Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]([O:21][CH3:22])([CH3:20])[C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].N1CCCCC1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([C:13](=[O:19])[C:12]([O:11][CH3:10])([O:21][CH3:22])[CH3:20])[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)CC(=O)C(C)(OC)OC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccccc1Cl)C(=O)C(C)(OC)OC
Yield: 112.6 %

Procedure:
A mixture of 2-chlorobenzaldehyde (2.81 g), methyl 4,4-dimethoxy-3-oxovalerate (3.81g) and piperidine (0.2 ml) in benzene (20 ml) was refluxed under azeotropic dehydration for 7.5 hours. A small amount of benzene was added to the reaction mixture and the resultant solution was washed with water and dried over magnesium sulfate. The solvent was removed from the solution to give a reddish oil (7.04 g) of methyl 2-(2-chlorobenzylidene)-4,4-dimethoxy-3-oxovalerate. The mixture of the oily product (6.39 g) obtained above and methyl 3-aminocrotonate (2.33 g) was heated at 132° C. for 3.5 hours, allowed to stand and then dissolved in ethyl acetate. The resultant solution was washed with water and an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed from the solution under reduced pressure to give a viscous and brown oil (8.28 g). This oil was subjected to column chromatography on silica gel with an eluant (a mixture of 20 parts of benzene and one part of ethyl acetate by volume) to give an oily substance (5.26 g). This substance was dissolved in a mixture of ethyl acetate and diethyl ether and the solvent was removed under reduced pressure to give colorless power (1.0625 g). This powder was recrystallized from a mixture of n-hexane and ethyl acetate to give faint yellow granules of dimethyl 2-methyl-4-(2-chlorophenyl)-6-1,1-dimethoxyethyl-1,4- dihydropyridine-3,5-dicarboxylate, m.p. 145° to 146° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:26][CH:27]([CH3:31])[C:28](Cl)=[O:29]>C1COCC1>[Cl:26][CH:27]([CH3:31])[C:28]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reactant: CC(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Cl)C(=O)Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 15 (0.10 g, 0.39 mmol) in THF (10 mL), was added triethylamine (0.059 g, 0.58 mmol) and 2-chloropropanoyl chloride (0.074 g, 0.58 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[C:20]([C:24](O)=O)=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][NH:22][N:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1

