Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][C:23]3[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:47]C=2C=1.CCN=C=NCCCN(C)C.[Cl-].[NH4+]>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]3[O:27][C:26]([C:28]([NH2:47])=[O:30])=[CH:25][CH:24]=3)=[CH:31][CH:32]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3ccc(C(=O)O)o3)cc2)c2ccccc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3ccc(C(N)=O)o3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 11 h
Yield: 61 %

Procedure:
(2S,4R)-5-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxymethyl)-furan-2-carboxylic acid (0.065 g, 0.12 mmol) was converted to the amide by dissolving in THF (1 mL) at room temperature. HOBt (0.024 g), EDCI (0.033 g), and ammonium chloride (0.013 g, 0.232 mmol) was added along with 2 drops of DMF and stirred at room temperature for 11 h. The reaction was diluted with ethyl acetate, washed with 1N NaOH, 1N HCl and brine. The organics were dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (10 ethyl acetate:1 methanol) to afford the product as a white solid in 61% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=1)[CH2:5]2.[CH3:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:11][C:9]1[CH:10]=[C:2]([C:32]2[CH:31]=[N:30][CH:29]=[C:28]([CH3:27])[CH:33]=2)[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:19]=1)[CH2:5]2
Reactant: Cc1cncc(B(O)O)c1
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cncc(-c2cc(C)c3c(c2)CN(Cc2ccc(Oc4ccccc4)cc2)C3=O)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 63.4 %

Procedure:
5-Bromo-7-methyl-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (100.0 mg, 0.24 mmol), 3-methylpyridine-5-boronic acid (67.1 mg, 0.49 mmol), 2M sodium carbonate (1 mL) and Pd(PPh3)4 (37.0 mg, 0.045 mmol) were suspended in DME (1 mL), and the mixture was heated to 110° C. After 15 hours, the reaction mixture was cooled to room temperature. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (30-35% EtOAc in hexanes) to provide the title compound as an off-white gum (64 mg, 62%.) 1H NMR (300 MHz, CDCl3): δ 8.66 (d, 1H), 8.47 (d, 1H), 7.70 (s, 1H), 7.28-7.41 (m, 6H), 7.12 (t, 1H), 6.98-7.03 (m, 4H), 4.79 (s, 2H), 4.33 (s, 2H), 2.85 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.O=[CH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:17]([O:18][CH3:19])[C:15]=1[OH:16]>[Cl-].[Cl-].[Zn+2].C(OC(=O)C)(=O)C>[OH:16][C:15]1[C:17]([O:18][CH3:19])=[CH:20][CH:21]=[CH:22][C:14]=1/[CH:13]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\1=2
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: COc1cccc(C=O)c1O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(/C=C2\CCCc3cc(C)cnc32)c1O

Procedure:
5,6,7,8-Tetrahydro-3-methylquinoline (20 ml), o-vanillin (25 g), acetic anhydride (50 ml), and ZnCl2 (1 g) were heated at reflux for 17 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate (100 ml) and acidified with 2N HCl solution. The solid obtained was removed by filtration and the aqueous layer was basified with Na2CO3 and shaken with diethyl ether. A solid was obtained in the ether layer which was removed by filtration. The combined solids were dissolved in 1N sodium hydroxide and the solution was extracted with ethyl acetate. The extracts were dried over MgSO4 and the solvent was removed by evaporation. The crystals obtained were washed with hexane and dried to give the title compound (6 g) m.p. 149°-153° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39](O)[CH:38]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:34][O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=3)[CH2:3]2)[CH:38]=1
Reactant: N#Cc1ccc(N2CC[C@@H](O)C2)cc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(O[C@H]2CCN(c3ccc(C#N)cc3)C2)c1
Temperature: 4 °C

