Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:34])[C:9]([N:11]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][N:28]=[C:27]3[CH3:33])[CH2:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I>CN(C=O)C.O.CCOC(C)=O>[CH3:37][N:29]1[C:30]2[C:26](=[CH:25][C:24]([N:11]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=3)[C:9](=[O:10])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:34])=[CH:32][CH:31]=2)[C:27]([CH3:33])=[N:28]1
Reactant: Cc1n[nH]c2ccc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)C(=O)c3ccc(F)cc3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c2ccc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)C(=O)c3ccc(F)cc3)cc12
Reaction time: 5 h

Procedure:
To a solution of 0.32 mmol 2-(4-Fluoro-phenyl)-N-(3-methyl-1H-indazol-5-yl)-2-oxo-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (step 1) in 5 ml dry DMF was added 1.1 eq. NaH and the RM stirred at RT for 30 min. 5 eq. MeI was added and stirring continued for 5 h. Addition of 5 ml H2O, concentration, repartioning between EtOAc and H2O, gave after separation of the layers and concentration the target compound (157 mg) MS(m/e): 485.1 [M+H]+ which was used directly for the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].CC1CCCCC1O.[OH:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[N:24][C:23]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:28][C:26]1[N:25]=[N:24][C:23]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:22]([OH:21])[CH:27]=1
Reactant: Cc1cccc(C2CC2)c1[O-]
Reactant: Oc1cc(Cl)nnc1Cl
Agent: CC1CCCCC1O
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a mixture of 25.5 g (150 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 2-methylcyclohexanol was added 2.5 g (purity: 99%; 15.0 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of pure water and 120 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.15 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 76.0%) and 9.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.2%) were obtained.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.08 g), commercially available 4-bromobenzoyl chloride (2.20 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. overnight. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 1.65 g of the title compound (yield: 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br>>[Br:10][CH2:11][CH2:12][O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1O
Reactant: BrCCBr
Product: Cc1cccc(C)c1OCCBr

Procedure:
2,6 Dimethylphenol (2 mmol) was reacted with 1,2-dibromoethane (10 eq) as described in Step 2A to yield the titled compound.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].Br.N([O-])=O.[Na+].[OH-:17].[Na+]>O>[CH3:11][C:7]1[C:3]2[C:4](=[O:5])[O:6][C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[O:17][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: [OH-]
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc2c1C(=O)Oc1ccccc1O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Cuprous bromide was added in one portion to a hot solution (90° C.) of 2-amino-6-methylbenzoic acid (10 g, 66 mmol) and HBr (26 mL, 40%) in H2O (160 ml). This was followed by the dropwise addition of a solution of NaNO2 (13.7 g, 198 mmol) in H2O (40 ml) over a period of 25 min. The reaction mixture was maintained at same temperature for 1 h and then was heated under reflux for another 0.5 h before it was cooled to room temperature and stirred for 2 h. Upon completion, the reaction mixture was carefully poured into ice water (1000 ml), and 5% NaOH solution was added until a pH of 14 was reached. The resulting suspension was filtered. The filtrate was acidified with diluted HCl to a pH of 1 and extracted with Et2O, Charcoal was added, and the resulting mixture was heated to reflux, filtered and evaporated by a rotatory evaporator to give a crude compound, which was recrystallized from Et2O/PE to afford the product (9.28 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([O:22][C:23](=[O:25])[CH3:24])=[C:17]([CH3:26])[CH:16]=4)[C:4]=2[C:3]=1[CH3:27])[CH:12]=[CH:11][CH:10]=[CH:9]3.[Br:28]Br>C(Cl)Cl>[Br:28][C:7]1[C:5]2[S:6][C:2]([CH3:1])=[C:3]([CH3:27])[C:4]=2[C:14]([C:15]2[CH:16]=[C:17]([CH3:26])[C:18]([O:22][C:23](=[O:25])[CH3:24])=[C:19]([CH3:21])[CH:20]=2)=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[CH:12]2
Reactant: CC(=O)Oc1c(C)cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C
Reactant: BrBr
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Yield: 55.3 %

