Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:33][C:34]([CH3:39])([CH3:38])[C:35](=[S:37])[NH2:36].O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:37][C:35]([C:34]([CH3:39])([CH3:38])[CH3:33])=[N:36][C:9]=2[C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C(N)=S
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (30 g, 85.9 mmol) (Intermediate 20) in DMA (300 mL), NBS (15.3 g, 85.9 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then 2,2-dimethylpropanethioamide (11.0 g, 94.5 mmol) was added at 0° C. The mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound. (11 g, 35.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (d, J=5.27 Hz, 1H), 8.12-8.19 (m, 1H), 7.12-7.25 (m, 2H), 6.80-6.88 (m, 2H), 5.85-5.98 (m, 1H), 5.20-5.37 (m, 2H), 4.61-4.67 (m, 2H). MS (ES+): 447 [M+H]+.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C@@H:13]([C:19]1[C:20]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:21]2[C:26](=[CH:27][C:28]=1[CH3:29])[N+:25]([O-])=[C:24]([CH3:31])[CH:23]=[CH:22]2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:11])([CH3:10])[CH3:9].C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(C)C=C2)C(OCC)=O)(C)(C)C>>[C:1]([O:4][CH2:31][C:24]1[CH:23]=[CH:22][C:21]2[C:26](=[CH:27][C:28]([CH3:29])=[C:19]([C@H:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:20]=2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:25]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(COC(C)=O)ccc2c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic anhydride was added to a flask containing (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide (compound of Example 14) (42 mg, 0.095 mmol). The mixture was stirred at 80° C. for 1 hour. Acetic anhydride was removed under vacuum. The residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with NaHCO3 solution and water, dried and concentrated in vacuo. The obtained residue was used for next step reaction without purification. LCMS-ESI+ (m/z): 484.2, 486.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[CH:4]=[CH:5][C:6]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=4)[N:15]=[CH:14][C:13]=3[CH:12]=[N:11]2)=[N:7][C:8]=1F.[NH:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]1.CN1CCOCC1.O>CN1CCCC1=O>[F:26][CH:2]([F:1])[C:3]1[C:8]([N:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:28]2)=[N:7][C:6]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=4)[N:15]=[CH:14][C:13]=3[CH:12]=[N:11]2)=[CH:5][CH:4]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)F)c(F)n2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)F)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 1-[5-(difluoromethyl)-6-fluoro-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.0977 mmol; 34.8 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.147 mmol; 29.3 mg), and N-Methylmorpholine (0.244 mmol; 24.9 mg; 0.0271 mL) in 1-methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford tert-butyl N-[(3S)-1-[3-(difluoromethyl)-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (˜52.4 mg, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[CH3:15][C:14]1[N:13]=[C:12]([NH2:16])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:17])[CH:23]=2)[CH:7]=1
Reactant: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cc(Oc3ccc(N)nc3C)ccn2)ccn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
A mixture of Example A7 (905 mg, 3.84 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.010 g, 4.61 mmol), potassium carbonate (1.592 g, 11.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (222 mg, 0.192 mmol) in dioxane (16 mL) and water (4 mL) was degassed with Ar, sealed and warmed to 85° C. overnight. The mixture was cooled to RT, diluted with EtOAc (40 mL) and water (50 mL), and filtered through diatomaceous earth. The organic phase was separated and washed with brine (50 mL). The organic phase was diluted with methanol (5 mL), treated with SiliaMetS Thiol, (1.42 mmol/g, 4 g, 5.68 mmol), and gently stirred for 3 h. The mixture was filtered, washing the slica gel plug with 3% MeOH/EtOAc (2×10 mL). The filtrates were evaporated at reduced pressure and the residue was purified by silica gel chromatography (0-10% MeOH/EtOAc) to give 6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine as a tan solid (806 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 9.07 (d, J=2.3 Hz, 1 H), 8.48 (d, J=5.7 Hz, 1 H), 8.25 (dd, J=8.1, 2.4 Hz, 1 H), 7.50 (d, J=2.4 Hz, 1 H), 7.33 (d, J=8.2 Hz, 1 H), 7.21 (d, J=8.7 Hz, 1 H), 6.67 (dd, J=5.7, 2.4 Hz, 1 H), 6.35 (d, J=8.7 Hz, 1 H), 5.96 (s, 2 H), 2.50 (s, 3 H), 2.08 (s, 3 H). MS (ESI) m/z: 293.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23](O)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>C(O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:31][CH:32]=1
Reactant: OC(c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2)c1ccccn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(Cc5ccccn5)cc43)CC2)cc1
Yield: 24.6 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)methyl]indoline (0.321 g) was dissolved in ethanol (86.4 ml) f ollowed by the addition of 1 N hydrochloric acid (3.7 ml) and palladium carbon. Then the resultant mixture was catalytically reduced under atmospheric pressure for 3 hr. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. To the residue were added a saturated aqueous solution of sodium bicarbonate and ethyl acetate and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate-methanol system) to give the title compound (0.076 g) as ayellow oil (yield: 24.6%).
