Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:2].CO[CH:17]=[CH:18][C:19](=O)[CH3:20].COCCO.CCCCCCCC>C(Cl)Cl>[CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][N:5]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:7]([C:8]#[N:9])[C:6]1=[O:10])[CH3:2]
Reactant: COC=CC(C)=O
Reactant: CCCCC(CC)CNC(=O)CC#N
Solvent: ClCCl
Solvent: COCCO
Solvent: CCCCCCCC
Product: CCCCC(CC)Cn1c(C)ccc(C#N)c1=O
Reaction time: 2 h
Yield: 90 %

Procedure:
N-(2-ethylhexyl) cyanoacetamide (60.4 g., 0.30 mole), 4-methoxy-3-butene-2-one (60.0 g., 0.60 mole), methylcellosolve (250 ml.) and 1,4-diazobicyclo [2.2.2.] octane (6.0 g.) are heated at reflux for 4 hours. Additional 4-methoxy-3-butene-2-one(30 g.) is added and reflux is continued for another 2 hours. The solvent is removed in vacuo to give an oil. The oil is dissolved in methylene chloride and extracted first with 2N-HC (150 ml.) and then with water (2 × 250 ml.). The organic layer is dried over sodium sulfate, filtered and evaporated to dryness to give a 90% yield of crude product which is characterized by nmr and ir analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[O:20][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[CH2:23][N:24]([C:25](Cl)=[O:26])[C:18]=2[CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[O:20][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[CH2:23][N:24]([C:25]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)=[O:26])[C:18]=2[CH:17]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 89.3 %

Procedure:
By the method described in Example 18, 4-aminopyridine (1.3 g, 14.0 mmol) in 40 mL of CH2Cl2 with molecular sieves #5A (5 g) and Et3N (1.4 g, 15.0 mmol) was reacted with the title compound of Example 2 (4.1 g, 14.0 mmol) to produce 4.4 g of the title product after HPLC purification on silica gel.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]CC#C)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1[CH2:25][CH2:24][O:23]CC1.O1CCOC[CH2:27]1>>[ClH:19].[ClH:19].[CH2:24]([O:23][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:25]#[CH:27]
Reactant: C1COCCO1
Reactant: C#CCCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: C#CCOCCN1CCNCC1
Temperature: 60 °C

Procedure:
To a solution of 10.70 g of 1-tert-butoxycarbonyl-4-(2-(2-propynyl)ethyl)piperazine in 1,4-dioxane was added 4N hydrochloric acid/1,4-dioxane, and the mixture was stirred at 60° C. After completion of the reaction, the mixture was concentrated and diethyl ether was added. The solid was collected by filtration and dried to give 11.83 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:11]([CH3:21])[C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[Li]CCCC.[I:33]I>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[N:11]([CH3:21])[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([I:33])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(Br)cc2)c1Sc1ccc(Cl)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(-c2ccccn2)nc(-c2ccc(I)cc2)c1Sc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 2-{4-(4-bromophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 15, 150 mg, 0.33 mmol) in THF (1 mL) was added BuLi (2.5 M in hexanes, 0.17 mL, 0.427 mmol) at −78° C. After stirring at −78° C. for 0.5 h, I2 (167 mg, 0.657 mmol) was added and the reaction was allowed to warm up to rt overnight. The reaction was quenched with aq NH4Cl, extracted with EtOAc. The combined extracts were washed with aq Na2S2O3, water, and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (1-20% EtOAc in hexanes) to give the title compound. 1H NMR (500 MHz, (CDCl3): 8.64 (d, 1H), 8.38 (d, 1H), 7.87 (d, 2H), 7.85 (t, 1H), 7.78 (d, 2H), 7.38 (t, 1H), 7.25 (d, 2H), 7.03 (d, 2H), 4.11). LCMS: [M+1]=504.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[C:22]4=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]4[N:20]=[C:19]3[CH2:29][CH3:30])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])(=[O:3])[NH2:2].[CH3:35][Si](C=[N+]=[N-])(C)C.C(O)(=O)C.CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[CH3:35][NH:2][C:1]([C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[C:22]4=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]4[N:20]=[C:19]3[CH2:29][CH3:30])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])=[O:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2C(N)=O)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2C(=O)NC)c1
Reaction time: 0.17 h

