Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[NH:8][C:7]2[CH:9]=[CH:10][N:11]=[CH:12][C:6]=2[S:5](=[O:14])(=[O:13])[N:4]=1>C(N)(C)C>[CH:7]([NH:8][C:3]1[NH:8][C:7]2[CH:9]=[CH:10][N:11]=[CH:12][C:6]=2[S:5](=[O:14])(=[O:13])[N:4]=1)([CH3:9])[CH3:6]
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Solvent: CC(C)N
Product: CC(C)NC1=NS(=O)(=O)c2cnccc2N1

Procedure:
A solution of 0.7 g of 3-methylthio-4H-pyrido[4,3-e][1,2,4]thiadiazine 1,1-dioxide obtained in Example 39 in 7 cm3 of isopropylamine is maintained in a sealed tube at 150° C. for 4 hours. After cooling, the solution is concentrated to dryness, the residue is taken up in 10 cm3 of water and the pH is adjusted to the value of 7. The precipitate obtained is collected on a filter, washed with water and recrystallized from hot water.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20].[OH:22][C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.CN(C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([OH:22])[CH:24]=3)[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: COC(=O)c1cc(-c2cc(Cl)nc(N)n2)c(C)cc1OC
Reactant: Oc1cccc(S)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cc(Sc3cccc(O)c3)nc(N)n2)c(C)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.5 %

Procedure:
5-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (154 mg, 0.5 mmol) obtained in Example 1-2 and 3-hydroxybenzenethiol (0.25 ml, 2.5 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (1.0 ml) and triethylamine (0.35 ml, 2.5 mmol) were added thereto. The solution was stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with water (50 ml), twice with a saturated aqueous sodium bicarbonate solution (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate) to yield 5-[2-amino-6-(3-hydroxyphenylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (170 mg) as a yellow solid material.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58]([C:60]1[O:61][C:62]2[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][C:63]=2[CH:64]=1)=[O:59]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:69][C:66]2[CH:67]=[CH:68][C:62]3[O:61][C:60]([C:58]([O:57][CH3:56])=[O:59])=[CH:64][C:63]=3[CH:65]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2o1
Reaction time: 0.33 h

Procedure:
A solution of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.9 mg, 0.130 mmol) in dichloromethane (3 ml) was reacted with DIPEA (66.8 mg, 0.517 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (75.8 mg, 0.320 mmol) and stirred for 20 min under argon. 5-AMINO-BENZOFURAN-2-CARBOXYLIC ACID METHYL ESTER (26.0 mg, 0.136 mmol, Biofine,) was added and stirred 2.5 hrs. The reaction mixture was diluted with dichloromethane and washed with water, sat. NaHCO3 and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral-methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate (46.2 mg., 55.4%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 640.15. found: 640.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[N:33]=[C:34]1[S:38]S[N:36]=[C:35]1Cl)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:27])([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH2:28][CH3:29])=[O:6].C(OCC)(=O)C>N1C=CC=CC=1.[Cu]I>[C:35]([C:34]1[S:38][C:2]2[CH:3]=[C:4]([C:5]([NH:7][C:8]3[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:27])([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=3[CH2:28][CH3:29])=[O:6])[CH:30]=[CH:31][C:32]=2[N:33]=1)#[N:36]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N=c2ssnc2Cl)c(Br)c1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2nc(C#N)sc2c1
Yield: 49.6 %

Procedure:
3-bromo-4-{[4-chloro-5H-1,2,3-dithiazol-5-ylidene]amino}-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]benzamide (0.195 g) and copper(I) iodide (0.057 g) were suspended in pyridine (5 ml), and irradiated(150° C., 20 minutes). After cooling, to the reaction mixture was added ethyl acetate. The mixture was washed with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain 2-cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]-1,3-benzothiazole-6-carboxamide (0.076 g, 49%).
Reaction SMILES: [C:1]([C:3]1[CH2:7][CH2:6][CH2:5][C:4]=1[NH:8][C:9]([NH:11]C(=O)C1C=CC=CC=1)=[O:10])#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[CH2:7][CH2:6][CH2:5][C:4]=2[NH:8][C:9](=[O:10])[N:11]=1
Reactant: N#CC1=C(NC(=O)NC(=O)c2ccccc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(=O)[nH]c2c1CCC2
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A solution of N-(2-cyanocyclopent-1-enylcarbamoyl)benzamide (example 75a) (500 mg, 1.96 mmol) and NaOH (2 N, 2.7 mL) in EtOH (20 mL) was stirred at 100° C. under nitrogen for 2 hours. After cooling to room temperature, the clear reaction solution was filtered and the filtrate was carefully neutralized with 10% AcOH with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, washed with warm water and then 20% EtOH in water to give the final product 4-amino-6,7-dihydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (200 mg, 68%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (brs, 1H), 6.93 (brs, 1H), 6.65 (brs, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.43 (t, J=7.6 Hz, 2H) 1.96-1.89 (m, 2H). MS 152 (MH+).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[O-2:4].[Mn+2:5]>O>[C:1]([O-:4])(=[O:3])[CH3:2].[Mn+2:5].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: [O-2]
Reactant: CCO
Agent: [Mn+2]
Solvent: O
Product: CC(=O)[O-]
Reaction time: 0.08 h

