Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCCN(C)C)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-dimethylaminoethylamine. ES-MS m/e (%): 457 (M+H+b , 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:31]3[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]3)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CN2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 400 mg (0.97 mmol) 4-benzyloxy-1-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 15c) in 5.0 mL of DMF is added 393 mg (3.88 mmol) 4-hydroxypiperidine. The reaction mixture is stirred 1 h at RT and is directly purified by HPLC (Waters Symmetry, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 0:100).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[C:2]=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH2:27])=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH:27][C:2]([NH:1][CH2:4][CH:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:3])=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[CH:14][CH:13]=1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Reactant: O=C=NCC1CCOCC1
Product: O=C(NCC1CCOCC1)Nc1nn2cccnc2c1-c1ccc(Cl)cc1

Procedure:
4-(Isocyanatomethyl)tetrahydropyran (Maybridge) and the product from Example 99A were processed using method analogous to that described in Example 99B to afford the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (dd, J=6.9, 1.8 Hz, 1H), 8.47 (dd, J=4.1, 1.8 Hz, 1H), 8.21-8.31 (m, 1H), 7.54-7.56 (m, 2H), 7.46-7.49 (m, 2H), 6.89-6.90 (bs, 1H), 6.81 (dd, J=6.9, 4.1 Hz, 1H), 4.01 (dd, J=11.1, 3.6 Hz, 2H), 3.41 (td, J=11.7, 1.8 Hz, 2H), 3.33 (t, J=6.3 Hz, 2H), 1.84-1.95 (m, 1H), 1.69-1.75 (m, 2H), 1.42 (qd, J=12.3, 4.5 Hz, 2H); MS (ESI) m/z 386 (M+H)+; Anal. calculated for C19H20ClN5O2: C, 59.14; H, 5.22; N, 18.15; Cl, 9.19. Found C, 58.96; H, 5.13; N, 17.99; Cl, 9.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:45]=[N+:46]=[N-:47].[Na+].Cl>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]4[NH:47][N:46]=[N:45][N:21]=4)=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(C)c1OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2nnn[nH]2)cc(C)c1OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 150 °C
Reaction time: 72 h

Procedure:
To a solution of 0.17 g (0.34 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-ethoxy}-3,5-dimethyl-benzonitrile in 4 ml o-xylene, were added 0.231 g (1.68 mmol) triethylamine hydrochloride and 0.109 g (1.68 mmol) sodium azide and the solution was heated at 150° C. (oil bath temperature) for 19.5 h. Another 0.231 g (1.68 mmol) triethylamine hydrochloride and 0.109 g (1.68 mmol) sodium azide were added and the reaction mixture was heated for an additional 4 h, then stirred for 3 days at room temperature. The reaction mixture was poured onto aqueous 1M hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was suspended in acetonitrile, filtered and washed with acetonitrile. The obtained crude material was purified on a preparative HPLC (Zorbax column) eluting with a gradient of acetonitrile and water containing 0.5% formic acid. White solid (18%). MS (Turbo Spray): m/z=549.199 [M+H].
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][C:20]1([CH3:27])[CH2:25][CH:24]([NH2:26])[CH2:23][CH2:22][O:21]1>>[CH3:19][C:20]1([CH3:27])[CH2:25][CH:24]([NH:26][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:23][CH2:22][O:21]1
Reactant: CC1(C)CC(N)CCO1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: CC1(C)CC(Nc2ncc(C#Cc3ccccc3)cn2)CCO1

