Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:7]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:13])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1.[Cl-].[Li+]>CC(N(C)C)=O.CS(C)=O>[OH:2][C:3]1[N:7]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:13])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1
Reactant: COc1c(-c2ccnc(C)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
Combined 6-(5-methoxy-4-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (25.8 mg, 0.063 mmol) and lithium chloride (13.42 mg, 0.317 mmol) in DMA (0.5 mL) and then heated at 50° C. using a heating block for 2 days. Additional portion of lithium chloride (13.42 mg, 0.317 mmol) was added and the reaction mixture was stirred at 100° C. for 17 hours. The reaction mixture was cooled to 23° C., filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with DMSO (2×0.5 mL), and purified via preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using a gradient of 10-40% ACN (with 0.035% TFA) in water (with 0.05% TFA) to give a residue. The residue was dissolved in DMSO, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with DMSO, and purified again via preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using an isocratic method of 17% ACN (with 0.05% TFA) in water (with 0.05% TFA) to give the title compound, as a TFA salt, (6.2 mg, 19.30% yield) as a green oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.26 (m, 2 H) 1.55-1.67 (m, 2 H) 1.77-1.84 (m, 1 H) 2.51 (br. s., 3 H) 3.17-3.24 (m, 2 H) 3.24-3.32 (m, 2 H) 3.83-3.88 (m, 2 H) 7.77-8.07 (m, 2 H) 8.07-8.22 (m, 1 H) 8.22-8.30 (m, 1 H) 8.36-8.44 (m, 1 H) 8.58-8.67 (m, 1 H) 8.67-8.81 (m, 1 H) 8.81-8.92 (m, 1 H) 13.58 (br. s., 1 H). MS m/z [M+H]+ 394.5.
Reaction SMILES: [F:1][C:2]1[C:20]([CH3:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([N+:24]([O-:26])=[O:25])[C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[F:1][C:2]1[C:20]([CH3:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([N+:24]([O-:26])=[O:25])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Yield: 93.3 %

Procedure:
A suspension of 45.3 g of diethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate and 30 mg of p-toluenesulfonic acid in 120 ml of water was heated at reflux for 50 minutes. After cooling, the reaction mixture was extracted with diethyl ether. The combined organic extracts were washed with brine, dried and evaporated to give 34.2 g of the desired compound as brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16]OS(C4C=CC(C)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C@@H:38]1[CH2:43][CH2:42][C@H:41]([NH2:44])[CH2:40][CH2:39]1>>[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C@@H:38]1[CH2:43][CH2:42][C@H:41]([NH:44][CH2:16][C@@H:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:40][CH2:39]1
Reactant: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc32)CC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)ccc4c3O2)cc1
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN[C@H]1CC[C@@H](c2c[nH]c4ccc(F)cc42)CC1)O3

Procedure:
This compound was prepared in a manner similar to Example 1, using toluene-4-sulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.5 g, 1.29 mmol) and cis-4-(5-fluoro-1H-indol-3-yl)-cyclohexylamine (0.4 g, 1.72 mmol) to give 0.116 g (20%) product as an oxalate salt: MS (ESI) m/z 446 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Si:5]([O:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH2:20][CH2:21][OH:22])[S:18][CH:19]=1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(N(CC)CC)C>C1COCC1>[C:1]([O:22][CH2:21][CH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][CH2:13][O:12][Si:5]([C:8]([CH3:9])([CH3:11])[CH3:10])([CH3:7])[CH3:6])[CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(CCO)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCc1cc(CCO[Si](C)(C)C(C)(C)C)cs1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A solution of acetyl chloride (0.36 mL) in dry THF (3 mL) was added dropwise over 10 minutes to a stirred solution at 20° C. of 2-(4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)ethanol [Aromatic Intermediate 20] (1.10 g) and triethylamine (1.18 mL) in dry THF (30 mL). The mixture was stirred at 20° C. for 20 minutes and then partitioned between ethyl acetate and brine. The organic layer was dried, filtered and the solvent evaporated under reduced pressure to give the subtitled compound. Yield 1.20 g.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.I[C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:46][O:45][C:43]([C:42]1[CH:47]=[CH:48][C:39]([CH:11]2[CH2:14][N:13]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[CH2:12]2)=[CH:40][CH:41]=1)=[O:44]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CCCCOC(=O)N1CC(I)C1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CC(c2ccc(C(=O)OC)cc2)C1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
