Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2([C:30](O)=[O:31])[CH2:29][CH2:28]2)=[O:26])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2([C:30]([NH:14][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:16][CH:15]=3)=[O:31])[CH2:29][CH2:28]2)=[O:26])=[CH:22][CH:23]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To a 0° C. suspension of 4-benzyloxyaniline hydrochloride (47.0 g, 200 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (49.1 g, 220 mmol) in CH2Cl2 (400 mL) was added EDCI (38.2 g, 200 mmol). Stirring was continued at rt for 24 h until the reaction was complete. CH2Cl2 was removed under reduced pressure. H2O (300 mL) and MeOH (200 mL) were added, and the resulting mixture was stirred at rt for 30 min. After filtration and wash with H2O, the solid was transferred to another flask containing 300 mL of sat. aqueous NaHCO3 solution. The mixture was stirred for another 30 min. The solid was filtered, washed with water, and dried over night on a lyophilizer, affording cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide (4-fluoro-phenyl)-amide (75.8 g, 95% yield) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6](I)[CH:5]=1.[CH:19]([C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.[Cu]I>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:19]([CH3:21])[CH3:20])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Reactant: CC(C)c1ncc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2ccnc2C(C)C)c1
Temperature: 100 °C
Yield: 56.7 %

Procedure:
To a solution of 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (500 mg, 1.42 mmol) in DMSO (10 ml) was added 2-Isopropylimidazole (312 mg, 2.83 mmol), CuI (54 mg, 0.283 mmol), N,N′-dimethylglycine HCl salt (79 mg, 0.567 mmol) and K2CO3 (391 mg, 2.83 mmol) under N2 atmosphere. The mixture was heated to 100° C. overnight. After cooling to room temperature, the mixture was diluted with H2O (15 ml). The mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (30%-75% EtOAc in hexanes) to afford 3-(2-isopropyl-imidazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester as an off-white solid (270 mg, 57%).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([OH:19])[CH2:11][CH2:10]1.CN1CCOCC1.N1C=CN=C1>C(Cl)Cl>[C:1]([Si:5]([O:19][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCOc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](C)(C)OC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl-chloro-dimethyl-silane (10.54 g, 70 mmol) was added to a CH2Cl2 (200 mL) solution of 4-chromanol (10.00 g, 66.6 mmol), N-methylmorpholine (10.98 mL, 100 mmol) and imidazole (0.20 g, 3 mmol) at 0° C. The mixture was stirred for 3 days at RT. The reaction was diluted with CH2Cl2 (200 mL), washed with dilute HCl and H2O, dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(OCC)(=O)C>C(#N)C>[CH2:16]([O:15][C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]2[N:24]=[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]3[CH:2]=2)[CH:11]=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)CBr
Reactant: Nc1ccccn1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=Cc2cn3ccccc3n2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
A mixture of 4-bromo-1-(3-benzyloxy-4-nitrophenyl)but-1-en-3-one (55.0 g) and 2-aminopyridine (42.3 g) in acetonitrile (380 ml) was stirred for 4 hours at ambient temperature. Ethyl acetate was added to the reaction mixture and the precipitate was collected by filtration. A mixture of water and ethyl acetate was added to the precipitate and the mixture was adjusted to pH 7.0 with 20% potassium carbonate. The precipitate was collected by filtration and washed with water to give 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]imidazo[1,2-a]pyridine (40.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Cl.O1CCOCC1>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccnc2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1

Procedure:
A solution of 4-Methyl-2-(5-pyridin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 33a (1.0 g, 2.27 mmol) in MeOH (75 ml), platinum oxide (51 mg, 0.97 mmol) and 4N HCl/dioxane (0.62 ml) was hydrogenated at 40 psi for 5.5 hours. The reaction mixture was filtered through celite, washed with MeOH and concentrated in vacuo. The residue was partitioned between dichloromethane and Na2CO3 to give the free base, (977 mg, 97% ). Calculated for C26H32F3NO2 (M+H) 447.53, Found 448.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=O.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[SH:23]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:23][C:14]3[CH:15]=[CH:16][C:17]([C:19]([F:20])([F:21])[F:22])=[CH:18][C:13]=3[N:12]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Solvent: CN(C)C=O
Product: Oc1c(Br)cc(-c2nc3cc(C(F)(F)F)ccc3s2)cc1Br
Temperature: 100 °C

