Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH:4]([C:16]([O:18]CC)=O)[C:3]1=O.[C:22]1([CH2:28][C:29]([NH2:31])=[NH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:28]([C:29]1[NH:31][C:16](=[O:18])[C:4]2[CH2:5][CH2:6][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:8][CH:2]([CH3:1])[C:3]=2[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC(C)C1=O
Product: CC1CN(C(=O)OC(C)(C)C)CCc2c1nc(Cc1ccccc1)[nH]c2=O
Yield: 70 %

Procedure:
The title compound was prepared by a similar method to that of Preparation 1, Step A, starting from 1-tert-butyl 4-ethyl 6-methyl-5-oxoazepane-1,4-dicarboxylate and 2-phenyl-acetamidine, yielding 70% of title compound.
Reaction SMILES: [NH2:1][C:2]([C:4]1[N:8]=[C:7]([C@H:9]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][C:11](O)=[O:12])[O:6][N:5]=1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:40][NH2:41]>O1CCCC1.CO>[CH:17]1([CH2:16][CH2:15][CH2:14][C@@H:9]([C:7]2[O:6][N:5]=[C:4]([C:2]([NH2:1])=[O:3])[N:8]=2)[CH2:10][C:11]([NH:41][OH:40])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C[Si](C)(C)ON
Reactant: NC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: NC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of (3R)-3-[3-(aminocarbonyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoic acid (Preparation 6) (6.00 g, 19.42 mmol) in anhydrous tetrahydrofuran (200 ml) was cooled to 0° C. then treated with N-methylmorpholine (2.40 ml, 22.0 mmol) and isobutyl chloroformate (2.8 ml, 22.0 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (7.0 ml, 60.0 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (50 ml) and stirred for a further 30 minutes. This mixture was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was recrystallised from isopropyl acetate (500 ml) to afford the title compound as a white solid (4.46 g). Chiral HPLC analysis indicated this material to be 87.6% ee. A sample of this material (2.9 g) was dissolved in ethyl acetate (450 ml) at reflux then allowed to cool. The precipitate was filtered off and the solvent was removed from the filtrate under reduced pressure to afford a white solid, which was then recrystallised from isopropyl acetate (120 ml) to afford the title compound (1.42 g). Chiral HPLC analysis showed this material to be 98.3% ee.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:14]C=C(C#N)C#N)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)#[N:2].Cl.[O:22]1CCOCC1>>[NH2:14][C:4]1[C:3]([C:1]#[N:2])=[CH:7][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=1.[NH2:14][C:4]1[C:3]([C:1]([NH2:2])=[O:22])=[CH:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=1
Reactant: N#CC(C#N)=CNc1nn(-c2ccccc2)cc1C#N
Reactant: C1COCCO1
Agent: Cl
Product: N#Cc1cn(-c2ccccc2)nc1N
Product: NC(=O)c1cn(-c2ccccc2)nc1N

Procedure:
{[(4-cyano-1-phenyl-1H-pyrazol-3-yl)amino]methylene}malononitrile (1.07 g, 4.11 mmol) was stirred in refluxing dioxane (80 mL)/2 N HCl (80 mL) for 3 days. Room temperature was attained and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (12-100% EtOAc-hexanes followed by 0-10% MeOH-EtOAc) gave 3-amino-1-phenyl-1H-pyrazole-4-carbonitrile as a beige solid (A) and 3-amino-1-phenyl-1H-pyrazole-4-carboxamide as a brown solid (B).
Reaction SMILES: [OH:1][CH:2]1[O:26][C:10]2=[CH:11][C:12]([O:14][CH:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:16])=[CH:13][C:8]3=[C:9]2[CH:4]([CH2:5][C:6]([CH3:28])([CH3:27])[O:7]3)[CH2:3]1.[CH2:29](O)C.CON>N1C=CC=CC=1>[CH3:29][O:1][CH:2]1[O:26][C:10]2=[CH:11][C:12]([O:14][CH:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:16])=[CH:13][C:8]3=[C:9]2[CH:4]([CH2:5][C:6]([CH3:27])([CH3:28])[O:7]3)[CH2:3]1
Reactant: CCO
Reactant: CC(CCCc1ccccc1)Oc1cc2c3c(c1)OC(C)(C)CC3CC(O)O2
Agent: CON
Solvent: c1ccncc1
Product: COC1CC2CC(C)(C)Oc3cc(OC(C)CCCc4ccccc4)cc(c32)O1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
In a stirred flask, under nitrogen, was placed (0.045 mole) 2-hydroxy-5,5-dimethyl-8-(5-phenyl-2-pentyloxy)-3,3a,4,5-tetrahydro-2H-pyrano[4,3,2-de]benzopyran, 250 ml ethanol and 250 ml pyridine. The solution was cooled to 0° C. and 3.94 g (0.047 mole) methoxyamine was added. The resulting mixture was stirred at 0° C. for 2.5 hours, the solvent evaporated in vacuo, the residue taken up in 500 ml ethyl ether and washed twice with water. The aqueous phase was backwashed with ether and the combined ether layers washed with brine and dried over anydrous magnesium sulfate. The solvent was evaporated in vacuo to obtain 19 g of residual oil. The structure of the product was verified by 1H-NMR. Mass spectrum (m/e): 411 (M+), 380 (M-OCH3), 364 (M-NH2OCH3).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][SH:5].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Cl>O.CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][S:5][NH:18][S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)(=[O:17])=[O:16]
Reactant: COCCS
Reactant: NS(=O)(=O)c1ccccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCSNS(=O)(=O)c1ccccc1
Reaction time: 3 h