Procedure:
The title compound, MS: m/e=308.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and rac-2,2-dimethyl-tetrahydro-pyran-4-ylamine.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH2:31][C:32]#[C:33][CH3:34])[C:20]3[C:25](=[O:26])[N:24]([CH2:27][C:28]#[N:29])[N:23]=[CH:22][C:21]=3[N:30]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C(O)(=O)C.[C:39]([OH:48])(=O)[C:40]1[C:41](=[CH:43][CH:44]=[CH:45][CH:46]=1)[NH2:42]>CO>[C:4]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH2:31][C:32]#[C:33][CH3:34])[C:20]3[C:25](=[O:26])[N:24]([CH2:27][C:28]4[NH:29][C:39](=[O:48])[C:40]5[C:41](=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:42]=4)[N:23]=[CH:22][C:21]=3[N:30]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(CC#N)c(=O)c21
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(Cc3nc4ccccc4c(=O)[nH]3)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40 mg sodium methoxide (95%) are added to a solution of 605 mg 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-cyanomethyl-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 9 ml of methanol. The mixture is stirred for one hour at ambient temperature and then neutralised with 41 μL glacial acetic acid. Then a solution of 195 mg anthranilic acid in 2 ml of methanol is added and the reaction mixture is heated to 70° C. After about two hours a white, voluminous precipitate is formed and the reaction mixture is cooled to ambient temperature. The precipitate formed is suction filtered, washed with cold methanol and dried.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10]/[N:11]=[C:12]1\[CH:13]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]\1=2)C.C[O-].[Na+].C(O)(=O)C>CO.O.O>[C:22]1([CH:14]2[CH:13]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)/[C:12](=[N:11]\[O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCCCO/N=C1/c2ccccc2OC(c2ccccc2)C1n1ccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCCCCO/N=C1/c2ccccc2OC(c2ccccc2)C1n1ccnc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 67.6 %

Procedure:
(+-)-(Z)-Ethyl-6-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-benzopyranylidene]aminoxy]hexanoate (300 mg; 0.67 mmoles) is dissolved in methanol-water (5:2; 7 ml), and to this solution sodium methylate (90 mg; 1.61 mmoles) is added portion-wise at 0° C. The resulting solution is stirred at r.t. for 28 hrs., then diluted with water, cooled at 0° C. and neutralized with acetic acid. The so formed precipitate is collected and recrystallized from ethyl acetate to give a white solid (190 mg), melting at 176°-178° C.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:36])([CH3:35])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CN(C(=O)OC(C)(C)C)CC3)C(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CNCC3)C(C)(C)C)n1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Intermediate 22D (170 mg, 0.34 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The resulting mixture was stirred for 2 h. The mixture was concentrated, neutralized with NaHCO3 saturated solution and extracted several times with EtOAc. The combined organic extracts were washed successively with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give of Compound 282 (125 mg, 87%). 1H-NMR (400 MHz, CDCl3-d) δ: 1.09 (s, 9H), 2.40 (s, 3H), 3.78 (m, 2H), 4.11 (m, 2H), 5.01 (m, 2H), 5.37 (d, 1H), 7.35 (m, 3H), 7.64(m, 2H), 7.78 (d, 1H), LCMS (+ESI) m/z 395.0 [M+H]+.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].O1CCCC1.[CH:18]([CH:20]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:21][CH:22]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[C:30]([O:37][CH2:38][CH2:39][O:40][CH3:41])[CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[CH:23]([CH3:25])[CH3:24])=[O:19]>CS(C)=O>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:29]=1[CH:28]=[C:27]([CH2:26][CH:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH:20]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH:18]1[CH2:7][O:19]1)[CH:36]=[CH:35]2
Reactant: CC(C)(C)[O-]
Reactant: COCCOc1cccc2ccc(CC(CC(C=O)NC(=O)OC(C)(C)C)C(C)C)cc12
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COCCOc1cccc2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Temperature: 0 °C