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]([F:21])([C:17]([F:18])([F:19])[F:20])[CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CCCCCOCCCC(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCCCOCCCC(F)(F)C(F)(F)F
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the product of step (b) in 1,4-dioxane (5 ml) was added 0.1M sodium hydroxide solution (5 ml) and the reaction was stirred at 20° C. for 4 hours. The reaction volume was reduced by 50% in vacuo and then partitioned between water (50 ml) and dichloromethane (50 ml). The aqueous layer was acidified to pH 1 by the addition of 2M hydrochloric acid and then extracted with dichloromethane (3×50 ml). The combined organic layers were dried over magnesium sulphate and the solvent was removed in vacuo to give the title compound as a white solid (30 mg).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=N)CCCCC1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>ClCCl.CN(C)C=O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[O:21])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(O)CCCOc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: N=C=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(CCCOc1ccc2c(c1)CCN(C1CCC1)CC2)N1CCOCC1
Reaction time: 0.75 h

Procedure:
4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoic acid (E283, Step 1) (0.15 g, 0.50 mmole) was dissolved in dry dichloromethane (5 ml) and dry dimethylformamide (2 ml) was treated with 1-hydroxybenzotriazole hydrate (0.14 g, 1.0 mmole) and N-cyclohexylcarbodiimide, N′-methyl polystyrene HL (0.53 g, 1.0 mmol, 1.7 mmol/g) and stirred for 45 minutes. Morpholine (0.056 ml, 0.65 mmol) was added and the mixture stirred for 3 hours at ambient temperature. The crude reaction mixture was applied to a SCX ion exchange cartridge (Varian bond-elute) and washed with water, methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were reduced in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95 to 1:9:90) to afford the title compound (E283); MS (ES+) m/e 373 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[C:15]([O:19][C:20](=[O:31])[C@@H:21]([NH2:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH3:18])([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:15]([O:19][C:20](=[O:31])[C@@H:21]([NH:30][C:11]([C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 500 mg, 2.54 mmol) in DMF (20 mL) was added 2-(S)-amino-3-(4-fluorophenyl)propionic acid tert-butyl ester hydrochloride (Preparation 114, 701 mg, 2.54 mmol), HOBt (344 mg, 2.54 mmol) and DIPEA (1.4 mL, 7.88 mmol). After 5 min, EDCI (634 mg, 3.31 mmol) was added and the reaction mixture stirred at rt for 72 h. The solvent was removed in vacuo and the solid partitioned between water (50 mL) and ethyl acetate (3×40 mL). The combined organic phase was washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:99) to give the title compound. δH (CD3OD): 1.42 (9H, s), 3.09 (1H, dd), 3.22 (1H, dd), 4.76 (1H, m), 6.98 (2H, m), 7.07 (1H, s), 7.27 (2H, m), 8.06 (1H, d), 8.28 (1H, d); m/z (ES+)=418 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH:21]=[O:22])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][OH:22])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC[C@@H](CC=O)CCCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC[C@@H](CCO)CCCCOCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of the crude methyl (S)-8-(benzyloxy)-4-(formylmethyl)octanoate (2.44 g crude) in ethanol (22 ml) is added sodium borohydride (0.307 g, 8.1 mmol). The reaction is stirred for 15 minutes and then poured into water. The pH of the mixture is adjusted to 8.0 using saturated sodium bicarbonate solution. The mixture is extracted with methylene chloride (3×30 ml) and the combined organic extracts are dried, filtered and evaporated to give an oil. This is purified by flash chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent to yield methyl (S)-8-(benzyloxy)-4-(2-hydroxyethyl)-octanoate (oil), [alpha]D25 -1.22° (c 1.02 in methanol).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15](Cl)([Cl:17])=[O:16]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:17][C:15]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: OC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)OC1CCCCC1

Procedure:
A mixture of cyclohexanol (500 mg, 5.0 mmol) and triethylamine (836 μl) in methylene chloride (4 ml) was added to a 0° C. solution of phosgene in toluene (5.3 ml, 20%). The resultant mixture was stirred at 0° C. for 2.5 hours. TLC showed completion of the reaction. The solvent was removed and anhydrous ether (50 m l) was added. The mixture was filtered and the filtrate was concentrated to give 726 mg of the desired product as a colorless oil which was used without further purification. IR (film) 1776 cm−1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]([Br:15])[C:12]([CH3:16])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:14]=[C:13]([Br:15])[C:12]([CH2:16][Br:24])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)c(Br)cc1OC(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)c(Br)cc1OC(C)=O
Temperature: 85 °C

Procedure:
To a solution of methyl 2-(acetyloxy)-4-bromo-5-methylbenzoate (may be prepared as described in Description 15; 705 mg, 2.46 mmol) in carbon tetrachloride (10 ml) was added NBS (437 mg, 2.46 mmol) and benzoyl peroxide (47.6 mg, 0.15 mmol). The solution was heated at 85° C. overnight, cooled and the solvent was removed in vacuo to give a residue. Purification by column chromatography (SiO2, 6:1 cyclohexane/ethyl acetate) yielded the title compound as an oil. 741 mg.
