Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[N:6]2[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9][C@H:5]2[CH2:4][O:3]1.Cl.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CO>[Si:20]([O:3][CH2:4][C@H:5]1[NH:6][C:7](=[O:12])[C:8]([CH3:10])([CH3:11])[CH2:9]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC1(C)C[C@H]2COC(C)(C)N2C1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CO
Product: CC1(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of (S)-3,3,6,6-tetramethyl-dihydropyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one in methanol (20 mL) was added HCl (4 N in 1,4-dioxane, 10 mL, 40 mmol). The reaction mixture was stirred at RT for 30 min, concentrated to dryness, and re-dissolved in DCM (50 mL). To the resulting solution were added imidazole (1.5 g, 22 mmol) and TBS-Cl (2.8 g, 18.6 mmol) respectively. The mixture was stirred at RT overnight and filtered. The filtrate was concentrated and the residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-5-((tert-butyldimethylsilyloxy)methyl)-3,3-dimethylpyrrolidin-2-one (3.1 g, 71.2%). LRMS (M+H+) m/z 258.3.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.C(OCC)C.[C:13]([O:17][C:18]([NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[C:27]([OH:29])=[O:28])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=CC=CC=1>CO>[CH3:1][O:28][C:27]([C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]1[NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])=[O:29]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)O
Solvent: CO
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether (5.0 mL, 10.0 mmol) was added over 10 min to a solution of (1S,2R)-2-tert-butoxycarbonylamino-1-cyclohexanecarboxylic acid (0.994 g, 4.09 mmol; purchased from NeoMPS) in a 1:1 mixture of benzene and methanol (50 mL) at 25° C. The resulting mixture was stirred at 25° C. for 30 min, and then was partitioned between half-saturated sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo to afford the desired product, (1S,2R)-2-tert-butoxycarbonylamino-1-cyclohexanecarboxylic acid methyl ester (1.00 g, 3.89 mmol, 95%), as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.44 (9H, s), 1.58-1.68 (3H, m), 1.72-1.81 (2H, m), 1.98-2.05 (2H, m), 2.77-2.80 (1H, m), 3.69 (3H, s), 3.82-3.90 (1H, m), 5.29-5.31 (1H, m). LC-MS (ESI) calcd for C13H23NO4 257.16, found 258.2 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)#[CH:2].Br[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=1.CCOC(C)=O.CCCCCC>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:21][C:20]([F:23])([F:22])[C:19]1[C:14]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1cccnc1Br
Reactant: C#Cc1ccc2ccccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccnc1C#Cc1ccc2ccccc2n1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To the solution in which 2-ethynylquinoline (50 mg, 0.33 mmol) was dissolved in triethylamine (0.4 mL), PdCl2(PPh3)2 (12 mg, 0.02 mmol), CuI (6 mg, 0.03 mmol), and 2-bromo-3-trifluoromethylpyridine (110 mg, 0.5 mmol) were added, followed by stirring at 85° C. for 3 hr. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:1). The reactant was cooled down to room temperature and filtered through Celite. The thus obtained filtrate was extracted with EtOAc (3×10 mL), to thereby obtain an organic layer. The organic layer was washed with a saturated aqueous solution of NaCl. The organic layer was then dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by column chromatography (EtOAc/hexane=1:1), to thereby obtain 2-((3-(trifluoromethyl)pyridine-2-yl)ethynyl)quinoline (48 mg, 49%) as a brown solid.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](=O)[CH:12]([CH3:14])[CH3:13]>>[CH:12]([CH:14]1[NH:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:10]1)([CH3:13])[CH3:11]
Reactant: NCC(O)c1ccccc1
Reactant: CC(C)C=O
Product: CC(C)C1NCC(c2ccccc2)O1

Procedure:
2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2isopropyl-5-phenyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2-hydroxyethylamine. The ethanolamine was reacted with SOCl2 followed by 2-chloro-4-(trifluoromethyl)phenyl isothiocyanate according to Method C2f to afford 2-(2-chloro-4-(trifluoromethyl)phenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:14][C:5]1[C:6]([C:10]([F:13])([F:12])[F:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CBr)c1OC(F)F
Yield: 115.2 %

Procedure:
To a solution of 11.5 g (50.0 mmol) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole in 50 ml of carbon tetrachloride were added 9.8 g (55.0 mmol) of N-bromosuccinimide and 0.41 (2.5 mmol) of α,α′-azobisisobutyronitrile, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light for 1 hour. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 17.8 g (purity: 72.0%, yield: 82.7%) of 4-bromomethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](NCCCCCC(NN)=O)=[O:11])[C@H:3]2[NH:22][C:23]([NH:25][C@@H:2]12)=[O:24].C(Cl)CCl.C1N(CCS(O)(=O)=O)CC[O:32]C1>CS(C)=O>[OH:32][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:25][C:23]([NH:22]2)=[O:24])[CH2:1][S:5]1)=[O:11]
Reactant: NNC(=O)CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=S(=O)(O)CCN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 20 h

Procedure:
Natural GAGs (NAH, HS, HA, HEP, Ch, CS-A(S), CS-A(W), CS-B, CS-C, CS-D, CS-E, and KS) were dissolved in 0.1 M MES buffer (pH 5.5) to prepare 10 mg/ml GAG solutions. 25 μl of 20 mM biotin-LC-hydrazide (manufactured by Pierce Biotechnology) dissolved in dimethylsulfoxide (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 1 ml of each GAG solution. Subsequently, 12.5 μl of a 100 mg/ml EDC (manufactured by Pierce Biotechnology) solution prepared with 0.1 M MES buffer (pH 5.5) was added thereto. The mixture was mixed well, and then allowed to react with stirring at normal temperature (15° C. to 25° C.) for 16 to 24 hours. After completion of the reaction, the reaction products were dialyzed by using a dialysis membrane (cutoff molecular weight: 10,000 or less) against phosphate buffered saline (pH 7.2 to 7.5, containing no divalent ions such as calcium ion: hereinafter, referred to as “PBS(−)”) as dialysis solution, to thereby sufficiently remove free biotin. After completion of dialysis, the concentration of Bi-GAG was adjusted to 5 mg/ml, followed by freeze preservation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4)cc3)cc2C1=O

Procedure:
The compound of example 15 was prepared analogous to compound of example 7 by reaction of compound of example 6 with phenyl isocyanate. The compound of example 15 was used directly without isolation for the preparation of compound of example 16.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:11]([C:12]2[CH:17]=[N:16][CH:15]=[N:14][CH:13]=2)[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(Nc2cncnc2)cc1
Reactant: BrCc1ccc(Br)cc1
Product: CS(=O)(=O)c1ccc(N(Cc2ccc(Br)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-methylsulfonylphenyl)amino]pyrimidine and 4-bromobenzyl bromide
Reaction SMILES: [N:1]([C@H:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH3:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][C@H:4]([NH2:1])[CH3:21])[CH3:20]
Reactant: CCOC1=C2C=c3c(cnn3C[C@@H](C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: CCOC1=C2C=c3c(cnn3C[C@@H](C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.3 %

Procedure:
1.76 g (6.21 mmol) of (R)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 100 ml of anhydrous ethanol were hydrogenated on 180 mg of platinum oxide for 17 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 100 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 721 mg (6.21 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 2.0 g (86%) of (R)-2-(7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 161° were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].[CH3:30][NH:31][CH:32]([CH3:34])[CH3:33]>CC(N(C)C)=O.C(OCC)(=O)C>[CH:32]([N:31]([CH3:30])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1)([CH3:34])[CH3:33]
Reactant: CNC(C)C
Reactant: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(OCCCl)cc3c2=O)c1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(OCCN(C)C(C)C)cc3c2=O)c1
Temperature: 150 °C
Yield: 63.3 %

Procedure:
3-[7-(2-Chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide (150 mg), potassium iodide (129 mg) and methylisopropylamine (244 μL, 2.34 mmol) were stirred in DMA (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 10% methanol/ethyl acetate and aqueous ammonia solution gave 3-[7-[2-(Isopropylmethylamino)ethoxy]-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide as a foam (104 mg); NMR Spectrum: (DMSO d6) 0.97 (d, 6H), 1.12 (t, 3H), 2.11 (s, 3H), 2.23 (s, 3H), 2.75 (t, 2H), 2.83 (m, 1H), 3.29 (m, 2H), 4.13 (m, 2H), 6.73 (d, 1H), 7.23 (d, 1H), 7.41 (m, 1H), 7.51 (d, 1H), 7.67 (d, 1H), 7.72 (d, 1H), 7.78 (d, 1H), 7.89 (m, 1H), 8.51 (t, 1H); Mass Spectrum: M+H+ 422.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-:24].[Na+].[C:26](#[N:28])[CH3:27]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([NH:28][C:26](=[O:24])[CH3:27])([CH3:16])[CH3:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: CC(C)(O)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: CC#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC(C)(C)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Temperature: 85 °C

