Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13](OC)=O)=[O:6])[CH:2]=[CH2:3].[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH2:28].[C:29]1([CH3:35])C=CC=[CH:31][CH:30]=1>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH:13]=[C:30]([CH3:31])[C:29](=[O:28])[CH3:35])=[O:6])[CH:2]=[CH2:3]
Reactant: Cc1ccccc1
Reactant: O
Reactant: C=CCOC(=O)N1CCCCC1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCCCC1C=C(C)C(C)=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-allyloxycarbonyl-2-methoxycarbonylpiperidine (10 g) in toluene (60 ml) was added dropwise diisobutylaluminum hydride (1M solution in toluene) (57 ml) at -70° C. After stirring at -70° C. for 30 minutes, the reaction mixture was poured into a mixture of concentrated hydrochloric acid (25 ml) and water (100 ml) at 5° C. After stirring at 5° C. for 15 minutes, the organic layer was separated, washed in turn with 1N hydrochloric acid (20 ml), 25% potassium sodium tartrate (20 ml) and brine (20 ml), dried over magncsium sulfate and filtered. The filtrate was concentrated to a volume of 40 ml. To this solution was added 3-triphenylphosphoranylidenebutan-2-one (16.1 g) and the mixture was stirred at 70° C. for 5 hours. After cooling to ambient temperature, the resulting precipitate was removed by filtration. The filtrate was evaporated to give a residue, which was taken up into ethyl acetate. The resulting precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (10:1-5:1 V/V) to give 1-allyloxycarbonyl-2-(2-methyl-3-oxo-1-butenyl)piperidine (10.9 g).
Reaction SMILES: [Br-:1].[CH3:2][N+:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8].[Br:11][CH2:12][CH2:13][CH2:14][Cl:15]>C(#N)C>[BrH:11].[Br-:1].[Cl:15][CH2:14][CH2:13][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH3:10])([CH3:9])[CH3:2])[CH3:8]
Reactant: ClCCCBr
Reactant: CNCCC[N+](C)(C)C
Agent: [Br-]
Solvent: CC#N
Product: Br
Product: CN(CCCCl)CCC[N+](C)(C)C

Procedure:
To a stirred solution of 3.02 g. (14.3 mmoles) of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 30 ml. of acetonitrile is added a solution of 2.25 g. (14.3 mmoles) of 3-bromo-1-chloropropane and the mixture is stirred at room temperature under nitrogen for 3.5 hours. The mixture is cooled in an ice-water bath and then the insoluble material is removed by filtration. The filtrate is evaporated and dried in vacuo and is extracted with chloroform. The chloroform extract is evaporated and dried to give 2.05 g. (100%) of oily product; NMR δ: 2.2 (3H, S, --NCH3); 3.43 (9H, S, --+N(CH3)3).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31].O>C1COCC1>[N:10]1([C:8]([C@@H:6]2[CH2:7][C@H:2]([NH:1][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N+:30]([O-:32])=[O:31])(=[O:40])=[O:41])[CH2:3][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]2)=[O:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@@H](C(=O)N2CCOCC2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])C[C@@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
tert-Butyl (3S,5R)-3-amino-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (3.13 g) and triethylamine (2.1 ml) were dissolved in THF (30 ml), 2-nitrobenzenesulfonyl chloride (2.44 g) was added at room temperature, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (4.68 g).
Reaction SMILES: ClC[Si](C)(C)C.[CH:7]([Li])([CH2:9][CH3:10])[CH3:8].CN(CCN(C)C)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]3CCCC3)=[C:30]([O:40][CH3:41])[CH:29]=2)=[CH:23][CH:22]=1.C1C[O:46][CH2:45]C1>>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:40][CH:41]3[CH2:10][CH2:9][CH2:7][CH2:8]3)[CH:29]=2)[CH:45]=[O:46])=[CH:25][CH:26]=1
Reactant: C1CCOC1
Reactant: COc1cc(C(=O)c2ccc(Br)cc2)ccc1OC1CCCC1
Reactant: [Li]C(C)CC
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)CCl
Product: COc1ccc(C(C=O)c2ccc(Br)cc2)cc1OC1CCCC1
Temperature: -55 °C
Reaction time: 0.67 h
Yield: 42.5 %