Procedure:
Dissolve 4-((R)-3-hydroxy-pyrrolidin-1-yl)-benzonitrile (188 mg, 1.00 mmol), triphenylphosphine (393 mg, 1.50 mmol) and 3-hydroxy-benzoic acid methyl ester (228 mg, 1.5 mmol) into 10 mL of dry THF under Ar. Cooled to 4° C. Add DEAD (0.26 mL, 1.50 mmol) in a drop-wise fashion. Stir mixture with warming to room temperature overnight. LC-MS analysis indicates the desired intermediate. Concentrate the mixture to dryness. Dissolve residue into CH2Cl2 and apply to a 2 mm SiO2 prep plate. Elute with 50% EtOAc/hexanes to give 113 mg of slightly impure 3-[(S)-1-(4-cyano-phenyl)-pyrrolidin-3-yloxy]-benzoic acid methyl ester.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14]1.C[O:20][C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1>CCCCCC.O1CCCC1>[C:17]([CH:16]([CH:13]1[CH2:15][CH2:14]1)[C:21]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1)=[O:20])#[N:18]
Reactant: N#CCC1CC1
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc(C(=O)C(C#N)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A 2.5 molar solution of n-butyl lithium (114 mL, 285 mmol) in hexane was added to a cooled (−78° C.) solution of diisopropylamine (38.3 mL, 273 mmol) in tetrahydrofuran (300 mL). This cooled reaction mixture was then allowed to stir for 1 hour, after which time cyclopropylacetonitrile (20.8 mL, 261 mmol) was added at such a rate as to keep the temperature below −60° C. This mixture was then allowed to stir at −78° C. for 1 hour, after which time a solution of 4-cyano-benzoic acid methyl ester (40 g, 248 mmol) in tetrahydrofuran (100 mL) was added at such a rate as to keep the temperature below −60° C. This mixture was then slowly warmed to room temperature and stirred for 18 hours after which time it was quenched onto an aqueous 10% solution (weight/volume) citric acid (600 mL) and extracted with ethyl acetate (2×2500 mL). The organic extracts were washed with brine (600 mL), dried over magnesium sulphate, filtered, and evaporated under reduced pressure to give a brown oil (52.7 g, 100%). This material was used for subsequent steps without further purification. 1H NMR (400 MHz, CDCl3): δ 0.60 (m, 2H), 0.80 (m, 2H), 1.40 (m, 1H), 4.10 (d, 1H), 7.85 (d, 2H), 8.10 (d, 2H). ESCI MS m/z 243 [M−H]−
Reaction SMILES: OCC(CO)O.C[C@@H]1O[C@@H](O[C@H:14]2[C@H:19](O)[C@@H:18](O)[C@H:17]([NH:22]C(N)=N)[C@@H:16]([OH:26])[C@@H:15]2[NH:27]C(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.[OH-:47].[K+]>O>[NH2:22][C@H:17]([C:16]([OH:26])=[O:47])[CH2:18][CH2:19][CH2:14][CH2:15][NH2:27]
Reactant: [OH-]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: [K+]
Solvent: O
Solvent: OCC(O)CO
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 20 h

Procedure:
The glycerol stocks of the Escherichia coli WC196ΔcadAΔldcC/pCABD2 strain were thawed, 100 μL of each was uniformly applied to an L-plate containing 25 mg/L of streptomycin, and culture was performed at 37° C. for 20 hours. The cells in an amount of about ⅛ of the cells obtained on one plate were inoculated in 20 mL of the fermentation medium described below containing 25 mg/L of streptomycin in a Sakaguchi flask, and cultured at 37° C. for 16 hours or 20 hours on a reciprocally shaking culture apparatus. Each of the samples derived from the alga obtained in of Example 7 (2) was suspended in distilled water, Tween 80 was added to the suspension at a concentration of 1%, and the mixture was adjusted to pH 7.0 with 3 N KOH, autoclaved at 120° C. for 20 minutes, and used as the carbon source solution. The medium composition used for the culture is shown below. The hydrolysate of the fat-and-oil fraction derived from the alga, or the water-soluble fraction derived from the alga was used as the carbon source. The totals of the measured aliphatic acid concentration and glycerol concentration of the carbon sources are indicated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]=2[CH3:17])=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].[CH3:24]I>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH3:17])=[C:10]([C:13]([F:14])([F:16])[F:15])[N:11]([CH3:18])[N:12]=2)=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:24])[N:11]=[C:10]([C:13]([F:14])([F:16])[F:15])[C:9]=2[CH3:17])=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1c(C(F)(F)F)n[nH]c1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(-c2ccc(Cl)cc2)nn(C)c1C(F)(F)F
Product: Cc1c(C(F)(F)F)nn(C)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.7 g of 5-(4-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole in 40 mL of acetone was added 5.9 g of potassium carbonate and 1.8 mL of methyl iodide. The mixture was allowed stir overnight at room temperature, filtered and concd in vacuo to give a white solid. This mixture of two isomeric pyrazoles was purified by chromatography on silica (5% ethyl acetate in hexanes) to give 1.8 g (high Rf) of 3-(4-chlorophenyl)-1,4-dimethyl-5-(trifluoromethyl)pyrazole and 2.15 g (low Rf) of 5-(4-chlorophenyl)-1,4-dimethyl-3-(trifluoromethyl)pyrazole. The low Rf material was distilled bulb to bulb (0.1 torr) to give a white, crystalline solid: mp 52°-54° C.; 1HNMR (CDCl3) δ 2.06 (q, 3H, J=1.0 Hz), 3.77 (s, 3H), 7.26 (d, 2H, J=8.5 Hz), 7.50 (d, 2H, J=8.4 Hz); 19FNMR (CDCl3) δ -61.6 (3F). Anal. Calcd for C12H10N2F3Cl1 : C, 52.47; H, 3.677 N, 10.20. Pound: C, 52.517 H, 3.70; N, 10.18.
Reaction SMILES: C[O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]3[CH:20]([N:26]([CH:28]4[CH2:30][CH2:29]4)[CH3:27])[CH2:19][CH2:18][C:17]([CH3:32])([CH3:31])[C:16]=3[CH:15]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>CO.O1CCCC1>[CH:28]1([N:26]([CH3:27])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:32])([CH3:31])[C:16]3[CH:15]=[C:14]([C:13]#[C:12][C:9]4[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]([OH:33])=[O:2])=[CH:11][CH:10]=4)[CH:23]=[C:22]([O:24][CH3:25])[C:21]2=3)[CH2:29][CH2:30]1
Reactant: COC(=O)/C=C/c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C#Cc2ccc(/C=C/C(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A solution of (E)-3-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylic acid methyl ester (Intermediate 86, 0.12 g, 0.27 mmol) in methanol (4 mL) and tetrahydrofuran (3 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 5% methanol in ethyl acetate as the eluent to afford the title product as a white solid (0.041 g, 35%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Na+].[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12]>CN(C)C=O>[N+:11]([CH:14]([CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:1]([O:8][CH3:9])=[O:7])[CH3:15])([O-:13])=[O:12]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: CC[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)O)C(C)[N+](=O)[O-]
Temperature: 60 °C