An oven dried glass vial was charged with zinc powder (120 mg, 1.837 mmol). THF (0.5 mL) was added, followed by 1,2-dibromoethane (15 μL, 0.17 mmol), and the resulting mixture was placed in a pre-heated (65° C.) oil bath. After 10 min, the mixture was allowed to cool to room temperature, TMSCl (18 μL, 0.141 mmol) was added, and the resulting mixture was stirred at room temperature. After 30 min, a solution of tent-butyl 3-iodoazetidine-1-carboxylate (400 mg, 1.41 mmol) in THF (1 mL) was added, and the mixture was stirred at room temperature. After 45 min, a solution of tris(dibenzylideneacetone)dipalladium (65 mg, 0.071 mmol) and tri(2-furyl)phosphine (66 mg, 0.283 mmol) in THF (1 mL) was added, followed by a solution of methyl 4-iodobenzoate (444 mg, 1.70 mmol) in THF (1 mL). The septum and nitrogen inlet were quickly replaced with a teflon cap, and the reaction mixture was heated at 65° C. After 18 h, the mixture was allowed to cool to room temperature, then was diluted with EtOAc and poured in sat aq NaHCO3. The organic phase was separated and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 235.9 [M-tBu]+; 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 4.35 (t, J=7.5 Hz, 2H), 3.99-3.95 (m, 2H), 3.92 (s, 3H), 3.81-3.76 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([NH2:15])=[CH:13][C:12]([C:16]#[N:17])=[N:11]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([NH2:15])=[CH:13][C:12]([C:16]#[N:17])=[N:11]1
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(Br)cc2Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cc(N)n(-c2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)n1
Temperature: 20 °C

Procedure:
A mixture of 1-(2,6-dichloro-4-bromophenyl)-3-cyano-5-aminopyrazole (45 g, prepared according to procedures reported in U.S. Pat. No. 5,232,940), 4-trifluoromethylphenylboronic acid (45 g), 2 M of Na2CO3 (75 mL), tris-(dibenzylideneacetone) dipalladium (6.4 g), toluene and ethanol was heated at 130° C. for 25 hours. After cooling to 20° C., the mixture was poured into water and extracted with diethyl ether. The ether solutions were combined, dried, filtered and the filtrate concentrated and purified via chromatography. The desired product as a solid (30.6 g, mp 195-199° C.) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:39])=O)=[CH:32][CH:31]=1)#[N:29]>>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([N:18]([CH:16]2[CH:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[O:39])=[CH:34][CH:35]=1)#[N:29]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1ccc(C#N)cc1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound 2-(4-Cyano-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-cyanophenylacetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a yellow oil. MS m/e: 553.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][C:9]=12.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=12
Reactant: CCOC(=O)c1ccn2nc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl
Yield: 98 %

Procedure:
A mixture of ethyl 3-(2,4-dichlorobenzyl)-2-methylpyrazolo[1,5-a]pyridine-5-carboxylate (230 mg), a 1N aqueous sodium hydroxide solution (2.0 ml) and ethanol (2.3 ml) was refluxed under heating for 25 min. The reaction mixture was adjusted to pH 4 under ice-cooling with 1N hydrochloric acid. The precipitate was collected by filtration and washed with water to give the objective compound (208 mg) as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5](B(O)O)[C:4]=2[CH:3]=[CH:2]1.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1/[C:16](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:17](=[O:23])[NH:18]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:1]1[C:9]2[C:4](=[C:5]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3/[C:16](=[CH:24]/[C:25]3[NH:26][CH:27]=[CH:28][C:29]=3[O:30][CH3:31])/[C:17](=[O:23])[NH:18]4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc4[nH]ccc34)c21