Procedure:
Chloromethyltrimethylsilane (1.875 g, 15.37 mmol) in dry THF (45 ml) at −78° C. was treated with sec-butyllithium (13.0 ml of 1.3 M solution in cyclohexane, 16.88 mmol) followed by TMEDA (2.4 ml, 16.1 mmol). The mixture was stirred for 40 min, then warmed to −55° C. 4′-Bromo-4-cyclopentoxy-3-methoxybenzophenone (4.0 g, 10.6 mmol) in THF (20 ml) was added and the mixture stirred at −40° C. for 0.5 h. It was then warmed to room temperature gradually and stirred for an additional 18 h. The reaction was quenched with aqueous ammonium chloride solution and the resultant mixture extracted three times with ethyl acetate. The combined organic extract was washed with water then brine, dried (sodium sulfate) and evaporated. The residue was purified by flash chromatography (silica gel, 4% ethyl acetate/96% hexane). The resulting yellow oil was stirred in 50 ml of 20% trifluoroacetic acid in dichlomethane for one hour then washed three times with water, once with dilute sodium bicarbonate, twice with water, once with brine and dried (sodium sulfate). The solvent was evaporated to provide the title compound as a yellow oil (1.757 g, 42.5%). 1H-NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 7.49 (d, 2H, J=8.4), 7.07 (d, 2H, J=8.4), 6.87 (d, 1H, J=8.2), 6.70 (dd, 1H, J=2.2, J=8.3), 6.68 (d, 1H, J=2.2).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:7](=O)[CH3:8])[CH2:3][CH2:4][C:5]#[N:6].N.CC1C(C)(C)CCC[NH:14]1>[O-2].[O-2].[Ti+4].[H][H]>[CH3:1][C:2]([CH3:10])([CH:7]([NH2:14])[CH3:8])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: CC(=O)C(C)(C)CCC#N
Reactant: [H][H]
Reactant: CC1NCCCC1(C)C
Agent: [Ti+4]
Agent: N
Agent: [O-2]
Product: CC(N)C(C)(C)CCCN
Yield: 93 %

Procedure:
10 g of 4,4,-dimethyl-5-oxohexanenitrile (purity 97.2%) and 195 g of liquid ammonia were pumped hourly from bottom to top at 250 bar and 80° C. through a tubular reactor (diameter 16 mm, fill level 50 cm, oil-heated twin jacket) arranged before the hydrogenation reactor and filled with 63.5 g (100 ml) of titanium dioxide (anatase) in the form of 1.5 mm pellets. 100 l (s.t.p.)/h of hydrogen were subsequently passed in, and the product discharged from the upstream imination reactor was passed through the hydrogenation reactor from bottom to top at 250 bar and 110° C. The mixture was decompressed to atmospheric pressure, the ammonia was removed by distillation, and the hydrogenation product was analyzed quantitatively by means of gas chromatography, giving a yield of 93.0% of 4,4-dimethyl-1,5-hexanediamine and 4.5% of 2,3,3-trimethylpiperidine.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:14]([C:17](=[O:18])[CH2:16][Cl:15])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1c[nH]c2ncc(Br)cc12
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a suspension of AlCl3 (3.38 g, 25.38 mmol) in dichloromethane (100 mL) was added 5-Bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5.07 mmol). After stirring for 30 min, chloroacetyl chloride (2.84 g, 25.38 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature. On completion, solvents were evaporated and quenched with aq. NaHCO3 solution at 0° C. Resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and filtered through a plug of silica gel. Solvent was evaporated to dryness to give 1-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-chloro-ethanone (1.3 g, 93% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][Si](C(C)C)(C(C)C)C(C)C)[CH:6]=1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N(CC)CC)C.Cl[CH2:50][C:51](=[O:53])[CH3:52]>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][CH2:50][C:51](=[O:53])[CH3:52])[CH:6]=1)[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)c1ccc(C)c(S[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C)c(SCC(C)=O)c1
Reaction time: 0.42 h