Procedure:
Into a 100 ml, one neck flask is placed 10 grams of sodium methyl maleate, 60 mls N,N-dimethyl formamide (DMF) and 40 grams nitroethane. The solution is heated at 60° C. for two hours and then partially distilled in vacuo to remove the DMF and nitroethane. The residue, by NMR analysis (D2O), has the following structure: ##STR41## CH3 (a) doublet of doublets one centered at 1.44δ, one centered at 1.57δ;
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>CCOCC>[CH:4]1[CH:3]=[CH:2][C:1]([NH:7][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccccc1)Nc1ccccc1
Yield: 94 %

Procedure:
20 parts freshly distilled ether, 1.19 parts (0.01 mole) phenyl isocyanate and 0.19 part (0.01 mole) of water were combined and reacted as described in Example 1. The isolation techniques described in Example 2 were conducted. 0.70 part (94% yield) diphenylurea was recovered having a melting point of 253° C. An isocyanate and water produce urea in the absence of a boron complexing agent.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:41])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:32]2[CH:31]=[C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:41])[NH:19][C:9]5[CH:10]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:12]([CH3:14])=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)[CH:35]=[CH:34][N:33]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CCCC4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C4CCCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M271) (360 mg, 0.619 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (135 mg, 47%).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH:32](=[C:10]1/[CH2:9][N:8]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:12][C:11]/1=[O:14])/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 1-(triphenylmethyl)piperidin-4-one (4.22 g) in benzene (50 ml) was added pyrrolidine (1.02 ml) at room temperature, and the resulting mixture was refluxed for 3 hours. After cooling to room temperature, benzaldehyde (1.26 ml) was added to the reaction mixture, and the resulting mixture was furthermore refluxed for 2 hours. After refluxing, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent to afford the title compound (3.92 g, yield: 74%) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11](Br)[C:12]([OH:14])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:16][C:17](N)=[S:18].Cl.S1(CCCC1)(=O)=[O:22]>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]2[S:18][C:17](=[O:22])[NH:16][C:12]2=[O:14])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(CC(Br)C(=O)O)cc1
Agent: Cl
Solvent: O
Product: CC(=O)c1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
A solution of 3-(4-acetylphenyl)-2-bromopropanoic acid (87 g, 0.32 mol, prepared according to Cleland, Org. Synth. vol. 51, p. 1, 1971), and thiourea (48.7 g, 0.64 mol) in sulfolane (100 mL) was heated to 105°-110° C. for 5 hours. To this mixture was added a 2N HCl solution (162 mL) and the resulting solution was heated to 105°-110° C. overnight. After cooling and diluting with water, present title product was collected, washed with water and dried (75 g, 94%); mp 171°-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.[C:11]([O-:14])([O-])=[O:12].[Na+].[Na+].Br[CH2:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:7][C:8]([C:11]([O:14][CH2:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[O:12])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccccc1Br
Reactant: O=C([O-])[O-]
Reactant: O=C(CBr)C1CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCC(=O)C1CC1)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a solution of bromobenzoic acid (9.97 g, 49.60 mmol) in DMF (65 mL) was added Na2CO3 (7.90 g, 74.54 mmol). After stirring for 15 min, 2-bromo-1-cyclopropylethanone (9.69 g, 59.44 mmol) was added, and the mixture was stirred at rt for 12 h. Water was added, and the mixture was extracted with Et2O (6×125 ml). The combined organic phases were dried with MgSO4 and concentrated in vacuo. Recrystallization from EtOH yielded 2-cyclopropyl-2-oxoethyl 4-bromobenzoate as white needles (8.53 g, 61%).