Procedure:
3.6 of 2-methoxyethyl-mercaptan is added dropwise to a mixture of 3.5 g of 55% sodium hydride and 80 ml of dimethylformamide. To this mixture 8.0 of 2-fluorophenylsulfonamide are added. The reaction mixture is stirred for 3 hours at a temperatur of 115°-120° C. After cooling the mixture is poured into water. To this mixture 10% of hydrochlorid acid are added, and the product is extracted with ethyl acetate. The organic phase is evaporated and the residue is purified by chromatography. Yield: 6.7 g of 2-methoxyethylthio-phenylsulfonamide, m.p. 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.[CH3:17][NH:18][CH3:19].O>>[CH3:17][N:18]([CH3:19])[S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:16])[CH:3]=[C:2]2[Cl:1])(=[O:14])=[O:13]
Reactant: Cc1cc(Cl)c2cccc(S(=O)(=O)Cl)c2n1
Reactant: CNC
Solvent: O
Product: Cc1cc(Cl)c2cccc(S(=O)(=O)N(C)C)c2n1

Procedure:
4-Chloro-2-methylquinoline-8-sulfonyl chloride (100 mg, 0.362 mmole) and a 40% solution of dimethylamine in water (408 mg, 3.62 mmole) were stirred at 60° C. for 1 h. The content of the flask was filtered off and a white solid was obtained (103 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[C:5]([CH3:9])[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:13][CH:12]=2)[N:3]=1.C(OP([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])(OCC)=O)C.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[C:6](/[CH:7]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:5]([CH3:9])[N:4]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:15][CH:16]=2)[N:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(C)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a solution of 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carbaldehyde (900 mg) and ethyl diethylphosphonoacetate (1.10 g) in N,N-dimethylformamide (20 ml), sodium hydride (60%, oily, 200 mg) was added at 0, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and ethyl(E)-3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoate (740 mg) was obtained. After the mother liquor was concentrated, the residue was subjected to silica gel column chromatography, and 150 mg of crystals were additionally obtained from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The total was 890 mg (yield: 87%). This was recrystallized from ethyl acetate-isopropyl ether. Melting point: 98–99° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].O.[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=[CH:16][CH:15]=1.[CH2:25]([OH:29])[CH2:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:19]([O:8][CH:7]([O:29][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(OCCCC)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-2-nitrobenzaldehyde (1-15, 75 g, 443 mmol), para-toluenesulfonic acid monohydrate (8.4 g, 44.3 mmol), and n-butanol (122 mL, 1.33 mol) was refluxed in toluene (630 mL) using a Dean-Stark apparatus for 15 h. The reaction was cooled, concentrated and partitioned between water (1 L) and EtOAc (1 L). The organic layer was washed with water (1 L) and brine (1 L), dried over Na2SO4 and concentrated. The crude reaction was purified by column chromatography (0 to 25% EtOAc in hexanes, 1% triethylamine buffer) to yield the 2-(dibutoxymethyl)-4-fluoro-1-nitrobenzene (1-16) as an oil. Data for 1-16: 1H NMR (500 MHz, CDCl3) δ 7.92 (dd, J=8.5, 4.5 Hz, 1H), 7.54 (dd, J=9.0, 3.0 Hz, 1H), 7.15-7.11 (m, 1H), 6.05 (s, 1H), 3.67-3.52 (m, 4H), 1.63-1.57 (m, 4H), 1.43-1.35 (m, 4H), 0.94-0.91 (m, 6H) ppm; ESI MS [M+H] for C15H22FNO4 (-acetal)=169.8.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[Cl:8][C:9]1[C:10]([N:19]2C(C=O)=[C:22]([C:26]#[N:27])[CH:21]=[N:20]2)=[N:11][N:12]([CH3:18])[C:13]=1[O:14][CH:15]([F:17])[F:16].[C:28]([O-])(=[O:30])[CH3:29].[Na+]>B(F)(F)F.CCOCC.C(OCC)(=O)C>[Cl:8][C:9]1[C:10]([N:19]2[C:2]([CH:1]([O:3][C:28](=[O:30])[CH3:29])[O:4][C:5](=[O:7])[CH3:6])=[C:22]([C:26]#[N:27])[CH:21]=[N:20]2)=[N:11][N:12]([CH3:18])[C:13]=1[O:14][CH:15]([F:17])[F:16]
Reactant: Cn1nc(-n2ncc(C#N)c2C=O)c(Cl)c1OC(F)F
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)OC(OC(C)=O)c1c(C#N)cnn1-c1nn(C)c(OC(F)F)c1Cl
Reaction time: 1.5 h

