Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[O:16]C)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C(C)C)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C(C)C)c(O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
step 3—A solution of 16 (3.38 g; 14.30 mmol) and CH2Cl2 (150 mL) were cooled to −78° C. and a solution of BBr3 (5.41 mL; 57.22 mmol) in 130 mL of CH2Cl2 were added dropwise over a 30 m period. The reaction mixture was stirred at −78° C. for 1 h, allowed to warm to rt for 4 h and re-cooled to −78° C. and carefully quenched with sat'd. NaHCO3 (80 mL). The aqueous layer was extracted with CH2Cl2 (1×100 mL), EtOAc (50 mL) and the combined aqueous layers washed with water and brine, dried (Na2SO4) and evaporated to yield a light brown oil. The phenol was purified by silica gel chromatography and eluted with CH2Cl2:hexane (3:1) to CH2Cl2 to CH2Cl2:EtOAc (100:4) to yield ethyl 4-iso-propyl-3hydroxyphenylacetate (18a; 3.0 g; 94%)
Reaction SMILES: C[O-].[Na+].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.[SH:13][CH:14]([CH3:18])[CH:15]([OH:17])[CH3:16]>C(O)C>[OH:17][CH:15]([CH3:16])[CH:14]([S:13][CH2:11][C:8]1[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=1)[CH3:18]
Reactant: CC(O)C(C)S
Reactant: ClCc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(O)C(C)SCc1ccncc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium methoxide (3.40 g., 63 mmoles) was dissolved in 30 ml. of absolute ethanol under nitrogen and cooled in an ice bath. To the chilled solution there was added a suspension of finely ground 4-picolyl chloride hydrochloride (5.07 g., 30 mmoles) suspended in approximately 30 ml. of absolute ethanol over 15 minutes, followed by the addition of a solution of 3-mercapto-2-butanol [3.19 g., 30 mmoles, Price et al., J. Am. Chem. Soc. 75, 2396 (1953)] in 6 ml. of absolute ethanol over 5 minutes. The reaction mixture was warmed to room temperature and allowed to stir for 14 hours. The reaction mixture was filtered, the solids being extracted with additional ethanol. The ethanol solutions were combined and evaporated to an oil containing solids (6.31 g.), which was taken up in chloroform, solids removed by filtration and concentrated to an oil. The resuling oil was chromatographed on 200 g. of silica gel with chloroform as eluant. Product fractions were combined and stripped to an oil (5.03 g.). Dissolution in approximately 50 ml. of ethyl acetate, filtration through diatomaceous earth and removal of solvent gave purified 4-(3-hydroxy-2-butylthiomethyl)pyridine [oil; ir (film: 3.08, 3.40, 3.45, 6.24, 7.08, 9.20, 12.27μ; m/e calcd: 197, found: 197; pnmr/CDCl3 /TMS/δ: 8.57 (m, 2H), 7.30 (m, 2H), 3.85 (m, 1H), 3.76 (s, 2H), 3.12 (s, broad, 1H, exchanges with D2O), 2.75 (m, 1H) and 1.20 (d, 6H)].
