Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C=Nc1ccccc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 30.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, phenyl isocyanate (0.33 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 7:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(phenylamino)carboxamide (0.23 g, 31%) as a white solid: mp 212-214° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 8.78 (s, 1H), 7.88-7.76 (m, 3H), 7.37 (d, J=7.7 Hz, 2H), 7.21 (t, J=7.7 Hz, 2H), 6.89 (t, J=7.3 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 5.20-5.13 (dd, J=5.3 and 12.5 Hz, 1H), 4.72 (d, J=5.9 Hz, 2H), 2.97-2.84 (m, 1H), 2.65-2.49 (m, 2H), 2.09-2.05 (m, 1H); 13C NMR (DMSO-d6) δ 172.72, 169.79, 167.58, 166.99, 155.22, 140.25, 134.69, 133.63, 131.59, 128.60, 127.18, 121.83, 121.18, 117.70, 48.86, 38.71, 30.92, 21.97; Anal. Calcd. For C21H18N4O5: C, 62.07; H, 4.46; N, 13.79. Found: C, 62.14; H, 4.49; N, 13.49.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][CH:15]=[N:14][N:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([CH2:30][CH:31]([C:37](=O)[CH2:38][CH2:39][CH3:40])[C:32](OCC)=[O:33])=[CH:27][CH:26]=1)#[N:18].N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:32](=[O:33])[C:31]([CH2:30][C:28]4[S:29][C:25]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[C:17]#[N:18])=[CH:26][CH:27]=4)=[C:37]([CH2:38][CH2:39][CH3:40])[N:13]4[N:14]=[CH:15][N:16]=[C:12]34)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)s1)C(=O)OCC
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A mixture of N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1.10 g), ethyl 2-{[5-(2-cyanophenyl)thiophen-2-yl]methyl}-3-oxohexanoate (3.30 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight. The mixture was allowed to cool and poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.85 g, 34%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CN1CCCC1=O>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:18]
Reactant: Oc1cnc2ccccc2c1
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccccc1Oc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
After 0.27 g of 3-hydroxyquinoline was dissolved in N-methyl-2-pyrrolidone, 0.087 g of sodium hydride (60% oil dispersion) was added under ice-cooling, and the mixture was stirred for 30 minutes. At the same temperature, 0.27 g of 2-fluorobenzonitrile was added and then the mixture was stirred for 6 hours at room temperature. After the reaction mixture was poured into ice water, extracted with ethyl acetate, and washed with saturated saline solution, the resultant was dried with magnesium sulfate. After the solvent was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography to obtain 0.37 g of 3-(2-cyanophenoxy)quinoline (Compound Number 62).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[C:18]([F:26])[CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>C(O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([NH:28][NH2:29])=[O:21])=[C:18]([F:26])[CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(Nc2nc(C)cc(Cc3ccccc3)n2)cc1F
Solvent: O
Solvent: CCO
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(C(=O)NN)c(F)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 81.8 %

Procedure:
A mixture of methyl 4-(4-benzyl-6-methyl-pyrimidin-2-ylamino)-2-fluoro-benzoate (420 mg, 1.20 mmol) and hydrazine monohydrate (1.4 mL, 28.8 mmol) in ethanol (9 mL) was stirred at 90° C. for 6 h. After cooling to 20° C., a white precipitate was formed which was isolated by filtration to afford the title compound (345 mg, 82%) as white solid. Mp 191-193° C.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](N)=[O:10])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(O)(=[O:16])C>Cl>[ClH:1].[C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:16])=[O:10])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3]
Reactant: CC(=O)O
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Agent: Cl
Product: N=C(N)c1ccc(C(=O)O)cc1
Temperature: 110 °C

