Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:20]=[N+]=[N-])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:20][C:42](=[O:44])[CH3:43])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1nc2c(s1)C(N=[N+]=[N-])COc1ccc(Br)cc1-2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc2c(s1)C(NC(C)=O)COc1ccc(Br)cc1-2
Temperature: 65 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of 4-Azido-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (280 mg, 0.735 mmol) in THF/water (15 mL/3 mL) was added PPh3 (192.5 mg, 0.735 mmol). The reaction mixture was heated to 65° C. overnight. The mixture was cooled to −5° C., and TEA (222 mg, 2.200 mmol) was added followed by acetyl chloride (86.5 mg, 1.101 mmol). Then the mixture was stirred at room temperature for 1 h. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude product which was triturated with EtOAc and hexane (1:1) and then filtered to afford 4-Acetylamino-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (160 mg, 51%). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, J=2.5 Hz, 1H), 8.48 (s, 1H), 7.53 (dd, J1=8.7 Hz, J2=2.6 MHz, 1H), 7.13 (d, J=8.6 Hz, 2H), 5.51 (m, 1H), 4.41 (m, 1H), 4.23 (m, 1H), 3.96 (s, 3H), 1.90 (s, 3H); LC-MS (ESI & APCI): 399.1 (M+2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Br)(Br)([Br:14])=O>>[Br:14][C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=c1[nH]c2ccc(Br)cc2[nH]1
Reactant: O=P(Br)(Br)Br
Product: Brc1ccc2[nH]c(Br)nc2c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
4.5 g (21.12 mmol) of 5-bromo-1,3-dihydrobenzimidazol-2-one is added batchwise at 60° C. to a melt of 30.27 g (105.6 mmol) of phosphorus oxybromide and the reaction mixture is stirred for 5 hours at 110° C. Then the reaction mixture is poured onto water and the precipitate formed is filtered off. The precipitate is stirred with DIPE/acetone (4:1) and the solid is filtered off. The solid is dried in the circulating air dryer at 50° C. Yield: 3.4 g (58% of theoretical); C7H4Br2N2 (M=275.92); calc.: molpeak (M+H)+: 275/277/279; found: molpeak (M+H)+: 275/277/279; Rf value: 0.6 (silica gel, DCM/MeOH 10:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH:16]([CH3:18])[CH3:17])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 93.8 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and isopropylamine (0.35 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-isopropyl-2-(trifluoromethyl)benzenesulfonamide (0.50 g, 95%) was provided after purification. MS (ESI) m/z 346. HPLC purity 100.0% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:18])[C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].CN1CCOCC1.[C:26]([O:29][C@H:30]([CH3:58])[C@H:31]([NH:36][C:37]([C:39]1([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:43][CH2:42][CH2:41][N:40]1[C:44]([C@@H:46]1[CH2:50][CH2:49][CH2:48][NH:47]1)=[O:45])=[O:38])[C:32]([O:34][CH3:35])=[O:33])(=[O:28])[CH3:27]>C(Cl)Cl.CN(C=O)C>[CH3:35][O:34][C:32](=[O:33])[C@@H:31]([NH:36][C:37]([C:39]1([CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:43][CH2:42][CH2:41][N:40]1[C:44]([C@@H:46]1[CH2:50][CH2:49][CH2:48][N:47]1[C:7](=[O:9])[C@@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:18])=[O:45])=[O:38])[C@H:30]([O:29][C:26](=[O:28])[CH3:27])[CH3:58]
Reactant: CC(=O)O[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)[C@@H]1CCCN1)[C@@H](C)OC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OC(C)=O)[C@@H](C)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
To a solution of compound (2S,3R)-3-acetoxy-2-(tert-butoxycarbonylamino)-butanoic acid 12 (199 mg, 0.76 mmol) in CH2Cl2 (6 mL) was under inert atmosphere were added IBCF (125 mg, 0.91 mmol) and NMM (154 mg, 1.52 mmol) at −15° C. and stirred for 1 h. A solution of (2S,3R)-methyl 3-acetoxy-2-(2-benzyl-1-((S)-pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamido)-butanoate 8 (350 mg, 0.76 mmol) in DMF (2 mL) was added to the reaction mixture and stirred for 1 h at −15° C. The resultant reaction mixture was allowed to warm to RT and stirred for 19 h. The reaction mixture was extracted with EtOAc and the separated organic layer was washed with water (20 mL), followed by brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford compound 13 (100 mg, 20%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:17]1([S:16][CH2:15][CH2:14][CH2:13][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCCSc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCSc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
0.69 g of 4-hydroxybenzaldehyde were dissolved in 30 ml of DMF, and the resultant solution was further added with 0.24 g of 60% NaH while cooling the solution with ice and then stirred for 1 hour after elevating the temperature of the solution to room temperature. Further, the solution was fed dropwise with 1.0 g of 1-chloro-3-phenylthio propane while cooling the solution with ice and then stirred for 1 hour at room temperature and further for a night at 50-60° C. After completed the reaction, the solution reacted was poured into ice-water and extracted with ethyl acetate. The organic layer resulted was then washed with aqueous solution of sodium hydroxide and dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 1.2 g of 4-(3-phenylthiopropyloxy)-benzaldehyde.
