Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:31][Si](C(C)(C)C)(C)C)=[C:24]([O:29][CH3:30])[CH:25]=3)[CH2:20]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:39][C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:31])=[C:24]([O:29][CH3:30])[CH:25]=3)[CH2:20]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(O[Si](C)(C)C(C)(C)C)cc3C2)Sc2ccc(C)cc2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)CC2
Reaction time: 5 h
Yield: 100.3 %

Procedure:
To a solution of 1.0 g of α-(3,4-dimethoxyphenyl)-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-6-methoxy-α-[(4-methylphenyl)thio]-2(1H)isoquinolineheptanenitrile in 30 mL of tetrahydrofuran is added 3.02 mL of a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran. This is sealed and stirred for 5 hours. The reaction mixture is evaporated and the residue taken up in ethyl acetate. The solution is washed three times with water, and the organic phase is separated and evaporated. The gum remaining is redissolved in chloroform and the solution evaporated in Vacuo at 66° C. This process is repeated twice more affording 0.83 g of the desired product as a brown gum.
Reaction SMILES: [C:1]([N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[O:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:21]Br.O.Cl>C(#N)C.C(O)C>[Br:21][C:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[O:7][CH2:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][C:9]=2[CH:11]=1
Reactant: BrBr
Reactant: CC(C)(C)N1COc2c(cccc2-c2ccccc2)C1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Temperature: 4 °C
Reaction time: 2.17 h

Procedure:
To a solution of 3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (9.420 g, 77.09 mmol) in acetonitrile (100 mL) was added dropwise bromine (1.8 mL, 1.0 equiv) at 5-10° C. After the addition, the mixture was stirred at 3-5° C. for 130 min. The resulting reaction mixture was allowed to stir at room temperature for 24 hours. To the reaction mixture was added water (200 mL) and the resulting mixture was concentrated under reduced pressure to remove most of the acetonitrile. The aqueous mixture was extracted with ethyl acetate and the combined organic layer was washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure to give a yellow solid. The solid was dissolved in ethanol and treated with 37% HCl (3.65 g). The resulting mixture was concentrated to removed ethanol to give the product which was crystallized from MTBE-EtOH to give 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (3.118 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C(N)=O)=[N:6][CH:7]=1.[CH2:11]([N:13](CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(Cl)Cl>[C:11]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)#[N:13]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C(N)=O)nc1
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(C#N)c1
Yield: 100.9 %

Procedure:
To a suspension of 5-methylpyridinylcarboxamide from step 2 (10.5 g, 0.077 mol) in triethylamine (23.3 g, 0.23 mol) and 400 mL of methylene chloride was added trifluoroacetic anhydride (21.0 g, 0.100 mol) rapidly at 0° C. The reaction was completed after a few minutes. Water was added and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated to give 9.18 g of 3-cyano-5-methylpyridine crude, which was used in the next step without purification.
Reaction SMILES: BrC1OC(C2N=C3C=CC(C#N)=CN3C=2)=CC=1.[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=O)[CH2:25]Br)=[CH:22][CH:21]=1)#[N:19].[NH2:30][C:31]1[C:36]([CH3:37])=[CH:35][C:34]([Br:38])=[CH:33][N:32]=1>>[Br:38][C:34]1[CH:35]=[C:36]([CH3:37])[C:31]2[N:32]([CH:25]=[C:24]([C:23]3[CH:28]=[CH:29][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[N:30]=2)[CH:33]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: N#Cc1ccc2nc(-c3ccc(Br)o3)cn2c1
Product: Cc1cc(Br)cn2cc(-c3ccc(C#N)cc3)nc12
Yield: 71 %

Procedure:
The same procedure described for 3a was used employing 4-Cyanophenacyl bromide and 2-Amino-5-bromo-3-methylpyridine. Yield 71%, mp 209-210° C. 1H NMR (DMSO-d6); δ 2.56 (s, 3H), 7.53 (s, 1H), 7.95 (d, J=8.1 Hz, 2H), 8.14 (d, J=8.1 Hz, 2H), 8.60 (s, 1H), 8.88 (s, 1H). 13C NMR; δ 143.3, 140.4, 133.3, 133.0, 128.1, 127.4, 127.0, 125.9, 119.2, 112.8, 111.2, 108.2, 16.7. MS (m/z, rel.int.); 312 (M+, 10), 230 (100), 217 (60), 205 (50).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][C:16](Cl)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][CH2:32][C:33]2[CH:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([NH:47][CH2:48][CH2:49][N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:46])[CH:40]=3)[CH:36]=[CH:37][CH:38]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C.O>[NH2:19][S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][N:31]([CH2:32][C:33]2[CH:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([NH:47][CH2:48][CH2:49][N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:46])[CH:40]=3)[CH:36]=[CH:37][CH:38]=2)[C:16](=[O:17])[CH2:15][O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: NS(=O)(=O)c1ccc(CCNCc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1ccc(CCN(Cc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)C(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pyridine (0.16 ml) and benzyloxyacetyl chloride (0.16 ml) were added to a solution of 3′-[{2-[4-(aminosulfonyl)phenyl]ethyl}aminomethyl]-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamide (506 mg) in DMF (10 ml). The reaction mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (dichloromethane/methanol=98/2), whereby the title compound (257 mg) was obtained.
Reaction SMILES: O=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5](OCC)[CH:4]=1.[C:13](OC)(=O)C1C(=CC=CC=1)N>>[CH2:13]=[CH:4][CH2:5][CH:9]([OH:10])[CH2:11][CH2:12][CH2:3][CH3:2]
Reactant: COC(=O)c1ccccc1N
Reactant: CCOc1cc(C=O)ccc1O
Product: C=CCC(O)CCCC

Procedure:
The Schiff Base of Ethyl Vanillin and Methyl Anthranilate
Reaction SMILES: C(=N[C@H](C1C=CC=CC=1)C)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C1CCCCC=1.C(#N)C.[C:27](OOC(C)(C)C)(=[O:34])[C:28]1C=CC=CC=1>[Cu].C(O)(=O)C>[C:27]([O:4][CH:3]1[CH2:2][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:34])[CH3:28]
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Reactant: C[C@H](N=Cc1ccccc1O)c1ccccc1
Agent: [Cu]
Solvent: CC(=O)O
Solvent: C1=CCCCC1
Solvent: CC#N
Product: CC(=O)OC1C=CCCC1
Reaction time: 6.5 h

Procedure:
A mixture of 0.451 g of (S)-(+)-N-salicylidene-1-phenylethylamine, 0.182 g of cupric acetate, 0.7 g of copper powder, 15 ml of cyclohexene, 15 ml of acetonitrile, 5 ml of acetic acid and 5 ml of t-butyl peroxybenzoate was stirred at 20° to 25° C for 6.5 hours in a nitrogen atmosphere. After the reaction, the reaction mixture was treated in the same manner as in Example 1 to obtain 1.60 g of 2-cyclohexenyl acetate.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][C@H:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C>ClCCl>[C:1]([NH:22][C@H:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
Tritylchloride (2.05 g. 7.36 mmol) was added to a solution of di-tert-butyl L-glutamate hydrochloride (2.15 g, 7.27 mmol) and triethylamine (5 mL, 36 mmol) in dichloromethane (20 mL). The solution was stirred for overnight (16 h) at room temperature. The solution was washed with sodium bicarbonate solution (3×10 mL) and water (2×5 mL). After drying over sodium sulphate, the solvent was evaporated. The crude product was purified by flash chromatography (ethyl acetate/n-hexane: 2/98 to 3/97) to give di-tert-butyl N-trityl-L-glutamate (3.2 g, 88%) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C:52]1[C:53](=[O:62])[NH:54][C:55]([CH3:61])=[CH:56][C:57]=1[CH2:58][O:59][CH3:60].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:50][CH2:51][C:52]2[C:53](=[O:62])[NH:54][C:55]([CH3:61])=[CH:56][C:57]=2[CH2:58][O:59][CH3:60])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:12])[CH3:13])[C:6]=2[N:7]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)nc21
Reactant: COCc1cc(C)[nH]c(=O)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CS(C)=O
Product: COCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To a solution of 6-bromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.155 g, 0.549 mmol) in DMSO (2 mL), PyBOP (0.429 g, 0.823 mmol) was added and reaction stirred at room temperature for 15 min. Then 3-(aminomethyl)-4-(methoxymethyl)-6-methylpyridin-2(1H)-one (0.1 g, 0.549 mmol) was added and reaction stirred overnight. On completion, water was added and solid that precipitates out was filtered and washed with water to obtain the desired intermediate (0.06 g, 24.5%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])=[CH:6][C:5]([CH2:32][C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:34][C:33](=[O:35])[CH2:32][C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])[C:2]([O:1][CH2:32][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:3][CH:4]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCc2ccccc2)ccc1OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 14, Step 3, using the following starting materials: [6-hydroxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid and benzyl bromide.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C.O>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH3:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC[O-]
Reactant: Cc1cnc(Cl)c(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ncc(C)cc1Br
Temperature: 100 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
To a solution of 3-bromo-2-chloro-5-methylpyridine (4.00 g, 19.37 mmol) in ethanol (100 mL) was added sodium ethoxide (6.59 g, 96.9 mmol) in three portions. The mixture was stirred under nitrogen at 100° C. for 2 days. The reaction was cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 20%, EtOAc/hexanes) afforded the title compound (3.00 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J=0.8, 2.3 Hz, 1H), 7.89-7.82 (m, 1H), 4.31 (q, J=7.0 Hz, 2H), 2.18 (t, J=0.8 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14](O)=[O:15])=[CH:10][N:9]=[C:8]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:29]1(=[O:36])[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1.C(N(CC)CC)C.OC(C)(C)C#N>ClCCl.CN(C)C=O>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([CH:30]3[C:31](=[O:35])[CH2:32][CH2:33][CH2:34][C:29]3=[O:36])=[O:15])=[CH:10][N:9]=[C:8]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(-c2ccccc2)n(C2CCCCC2)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCC(=O)C1C(=O)c1cnc(-c2ccccc2)n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-cyclohexyl-1,6-dihydro-6-oxo-2-phenyl-5-pyrimidinecarboxylic acid (i.e. the product from Example 11, Step B) (0.58 g, 1.5 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.490 g, 3.9 mmol) and one drop of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The crude oil was then redissolved in 10 mL of dichloromethane and then treated with 1,3-cyclohexanedione (0.24 g, 2.1 mmol) and triethylamine (0.39 g, 3.8 mmol) stirred for 30 min, then treated with a catalytic amount of 2-hydroxy-2-methyl-propanenitrile (0.015 g, 0.15 mmol) and triethylamine (0.393 g, 3.8 mmol) and stirred at ambient temperature for 16 h. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 10% methanol in chloroform to provide 0.570 g of the title compound, a compound of the invention, as a solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1.C1(NC2C=CC=CC=2)C=CC=CC=1.[CH:27](=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(O)(=O)C.[OH-].[Na+]>>[CH2:29]([C:28](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:27]=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=Cc1ccccc1
Reactant: CCCCCCCC=O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: CCCCCCC(C=O)=Cc1ccccc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
The reaction was carried out in a 2.5 litre double-walled glass reactor provided with a cooler, turbine stirrer (6 blades), thermocouple and a submerged metering tube. A mixture of 1065 grams of benzaldehyde (10.0 mol), 48.8 grams of pyrrolidine (0.679 mol) and 1.8 grams of diphenylamine was heated to 85° C. Over a period of 180 minutes, 878 grams of acidified (0.34 meq/gram) octanal (6.648 mol) were metered in at 85° C. Acidification of the octanal was effected with 16.9 grams of acetic acid (0.281 mol). The reaction was allowed to continue at 85° C. for a further 15 minutes. The reaction mixture was cooled to 65° C. and washed at 50° C., for 15 minutes, with 500.3 grams of 5% strength aqueous NaOH solution (0.625 mol). After neutralization with 78 grams of acetic acid (1.30 mol) for 15 minutes at 50° C., the reaction mixture was separated at 50° C., over a period of 5 to 6 minutes. The organic layer (1869.8 grams) contained 25.5% of benzaldehyde, 2.1% of octanal, 59.8% of α-hexylcinnamaldehyde and 4.6% of α-hexyldecenal. The degrees of conversion of benzaldehyde and octanal were 55.2% and 95.5%, respectively. The selectivity in producing α-hexylcinnamaldehyde was 93.5% with respect to benzaldehyde and 81.4% with respect to octanal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.Cl[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(OCC)(=O)C.O>[F:11][C:12]([F:20])([F:21])[C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a 12-L three-necked round-bottom flask fitted with a mechanical stirrer and a thermocouple was charged solid potassium carbonate (709.4 g, 5.140 mol, 1.2 molar equivalents) and acetone (5300 mL). The mixture was stirred and 3-trifluoromethylphenol (694.4 g, 4.28 mol, 1.0 molar equivalent) was added dropwise