Procedure:
To a solution of 2-(5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-propan-2-ol (Example 2.80; step1) (1 eq, 0.135 mmol, 50 mg) in acetonitrile (2 ml) is added tetrafluoroboric acid diethyl ether complex (3.5 eq, 0.473 mmol, 0.06 ml) and the reaction mixture is heated at 85° C. overnight. The pH of the reaction mixture is adjusted to 8-9 by addition of sodium hydroxide (2M). The solution is dissolved in DCM and washed with water. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound; [M+H]+ 411/413
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:34][C:35]1([F:40])[CH2:39][CH2:38][N:37]([C:12]2[N:11]=[C:10]([F:22])[C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:29]2[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:7][CH:6]=4)[CH2:36]1
Reactant: FC1(F)CCNC1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Agent: Cl
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(N2CCC(F)(F)C2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method CC4 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared by steps analogous to those described in Method BB33), 2-fluoropyridin-3-ylboronic acid and 3,3-difluoropyrrolidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:14]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:16]4[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=4[C:13]#[N:14])[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: N#Cc1ccc(F)cc1N1CCNCC1
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 63.5 %

Procedure:
Following the general procedure of Example 39, Step 2, and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.298 g), 1-(2-cyano-5-fluorophenyl)piperazine (0.309 g), and THF (2 mL) are converted to product, which is then chromatographed on silica gel using methanol/dichlormethane (2/98 to 4/96). Crystallization from dichloromethane/hexane, gives 0.348 g of material, which is recrystallized from ethyl acetate/dichloromethane to give 0.201 g of the title compound; mp 149-150° C.; MS m/z 369, 371; IR (mineral oil) 1625, 1260, 2221, 1514, 1332 cm-1 ; 1H NMR (CDCl3) δ2.69, 3.37, 3.76, 3.53, 6.61, 7.13, 7.39, 7.52, 7.53, 8.14.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li][C:17]([CH3:20])([CH3:19])[CH3:18].CCCCC.C(Br)C(=C)C>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH2:19][C:17]([CH3:20])=[CH2:18])([CH3:7])([CH3:6])[CH3:5]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1
Agent: C=C(C)CBr
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C(C)Cc1cc(F)ccc1NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A solution of N-Boc-4-fluoroaniline (9.02 g, 42.7 mmol) in THF (112 mL) was cooled to −60° C. using a cryocool instrument. The solution was treated with 1.7 M t-BuLi in pentane (63 mL, 106.7 mmol) dropwise. After the first equivalent of base was consumed, a yellow solution formed. The reaction was allowed to warm to −20° C. and was stirred at that temperature for 2.5 hours. The reaction was then treated with a solution of methallyl bromide (5.67 g, 42.7 mmol) in THF (35 mL) dropwise and stirred for an additional 1.5 hours at −20° C. The reaction was then quenched by addition of water. After coming to room temperature, the reaction was treated with ethyl acetate and extracted with water and brine, dried over MgSO4 and filtered. The solvent was then removed and the residue was purified on silica gel using a gradient of 0-25% ethyl acetate in hexane to afford 11.3 g (80% yield) of [4-Fluoro-2-(2-methyl-allyl)-phenyl]-carbamic acid tert-butyl ester as a white solid; 1H NMR (CDCl3, 400 MHz) δ 1.50 (s, 9H), 1.72 (s, 3H), 3.28 (s, 2H), 4.71 (s, 1H), 4.92 (s, 1H), 6.32-6.50 (m, 1H), 6.86 (dd, 1H, J=3.0, J2=9.1), 6.93 (ddd, 1H, J=3.0, J2=8.5, J3=11.5), 7.65-7.82 (m, 1H); HPLC-MS calcd. for C15H20FNO2 (M+H+-tBu) 210.1, found 210.3.
Reaction SMILES: Cl.[CH2:2]([NH2:5])[CH2:3][CH3:4].[O:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[C:10]=2[O:9][CH:8]=[CH:7]1.C(Cl)CCl>CN(C)C=O>[CH2:2]([NH:5][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]1[C:10]2[O:9][CH:8]=[CH:7][O:6][C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH2:3][CH3:4]
Reactant: CCCN
Reactant: O=C(O)CCCc1cccc2c1OC=CO2
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCNC(=O)CCCc1cccc2c1OC=CO2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A suspension of 0.29 g (2.6 mmol) of n-propylamine hydrochloride in 7 ml of anhydrous N,N-dimethylformamide is cooled to 0° C. and then 0.33 g (3.54 mmol) of N,N-dimethylaminopyridine are added to the mixture. After the addition of 0.41 g (2.36 mmol) of the acid obtained in Step F of Example 40, 0.5 g (2.6 mmol) of EDC is added to the mixture. The solution is stirred for 12 hours under argon at room temperature and then the solvent is evaporated off in vacuo. The residue is taken up in a water/ethyl acetate (1/1) mixture and then the aqueous phase is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. Chromatography over silica gel (eluant:AcOEt/PE:70/30) yields the title amide in the form of a clear syrup.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:9][O:10][S:11]([O:14]C)(=[O:13])=[O:12]>>[CH3:9][O:8][C:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]=1.[CH3:9][O:10][S:11]([O-:14])(=[O:13])=[O:12]
Reactant: O=C1CCOCCN1
Reactant: COS(=O)(=O)OC
Product: COC1=NCCOCC1
Product: COS(=O)(=O)[O-]
Reaction time: 19 h