Procedure:
reacting 4-morpholin-4-ylmethyl-benzene-1,2-diamine with 4-nitro-1H-pyrazole-3-carboxylic acid in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in N,N-dimethyl formamide (DMF) to give 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl) 1H-benzimidazole; and (ii) reducing the nitro group by treatment with palladium on carbon under a hydrogen atmosphere; or (i) reacting the 4-amino-1H-pyrazole-3-carboxylic ester with the appropriate carboxylic acid in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in N,N-dimethyl formamide (DMF) or with the appropriate acid chloride in the presence of triethylamine to form the 4-amide-1H-pyrazole carboxylic acid; and (ii) reacting 4-morpholin-4-ylmethyl-benzene-1,2-diamine with the appropriate 4-amide-1H-pyrazole carboxylic acid in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in dimethyl form amide (DMF) to give the [3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide.
Reaction SMILES: [C:1]([N:4](C(=O)C)[C:5](=[N:8][CH3:9])[S:6][CH3:7])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([NH:4][C:5](=[N:8][CH3:9])[S:6][CH3:7])(=[O:3])[CH3:2]
Reactant: CN=C(SC)N(C(C)=O)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN=C(NC(C)=O)SC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a solution of 1,1-diacetyl-2,3-dimethyl-isothiourea (0.17 g, 0.90 mmol) in MeOH (10 ml) was added K2CO3 (250 mg, 1.81 mmol) and the reaction stirred at room temperature for 1.5 h. The mixture was concentrated, diluted with CH2Cl2 (25 ml) and water (20 ml) and the aqueous layer was extracted with CH2Cl2 (2×10 ml), dried (Na2SO4) and concentrated to afford 1-acetyl-2,3-dimethyl-isothiourea (112 mg, 85%) as a white solid. 1H NMR (CDCl3) δ 2.10 (s, 3H), 2.43 (s, 3H), 2.93 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][OH:20])=[N:9][N:10]=2)[CH:7]=1.N1C=CN=C1.CN(C1C=CC=CN=1)C.Cl[Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38]>CC1CCCO1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][O:20][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])=[N:9][N:10]=2)[CH:7]=1
Reactant: OCCSc1ccccc1-c1nnc2ccc(Br)cn12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CC1CCCO1
Product: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Br)cn12)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
To a slurry of alcohol of Example 6 (51.3 g, 0.146 moles) in 2-methyltetrahydrofuran (257 ml) was added imidazole (11.9 g, 0.175 moles) and dimethylaminopyridine (1.79 g, 0.015 moles). Chlorotriisopropylsilane (33.9 g, 0.175 moles) was added over 10 minutes and the resultant mixture heated at 50° C. for 18 hours. The reaction was cooled to 20° C. and washed with 1M hydrochloric acid solution (257 ml) and the aqueous extracted with 2-methyltetrahydrofuran (103 ml). The combined organics were washed with 10% w/w sodium chloride solution, then distilled under reduced pressure, and replaced with n-heptane to give a final volume of 513 ml. The resultant slurry was cooled to 5° C. and granulated for 18 hours. The solid was collected by filtration to give the title compound as a white solid (63.0 g, 87%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22](O)[CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH:28]=[CH:29][CH2:30][CH3:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:20][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31]
Reactant: BrBr
Reactant: CCC=CCC=CCCCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC/C=C\C/C=C\CCCBr
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
A solution of triphenylphosphine (20.9 g, 80 mmol) in CH2Cl2 (100 ml) was treated with Br2 (7.8 g, 49 mmol) in CH2Cl2 (15 mL, 0° C.) and the mixture was stirred at room temperature for 20 min. Into the slightly yellow suspension that formed, the crude mixture of 4 and 4Z,7Z)-4,7-decadien-1-ol (12.4 g) in CH2Cl2 (15 ml) was added dropwise. After stirring for 1 hour, a solution of saturated NaHCO3 (50 mL) and water (50 ml) were added. The mixture was extracted with pentane and combined extracts were stored overnight in a freezer. In this way, triphenylphosphine oxide could be crystallized and removed by filtration. Column chromatography followed by distillation at reduced pressure afforded 5 (3.48 g, 32% yield based on 1 of b.p. =80°-85° C./2.5 torr. 1H NMR (200 MHz) δ: 5.37 (m, 4H, CH=CH), 3.41 (t, J=6.6, 6.6 Hz, 2H, CH2 --Br), 2.80 (dd, J=6.4, 6.5 Hz, 2H, =CH--CH2 --CH=), 2.21 (dt, J=7.0, 6.9, 6.8, 6.9 Hz, 2H, CH2 -3), 2.07 (dq, J=7.4 Hz, CH2 -9), 1.91 (tt, J=6.7, 6.6, 7.0, 7.0, 2H, CH2 -2), 0.97 (t, J=7.5, 7.5 Hz, 3H, CH3). 13C NMR (100.6 MHz) δ: 132.1 (8), 129.8 (5), 127.6 (7), 127.0 (4), 33.4 (1), 32.5 (2), 25.6 (3), 25.5 (6), 20.6 (9), 14.3 (10). MS [EI, m/z (%)] 218 (M+, 15), 216 (17), 137 (6), 109 (13), 107 (18), 96 (14), 95 (78), 82 (18), 81 (74), 79 (22), 68 (27), 67 (100), 55 (17), 53 (15), 42 (11), 41 (38), 40 (40).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10](COCCOC)[N:9]=2)=[CH:4][CH:3]=1.[CH:26](=O)[CH3:27]>C(O)C.[Pd].[C]>[CH2:26]([NH:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:27]
Reactant: CC=O
Reactant: COCCOCn1nc(-c2ccc(F)cc2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCNc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of 1-{[3-(4-fluorophenyl)-5-nitro(1H-indazolyl)]methoxy}-2-methoxyethane (100 mg, 0.29 mmol) in ethanol (30 mL, containing a contaminant of acetaldehyde) was added a scoup of Pd/carbon. The reaction was stirred overnight at room temperature under an atmosphere of hydrogen. It was filtered over celite and the solution concentrated to an oil. The oil was taken up in methanol (20 mL) and 6N HCl (20 mL) and heated to 75° C. for 3 hours. The solution was concentrated under vacuo, added to saturated bicarbonate (100 mL), and extracted with ethyl acetate (3×30 mL). The organic layers were dried (Na2SO4), concentrated to an oil and chromatographed on silica gel, eluting with 50% ethyl acetate/hexane to give the title compound (8 mg, 11% yield). 1H NMR (CDCl3) δ 10.4 (br s, 1H), 7.91 (dd, 2H), 7.26–7.17 (m, 3H), 6.99 (s, 1H), 6.84 (dd, 1H), 3.21 (q, 2H), 1.31 (t, 3H); ES-MS (m/z) 256 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([CH:14]=[O:15])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1CCCCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([CH:14]1[O:18][CH2:17][CH2:16][O:15]1)[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(C=O)C2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC(C)(C)c1ccc2c(c1)CC(C1OCCO1)C2