Procedure:
3.87 g of trimethylsulphoxonium iodide and 1.98 g of potassium tert-butoxide are stirred under high vacuum overnight, admixed with 24 ml of tetrahydrofuran and subsequently cooled to 0° C. A solution of 3.03 g of tert-butyl {1-formyl-3-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-4-methylpentyl}carbamate in 24 ml of dimethyl sulphoxide is added dropwise. On completion of reaction (TLC monitoring), the reaction mixture is partitioned between water and tert-butyl methyl ether, and the aqueous phase is extracted once again with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water (3×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.CN(C=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:31]=[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH3:33]>>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34](/[C:32](/[CH3:33])=[CH:31]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)=[CH:35][CH:36]=1
Reactant: COc1ccc(C(C)=CBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (78 mg, 0.36 mmol) was dissolved in DMF (5 mL) Copper (I) iodide (7 mg, 0.036 mmol) L-proline (8 mg, 0.073 mmol) and K3PO4 (156 mg, 0.734 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1HNMR (DMSO-d6 , Oxalate salt) δ (ppm): 7.62 (d, 2H), 7.30 (s, 1H), 7.0 (m, 4H), 6.95 (d, 1H), 3.80 (s, 3H), 3.40 (m, 4H), 3.10 (m, 4H), 2.80 (s, 3H), 2.40 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=2)[O:4][CH:3]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:16][C:13]1[O:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([C:23]4[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:25][CH:24]=4)=[CH:3][O:4][C:5]3=[CH:6][N:7]=2)=[N:15][N:14]=1
Reactant: Cc1nnc(-c2cc3c(Br)coc3cn2)o1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cc1nnc(-c2cc3c(-c4ccc(OC(F)(F)F)cc4)coc3cn2)o1
Yield: 25 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole and using [4-(trifluoromethoxy)phenyl]boronic acid instead of (4-fluorophenyl)boronic acid, the title compound (yield 25%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(CNC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(aminomethyl)piperidine-1,4-dicarboxylate (0.300 g, 1.1 mmol) and N,N-diisopropylethylamine (0.229 mL, 1.32 mmol) in CH2Cl2 (5 mL) at 0° C. was added benzyl chloroformate. The reaction was stirred overnight, and then diluted with CH2Cl2 and washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc:hexanes gradient) to give the title compound in 82% yield. MS (ES+) [M+H]+=407.
Reaction SMILES: O=C(CCC=C(C)CCC=C(C)CCC=C(C)C)CP(=O)(OC)OC.[C:26]([CH:29]([P:45](=[O:50])([O:48]C)[O:46]C)[CH2:30][CH:31]=[C:32]([CH3:44])[CH2:33][CH2:34][CH:35]=[C:36]([CH3:43])[CH2:37][CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])(=[O:28])[CH3:27]>>[C:26]([CH:29]([P:45](=[O:46])([OH:48])[OH:50])[CH2:30][CH:31]=[C:32]([CH3:44])[CH2:33][CH2:34][CH:35]=[C:36]([CH3:43])[CH2:37][CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])(=[O:28])[CH3:27]
Reactant: COP(=O)(OC)C(CC=C(C)CCC=C(C)CCC=C(C)C)C(C)=O
Agent: COP(=O)(CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C)OC
Product: CC(=O)C(CC=C(C)CCC=C(C)CCC=C(C)C)P(=O)(O)O

Procedure:
This compound was prepared exactly by the method described in Step 2 of Example 2 except that dimethyl [2-oxo-6,10,14-trimethylpentadeca-5,9,13-trienyl]phosphonate was replaced by dimethyl [1-acetyl-4,8,12-trimethyltrideca-3,7,11-trienyl]phosphonate. Thereby was obtained title compound as a colorless gum.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Br:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(Cl)Cl>[Br-:28].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Reaction time: 8 h
Yield: 115.5 %

Procedure:
To a solution of triphenylphosphine (25.92 g) in 300 mL CH2Cl2 is added 4-nitrobenzylbromide (31.47 g). The solution is allowed to stir overnight. The mixture is concentrated. The resulting solid is triturated with Et2O, filtered and dried to yield 54.58 g (95%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](=[O:13])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8](=[O:13])[CH:9]=[CH:10][C:11]=1[CH2:12][Br:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)ccc(=O)n1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)ccc(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of 1-benzyl-3-methyl-6-oxo-1,6-dihydro-pyridine-2-carboxylic acid ethyl ester (158 mg, 0.58 mmol), N-bromosuccinimide (114 mg, 0.64 mmol) and benzoyl peroxide (14 mg, 0.058 mmol) in CCl4 (6 mL) was refluxed for 16 h. After cooling to r.t., solvent was evaporated in vacuo. The residue was chromatographed (0-35% EtOAc/hexanes) to give 147 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ=7.10-7.40 (m, 6H), 6.72 (d, 1H, J=9.2 Hz), 5.32 (s, 2H), 4.24, (s, 2H), 4.19 (q, 2H, J=7.0 Hz), 1.16 (t, 3H, J=7.0 Hz).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N)CN.[O:10]=O>C(O)=O>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:2]([OH:10])(=[O:3])[C:1]([OH:5])=[O:4]
Reactant: O=O
Reactant: O=C(O)CO
Solvent: NCCN
Solvent: O=CO
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Reaction time: 77 h
Yield: 0.2 %
Yield: 99.6 %

