Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:28][C:29]1[N:30]=[CH:31][NH:32][C:33]=1[CH:34]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH:16][CH2:34][C:33]2[NH:32][CH:31]=[N:30][C:29]=2[CH3:28])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: Cc1nc[nH]c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1nc[nH]c1CNC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
To a solution of 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (0.02 g, 0.051 mmol) in dichloroethane (0.5 mL) in a two dram vial was added 4-methyl-1H-imidazole-5-carbaldehyde (6 mg, 0.051 mmol), followed by a drop of acetic acid. The reaction mixture was shaken for 20 minutes at room temperature and then NaBH(OAc)3 was added (12 mg, 0.056 mmol). The reaction was stirred at room temperature overnight. The solvents were removed and the residue was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5μ) using MeOH/H2O (with 0.1% TFA) to give 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-N-((4-methyl-1H-imidazol-5-yl)methyl)-2-phenylethanamine as a white solid (23.4 mg, 76% yield). LCMS: 3.6 min [M+1] 489.2 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 2.27 (s, 3 H), 3.45-3.52 (m, 1 H), 3.88-3.99 (m, 2 H), 4.01-4.07 (m, 1 H), 6.64 (d, J=7.09 Hz, 2 H), 7.02 (d, J=8.56 Hz, 1 H), 7.10 (t, J=7.46 Hz, 2 H), 7.18 (t, J=7.46 Hz, 1 H), 7.49 (d, J=7.58 Hz, 1 H), 7.61 (d, J=9.54 Hz, 1 H), 7.69 (s, 1 H), 7.76 (dd, J=8.56, 2.45 Hz, 1 H), 8.28 (s, 1 H), 8.60 (d, J=1.96 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:17](=[O:18])[C:16]2[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]3[NH:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:5]=3[C:4]=2[C:3]1=[O:26].[C:27]([NH2:31])(=[O:30])[CH:28]=[CH2:29].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:27]([CH2:28][CH2:29][N:19]1[C:6]2[C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[C:16]3[C:17](=[O:18])[N:2]([CH3:1])[C:3](=[O:26])[C:4]=3[C:5]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:30])[NH2:31]
Reactant: C=CC(N)=O
Reactant: CN1C(=O)c2c(c3c4ccccc4[nH]c3c3[nH]c4ccccc4c23)C1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)c2c(c3c4ccccc4n(CCC(N)=O)c3c3[nH]c4ccccc4c23)C1=O

Procedure:
500 mg (1.47 mmol) 6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole in 50 ml acetonitrile are stirred for 4 days at 20° C. with 1.05 g (14.8 mmol) acrylamide and 0.1 ml DBU. The suspension is evaporated, stirred with 30 ml dichloromethane/methanol (95:5 v/v) and the undissolved crystals are filtered off. 12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole is obtained in the form of yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=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>[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:29]([CH2:28][C@H:25]2[CH2:24][CH2:23][C:22]3[S:21][C:20]4[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]5[CH2:13][CH2:14][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]5)[C:27]=4[C:26]2=3)=[O:30])=[N:38][CH:39]=1
Reactant: Nc1ccc(F)cn1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)Nc2ccc(F)cn2)CC4)CC1
Yield: 83.7 %

Procedure:
A solution of 35.1 (200 mg, 0.43 mmol, 1.00 equiv), 5-fluoropyridin-2-amine (55 mg, 0.49 mmol, 1.13 equiv), HATU (200 mg) and DIPEA (170 mg) in distilled DMF (8 mL) was stirred at room temperature under nitrogen for 2 h. The reaction was then quenched with water and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) to give tert-butyl N-(4-[[(3R)-3-[[(5-fluoropyridin-2-yl)carbamoyl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (36.1, 200 mg, 83%) as a yellow oil. MS: m/z 556 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)=[N:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:30]2[CH2:29][CH2:28][N:27]([C:25]([CH:22]3[CH2:23][CH2:24][N:19]([C:16]4[CH:17]=[CH:18][N:13]=[CH:14][N:15]=4)[CH2:20][CH2:21]3)=[O:26])[CH2:32][CH2:31]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(C1CCN(c2ccncn2)CC1)N1CCNCC1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCN(C(=O)C3CCN(c4ccncn4)CC3)CC2)cc1
Yield: 42.4 %

