Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2].[CH:30]([C:32]([CH3:34])=[O:33])=[CH2:31]>>[C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][C:32](=[O:33])[CH3:34])[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2]
Reactant: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C=CC(C)=O
Product: CC(=O)CCN1CCC[C@H]2CN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3C#N)C[C@H]21

Procedure:
300 mg (0.76 mmol) of 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 0.63 ml (7.6 mmol) of methly vinyl ketone are heated under reflux in 5 ml of methylglycol for 2 hours. The reaction solution is concentrated in vacuo and the residue is stirred with water and filtered off with suction.
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]1([N:13]([CH:35]2[CH2:37][CH2:36]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]([NH2:31])=[S:30])=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:12][CH2:11]1>>[CH:35]1([N:13]([CH:10]2[CH2:11][CH2:12]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]4[S:30][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8][N:31]=4)=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:36][CH2:37]1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Product: CCOC(=O)c1cnc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)s1
Yield: 17 %

Procedure:
This compound was prepared according to example 2 using ethyl 2-chloro-2-formylacetate and N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) to provide ethyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylate (18.5 mg, 17% yield) as a pale yellow solid.
Reaction SMILES: N1C=CN=C1.Cl[Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[CH:21]=[O:22].O>CN(C=O)C.C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[O:26][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:21]=[O:22]
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(F)c1O[Si](C(C)C)(C(C)C)C(C)C

Procedure:
After adding 0.52 g of imidazole and 1.49 ml of chlorotriisopropylsilane to a solution of 1.0 g of 3-fluoro-5-methoxy-4-hydroxybenzaldehyde [CAS No. 79418-78-3] in 15 ml of DMF, the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.67 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(N)ccc1SCCCO
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(SCCCO)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 25.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (3.9 g) and 5-amino-2-(3-hydroxypropylthio)benzonitrile (2.9 g), the title compound (1.5 g) was obtained, melting point: 165° C.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH:19]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)[N:18]([C:35](Cl)=[O:36])[CH2:17][CH2:16]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH:7][C:35]([N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:19]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)=[O:36])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)Cl)cc1OC
Reactant: CC(C)N(CCN)C(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)NCCN(C(C)C)C(C)C)cc1OC
Reaction time: 3.5 h

Procedure:
4.0 Parts of 2-diisopropylaminoethylamine in 75 parts of chloroform is added portionwise, at room temperature, to a mixture of 8.0 parts of 6,7-dimethoxy-1-(3,4-dimethoxyphenyl)-3,4-dihydro-2(1H)-isoquinolinecarbonyl chloride and 15 parts of triethylamine in 225 parts of chloroform. After the addition is complete, the mixture is stirred for 3 to 4 hours, allowed to stand overnight, and then washed with water. The chloroform layer is separated, dried over anhydrous calcium sulfate and concentrated under reduced pressure. The solid material obtained in this manner is crystallized from ether to give N-(2-diisopropylaminoethyl)-6,7-dimethoxy-1-(3,4-dimethoxyphenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxamide, melting at about 114°-115°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[N:27]=[C:28]=[O:29]>>[Cl:16][C:12]1[CH:13]=[CH:14][N:15]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][C:20]3[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[O:18][CH3:17])=[O:29])=[CH:7][CH:6]=2)[C:9]=1[C:10]#[N:11]
Reactant: COc1ccc(N=C=O)c(OC)c1
Reactant: N#Cc1c(Cl)ccnc1-c1ccc(N)cc1
Product: COc1ccc(NC(=O)Nc2ccc(-c3nccc(Cl)c3C#N)cc2)c(OC)c1

Procedure:
2-(4-Aminophenyl)-4-chloronicotinonitrile is reacted with 2,4-dimethoxyphenyl isocyanate under conditions similar to those described in Example 27. 1-[4-(4-Chloro-3-cyanopyrid-2-yl)phenyl]-3-(2,4-dimethoxyphenyl)urea is obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[F-].[K+].Br[CH2:15]Br.O>CN(C=O)C>[Br:1][C:2]1[C:9]2[O:10][CH2:15][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Reactant: BrCBr
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c2c(c1)OCO2
Temperature: 140 °C
Yield: 60.5 %

