Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(Cl)Cl.C(N(CC)CC)C.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>O>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
A 1 L round-bottomed flask was charged with tert-butyl piperazine-1-carboxylate (20.70 g, 111 mmol, Sigma-Aldrich, St. Louis, Mo.), 300 mL of CH2Cl2, and triethylamine (17.81 mL, 128 mmol). After cooling to 0° C., 2-thiophenesulfonyl chloride (21.31 g, 117 mmol, Sigma-Aldrich, St. Louis, Mo.) was added and the reaction was stirred at 0° C. for 30 min. The mixture was diluted with water (200 mL) and the layers were separated, dried (MgSO4) and concentrated to give tert-butyl 4-(thiophen-2-ylsulfonyl)piperazine-1-carboxylate (37.0 g) as a white solid. To this solid was added 300 mL of EtOAc, and 4 N HCl in dioxane (100 mL). The mixture was heated to 65° C. to give a clear solution. Over the course of 2 h, a white precipitate formed. The white precipitate was collected by filtration and dried under reduced pressure to give 4-(thiophen-2-ylsulfonyl)piperazine hydrochloride (26.0 g).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ncccc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
0.91 g of sodium ethanethiolate was added to a mixture of 1.29 g of 3-chloro-N-(4-trifluoromethylphenyl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.37 g of 3-ethylsulfanyl-N-(4-trifluoromethylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 9).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>CC(O)C>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: [H][H]
Agent: *C(F)(F)C(*)(F)F
Solvent: CC(C)O
Product: C[C@@H](O)c1ccccc1
Reaction time: 12 h
Yield: 95 %

Procedure:
Chiral hydrogenation of acetophenone was carried out (generally-used procedures; see formula (6) below). The (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 was weighed and placed in a 100 mL glass autoclave equipped with a stirrer coated with polytetrafluoroethylene, and after depressurizing the interior of the vessel to eliminate air, argon was introduced. Acetophenone (600 mg; 5.0 mmol) (made by Nacalai Tesque, Inc.) and 2-propanol (2.5 mL), both of which had been deaerated by argon bubbling in advance, were then added into the vessel by means of a syringe and under an argon gas flow. The procedure of performing pressure reduction and argon introduction while stirring the solution obtained was then repeated 5 times for deaeration. A hydrogen tank was then connected to the autoclave using a hydrogen introduction tube and the replacement of the air inside the introduction tube with hydrogen at 2 atmospheres was performed 5 times. The pressure inside the autoclave was then adjusted to 5 atmospheres and then hydrogen was released carefully until the pressure dropped to 1 atmosphere. After repeating this procedure 10 times, the hydrogen pressure was adjusted to 8 atmospheres and vigorous stirring at 25° C. was performed for 12 hours. After completion of reaction, the solution obtained was concentrated by depressurization. The crude product was then subject to simple distillation under reduced pressure (1 mmHg) to obtain (R)-1-phenylethanol (582 mg; 4.75 mmol; yield: 95%) at an ee of 99% as a colorless oily substance. Both conversion rate and enantiomeric excess were 99% in accordance with GC analysis: GC (column: Chirasil-DEX CB; inner diameter (df): 0.25 mm; size: 0.32 mm×25 m; made by Chromopack, Inc.; column temperature: 105° C.; injection and detection temperature: 200° C.; helium pressure: 41 kPa; retention time (tR) of (R)-1-phenylethanol: 21.7 minutes (99.56%); tR of (S)-1-phenylethanol: 23.5 minutes (0.43%); tR of acetophenone: 9.5 minutes (0.01%)); 1HNMR (400 MHz, CDCl3)δ1.50 (d, 3, J=6.6 Hz, CH3), 4.90 (dq, 1, J=3.3 and 6.6 Hz, CHOH), 7.21-7.41 (m, 5, aromatics); [α]28D: +51.8° (c: 0.984; CH2Cl2); absolute structure: R; literature value: [α]23D+48.6° (c: 0.9-1.1; CH2Cl2), 96% ee (R).