Procedure:
A solution of 4 -cyanobenzenesulphonyl chloride (363 mg) in methylene chloride (10 ml) was added to a stirred mixture of 1-[1-(4-pyrimidinyl) piperidin-4-ylcarbonyl]piperazine (412.5 mg) and triethylamine (0.28 ml) in methylene chloride (15 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between methylene chloride and water. The organic phase was washed with water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography using 0.5% methanol in methylene chloride. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-cyanobenzenesulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine (280 mg), mp 180-181° C.;
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1>[OH-].[K+]>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Quinoline-4-carboxylic acid (580 mg, 3.35 mmol) was dissolved in an aqueous potassium hydroxide solution (1 M, 10 mL). Nickel/aluminum amalgam (3 g) was added in portions over 1.5 hours. The heterogeneous mixture was stirred at room temperature for 48 hours. Upon completion, the reaction was filtered through Celite® and washed with ethyl acetate. The pH of the aqueous layer was adjusted with concentrated hydrochloric acid to 4-5. Solid sodium chloride was added until the aqueous layer was saturated. The ethyl acetate layer was separated. The aqueous phase was extracted with ethyl acetate. The extracts were combined, washed with minimal brine, dried over sodium sulfate, filtered, and concentrated. 1,2,3,4-Tetrahydro-quinoline-4-carboxylic acid was used without further purification (389 mg, 66%). 1H-NMR (CDCl3) δ: 1.95-2.08 (m, 1H), 2.22-2.37 (m, 1H), 3.23-3.34 (m, 1H), 3.39-3.49 (m, 1H), 3.79 (dd, 1H), 6.56 (d, 1H), 6.69 (dd, 1H), 7.07 (dd, 1H), 7.17 (d, 1H). MS m/z: 178 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[C:37](Cl)=[O:38]>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:10]=[C:11]([C:37]([C:36]3[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:34]([O:33][CH3:32])[CH:35]=3)=[O:38])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=S(=O)(c1ccccc1)n1ccnc1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3ccc(Cl)cc3)n2)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
To a solution of 2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazole (10f) (6.0 mmol) in anhydrous THF (30 mL) at −78° C. was added 1.7 M tert-butyllithium in pentane (5.3 mL, 9.0 mmol) and stirred for 10 min. 3,4,5-Trimethoxybenzoyl chloride (7.2 mmol) was added at −78° C. and stirred for overnight. The reaction mixture was diluted with 100 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 4:1) to give a white solid. Yield: 36.8%; 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J=7.5 Hz, 2H), 7.77 (t, J=7.5 Hz, 1H), 7.62 (t, J=8.0 Hz, 2H), 7.48 (s, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.37 (s, 2H). MS (ESI): calculated for C25H21ClN2O6S, 512.1. found 513.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([OH:25])(=[O:24])[CH:21]([CH3:23])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH:21]([C:20]([OH:25])=[O:24])[CH3:23])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)C(=O)O
Reactant: O=C(O)Cc1ccc(NCCC2CCCCC2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)Cc1ccc(NCCC2CCCCC2)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-(2-cyclohexylethylamino)phenylacetic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1-carboxyethyl 4-(2-cyclohexylethylamino)phenylacetate separates as off-white crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][C:16]([OH:18])=[O:17])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A mixture of 4-Fluoro-2-trifluoromethyl-benzaldehyde (2 g, 10.2 mmol), malonic acid (1.2 g, 11.2 mmol), piperidine (0.087 g, 1 mmol) and pyridine (7 ml) was kept at reflux temperature until carbon dioxide formation ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 40 g ice and 20 ml 6N HCl. The precipitate was isolated, washed with water and dried yielding 1.16 g (49%) 3-(4-fluoro-2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:33])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:33])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 88.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(cyclohexyl{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoic acid (128 mg) as well as ethyl 3-(methylamino)propanoate (45 mg) to give the title compound (134 mg, 88%) as an amorphous compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH2:24]Br)[C:18]([CH2:22]Br)=[C:19]([F:21])[CH:20]=1.O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[C:19]([F:21])[CH:20]=1)[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:24]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Fc1cc(Br)cc(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(Br)cc(F)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
In 30 ml of N,N-dimethylformamide was suspended 1.30 g of sodium hydride (purity: 60%), and 15 ml of a N,N-dimethylformamide solution containing 2.80 g of p-toluenesulfonamide was added thereto at room temperature, after which the resulting mixture was stirred at the same temperature for 30 minutes and then at 60° C. for 1 hour. A solution of 5.70 g of 5-bromo-2,3-di(bromomethyl)fluorobenzene in 15 ml of N,N-dimethylformamide was added to the reaction mixture at 60° C. and the resulting mixture was stirred at the same temperature for 10 minutes. The reaction mixture was added to 200 ml of water and the precipitate was collected by filtration to obtain 2.40 g of 5-bromo-7-fluoro-2-(p-toluenesulfonyl)isoindoline as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([CH3:19])[CH3:18])#[N:16]>O1CCCC1>[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1)=[O:24])([CH3:19])[CH3:18])#[N:16]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (5.00 g, 26.4 mmol) in tetrahydrofuran (50 mL) were added N,N-dimethylformamide (40 μL) and oxalyl chloride (3.20 mL, 36.5 mmol), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)benzoyl chloride. To a solution of 5-amino-2-methylphenol (3.00 g, 24.3 mmol) in tetrahydrofuran (20 mL) was added an aqueous suspension (30 mL) of sodium hydrogen carbonate (3.00 g, 36.5 mmol), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise under ice-cooling a solution of the above-mentioned 3-(1-cyano-1-methylethyl)benzoyl chloride in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 5 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate (200 mL) and washed with saturated brine (200 mL). The extract was dried over anhydrous magnesium sulfate and decolored with activated carbon. The insoluble material was filtered off through a pad packed with silica gel and celite in two layers. The solvent was evaporated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (6.75 g, 94%) as a white powder.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH3:8].[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:2]2[CH2:6][CH2:5][C:4](=[O:7])[C:3]=2[CH3:8])=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC1=C(Br)CCC1=O
Product: COc1ccc(C2=C(C)C(=O)CC2)cn1
Yield: 92 %