Reaction SMILES: [CH2:1]([C:8]1[C:29](=[O:30])[N:11]2[CH:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:14][C:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31](N(C(C)C)CC)(C)C.CI>CN(C=O)C.ClCCl>[CH2:1]([C:8]1[N:9]=[C:10]2[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:12][N:11]2[C:29]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1c(Cc2ccccc2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Cc2ccccc2)nc2c(Cc3ccccc3)nc(-c3ccccc3)cn12
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred solution of 2,8-dibenzyl-6-phenyl-7H-imidazo[1,2-a]pyrazin-3-one (0.25 g, 0.6 mmol) in dry DMF (10 mL) at ambient temperature under argon was added diisopropylethylamine (1.1 mL, 6.0 mmol) all at once, followed by dropwise addition of methyl iodide (0.4 mL, 6.0 mmol). After stirring for 1 h the reaction was complete by TLC analysis. The reaction mixture was diluted with dichloromethane (75 mL) and washed twice with water. The organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to provide a brown oil. The crude oil was purified by flash chromatography on silica gel (30 g) using dichloromethane as mobile phase. Appropriate fractions were pooled and evaporated to afford 200 mg (77%) of the desired compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][CH:28]=2)[CH:20]=[CH:19][C:18]=1[OH:36]>O1CCOCC1.N1C=CC=CC=1.CN(C1C=CN=CC=1)C.[OH-].[Na+]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:36][C:18]1[CH:19]=[CH:20][C:21]([C:23]2[CH:24]=[N:25][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][CH:28]=2)=[CH:22][C:17]=1[F:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(-c2cnc(Nc3ccccc3)nc2)cc1F
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cc2nccc(Oc3ccc(-c4cnc(Nc5ccccc5)nc4)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.064 g, 0.28 mmol) and 2-fluoro-4-(2-(phenylamino)pyrimidin-5-yl)phenol (Step 3, 0.48 g, 0.17 mmol) in dioxane (1.0 mL) and pyridine (0.5 mL) was treated with a catalytic amount of DMAP (0.12 g, 0.1 mmol). The mixture was heated under microwave irradiation at 180° C. for 30 min. After cooling to RT, the mixture was diluted with NaOH (0.2 N, 6 mL), and the suspension was filtered. The resulting solid was further purified on silica with 0-5% (NH3-MeOH in DCM) to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 469. Calc'd for C27H21FN4O3: 468.16.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:9][CH2:10]P(OCC)(=O)OCC.[CH3:25][CH:26]([CH:29]([O:32][CH3:33])[O:30][CH3:31])[CH:27]=O.O>O1CCCC1.CCOCC>[CH3:25][CH:26]([CH:27]=[CH:10][CH:9]=[C:8]([CH3:7])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:29]([O:32][CH3:33])[O:30][CH3:31]
Reactant: CCOP(=O)(CC=C(C)CCC=C(C)C)OCC
Reactant: COC(OC)C(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)C(C)C=CC=C(C)CCC=C(C)C
Temperature: -27.5 °C
Yield: 65.7 %

Procedure:
To a 500 mL three-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a solution of 2.4 g potassium t-butoxide (0.11 mol) in 60 mL of anhydrous tetrahydrofuran was added with an external cold bath to maintain the internal temperature of approximately −30 to −25° C. Then diethyl 3,7-dimethyl-2,6-octadiene-phosphonate (3B) (0.10 mol) was added dropwise over 30 min under mechanical stirring and the reaction mixture was subsequently stirred in the cold for 60 min to ensure the formation of carbanion thoroughly. Then 13.2 g of 2-methyl-3,3-dimethoxy-1-propanal (4A) (0.10 mol) was added dropwise at −30˜25° C. over 1 h and the reaction mixture was subsequently stirred for 30 min at this temperature until the reaction completed according to GC. Followed by the addition of 50 mL water and 100 mL ether and stirring for 10 min, after stratification, the organic layer was washed with 5% aqueous sodium chloride (3×25 mL), then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents in vacuo, the residue subsequently was fractional distillated to afford 17.9 g of (5-E and 5-Z)-2,6,10-trimethyl-1,1-dimethoxy-3,5,9-undecatriene (2C) of 99-103° C./1 mmHg, as a colorless liquid with GC content of 92.5% (total content of cis and trans) and the yield of 65.7%. There are 2 peaks according to GC and GC-MS. ascertained is the same with that of Example II
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:21][N:20]=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Yield: 79.7 %

Procedure:
Prepared according to Method D Step A from (2,3-difluorophenyl)-(4-methoxyphenyl)-methanone (1.1 g, 4.4 mmol), hydrazine hydrate (1.37 mL, 44 mmol) and DMAP (0.54 g, 4.4 mmol) to give the product (0.85 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[CH3:12].C([O:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])C.[O-]CC.[Na+].Cl>C(O)C.O.O1CCCC1>[F:18][C:17]([F:20])([F:19])[C:16](=[O:15])[CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=1)=[O:11]
Reactant: COc1ccc(C(C)=O)cc1C
Reactant: CCOC(=O)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C
Yield: 91.5 %

Procedure:
At room temperature, to a mixture of 1 (4 methoxy-3-methylphenyl)-ethanone (described in Reference Preparation example 48) 6.9 g and tetrahydrofuran 200 ml was added trifluoroacetic acid ethyl ester 11.9 g and 20% solution of sodium ethoxide in ethanol 28.5 g. The resulting mixture was stirred with heating under reflux for six hours. To the reaction mixture was added water, and the resulting mixture was acidified with 6N aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4,4,4-trifluoro-1-(4-methoxy-3-methyl-phenyl)-butane-1,3-dione 10 g.
