NMR (CDCl3): 2.50-2.53 (4H, m, CH2), 2.75 (6H, s, Me), 3.21-3.24 (4H, m, CH2), 3.68-3.71 (6H, m, CH2), 3.94-3.98 (4H, m, CH2), 4.01 (3H, s, Me), 4.04 (3H, s, Me), 7.20 (1H, s, Ar) and 8.87 (1H, s, Ar). MS: (ESI+): MH+=565.44
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl>C1COCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:4]([F:9])[CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cooled (0° C.) solution of 3.64 g (25.0 mmol) of 4-chloro-2-fluoroaniline and 4.2 mL (30 mmol) of triethylamine in 50 mL of THF was added 4.18 mL (26 mmol) of pivaloyl chloride. After stirring for 10 min. at 0° C. the mixture was warmed to ambient temperature and poured into 0.5N HCl. The mixture was extracted with 100 mL of ether, and the organic extract was washed sequentially with NaHCO3 and brine. The solution was dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica gel (elution with 3:1 hexanes-ether) to give, after removal of solvent, 5.2 g (92%) of 4′-chloro-2′-fluoro-2,2-dimethylpropionanilide as a pale pink solid (IX), mp 70.5-71° C. 1H NMR (300 MHz, CDCl3) δ8.36(t, 1H, J=8.4 Hz); 7.57(br. s, 1H); 7.10-7.17(m, 2H); 1.30(s, 9H). 19F NMR (282 MHz, CDCl3) δ−129.8. High resolution mass spec: calculated for C11H14NOClF(M+H)+: 230.0748, found: 230.0760.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.CON(C)C(=O)CCC>CC(C)=O.O>[S:4]1[CH:5]=[CH:6][C:2]([C:9](=[O:10])[CH2:8][CH2:7][CH3:11])=[CH:3]1
Reactant: Brc1ccsc1
Reactant: C1CCOC1
Agent: CCCC(=O)N(C)OC
Solvent: O
Solvent: CC(C)=O
Product: CCCC(=O)c1ccsc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
3-Bromothiophene (11 g, 67 mmol) dissolved in hexanes (110 ml) was cooled to −20 C in acetone/water bath, and n-Bu Li (28 ml, 71 mmol, 2.5 N solution in hexanes) was added slowly, over 10 min, then stirred 10 min at −20 C. THF was added (10 ml) over 5 min with rapid stirring. Precipitate formed after about 2/3 of addition. After adding all of the THF, the reaction mixture was stirred 20 min at −20 C, then 20 ml hexanes was added and the reaction mixture was allowed to warm to zero degrees C. N-Methoxy-N-methyl-butyramide (9.29 g, 71 mmol) dissolved in 20 ml hexanes was added via cannula over 5 minutes, and the reaction mixture was stirred at zero degrees C. for 1.5 hours. The reaction mixture was quenched with water, then 1 N HCl (75 ml), extracted twice with ether, washed 1 N HCl, brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure to give an oil, which was chromatographed by flash chromatography (5% EtOAc/hexanes) to give 6.7 g, 64% of 1-Thiophen-3-yl-butan-1-one as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[C:14](Cl)(C1C=CC=CC=1)([C:21]1C=CC=CC=1)[C:15]1C=CC=CC=1>C(Cl)Cl>[CH3:4][C:3]1([CH3:5])[CH2:2][NH:1][CH2:15][C@@H:14]([CH3:21])[NH:6]1
Reactant: CC(C)(N)CN
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CNCC(C)(C)N1
Reaction time: 40 h

