Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.C(N(CC)CC)C>O1CCOCC1.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC1(C)OBOC1(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A suspension of (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 1010 (20.0 g, 52.8 mmol, prepared as described in Example 1, above) in anhydrous 1,4-dioxane (130 mL) was treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol, 1.5 equiv) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II) (Pd(dppf)2Cl2, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 7 h. When HPLC/MS showed the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, and concentrated in vacuo. The residual brown oil was further dried in vacuo to afford the (5S)—N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide 1037 (18.8 g, 94%) as brown solids. This product was directly used in subsequent reactions without further purification. C13H24BFN2O5, HPLC/MS (ESI) m/e 379 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>CO.CCCCCC>[CH3:19][O:16][C:15]([CH:9]1[CH2:10][C:11](=[O:14])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (2S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.52 g, 2.15 mmol) in methanol (10 mL), 2 M solution of TMS-diazomethane (2 mL, 4 mmol) in hexane was added and stirred at room temperature for 15 min. The reaction solvent was removed and the methyl ester product obtained (4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester) was used as such for the next reaction (0.55 g, 100%): MS (ESPOS): 258 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 5.13, 4.86 (bs, 1), 4.02-4.11 (m, 1), 3.73 (s, 3), 3.67-3.72 (m, 1), 2.78 (d, J=4.2 Hz, 2), 2.51 (bs, 2), 1.46 (bs, 9).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C:12]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11](/[CH:33]=[CH:34]/[C:35](OCC)=[O:36])[CH:10]=[N:9]1.[F-].[K+].O>O1CCCC1>[CH3:7][N:8]1[C:12]([NH:13][C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:11]([CH2:33][CH2:34][CH2:35][OH:36])[CH:10]=[N:9]1
Reactant: CCOC(=O)/C=C/c1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(CCCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a suspension of lithium aluminum hydride (5.7 g, 150 mmol) in tetrahydrofuran (200 ml) was added ethyl (E)-3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)acrylate (21.9 g, 50 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. After cooling on an ice bath, potassium fluoride (34 g) and water (10 ml) were added to the reaction mixture. The insoluble materials were removed by filtration. The filtrate was concentrated in vacuo, and the residue was dissolved in chloroform. The solution was washed with 10% aqueous citric acid solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with chloroform to give 3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propanol (14.8 g) as a solid.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][N:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[S:5](=[O:18])(=[O:17])[N:4]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:3]1.C(OCC)(=O)C.Cl>C1COCC1.CO.O>[F:25][C:2]1([F:1])[CH2:7][N:6]([C:8]2[C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12][C:13]=2[Cl:14])[S:5](=[O:18])(=[O:17])[N:4]([CH2:19][C:20]([OH:22])=[O:21])[CH2:3]1
Reactant: CCOC(=O)CN1CC(F)(F)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CN1CC(F)(F)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To ethyl 2-(4,4-difluoro-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetate (40 mg, 0.10 mmol) in THF (10 mL) and MeOH (10 mL), was dropwisely added LiOH monohydrate (21 mg, 0.50 mmol) in water (3 mL) and agitated for 5 hr at room temperature. After addition of ethyl acetate (30 mL) and water (30 mL), pH of the resultant was adjusted to 3 with 1 N HCl and extracted to obtain the organic layer. The organic layer was dried over MgSO4, concentrated under reduced pressure, and crystallized with ethyl acetate (1 mL) and hexane (10 mL), giving the compound of interest (33 mg, 80%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.44 (s, 2H), 4.35 (s, 2H), 4.14-4.03 (m, 4H).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.S(=O)(=O)(O)O>O1CCOCC1>[C:3]([CH2:2][S:1][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:17][CH:16]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)CSC(CC(=O)O)c1ccc(Cl)cc1