Temperature: 90 °C
Yield: 38.1 %

Procedure:
A solution of 4-indoleboronic acid (64 mg, 0.40 mmol) (from Step A above), (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 7), and sodium carbonate (35 mg, 0.33 mmol) in 3 mL DME and 1 mL water was degassed for 15 min. by bubbling argon through the solution. Dichlorobis(triphenylphosphine)palladium (II) (13 mg) (Aldrich) was then added and the reaction was heated at 90° C. for 2 days. The reaction was then poured into 100 mL water and the product was extracted with ethyl acetate (4×50 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified via flash column chromatography (1% CH3OH in CHCl3) to yield 42 mg (38%) orange powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1
Reactant: CCCc1cc(I)ccc1N=C1NC2(CCCC2)CS1
Reactant: BrC1CCCC1
Product: CCCc1cc(I)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
4-Iodo-2-n-propylaniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-iodo-2-n-propylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-n-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2-n-propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2-n-propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: C1(O)C=CC=CC=1.SCC(O)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)([CH2:22][CH2:23]C(C)C)[CH3:21])=[CH:16][CH:15]=1.Cl>CC(=O)CC>[OH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)([CH2:22][CH3:23])[CH3:21])=[CH:18][CH:19]=1
Reactant: CC(C)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: O=C(O)CS
Solvent: Oc1ccccc1
Solvent: CCC(C)=O
Product: CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
In a procedure substantially like that of Example 1, a mixture of 60 grams of phenol and 8 grams of 2-butanone was reacted in the presence of 1 ml. of mercaptoacetic acid (a catalyst used in place of the octanethiol of Example 1) and 40 ml. of concentrated hydrochloric acid. The Parr bomb and gaseous nitrogen were not used in this procedure. The reaction temperature was about 55° C. The crude reaction product was recrystallized from benzene to yield 5.2 grams of the title compound, which was dried overnight at about 95° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].C1C=CC=CC=1.[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>O>[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[N:8][C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)=[O:25]
Reactant: CN1CCCC1=N
Reactant: Cc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)N=C2CCCN2C)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 6.73 g. (0.05 mole) of 1 -methyl-2 -iminopyrrolidine hydrochloride in 100 ml. of benzene is added 2 ml. of water followed by 5 ml. of 50 % NaOH. After stirring for 5 min., the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice with 75 ml. portions of fresh benzene. The combined extracts are filtered from drying agent (dicalite pad and suction). To the filtrate is added in one portion with stirring 6.66 g. (0.05 mole) of p-tolylisocyanate. After stirring for 5 hours, the solution is taken to dryness in vacuo and the resulting solid is recrystallized from ethyl acetate to give 1 -(1 -methyl-2 -pyrrolidylidene)-3 -p-tolylurea, m.p. = 136°-137° C. A final recrystallization from acetone shows the product melting at 149°-150° C. Thin layer chromatography (TLC) indicates both samples to be identical in purity. Apparently the two melting points represent polymorphic forms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[NH:6][CH3:7].Cl[CH:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13]#[N:14]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[N:6]([CH:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13]#[N:14])[CH3:7]
Reactant: CNc1cccc(OC)c1
Reactant: CCCCCC(=O)C(Cl)C#N
Solvent: CCO
Product: CCCCCC(=O)C(C#N)N(C)c1cccc(OC)c1
Yield: 65.5 %

Procedure:
A solution of 3-methoxy-N-methylaniline (9.8 g) and 2-chloro-3-oxooctanenitrile (6.2 g) in ethanol (25 mL) was heated at reflux for 17 hours then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (100 mL) and washed with 1N hydrochloric acid (3×50 mL). The aqueous layers were backwashed in turn with dichloromethane (50 mL) and the combined organic layers were dried (K2CO3) and evaporated. The residual oil was purified by HPLC (diethyl ether-hexane; 3:7) to yield 6.42 g of 2-(3-methoxy-N-methylanilino)-3-oxooctanenitrile as an oil. The above material was dissolved in trifluoroacetic acid (15 mL) and the solution was allowed to stand overnight at ambient temperature. The solvent was then evaporated and the residue was partitioned between dichloromethane (100 mL) and 1N sodium hydroxide solution (100 mL). The dried (K2CO3) organic layer was evaporated and the residue was purified by HPLC (diethyl ether-hexane; 1:1) to give 3.2 g of 6-methoxy-1-methyl-3-pentyl-2-indolecarbonitrile as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH:4]=[C:20]([CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])[C:21]([NH2:22])=[N:1]2
Reactant: COc1ccccc1CCC#N
Reactant: Nc1cccc(Cl)c1C=O
Product: COc1ccccc1Cc1cc2c(Cl)cccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-6-chlorobenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[Cl-].[Zn+2:16].[Cl-]>O>[CH3:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Zn+2:16].[CH3:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C=CC(=O)[O-])cc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
A solution of 47% (w/w) sodium hydroxide (5.5 g) is added to slurry of 4-methylcinnamic acid (8.1 g, 0.05 mol) in water (100 mL) at 70° C. to give a clear slightly alkaline solution. A solution of zinc chloride (3.4 g, 0.025 mol) in water (50 mL) is added and a precipitate is formed immediately. The mixture is stirred at 70° C. for further 2.5 hours. The precipitate is then filtered and dried to yield 7.7 g (80%) zinc 4-methylcinnamate as a fine white powder. IR absorption bands: 1530, 1509, 1425 and 1382 cm−1.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH2:19][OH:20])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:11]([CH:19]=[O:20])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnn(Cc2ccccc2)c1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
A mixture of (1-benzyl-5-phenyl-1H-pyrazol-4-yl)methanol (9.76 g), activated manganese dioxide (20.0 g), and tetrahydrofuran (200 ml) was stirred at room temperature for 12 hours. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 1-benzyl-5-phenyl-1H-pyrazole-4-carbaldehyde (7.30 g, yield: 75%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 99–100° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH3:13])[CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CC(=O)Oc2cc(O)ccc21
Temperature: 30 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A Parr hydrogenator (1 L) was charged with 7-hydroxy-4-methylcoumarin, i.e., Compound of formula A1, (60 g, 0.34 mol) and acetic acid (350 ml). A suspension of 10% Pd/C (6.0 g) in acetic acid (150 ml) was added and the reactor sealed, evacuated and purged with nitrogen (4×). The reactor was pressurized to 320 psi with hydrogen and stirred at 30° C. for 16 hr, at which point no hydrogen was consumed and TLC (4% methanol:chloroform) showed the clean formation of product at the expense of starting material. The reactor was evacuated, purged with nitrogen and the mixture filtered through celite. The solvent was removed to give a white solid (60.5 g, 100%). Recrystallization from ethyl acetate:hexane afforded pure product as a white solid: m.p. 109-110° C.; 1H NMR (DMSO-d6) d 1.19 (d, JJ=6.7, 3H), 2.52 (dd, JJ=15.9, 7.3, 1H), 2.84 (dd, JJ=15.9, 5.5, 1H), 3.08 (m, 1H), 6.46 (d, JJ=2.4, 1H), 6.58 (dd, JJ=8.2, 2.4, 1H), 7.10 (d, JJ=8.2, 1H), 9.66 (s, 1H); 13C (DMSO-d6) d 19.84, 27.87, 36.45, 103.17, 111.38, 118.29, 127.17, 151.45, 157.17, 168.11; m/z (EI; TMS derivatized; M+) 250; IR (neat; cm−1) 3379.6, 2969.2, 2930.2, 2871.5, 1748.0, 1630.7, 1601.4, 1518.4, 1454.89, 1352.3, 1283.9, 1249.7, 1239.9, 1152.0, 1117.8, 1078.7, 1020.1, 995.7, 942.0, 854.0, 814.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:33](Br)[CH:34]=[CH2:35]>O1CCCC1>[CH2:1]([O:3][C:4]([CH:5]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:35][CH:34]=[CH2:33])=[O:22])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a −78° C. solution of benzyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (5.02 g, 16.4 mmol) in tetrahydrofuran (90 mL) was added lithium hexamethyldisilazide (1.0 M in THF, 18.1 mL, 18.1 mmol). After 1 h, allyl bromide (2.19 g, 18.1 mmol) was added, the reaction stirred at this temperature for 0.5 h, then warmed to 25° C. After 3 h, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% hexanes→40% hexanes/ethyl acetate) to give the title compound (4.08 g). MS 346.1 (M+1).