Procedure:
To a solution of 12.1 mg of the product of Example 6 in CH2Cl2 at 0° C. was added 0.2 mL of 10% trimethylsilyl-diazomethane. After stirring for 10 minutes, 0.2 mL of acetic acid was added. The volatiles were removed in vacuo. The product was isolated using preparative TLC with 1:1 hexane/ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@@H:12]2[CH2:16][CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.Cl>O>[Br:1][C:2]1[N:3]=[C:4]([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: Cc1nccn2c([C@@H]3CCN(C(=O)OCc4ccccc4)C3)nc(Br)c12
Agent: Cl
Solvent: O
Product: Cc1nccn2c([C@@H]3CCNC3)nc(Br)c12
Temperature: 25 °C
Yield: 118.2 %

Procedure:
(R)-Benzyl 3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (1.264 mmol, 525 mg) was dissolved in 37% hydrochloric acid (76 mmol, 6 mL) and stirred at room temperature. After four hours water (10 ml) was added and the mixture was washed twice with diethyl ether. The aqueous layer was concentrated under reduced pressure and coevaporated with toluene and ethanol to give 0.42 g of (R)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine as hydrochloride. To 100 mg of this material in dichloromethane (5 ml) and N,N-diisopropylethylamine (1.778 mmol, 0.31 mL) were added N,N-dimethylglycine (0.534 mmol, 55.0 mg) and O-(7-azabenzotriazol-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.534 mmol, 203 mg) and stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane/methanol (gradient 0->35% methanol)) to give (R)-1-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-2-(dimethylamino)ethanone (77 mg).
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([O:71][C:72]([F:75])([F:74])[F:73])=[CH:67][CH:66]=2)[CH2:60][CH2:59]1>CN(C)C=O.ClCCl.O1CCCC1>[F:75][C:72]([F:73])([F:74])[O:71][C:68]1[CH:67]=[CH:66][C:65]([NH:64][CH:61]2[CH2:62][CH2:63][N:58]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:23])([F:2])[F:22])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:59][CH2:60]2)=[CH:70][CH:69]=1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: FC(F)(F)Oc1ccc(NC2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 3), diisopropylethyl amine (18 μL; 0.10 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution piperidin-4-yl-(4-trifluoromethoxy-phenyl)-amine hydrochloride (15 mg; 0.05 mmol, prepared in accordance with Example 53) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 105 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (23 mg; 0.04 mmol). The structure was confirmed using Protocol I-B. Calculated mass=559; observed mass=559; HPLC retention time=4.78 min.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:11][C:12]3[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:14](=[O:16])[C:23]=2[CH:24]=1
Reactant: COc1ccc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COc1ccc2oc3ccc(Br)cc3c(=O)c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 259.8 %

Procedure:
Sulfuric acid (1.6 L) was added to 2-(4-bromophenoxy)-5-methoxybenzoic acid (530 g, 1.6401 mol) at RT. The resulting dark mixture was heated to 60° C. for 1 hour. The brown solution was cooled to RT and poured onto ice while stirring. The resulting tan precipitate was collected by filtration, washed sequentially with water (2 L), 1N NaOH (2.0 L) and ethanol (800 mL). The derived solid was suspended in 2 L of acetone and stiffed vigorously for 1 hour. The mixture was filtered and dried under a vacuum to afford 1.3 kg of 2-bromo-7-methoxy-9H-xanthen-9-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:37]([CH2:36][C:35]3[CH:46]=[C:47]([Cl:49])[CH:48]=[C:33]([Cl:32])[CH:34]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:28])=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Fc1ccc(CNCc2cc(Cl)cc(Cl)c2)cc1
Reactant: O=C(O)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of 4-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)benzoic acid (48 mg, 0.10 mol) in DMF, were added. N-(3,5-dichlorobenzyl)-1-(4-fluorophenyl)methanamine (28 mg, 0.1 mmol), HATU (48 mg, 0.15 mmol), and DIPEA (0.052 mL, 0.30 mmol). The reaction mixture was stirred at room temperature for 2 h and purified by preparative HPLC (Column YMC S5 ODS C18 20×100 mm; Solvent A=10% MeOH-90% H2O with 0.1% TFA; Solvent B=10% H2O-90% MeOH with 0.1% TFA). The desired fractions were combined, concentrated and lyophilized to give the title compound (40 mg, 51%) as a white solid. 1H NMR (CD3OD) δ 7.71 (d, 1H, J=2.5 Hz), 7.54 (d, 1H, J=2.5 Hz), 7.37-7.05 (m, 13H), 6.85 (t, 2H, J=8.8 Hz), 4.70 (br, 1H), 4.64 (br, 1H), 4.54 (s, 2H), 4.50 (s, 2H), 4.46 (br, 1H), 4.42 (br, 1H). MS (ESI): 750.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][CH:13]1[O:18][CH:17]([CH3:19])[CH2:16][N:15]([C:20](Cl)=[O:21])[CH2:14]1>>[CH3:12][CH:13]1[O:18][CH:17]([CH3:19])[CH2:16][N:15]([C:20]([O:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([C:20]([N:15]3[CH2:16][CH:17]([CH3:19])[O:18][CH:13]([CH3:12])[CH2:14]3)=[O:21])[N:7]=2)=[O:21])[CH2:14]1
Reactant: Oc1n[nH]c2cc(F)ccc12
Reactant: CC1CN(C(=O)Cl)CC(C)O1
Product: CC1CN(C(=O)Oc2nn(C(=O)N3CC(C)OC(C)C3)c3cc(F)ccc23)CC(C)O1