Procedure:
In a N,N-dimethylformamide (DMF) solvent, a suspension of 3,5-dibromo-4-hydroxybenzaldehyde (1.0 eq.) and 2-amino-4-(trifluoromethyl)benzenethiol (1.0 eq.) was heated at a temperature of 100° C. After cooling, DMF was removed therefrom under reduced pressure. Methylene chloride was added to the resultant solid, and the produced precipitate was filtered, and washed with methylene chloride to obtain a solid target product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.Cl.Cl.[NH2:30][CH:31]1[CH2:34][NH:33][CH2:32]1.CN1CCCC1>CN(C)C=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH:31]([NH2:30])[CH2:32]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(F)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(N4CC(N)C4)c(F)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To 210 mg of N,N-dimethylformamide were added 50 mg of 5-amino-1-(6-amino-3,5-difluoropyridine-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour, and concentrated under reduced pressure. The procedure of adding 2 ml of diisopropylether to the residue, stirring and decanting was repeated twice. 2 ml of ethanol and 40 mg of N-methylpyrrolidine were added to the residue, and the mixture was allowed to stand overnight, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 26 mg of the title compound as a pale yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:14]1([CH:13]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
A solution of tryptamine (15 g, 94.0 mmol) and benzaldehyde (10.9 g, 1.1 equiv.) in DCM (800 mL) was treated with TFA (15 mL, 2 equiv.). The resulting mixture was stirred at rt for one day and then neutralized to pH 7 with a saturated aqueous solution of sodium carbonate. After filtration and concentration to dryness the residue was recrystallized from 2-propanol to give the title compound (11.0 g, 47%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9]Br>C(Cl)Cl>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2](=[O:1])[NH:3][CH:4]=1
Reactant: Cc1cccnc1O
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cc(Br)c[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-hydroxy-3-methylpyridine (0.500 g, 4.58 mmol, Acros Organics) in DCM (15 mL) was slowly added bromine (0.282 mL, 5.50 mmol). After addition, the mixture was stirred at rt for 18 h. The mixture was cooled to 0° C. and was quenched with saturated aqueous NaHCO3 (5 mL). The mixture was then extracted with EtOAc (3×20 mL). The combined organic layer were dried over MgSO4 and concentrated. The residue was then dissolved in MeOH (20 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The resulting mixture was then purified by silica gel flash column chromatography (solid loading, 0%-100% EtOAc/hexane) to afford the title compound as a light pink solid. MS (ESI, positive ion) m/z: 188,190 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: CC(C)(C)O
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Product: CC(C)(C)Oc1cccc(C#N)c1C#N
Yield: 70 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-3-nitrobenzene and 2.20 grams of t-butylalcohol, there was obtained 1.40 grams of 1,2-dicyano-3-t-butoxybenzene (yield of 70%). Next, as in Synthesis Example 1 but using 1.40 grams of this benzene compound and 0.58 gram of BBr3, there was obtained 2.9 grams of the end product (yield 60%, mp 184°-186° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I:10]I.[OH-].[K+]>CN(C)C=O>[I:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ccccc12
Reaction time: 3 h

Procedure:
To a stirred solution of indole 7 (1.0 eq.) in dimethylformamide (4.4 mL/mmol) under argon was added iodine (1.98 eq.) and potassium hydroxide (1.0 eq.). The reaction mixture was stiffed for 3 hours. The reaction mixture was quenched by addition of water (8.8 ml/mmol) and product precipitated, which was filtered and dried. The solid was resubmitted to reaction conditions (dimethylformamide (4.4 mL/mmol) under argon, iodine (0.4 eq.) and potassium hydroxide (0.2 eq.) and stiffed for 1 h) to convert the remaining starting material. The reaction mixture was quenched by addition of water (8.8 ml/mmol) and product precipitated, which was filtered and dried to afford 3-iodoindole 8. Beige solid. 1H NMR (d6-DMSO, 400 MHz) δ 1.39 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.2 Hz, 2H), 7.35-7.42 (m, 2H), 12.66 (s, 1H), 19F NMR (d6-DMSO, 376 MHz) δ −126.87, MS (ESI−) m/z=366.13 (M−H)− 100%, 368.15 (M−H)− 35%.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N:18]4[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH:21][C:27]4=[O:29])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2cnc(Oc3cccc4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 147 %

