Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCBr
Reactant: COC(=O)c1cc(O)ccc1O
Product: CCCCCCOc1ccc(O)c(C(=O)OC)c1
Yield: 58 %

Procedure:
Synthesis was carried out in the same manner as in Example 1, except for replacing methyl 2,4-dihydroxybenzoate with methyl 2,5-dihydroxybenzoate and replacing 2-ethylhexyl bromide with n-hexyl bromide, to obtain methyl 5-n-hexyloxy-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 12) as a colorless, clear and oily substance in a yield of 58%. The analytical results are shown below. ##STR33##
Reaction SMILES: [C:1]([CH:3]([C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]1)[CH2:4][CH2:5][C:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])#[N:2].CO.[BH4-].[Na+]>C1COCC1.O>[C:1]([CH:3]([C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]1)[CH2:4][CH2:5][CH:6]([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])#[N:2]
Reactant: CCCCCCC(=O)CCC(C#N)[C@H]1CC[C@H](OC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(O)CCC(C#N)[C@H]1CC[C@H](OC)CC1

Procedure:
A solution of 1-cyano-1-(trans-4-methoxycyclohexyl)-4-decanone (48) (5.1 g, 17.4 mmol) obtained in the second step dissolved in 100 mL of THF and 50 mL of methanol was cooled with ice, to which sodium borohydride (0.79 g, 20.9 mmol) was then gradually added, followed by stirring under cooling with ice for 1 hour. The reaction mixture was put in 100 mL of iced water, and then extracted with 100 mL of ethyl acetate. The resulting organic layer was washed with water (100 mL×2) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (developing solvent: heptane/ethyl acetate=4/1, column packing: silica gel) to obtain 1-cyano-1-(trans-4-methoxycyclohexyl)-4-decanol (49) (5.1 g, 17.4 mmol). The resulting compound was in the form of colorless crystals, and the yield based on the compound (48) was 100%.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[C:9]([F:14])[C:8]([O:15][CH3:16])=[CH:7][CH:6]=2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[OH-:51].[K+].Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[F:14][C:9]1[C:8]([O:15][CH3:16])=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]([CH:12]=[O:13])=[C:2]([OH:51])[CH:3]=[N:4]2
Reactant: COc1ccc2ncc(Cl)c(C=O)c2c1F
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ncc(O)c(C=O)c2c1F
Yield: 36 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.04 mmol, 0.02 eq) is added at room temperature to a stirred solution of 3-chloro-5-fluoro-6-methoxy-quinoline-4-carbaldehyde (500 mg, 2.10 mmol, 1.0 eq) in dioxane (6 mL), followed by 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (100 mg, 0.21 mmol, 0.1 eq) and a 1.6 M potassium hydroxide aqueous solution (2 mL). The reaction mixture is irradiated by microwaves at 125° C. for 15 minutes, then water (10 mL) is added, the resulting mixture is neutralized with 2.0 N hydrochloric acid aqueous solution and extracted with ethyl acetate (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 5-fluoro-3-hydroxy-6-methoxy-quinoline-4-carbaldehyde as a light yellow solid (168 mg, 36% yield).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][NH:4][C:5](=[O:10])[CH2:6][CH2:7][C:8]#[CH:9].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[O:1]=[C:2]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:3][NH:4][C:5](=[O:10])[CH2:6][CH2:7][C:8]#[CH:9]
Reactant: C#CCCC(=O)NCC(O)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C#CCCC(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
169 mg (0.78 mmol) of N-(2-hydroxy-2-phenylethyl)pent-4-ynamide in DCM (1 mL) were added to a solution of PCC (326 mg, 1.48 mmol) in DCM (4 mL). The reaction mixture was stirred for 4 hours at room temperature, dissolved in DCM and then quenched with NaOH 1N. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to yield 160 mg (0.74 mmol, 95%) of pent-4-ynoic acid (2-oxo-2-phenyl-ethyl)-amide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[O:30]([CH2:34][CH2:35][NH2:36])[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][O:30][CH2:34][CH2:35][NH:36][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[NH:10]1)=[O:29]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCOCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2,2′-oxybis(ethylamine) (31.3 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(2-amino-ethoxy)-ethyl]-amide (20.3 mg, 19.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H34Cl2N4O2S+H [(M+H)+]: 517.2132. found: 517.2133.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.O1CCC[CH2:43]1>CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH:31]([CH3:32])[CH3:43])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(CC)c2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(1-ethylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (392 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-isopropylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (229 mg) as yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Oc1cccc(Cl)c1
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(=O)c1ccc([N+](=O)[O-])c(Oc2cccc(Cl)c2)c1
Yield: 54.7 %

