Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:59])[C@H:41]([CH:56]([CH3:58])[CH3:57])[NH:42][C:43]([N:45]([CH2:47][C:48]1[N:49]=[C:50]([CH:53]([CH3:55])[CH3:54])[S:51][CH:52]=1)[CH3:46])=[O:44])[CH2:9][C@H:10]([O:29][CH:30](SCC(C)C)[CH:31]([CH3:33])[CH3:32])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:60](=[O:64])([OH:63])([OH:62])[OH:61].IN1C(=O)CCC1=O.C([O-])([O-])=O.[Na+:77].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CO>[CH2:1]([C@H:8]([NH:39][C:40](=[O:59])[C@H:41]([CH:56]([CH3:58])[CH3:57])[NH:42][C:43]([N:45]([CH2:47][C:48]1[N:49]=[C:50]([CH:53]([CH3:55])[CH3:54])[S:51][CH:52]=1)[CH3:46])=[O:44])[CH2:9][C@H:10]([O:29][CH:30]([O:64][P:60]([O-:63])([O-:62])=[O:61])[CH:31]([CH3:33])[CH3:32])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:77].[Na+:77]
Reactant: O=P(O)(O)O
Reactant: CC(C)CSC(O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C(C)C
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](OC(OP(=O)([O-])[O-])C(C)C)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution containing the product from Example 13A (0.888 g, 1.03 mmol), molecular sieves (4 Å, 3.5 g), and phosphoric acid (0.50 g) in DMF (20 mL) at 0° C. was added N-iodosuccinimide (0.46 g), and the mixture was stirred at 0° C. for 1 hour. To the cold reaction mixture was added 10% Na2CO3 to adjust the pH to 9, and the mixture was diluted with methanol, treated with 1 M Na2S2O3 until it was clear, and filtered to remove the solids. The solvent was evaporated, and the crude product was purified by HPLC using C18 column, eluting with a gradient starting with water and ending with methanol to give the product (0.49 g, 52% yield). 1H NMR (300 MHz, MeOH-d4), δ ppm 0.86-1.03 (m, 12H), 1.33-1.36 (m, 6H), 1.44-1.75 (m, 1H), 1.85-2.27 (m, 3H), 2.54-2.9 (m, 5H), 3.01 (s, 3H), 3.78-4.38 (m, 4H), 4.46-4.68 (m, 2H), 4.91-5.15 (m, 3H), 6.97-7.26 (m, 11H), 7.64-7.73 (m, 1H), 8.91-8.92 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[N:19]3)[N:16]=2)[N:11]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:10]=1)=[O:8])([CH3:5])[CH3:4]>FC(F)(F)CO>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[N:19]3)[N:16]=2)[N:11]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:46])([CH3:45])[CH3:47])[CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(C4CCN(C(=O)OC(C)(C)C)CC4)c4ccccc43)nc12
Solvent: OCC(F)(F)F
Product: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(C4CCNCC4)c4ccccc43)nc12

Procedure:
A stirred solution of tert-butyl 4-(1-(7-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-3-yl)piperidine-1-carboxylate (120 mg, 181 μmol) in 2,2,2-trifluoroethanol (2 mL) was heated in a microwave at 150° C. for 4 h. The mixture was concentrated in vacuo and used in the next step without purification.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]([NH2:11])([CH2:7][CH2:8][CH2:9][NH2:10])[C:4]([OH:6])=[O:5].Cl.O.FC(F)C(N)(CCCN)C(O)=O.[CH2:27]([O:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S>O.[Cu].C(=O)([O-])[O-].[Cu+2]>[NH2:11][C:3]([CH:2]([F:12])[F:1])([CH2:7][CH2:8][CH2:9][NH:10][C:35]([O:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:36])[C:4]([OH:6])=[O:5]
Reactant: NCCCC(N)(C(=O)O)C(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cu+2]
Agent: [Cu]
Agent: Cl
Solvent: O
Product: NC(CCCNC(=O)OCc1ccccc1)(C(=O)O)C(F)F

Procedure:
To a solution of the copper salt of 2-difluoromethyl-2,5-diaminopentanoic acid in water, prepared by reacting 2-difluoromethyl-2,5-diaminopentanoic acid monohydrate hydrochloride (2.4 g) with copper carbonate (6 g), is added slowly at 0° C. with stirring 1.1 g of benzylchloroformate. The reaction mixture is stirred for an additioal 3 hours at room temperature after which hydrogen sulfide is passed through the solution until it becomes colorless. The precipitate is filtered off, and the pH of the aqueous solution is adjusted to 6 by the addition of hydrochloric acid. Upon concentration 2-amino-5-benzyloxycarbonylamino-2-difluoromethylpentanoic acid is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O.[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:14][C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(C(=O)Nc2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 817.5 %

Procedure:
4-Acetylbenzoic acid (4.00 g, 24.4 mmol), 5-aminotetrazole monohydrate (3.00 g, 2.91 mmol) and ethyl dimethylaminopropyl carbodiimide hydrochloride (7.00 g, 3.55 mmol) were dissolved in DMF (25 mL) and stirred at ambient temperature for 48 hours. The reaction mixture was poured into ice-water, and the precipitate collected by filtration to afford 5.50 g (98%) of pure 4-acetyl-N-(2H-tetrazol-5-yl)benzamide after drying overnight in a vacuum oven.