Procedure:
A mixed solution of 1 mole of manganese acetate, ethanol, and water was prepared. This mixed solution and Ketjen Black (KB) were introduced into a rotary reactor, the inner tube was rotated at a centrifugal force of 66,000 N (kgms−2) for 5 minutes to form a thin film of the reactant on the inner wall of the outer tube, and sheer stress and centrifugal force were applied to the reactant to allow promotion of chemical reaction, yielding KB supporting highly dispersed manganese oxide precursor.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([O:12]COC)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]1[CH:21]=[C:20]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[CH:25]=[C:24]([CH2:36][OH:37])[C:23]=2[CH2:38][OH:39])[CH:19]=[CH:18][N:17]=1.Cl>O1CCOCC1.CO>[O:1]=[C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]1[CH:21]=[C:20]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[CH:25]=[C:24]([CH2:36][OH:37])[C:23]=2[CH2:38][OH:39])[CH:19]=[CH:18][N:17]=1
Reactant: COCOc1cc(=O)n(-c2cc(-c3c(CO)c(CO)cc4cc(OC)c(OC)cc34)ccn2)c2ccccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cc(O)c5ccccc54)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
1-[2-(2-Oxo-4-methoxymethoxy-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (1.39 g) is dissolved in a mixture of dioxane (10 ml) and methanol (5 ml), and thereto is added 2M hydrochloric acid (2 ml). The mixture is warmed to 50° C., and stirred for 7 hours, and then concentrated under reduced pressure to remove the solvent. To the residue are added chloroform and water, and the chloroform layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1) to give 1-[2-(2-oxo-4-hydroxy-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.79 g) which is listed in Table 7.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:13]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:1][C:2]=12)#[N:8]
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A mixture of 6.0 g of 3-aminopyrazole-4-carbonitrile, 13.0 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide and 100 ml of glacial acetic acid was heated at reflux for 4 hours. On standing at room temperature a precipitate formed. The precipitate was isolated, washed with hexane, then ether and dried. The solid was recrystallized from acetonitrile-N,N-dimethylformamide and gave the product of the example, mp 252°-254° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][NH:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: NCCCO
Reactant: COc1ccc(Br)c(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc(Br)c(CNCCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromo-5-methoxybenzaldehyde (1 eq) in dichloroethane was added 3-aminopropanol (1.5 eq) followed by NaBH(OAc)3 (2 eq) and acetic acid (4 eq) and the resulting mixture was stirred at RT under nitrogen for 8 h. The reaction mixture was quenched by careful addition of 2M Na2CO3 solution and stirred 1 h. The mixture was concentrated in vacuo and poured into diethyl ether. The phases were separated and the organic phase washed with 1N HCl solution. The aqueous phase was then washed with diethyl ether and subsequently basified with 1N NaOH solution. The aqueous phase was extracted with diethyl ether, dried over Na2SO4 and concentrated in vacuo to give 3-(((2-bromo-5-methoxyphenyl)methyl) amino)propan-1-ol as a clear oil. EI-MS m/z 274, 276 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](=[CH2:24])[C:20]([F:23])([F:22])[F:21])=[N:14][N:13]=[CH:12]3)=[CH:4][CH:3]=1.[H][H]>C1COCC1.CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([CH:19]([CH3:24])[C:20]([F:22])([F:21])[F:23])=[N:14][N:13]=[CH:12]3)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C=C(c1nncc2cc(Nc3ccc(F)cc3)ccc12)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(c1nncc2cc(Nc3ccc(F)cc3)ccc12)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution of N-(4-fluorophenyl)-1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-amine (0.067 g, 0.20 mmol) in 4 mL of THF/EtOH (3/1) was treated with palladium (10% wt. on activated carbon, 0.021 g, 0.020 mmol); and stirred at RT with a balloon of hydrogen. After 3 h, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give the crude product. The material was purified on an ISCO column (12 g, 50-75% EtOAc in hexanes) to afford the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: M+1=366.0.
Reaction SMILES: [NH2:1][C:2](=[N:32][OH:33])[C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C>[NH2:1][C:2](=[N:32][O:33][C:34](=[O:36])[CH3:35])[C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[O:26])=[CH:28][CH:29]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Solvent: CC(=O)O
Product: CC(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
To an acetic acid (15 mL) suspension of 1.00 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=oxime was added 0.48 mL of acetic anhydride at room temperature, which was then stirred at the same temperature for one hour. The solvent was distilled off under reduced pressure, and the resultant residue was subsequently added to a mixture of water and chloroform, which was then adjusted to pH 7.5 using a saturated sodium bicarbonate aqueous solution. The precipitate was collected by filtration and washed with water and chloroform to provide 1.07 g of 4-{3-[4-(3-{4-[amino(acetyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-acetyloxime as white solid form.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CC(C)([O-])C.[K+].[C:18]([O:22][C:23]([N:25]1[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28]OS1(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl>CN(C=O)C>[C:18]([O:22][C:23]([NH:25][C:30]([CH3:31])([CH3:32])[CH2:29][CH2:28][N:8]1[C:9]2[C:5](=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CSc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc2c(ccn2CCC(C)(C)NC(=O)OC(C)(C)C)c1