Procedure:
A solution of acetic acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester (10.0 g, 26.7 mmol) and ferric chloride (0.23 g, 1.4 mmol) in anhydrous methylene chloride (231 mL) was placed at −78 C. under nitrogen. The reaction mixture was protected from light and a solution of bromine (1.5 mL, 29.4 mmol) in anhydrous methylene chloride (38 mL) was added dropwise over a period of 50 min. After 30 min the reaction was quenched with dilute sodium bisulfite, diluted with water, and the resulting mixture was extracted with diethyl ether. The diethyl ether layer was washed twice with water, brine, and then dried (MgSO4). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (97:3, then 95:5) gave the title compound as a white solid (6.7 g, 55%): NMR (DMSO-d6): δ8.27 (d, 1H), 7.60 (d, 1H), 7.56-7.52 (ddd, 1H), 7.38-7.34 (ddd, 1H), 7.06 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.22 (s, 6H), 1.64 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 452/454; Anal. Calc. for C24H21BrO2S: C, 63.58; H, 4.67; N, 0.00. Found: C, 63.41; H, 4.45; N, 0.08.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:16]2[NH:17][N:18]=[C:19]([NH:20][CH3:21])[C:15]=2[C:14](=[O:22])[N:13]([CH2:23][CH2:24][CH2:25][CH3:26])[C:12]1=[O:27])C1C=CC=CC=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[CH2:23]([N:13]1[C:14](=[O:22])[C:15]2[C:19]([NH:20][CH3:21])=[N:18][NH:17][C:16]=2[N:11]([CH2:10][CH2:9][OH:8])[C:12]1=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCOCc2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCO)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a mixture of 7-(2-benzyloxyethyl)-5-butyl-3-methylaminopyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.0 g, 2.7 mM) and sodium iodide (3 g, 20 mM) in acetonitrile (20 ml) was added dropwise trimethylsilyl chloride (2.6 g, 20 mM) at room temperature. The mixture was stirred at room temperature for 2 hours and poured onto ice-water to give crystals. Recrystallization from DMF/methanol/water gave pale yellow crystals (0.3 g, 40%), m.p. 248°-253° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.Br[CH2:10][C:11]1[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([C:21]([O:23]CC)=[O:22])[CH:12]=1.O.[OH-].[Li+]>C(Cl)Cl>[CH3:1][N:2]([CH2:10][C:11]1[N:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[N:14]=[C:13]([C:21]([OH:23])=[O:22])[CH:12]=1)[CH3:3]
Reactant: CNC
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.0 M dimethylamine in THF (5.27 mL, 10.5 mmol) was added a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.33 g, 1.0 mmol, from Step A) in methylene chloride (5.0 mL). The reaction was stirred at room temperature for 2 hours, then concentrated. The residue was dissolved in tetrahydrofuran (20 mL), water (6 mL) was added, followed by lithium hydroxide monohydrate (0.4 g, 10 mmol). The mixture was stirred for one hour, then was rotovapped to remove most of the THF. The pH was adjusted to 7 by the addition of cone. HCl. Acetonitrile (10 mL) was added, the mixture was filtered and then purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as a light yellow solid. Yield: 0.153 g (58%); LC-MS: 250.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 8.02 (s, 1H), 3.70 (s, 2H), 2.27 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:13][CH:14]3[N:19]([C:20]([C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=4I)=[O:21])[CH2:18][CH2:17][CH2:16][O:15]3)[N:9]=2)=[CH:4][CH:3]=1.C([Sn]([C:43]1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1)(CCCC)CCCC)CCC.[F-].[Cs+].[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:13][CH:14]3[N:19]([C:20]([C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=4[C:43]4[N:48]=[CH:47][CH:46]=[CH:45][N:44]=4)=[O:21])[CH2:18][CH2:17][CH2:16][O:15]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Cc1ccc(I)c(C(=O)N2CCCOC2Cn2ccc(-c3ccc(F)cc3)n2)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCCOC2Cn2ccc(-c3ccc(F)cc3)n2)c1
Temperature: 130 °C