Procedure:
A mixture of 3'-chloro-4'-nitroacetophenone (3 g), m-chlorophenol (2.3 g) and potassium carbonate (2.5 g) in xylene (30 ml) was stirred and refluxed for 7 hours. The insoluble was filtered and the filtrate was washed with an aqueous solution of sodium hydroxide (10%) and water, dried, and concentrated. The residue was purified by column chromatography on silica gel eluting with toluene to give an oil of 3'-(3-chlorophenoxy)-4'-nitroacetophenone (2.4 g).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:16](=[O:25])[C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[CH:12]=[CH:11][N:10]=1>N1C=CC=CC=1>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[C:16]([NH:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:2](=[O:3])[O:4][CH:5]([CH3:7])[CH3:6])[CH:14]=1)=[O:25]
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
To a stirred solution of isopropyl chloroformate (0.066 g, 0.53 mmol) in 3 ml of pyridine was added N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (0.1 g, 0.36 mmol). The resulting mixture was stirred for another 30 min and then concentrated under reduced pressure. The residue was purified via prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product as a white solid (0.025 g, yield: 19%). 1H NMR (DMSO-d6, 500 MHz): δ 11.17 (s, 1H), 9.97 (s, 1H), 8.21-8.17 (m, 2H), 7.61-7.53 (m, 3H), 7.40 (m, 1H), 4.90 (m, 1H), 1.25 (t, J=5.5 Hz, 6H). LCMS (ESI) m/z: 368.0 [M+H+].
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-])=[O:5].C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C(Cl)Cl>[C:1]([CH2:2][CH2:3][C:4]([Cl:13])=[O:5])([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCC(=O)Cl

Procedure:
Mono-methyl succinate (1), wherein alk is methyl, was chlorinated with oxalyl chloride in dimethyl formamide and methylene chloride to afford 3-carbomethoxypropionyl chloride (2). Compound (2) was catalytically hydrogenated over palladium-charcoal catalyst in the presence of 2,6-lutidine to yield 3-carbomethoxypropionaldehyde (3) which was reacted with formylmethylene triphenylphosphorane under Wittig reaction conditions to obtain 5-carbomethoxy-2-pentanal (4). Compound 4 was epoxidized with aqueous hydrogen peroxide in the presence of 1N sodium bicarbonate to afford methyl-4,5-epoxy-6-oxohexanoate (5). Compound (5) was reacted with tridecyltriphenylphosphonium ylid to give methyl-4,5-epoxy-6(Z)-nonadecenoate (6).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:41]1[CH:40]=[C:39]([Cl:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 44.9 %

Procedure:
Following general procedure II, (S)-tert-butyl (1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)-amino]pyridin-2-yl}piperidin-3-yl)carbamate (98 mg, 0.20 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (85 mg, 0.30 mmol) to afford the product (56 mg) which was carried forward without any purification: ESI MS m/z 625 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[O:21]1[CH2:26][CH2:25][O:24][C:23]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:22]1=2.C(=O)([O-])[O-].[Na+].[Na+]>CCO.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>[Cl:8][C:5]1[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:3][C:2]([C:28]2[CH:29]=[CH:30][C:22]3[O:21][CH2:26][CH2:25][O:24][C:23]=3[CH:27]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
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: [Na+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4c(c3)OCCO4)cnc2Cl)cc1
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
A 15 mL sealed pressure tube was charged with N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (190 mg, 0.503 mmol), 2,3-dihydrobenzo[b][1,4]dioxin-6-ylboronic acid (100 mg, 0.553 mmol) in EtOH (1.5 ml). Pd(PPh3)4 (29 mg, 0.025 mmol) was added, followed by sodium carbonate (2M, 0.629 mL). The tube was purged with argon, backfilled with argon, sealed and stirred at 85° C. for 1.5 hours. The crude was partitioned between water and methylene chloride and extracted with methylene chloride (3×, 10 ml). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The solid was purified by ISCO with a 20-50% gradient of EtOAc in hexanes to afford desired product. MS (ESI pos. ion) m/z calcd for C20H12ClN2O5S: 432.8; found 433.3 1H NMR (400 MHz, DMSO-d6) δ ppm 3.83 (s, 3 H), 4.30 (s, 4 H), 6.99 (d, J=8.3 Hz, 1 H), 7.06-7.15 (m, 4 H), 7.61-7.72 (m, 2 H), 7.78 (d, J=2.3 Hz, 1 H), 8.47 (s, 1 H), 10.21 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[C:4]([N:6]([CH2:11][C:12]1[N:13]=[N:14][C:15](CCCNN)=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5]>CC(O)=O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[C:4]([N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:11][C:12]1[C:17]([CH2:3][CH2:2][CH3:26])=[CH:16][C:15]2[N:14]([C:12]([CH3:11])=[N:13][N:14]=2)[N:13]=1)=[O:5]
Reactant: CC(C)CN(Cc1ccc(CCCNN)nn1)C(=O)c1cc(F)ccc1F
Solvent: CC(=O)O
Product: CCCc1cc2nnc(C)n2nc1CN(CC(C)C)C(=O)c1cc(F)ccc1F