Procedure:
To a solution of 3-bromo-4,5-dihydroxy-benzaldehyde (1.52 g, 7.02 mmol) in DMF (20 mL), were added KF (4.077 g, 70.18 mmol) followed by dibromomethane (1 mL, 14.04 mmol) and the mixture heated at 140° C. for 4 hours. The solution was cooled to room temperature, water was added and the mixture extracted with ether. The organic layer was further washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and evaporated to give 973 mg of 7-bromo-benzo[1,3]dioxole-5-carbaldehyde. 1H NMR (300 MHz; CDCl3): δ 6.16 (s, 2H), 7.26 (s, 1H), 7.54 (s, 1H), 9.76
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[CH:7]=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([OH:14])=[C:10]([CH:13]=1)[CH:11]=[O:12]>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([O:14][CH2:1][O:2][CH3:3])=[C:10]([CH:13]=1)[CH:11]=[O:12]
Reactant: CC(C)(C)c1cc(Br)cc(C=O)c1O
Reactant: COCCl
Solvent: ClCCl
Product: COCOc1c(C=O)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
I-PrNEt2 (834 g, 6.46 g) and chloromethyl methyl ether (451 g, 5.60 mol) were gradually added to a solution of the 5-bromo-3-(tert-butyl)-2-hydroxybenzaldehyde (1333 g, 4.67 mol) in methylene chloride (4000 ml) while cooling on ice, and the mixture was stirred at room temperature for 2 days. After first distilling off the solvent under reduced pressure, ethyl acetate was added to the residue, washing was performed twice with brine, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1338 g) as a light yellow oil.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([CH:13]([CH2:16][CH3:17])[CH2:14][OH:15])[CH3:12]>>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([O:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])[O:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CCC(CC)CO
Product: CCCC[Sn](CCCC)(OCC(CC)CC)O[Sn](CCCC)(CCCC)OCC(CC)CC
Reaction time: 0.67 h

Procedure:
672 g (2.7 mol) of dibutyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 1102 g (10.8 mol) of 2-ethyl-1-butanol (made by Chisso Corporation, Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to 157° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational stirring and heating were carried out for approximately 40 minutes at normal pressure, and then the purge valve was closed, and the pressure in the system was gradually reduced, and water-containing 2-ethyl-1-butanol was distilled off with the pressure in the system at from 84 to 65 kPa. This state was maintained for 2 hours, and then the pressure in the system was further reduced, and excess 2-ethyl-1-butanol was distilled off. Once distillate stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 883 g of reaction liquid was obtained in the flask. According to 119Sn—, 1H—, and 13C-NMR analysis results, the product 1,1,3,3-tetrabutyl-1,3-bis(2-ethylbutyloxy)-distannoxane was obtained at a yield of. 99% based on the dibutyltin oxide. The same procedure was carried out so as to produce 1,1,3,3-tetrabutyl-1,3-bis(2-ethylbutyloxy)-distannoxane to be used in the following step B.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][CH:16]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[CH3:17]>C(O)C>[CH3:17][CH:16]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1)[CH3:15]
Reactant: CC(C)Oc1ccccc1N
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2OC(C)C)[nH]c1=O
Reaction time: 17 h
Yield: 38.3 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (15 g) and 2-(1-methylethoxy)aniline (11.5 g) are added to ethanol (100 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-[2-(1-methylethoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (8.5 g). M.p. 205°-207° C.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][C@@H:13]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:12]3)[C:4]=2[CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:33])[C@@H:13]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:12]3)[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(N1CCN[C@@H](CCc3ccccc3)C1)=Nc1ccccc1N2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc2c(c1)C(N1CCN(C)[C@@H](CCc3ccccc3)C1)=Nc1ccccc1N2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
Combine 2-methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (300.0 mg, 0.76 mmol), formaldehyde (67.5 μL, 0.83 mmol, 37% in water), and 1,2-dichloroethane (25.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (240.5 mg, 1.13 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 279.7 mg (90%) of the title compound as a yellow foam: mp 65°, dec; mass spectrum (ion spray): m/z=411.2 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=O>C1(C)C=CC=CC=1>[C:1]1([C@H:7](/[N:9]=[CH:11]\[C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=O
Reactant: C[C@H](N)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=N\[C@H](C)c1ccccc1
Reaction time: 1 h