Procedure:
To a solution of (±)-(2-{[3-(4-fluorophenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl)(2-iodo-5-methylphenyl)methanone obtained in Reference Example 23 (0.19 g, 0.38 mmol) and (tributylstannanyl)pyrimidine (0.15 mL, 0.46 mmol) in toluene (4 mL), Pd(PPh3)4 (0.044 g, 0.04 mmol), copper iodide (0.0070 g, 0.040 mmol) and cesium fluoride (0.12 g, 0.76 mmol) were added, and the resulting mixture was stirred with heating for 0.5 hours at 130° C. under irradiation of microwave. An aqueous solution of potassium fluoride was added to the reaction mixture, followed by extraction with CHCl3. The organic layer was washed with an aqueous solution of potassium fluoride, water and a saturated aqueous solution of sodium chloride. The organic layer was dried over Na2SO4, the drying agent was filtered off, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane/EtOAc=80/20 to 0/100) (KP-NH 12 g, hexane/EtOAc=80/20 to 0/100) to obtain the racemic mixture of title compound (0.099 g) (colorless oil). The obtained racemic mixture was divided using a semi-preparative column based on the racemic compound analysis conditions described earlier (condition 4, Rt1=3.9 min, Rt2=13.7 min) to obtain the title compound (0.036 g) having a short relative retention time (Rt1=3.9 min) (colorless oil).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)N)=[CH:5][CH:4]=1.C(O[CH:23](OCC)[CH2:24][CH2:25][CH2:26][NH:27][CH3:28])C>C(O)C.O>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:9]([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:23]=[C:24]2[CH2:25][CH2:26][NH:27][CH3:28]
Reactant: CCOC(CCCNC)OCC
Reactant: NN(CCCc1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNCCc1cn(CCCc2ccccc2)c2ccc(Cl)cc12
Temperature: 90 °C
Yield: 74.3 %

Procedure:
28% aqueous HCl (0.07 mL, 0.54 mmol) was added to a solution of N-(4-Chloro-phenyl)-N-(3-phenyl-propyl)-hydrazine (261 mg, 1 mmol) in ethanol (1 mL) and water (0.5 mL) under a nitrogen atmosphere. The reaction was heated to 60° C. (oil bath temperature) and 4,4-diethoxy-N-methylbutan-1-amine (175 mg, 1 mmol) was added. The reaction was heated to 90° C. and 28% aqueous HCl (0.08 mL, 0.61 mmol) was added. The reaction was heated at reflux for 6 h. More 4, 4-diethoxy-N-methylbutan-1-amine (90 mg, 0.51 mmol) was added at 60° C. and more 28% aqueous HCl (0.19 mL, 1.46 mmol) was added at 90° C. The reaction was heated to reflux for a further 8 h. The reaction was cooled and concentrated under reduced pressure. The red-brown residue was subjected to column chromatography (silica gel, eluent: EtOAc followed by EtOAc:EtOH:NH4OH 90:10:1) to give a brown oil (243 mg, 74%).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[O:14]1[C@H:16]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15]1.Cl>CO>[CH2:19]([O:18][CH2:17][C@H:16]([OH:14])[CH2:15][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@@H](O)COCc2ccccc2)cc1