Procedure:
Under a nitrogen atmosphere 500 mg (2.6 mmol) 5-(methylsulphanyl)-indole (Yang et al., Heterocycles, 1992, vol. 34, No. 6, page 1169-1175) are dissolved in 6 ml DMF and combined with 357 mg (3.2 mmol) potassium-tert-butoxide with stirring and cooling with ice. Then the mixture is stirred for 10 minutes at 0° C. 768 mg (2.9 mmol) N-tert-butoxycarbonyl-4,4-dimethyl-[1,2,3]oxathiazinane-2,2-dioxide (Component XI) are added. The mixture is then stirred for three hours at ambient temperature. Then the reaction solution is poured onto water and hydrochloric acid (1.2 mmol) and extracted with ethyl acetate. The organic phases are combined, dried on sodium sulphate and freed from the solvent in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15](Cl)=[O:16])=[CH:9][CH:8]=1.[NH3:21]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([NH2:21])=[O:16])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C=Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: N
Solvent: ClCCl
Product: NC(=O)C=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 19 %

Procedure:
500 mg (1.72 mmol) of the crude 3-[4-(3-fluoro-benzyloxy)-phenyl]-acryloyl chloride as prepared in Example 8c) is dissolved in 2 ml dichloromethane and 4 ml of concentrated ammonia is added. The mixture is hold at reflux temperature for about 4 hours, cooled and filtered. The solid is subjected to column chromatography (silica gel, dichloromethane/methanol/ammonia 140:10:1) to give 89 mg (19%) of a colorless solid. MS: m/e=272.2 (M++H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][NH2:8])[CH2:3][NH2:4].[C:9]([O:18][CH2:19][CH3:20])(=[O:17])/[CH:10]=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][NH:8][CH:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]([O:18][CH2:19][CH3:20])=[O:17])[CH2:3][NH:4][CH:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(CN)CCCN
Reactant: CCOC(=O)/C=C\C(=O)OCC
Product: CCOC(=O)CC(NCCCC(C)CNC(CC(=O)OCC)C(=O)OCC)C(=O)OCC

Procedure:
1 mol of 2-methyl-1,5-diaminopentane was slowly added dropwise, under a nitrogen atmosphere, to 2 mol of diethyl maleate, in such a manner that the reaction temperature did not exceed 60° C. Heating was then carried out at 60° C. until no further diethyl maleate could be detected in the reaction mixture. The product was obtained quantitatively in the form of a yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([CH2:31][O:32][CH2:33][O:34][CH3:35])([CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:43](Br)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([CH2:31][O:32][CH2:33][O:34][CH3:35])([CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCBr
Reactant: COCOCC(CCOC1CCCCO1)(CCc1ccc(O)c(C(F)(F)F)c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1ccc(CCC(CCOC2CCCCO2)(COCOC)NC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 21-6 (1.24 g) was dissolved in N,N-dimethylformamide (20 ml), potassium carbonate (986 mg) and n-heptyl bromide (0.458 ml) were added, and the mixture was stirred at 80° C. for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (1.49 g) as a pale-yellow oil.
Reaction SMILES: C1N(CCS(O)(=O)=O)CC[O:3]C1.[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16].O=C(CCC([O-])=O)C([O-])=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:3][C@H:19]1[CH2:20][NH:13][C@H:14]([C:15]([OH:17])=[O:16])[CH2:18]1
Reactant: O=S(=O)(O)CCN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])CCC(=O)C(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 0.5 h