Reaction SMILES: [C:1]([OH:9])(=O)/[C:2](=[C:4](\[CH:6]=O)/[Br:5])/[Br:3].Cl.[F:11][C:12]1[CH:13]=[C:14]([NH:19][NH2:20])[CH:15]=[C:16]([F:18])[CH:17]=1.C(N(CC)CC)C>C(O)C>[Br:3][C:2]1[C:1](=[O:9])[N:19]([C:14]2[CH:13]=[C:12]([F:11])[CH:17]=[C:16]([F:18])[CH:15]=2)[N:20]=[CH:6][C:4]=1[Br:5]
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: NNc1cc(F)cc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1c(Br)c(Br)cnn1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Mucobromic acid (2.8 g, 0.011 moles) was dissolved in ethanol (75 ml) and 3,5-difluorophenyl hydrazine hydrochloride (1.8 g, 0.01 moles) was added. After 30 minutes, triethylamine (1.4 ml, 0.01 moles) was added. The reaction mixture was stirred at room temperature for 3 hours. Evaporated to a low bulk and the residue was suspended in glacial acetic acid (80 ml). Refluxed with stirring overnight to give a brown solution. Evaporated to dryness and triturated with methanol to give the required product as a pale brown solid. (3.4 g, 93%)
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.CS(OC1CCN(C2N=CC(C3CC3)=CN=2)CC1)(=O)=O.[Cl:39][C:40]1[C:41](O)=[CH:42][C:43](=[O:56])[N:44]([C:46]2[CH:51]=[CH:50][C:49]([S:52]([CH3:55])(=[O:54])=[O:53])=[CH:48][C+:47]=2)[CH:45]=1.OC1C(C#N)=CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)C=1>>[Cl:39][C:40]1[C:41]([O:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:42][C:43](=[O:56])[N:44]([C:46]2[CH:47]=[CH:48][C:49]([S:52]([CH3:55])(=[O:53])=[O:54])=[CH:50][CH:51]=2)[CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)C1=C[C+]=C(n2cc(Cl)c(O)cc2=O)C=C1
Agent: CS(=O)(=O)OC1CCN(c2ncc(C3CC3)cn2)CC1
Agent: CS(=O)(=O)c1ccc(-n2cc(C#N)c(O)cc2=O)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)cc2Cl)CC1

Procedure:
Example 226 was prepared according to the procedures described in Example 221 substituting tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate for 1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl methanesulfonate, 2-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-5-(methylsulfonyl)benzene-1-ylium for 4-hydroxy-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile in Step B. 1H NMR (500 MHz, CDCl3) δ ppm 8.07 (d, J=8.25 Hz, 2 H), 7.61 (d, J=8.80 Hz, 2 H), 7.42 (s, 1 H), 6.03 (s, 1 H), 4.52-4.68 (m, 1 H), 3.57-3.73 (m, 2H), 3.40-3.56 (m, 2 H), 3.08 (s, 3 H), 1.76-2.02 (m, 4 H), 1.46 (s, 9H). MS (ESI) 482 (M+H).