Procedure:
5 ml acetic anhydride is cooled to 0-5° C. and 2 drops boron trifluoride-etherate are added. Then 2.3 g (7.6 mmol) 1-(4-chlor-5-difluormethoxy-1-methyl-3-pyrazolyl)-5-formyl-4-pyrazol-carbonitrile is slowly added dropwise and stirring is continued for another 1.5 hours at room temperature. 9 ml of 10% sodium acetate solution is added, stirring is continued for 20 minutes at room temperature and then the mixture is shaken up with ethyl acetate. The combined ethyl acetate phases are washed with a solution of sodium hydrogen carbonate and sodium chloride, dried and concentrated. Purification is by column chromatography using a hexane/ethyl acetate mixture.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]([CH3:31])[CH2:25][C:26]([O:28]CC)=[O:27])=[N:22][CH:23]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C.[OH-].[Na+]>CO.O>[OH:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]([CH3:31])[CH2:25][C:26]([OH:28])=[O:27])=[N:22][CH:23]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(OC(C)=O)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CC(=O)O)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)cn1
Temperature: 50 °C
Yield: 40.6 %

Procedure:
A solution of (RS) ethyl 3-{5-[2-(3-acetoxy-4-nitrophenyl)-acetylamino]-pyridin-2-yl}-butanoate (6.18 g, Reference Example 27) in methanol (100 mL) was treated with a solution of sodium hydroxide (3.5 g) in water (20 mL). The mixture was heated at 50° C. for 5 hours and then evaporated. The residue was dissolved in water and the resulting solution was washed with ethyl acetate, then acidified to pH 5 by addition of glacial acetic acid and then extracted with ethyl acetate. The extracts were washed with water, then dried over magnesium sulphate and then evaporated. The residual dark oil was subjected to flash chromatography on silica eluting with ethyl acetate to give the title compound (2.1 g) as a brown solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].[Br:23][C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=1>CN(C)C=O.O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:14][CH:12]2[CH2:13][N:10]([CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11]2)=[CH:26][CH:25]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [H][H]
Reactant: Fc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A stirred slurry of 8.8 g (0.22 mole) of 60% sodium hydride (mineral oil suspension) in 200 ml of dry dimethylformamide was heated under nitrogen atmosphere to 70° C. then 48 g (0.2 mole) of 1-diphenylmethyl-3-azetidinol in 150 ml of dry dimethylformamide was added dropwise at a rate which maintained the temperature below 90° C. and allowed a steady hydrogen evolution. The reaction mixture was stirred for 1 hr at 90° C., treated with 38.5 g (0.22 mole) of 4-bromofluorobenzene and heated at 90° C. for 36 hr. The reaction mixture was diluted with 1200 ml of water and after stirring for 3 hr, the solid precipitate was collected by filtration to yield 112 g of crude, wet product. Recrystallization from ligroin yielded 65.6 g (83.2%) of white crystals, m.p. 116°-117° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1.[F:16][C:17]([F:22])([F:21])[C:18](O)=O.FC(F)(F)S(OCC(F)(F)F)(=O)=O.C(N(CC)CC)C>CC(C)=O>[F:16][C:17]([F:22])([F:21])[CH2:18][N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1Nc2ccccc2C12CCNCC2
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2C12CCN(CC(F)(F)F)CC2