Procedure:
3.50 g (30.4 mmol) 4-oxacaprolactam are heated to 55° C. in 3.90 ml (41.1 mmol) dimethylsulphate with stirring for 19 h. Then the mixture is evaporated down i. vac., and the residue is taken up twice in toluene and dichloromethane and completely concentrated by evaporation. The residue is further reacted directly.
Reaction SMILES: [OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>C(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1)=[O:5]
Reactant: O=C(O)CC(O)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CC(O)Cc1ccc(-c2ccccc2)cc1)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of 7.7 g of 3-hydroxy-4-(4-biphenylyl)butyric acid in 40 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophtalide in 20 ml of chloroform. The solution thus obtained is stirred for 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to yield the phthalidyl 3-hydroxy-4-(4-biphenylyl)butyrate; yield 71%.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N)CN.C(O)(=[O:13])CC.[C:15]([O-:19])(=[O:18])[CH2:16][OH:17].O=O>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:16]([OH:13])(=[O:17])[C:15]([OH:19])=[O:18]
Reactant: O=C(O)CO
Reactant: O=C([O-])CO
Reactant: CCC(=O)O
Agent: O=O
Solvent: NCCN
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A 300-mL EZE-Seal stirred autoclave (Autoclave Engineers) was charged with 100 mL of a solution containing glycolic acid (0.75M), ethylenediamine (0.86M, pH 9.0), propionic acid (0.075M, HPLC internal standard), and flavin mononucleotide (0.01 mM), and the solution cooled to 15° C. To the autoclave was then added 89 IU of spinach glycolate oxidase and 72,600 IU of Aspergillus niger catalase co-immobilized on ca. 28 g of Eupergit C. The resulting mixture was stirred at 500 rpm and 15° C. under 70 psig (483 kPa) of oxygen, while bubbling oxygen through the mixture at 100 mL/min. The reaction was monitored by taking a 100 μL aliquot of the reaction mixture at regular intervals, mixing the aliquot with 300 μL of 0.1N sulfuric acid to quench the reaction, filtering the aliquot and analyzing by HPLC. After 3 hours, the yields of glyoxylic acid, oxalic acid, and formic acid were 100%, 0%, and 0%, respectively, with complete conversion of glycolic acid. The final activities of glycolate oxidase and catalase were 100% and 100% of their initial values.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10](OC(OCC)OCC)C>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: Brc1cnc2[nH]cnc2c1
Temperature: 100 °C
Yield: 61 %

Procedure:
A stirred mixture of 5-bromopyridine-2,3-diamine (5 g, 26.6 mmol), formic acid (2.5 mL), and triethylorthoformate (70 mL) was heated at 100° C. for 2.5 h. The reaction mixture was cooled to rt and the solid precipitate was collected by filtration, washed with Et2O and dried to afford 6-bromo-3H-imidazo[4,5-b]pyridine as a solid (3.22 g, 61%) which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.50 (s, 1H), 8.44 (d, J=2.1 Hz, 1H), 8.31 (d, J=1.9 Hz, 1H). LCMS (ESI) m/z 198 and 200 (M+H)+.