Procedure:
To a stirred mixture of mercaptoacetic acid (5.04 g, 3.8 ml, 54.7 mmol) and 4-chlorocinnamic acid (10.0 g, 54.7 mmol) in 20 ml of dioxane is added dropwise a solution of triethylamine (6.90 g, 9.53 ml, 68.0 mmol) in 20 ml of dioxane. The mixture is heated under reflux for 5 hours, then cooled and poured into ice, acidified with conc. sulfuric acid and extracted with ether. The combined ether extracts are washed with water and with brine, dried and stripped of the solvent. The residue is washed with chloroform to give 3-carboxymethylthio-3-(4-chlorophenyl)propionic acid, a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=O.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1CCl.[OH-].[K+].Cl.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C(O)C.O.ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]2[C:15]=1[CH2:8][CH:2]([CH3:1])[C:3]2=[O:5]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CC1Cc2c(Cl)cc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium ethoxide in ethanol obtained from 4.80 g (0.21 mol) of sodium and 120 ml of anhydrous ethanol, a solution of 36.5 g (0.21 mol) of diethyl methylmalonate in 50 ml of ethanol was added dropwise while vigorously stirring for 15 min. Then, 39.1 g (0.20 mol) of 2,4-dichloro-1-(chloromethyl)benzene was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then cooled to room temperature, and a solution of 40 g of potassium hydroxide in 100 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2×200 ml of cold water, and dried in air. The dibacic acid obtained was then dehcarboxylated by heating it at 160° C. for 2 h. To the viscous oil obtained, 40 ml of dichloromethane and 60 ml of SOCl2 were added, and the resulting mixture was refluxed for 2 h. Dichloromethane and an excess of SOCl2 were distilled off, and the residue was dissolved in 50 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 25.3 g (0.19 mol) of AlCl3 in 260 ml of dichloromethane for 1 h at 0° C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 500 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3×300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated fractional distillation in vacuum, bp 135-138° C./1 mm Hg. Yield 37.0 g (86%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([NH:25][C@H:26]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([NH:25][C@@H:26]5[CH2:30][CH2:29][NH:28][CH2:27]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(N[C@H]5CCN(C(=O)OC(C)(C)C)C5)c4n3)cnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1ccn2c(-c3ccc4cccc(N[C@@H]5CCNC5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of (S)-tert-butyl 3-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ylamino)pyrrolidine-1-carboxylate (0.127 g, 0.252 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.389 ml, 5.04 mmol). The resulting mixture was stirred for 2 hours at ambient temperature. The dichloromethane reaction mixture was concentrated under reduced pressure and then diluted with dichloromethane. The resulting solution was washed twice with saturated sodium bicarbonate and twice with a brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification via flash column chromatography (40:1 CH2Cl2/MeOH to 20:1 CH2Cl2/MeOH to 10:1 CH2Cl2/MeOH) produced the title compound (53 mg, 52% Yield). MS APCI (+) m/z 404.3 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.O.Cl.[O:13]=[C:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][N:17]1[CH2:18][CH2:19][C:14](=[O:13])[CH2:15][CH2:16]1
Reactant: O=C1CCNCC1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of 3,4-dichlorobenzyl chloride (2.8 ml), 4-ketopiperidine hydrochloride monohydrate and triethylamine (8 ml) in dimethylformamide (30 ml) was stirred at room temperature for 20 h. The mixture was partitioned between water and ethyl acetate, the organic layer dried and evaporated under reduced pressure. Purification was by chromatography eluting with 40-50% ethyl acetate/isohexane. Yield 2.1 g.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[N:32]1[O:36][N:35]=[C:34]2[C:37]([CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:38][CH:39]=[CH:40][C:33]=12.Cl>>[N:32]1[O:36][N:35]=[C:34]2[C:37]([CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:6][N:5]([C@H:14]([CH2:27][CH:28]5[CH2:29][CH2:30][CH2:31]5)[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[O:16])[CH2:4]4)[CH2:46][CH2:45]3)=[CH:38][CH:39]=[CH:40][C:33]=12
Reactant: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1cc(CCCC2CCNCC2)c2nonc2c1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](CN3CCC(CCCc4cccc5nonc45)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 40.7 %