Procedure:
A solution of 2,5-difluoro-N-(6-hydrazinopropyl-pyridazin-3-ylmethyl)-N-isobutyl-benzamide (63 mg, 0.17 mmol) in HOAc (3 ml) is heated at 110° C. overnight. The solvent is removed in vacuo and to the residue is added EtOAc (10 ml) and saturated NaHCO3 aqueous solution (10 ml). The layers are separated and the aqueous layer is extracted with EtOAc (10 ml). The combined extracts are washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. Preparative TLC separation of the residue with 5% MeOH in CH2Cl2 provides the title compound as a light yellow oil. 1H NMR (CDCl3) (mixture of rotamers) 7.79 (s, 0.75H), 7.71 (s, 0.25H), 6.95-7.12 (m, 3H), 4.91 (s, 1.5H), 4.62 (s, 0.5H), 3.17 (d, 2H), 2.81 (s, 0.75H), 2.79 (s, 2.25H), 2.69 (t, 1.5H), 2.39 (t, 0.5H), 2.06-2.17 (m, 0.25H), 1.91-2.01 (m, 0.75H), 1.72-1.82 (m, 1.5H), 1.45-1.55 (m, 0.5H), 1.08 (t, 2.25H), 1.00 (d, 4.5H), 0.93 (t, 0.75H), 0.82 (d, 1.5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:55]=[CH:54][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13][C@H:12]2[CH2:36][NH:37][S:38](=[O:53])(=[O:52])[NH:39][C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)=[O:41])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1>ClCCl.CO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([SH:16])[CH2:13][C@H:12]2[CH2:36][NH:37][S:38](=[O:52])(=[O:53])[NH:39][C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=2)=[O:41])=[O:10])=[CH:54][CH:55]=1
Reactant: COc1ccc(COC(=O)NS(=O)(=O)NC[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc(OC)cc2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)NS(=O)(=O)NC[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc(OC)cc2)cc1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-p-methoxybenzyloxycarbonylsulfamoylaminomethyl-4-tritylthiopyrrolidine (2.35 g: 3.13 mmole) in a mixture of dichloromethane (60 ml) and methanol (30 ml), a solution of pyridine (0.38 ml: 4.75 mmole: 1.5 eq.) and silver nitrate (0.80 g: 1.5 eq.) in water (2 ml) is added under ice cooling. The mixture is stirred for 10 minutes. The reaction mixture is poured into water and extracted with dichloromethane. The extract is dried over magnesium sulfate and filtered. Hydrogen sulfide is passed through the filtrate and the resulting precipitate is filtered off. The filtrate is concentrated in vacuo and the residue is purified by silica gel column chromatography to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-p-methoxybenzyloxycarbonylsulfamoylaminomethyl-4-mercaptopyrrolidine (1.56 g). Yield: 92.4%. NMR δ(CDCl3) ppm: 2.42 to 2.58(m, 1H), 3.80(s, 6H), 5.08, 5.02(ABq, J=12 Hz, 2H), 5.12, 5.07(ABq, J=16 Hz, 2H). IR ν (CHCl3)cm-1 : 3380, 1740, 1685, 1610.
Reaction SMILES: [OH-].[K+].[Br-].[Na+].[OH:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl>O.CO.C(O)C>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Cc1cc(=O)n2cccc(O)c2n1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1cc(=O)n2cccc(OCc3ccc(Cl)cc3Cl)c2n1
Reaction time: 0.25 h