Procedure:
A mixture of 5-tert-butyl-2-indancarbaldehyde (ex. 4; 9.8mmole), ethyleneglycol (6.1 g, 98 mmole) and p-toluenesulfonic acid (95 mg, 0.5 mmole) in cyclohexane (25 ml), was heated to reflux (80°) during 3 h with a Dean-Stark type trap. The cooled mixture was poured on ether and aq. sat. NaHCO3, and the organic phase was washed with aq. sat. NaHCO3, dried over K2CO3 and concentrated. After bulb-to-bulb distillation, the desired dioxolane was obtained.
Reaction SMILES: [CH:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([NH:14][CH:15]=[O:16])[CH2:4]1)=[O:2].[N+:17]([O-])([O-:19])=[O:18].[Na+]>FC(F)(F)C(O)=O>[CH:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][C:11]=2[N+:17]([O-:19])=[O:18])[CH2:6][CH:5]([NH:14][CH:15]=[O:16])[CH2:4]1)=[O:2]
Reactant: O=CNC1Cc2cc(Br)ccc2N(C=O)C1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=CNC1Cc2cc(Br)cc([N+](=O)[O-])c2N(C=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
A mixture of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-3-quinolyl)formamide (12.8 g, 5.2 retool) and sodium nitrate (12.8 g, 150 mmol) in trifluoracetic acid (100 mL) was stirred at room temperature for 18 hours. The bulk of the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate was washed with sodium hydroxide and water, and the ethyl acetate was removed to give 14.2 g of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolyl)formamide (compound XXVIII) as a solid. This was dissolved in ethanolic hydrogen chloride (100 mL of 4.0 N), the mixture was refluxed for 1 hour, ether (200 mL) was added, and the precipitate was filtered off, washed with ether and dried to give 12.8 g (82%) of 6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolinamine dihydrochloride, mp >300° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:11]2([CH3:18])[NH:16][C:15](=O)[CH2:14][O:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C@@:11]2([CH3:18])[NH:16][C:15](=[S:28])[CH2:14][O:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)cc([N+](=O)[O-])c2)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: C[C@@]1(c2cc(Br)cc([N+](=O)[O-])c2)COCC(=S)N1

Procedure:
(R)-5-(3-Bromo-5-nitro-phenyl)-5-methyl-morpholin-3-one (2.60 g, 7.84 mmol) and Lawesson's reagent (2.54 g, 6.27 mmol) were stirred at 80° C. for 2 hrs. Volatiles were removed under reduced pressure and the crude product mixture was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as yellow foam. 1H-NMR (360 MHz, DMSO-d6): 11.28 (1H, NH), 8.38 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 4.44 (m, 1H), 4.22 (d, 1H), 3.81 (m, 1H), 1.60 (s, 3H); MS: 331 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isoproyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J37) (500 mg, 1.44 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert-butyl ester (Example K3) (355 mg, 1.44 mmol) according to the general procedure M. Obtained as a light orange oil (670 mg, 90%).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C(Cl)Cl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH3:23][S:24]([O:1][CH2:2][C:3]#[C:4][CH:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:26])=[O:25]
Reactant: OCC#CC1c2ccccc2C=Cc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC#CC1c2ccccc2C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
This preparation illustrates methods according to step 3 of the process for preparing the compounds of formula A. In this preparation a solution containing 0.25 g. of 5-(3-hydroxy-prop-1-ynyl)-5H-dibenzo[a,d]cycloheptene in 25 ml. of anhydrous methylene chloride containing 0.25 ml. of triethylamine is stirred and cooled to maintain the temperature between 0°C and -10°C and 0.15 ml. of methanesulfonyl chloride is added. Cooling is then discontinued and the temperature of the mixture allowed to rise, with stirring, for 15 minutes. The solution is then poured into ice water, resulting in a two-phase organic-aqueous mixture. The organic layer is separated and washed successively with ice cold 1Normal aqueous hydrochloric acid, water, and saturated brine, and then dried over sodium sulfate and evaporated under vacuum yielding 5-(3-methanesulfonyloxyprop-1-ynyl)-5H-dibenzo[a,d] cycloheptene which is of sufficient purity to be used directly as starting material for subsequent examples.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[S:33]>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:33]
Reactant: COc1ccccc1N=C=S
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccccc4OC)CC3)nc21