Procedure:
In analogy to example 1, 200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were reacted with 280.3 mg (1.578 mmol) of 2,6-dimethylmorpholine-4-carbonyl chloride.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1>CO.[Pd]>[CH:9]1([N:6]2[C:7](=[O:8])[CH:2]=[CH:3][C:4]([C:14]([O:16][CH3:17])=[O:15])=[CH:5]2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)c1cc(Br)c(=O)n(C2CCCC2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(=O)n(C2CCCC2)c1

Procedure:
Through a solution of methyl 5-bromo-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (300 mg, 1 mmol) and Pd/C (300 mg) in methanol (30 mL) was bubbled H2 through a balloon for 48 h. The mixture was filtered through Celite® and concentrated to afford the title compound. MS m/z: 222 (M+1).
Reaction SMILES: CC(C)C[O:4][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[C:18]([CH2:21][NH:22][C:23]1[C:24]([I:39])=[C:25]([C:29]([I:38])=[C:30]([NH:33][CH2:34][C:35](=[O:37])[CH3:36])[C:31]=1[I:32])[C:26](Cl)=[O:27])(=[O:20])[CH3:19]>CC(N(C)C)=O>[C:35]([CH2:34][NH:33][C:30]1[C:29]([I:38])=[C:25]([C:26]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][C:5]([OH:4])=[O:16])=[CH:14][CH:13]=2)=[O:27])[C:24]([I:39])=[C:23]([NH:22][CH2:21][C:18](=[O:20])[CH3:19])[C:31]=1[I:32])(=[O:37])[CH3:36]
Reactant: CC(C)COC(=O)CCCc1ccc(N)cc1
Reactant: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CCCC(=O)O)cc2)c1I
Temperature: 92.5 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 4-aminobenzenebutyric acid 2,2-dimethylethyl ester IXb (2.0 g, 7.5 mmol) in dimethylacetamide (DMA 25 mL), was added 3,5 bis(acetylmethylamino)-2,4,6 triiodobenzoyl chloride X (1.98 g, 3 mmol), and the mixture stirred at 90-95° C. for 6 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (200 mL). The organic extract was washed with saturated sodium bicarbonate (250 mL), water and saturated sodium chloride and dried over sodium sulfate. The solvent was removed in vacuum and the residue purified by a silica gel column (150 g) using hexane/EtOAc to obtain the title compound XIb (1.98 g, yield 74%). (MS: m/e 858 (M-H)-.
Reaction SMILES: Br[CH2:2]Br.[CH3:4][C:5]1([C:12]([OH:14])=[O:13])[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[Cl-].[Na+]>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH3:4][C:5]1([C:12]([OH:14])=[O:13])[CH2:10][CH2:9][C:8](=[CH2:2])[CH2:7][CH2:6]1
Reactant: CC1(C(=O)O)CCC(=O)CC1
Reactant: BrCBr
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CCC(C)(C(=O)O)CC1

Procedure:
Under an argon stream, 3 ml of dibromomethane and 30 ml of titanium tetrachloride (methylene chloride 2M solution) were added to a solution of 7 g of zinc suspended in 200 ml of THF, under ice-cooling. The resultant solution was stirred for one hour. Then, a solution of 4.1 g of 1-methyl-4-oxo-1-cyclohexanecarboxylic acid (Example 26) in 40 ml of THF was added to the solution. The resultant solution was reacted for 12 hours. After reaction, 500 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was extracted three times with 100 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed in vacuo. The oily substance formed was subjected to column chromatography using 20 g of silica gel. From the fraction eluted with hexane and ethyl acetate=2:1, the solvent was removed in vacuo, yielding 1.3 g of 1-methyl-4-methylene-1-cyclohexanecarboxylic acid as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([O:13][CH3:19])=[O:12]
Reactant: CO
Reactant: O=C(O)Cc1cc2ccccc2o1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc2ccccc2o1