Procedure:
4-Amidinobenzamide hydrochloride (10 g) was dissolved in a mixed solution of 6N HCl (300 ml) and acetic acid (50 ml) and the solution was refluxed at 110° C. for 6 hours. The reaction solution was cooled with ice and the resulting precipitate was filtered to yield a crystal of 4-amidinobenzoic acid hydrochloride (10.4 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:69][C:70]1[S:71][CH:72]=[CH:73][N:74]=1>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:69][C:70]3[S:71][CH:72]=[CH:73][N:74]=3)=[O:33])=[CH:34][CH:35]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: Nc1nccs1
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)Nc3nccs3)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2-aminothiazole (8.26 mg, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (5.8 mg, 18%).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[N:26]3[C:33](=[O:43])[N:34]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)[N:35]=[C:25]3[C:24]=2[CH:23]=1>CN(C=O)C.CCN(CC)CC.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>[CH2:1]([C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[N:26]3[C:33](=[O:43])[N:34]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)[N:35]=[C:25]3[C:24]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc3c4cc(Cc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a stirred solution of benzyltributyltin (69 mg, 0.184 mmol) and 8a (19.5 mg, 0.0525 mmol) in a mixture of 2 mL of DMF and 1 mL of NEt3, was added Pd(PPh3)4 (6.0 mg, 5.3 μmol). The seal tube was sealed under argon and the mixture was stirred at 110° C. for 18 h. The reaction the mixture was cooled and concentrated to dryness in vacuo and the crude product was purified by chromatography on a silica gel column. Elution with n-heptane/EtOAc (2:1) as eluent yielded 16a as a white solid (13 mg, 65%). mp: 299° C.,
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=[O:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[O:34](S(C(F)(F)F)(=O)=O)[S:35]([C:38]([F:41])([F:40])[F:39])(=O)=[O:36]>ClCCl.N1C=CC=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([O:21][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:36])=[O:34])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a stirred solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (8J) (200 mg, 0.43 mmol) in dichloromethane (10 mL) and pyridine (0.35 mL) was added Tf2O (0.1 mL, 0.87 mmol) at −78° C. The temperature was slowly raised to 0° C. The mixture was stirred at 0° C. for 2 hours, quenched with slowly addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to provide a brown colored solid. The obtained residue was purified by flash chromatography to provide the desired product (200 mg, 77%). LCMS-ESI+ (m/z): 602.0, 604.0 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH3:28])(=[O:3])[CH3:2].N(S([O-])(=O)=O)(S([O-])(=O)=[O:32])[O].[K+].[K+].O.P([O-])(O)(O)=O.[K+]>CN(C)C=O.CO>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:32])[C:18]=1[CH3:28])(=[O:3])[CH3:2]
Reactant: COc1cc(C)c(CCCCCCCCCCCCOC(C)=O)c(O)c1OC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCOC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 720 h
Yield: 76 %

Procedure:
To a solution (300 ml) of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylphenol (6.1 g) in dimethylformamide are added potassium nitrosodisulfonate (18 g), water (300 ml), methanol (50 ml) and potassium dihydrogen phosphate (0.5 g), and the mixture is stirred at room temperature for 30 days. The product is extracted with dichloromethane, and the organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off to give crude crystals. This product is recrystallized from hexane to give orange-yellow needles of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (4.8 g). m.p. 47° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CC(C)=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCBr

Procedure:
Potassium phthalimide (92.5 g) was added in six portions over 4 hours to a boiling solution of 1,5-dibromopentane (230 g) in acetone (670 ml). The mixture was boiled under reflux for 24 hours, then cooled and filtered. The filtrate was evaporated to dryness and the residue dissolved in petroleum ether, b.p. 60-80° C./ethyl acetate (1:1) and the solution filtered. The filtrate was evaporated to dryness and the residue washed with several portions of petroleum ether, b.p. 60-80° C. to remove excess dibromopentane. The remaining oil was dried under vacuum at 50° C. The petrol washings were evaporated to dryness and distilled under vacuum to give recovered dibromopentane and a second fraction b.p. 86-120° C. at 17 mbar. This fraction solidified on cooling and scratching. A little of this solid was used to seed the remaining oil and the combined solids were recrystallised from absolute ethanol (300 ml) to give N-(5-bromopentyl)phthalimide, m.p. 62-63° C.
Reaction SMILES: C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)C[OH:10])=CC=C([N+]([O-])=O)C=1.[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]>>[NH:21]1[CH2:28][C@H:27]([OH:10])[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
A plasmid (pHuCol(α2)Ec, FIG. 66) containing the gene for Type I (α2) collagen with optimized E. coli codon usage (FIGS. 50A-50E) (SEQ. ID. NO. 31) under control of the tac promoter and containing the gene for chloramphenicol resistance was used to transform by electroporation proline auxotrophic E. coli strain JM109 (F-). Transformation cultures were plated on LB agar containing 20 μg/ml chloramphenicol. After overnight incubation at 37° C., a single colony from a fresh transformation plate was used to inoculate 100 ml of LB media containing 20 μg/ml chloramphenicol. This culture was grown to an OD600 nm of 0.5 and 100 μl aliquots transferred to 1.5 ml tubes. The tubes were stored at −80° C. For expression, a tube was thawed on ice and used to inoculate 25 ml of LB media containing 20 μg/ml chloramphenicol. After overnight growth at 37° C., a four ml aliquot was withdrawn, centrifuged, the cell pellet washed once with 1 ml of 2×YT media containing 20 μg/ml chloramphenicol, and the washed cells used to inoculate 1 L of 2×YT medium containing 20 μg/ml chloramphenicol. This culture was grown at 37° C. to an OD600 nm of 0.8. The culture was centrifuged and the cell pellet washed once with 100 ml of M9 medium (1×M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 20 μg/ml chloramphenicol). The cells were resuspended in 910 ml of M9 medium (1×M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 20 μg/ml chloramphenicol) and allowed to grow at 37° C. for 30 minutes. NaCl (80 ml of 5 M), hydroxyproline (7.5 ml of 2M), and IPTG (500 μl of 1 M) were added and growth continued for 3 hours. Cells were harvested by centrifugation and stored at −20° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:20])C=CC=CC=1.C([N:32]([CH2:35]C)CC)C>O1CCCC1>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([N:32]=[C:35]=[O:20])[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1cccc(N=C=O)c1
Reaction time: 1 h

Procedure:
3-Dimethylaminobenzoic acid (1.65 g), diphenylphosphoryl azide (2.16 ml) and triethylamine (1.4 ml) were dissolved in tetrahydrofuran (20 ml), and the reaction mixture was kept at 60° C. for 1 hour to give 3-dimethylaminophenyl isocyanate. The reaction mixture was cooled to 0° C. Triethylamine (4.2 ml) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.42 g) were added, and the mixture was stirred for 2 hours. The reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated. The obtained residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol (10:1) as an eluent and by silica gel column chromatography using a mixed solvent of chloroform and methanol (50:1) as an eluent, and crystallized from ethyl acetate to give 140 mg of N-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-yl)methyl)-N'-(3-dimethylaminophenyl)urea.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.F[C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[NH:22][C:21]2=[O:28])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:26][C:23]1([CH3:27])[NH:22][C:21](=[O:28])[N:20]([C:17]2[CH:18]=[N:19][C:14]([O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)=[CH:15][CH:16]=2)[C:24]1=[O:25]
Reactant: CC1(C)NC(=O)N(c2ccc(F)nc2)C1=O
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc(OC(F)(F)F)c3)nc2)C1=O
Temperature: 120 °C
Reaction time: 22 h
Yield: 53.9 %