Procedure:
Pipemidic acid (53 mg, 0.175 mmol) and 2-methoxyphenyl isothiocyanate (20 μL, 0.145 mmol) were used. Purification on silica yielded compound 21 in Table 1, below (36 mg, 53%). 1H NMR (250 MHz, CDCl3) δ 9.33 (s, 1H), 8.68 (s, 1H), 7.84 (d, J=7.30 Hz, 1H), 7.54 (s, 1H), 7.20-7.04 (m, 1H), 7.03-6.85 (m, 2H), 4.44-3.73 (m, 13H), 1.49 (t, J=6.60 Hz, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].I[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCI
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Product: CCCCCCCNc1c(F)c(C)c(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Yield: 45.6 %

Procedure:
Substantially the same manner as that in Example 107 (2) was repeated except that 650 mg (1.61 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one obtained in Example 107 (1) and 0.53 mL (3.22 mol) of 1-iodoheptane were used, to give 369 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(1-heptylamino)-7-methyl-4H-1-benzopyran-4-one (yield: 46%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>>[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=S(=O)(Cc1ccc(F)cc1)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)Cc3ccc(F)cc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 34 step (i).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C([Li])CCC.Br[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[OH:8])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc(C(O)c2cc(Br)cs2)cc1
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
Under a nitrogen stream, to a solution of 4-bromo-2-thiophenecarboxaldehyde (10.0 g, 52.3 mmol) in anhydrous THF (100 ml), a hexane solution of n-butyllithium (1.6 M, 34.35 ml, 55.0 mmol) was added dropwise at −78° C. over 5 minutes. After stirring at the same temperature for 10 minutes, a solution of 1-bromo-4-ethylbenzene (10.2 g, 55.0 mmol) in THF (50 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hours and, after addition of saturated aqueous ammonium chloride, was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:10)) to give the titled compound (7.1 g, 45%).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[N:3][C:2]=1[CH:10]=O.[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([CH2:33][CH3:34])[C:30]([OH:35])=[C:29]([CH2:36][CH3:37])[CH:28]=3)[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([CH2:33][CH3:34])[C:30]([OH:35])=[C:29]([CH2:36][CH3:37])[CH:28]=3)[O:22][C:21](=[O:23])[C:20]([CH2:10][C:2]3[N:3]=[C:4]4[N:9]=[CH:8][CH:7]=[CH:6][N:5]4[N:1]=3)=[C:19]([OH:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1nc2ncccn2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(CC)c1O
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncccn4n3)C(=O)O2)cc(CC)c1O

Procedure:
The title compound was prepared analogously to Example A(224) where [1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (Example A(235)) was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.20 (t, J=2.56 Hz, 6H), 1.30–1.80 (brm, 6H), 2.00–2.18 (brm, 5H), 2.40 (q, J=20.06 Hz 4H), 2.80 (m, 4H), 3.45 (m, 3H), 6.70 (s, 2H), 7.17 (d, J=2.54 Hz, 1H), 8.80 (m, 2H), 9.29 (s, 1H). Anal. Calcd. For C28H34O4N4, C, 68.55; H, 6.99, N, 11.42. Found: C, 68.80; H, 7.31; N, 11.45.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Into 6 ml of N,N-dimethylformamide was dissolved 0.23 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol. After adding 0.22 g of anhydrous potassium carbonate, 0.13 g of methyl 2-bromopropionate was added at room temperature with stirring and then the mixture was stirred at 80° C. for 3 hours. After cooling the reaction solution to room temperature, the reaction solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica-gel column chromatography to give 0.23 g of methyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound A-3].