Reaction SMILES: [CH3:1]C(C)=CCCC(=O)C.[CH3:10][C:11]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:12][CH2:13][C:14]([OH:16])=[O:15].[Cl-].[C:24]([CH2:27]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O>CS(C)=O>[CH3:10][C:11]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:12][CH2:13][C:14]([O:16][CH3:1])=[O:15].[CH3:10][C:11]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:12][CH2:13][C:14]([O:16][CH2:24][CH3:27])=[O:15]
Reactant: CC(=O)CCC=C(C)C
Reactant: CC(C)=CCCC(C)=CCC(=O)O
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CS(C)=O
Product: CCOC(=O)CC=C(C)CCC=C(C)C
Product: COC(=O)CC=C(C)CCC=C(C)C

Procedure:
6-Methyl-5-hepten-2-one is converted into 4,8-dimethylnona-3,7-dienoic acid by reaction with β-carboxyethyltriphenylphosphonium chloride in dimethylsulfoxide using the method of H. S. Corey et al., J. Am. Chem. Soc. 86, 1884 (1964). The trans and cis isomer can be separated by chromatography at this point or a mixture of the two isomers employed in further reactions. The acid is then converted into the acid chloride using thionyl chloride at roomm temperature or slightly higher. The acid chloride is then treated with an alcohol, such as methanol or ethanol, at a temperature of about 40° for a few minutes to yield the ester, methyl 4,8-dimethylnona-3,7-dienoate and ethyl 4,8-dimethylnona-3,7-dienoate.
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].S(C)C.[C:18]([Mg]Br)([CH3:20])=[CH2:19]>C1COCC1>[C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[CH2:7][CH2:8][CH:9]([C:18]([CH3:20])=[CH2:19])[CH2:10][C:11]1=[O:12])([O:3][CH3:4])=[O:2]
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Reactant: C=C(C)[Mg]Br
Solvent: C1CCOC1
Solvent: CSC
Product: C=C(C)C1CCC(CC)(CC(=O)OC)C(=O)C1
Yield: 71 %

Procedure:
The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexene-1-one, (X), prepared in Example 1, Step (c), (33.12 mmol, 6.50 g), CuBr.Me2S (3.312 mmol, 681 mg) and Me2S (6.63 ml) were stirred in 97.5 ml of dry THF at -40° C. under nitrogen and treated with 49.68 mmol (66.24 ml of 0.75M in THF, prepared from treating isopropenyl bromide with 1.1 equivalents of Mg) of isopropenylmagnesium bromide added dropwise. The reaction was quenched with 120 ml of 1M HCl (aq.) and extracted with 4×60 ml of petroleum ether. Drying (Na2SO4) and flash chromatography afforded 5.6 g (23.53 mmol, 71%) of colorless oil as a mixture of diastereomers. The diastereomers were separted by preparative HPLC on a Prep 500A using a brand of silica gel available from Waters Associaes, Milford, Ma., to provide a "less polar isomer" and a "more polar isomer."
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCOCC.CC(C)=O>C(Cl)(Cl)Cl>[Cl-:1].[C:4]([CH2:3][CH2:2][P+:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:6])=[O:5]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCl
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of 5.4 g (50 mmol) of 3-chloropropionic acid and 13.1 g (50 mmol) of triphenylphosphine were heated for 2 hours at 145° C. and 2 hours at 95° C. The product, a glassy solid, was dissolved in 200 mL of CHCl3, to which was added 100 mL of Et2O. The volume was reduced to 250 mL. 5 mL of acetone was added to the solution. After 2 hours, 10.98 g of a solid was collected and used immediately in the manner described in Example 29, below.