Reaction SMILES: [C:1]([NH:5][C:6]([NH2:8])=[S:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[C:11](=O)[C:12]([O:14][CH3:15])=[O:13]>CO>[CH3:2][C:1]([NH:5][C:6]1[S:7][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:11]([C:12]([O:14][CH3:15])=[O:13])[N:8]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1Cl
Reactant: CC(C)(C)NC(N)=S
Solvent: CO
Product: COC(=O)c1nc(NC(C)(C)C)sc1-c1ccccc1Cl
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A reaction vessel was charged with 50 ml methanol and 4 g (30 mmol) of tert-butyl thiourea. With this mixture stirred and cooled in an ice bath, there was added over a 5-minute period 7.41 g of (30 mmol) methyl 3-chloro-3-(o-chlorophenyl)pyruvate. The reaction mixture was refluxed for 16 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure to yield 9.18 g of a yellow solid which became a hard, glass-like material. This material was recrystallized from an acetone-water solution to yield 7.0 g of a yellow solid product (m.p.=159°-161° C.) identified in Table I.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16]2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.Cl>O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Temperature: 130 °C
Yield: 67.1 %

Procedure:
In a 10 L 3-necked round bottom flask equipped with reflux condenser, mechanical stirrer and a stopper, a mixture of crude N-(4-bromophenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (108.29 g, 63% purity, 167 mmol) and potassium carbonate (115 g, 833 mmol) in water (6 L) was stirred at reflux (variac heating mantle ˜130° C.) for 18 h. The variac heating was turned off and the flask was removed from the mantle and allowed to cool to ˜70° C. White solid settled to the bottom of the flask during this time. The liquid layer was siphoned into 2 L Erlenmeyer flasks using gravity and tygon tubing initially filled with water. When no more liquid could be siphoned, the remaining slurry was filtered. The filtrate was added to an Erlenmeyer flask and all the contents of these flasks were concentrated in vacuo using a large Buchi rotovap. LCMS analysis of the filtered white solid showed that it contained desired product. The filtered solid was added to the solid obtained from rotovapping. Ethyl acetate (2 L) and water (500 mL) were added to the contents of the flask and the mixture was acidified to pH˜5.5 using 6N aq HCl solution. The aqueous layer was extracted with ethyl acetate (5×500 mL). Then the aqueous layer was divided into 3 smaller portions and each was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a white solid. Trituration of the solid with dichloromethane (50 mL) followed by vacuum suction drying provided the title compound as a white solid (59.27 g, 74% pure, 112 mmol, 67% yield). MS(ES)+ m/e 391.1, 393.3 [M+H]+. The filtrate was concentrated in vacuo, dissolved in minimal dichloromethane and loaded directly onto a silica gel column. Purification by silica gel chromatography (Analogix IF280, 0-100% 10% MeOH in CH2Cl2/CH2Cl2 (effectively 0-10% MeOH/CH2Cl2), SF65-400 g, 60 min) provided another batch of the title compound as a white solid (9.5 g, 90% pure, 22 mmol, 13%). Impure product could be further purified by silica gel chromatography (Analogix IF280, 0-5% MeOH/CH2Cl2 over 30 min, then 5-10% MeOH/CH2Cl2 over 15 min) to afford clean desired product as a white solid. Purified material was used in subsequent reactions. MS(ES)+ m/e 391.1, 392.8 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH2:8][C:9]#[N:10])[N:5]=[CH:4]1.F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(Cl)Cl>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:3]1[CH:7]=[C:6]([CH2:8][C:9]#[N:10])[N:5]=[CH:4]1
Reactant: Fc1ccccn1
Reactant: N#CCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCc1cn(-c2ccccn2)cn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
Sodium hydride (63% mineral oil dispersion, 4.71 g) was added over 15 minutes to a solution of 1H-imidazol-4-ylacetonitrile (13.25 g) in N,N-dimethylformamide (46 mL) cooled to 0° C. Then, a solution of 2-fluoropyridine (12.61 g) in N,N-dimethylformamide (23 mL) was added thereto at room temperature, and the mixture was stirred at 100° C. for 5 hours. To the reaction solution, ice water was added, and methylene chloride was added. The formed solid was removed by suction filtration, and the organic layer was then separated and dried over anhydrous magnesium sulfate. Volatile matter was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (18.5 g, mixture with N,N-dimethylformamide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:16]=3[O:15][CH2:14]2)=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]([O:44][C:45]([NH:47][CH:48](P(OC)(OC)=O)[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl.O>[CH3:52][O:51][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[O:46])=[CH:23][C:21]1[CH:20]=[CH:19][C:17]2[O:18][C@@H:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)=[CH:12][CH:11]=3)[CH2:14][O:15][C:16]=2[CH:22]=1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: O=Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COC(=O)C(=Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (9.9 g) was dissolved in 80 mL dry DCM under nitrogen at rt and 7.2 mL DBU (7.33 g) was added by syringe. 