Procedure:
3-[(trifluoromethyl)oxy]phenol (19.95 mg, 0.112 mmol) was dissolved in 1 mL of dimethylformamide. 3-(6-fluoro-3-pyridinyl)-5,5-dimethyl-2,4-imidazolidinedione (Intermediate 106, 25 mg) and potassium carbonate (31.0 mg, 0.224 mmol) were added. The reaction mixture was stirred at 120° C. during 22 hours. Some diethylether (4 mL) and water (4 mL) were added. The aqueous layer was extracted 4 times with diethylether. The gathered organic layers were dried over sodium sulphate and evaporated giving a residue, which was purified by mass directed purification (METHOD I). After evaporation of the fraction, addition of a solution of saturated NaHCO3 (3 mL) and extraction with dichloromethane (four times 4 mL), evaporation afforded the title compound as a white solid (23 mg).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>N1C=CC=CC=1.C(OCC)(=O)C.CO>[Cl:35][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14]
Reactant: Cc1cn(COCCO)c(=O)[nH]c1=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cn(COCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
150 mg (0.75 mmol) 1-[(2-hydroxyethoxy)methyl]-5-methyl-2,4(1H,3H)-pyrimidinedione were dissolved in 10 ml pyridine and 1 g PS-triphenylphosphine resin (3 mmol/g) and 147 μl carbontetrachloride were added. The reaction was stirred at room temperature for 3 days. The reaction mixture was diluted with a mixture of ethyl acetate and methanol and centrifuged. The supernatant was decanted and the solvent was evaporated under reduced pressure. The residue, dissolved in ethyl acetate and a small amount of methanol, was purified by flash chromatography on silica gel (ethyl acetate). The fractions containing the product were pooled and the volume was reduced to about 3 ml. Upon addition of hexane the product crystallized to give 97 mg of white crystals. MS (ISP): 217.1 (M−H+). 1H-NMR (DMSO-d6): 1.77 (d, 3H), 3.69–3.77 (m, 4H), 5.10 (s, 2H), 7.59 (d, 1H), 11,32 (s, br, 1H).
Reaction SMILES: [C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH:2]=1.[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12](O)[CH:13]=1.CCOC(/N=N/C(OCC)=O)=O>>[CH:1]1([O:6][C:10]2[CH:9]=[C:8]([F:7])[CH:13]=[CH:12][C:11]=2[N+:15]([O-:17])=[O:16])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OC1=CCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Product: O=[N+]([O-])c1ccc(F)cc1OC1CC=CC1

Procedure:
Prepared analogously to XVI.1 from 1 g cyclopentenol, 1.57 g 5-fluoro-2-nitro-phenol and 1.89 ml DEAD.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]([CH3:20])=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:26]O.O>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:11]2[C:19]([CH3:20])=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)=[O:26])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1c(Sc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c(O)c1C(=O)O
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(S(=O)c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c(O)c1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 5-(4-nitrophenylthio)-3-t-butyl-6-methylsalicylic acid (2.0 g.) in acetic acid (200 ml.) is mixed with 30% w/v aqueous hydrogen peroxide solution (11 ml.). The mixture is stirred at room temperature for 6 hours and then added to water (700 ml.). The precipitated solid thus formed is separated by filtration and crystallised from acetic acid to give 5-(4-nitrophenylsulphinyl)-3-t-butyl-6-methylsalicylic acid, m.p. 201°-202° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH3:21])=[O:13])(OCC)=O)C.[CH3:22][C:23]1[C:24]2[N:25]([N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[CH:32]=O)[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:22][C:23]1[C:24]2[N:25]([N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[CH:32]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH3:21])=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccn2nc(-c3ccccc3)c(C=O)c12
Reactant: CCOP(=O)(CC(=O)N1CCCCC1CC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2cccc(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Sodium hydride (60%, 110mg) was added to a solution of 1-(2-diethoxyphosphorylacetyl)-2-ethylpiperidine (0.80 g) in tetrahydrofuran (5 ml) at 7° C. under nitrogen atmosphere. A solution of 4-methyl-2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.50 g) in tetrahydrofuran (5 ml) was added dropwise to the above solution at 10° C., and then stirred at room temperature for 1 hour. After evaporating the solvent, in vacuo saturated sodium chloride aqueous solution (20 ml) was added to the residue and extracted with ethyl acetate (20 ml×2). Combined extracts were washed with saturated sodium chloride aqueous solution (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(4-methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine (trans isomer) (788 mg) as an oil.