Reaction SMILES: O.[C:2]([O-:9])(=[O:8])[C:3]([C:5]([O-:7])=[O:6])=O.[Na+].[Na+].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl>[C:12]1([NH:18][N:19]=[C:3]([C:5]([OH:7])=[O:6])[C:2]([OH:9])=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccc1
Reactant: O=C([O-])C(=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=NNc1ccccc1)C(=O)O

Procedure:
Sodium mesoxalate monohydrate (5.00 g, 27.8 mmol) was dissolved in 1 M hydrochloric acid (50 ml) to give a colourless cloudy solution. Phenylhydrazine (3.00 g, 2.72 ml, 27.8 mmol) was added dropwise at room temperature to the stirred mixture. A yellow precipitate formed, was collected by filtration after 90 min and washed with water (50 ml). The filter cake was triturated with ethyl acetate/hexane [1:1], filtered and dried under vacuum. The title compound was isolated as a yellow powder (4.74 g, 22.7 mmol, 82%). LCMS: m/z 207 [M−H]+.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([CH:14]3[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1C=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][N:33]=1.BrC1[N:48](C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:35]4[C:36]([O:38][CH3:39])=[N:48][C:32]([O:31][CH3:30])=[N:33][CH:34]=4)=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[CH:14]2[CH2:15][N:16]([CH3:22])[C:17](=[O:21])[N:18]([CH3:20])[CH2:19]2)=[CH:24][CH:25]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(C1CN(C)C(=O)N(C)C1)C2=O
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Reactant: COc1cc(OC)c(B(O)O)cn1
Agent: COc1ccc(C#N)cc1B(O)O
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(C2CN(C)C(=O)N(C)C2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-phenyl)-5-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate P) and 2,4-dimethoxypyridine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 2.95 min (HPLC 5); ESI-MS: tR=0.99 min, [M+H]+539/541 (LC-MS 1); 1H-NMR (d6-DMSO, 400 MHz): 8.26 (s, 1H), 7.51 (m, 2H), 7.24-7.48 (m, 2H), 6.25 (s, 1H), 5.85 (s, 1H), 4.08 (m, 1H), 3.95 (s, 3H), 3.90 (m, 1H), 3.89 (s, 3H), 3.81 (m, 1H), 3.23 (m, 1H), 3.11 (m, 1H), 2.93 (m, 1H), 2.70 (s, 3H), 2.61 (s, 3H), 1.28 (m, 3H), 0.40 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:16]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=[C:23]([CH3:35])[C:22]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=1)(=[O:18])[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:16]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=[C:23]([CH3:35])[C:22]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH:37]=1)(=[O:18])[CH3:17]
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: CC(=O)OCc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4COC(C)=O)c3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {3′-(hydroxymethyl)-6-methyl-4-[3-(methylsulfonyl)propoxy]biphenyl-2-yl}methyl acetate (0.360 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 3 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.432 g, yield 79%) as a colorless oil.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:26]C(=O)OC(C)(C)C)([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.[CH2:35]([O:42][C:43]1[CH:44]=[C:45]([SH:49])[CH:46]=[CH:47][CH:48]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[NH2:26][C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:49][C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:44]=3)[CH:14]=2)[CH:9]=1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)COC(C)(C)OC1
Reactant: Sc1cccc(OCc2ccccc2)c1
Product: NC(CO)(CO)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1

Procedure:
The compound was prepared from tert-butyl 2,2-dimethyl-5-(6-(trifluoromethylsulfonyloxy)naphthalen2-yl)-1,3-dioxan-5-ylcarbamate and 3-benzyloxy-benzenethiol in reactions analagous to those described in Examples 154 and 191. 1H NMR (MeOD) δ: 7.82 (s, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.71 (s, 1H), 7.48 (dd, J=8.6, 2.0 Hz, 1H), 7.31 (dd, J=8.6, 1.5 Hz, 1H), 7.11-7.26 (m, 6H), 6.80-6.89 (m, 3H), 4.93 (s, 2H), 3.95-4.03 (m, 2H), 3.86-3.94 (m, 2H). MS (M+1): 432.0.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]=O)=[C:5]([CH3:11])[N:4]([CH:12]([CH3:14])[CH3:13])[C:3]1=[O:15].BrBr.C(O[CH2:22][CH3:23])(=O)C>C(Cl)(Cl)Cl.ClCCl>[CH2:13]1[C:22]2[C:23](=[CH:11][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH:12]1[N:4]1[CH:9]=[C:6]2[C:5]([N:4]([CH:12]([CH3:14])[CH3:13])[C:3](=[O:15])[N:2]([CH3:1])[C:7]2=[O:8])=[CH:11]1
Reactant: CCOC(C)=O
Reactant: Cc1c(C=O)c(=O)n(C)c(=O)n1C(C)C