7.44 g of Boc-phosphonoglycine trimethyl ester in 40 mL dry DCM was added by syringe all at once and the mixture stirred at rt for 18 h. It was then diluted with 0.5 L each of DCM and water and extracted, and the organic layer was dried with brine and Na2SO4 and evaporated. The residue was purified by crystallization from EtOAc/hexanes to give 12 g desired product after drying under vacuum. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.34 (m, 2H), 7.28-7.24 (m, 1H), 7.23-7.17 (m, 2H), 7.11 (m, 1H), 6.98 (m, 2H), 6.93 (d, 1H), 5.10 (m, 1H), 5.03 (s, 2H), 4.32 (m, 1H), 4.01 (m, 1H), 3.84 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH2:15][CH2:16][CH2:17][C:18](=O)[C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1>CCO.O>[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH2:15][CH2:16][CH2:17][C:18](=[N:2][OH:3])[C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3ccc(Br)cc31)CCCC2=NO
Yield: 88.4 %

Procedure:
Hydroxylamine hydrochloride (0.56 g, 8.1 mmol) and sodium acetate (0.66 g, 8.1 mmol) were added to a suspension of 7-bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.5 g, 5.4 mmol) in EtOH (14 mL) and H2O (5.0 mL), and the resulting suspension was heated at reflux for 18 h. The reaction was cooled and concentrated to dryness. The resulting solid was triturated with MeOH (100 mL), and the solids were dried to yield the title compound (1.4 g, 90%) as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.66 (s, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.15 (dd, J=8.5, 1.0 Hz, 1H), 3.95 (s, 3H), 2.79-2.72 (m, 4H), 1.88-1.83 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH:2]=[CH2:3].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:12])[C:10](=[N:14][OH:15])[NH2:11])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C#N)ccc1O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCc1cc(C(N)=NO)ccc1O
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A solution of 2-allyl-4-cyanophenol (5.5 g), hydroxylamine hydrochloride (8.5 g) and sodium carbonate (6.1 g) in aqueous ethanol was heated at reflux for 3 hours. The solution was cooled to ambient temperature and the ethanol was removed by evaporation. The solid was collected by filtration, dissolved in ethanol and the solution was filtered. The filtrate was evaporated and the residual solid was triturated with hexane to give 3-allyl-4-hydroxybenzamidoxime as a solid (5.5 g), m.p. 144° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.[C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:26][CH2:25][CH2:24][N:23]([CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:28](=[O:30])[CH3:29])[CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCNCC4)n3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)OCCCCN1CCCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS401 starting from 68 mg (0.19 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pyridin-2-yl]-1,4-diazepane and 34 μl of bromobutyl acetate using 2 equiv. of potassium carbonate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:7][N:6]=[CH:5]2.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[F:50][C:51]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:52]=1[NH2:53]>C1(C)C=CC=CC=1.CO.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]>[F:50][C:51]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:52]=1[NH:53][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:7][N:6]=[CH:5]2
Reactant: CC(Oc1nncc2cc(Br)ccc12)C(F)(F)F
Reactant: Nc1ccc(F)cc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(Oc1nncc2cc(Nc3ccc(F)cc3F)ccc12)C(F)(F)F
Temperature: 140 °C

Procedure:
A mixture of 6-bromo-1-(1,1,1-trifluoropropan-2-yloxy)phthalazine (0.130 g, 0.40 mmol), sodium t-butoxide (0.056 g, 0.58 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.016 g, 0.017 mmol), 2-(dicyclohexylphosphino)biphenyl (0.022 g, 0.063 mmol) and 2,4-difluoroaniline (0.060 ml, 0.60 mmol) in 1.5 mL of toluene was heated at 140° C. for 15 min in the microwave (Initiator by Biotage). The mixture was diluted with MeOH, evaporated onto silica gel and purified by flash chromatography (ISCO 12 g, eluting with 15-75% EtOAc in hexanes) to give the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion) m/z: M+1=370.1