Procedure:
Demonstration of the enzymatic synthesis of glyoxylic acid on a large scale was performed in an Amicon Model 2000 High-Output Stirred Cell, where a 1.6 mm thick Teflon® sheet was substituted for the filtration membrane, and which had a magnetically driven paddle stirrer. Glycolate oxidase (2000 IU, isolated from spinach) was added to 2.0L of solution containing glycolic acid (113 g, 1.49 moles), ethylenediamine (95 g, 1.58 moles), FMN (9.7 mg, 0.02 mmoles), and catalase [2.8×106IU, from Aspergillus niger (Sigma)], and the resulting mixture (final pH=8.9) was stirred at 15° C. under 6 atmospheres of oxygen. Aliquots were removed at regular intervals for analysis by HPLC to monitor the progress of the reaction. After 77 hours, HPLC analysis of the reaction mixture indicated that glyoxylic acid (110 g, 99.6% yield), formic acid (0.2%), and oxalic acid (0.2% yield) were the only reaction products; complete conversion of glycolic acid was attained. Glycolate oxidase and catalase activities were 74% and 87% of their initial activities, respectively. The reaction was terminated by sparging the solution with nitrogen, then heating the reaction mixture to 70° C. for 5 minutes under a nitrogen blanket. Precipitated protein was removed by centrifugation, and FMN removed by filtration of the reaction mixture through activated carbon. Any remaining soluble protein was removed by filtration using a Millipore Minitan Filtration System with a 10,000 mw cutoff filter, then glyoxylate and ethylenediamine (EDA) were separated by ion exchange chromatography.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.Cl.[NH2:17][OH:18]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[N:17][OH:18]
Reactant: CC(C)(C)Sc1c(Br)cc(F)cc1C=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)Sc1c(Br)cc(F)cc1C=NO
Temperature: 90 °C

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-5-fluorobenzaldehyde (4 g, 13.7 mmol) and hydroxylamine hydrochloride in isopropanol (160 mL) and water (33 mL) was heated to 90° C. for 16 h. The reaction mixture was cooled and 2-propanol was removed in vacuo. Water was added to residue, followed by saturated aqueous sodium bicarbonate until the pH was ˜8. The mixture was extracted with dichloromethane (2×30 mL). The combined organic fractions were dried sodium sulfate, filtered, and concentrated to afford 3.8 g of the crude title compound, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#N)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:16](I)[CH2:17][CH2:18][CH3:19].Cl.[OH-:22].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCC(=O)c1ccc(-c2ccc(F)cc2)nc1

Procedure:
A solution of 2-(4-fluorophenyl)-5-cyanopyridine (3.1 g) of Example 11 in tetrahydrofuran (30 ml) was added to a tetrahydrofuran solution (50 ml) of a Grignard reagent prepared from metallic Mg (0.6 g) and n-butyl iodide (4.4 g), followed by reacting the mixture at 60° C. for 5 hours, pouring the resulting solution in cooled 2N-HCl aqueous solution (100 ml), adding 2N-NaOH aqueous solution to make the solution alkaline, adding toluene (200 ml) to the solution, withdrawing the separated toluene layer, washing it with water till the washing water became neutral, distilling off toluene from the toluene layer and recrystallizing the residue from ethanol to obtain 2-(4-fluorophenyl)-5-valeroylpyridine (1.8 g) having a m.p. of 104.4° C. To this compound were added hydrazine hydrate (4 g), diethylene glycol (20 ml) and KOH (2.2 g), followed by agitating the mixture at 110° C. for one hour and further at 200° C. for 3 hours, cooling, adding chloroform (100 ml), washing the separated chloroform layer with water till the washing water became neutral, distilling off the solvent from the chloroform solution and distilling the residue to obtain the objective 2-(4-fluorophenyl)-5-n-pentylpyridine (0.3 g). B.P.: 152.0° C./2 mmHg. M.P.: 27.0° C.