Procedure:
A mixture of 1,2-diamino-2-methylpropane (XXVI, 10 ml) and triethylamine (20 ml) in methylene chloride (400 ml) is cooled to -40°. Trityl chloride (26 g) in methylene chloride (75 ml) is added dropwise and the reaction is allowed to warm to 20-25° and stir for 40 h. After a standard basic workup (methylene chloride, sodium bicarbonate and magnesium sulfate) the residue is chromatographed (silica gel; ethyl acetate/methanol, 9/1), to provide the desired compound, mp 97-98°; IR (mineral oil) 2956, 2925, 2869, 2855, 1487, 1462, 1449, 747 and 708 cm-1 ; NMR (CDCl3) 7.51, 7.27, 7.17, 1.94-2.01, 1.71-1.82 and 1.12 δ; MS (m/e) 273, 258, 243, 165 and 58.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1)([O-])=O.[Cl-].[NH4+:29].C(O)C>O>[NH2:29][C:25]1[CH:26]=[CH:27][CH:4]=[CH:5][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1occc1-c1cccc(OCc2cccc([N+](=O)[O-])c2)c1
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1occc1-c1cccc(OCc2ccccc2N)c1
Yield: 78.8 %

Procedure:
A mixture of ethyl 3-[3-(3-nitrobenzyloxy)phenyl]-2-furancarboxylate (2.21 g), reduced iron (1.75 g), ammonium chloride (0.67 g), ethanol (30 ml) and water (10 ml) was heated at reflux for 1 hour. After filtering the reaction solution through celite, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/3), thereby giving 1.60 g of ethyl 3-[3-(2-aminobenzyloxy)phenyl)-2-furancarboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33].C(N(CC)CC)C>CO>[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33][CH:17]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: Nc1ccccc1S
Reactant: COC(=O)/C(=C/c1ccc(Cl)c(Cl)c1)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a deoxygenated solution of methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(3,4-dichlorophenyl)acrylate (10a) (2.17 g, 5.7 mmol) in anhydrous methanol (40 ml) (warmed to dissolve) under nitrogen was added the 2-aminothiophenol (3.1 ml, 28.5 mmol) followed by addition of triethylamine (400 ul, 2.85 mmol). The mixture stirred 3 days at ambient temperature, concentrated to ca. 10 mL, partitioned between cold 1N hydrochloric acid (75 mL) and ethyl acetate (100 mL). The organic phase was separated and consecutively washed with 1N hydrochloric acid (4×), dilute aqueous sodium bicarbonate and brine, dried, filtered and evaporated to give the title compound (10b) as an 4:1 mixture (erythro:threo) (2.8 g, 96%). A 100 mg sample was converted to the HCl salt to provide an analytically pure title compound (32 mg) as a (4:1) mixture. MS APCI, m/z=505 (M+1), 507 (M+3). LC/MS: 2.94 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[CH:13](NC(C)C)(C)[CH3:14].[Li]CCCC.ICC.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[CH2:13][CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c(Cl)ccc(NC(C)=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-chloro-2-fluorophenyl)acetamide (10.0 g, 53.3 mmol) and diisopropylamine (7.5 mL, 53.3 mmol) in THF (300 mL) at −78° C. is added dropwise n-BuLi (2.5 M in hexanes, 42.6 mL, 106.6 mmol) keeping the reaction temperature below −60° C. After 2 hours, iodoethane (12.4 g, 80 mmol) is added dropwise at −78° C. The reaction mixture is stirred at −78° C. for additional 1.5 hours. A 1N solution of aqueous HCl is added slowly until a pH between 4 and 5 is reached. The mixture is extracted with EtOAc (200 mL×3) and the organic layers are combined washed with water and brine, then dried over MgSO4. The solvent is removed under reduced pressure and the solid residue is stirred in ether and hexane (1:4, 80 mL) for 1 hour. The filtered solid is dried to give N-(4-chloro-3-ethyl-2-fluorophenyl)acetamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH3:17])[N:19]=[CH:20][CH:21]=2)[C:7]([C:11]([F:14])([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(C)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(C)(F)F)cc1N
Temperature: 90 °C
Reaction time: 72 h
Yield: 62.1 %