Reaction SMILES: C([O:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:9]1)(=O)CCC.C[O-].[Na+].CO.C(Cl)(Cl)Cl.Cl>CO>[F:20][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][C@H:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: CCCC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1

Procedure:
A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl butyrate (PREPARTION 12, 2.789 g, 9.91 mmol) in methanol (10 ml) is treated with a 25 wt. % mixture of sodium methoxide in methanol (57 μl, 0.99 mmol) at 20-25°. After 45 min as measured by TLC (methanol/chloroform, 5/95) the starting material has been consumed. The reaction mixture is carefully quenched by the addition of hydrochloric acid (1N, 0.99 ml, 0.99 mmol) and then concentrated under reduced pressure. Chromatography of the concentrate over silica gel, eluting first with hexane/ethyl acetate (1/1), and then ethyl acetate, pooling and concentratig the appropriate fractions gives the title compound, mp 106.5-107.5°; [α]25D -66.8° (c 1.1, CH3CN); IR (mineral oil mull): 3520, 1724, 1612, 1590, 1496, 1428, 1420, 1232 and 1199 cm-1 ; NMR (CDCl3, 300 MHz) δ 7,44, 7.32, 7.23, 6.84, 4.77, 4.07-3.96, 3.76 and 2.44; MS (m/z) 211, 180, 136, 124, 95; HRMS (m/z) 211.0641 (calc'd for C10H10FNO3 : 211.0645).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][C:15]2=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][C:15]2=[O:18])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
To a solution of 4-(2-methoxycarbonyl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 12.0 mmol) in anhydrous THF (75 mL) was slowly added a solution of methyl magnesium bromide in diethyl ether (3 M, 6 mL, 18 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h, then allowed to warm to RT and stirring was continued for 72 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc and an aqueous solution of ammonium chloride. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(2-oxo-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (598 mg, 20%). To a solution of 4-(2-oxo-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (595 mg, 2.34 mmol) in DCM (6 mL) was added TFA (2 mL). The resulting mixture was stirred at RT for 1.5 h, then concentrated in vacuo. The resultant residue was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (325 mg, 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1CC(=O)[C@H](CC1C=CC=CC=1)NC(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].C(O)C.CO.[BH4-].[Na+]>C(O)(C)C>[C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
2 g (4.3 mmol) of N-[[N-(benzyloxycarbonyl)-L-phenylalanyl]methyl]-L-proline tert.butyl ester (prepared as described in Example 1) were dissolved in 25 ml of isopropanol, 25 ml of ethanol and 25 ml of methanol and the solution was stirred at room temperature for 4 hours in the presence of 0.4 g (10.7 mmol) of sodium borohydride. The solvent was removed by evaporation and the residue was partitioned between 50 ml of ethyl acetate and 25 ml of water. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent was removed by evaporation and there were obtained 2 g of N-[3(S)-(benzyloxyformamido)-2(R and S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a clear gum: Rf (System C): 0.68 and 0.57.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1([F:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:18]2[CH2:19][CH2:20][C:15]([F:21])([F:14])[CH2:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: FC1(F)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 83.2 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.51 g, 3 mmol), 4,4-difluoropiperidine hydrochloride (0.71 g, 4.5 mmol) and 4 Å molecular sieves (0.8 g) in DCE (8 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (1.27 g, 6 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc: cyclohexane, gradient 0:100 to 75:25) to give 3-(4,4-Difluoropiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.69 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 3.94 (dd, J=8.7, 7.1 Hz, 2 H); 3.78 (dd, J=8.7, 5.3 Hz, 2 H); 3.17-3.10 (m, 1 H); 2.45-2.41 (m, 4 H); 2.10-1.94 (m, 4 H); 1.43 (s, 9 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[NH:5][CH2:6][O:7][CH:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH3:9].C(N(C(C)C)CC)(C)C.[CH:34]12[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[CH:35]1[O:44][C:45](Cl)=[O:46])[CH2:41]2>C1COCC1.O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[N:5]([CH2:6][O:7][CH:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH3:9])[C:45]([O:44][CH:35]1[CH:34]2[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]1[CH2:37]3)[CH2:41]2)=[O:46]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)NCOC(C)[Si](C)(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(Cc1c[nH]c2ccccc12)N(COC(C)[Si](C)(C)C)C(=O)OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