Reaction SMILES: [Li]C(CC)C.Br[C:7]1[C:8]2[C:13]([CH:14]=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl>CCOCC.CO>[CH:19]1[C:20]2[C:15](=[CH:14][C:13]3[C:8]([C:7]=2[B:25]([OH:26])[OH:24])=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CO
Solvent: CCOCC
Product: OB(O)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
sec-BuLi (4.3 mL, 6.0 mmol, 1.4M solution in cyclohexane) was added dropwise to a solution of 9-bromoanthracene (1.29 g, 5.0 mmol) in Et2O (20 mL) at 0° C. under N2. The reaction was held at 0° C. for 15 minutes then warmed to rt and stirred an additional 45 minutes. Triisopropylborate (1.5 mL, 6.5 mmol) was added and the reaction was stirred at rt for 18 h. Concentrated HCl (1.0 mL) and MeOH (1.0 mL) was added and the reaction was stirred for 30 minutes. The layers were separated and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with H2O, sat. NaHCO3 (aq.), brine, and then dried over Na2SO4. Filtration and concentration gave 1.05 g of 9-anthraceneboronic acid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:44]=[CH:43][N:42]=[C:41]([C:45]([OH:47])=O)[CH:40]=2)[CH2:35][CH2:34]1.Cl.Cl.[CH3:50][C:51]1([CH3:60])[CH2:56][NH:55][CH2:54][C:53]2[CH:57]=[N:58][NH:59][C:52]1=2.C(N(CC)CC)C>CN(C=O)C>[CH3:50][C:51]1([CH3:60])[CH2:56][N:55]([C:45]([C:41]2[N:42]=[CH:43][N:44]=[C:39]([N:36]3[CH2:37][CH2:38][CH:33]([N:25]4[C:26]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:32][C:24]4=[O:23])[CH2:34][CH2:35]3)[CH:40]=2)=[O:47])[CH2:54][C:53]2[CH:57]=[N:58][NH:59][C:52]1=2
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)Cc2cn[nH]c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.26 mmol) TBTU were added to 80 mg (0.24 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 70.0 mg (0.31 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 1.0 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was purified by preparative HPLC, the product fractions were combined and then lyophilised.
Reaction SMILES: C([O:4][C:5]1[C:43]([Cl:44])=[CH:42][C:8]([C:9]([NH:11][CH:12]2[CH2:18][CH2:17][CH2:16][N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[N:14]([CH2:23][C:24](=[O:40])[NH:25][CH:26]3[CH2:30][C:29](=[O:31])[O:28][CH:27]3[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:13]2=[O:41])=[O:10])=[CH:7][C:6]=1[Cl:45])C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1>ClCCl.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>[CH2:33]([O:32][CH:27]1[CH:26]([NH:25][C:24]([CH2:23][N:14]2[C:13](=[O:41])[CH:12]([NH:11][C:9](=[O:10])[C:8]3[CH:7]=[C:6]([Cl:45])[C:5]([OH:4])=[C:43]([Cl:44])[CH:42]=3)[CH2:18][CH2:17][CH2:16][N:15]2[S:19]([CH3:22])(=[O:20])=[O:21])=[O:40])[CH2:30][C:29](=[O:31])[O:28]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C=CCOc1c(Cl)cc(C(=O)NC2CCCN(S(C)(=O)=O)N(CC(=O)NC3CC(=O)OC3OCc3ccccc3)C2=O)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC(NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N1CC(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 47 %

Procedure:
4-Allyloxy-N-{2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-1-methanesulfonyl-3-oxo-[1,2]diazepan-4-yl}-3,5-dichloro-benzamide (26a) (178 mg, 0.26 mmol) in dichloromethane (6 mL) was treated with DMBA (45 mg, 0.29 mmol) and Pd(PPh3)4 (20 mg, 0.017 mmol) at room temperature for 16 hours. The mixture was diluted with dichloromethane (40 mL), washed with water three times. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a pale yellow solid, that was purified by flash chromatography using dichloromethane/methanol (99.2/0.8 to 97.5/2.5) to afford 78 mg (47% yield) of syn diastereomer (higher Rf) of the title compound and 59 mg (35% yield) of anti diastereomer (lower Rf). 