Procedure:
A mixture of spiro[indoline-3,4′-piperidin]-2-one, [PCT Int. Appl. WO 0145707 A1 (2001)] trifluoroacetic acid salt (3.66 g, 11.6 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.63 mL, 11.6 mmol), and triethylamine (8.06 mL, 57.9 mmol) in acetone (30 mL) was heated at reflux for 16 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was further extracted with CH2Cl2 (2×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=285 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)CCOC(=O)[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:34])[CH3:33])=[C:28]([Cl:35])[CH:27]=1>O1CCCC1>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:34])[CH3:33])=[C:28]([Cl:35])[CH:27]=1
Reactant: CC(O)c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)c1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL) is added to [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester (0.5 g) and the mixture is stirred at room temperature for approximately 3.5 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Br:12])[CH:7]=1)[CH3:2].[CH2:14]=[O:15].N12CCCN=C1CCCCC2.[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)C[C:28]2=[O:29]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[C:5]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Br:12])[CH:7]=1)([CH2:28][OH:29])[CH2:14][OH:15])[CH3:2]
Reactant: CCOC(=O)Cc1ccnc(Br)c1
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Reactant: C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(CO)(CO)c1ccnc(Br)c1
Temperature: 0 °C

Procedure:
To an ice cooled stirred mixture of (2-bromo-pyridin-4-yl)-acetic acid ethyl ester (40.0 g, 163.93 mmol) and paraformaldehyde (9.84 g, 327.8 mmol) in dry DCM was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.49 g, 1.49 ml, 9.83 mmol) and stirred for 2 h. Reaction mixture was treated with (1R)-(−)-10-camphor sulphonic acid (2.283 g, 9.83 mmol) at 0° C. and the organic layer was washed with brine and dried over anhydrous Na2SO4. Concentration of organic layer afforded gummy oily material. The crude compound was purified over triethyl amine treated silicagel using 5-8% methanol in DCM as eluent furnished title compound as a brown liquid. Yield=20.0 g (40%). TLC (30% ethyl acetate in hexane) Rf=0.06; LCMS: RtH7=0.191; [M+1]+=303.9 and 305.8; HPLC RtH9=6.019 min (43%); 1H NMR (400 MHz, CDCl3): b 8.36-8.31 (m, 1H), 7.34-7.25 (m, 1H), 6.37-6.33 (m, 1H), 4.6 (d, 1H), 4.14-4.08 (m, 2H), 4.04-3.91 (m, 4H), 1.13 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][C:22]([CH:25]=O)=[CH:23][N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+]>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Cl:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:25]/[C:22]1[S:21][C:20]([CH:17]([CH3:19])[CH3:18])=[N:24][CH:23]=1
Reactant: CC(C)c1ncc(C=O)s1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)/C=C/c3cnc(C(C)C)s3)c(N)c2c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7G (3 g, 12.5 mmol) was dissolved in THF (tetrahydrofuran, 30 mL). To the solution was added 2-isopropyl-thiazole-5-carbaldehyde (2.33 g, 15 mmol, 1.2 eq), followed by crushed NaOH powder (1 g, 25 mmol, 2 eq). The reaction mixture was stirred at room temperature for 10 min. The solution became dark and some solids formed. The mixture was poured into ice-water under stirring.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][C@H:16]([C:28]([OH:30])=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C(OCC)(=O)C.O.C(O)(=O)C(O)=O>CCCCCC>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:28]([OH:30])=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:24])([F:25])[F:26])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Agent: O=C(O)C(=O)O
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
10 g of crude N2-[1-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine rich in 1S-isomer (the molar ratio of the 1S- to the 1R-isomer was 80:20) was suspended in 10-fold volume mixed solutions of 80 ml of ethyl acetate and 20 ml of n-hexane. 1.46 g (0.5 eq.) of oxalic acid monohydrate was added, and the reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure at a temperature lower than 40° C. The filtered cake was dissolved in 80 ml water, and 1N sodium hydroxide solution was added to adjust the pH value to 4.0 to 6.0. The solution was cooled to 0 to 5° C., and stirred for 3 hrs. After filteration, and the solid was dried in vacuum at a temperature lower than 40° C. to give 5.8 g of pure N2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N6-trifluoroacetyl-L-lysine. The yield is 58%, and the molar ratio of the 1S- to the 1R-isomer is 99.0:1.0.
Reaction SMILES: COC(SC)=C(C#N)C#N.N#CN.[C:14]([C:16](=[C:19]([NH:22][C:23]#[N:24])[S:20][CH3:21])[C:17]#[N:18])#[N:15].[ClH:25]>>[NH2:15][C:14]1[C:16]([C:17]#[N:18])=[C:19]([S:20][CH3:21])[N:22]=[C:23]([Cl:25])[N:24]=1
Reactant: CSC(NC#N)=C(C#N)C#N
Reactant: Cl
Agent: COC(SC)=C(C#N)C#N
Agent: N#CN
Product: CSc1nc(Cl)nc(N)c1C#N