Procedure:
To a solution of 2-amino-4-(1,1-difluoro-ethyl)-5-iodo-benzoic acid methyl ester (0.80 g, 2.35 mmol) in dioxane (10 mL) were added 1-methyl-5-tributylstannanyl-1H-pyrazole (1.05 g, 2.81 mmol) and Pd(PPh3)2Cl2 (168 mg, 0.235 mmol) and the resulting mixture was stirred at 90° C. for 72 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:10 to 3:7)) to give 2-amino-4-(1,1-difluoro-ethyl)-5-(2methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (430 mg, 1.46 mmol, 62%). ES-MS: m/z 296 [M+H]+, rt 6.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][C@@H:10]1[CH3:14])=[O:25]
Reactant: C[C@H]1CN(c2ccc(Cl)cc2)CCN1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(c2ccc(Cl)cc2)CCN1C(=O)CCl

Procedure:
Protocol S was followed using 1-(4-Chloro-phenyl)-3-(S)-methyl-piperazine, Et3N, chloroacetyl chloride and methylene chloride. Column chromatography afforded the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:12](=[O:22])[CH:11]=3)=[CH:4][C:3]=2[O:2]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(=O)([O-])[O-].[Ag+2].CN(C)C=O>[CH3:34][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][O:22][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)[nH]1
Reactant: CCOC(=O)C(C)CCCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)CCCCOc1cc(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
The procedure in Example 5 is followed but using 4-(3,4-methylenedioxyphenyl)-6-phenyl-2-pyridinone (2.5 g), ethyl 6-bromo-2-methylhexanoate (4 g), silver carbonate (1.2 g) and dimethylformamide (100 cc). The reaction mixture is heated at 100° C. for 72 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1 ). (yellowish oil)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1.CC#N.C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:15]([CH3:20])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCC(CC)(c1ccc(Br)cc1)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CCC(CC)(c1ccc(Br)cc1)c1ccc(OCc2ccccc2)c(C)c1
Reaction time: 20 h
Yield: 82.5 %

Procedure:
To a solution of 4-[1-(4-bromophenyl)-1-ethylpropyl]-2-methylphenol (2.1 g, 6.3 mmol) in anhyd MeCN (30 mL) added anhyd K2CO3 (2.9 g, 21 mmol) and benzyl bromide (0.83 mL, 7.0 mmol). The reaction mixture was heated at reflux. After 20 h, the reaction mixture was cooled, diluted with Et2O (100 mL) and filtered. The filtrate was washed with H2O (2×50 mL) and brine, dried (anhyd Na2SO4), concentrated under reduced pressure and chromatographed (silica, EtOAC/Hex, 0:100 to 15:85) to give 5-[1-(4-bromophenyl)-1-ethylpropyl]-2-benzyloxytoluene (2.2 g, 82%), as a colorless liquid: 1H-NMR (CDCl3) δ 7.43-7.48 (2H, m), 7.31-7.42 (5H, m), 7.06 (2H, d, J=8.6), 6.94 (1H, dd, J=2.3, 8.3), 6.89 (1H, d, J=2.3), 6.79 (1H, d, J=8.3), 5.05 (2H, s), 4.23 (1H, s), 2.23 (3H, s), 2.05 (4H, q, J=7.3), 0.62 (6H, t, J=7.3).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:10]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:6])[OH:3])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCO
Reactant: O=C(O)CC(O)C(=O)O
Product: CCCCCOC(=O)CC(O)C(=O)OCCCCC
Temperature: 115 °C