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1c(=O)n(C)c(=O)c2cn(C3Cc4ccccc4C3)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,6-Dimethyl-5-formyl-1-(1-methylethyl)pyrimidine-2,4-dione (J. Med. Chem., 1995, 38, 2557; 1.70 g) was dissolved in chloroform (25 ml) and the solution was heated to 50° C. A solution of bromine (0.413 ml) in chloroform (20 ml) was added dropwise to the aldehyde solution over 24 minutes. The reaction was maintained at 50° C. for a further 15 minutes, then allowed to cool to ambient temperature. The reaction mixture was diluted with dichloromethane and was washed successively with water, dilute sodium thiosulphate solution (twice) and brine. The resultant solution was dried, filtered and evaporated to a crude oil which was dissolved in ethanol (50 ml). Triethylamine (3.38 ml) was added to the solution followed by 2-aminoindane (1.49 g) and the mixture was stirred under nitrogen overnight. The reaction mixture was filtered, the white solid collected was washed with a little ethanol and the filtrate was evaporated to give a brown oil. Ethyl acetate was added to the oil and the resultant precipitate was collected by filtration and was washed with a little ethyl acetate. The filtrate was washed with hydrochloric acid (HCl) (2.5 M) and then brine. The resultant ethyl acetate phase was dried, filtered and evaporated to an oil. The oil was purified by chromatography, eluting with isohexane:acetone (4:1) to give a solid which was triturated with hot ethyl acetate:isohexane (3:1) to give the subtitle compound (0.50 g).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:32]([OH:35])(=[S:34])[CH3:33].[Na].C(O)(=S)C.[H-].[Na+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][S:34][C:32](=[O:35])[CH3:33])[CH2:16][CH2:17]2)=[O:11])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: CC(O)=S
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of N-p-nitrobenzyloxycarbonyl-4-p-toluenesulfonyloxymethylpiperidine (3.72 g) in dry dimethylformamide (10 ml) was added to a solution of sodium thioacetic acid (1 g) prepared from thioacetic acid and sodium hydride in dry dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 4 hours, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give a residue which was then purified by silica gel column chromatography to give N-p-nitrobenzyloxycarbonyl-4-acetylthiomethylpiperidine.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1>>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:29]3[CH:30]=[N:31][CH:32]=[C:27]([F:26])[CH:28]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1cncc(F)c1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3cncc(F)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 5-fluoropyridine-3-boronic acid using a procedure analogous to that described in Example 64. LC-MS Method 1 tR=1.84 min, m/z=417 (M+1); 1H NMR (CDCl3) 8.58 (s, 1H), 8.45 (d, 1H, J=3 Hz), 7.57-7.54 (m, 1H), 7.39-7.30 (m, 5H), 7.27-7.25 (m, 2H), 6.93 (d, 2H, J=8 Hz), 5.80-5.68 (m, 2H), 5.11-5.03 (m, 2H), 2.97-2.91 (m, 1H), 2.69-2.55 (m, 2H), 2.41-2.21 (m, 3H), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([C@H:8]1[C:13](=[O:14])[N:12]([CH2:15][C:16]#[N:17])[CH:11]=[CH:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-:29].[NH4+]>CN(C)C=O>[ClH:29].[CH2:1]([C@@H:8]1[NH:9][CH2:10][CH2:11][N:12]([CH2:15][C:16]2[NH:17][N:27]=[N:26][N:25]=2)[C:13]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C=CN(CC#N)C(=O)[C@@H]1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: O=C1[C@H](Cc2ccccc2)NCCN1Cc1nnn[nH]1
Temperature: 100 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
A mixture of 1.0 g of (S)-2-benzyl-1-t-butoxycarbonyl-4-cyanomethyl-1,2,3,4-tetrahydropyrazin-3-one, 0.31 g of sodium azide, 0.25 g of ammonium chloride and 6 ml of N,N-dimethylformamide was stirred for 6 hours at 100° C. The reaction mixture was poured into ice-water, which was subjected to extraction with methylene chloride. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. To the solution of 1.0 g of the residue in 15 ml of ethanol was added 0.5 g of 10% palladium-carbon. The mixture was stirred for 20 hours in a hydrogen stream. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. To 1.0 g of the concentrate was added 8 ml of an ethyl acetate solution of 4N HCl, and the mixture was stirred for 3 hours at room temperature. Resulting precipitates were collected by filtration and recrystallized from methanol to afford 0.7 g of the title compound as colorless crystals, m.p.245°-247° C. (decomp.).