Reaction SMILES: S[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:16].[Na+].[Cl-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[C:48]1(=[O:60])[N:52]([CH2:53][CH2:54][CH2:55][C:56]([NH2:58])=[O:57])[C:51](=[O:59])[CH:50]=[CH:49]1>C(O)C>[C:51]1(=[O:59])[N:52]([CH2:53][CH2:54][CH2:55][C:56]([NH2:58])=[O:57])[C:48](=[O:60])[CH:49]=[CH:50]1.[OH:16][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: OC[C@H]1O[C@@H](S)[C@H](O)[C@@H](O)[C@H]1O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: NC(=O)CCCN1C(=O)C=CC1=O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Cl-]
Solvent: CCO
Product: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
1-thio-b-galactopyranose (1.5 mg) is dissolved in 150 μl of buffer A (20 mM citric acid, 35 mM Na2HPO4, 108 mM NaCl, 1 mM ethylenediamine-tetraacetic acid (EDTA)) and 150 μl of ethanol, N-(m-(3-trifluoromethyl)diazirine-3-yl)phenyl)-4-maleimido-butyramide (MAD, 3.3 mg, preparation according to A. Collioud et al., Bioconjugate Chemistry 4, 528-536 (1993)) is dissolved in 150 μl of ethanol and an additional 150 μl of buffer A. Both solutions are mixed. The mixture is stirred and allowed to react at room temperature for 90 min, to give the compound MAD-Gal. The product is purified by HPLC. The HPLC flow rate is 2 ml/min. For gradient elution (0 min.-100% A; 5 min.-100% A; 20 min.-70% A; 30 min.-0% A; 40 min. 0%A), solvent B is added to solvent A (solvent A, 0.1% TFA in water; solvent B, 0.1% TFA in acetonitrile/water (4:1 by volume)). Detection is performed at 254 nm and fractions of the eluant are collected. 13C.NMR (D2O chemical shift (δ) in parts per million): 179.14, 178.40, 177.99, 177.86, 173.30, 137.79, 129.53, 129.38, 122.46, 121.84, 118.32, 84.42, 84.27, 78.99, 78.91, 73.84, 73.66, 69.73, 69.68, 68.58, 68.49, 60.80, 60.69, 39.61, 38.66, 38.46, 37.71, 35.83, 33.57, 22.68, 22.57 ppm. Mass Calc (M−H): 561.1 Da/e, found: 561.1 Da/e.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:13][C:14](=[O:17])[CH2:15][CH3:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl>CO>[C:3]1([CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CCC(=O)Cc1cccc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(O)Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Sodium borohydride (1.80 g, 47.4 mmol) was added portion wise at 0° C. to a solution of 1-naphthyl-2-butanone (4.70 g, 23.7 mmol) in CH3OH (100 mL). The mixture was stirred at 0° C. for 3 h. A solution of 1 N HCl (10 mL) was added, and the solvent was removed in vacuo. Water (50 mL) was added to the residue, and the aqueous was extracted with EtOAc (300 mL). The combined organic extracts were washed with the H2O (100 mL) and brine (50 mL), and the solvent was removed by rotary evaporation. Silica gel flash chromatography (10% EtOAc in hexanes) yielded 4.10 g (86%) of 1-naphthalen-1-ylmethyl-propanol as a colorless oil: 1H-NMR (400 MHz, CDCl3) δ 8.04 (dd, 1 H), 7.85 (dd, 1 H), 7.74 (dd, 1 H), 7.54-7.43 (m, 2 H), 7.41-7.24 (m, 2 H), 3.93-3.87 (m, 1 H), 3.36 (dd, 1 H), 3.05 (dd, 1H), 1.71-1.57 (m, 2 H), 1.45 (br s, 1 H), 1.05 (t, 3 H).
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=O)C(OCC)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].C=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=C(C)C=1.C(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:21](=[CH2:3])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1cccc(C)c1
Solvent: CCO
Product: C=C(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71 %

Procedure:
To a solution of sodium hydride (60% in oil, 6.56 g) in m-xylene (100 mL) was slowly added ethanol (15.7 mL) at 0° C. and then diethyl oxalate (32.0 g) was added. Furthermore, a solution of ethyl 3,4-dichlorophenylacetate (51.0 g) in m-xylene (30 mL) was added at 0° C., and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added 37% aqueous formalin solution (140 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Furthermore, potassium carbonate (115 g) was added at room temperature, and the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered off, and the filtrate was partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer was separated, washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 5% ethyl acetate/hexane) to give crude ethyl 2-(3,4-dichlorophenyl)acrylate (38.1 g, 44%) as a colorless oil.