Reaction SMILES: C(Cl)Cl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:14]([O:17][C:18]1[C:19]([CH3:32])=[C:20]([CH3:31])[C:21]2[O:25][C:24]([CH2:27][OH:28])([CH3:26])[CH2:23][C:22]=2[C:29]=1[CH3:30])(=[O:16])[CH3:15]>C(N(CC)CC)C>[C:14]([O:17][C:18]1[C:19]([CH3:32])=[C:20]([CH3:31])[C:21]2[O:25][C:24]([CH:27]=[O:28])([CH3:26])[CH2:23][C:22]=2[C:29]=1[CH3:30])(=[O:16])[CH3:15]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(CO)O2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(C=O)O2
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
To a methylene chloride solution (50 ml) of oxalyl chloride (2 ml) was added dropwise at -60° C. dimethylsulfoxide (4 ml). The mixture was stirred for 10 minutes, and there was then added dropwise a methylene chloride solution (10 ml) of 5-acetoxy-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran [5.0 g (19 mmol)]. The reaction mixture was stirred for 15 minutes, and there was added triethylamine (15 ml), and the mixture was stirred for further 10 minutes. The reaction mixture was washed with water and dried, followed by distilling off the solvent. The residue was crystallized from isopropylether-hexane to obtain 5-acetoxy-2-formyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (yield 96.7%), m.p. 78°-79° C.
Reaction SMILES: CS([S:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([CH3:20])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl.CCOCC>[N+](C)([O-])=O>[CH3:20][C:10]1[C:9]2[O:8][CH2:7][CH2:6][S:5][C:19]=2[CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cccc(OCCSS(C)(=O)=O)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)c1ccc2c(c1C)OCCS2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.0 g (3.4 mmol) of ethyl 3-(2-methylsulfonylthioethoxy)-2-methylbenzoate are dissolved in 5 ml of nitromethane. 0.42 g (3.14 mmol) of aluminum trichloride is added. The mixture is stirred at room temperature for 45 min. Working-up is carried out by addition of 10 ml of 2N hydrochloric acid and subsequent extraction with MTB ether. The combined organic phases are washed with water and sodium carbonate solution, dried over sodium sulfate and the solvent is distilled off.
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]([C:9]1[C:13]([CH2:14]O)=[CH:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)[N:10]=1)([CH3:8])[CH3:7].C(OCC)(=O)[CH2:38][C:39]([O:41]CC)=[O:40].[H-].[Na+].Cl>O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:6]([C:9]1[C:13]([CH2:14][CH2:38][C:39]([OH:41])=[O:40])=[CH:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)[N:10]=1)([CH3:7])[CH3:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(C(C)C)n2)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(C(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
Methanesulfonyl chloride was added dropwise to a mixture of [3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]methanol (2.02 g), triethylamine (0.8 ml) and ethyl acetate (30 ml) at 0° C., which was stirred at room temperature for 3 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was dissolved in tetrahydrofuran (20 ml). This solution was added dropwise at 0° C. to separately-prepared tetrahydrofuran solution (30 ml) of sodium diethyl malonate using diethyl malonate (2.35 g) and sodium hydride (60%, oily, 0.55 g). The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was dissolved in ethanol (50 ml), then 1N aqueous sodium hydroxide solution (15 ml) was added to the solution, which was stirred at 60° C. for 2 hours. After the reaction solvent was removed under reduced pressure, water was added to the mixture, which was acidified with dilute hydrochloric acid. After the crystals obtained were filtered and washed with water, the crystals were dissolved in pyridine (50 ml), which was stirred at 120° C. for 2 hours. After pyridine was removed under reduced pressure, the residue was dissolved in ethyl acetate, which was washed with dilute hydrochloric acid, then with saturated aqueous sodium chloride solution, and dried (MgSO4), then concentrated. The crystals obtained were collected by filtration to yield 3-[3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl]-1H-pyrazol-4-yl]propionic acid (1.23 g, yield: 55%). This was recrystallized from ethyl acetate-hexane. Melting point: 97–98° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][C@@H:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[OH:12].[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[OH:12][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[CH2:3][NH:2][CH2:37][C@H:35]([OH:36])[C:26]1[CH:27]=[CH:28][C:29]2[C:30](=[O:34])[O:31][CH2:32][C:33]=2[C:25]=1[CH3:24]
Reactant: Cc1c([C@@H](O)CN2CCCCC2CN)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNCC2CCCCN2C[C@H](O)c2ccc3c(c2C)COC3=O)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[2-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)piperidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(1R)-2-[2-(Aminomethyl)piperidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 6] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].