Procedure:
Dipentyl-DL-malate was prepared using a procedure similar to that in Example 4. To the reaction flask, DL-malic acid (100.43 g), 1-pentanol (325 mL) and Amberlyst®15 ion exchange resin (14.2 g) were added. The mixture was placed under nitrogen and heated to reflux. At 108° C., two phases started to collect in the Dean-Stark trap. The reaction was maintained at 110-120° C. for 4 hr 15 min and water was continuously removed. The product was separated from the catalyst via filtration over silica using 300 mL diethyl ether. The organic layer was washed 4 times with saturated sodium bicarbonate, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Dipentyl-DL-malate was obtained as a low viscosity, slightly hazy, very light yellow liquid with a slight pleasant odor (116.5 g, 55.6% yield) after pumping on the sample in vacuo to remove residual 1-pentanol.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[C:15](O)=[O:16])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].S(Cl)([Cl:23])=O>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[C:15]([Cl:23])=[O:16])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Reactant: O=S(Cl)Cl
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)Cl)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3.81 g (14 mmol) of the above pyridone acid and 100 ml of thionyl chloride is stirred at 45° for 1 hr and at room temperature overnight. The reaction mixture is stirred for 3 hrs at 52°, cooled, and filtered. The solid is washed with hexane and dried under high vacuum over phosphorus pentoxide to give 3.57 g of 6-[3-(acetylamino)phenyl]-1,2-dihydro-2-oxonicotinoyl chloride.
Reaction SMILES: C(OC(=O)[N:7]([C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]3[N:23]=[C:22]2[CH2:32][CH3:33])=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.O1CCOCC1.[ClH:41]>CO>[ClH:41].[CH2:32]([C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[N:19][C:14]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:15][CH:16]=2)[C:25]2=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]2[N:23]=1)[CH3:33]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cnc(N(C(=O)OC(C)(C)C)c2ccccc2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cnc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
[5-(2-Ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)pyrimidin-2-yl]phenylcarbamic acid tert-butyl ester (310 mg, 0.676 mmol) obtained in Step 7 was dissolved in methanol (5 mL), and a 4 mol/L hydrogen chloride-1,4-dioxane solution (4 mL) was added to the solution, followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from diethyl ether to obtain Compound 167 (255 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:26])([CH:23]([CH3:25])[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31].[Cl-].[Na+]>C1COCC1>[CH2:31]([O:26][C:16]([C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:7][C:2]=1[Cl:1])([CH:23]([CH3:24])[CH3:25])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH:30]=[CH2:29]
Reactant: CC(C)C(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: C=CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(Cn1cncn1)(c1ccc(Oc2ccc(Cl)cc2)cc1Cl)C(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol (0.50 g) in 15 mL of THF was added sodium hydride (40 mg) at room temperature. The reaction mixture was then stirred for 30 min followed by the addition of allyl bromide (130 mg) and stirred at room temperature for 18 hours, then at 70° C. for 6 hours and then at 120° C. for 10 hours. An aq. solution of sodium chloride was then added, the mixture was extracted with dichloromethane, dried, evaporated. The crude residue was purified by flash column chromatography on silica gel to give 1-[2-allyloxy-2-[2-chloro-4-(4-chlorophenoxy)phenyl]-3-methyl-butyl]-1,2,4-triazole as a colorless oil (136 mg, 27%; HPLC-MS Rt=1.43 min; masse=432).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](O)=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C.O=P(Cl)(Cl)[Cl:38]>>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([Cl:38])=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1

Procedure:
6.6 g of 1-benzyl-3-(2-furyl)-4-hydroxypyrazolo[3,4-d]pyrimidine are boiled for 12 h in 100 ml of POCl3. The mixture is evaporated in vacuo, the residue is stirred with aqueous K2HPO4 solution and the mixture is extracted with ethyl acetate. After drying using Na2SO4 and concentrating in a rotary evaporator, 7.47 g of a solid are obtained which can be reacted directly for the next stage (Rf=0.8, SiO2, toluene/ethyl acetate=1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][CH:33]=1)([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:24]=3)[C:27]2=[O:28])=[O:8])=[CH:17][CH:18]=1
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
A slurry of N1-(4-methoxybenzoyl)-1,2-benzenediamine (100 mg, 0.413 mmol) and 4-tert-butylphthalic anhydride (84.3 mg, 0.413 mmol) in toluene (1.5 mL) was placed in a bath heated to 110° C. After 16 h, the mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, hexanes/ethyl acetate) to afford 149 mg (85%) of the title compound. The material was further purified by recrystallization from hexanes/ethyl acetate.