Procedure:
To a solution of 6.6 g of potassium hydroxide (85%) and 10.3 g of sodium bromide in 100 ml of water and 150 ml of methanol is added, in portions, 17.6 g of 9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one and the mixture stirred for 0.25 hours. To this is then added 19.6 g of 2,4-dichlorobenzyl chloride dissolved in 50 ml of 95% ethanol and the mixture stirred and refluxed for about 6 hours. The mixture is concentrated to dryness in vacuo and the residue is distributed between 500 ml of chloroform and 250 ml of water. Workup of the chloroform solution yields 9-[ (2,4-dichlorobenzyl)oxy]-2-methyl-4H-pyrido[ 1,2-a]-pyrimidin-4-one, m.p. 180°-182° after recrystallization from acetonitrile.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[OH:20].COC1C=CC(O)=CC=1.N1C=CC=CC=1.[C:36](Cl)(=[O:40])[C:37]([CH3:39])=[CH2:38]>C1COCC1>[C:36]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[OH:20])(=[O:40])[C:37]([CH3:39])=[CH2:38]
Reactant: COc1ccc(N=Nc2cc(C)cc(CO)c2O)cc1
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCc1cc(C)cc(N=Nc2ccc(OC)cc2)c1O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a 500 ml round bottom flask equipped with a magnetic stirrer and gas inlet was dissolved 8.75 g (32.1 mmol) of 2-(hydroxymethyl)-6-((4-methoxyphenyl)-diazenyl)-4-methylphenol in 300 ml anhydrous THF. ˜50 mg 4-methoxyphenol (MEHQ) was added followed by 16.5 g (209 mmol) anhydrous pyridine. The reaction mixture was cooled to −20° C. and 4.91 g (47.0 mmol) methacryloyl chloride was added dropwise. The reaction mixture was stirred for 1 hour at −20° C. and then 20 hours at ambient temperature. The solid was filtered and diethyl ether (200 ml) and ethyl acetate (200 ml) were added to the filtrate. The organic layer was washed with 0.5 N HCl, and then dried over magnesium sulfate. The solvent was removed under removed pressure and the crude product was recrystallized in methanol to give an orange solid which was rinsed with cold ethanol and then for 20 hours under vacuum (0.1 mm Hg) at room temperature to afford 7.0 g (64%). 1H NMR (CDCl3) delta: 13.12 (s, 1H, Ar—OH), 7.84 (m, 2H, Ar—H), 7.68 (s, 1H, Ar—H), 7.23 (s, 1H, Ar—H), 7.02 (m, 2H, Ar—H), 6.16 (s, 1H, vinyl-H), 5.58 (s, 1H, vinyl-H), 5.31 (s, 2H, Ar—CH2), 3.89 (s, 3H, CH3O—Ar), 2.38 (s, 3H, Ar—CH3), 1.98 (s, 3H, C═C—CH3).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[F:15][C:2]([F:1])([F:14])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccccc21)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2,2-trifluoro-1-(indolin-1-yl)ethanone (5 g, 16 mmol) was added to neat chlorosulfonic acid at 0° C. and then the solution was allowed to warm to rt and stirred for an additional 2 hrs. Reaction mixture was slowly added to ice chips and stirred for 10 min then filtered off 4.2 g of the title compound as a dark red colored solid.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[C:15]([CH3:28])[CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[CH:42][N:41]([CH:44]2[CH2:46][CH2:45]2)[C:40](=[O:47])[CH:39]=1>>[CH:44]1([N:41]2[CH:42]=[CH:43][C:38]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:36])[CH3:35])([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][C:15]=3[CH3:28])=[CH:39][C:40]2=[O:47])[CH2:46][CH2:45]1
Reactant: Cc1cc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1cc(Br)ccn1C1CC1
Product: Cc1cc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)ccc1-c1ccn(C2CC2)c(=O)c1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one and 4-bromo-1-cyclopropyl-1H-pyridin-2-one following a procedure analogous to that described in Step 5 of Example 96. LC-MS (Method 5): tR=3.42 min; Mass spectrum (ESI+): m/z=501 [M+H]+.