Procedure:
To a solution of N1-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2-methylalaninamide (Intermediate 143, 18 mg, 0.053 mmol) in dry Dichloromethane (DCM) (3 mL) TEA (0.037 ml, 0.263 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (7.02 mg, 0.024 mmol) in dry Dichloromethane (1 mL) was slowly added and the reaction mixture was stirred for 2 hours while the temperature was allowed to reach r.t. The reaction was quenched with water (3 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column SNAP 10 g and cyclohexane/ethyl acetate from 8:2 to 1:1 as eluents affording the title compound (13 mg) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:34](=O)([O:40]C(C)(C)C)[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[C:36]([O:35][C:34]([N:18]1[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:16]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:15]=[C:14]1[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Fc1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)[nH]c2-c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Oc3ccccc3)cc2)nc(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-phenoxyphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (prepared by the method described in Example 2; 150 mg, 0.37 mmol) in DMF (1 mL) was added solid sodium hydride (8.9 mg of a 60% oil dispersion, 0.37 mmol). The reaction was stirred for 1 h at room temperature and then cooled to -20° C. Di-t-butyl carbonate (85 μL, 0.37 mmol) was added and the reaction was placed in a refrigerator for 4 days. The reaction was quenched by the addition of water and the mixture was extracted with ethyl acetate (3 times). The combined extracts were successively washed with water (2 times) and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-1.5% methanol in methylene chloride to yield the title compound, mass spectrum (CI) m/e=508 (M+1)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(4-bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:31])[C:22]=1[N:23]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[CH2:25][CH2:24]1)=[O:16].[CH3:32]B(O)O>>[NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:32])[C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:31])[C:22]=1[N:23]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[CH2:25][CH2:24]1)=[O:16]
Reactant: CB(O)O
Reactant: Cn1ncc(NC(=O)c2nc(-c3cccc(Br)c3F)sc2N)c1N1CCC[C@@H](N)CC1
Product: Cc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](N)CC3)c(N)s2)c1F

Procedure:
Boc and Cbz protected intermediate of 373 from Example 373, was subjected to standard Suzuki conditions, following procedures in Example 141 with methyl boronic acid to give the methylated intermediate. Deprotection according to procedures for Example 373, gave 381. 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.07 (t, J=7.2 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 2H), 7.32 (t, J=6.9 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 6.74 (s, 1H), 3.65 (s, 4H), 3.23-2.95 (m, 8H), 2.31 (s, 3H), 1.95-1.72 (m, 4H), 1.72-1.44 (m, 4H). MS (ESI) m/z: 444.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][NH2:16])[CH:10]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:26])=O)=[CH:20][CH:19]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][N:16]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)[CH3:26])[CH:10]=1
Reactant: COc1ccccc1-c1cc(NN)ncn1
Reactant: CC(=O)c1ccc(C)cc1
Solvent: CCO
Product: COc1ccccc1-c1cc(NN=C(C)c2ccc(C)cc2)ncn1

Procedure:
The title compound was prepared from [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-hydrazine (500 mg, 2.3 mmol) and 4-methylacetophenone (310 μL, 2.3 mmol) in 10 mL of ethanol by a procedure similar to example 1, step 4 yielding 302 mg (39%) of a pale solid. HPLC Purity: 91%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([OH:16])[C:14]#[CH:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:23][C:24]1([CH3:42])[C:36]2[CH:35]=[C:34](O)[C:33]3[CH:38]=[CH:39][CH:40]=[CH:41][C:32]=3[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=2>>[C:17]1([C:13]2([C:10]3[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:12][CH:11]=3)[O:16][C:34]3[C:33]4[CH:38]=[CH:39][CH:40]=[CH:41][C:32]=4[C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([CH3:42])([CH3:23])[C:36]=4[C:35]=3[CH:15]=[CH:14]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#CC(O)(c1ccccc1)c1ccc(N2CCOCC2)cc1
Reactant: CC1(C)c2ccccc2-c2c1cc(O)c1ccccc21
Product: CC1(C)c2ccccc2-c2c1c1c(c3ccccc23)OC(c2ccccc2)(c2ccc(N3CCOCC3)cc2)C=C1

Procedure:
The process for Step 3 of Example 1 was followed except that 1-(4-morpholinophenyl)-1-phenyl-2-propyn-1-ol (from Step 2) was used instead of 1-ferrocenyl-1-phenyl-2-propyn-1-ol to react with 7,7-dimethyl-7H-benzo[C]fluoren-5-ol to provide 3-phenyl-3-(4-morpholinophenyl)-13,13-dimethyl-3H,13H-indeno[2′,3′:3,4]naphtho[1,2-b]pyran. Mass spectrometry analysis supported a molecular weight consistent with 3-phenyl-3-(4-morpholinophenyl)-13,13-dimethyl-3H,13H-indeno[2′,3′:3,4]naphtho[1,2-b]pyran.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[CH:8]=[C:9]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2C)[CH:10]=[N:11][C:12]=1[Cl:13].[CH3:24][C:25]1[S:26][C:27]([C:31](O)=[O:32])=[C:28]([CH3:30])[N:29]=1>C(#N)C>[C:20]([NH:19][C:17]1[S:18][C:14]([C:9]2[CH:8]=[C:7]([NH:6][C:31]([C:27]3[S:26][C:25]([CH3:24])=[N:29][C:28]=3[CH3:30])=[O:32])[C:12]([Cl:13])=[N:11][CH:10]=2)=[CH:15][N:16]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)Nc1ncc(-c2cnc(Cl)c(NC(=O)c3sc(C)nc3C)c2)s1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
Phosphorus oxychloride (296 mg) was added to a stirred mixture of N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (180 mg), 2,4-dimethylthiazole-5-carboxylic acid (J. Med. Chem., 1999, 42, 5064; 109 mg) and acetonitrile (10 mL) that had been heated to reflux. The resultant mixture was stirred and heated to reflux for 1 hour. The mixture was cooled to room temperature and the precipitate was collected by filtration, washed with acetonitrile and dried under vacuum. There was thus obtained the title compound (172 mg); 1H NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 2.39 (s, 3H), 2.62 (s, 3H), 2.68 (s, 3H), 8.21 (s, 1H), 8.40 (s, 1H); Mass Spectrum: M+H+ 422.
Reaction SMILES: B.[CH3:2][O:3][CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=O.CO.Cl>C1COCC1>[CH3:2][O:3][CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1
Reactant: COCCC1C(=O)Nc2ccccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COCCC1CNc2ccccc21
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere 12.6 mL (12.6 mmol) of a 1M borane in THF solution was added dropwise to 1.2 g (6.3 mmol) 3-(2-methoxy-ethyl)-1,3-dihydro-indol-2-one in 50 mL THF. The reaction mixture was refluxed for 3 h, cooled to 0° C. and combined with 10 mL methanol and then with 15 mL semi-concentrated hydrochloric acid solution. The reaction mixture was refluxed for 3 h with stirring, cooled and washed twice with ethyl acetate. The aqueous phase was made alkaline with an aqueous 4M sodium hydroxide solution and extracted three times with ethyl acetate. The organic phases were combined, dried on sodium sulphate and evaporated down.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:14])[CH:2]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CC1C(C)=NC=CC=1>ClCCl>[C:22]([O:14][C:3]1[CH:2]=[CH:1][C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:5][CH:4]=1)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC(=O)Cl
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: Cc1cccnc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 159.7 %

Procedure:
4,4'-Diphenol (0.1 g) and triethylamine (0.57 g) were dissolved in dichloromethane (20 ml). Nonanoyl chloride (1.0 g) and dimethylpyridine (0.2 g) were added thereto, and the mixture was stirred at room temperature for about 20 hours. The reaction mixture was poured into ice-water and subjected to extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and removed by evaporation to give a crude product. It was purified by silica gel column chromatography (developer: hexane/ethyl acetate=3/2) to give the titled compound (0.28 g).