Procedure:
Synthesized from 3-bromo-2-methylcyclopent-2-enone and 6-methoxypyridine-3-boronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography yielded the product (138 mg, 92%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.41 (d, J=2.2 Hz, 1H), 7.77 (dd, J=8.5, 2.5 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 3.99 (s, 3H), 2.92-2.87 (m, 2H), 2.56-2.53 (m, 2H), 1.99 (t, J=1.9 Hz, 3H). 13C (75 MHz, CDCl3): δ 208.9, 164.4, 162.6, 146.4, 137.4, 135.9, 125.4, 110.9, 53.8, 33.8, 28.7, 10.2. LCMS (ESI): mass calcd for (C12H13NO2) m/z 203.09; measured [M+H]+: m/z 204.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([OH:12])[C:7]([CH3:13])=[CH:6][C:4]=1[OH:5].[C:14]1([CH:20]2O[C:23](=[O:24])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:11][O:10][C:9]1[C:8]([OH:12])=[C:7]([CH3:13])[C:6]2[CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22][C:23](=[O:24])[O:5][C:4]=2[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(c2ccccc2)O1
Reactant: COc1c(O)cc(C)c(O)c1OC
Product: COc1c(O)c(C)c2c(c1OC)OC(=O)CCC2c1ccccc1
Temperature: 0 °C
Yield: 18.6 %

Procedure:
An amount of 18.4 g of 2,3-dimethoxy-5-methylhydroquinone and 16.2 g of γ-phenyl-γ-butyrolactone was stirred in 150 ml of polyphosphoric acid at room temperature for 5 hours. The reaction mixture obtained was poured into ice-water and extracted with ether, and the ether extract was washed with water and then dried over magnesium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography/hexaneethyl acetate (2:1), and thus 6.10 g (18.6%) of the desired compound was obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22](=O)[CH3:23])=[C:6]([CH3:21])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([CH3:19])[C:11]=2[CH3:20])[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:25][NH2:26]>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:22]([CH3:23])=[N:25][N:26]=[C:1]3[CH3:2])=[C:6]2[CH3:21])=[C:11]([CH3:20])[C:12]=1[CH3:19])[CH3:18]
Reactant: NN
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(C)c1C
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(C)c1C