1H-NMR (500 MHz, CDCl3) for the syn diastereomer: δ 1.60-1.70 (m, 1H), 1.88-1.91 (m, 1H), 2.22-2.32 (m, 2H), 2.48-2.58 (m, 1H), 2.84-2.90 (m, 1H), 3.00 (s, 3H), 3.27-3.40 (m, 1H), 4.05-4.18 (m, 2H), 4.22-4.35 (m, 1H), 4.55-4.80 (m, 2H), 4.86-4.89 (d, 1H), 5.10-5.15 (m, 1H), 5.59-5.61 (d, 1H), 6.75-6.77 (d, 1H), 7.05-7.07 (d, 1H), 7.25-7.37 (m, SH), 7.70 (s, 2H); and for the anti diastereomer: δ 1.60-1.80 (m, 1H), 1.85-1.95 (m, 1H), 2.20-2.39 (m, 2H), 2.39-2.50 (m, 1H), 3.00-3.10 (m, 1H), 3.12 (s, 3H), 3.28-3.42 (m, 1H), 4.05-4.15 (m, 2H), 4.28-4.47 (m, 2H), 4.56-4.62 (m, 1H), 4.77-4.83 (d, 1H), 5.10-5.20 (m, 1H), 5.43 (s, 1H), 6.93-6.94 (d, 1H), 7.09-7.11 (d, 1H), 7.25-7.39(m, SH), 7.80 (s, 2H). Analytical HPLC: 11.13 and 11.36 min. LC-MS (ES+) for the mixture of diastereomers: m/e=643, 645 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:17](O)(=O)C>>[NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:2][C:3]([CH3:12])([CH3:17])[CH:4]=[O:11]
Reactant: CC(=O)O
Agent: Nc1ccc(Br)cc1C(O)c1ccccn1
Product: CC(C)(C)C=O

Procedure:
In 20 ml of acetic acid was dissolved 2.0 g of 2-amino-5-bromo-α-(2-pyridyl)benzyl alcohol obtained in (1) together with 0.86 ml of trimethylacetoaldehyde. To the solution was added 0.36 g of sodium borohydride under ice-cooling. The reaction mixture was stirred for 30 minutes at room temperature and then subjected to extraction with a mixture of 100 ml of water and 150 ml of ethyl acetate. The ethyl acetate layer was washed with 1N sodium hydroxide, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=5:1) to afford 5-bromo-2-neopentylamino-α-(2-pyridyl)benzyl alcohol (2.4 g) as an oily product.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.Cl.[CH3:20][NH:21][CH3:22]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:22])[C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC[K]
Reactant: O=C(O)C1OC1C(=O)O
Reactant: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1OC1C(=O)N(C)C
Yield: 39.6 %

Procedure:
Following the procedure of Example 53, monoethyl potassium epoxysuccinate (1.0 g) was successively treated with oxalyl chloride (0.75 g) and a mixture of dimethylamine hydrochloride (1.23 g) and triethylamine (2.04 g) to give 0.37 g of ethyl N,N-dimethyl-2,3-epoxysuccinamate (Compound No. 85) as colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(N(CC)CC)C.[C:20]([Cl:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C1C=CN=CC=1)C.C1COCC1>[ClH:28].[NH:4]1[CH2:3][CH:2]([O:1][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(OC1CNC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g), triethylamine (1.2 mL) and DMAP (7 mg) in THF (10 ml) was added benzoylchloride (0.81 g) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), and 4M hydrogen chloride in ethyl acetate solution (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hr, and the precipitate was collected by filtration to give the title compound (710 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:25][C:26](O)=[O:27])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl>CN(C=O)C.C1(C)C=CC=CC=1.ClCCl>[CH2:19]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([C:8]3[C:7](=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:26](=[O:27])[CH2:25]2)[C:11]1=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCN1C(=O)C(CC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C2(CC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of [3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetic acid (0.28 g, 0.73 mmol) was added one drop of DMF and oxalyl chloride (0.32 mL, 3.7 mmol) in toluene (10 mL). The mixture was stirred at ambient temperature overnight and concentrated under vacuum to dryness to afford a brown oil. This substance was dissolved in dichloromethane (15.0 mL) followed by the addition of tin (IV) chloride (0.07 mL, 0.57 mmol) at 0° C. The mixture was stirred at ambient temperature overnight and quenched with ice water. The mixture was poured into water (100 mL), and the mixture was extracted with dichloromethane (150 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.09 g, 67%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.31 (td, 1H), 7.14 (s, 1H), 7.02 (td, 1H), 6.97-6.92 (m, 2H), 6.22 (s, 1H), 6.03-5.98 (m, 2H), 3.87-3.63 (m, 2H), 3.17 (d, 1H), 2.85 (d, 1H), 1.79-1.66 (m, 2H), 1.41-1.30 (m, 4H), 0.88 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 201.4, 177.5, 154.8, 151.8, 149.6, 143.1, 132.5, 131.6, 128.9, 123.4, 123.2, 108.9, 103.5, 102.6, 102.5, 53.8, 47.7, 40.5, 29.0, 27.1, 22.3, 14.0; MS (ES+), m/z 386.1 (M+23), 364.1 (M+1).