A mixture of α-trimethylsilylethoxymethyl-DL-tryptophan methyl ester (1.0 g, 2.8 mmol), diisopropylethylamine (0.4 g, 3 mmol) and 2-adamantylchloroformate (0.65 g, 3 mmol) in 20 mL dry THF was stirred at room temperature for 4 hours. The reaction mixture was diluted with distilled water and extracted with ethyl acetate (4×50 mL). The organic extract was washed with brine and dried over Na2SO4. Evaporation of the organic solvent gave the title compound as a colorless foam (1.0 g, 67.8%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[C:21]1(=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[NH:22]1>>[O:31]=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1)c1ccccc1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and isoindole-1,3-dione. NMR (400 MHz; CDCl3): δ 2.98 (t, 2H), 3.41 (br s, 2H), 3.89 (t, 3H), 7.04 (br d, 2H), 7.20–7.40 (m, 7H), 7.68–7.71 (m, 2H), 7.80–7.83 (m, 2H); HPLC-MS: m/z=401.1 (M+1); Rt=4.41 min.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Si:5]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][Cl:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: OCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCCCCCl
Reaction time: 4 h

Procedure:
t-Butylchlorodimethylsilane (8.3 g, 55 mmol) was added to a stirred mixture of 4-chlorobutanol (5.0 mL, 50 mmol), silver nitrate (12.8 g, 75.1 mmol), and pyridine (4.0 mL, 50 mmol) in 40 mL of dry THF. After 4 hr, the reaction mixture was filtered through Celite and evaporated to give a yellow oil. The material was purified by distillation to provide 4-chlorobutyl t-butyldimethylsilyl ether as a colorless oil (11 g, quantitative). To a solution of triphenylmethane (5.10 g, 20.8 mmol) in 25 mL of dry THF at -78° C., 13.1 mL (21 mmol) of 1.6M n-butyllithium was added dropwise under nitrogen. Shortly thereafter, 4.29 g (19.3 mmol) of 4-chlorobutyl t-butyldimethylsilyl ether was added. After addition of water and extraction with hexane, the product was purified by chromatography on silica gel with 1:3 dichloromethane-hexane, providing t-butyldimethylsilyl 5,5,5-triphenylpentyl ether as an oil (6.85 g). This material was dissolved in THF (30 mL) and 16 mL of 1.0M tetrabutylammonium fluoride in THF was added. After 3 hr, the mixture was acidified with 1N HCl, extracted with three portions of ethyl acetate, and the extracts dried over magnesium sulfate and evaporated in vacuo. The product was purified by chromatography on silica gel with a 10%-20% gradient of ethyl acetate in hexane, providing the title compound as a white solid, 3.83 g (63% overall).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.C(Cl)(=O)C(Cl)=O.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1>C(Cl)Cl.O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:39][CH:40]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccc(Cl)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.64 mmol) (from Example 7, Step 2c), in methylene chloride (10 mL) was treated with oxalyl chloride (0.07 mL, 0.64 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for additional 2 hours. Then, the reaction mixture was cooled to 0° C., and N,N′-diisopropylethyl amine (0.34 mL, 1.92 mmol) and commercially available 5-chloro-pyridin-2-ylamine (83 mg, 0.64 mmol), were added. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)—N-(5-chloro-pyridin-2-yl)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide (68 mg, 26.3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.07 (s, 1H), 8.39 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.07 (d, J=5.9 Hz, 1H), 4.37 (d, J=18.6 Hz, 1H), 4.03 (d, J=19.1 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 2H), 1.48-2.00 (m, 7H), 0.85-1.32 (m, 6H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[NH:10][N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+].O>CC#N>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:24][C:23]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=3[F:21])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2[nH]nc(-c3cccc(C#N)c3)c2C1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
A mixture of 3-(5-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile (3a) (0.48 g, 1.8 mmol), 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol) and K2CO3 (498 mg, 3.6 mmol) in 14 ml CH3CN was stirred at 80° C. for 16 h. A second portion of 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol) was added and the mixture was stirred for additional 7 h. Water was added, the mixture was extracted 3 times with ethyl acetate, the combined organic layers were dried over MgSO4, filtrated and the solution was evaporated to dryness. The crude product was crystallized from 10 ml 2-propanol and dried in vacuo to give 0.364 g of 3-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (6a).