Procedure:
Benzofurane-2-acetic acid 4 (305 g, 1.73 mol) was dissolved in methanol (1,000 ml) and concentrated sulfuric acid (20 ml). The mixture, which was originally a suspension, was stirred at reflux for 120 minutes. Half of the methanol was distilled off and a mixture consisting of water, KOH, and ethyl acetate (2,000 ml/65 g/1,000 ml) was added. After mixing well, the organic layer was allowed to separate and was isolated. The aqueous phase was extracted once more with ethyl acetate (500 ml) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The crude product was a reddish oil weighing 316 g, which was purified by flash vacuum distillation at 0.1 mm Hg (bp 80-90° C.). The yield of distilled product, a colorless oil, was 288 g (1.51 mol, 86%). Anal. (C11H10O3) C, H: calculated 69.46, 5.30; found 69.49, 5.36.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][OH:28])[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][S:41]([CH3:40])(=[O:43])=[O:42])[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COS(C)(=O)=O)C3)C(C)C12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution, under argon, of 0.821 g of product from Example 56 and 3.4 ml of pyridine is added 148 microliter of methanesulfonyl chloride. The reaction is stirred at 0° C. for 2 hours, diluted with water and extracted with chloroform. The organic layer washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (Silica Gel; 80% ethyl acetate/hexane) to give 0.632 g of the desired product.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[N:21]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[NH:16][CH2:17]3)[CH:25]=[C:24]([CH3:26])[CH:23]=2)=[CH:28][CH:29]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(N2C=C(c3cccc(S(N)(=O)=O)c3)NC2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
To N-tert-butyl-3-{1-[6-(4-chloro-phenyl)-4-methyl-pyridin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (example 298) (0.028 g, 0.058 mmol) was added TFA (2 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as an off-white solid (0.025 g, 101%). MS (ISP) 425.1 [(M+H)+] and 427 [(M+2+H)+].
Reaction SMILES: [ClH:1].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:23][N:24]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[C:28](=[O:34])[N:27]([CH3:35])[C:26]2[CH:36]=[C:37]([O:40][CH2:41][CH2:42][CH2:43][N:44]([CH2:52][CH2:53][NH:54][CH3:55])[CH2:45][C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)[CH:38]=[CH:39][C:25]1=2.[C:56](O)(=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(OCC)(=O)C.O.CN(C=O)C>[ClH:1].[ClH:1].[CH3:55][N:54]([CH2:53][CH2:52][N:44]([CH2:45][C:46]1[CH:47]=[CH:48][N:49]=[CH:50][CH:51]=1)[CH2:43][CH2:42][CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:25]2[N:24]([CH3:23])[C:30](=[O:31])[C:29]([CH3:32])([CH3:33])[C:28](=[O:34])[N:27]([CH3:35])[C:26]=2[CH:36]=1)[C:56](=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CNCCN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (WSC) (144 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (115 mg, 0.75 mmol) were added to a DMF solution (5 ml) of 1,3,3,5-tetramethyl-7-{3-[(2-methylaminoethyl)pyridin-4-ylmethyl amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (227 mg, 0.5 mmol) and benzoic acid (92 mg, 0.75 mmol), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was concentrated under reduced pressure, and a 4N-hydrogen chloride ethyl acetate solution (0.14 ml) was added to the residue (an ethyl acetate solution). The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to thereby obtain 120.5 mg (yield: 40%) of N-methyl-N-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)benzamide dihydrochloride as a white powder.
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=O)=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:24]([C:26]1[C:27](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[O:28][C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:32]([F:35])([F:34])[F:33])[C:30]=1[CH3:31])#[N:25]>C(O)C>[CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:31][C:30]2[C:29]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:32]([F:35])([F:33])[F:34])[O:28][C:27](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[C:26]=2[C:24]#[N:25])=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=CC=CC=O)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(c2ccccc2)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Yield: 88.2 %

Procedure:
To 5 ml of ethanol were added 100 mg (0.32 mmol) of 5-(4-dibutylamino-2-methoxyphenyl)-2,4-pentadienal and 110 mg (0.35 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile, and the mixture was stirred with heating at 50° C. for 2.5 hours. The precipitate was separated by filtration and purified by silica gel column chromatography to give 173 mg of a yellowish brown crystal (yield: 89.1%; mp: 208-210° C.)