Procedure:
The enzyme reaction with purified L-proline-4-hydroxylase obtained in Example 5 was carried out. The reaction mixture was composed of 200 mM MES buffer (pH 6.5), 20 mM L-proline, 20 mM 2-ketoglutarate, 5 mM L-ascorbic acid, 2 mM ferrous sulfates and 90 U of purified enzyme preparation in total volume of 50 μl. The reaction was carried out at 35° C. for 30 min. As a result of the reaction, 12.9 mM (1.7 g/l) of trans-4-hydroxy-L-proline was produced in the reaction mixture.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[N:6]2[CH3:12].[NH3:20]>>[F:19][C:15]1[CH:14]=[C:13]([C:5]2[N:6]([CH3:12])[C:7]3[C:3]([N:4]=2)=[C:2]([NH2:20])[N:10]=[C:9]([I:11])[N:8]=3)[CH:18]=[CH:17][CH:16]=1
Reactant: N
Reactant: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(I)nc21
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(I)nc21

Procedure:
6-Chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine (200 mg) was reacted with an ammonia-saturated methanol at 70° C. for 30 minutes in a sealed tube. The reaction mixture was evaporated and then filtered to give 138 mg of 8-(3-fluorophenyl)-2-iodo-9-methyl-9H-6-purinamine.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][N:31]([C:38]([CH:35]2[CH2:37][CH2:36]2)=[O:39])[CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester, hydrochloride and cyclopropanecarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11](OS(C)(=O)=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:38]([OH:41])[CH2:39][CH3:40]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:41][CH2:38][CH2:39][CH3:40])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCCO
Reactant: C#CCOc1ccc(CCN(OS(C)(=O)=O)C(=O)Cc2ccc(Cl)cc2)cc1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCOc1ccc(CCNC(=O)C(OCCC)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-(4-chloro-phenyl)-N-mesyloxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (452 mg, 1 mmol) in a mixture of 6 ml acetonitrile and 6 ml n-propanol during a period of 12 hours a solution of triethylamine (0.146 ml, 1.05 mmol) in 12 ml of acetonitrile is added dropwise. The mixture is stirred for 20 hours at room temperature. The solvent and excess n-propanol is removed under reduced pressure and the residue was diluted with ethyl acetate (30 ml), washed with water, 1N HCl, and brine, and dried with Na2SO4. After evaporation of the solvent the product is purified by flash chromatography (ethyl acetate:hexane, 1:2) to yield 2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-propoxy-acetamide in form of an oil. 1H-NMR (300 MHz, CDCl3): 0.89(t, 3H, CH3), 1.58(q, 2H, CH2), 2.50(t, 1H, C≡CH), 2.79(t, 2H, CH2CH2), 3.35(t, 2H, OCH2), 3.52(dt, 2H, CH2CH2), 3.83(s, 3H, OCH3), 4.63(s, 1H, CHOH), 4.74(d, 2H, OCH2), 6.67-7.30(m, 8H, CH arom., NH).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[N:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=O.CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:12][O:11][C:10]1[C:5]([CH2:3][OH:2])=[N:6][CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1
Reactant: COC(=O)c1ncc(-c2ccccc2)nc1OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1nc(-c2ccccc2)cnc1CO
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
To a solution of 3-methoxy-5-phenyl-pyrazine-2-carboxylic acid methyl ester (150 mg, 0.58 mmol) in THF (20 mL) is added DIBAL-H (1 M in DCM, 1 mL, 1 mmol) dropwise at 0° C. under N2. The mixture is stirred at this temperature for 0.5 hour. Another portion of DIBAL-H (1 M in DCM, 0.8 mL, 0.8 mmol) is added. After 0.5 hour, the reaction is quenched with saturated NH4Cl (1 mL), and then NaOH (1.5 M, 2 mL). The mixture is extracted with EtOAc (3×20 mL). The combined organic layers are dried and the solvent removed. The crude product is purified by PTLC (silica gel; 10% MeOH in DCM) to give 60 mg of (3-methoxy-5-phenyl-pyrazin-2-yl)-methanol as an oil.