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.[CH2:24]([O:31][C:32](=[O:45])[NH:33][C:34]1[C:35]([OH:44])=[N:36][C:37]([CH2:40][CH2:41][CH:42]=[CH2:43])=[CH:38][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:45])[NH:33][C:34]1[C:35]([O:44][CH3:6])=[N:36][C:37]([CH2:40][CH2:41][CH:42]=[CH2:43])=[CH:38][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[O+](C)C
Reactant: C=CCCc1ccc(NC(=O)OCc2ccccc2)c(O)n1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C=CCCc1ccc(NC(=O)OCc2ccccc2)c(OC)n1
Reaction time: 65 h
Yield: 90.7 %

Procedure:
Trimethyloxonium tetrafluoroborate (2.0 g, 13.5 mmol, 1.2 equiv) and 2,6-di-tert-butylpyridine (1.52 mL, 6.76 mmol, 0.6 equiv) were added to a solution of d1 (3.36 g, 11.26 mmol, 1 equiv) in CH2Cl2 (80 mL) at 23° C. The reaction mixture was stirred at that temperature for 65 h, then was partitioned between water (2×50 mL) and CH2Cl2 (2×200 mL) and combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (5% EtOAc in hexanes) to afford e1 (3.19 g, 91%) as colorless oil: IR (cm−1) 3432, 1733; 1H NMR (CDCl3) δ 2.42-2.49 (m, 2H), 2.73 (t, 2H, J=7.6), 3.96 (s, 3H), 4.94-5.07 (m, 2H), 5.20 (s, 2H), 5.80-5.94 (m, 1H), 6.71 (d, 1H, J=7.9), 7.11 (s, br, 1H), 7.32-7.43 (m, 5H), 8.16 (s, br, 1H); Anal. C18H20N2O3: C, H, N.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[C:25]([CH3:27])[CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[F:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:48]=1[C:49](O)=[O:50].C(Cl)Cl>C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:28]3[CH2:29][CH2:30][N:31]([C:49](=[O:50])[C:48]4[C:47]([F:46])=[CH:55][CH:54]=[CH:53][C:52]=4[F:56])[CH2:32][CH2:33]3)=[C:25]([CH3:27])[CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(N3CCNCC3)c(C)c2)cc1
Reactant: O=C(O)c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(N3CCN(C(=O)c4c(F)cccc4F)CC3)c(C)c2)cc1

Procedure:
Place 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(5-methyl-6-piperazin-1-yl-pyridin-3-yl)-urea (300 mg, 0.670 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (154 mg, 0.804 mmol), 2,6-difluorobenzoic acid (127 mg, 0.804 mmol), and 4-N,N-dimethylaminopyridine (15 mg, 0.134 mmol) in acetonitrile (10 mL). Heat the reaction to 60° C. for 18 hours. Cool reaction to room temperature and add CH2Cl2 and water. Separate organic layer and extract aqueous layer with CH2Cl2 (2×20 mL). Combine organic layers, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 10-70% EtOAc:hexane to yield the title compound. MS(ES+): m/z=588.3 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH:18]([CH3:20])[CH3:19])[C:14](OC)=[O:15])[CH2:8]1.[BH4-].[Li+].O1CCCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH:18]([CH3:19])[CH3:20])[CH2:14][OH:15])[CH2:8]1
Reactant: COC(=O)C(C(C)C)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Yield: 97.5 %

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 1.14 g of methyl 2-[5-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]-3-methylbutanoate (less polar isomer), obtained as described in Preparation 99, 144 mg of lithium borohydride, 12 ml of anhydrous tetrahydrofuran and 105 mg of anhydrous methanol were used, to give 1.02 g of the title compound having an Rf value of 0.26 (on silica gel thin layer chromatography, using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) from the less polar diastereomer.