Procedure:
The title compound was prepared from 20 mg (0.07 mmol) of 2-(R)-(3-(R)formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 19, Step F) and 13.7 mg (0.04 mmol) of 4-(3-(benzofurazanyl)propyl)piperidine.HCl (from EXAMPLE 117, Step B) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 10.6 mg (35%) of the title compound: RF: 0.36 (1:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 0.80-3.32 (m, 33H), 3.80 (s, 31), 5.04-5.13 (m, 2H), 6.88 (d, J=8.6, 21), 7.15-7.37 (m, 8H), 7.51 (s, 1H), 7.73 (d, J=9.3, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[OH-].[Na+].O.NC(C)(CC1C=CC=CC=1OC)C(O)=[O:24]>C(#N)C>[C:13]([NH:14][C:10]([CH3:17])([CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:11]([OH:24])=[O:16])(=[O:15])[NH2:12]
Reactant: COc1ccccc1CC(C)(N)C(=O)O
Reactant: COc1ccccc1CC1(C)NC(=O)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1CC(C)(NC(N)=O)C(=O)O

Procedure:
First, 4.40 g of 5-(2-methoxyphenylmethyl)-5-methyl-hydantoin was mixed with 2.64 g of sodium hydroxide and 3.5 g of water, and the mixture was subjected to reaction at 94° C. to 96° C. for 30 hours. The HPLC analysis (column: COSMOSIL 5C18-ARII (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=20/80, flow rate: 1.0 ml/min, detection wavelength: 210 nm, column temperature: 40° C.) of the reaction mixture showed the production of the title compound, 2-amino-3-(2-methoxyphenyl)-2-methyl propionic acid, and the raw material at an area ratio of 78.8:5.5:15.5.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[N:9]1[C:17](=[O:34])[CH:18]([NH:23]C(OCC1C=CC=CC=1)=O)[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([CH:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[N:9]1[C:17](=[O:34])[CH:18]([NH2:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CC2CCCCC2N1C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CC2CCCCC2N1C(=O)C(N)C(C)(C)C
Yield: 100 %

Procedure:
Ester 13b (4.0 g, 8.4 mmol) was stirred in EtOH (40 mL) charged with 400 mg 10%Pd(OH)2/C. H2 gas was bubbled into the suspension until the reaction was complete. Catalyst was removed by filtration and the filtrate concentrated in vacuo to give 1-(2-amino-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic acid tert-butyl ester 14b (2.8 g, 8.4 mmol, 100%) which was used as is in the next step without further purification.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C>O1CCOCC1.O>[CH2:13]([O:12][C:10]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([OH:2])[CH2:4]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCC(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypiperidine hydrochloride (20.0 g, 0.145 mol) in dioxane (500 ml) and water (500 ml) was added benzyl chloroformate (24.88 ml, 0.17 mol) and triethylamine (101 ml, 0.73 mol). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ether and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified through chromatography on silica gel (eluent: 1:1 ethyl acetate/hexane) and the title compound was obtained as a pale yellow viscous oil (20.7 g, 88 mmol, yield 61%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=[C:23]([CH3:25])[N:24]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.C1CC=CCC=1>CO.[Pd]>[CH3:25][C:23]1[N:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][NH2:10])=[CH:15][CH:16]=2)[O:21][CH:22]=1
Reactant: Cc1coc(-c2ccc(OCCNC(=O)OCc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCC=CC1
Product: Cc1coc(-c2ccc(OCCN)cc2)n1
Yield: 90 %

Procedure:
The title compound of Example 1, {2-[4-(4-Methyl-oxazol-2-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester, (166 mg, 0.47 mmol) was dissolved in methanol (5 ml) and 10% Pd/C (50 mg) and 1,4-cyclohexadiene (192 mg, 2.4 mmol) were added to the resulting solution. The mixture was allowed to stir for about sixteen hours, and then it was filtered through diatomaceous earth, and the filter pad was washed with methanol. The filtrate was concentrated in vacuo to dryness, and the resulting material (92 mg, 90% yield), which was determined to be pure by 1H NMR, was used directly without further purification. LRMS ([M+H]+)=219.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 17.5 °C
Reaction time: 0.5 h