Procedure:
Sodium (2.3 g; 0.1 mol) was dissolved in 500 ml anhydrous MeOH and to this was added a solution of 194.3 g (1.17 mol) 4-hydroxyphenylacetic acid, methyl ester in 250 ml MeOH followed by a solution of 167.3 g. (1.018 mol) (S)-1,2-epoxy-3-benzyloxypropane in 250 ml MeOH. The solution was stirred under reflux for 12 hours. The cooled solution was treated with 8.3 ml (0.1 mol) of concentrated HCl and the methanol was removed in vacuo. The crude product was dissolved in benzene and washed with 2×200 ml portions of cold 1 N NaOH solution and with H2O (1×300 ml). The aqueous layers were backwashed with benzene (2×500 ml). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to give crude (S)-4-(3-benzyloxy-2-hydroxypropoxy)phenyl acetic acid, methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(C(C)C)CC)(C)C.ClCCl.[C:22]12([C:32](Cl)=[O:33])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:32]([C:22]23[CH2:31][CH:26]4[CH2:25][CH:24]([CH2:30][CH:28]([CH2:27]4)[CH2:29]2)[CH2:23]3)=[O:33])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Bromo-2-methylaniline (800 mg) and diisopropylethylamine (1667 mg) were added to dichloromethane (12 mL). 1-Adamantanecarbonyl chloride (940 mg) was added and the solution was stirred at room temperature for 16 hours. The solution was diluted with 50% ethyl acetate (hexanes), washed three times with 1 M aqueous HCl, washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent volume was partially reduced under vacuum, and the solid material precipitated out of solution, which was isolated by filtration to provide the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1.[CH2:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>C(#N)C>[CH3:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=[C:3]1[CH2:2][NH:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CCN
Reactant: Cc1ccccc1Cn1c(CCl)nc2ccccc21
Solvent: CC#N
Product: Cc1ccccc1Cn1c(CNCCC(C)C)nc2ccccc21
Yield: 92 %

Procedure:
A solution of 5.4 mmole 2-(chloromethyl)-1-[(2-methylphenyl)methyl]benzimidazole in 20 mL of dry Acetonitrile is treated with 10 mL of isoamylamine for 16 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 1.6 g 92% ({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl) (3-methylbutyl)amine. 2,4-dimethoxybenzoylchloride 1.5 eq is treated with 1.0 eq of ({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl) (3-methylbutyl)amine in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried with Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 95% of (2,4-dimethoxyphenyl)-N-({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide (Compound 1). Mass Spec M+ 486.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[O:10][C:9](=[O:17])[CH:8]=[C:7]2[CH3:18])[CH:2]=C.O.I([O-])(=O)(=O)=[O:21].[K+]>CO.[Os](=O)(=O)(=O)=O>[OH:21][CH:2]1[O:14][C:13]2=[C:12]([O:15][CH3:16])[C:11]3[O:10][C:9](=[O:17])[CH:8]=[C:7]([CH3:18])[C:6]=3[CH:5]=[C:4]2[CH2:1]1
Reactant: C=CCc1cc2c(C)cc(=O)oc2c(OC)c1O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c2c(cc3c(C)cc(=O)oc13)CC(O)O2
Reaction time: 3.5 h

Procedure:
A solution of 2.0 g (8.12 mmols) of 6-allyl-7-hydroxy-8-methoxy-4-methylcoumarin in 20 ml of methanol was treated (mechanical stirring) with 10 ml of water, 5.0 g potassium periodate, and 1.0 ml of a 10% aqueous solution of osmium tetroxide (10 mg/ml). After 3.5 hrs, the mixture was partitioned between water/methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic extracts were dried and evaporated to yield 2-hydroxy-9-methoxy-5-methyl-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one. The compound was dissolved in 40 ml of 98% formic acid and heated under reflux for 1.0 hr. The solution was cooled and evaporated to dryness. The residue was chromatographed over silica, eluting with ethyl acetate/benzene, 1:4, to afford pure 9-methoxy-5-methyl-7H-furo[3,2-g][1]benzopyran-7-one, m.p. 167°-168° (ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])=[C:19]=[O:20]>>[C:24]([C:23]1[CH:22]=[C:21]([NH:18][C:19]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:20])[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: N#Cc1cccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Yield: 67.5 %

Procedure:
Example 5 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 3-isocyanatobenzonitrile (0.0196 g) to give the title compound (0.0257 g). LC-MS (System A): Rt 2.29 mins, Mass Spectrum m/z 419 [MH+].
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.S(Cl)(Cl)=O>O>[NH2:6][C:7]1[N:12]=[CH:11][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ncccn1
Solvent: O=S(Cl)Cl
Solvent: O
Product: Nc1ncc(S(=O)(=O)Cl)cn1
Temperature: 0 °C
Yield: 27.4 %