Reaction SMILES: CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.N([S:48][CH2:49][CH2:50][NH:51][C:52](=[O:95])[CH2:53][CH2:54][NH:55][C:56](=[O:94])[C@H:57]([OH:93])[C:58]([CH3:92])([CH3:91])[CH2:59][O:60][P:61]([OH:90])(=[O:89])[O:62][P:63]([OH:88])(=[O:87])[O:64][CH2:65][C@H:66]1[O:70][C@@H:69]([N:71]2[C:80]3[N:79]=[CH:78][N:77]=[C:75]([NH2:76])[C:74]=3[N:73]=[CH:72]2)[C@H:68]([OH:81])[C@@H:67]1[O:82][P:83]([OH:86])([OH:85])=[O:84])[C@@H](CCC(N[C@H](C(NCC(O)=O)=O)CS)=O)C(O)=O.CC(C(O)C(NCCC(NCCS)=O)=O)(COP(OP(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(O)=O)(O)=O)C.[N+](C1C=CC(SSC2C=CC([N+]([O-])=O)=C(C=2)C(O)=O)=CC=1C(O)=O)([O-])=O.C1C=C2C(C(O)=O)=CC(C3C=C(C(O)=O)C4C(=CC=CC=4)N=3)=NC2=CC=1.C1(CS(F)(=O)=O)C=CC=CC=1.CC([C@@H](O)C(NCCC(NCCS)=O)=O)(COP(OP(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(O)=O)(O)=O)C>C(O)C(N)(CO)CO.Cl.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].[Cu]>[CH3:92][C:58]([C@@H:57]([OH:93])[C:56]([NH:55][CH2:54][CH2:53][C:52]([NH:51][CH2:50][CH2:49][SH:48])=[O:95])=[O:94])([CH2:59][O:60][P:61]([O:62][P:63]([O:64][CH2:65][C@H:66]1[O:70][C@@H:69]([N:71]2[C:80]3[N:79]=[CH:78][N:77]=[C:75]([NH2:76])[C:74]=3[N:73]=[CH:72]2)[C@H:68]([OH:81])[C@@H:67]1[O:82][P:83]([OH:86])([OH:85])=[O:84])([OH:88])=[O:87])([OH:90])=[O:89])[CH3:91]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSN[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: [Cu+2]
Agent: [Cu]
Agent: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C(O)C(=O)NCCC(=O)NCCS
Solvent: O
Product: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS

Procedure:
Reduced nicotinamide adenine dinucleotide phosphate (NADPH), riboflavin, flavin adenine mononucleotide (FMN), flavin adenine dinucleotide (FAD), coenzyme A disulfide, glutathionyl-coenzyme A mixed disulfide, 3'-dephospho coenzyme A, 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB), lysostaphin, bicinchoninic acid solution, 4% copper sulphate pentahydrate solution, 2',5'-adenosine diphosphate (ADP)-Sepharose®; and phenylmethylsulphonyl fluoride (PMSF) were from Sigma (Mississauga, ON). 3'-dephospho CoA was oxidized to the disulfide by incubation at room temperature overnight in Tris-HCl (20 mM), pH 9.0, containing copper (5 μM). 4,4'-phosphopantetheine was formed by incubation of CoA with nucleotide pyrophosphatase. The thiol was oxidized as described above, and the disulfide was purified by high performance liquid chromatography (HPLC). All other chemicals were of reagent grade or better and were used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]/OCC)[CH:5]=[CH:6][CH:7]=1>OS(O)(=O)=O>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:5]([CH:11]=[CH:10][C:9]([OH:15])=[N:8]2)=[CH:6][CH:7]=1
Reactant: CCO/C=C/C(=O)Nc1cccc(Br)c1OC
Agent: O=S(=O)(O)O
Product: COc1c(Br)ccc2ccc(O)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To stirred concentrated H2SO4 (30 mL), (E)-(N)-(3-bromo-2-methoxyphenyl)-3-ethoxypropenamide (3c) (2.11 g, 7.03 mmol) was added and allowed to stir overnight at room temperature. The solution was poured over ice and the resulting solid was filtered off, washed and dried. The desired product was obtained as a yellow solid (1.75 g, 98% yield): 1H NMR (400 MHz, DMSO-d6) 11.44 (bs, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.37 (s, 2H), 6.53 (d, J=8.8 Hz, 1H), 3.79 (s, 3H).