Procedure:
To 2-(4-hydroxyphenyl)acetic acid in DMF cooled to 0° C. was added K2CO3 and the solution was stirred for 30 min. Then, benzyl bromide was added and the solution stirred at 0° C. and was allowed to slowly warm to 15-20° C. After all the ice was melted the solution was poured into NH4Cl(sat) and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-35% EtOAc/Hex) gave pure benzyl 2-(4-hydroxyphenyl)acetate (E301).
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16](O)=[O:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[NH2:44][C@H:45]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[C:61]([O:60][C:58](=[O:59])[CH:45]([NH:44][C:16]([C:15]1[CH:14]=[N:13][N:12]2[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:8]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:9]=[N:10][C:11]=12)=[O:17])[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][C:54]([CH3:57])([CH3:55])[CH3:56])=[CH:51][CH:52]=1)([CH3:64])([CH3:63])[CH3:62]
Reactant: O=C(O)c1cnn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc12
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 15.0 mg (0.044 mmol) of 7-cyclohexyl-6-(4-fluoro-phenyl)-pyrazolo[1,5-α]pyrimidine-3-carboxylic acid in 2 mL of dimethylformamide (DMF) was added 0.019 mL (0.132 mmol) of diisopropylethylamine (DIEA), a few crystals of dimethylaminopyridine (DMAP cat), 17.4 mg (0.053 mmol) of H-Tyr(tBu)-OtBu.HCl, followed by 20 mg (0.053 mmol) of HATU, and the resulting mixture was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide solution (2 times) and brine. The separated organic layer was dried over sodium sulfate and concentrated to give 3-(4-tert-butoxy-phenyl)-2-{[7-cyclohexyl-6-(4-fluoro-phenyl)-pyrazolo[1,5-α]pyrimidine-3-carbonyl]-amino}-propionic acid tert-butyl ester, which was used without any further purification in the next step.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1.N1C=CC=CC=1>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1)=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1ccccc1C1Cc2ccccc2N1
Reactant: CCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOC(=O)Nc1ccccc1C1Cc2ccccc2N1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Octyl chloroformate (2.00 ml) was added dropwise to a solution of 2.15 g 2-(2-aminophenyl)-2,3-dihydro-1H-indole and 2.00 ml pyridine in 35 ml CH2Cl2 at 0° C. The solution was stirred five hours at 0° C. and then quenched with water. The organic layer was separated, washed with 5% HCl and saturated NaCl solution, dried (MgSO4), and concentrated to yield a solid. Purification by flash chromatography using CH2Cl2 /hexane (1:2) as eluent gave 1.74 g solid, m.p. 99°-102° C.
Reaction SMILES: C(OC1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)C2C(=CC=C(C)C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.[C:36]([O:44][CH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:46]1=[O:58])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:44][C:45]1([CH2:23][C:24]2[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=2)[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]([CH2:54][CH:55]([CH3:56])[CH3:57])[C:46]1=[O:58])(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CC(C)CN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Product: COc1cc(CC2(OC(=O)c3ccccc3)C(=O)N(CC(C)C)c3ccccc32)cc(OC)c1OC

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 1-isobutyl-2-oxoindolin-3-yl benzoate. 1H-NMR δ 8.05 (d, 2H), 7.57 (dd, 1H), 7.43 (dd, 2H), 7.27 (m, 1H), 7.17 (d, 1H), 7.01 (dd, 1H), 6.73 (d, 1H), 6.17 (2H), 3.78 (s, 3H), 3.66 (s, 6H), 3.51 (m, 2H), 3.25 (m, 2H), 1.97 (m, 1H), 0.82 (dd, 6H). Calculated mass for C29H31NO6, 489.22. Observed 512.3 (M+Na).