Procedure:
Process for the production of 4-amino-2-chloro-5-cyano-6-(methylthio)pyrimidine of the formula: ##STR9## comprising reacting malononitrile with carbon disulfide in the presence of a strong base to obtain a dianion of dicyanodithioacetic acid of the formula: ##STR10## and then is methylating the dianion of dicyanodithioacetic acid of formula II with a methylating agent to obtain a dicyanoketene dimethyl thioacetal of the formula: ##STR11## condensing the dicyanoketene dimethyl thioacetal of formula III with cyanamide in the presence of a base to obtain an anion of 2-cyano-3-cyanamino-3-methylthio-acrylonitirile of the formula: ##STR12## and then the anion of 2-cyano-3-cyanoamino-3-methylthio-acrylonitrile of formula IV is cyclized in the presence of hydrochloric acid to obtain the 4-amino-2-chloro-5-cyano-6-(methylthio)pyrimidine.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([N:7]=[C:8]=[S:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH3:16]>C(O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:16])=[S:9]
Reactant: S=C=Nc1ccccc1-c1ccccc1
Reactant: N
Solvent: CCO
Product: NC(=S)Nc1ccccc1-c1ccccc1

Procedure:
Reaction of 2-biphenylyl isothiocyanate (9.1 g) in ethanol (25 ml) with 25% aqueous ammonia solution (50 ml) at ambient temperature for 18 hours gave N-(2-biphenylyl)thiourea (m.p. 187°-188° C.).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[N:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:5](=[N:6][CH:7]([CH3:9])[CH3:8])[NH:4][CH:1]([CH3:3])[CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)N=C=NC(C)C
Reactant: OCc1ccccc1
Product: CC(C)N=C(NC(C)C)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A neat solution of 18.6 mL (15 g, 118.8 mmol) of 1,3-diisopropylcarbodiimide and 60 mg (0.6 mmol) of cuprous chloride was placed under a blanket of argon and then cooled to 0° C. in an ice bath. To this reaction mixture was added dropwise (via syringe) 12.9 mL (13.5 g, 124.7 mmol) of benzyl alcohol. The resultant green reaction mixture was allowed to stir at 0° C. overnight, filtered through celite (rinsing with hexane) and the filtrate then Kugelrohr distilled (105° C., 2 mm Hg) to give 2-benzyl-1,3-diisopropyl isourea as a clear, colorless oil. To a solution of 650 mg (4.7 mmol) of 4-hydroxybenzoic acid in 20 mL of tetrahydrofuran was added 1.1 g (4.7 mmol) of 2-benzyl-1,3-diisopropyl isourea. The reaction mixture was allowed to stir at ambient temperature overnight, filtered (rinsing with tetrahydrofuran) and then concentrated in vacuo. Purification by flash chromatography (silica, 3 25% ethyl acetate in hexane) gave the title compound as a white solid.