Procedure:
To a stirred solution of 4-Methyl-3-triisopropylsilanylsulfanyl-benzoic acid ethyl ester (crude from step 1) in THF (50 mL) at 0° C. was added TBAF (13.9 mmol, 13.9 mL of a 1.0 M solution in THF). After 25 minutes, triethylamine (34.7 mmol, 4.74 mL) was added, followed by chloroacetone (16.7 mmol, 1.33 mL). The reaction was stirred for an additional 5 minutes, then subjected to standard aqueous workup. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>O.C(O)C>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[NH:4][C:1](=[O:3])[CH3:2])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 67.8 g of N-acetyl-L-cysteine and 100.8 g of sodium bicarbonate in 300 ml of water is added to 55.4 ml of o-fluoronitrobenzene in 1 l of ethanol. The reaction is heated to reflux for 3 hr with mechanical stirring and allowed to cool to room temperature. After removing the solids by filtration, the solution is concentrated to one fourth of the original volume and diluted with 1 l of water. The aqueous suspension is washed with 200 ml of ether and acidified to pH 1 with 12N aqueous hydrochloric acid. The resulting yellow precipitate is collected by filtration and dried in vacuo at 70° C. over phosphoruos pentoxide to afford S-(o-nitrophenyl)-N-acetyl-L-cysteine; m.p. 175°-176° C.; [α]D =+87.8° (c=1.15, absolute ethanol).
Reaction SMILES: [C:1]([O:6]C(=O)C(C)=C)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(#N)C.[Br:15][C:16]([F:26])([F:25])[C:17]([F:24])([F:23])[CH2:18][CH2:19][CH2:20][CH2:21]O.C(N(CC)CC)C>O>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Br:15][C:16]([F:25])([F:26])[C:17]([F:23])([F:24])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OCCCCC(F)(F)C(F)(F)Br
Reactant: C=C(C)C(=O)OC(=O)C(=C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)O
Product: CCCCC(F)(F)C(F)(F)Br
Reaction time: 10 h
Yield: 90 %

Procedure:
A 300 mL reactor was charged under nitrogen with 18.2 g (119 mmol/1.5 equivalents) of methacrylic anhydride and 150 mL of acetonitrile, followed by putting it in an ice bath. 20.0 g (79.0 mmol/1.0 equivalent) of 6-bromo-5,5,6,6-tetrafluorohexan-1-ol was added thereto, followed by adding dropwise of 12.0 g (119 mmol/1.5 equivalents) of triethylamine. After the dropping, stirring was conducted at 60 degrees for 10 hours. Then, 100 mL of water was added, and extraction was conducted two times with 200 mL of diisopropyl ether. The obtained organic layer was washed further with diluted hydrochloric acid, sodium bicarbonate water and brine, followed by removing water by sodium sulfate and conducting filtration. Then, isopropyl ether was distilled out, thereby obtaining 23.8 g of the target 6-bromo-5,5,6,6-tetrafluorohexane methacrylate. Upon this, purity was 96%, and yield was 90%.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][O:5][C:3]1=[O:4].[OH-:9].[K+].Cl>O>[OH:5][CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[C:3]([OH:9])=[O:4]
Reactant: [OH-]
Reactant: CC1(C)CCOC1=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(CCO)C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 g) in H2O (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature and acidified to pH 5 with aqueous HCl solution. The mixture was then extracted with ethyl acetate 3 times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure to give 4-hydroxy-2,2-dimethyl-butanoic acid compound 54-B (4 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:43]=3[CH:44]=[CH:45][CH:46]=[N:47]4)[CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCNCC1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
1-(Piperidine-4-carbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (76) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (250 mg) as a white solid. ESMS: MH+ 691.6
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7]C)[C:4]=1[OH:5].Br>C(O)(=O)C>[OH:5][C:4]1[C:6]([OH:7])=[CH:9][CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: COc1cccc(C=O)c1O
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1cccc(O)c1O
Yield: 70.2 %