via 500-mL addition funnel over one hour. The internal temperature rose from 19.6° C. to 28.1° C. during the addition. The addition funnel was rinsed with acetone (100 mL). The rinse was charged to the vessel. The mixture was stirred and methyl chloroacetate (786.3 g, 5.140 mol, 1.2 molar equivalents) was charged dropwise via 500-mL addition funnel over one hour. The addition funnel was rinsed with acetone (100 mL). The rinse was charged to the vessel. The resulting mixture was stirred and heated to reflux for no less than 15 hours. After completion of reaction, as judged by TLC, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (2000 mL) and water (2000 mL). Some solids did not dissolve but that did not prevent a clean layer separation. The layers were separated (pH of lower aqueous layer: 11). The upper organic layer was treated (slow addition) with 10% w/w aqueous citric acid (2000 mL). All solids dissolved and the layers were separated (pH of lower aqueous layer: 8). The organic layer was concentrated in vacuo (20 mmHg, bath at 30-35° C.). The resulting biphasic residue was dissolved in isopropyl acetate (3000 mL). The layers of the resulting biphasic mixture were separated (pH of lower aqueous layer: 8). The upper organic layer was concentrated in vacuo (20 mmHg, bath at 30-35° C.). The resulting residue was distilled under reduced pressure (boiling point: 126-130° C., 10 mmHg) to afford the title intermediate (861.93 g, 86% yield) as a colorless liquid.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]=O.C[O:6][C:7](=O)[C:8]([OH:29])=[CH:9][C:10](=[O:28])[N:11]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1>CC(O)=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:10]([C:9]2[CH2:1][N:2]([CH3:3])[C:7](=[O:6])[C:8]=2[OH:29])=[O:28])=[CH:18][CH:17]=1
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Reactant: CN
Reactant: C=O
Solvent: CC(=O)O
Product: CN1CC(C(=O)N(Cc2ccc(F)cc2)Cc2ccc(F)cc2)=C(O)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To 2 mL of AcOH at 60° C. was added 1 mL 2M MeNH2 (THF) and 60 mg paraformaldehyde. After stirring for 5 min 3-[bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (723 mg, 2.0 mmol) was added and the resulting solution stirred at 60° C. for 2 h. The reaction mixture was then cooled to room temperature and transferred to a separatory funnel. The solution was extracted with EtOAc, the organic layer separated, washed with H2O, satd NaCl, then dried over Na2SO4. After filtration the solvent was removed to isolate 500 mg (67% yield) of 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid bis-(4-fluoro-benzyl)-amide as an orange solid. MS (M+H) calcd for C20H19F2N2O3: 373.1. found: 373.0. 1H NMR (500 MHz, DMSO) δ: 2.94 (s, 3), 4.01 (s, 2), 4.46 (br s, 2), 4.55 (br s, 2), 7.13–7.22 (overlapping m, 8).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=2)[NH:28][C:27]1=[O:32])([OH:16])=[O:15]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Temperature: 90 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (562 mg), 5-methoxy-2-oxindole (326 mg), and piperidine (2 drops) in ethanol (2 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added, the temperature was increased to 95° C. and held there for 1 hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 240 mg (65%) of 4-(2-carboxy-ethyl)-3-methyl-5-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([N:17]2[C:22](=[O:23])[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]3[N:42]=[C:43]([CH3:45])[N:44]=[C:18]23)[CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([N:17]2[C:22](=[O:23])[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:3][C:4](=[O:7])[O:5][N:38]=4)=[CH:29][CH:30]=3)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]3[N:42]=[C:43]([CH3:45])[N:44]=[C:18]23)[CH2:16][CH2:15][CH2:14]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC2)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-[(4-cyclobutyl-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.38 g, 57%).