Procedure:
Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K2CO3 (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (108 mg, 0.3) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as off-white solid: 1H NMR (CDCl3, 500 MHz) δ 6.92 (d, 1H), 6.86 (d, 1H), 4.14 (q, 2H), 2.83 (s, 6H), 2.36 (s, 6H), 2.28 (s, 3H), 1.72 (s, 3H), 1.52 (t, 3H); MS (ESI) 324 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:10]([C:9]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:15][CH2:14][CH2:13][O:12]1)[CH3:11]
Reactant: OCCO
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(c2ccc(OC)cc2)OCCO1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a solution of 4′-methoxypropiophenone (250.0 mg, 1.52 mmol) in toluene (20.0 mL) was added ethylene glycol (255.0 μL, 4.57 mmol) and p-toluenesulfonic acid monohydrate (13.0 mg, 0.04 mmol) and the reaction mixture refluxed overnight using a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, then washed with saturated aqueous sodium bicarbonate solution followed by water. The toluene solution was then dried (MgSO4) and evaporated under reduced pressure to afford 2-ethyl-2-(4-methoxyphenyl)-1,3-dioxolane (16) as a yellow oil (184 mg, 58%). 1H nmr (CDCl3, 300 MHz) 0.76, t (6.6 Hz), CH3; 1.78, q (6.9 Hz), CH2; 3.65, m, CH2O, 3.73, s, 4′-OMe; 3.95, m, CH2O; 6.88, d (7.2 Hz), H3′,5′; 7.02, d, (7.5 Hz), H2′,6′. ESI (+ve) MS m/z 209 (M+H, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](C)([C:21](OCC)=O)[C:16]([O:18]CC)=[O:17])[CH:5]=[CH:6][C:7]=1[C:8](=[O:14])[C:9]1[S:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8](=[O:14])[C:9]1[S:13][CH:12]=[CH:11][CH:10]=1)[CH:15]([CH3:21])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(C(=O)c2cccs2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc(C(=O)c2cccs2)c(Cl)c1

Procedure:
A mixture of 29.7 parts of diethyl 2-[3-chloro-4-(2-thenoyl)phenyl]-2-methylmalonate and 200 parts of sodium hydroxide solution 5% is stirred and refluxed for 5 hours. The reaction mixture is cooled and washed twice with 80 parts of benzene. The aqueous phase is acidified with concentrated hydrochloric acid solution and the product is extracted with chloroform. The extract is dried, filtered and evaporated. The oily residue is dissolved in 160 parts of ether. This solution is stirred with activated charcoal, filtered and evaporated. The oily residue is purified by column-chromatography, using a mixture of chloroform and 5% of methanol. The pure fractions are collected and the solvent is evaporated. The oily residue which solidifies on standing, is triturated in a mixture of benzene and petroleumether, yielding 3-chloro-4-(2-thenoyl)-hydratropic acid; mp. 82.5° C; also named 3-chloro-4-(2-thenoyl)-α-methyl-phenylacetic acid.
Reaction SMILES: [CH:1](=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H].CN(C)C=O>[Pd].CO>[CH2:1]([CH:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCCCC=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCCC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 35.9 %

Procedure:
1.3 g of 10-hexylidene-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one are hydrogenated at a temperature in the region of 20° C. and at a pressure of 9.4 bar of hydrogen in the presence of 120 ml of dimethylformamide, 20 ml of methanol and 0.3 g of 10% palladium on charcoal for 17 hours. After filtration of the catalyst under inert atmosphere, the solvents are evaporated off and the crude product (1.2 g) is purified by chromatography on a column of silica (120 g partially deactivated with 2 ml of water), eluting with a mixture of dichloromethane and methanol (90/10 by volume). 0.47 g of 10-hexyl-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one is thus obtained, in the form of a beige solid melting at about 185° C. (Analysis % calculated C: 74.24, H: 6.89, N: 13.67, O: 5.20, % found C: 74.3, H: 7.0, N: 13.6).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2]1.[CH3:12][C:13]([NH2:24])([CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][NH:24][C:13]([CH3:23])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: CCCCCCCCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCCCCCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 21.8 %

Procedure:
Using the method of Example 5, supra, 1,2-epoxydecane (204 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine (197 mg, 1.1 mmol) were used to prepare 73 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 214 (M−121, 100), 196 (27.8), 163 (10), 121 (2.2); 1H-NMR (CDCl3) δ 7.08 (2H, d, J=5.6), 6.83 (2H, d, J=8.6), 3.79 (3H, s), 3.53 (1H, m), 2.79 (1H, dd, J=11.7 and 2.9), 2.67 (2H, s), 2.42 (1H, dd, J=12.6 and 9.6), 1.26 (18 H, m), 1.08 (3H, s), 0.88 (3H, t, J=6.6); 13C-NMR (CDCl3) δ 158.2, 131.4, 129.8, 113.5, 77.2, 69.8, 55.2, 53.8, 47.8, 46.5, 35.1, 31.9, 29.8, 29.7, 29.6, 29.3, 26.6, 26.4, 25.7, 22.7, 14.1; FT-IR (film) cm−1 3399 (broad s), 1612, 1512, 1246, 1039, 823.