Procedure:
152.0 g (1.0 mol) of o-vanillin and 200 ml of azeotropic hydrobromic acid (47.5% strength) are stirred under reflux in 500 ml of glacial acetic acid for 2.5 hours. The acid mixture is then distilled off and the residue is subjected to fractional vacuum distillation. The redistilled fraction having a boiling point of 120°-125° C./12 mbar is purified by recrystallisation from 11 of heptane (hexane is also possible and is recovered). 97 g (70% of theory) of 2,3-dihydroxybenzaldehyde of melting point 105°-107° C. are obtained.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C@H:10]([CH3:12])[OH:11].ClC(Cl)(Cl)C(=N)O[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1CCCCC1.C(Cl)Cl>[CH2:21]([O:11][C@@H:10]([CH3:12])[C:9]([O:14][CH2:15][CH3:16])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](C)O
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCOC(=O)[C@H](C)OCc1ccccc1
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Trifluoromethanesulfonic acid (1.13 g) was added to a stirred mixture of ethyl (S)-(−)-lactate (5.90 g) and benzyl 2,2,2-trichloroacetimidate (15.15 g) in cyclohexane (70 ml) and methylene chloride (35 ml) at room temperature under nitrogen atmosphere. After being stirred for 18 hours, the reaction mixture was filtered. The filtrate was diluted with cyclohexane, and then washed successively with saturated NaHCO3 solution (100 ml)and H2O (100 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel (260 g) chromatography eluted with hexane/ethyl acetate (30:1) to give ethyl (S)-2-(benzyloxy)propionate (6.48 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10]O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.CS(Cl)(=O)=O.Cl.Cl.[C:19]([O:23][C:24]([N:26]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)[C:27]1[N:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CCN(CC)CC.C1COCC1>[C:19]([O:23][C:24]([N:26]([C@@H:40]1[CH2:44][CH2:43][N:42]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[CH2:41]1)[C:27]1[N:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: OCc1ccc2c(c1)CCO2
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc4c(c3)CCO4)C2)nc1
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a mixture of 2,3-dihydro-1-benzofuran-5-ylmethanol (95.1 mg), Et3N (0.120 mL), and THF (3 mL) was added methanesulfonyl chloride (0.053 mL) at 4° C. The reaction mixture was stirred for 3 hours, and added ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (250 mg) and Et3N (0.281 mL). After stirring for 2 hours at 60° C., the resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (134 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:16]>>[OH:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: CCOC(=O)CCCCC(=O)Cl
Product: COc1cc(C)c(C(=O)CCCCC(=O)O)c(O)c1OC

Procedure:
3,4,5-Trimethoxytoluene(formula VII wherein R=H3CO, X=H, Y=H3CO)(2.09 parts) and ethyl 5-chloroformylpentanoate (2.66 parts) were treated in the same manner as Example 4. The procedure provided 5-(2'-hydroxy-3', 4'-dimethoxy-6'methylbenzoyl)pentanoic acid (formula II-1 wherein R=H3CO, X=H, Y=OH, n=4, in the free form)(1.97 part) as pale-brown needles melting at 111°-112° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2]>C(O)(=O)C.O=[Mn]=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1cc(CO)cc(C)c1CCC(=O)O
Agent: O=[Mn]=O
Solvent: CC(=O)O
Product: CCc1cc(C=O)cc(C)c1CCC(=O)O
Temperature: 80 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
A solution of 3-(2-ethyl-4-hydroxymethyl-6-methyl-phenyl)-propionic acid (2.8 g, 12.6 mmol) in acetic acid (50 mL) is treated with MnO2 (3.9 g, 45.4 mmol) and the resulting mixture is stirred at 80° C. for 4 h. The mixture is filtered and the filtrate is concentrated. The crude product is purified by CC on silica gel eluting with DCM to give 3-(2-ethyl-4-formyl-6-methyl-phenyl)-propionic acid (1.76 g) as a beige solid; LC-MS: tR=0.86 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][C:6]#[N:7].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[C:6]([NH2:7])=[N:19][C:17]2[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=2[CH:20]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: COc1ccccc1CC#N
Product: COc1ccccc1-c1cc2cnc(N)nc2nc1N

Procedure:
The title compound was prepared according to Example 1, starting from 2-methoxybenzyl cyanide and 2,4 -diamino-5-pyrimidine-carboxaldehyde; mp 304-306° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([CH2:9][C:10](=[O:15])[C:11]([O:13]C)=O)=[O:8])=[CH:5][CH:4]=1.[O:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)=[N:19]1.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O.C(OCC)C>O1CCOCC1>[F:30][C:31]1[CH:32]=[C:33]([CH:34]2[N:27]([C:26]3[CH:28]=[CH:29][C:23]([C:20]4[CH:21]=[CH:22][O:18][N:19]=4)=[CH:24][CH:25]=3)[C:11](=[O:13])[C:10]([OH:15])=[C:9]2[C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Reactant: O=Cc1cccc(F)c1
Reactant: Nc1ccc(-c2ccon2)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(-c4ccon4)cc3)C2c2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To a mixture of methyl (4-methoxybenzoyl)pyruvate (0.24 g, 1 mmol) and 4-isoxazol-3-ylaniline (0.16 g, 1 mmol) in dioxane (1 mL) was added 3-fluorobenzaldehyde (0.11 mL, 1 mmol). The mixture was stirred at r.t. for two days. Diethyl ether (3 mL) was then added to the mixture, and the precipitate was collected by filtration to give 5-(3-fluorophenyl)-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-4-(4-methoxybenzoyl)-1,5-dihydropyrrol-2-one (0.16 g, 34%) as slightly yellow crystals.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([S:12](Cl)=[O:13])([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1.O>O1CCCC1>[CH3:8][C:9]([S:12]([NH:26][C@H:27]1[CH2:28][CH2:29][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:31][CH2:32]1)=[O:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)S(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](NS(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (1658 mL, 2.7 eq) was added dropwise to a solution of 2-methylpropane-2-sulfinyl chloride (3) (900 g, 1.3 eq) and methyl trans-4-amino-1-cyclohexane carboxylate p-toluenesulfonate (10) (1452 g, 4.407 mol) in tetrahydrofuran (9.5 L) with ice-cooling. The mixture was stirred for 1.5 hours at room temperature, poured into water (9.5 L) and extracted with ethyl acetate (9.5 L, 5 L). Each of organic layer was washed with brine twice, dried over sodium sulfate, and concentrated under reduced pressure to obtain (11) (1.26 kg).
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.CS[C:11]([S:21][CH3:22])=[C:12]([C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:13]#[N:14]>>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:11]1=[C:12]([C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:13]#[N:14].[S:21]1[C:22]2[CH:4]=[CH:5][CH:6]=[CH:1][C:2]=2[NH:7][C:11]1=[C:12]([C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:13]#[N:14]
Reactant: CSC(SC)=C(C#N)c1ncccn1
Reactant: Nc1ccccc1N
Product: N#CC(=C1Nc2ccccc2N1)c1ncccn1
Product: N#CC(=C1Nc2ccccc2S1)c1ncccn1

Procedure:
In the first step of the synthesis, a benzene-1,2-diamine (1, X═NH) or 2-aminothiophenol (1, X═S) is coupled with a 3,3-bis(methylthio)-2-(pyrimidin-2-yl)acrylonitrile 9 to give a 2-[1H-benzimidazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetonitrile or 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetonitrile 6. The reaction is carried out under generally the same conditions as are used in the first step of the first half of Reaction Scheme 1. In the second step, the compound of formula 6 is hydrolyzed to a 2-[1H-benzimidazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamide or 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamide 8, as in Reaction Scheme 1.