Procedure:
To a (1S)-1-phenylethanamine (77.4 mL), was added a solution of ethyl glyoxylate in toluene (45–50%, 123 mL) at room temperature. After 1 hr, the mixture was evaporated in vacuo. The residue (120 g) was used in the next step without further purification.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]=1[OH:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>C(O)C>[CH3:24][N:25]=[C:1]([C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cn1c(-c2ccccc2)cc(O)c(C(=O)c2ccccc2)c1=O
Solvent: CCO
Product: CN=C(c1ccccc1)c1c(O)cc(-c2ccccc2)n(C)c1=O

Procedure:
Three grams (0.0098 mole) of 3-benzoyl-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone is added to 30 milliliters of ethanol saturated with methylamine. The mixture is refluxed for two hours with a stream of methylamine passing through. The mixture is cooled and the resulting solid filtered and washed with ethanol and then ether to give 3-(α-N-methyliminobenzyl)-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone; m.p. 225°-227° C.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].[CH3:12][N:13]([C+:15]([N:17]([CH3:19])[CH3:18])Cl)[CH3:14].[CH3:20][N-:21][CH3:22].[Li+]>C(#N)C>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].[CH3:12][N:13]([CH3:14])[C:15](=[N+:21]([CH3:22])[CH3:20])[N:17]([CH3:19])[CH3:18]
Reactant: C[N-]C
Reactant: CN(C)[C+](Cl)N(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C(N(C)C)=[N+](C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.50 g (4.89 mmol) of bis(dimethylamino)chlorocarbenium tosylate and 0.25 g (4.90 mmol) of lithium dimethylamide are dissolved in 15 ml of acetonitrile under a protective-gas atmosphere (argon). The reaction mixture is stirred for 5 hours at room temperature, and LiCl is subsequently filtered off. The salt LiCl is washed with 5 ml of acetonitrile, and the organic phases are combined. The solvent is distilled off, and the residue is dried under reduced pressure at 7 Pa and 50° C., giving 1.49 g of hexamethylguanidinium tosylate, corresponding to a yield of 96.6%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10].Cl.[O:24]([NH2:26])[CH3:25].Cl.CN(C)CCCN=C=NCC>O.C(Cl)Cl.O1CCCC1>[CH3:25][O:24][NH:26][C:13](=[O:15])[C@H:12]([NH:11][C:9]([O:8][CH3:7])=[O:10])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CON
Reactant: COC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CONC(=O)[C@@H](Cc1ccccc1)NC(=O)OC
Reaction time: 22 h