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7])[CH:2]([CH3:4])[CH3:3].[OH-].[K+]>CCO.O>[CH2:1]([CH:5]([C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CC(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a solution of 8.34 g (38.6 mmol) of diethyl isobutylmalonate in 35 mL of 95% EtOH was added a solution of 9.0 g (161 mmol) of KOH in 110 mL of 95% EtOH. The mixture was stirred at 25° C. for 16 hours and then at reflux for 1 hour. The mixture was cooled, diluted with water and extracted with CH3Cl. The aqueous layer was cooled to 0° C. and acidified to pH<1 with 30 mL of concentrated HCl, then it was extracted with CHCl3. The aqueous layer was further continuously extracted with CHCl3 overnight. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated to afford 5.44 g (33.9 mmol, 88%) of isobutylmalonic acid as a solid which was essentially pure according to 1H NMR and which was used without further purification. Characteristic analytical data are as follows: mp 108°-110° C.; 1H NMR (300 MHz, CDCl3) δ3.52 (t, J=8 Hz, 1H), 1.84 (t, J=8 Hz, 2H), 1.66 (m, 1H), 0.94 (d, J-7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ175.6 (C=O), 49.7 (CH), 37.1 (CH2), 25.7 (CH), 21.7 (CH3).
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:2]1[O:1][C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:5][C:4]=2[CH:3]=1)[CH3:26]
Reactant: O=C(CCCCCc1ccc(F)cc1)N1CCc2occc2C1
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)CCCCCc1ccc(F)cc1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.315 g (1.000 mmol) of 1-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-6-(4-fluorophenyl) hexan-1-one in 20 ml of acetic acid, 0.135 ml (1.50 mmol) of 50% aqueous dimethylamine and 0.122 ml (1.50 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][C:11]([CH2:15][C:16]([O:18]CC)=O)=[CH:12][C:13]=3[CH2:14][C:5]=2[N:4]2[CH:21]=[CH:22][N:23]=[C:3]12.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH2:24]([NH:31][C:16](=[O:18])[CH2:15][C:11]1[CH:10]=[CH:9][C:8]2[C:6]3[NH:7][C:2](=[O:1])[C:3]4[N:4]([CH:21]=[CH:22][N:23]=4)[C:5]=3[CH2:14][C:13]=2[CH:12]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12)NCc1ccccc1
Temperature: 140 °C

Procedure:
A mixture of 0.618 g of ethyl [4,5-dihydro-4-oxo-10H -imidazo[1,2-a]indeno[1-,2-e]pyrazin-8-yl]acetate and 10 ml of benzylamine is heated at 140° C. for 17 hours under a nitrogen atmosphere. After returning to room temperature, 50 ml of dichloromethane are added to the reaction mixture. The solid formed is filtered, washed with dichloromethane and then recrystallized from 25 ml of dimethylformamide. After drying under reduced pressure (1 mbar) at 60° C., 0.65 g of N-benzyl-2-(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl)acetamide is thus obtained, which product has a melting point greater than 260° C. (Analysis; % Calculated C: 71.34, H: 4.90, N: 15.13, O: 8.64; % Calculated C: 71.1, H: 5.0, N: 15.2, O: 9.1).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CN(C)C=O.[H-].[Na+]>O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH2:9][OH:10])=[CH:2][CH:3]=1
Reactant: Fc1ccccn1
Reactant: OCc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(COc2ccccn2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixture of 1,4-benzenedimethanol (5.5 g, 40 mmol), 2-fluoropyridine (1.3 g, 13 mmol) and N,N-dimethylformamide (15 mL) was added sodium hydride (1.4 g, 40 mmol, 66% in oil) at 0° C., which was stirred for 20 minutes at room temperature and for 1 hour at 70° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (1.9 g, 66%).