Procedure:
21 ml (0.316 mol) of chlorosulfonic acid was cooled in ice-water and 3 g (0.032 mol) of 2-aminopyrimidine was added thereto little by little under stirring. 9.2 ml (0.126 mol) of thionyl chloride was further added thereto, followed by stirring at 150° C. for 70 hours. The reaction solution was returned to room temperature, poured into water and extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated to dryness, to give 1.7 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH:15]=[C:16]([C:19]3[CH2:28][CH2:27][C:22]4([O:26][CH2:25][CH2:24][O:23]4)[CH2:21][CH:20]=3)[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:36]>C(OCC)(=O)C.[Pt]=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH:15]=[C:16]([CH:19]3[CH2:28][CH2:27][C:22]4([O:26][CH2:25][CH2:24][O:23]4)[CH2:21][CH2:20]3)[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:36]
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(C3=CCC4(CC3)OCCO4)cc2N1c1c(Cl)cccc1Cl
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: O=C1NCc2c(-c3ccccc3Cl)cc(C3CCC4(CC3)OCCO4)cc2N1c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
To 1-(2,6-dichlorophenyl)-5-(2-chlorophenyl)-7-(1,4-dioxaspiro(4.5)dec-7-ene-8-yl)-3,4-dihydro-2(1H)-quinazolinone (818.8 mg, 1.51 mmol) (INTERMEDIATE 71) in ethyl acetate (25 mL) under a nitrogen atmosphere was added platinum oxide (Adam's catalyst, 164 mg). The reaction mixture was purged with H2 (via balloon) and stirred for 2 hours. Proton NMR analysis of an aliquot showed incomplete reduction. An additional 82 mg of PtO2 was added and the solution stirred under a H2 atmosphere for another hour. The reaction mixture was filtered over Celite, rinsed with 10% MeOH in DCM and concentrated. The crude material purified by silica gel chromatography eluting with 1% MeOH in DCM to give 1-(2,6-Dichlorophenyl)-5-(2-chlorophenyl)-7-(1,4-dioxaspiro(4.5)dec-8-yl)-3,4-dihydro-2(1H)-quinazolinone. 1H NMR (CDCl3, 500 MHz): selected data δ 1.61 (m, 4H), 1.78 (m, 4H), 2.38 (m, 1H), 3.92 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[C:25]([F:28])([F:27])[F:26])[NH:21][C:20](=[O:29])[N:19]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:18]3=[O:35])[N:5](CCOC[Si](C)(C)C)[N:6]=1.Cl.CCO>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[C:25]([F:27])([F:28])[F:26])[NH:21][C:20](=[O:29])[N:19]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:18]3=[O:35])[NH:5][N:6]=1
Reactant: Cc1cc(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)n(CCOC[Si](C)(C)C)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)[nH]n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
To a solution of N-{6-[5-methyl-2-(2-trimethylsilanylmethoxy-ethyl)-2H-pyrazol-3-yl]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl}-methanesulfonamide (140 mg, 0.26 mmol) in dioxane (5 mL) was added a solution of HCl in EtOH (1N, 0.6 mL, 2 equiv). The solution was stirred at 60° C. for 4 h. The solvent was removed in vacuo and the resulting paste was sonicated in 5 mL of DCM. The solid was filtered off, washed with DCM and dried in vacuo to afford N-[6-(5-methyl-2H-pyrazol-3-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (59 mg, 56%) as a white solid. (ESI-MS: m/z 445.4 [M+CH3CN+H]+, rt 4.16 min)) 1H-NMR (DMSO-d6, 400 MHz) 12.0 (s, 1H), 10.36 (s, 1H), 8.13 (s, 1H), 7.62 (s, 1H), 6.22 (s, 1H), 3.15 (s, 3H), 2.28 (s, 3H).