Procedure:
A mixture of sodium carbonate (10.20 g, 96.2 mmol) in water (170 ml) is added to a mixture of (R)-2-(methoxycarbonylamino)-3-phenylpropanoic acid (II, EXAMPLE 1, ˜0.148 mol crude) in methylene chloride. Methoxylamine hydrochloride (14.2 g, 0.170 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (31.21 g, 0.163 mol) are added, and the mixture is stirred at 20-25° for 22 hours. The mixture is diluted with tetrahydrofuran (to dissolve the precipitate) and the layers are separated. The aqueous layer is extracted with 1:1 tetrahydrofuran/ether, and the combined organic extracts are washed with hydrochloric acid (10%) and saturated sodium bicarbonate solution. The mixture is dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. Crystallization from ethyl acetate gives the title compound, mp=154-155°; NMR (CDCl3) 3.05, 3.58, 3.61, 4.34, 5.66, 7.15-7.31 and 9.44 δ; IR (mineral oil) 1694 and 1668 cm−1; [a]25D=+5.2° (CH3OH, c=1.045).
Reaction SMILES: [C:1]1([C:7]([CH3:12])([CH3:11])[CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:8][C:7]([CH3:12])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])[CH3:18]
Reactant: CC(C)(C[Mg]Br)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(C)(C)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
2-Phenyl-2,2-dimethylethylmagnesium bromide (10 mmol, 20 mL of 0.5 M solution in diethyl ether) was added to solution of diethyl oxalate (1.5 g, 10.5 mmol) in anhydrous THF (20 mL) cooled to −78° C. and maintained under argon. After 1 hour, TLC in hexanes-EtOAc (7:1) indicated most of the diethyl oxalate had been consumed. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give a light brown, thick oil which was purified by flash column chromatography over silica gel eluting with 5% EtOAc in hexanes to yield 4-methyl-2-oxo-4-phenylpentanoic acid ethyl ester as a light yellow oil (1.1 g, 51%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([Sn](C)(C)C)=[CH:3][CH:2]=1.N#N.Br[C:15]1[C:19]([Br:20])=[CH:18][S:17][CH:16]=1.CCOC(C)=O>C1(C)C=CC=CC=1.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>[Br:20][C:19]1[C:15]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)=[CH:16][S:17][CH:18]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: Brc1cscc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cscc2Br)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Through a solution of p-tolyltrimethyltin (3.17 g, 12.4 mmol) in dry toluene (8 mL) was bubbled N2 for 5 min to degas the solution. To this was added 3,4-dibromothiophene (2.31 g, 9.56 mmol) and a catalytic amount of Pd(PPh3)4 (552 mg, 5 mol %). The reaction mixture was brought to reflux (120° C.) and left overnight. The reaction was cooled to rt and the toluene was replaced by EtOAc. The insoluable salts were removed by filtration through a plug of celite. The product was purified by flash chromatography on a silica column eluting with hexane to afford 1.09 g (45%) of the titled compound as a clear, colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2].[Cl:12]N1C(=O)CCC1=O>C(O)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:12])=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CO)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CO)c(Cl)s1
Temperature: 40 °C
Yield: 86.9 %

Procedure:
A mixture of 2-acetylamino-4-hydroxymethylthiazole (7.0 g) and N-chlorosuccinimide (6.5 g) in acetic acid (70 ml) was heated at 40° C. for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was added the aqueous sodium bicarbonate. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1), washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was triturated with isopropyl ether. The precipitates were collected by filtration, washed with isopropyl ether and dried in vacuo to give 2-acetylamino-5-chloro-4-hydroxymethylthiazole (7.3 g, yield : 78.5%). mp: 145°-146° C. IR (Nujol) : 3150, 1690, 1550, 1285 cm-1
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:34]=[CH:33][C:14](/[CH:15]=[CH:16]/[C:17]([NH:19][CH:20]2[CH2:25][CH2:24][C:23]([CH3:32])([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:22][CH2:21]2)=[O:18])=[CH:13][C:12]=1[O:35][CH3:36])(=O)C.Cl>CO>[OH:10][C:11]1[CH:34]=[CH:33][C:14](/[CH:15]=[CH:16]/[C:17]([NH:19][CH:20]2[CH2:25][CH2:24][C:23]([CH3:32])([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:22][CH2:21]2)=[O:18])=[CH:13][C:12]=1[O:35][CH3:36]
Reactant: C=CCOC(=O)C1(C)CCC(NC(=O)/C=C/c2ccc(OC(C)=O)c(OC)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCOC(=O)C1(C)CCC(NC(=O)/C=C/c2ccc(O)c(OC)c2)CC1
Yield: 71.1 %

Procedure:
10 g of potassium carbonate was added to a solution of 4.4 g of allyl trans-4-(4-acetoxy-3-methoxycinnamamido)-1-methyl-1-cyclohexanecarboxylate (Example 23) in 100 ml of methanol. The resultant solution was stirred for 2 hours at room temperature. After reaction, 2N hydrochloric acid was added to the reaction solution, acidifying the solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed once with an aqueous sodium hydrogencarbonate solution and once with an aqueous sodium chloride solution, and was then dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo, yielding 2.81 g of allyl trans-4-(4-hydroxy-3-methoxycinnamamido)-1-methyl-1-cyclohexanecarboxylate (a compound of the present invention) as a yellow oil, which had the following physiochemical properties: