Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[Si:14]([O:21][CH2:22][C:23]([CH3:26])([NH2:25])[CH3:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:25][C:23]([CH3:26])([CH3:24])[CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (310 mg, 1.28 mmol), 1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-amine (390 mg, 1.92 mmol), EDCI (489 mg, 2.56 mmol) and DMAP (312 mg, 2.56 mmol) in 5 mL of DMF was stirred at room temperature for 16 hours. Then the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was used in the next step without further treatment. MS: (M+H)+=427.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:16]1([CH2:22][CH2:23][CH2:24]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[C:16]1([CH2:22][CH2:23][CH2:24][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: BrCCCc1ccccc1
Solvent: CCO
Product: c1ccc(CCCSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol), and phenylpropylbromide (0.228 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][C:37]=4[F:40])[CH2:32]3)=[O:30])[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([O:45]CC)=[O:44])[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOCC>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][C:37]=4[F:40])[CH2:32]3)=[O:30])[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([OH:45])=[O:44])[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@H]1CCOCC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCOCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylate (0.093 g, 0.14 mmol) in THF (2 mL) was added 0.1 N NaOH solution (3.53 ml, 0.35 mmol) in H2O. The reaction was stirred at rt for 3 days. Water (5 mL) and ether (15 mL) was added. The aqueous layer was separated and acidified by saturated potassium hydrogen sulfate solution to pH=2˜3. The aqueous layer was extracted with EA (2×15 mL), washed with brine and dried over sodium sulfate. After removal of solvent, it (2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylic acid as white solid (0.074 g, 83%). MS: Calcd.: 630; Found: [M+H]+ 631. 1H NMR (400 MHz, d6-DMSO) δ12.25 (s, 1H), 8.77 (s, 1H), 7.37 (m, 1H), 7.07-7.21 (m, 3H), 5.34-5.44 (m, 2H), 5.29 (s, 1H), 4.67 (s, 4H), 4.44 (m, 1H), 4.20 (m, 1H), 3.95 (m, 1H), 3.68 (m, 1H), 3.50 (m, 1H), 3.43 (m, 2H), 3.32 (m, 1H), 2.39 (m, 1H), 2.33 (m, 2H), 2.16 (m, 2H), 1.85 (m, 1H), 1.74 (m, 1H), 1.53 (m, 1H), 1.50 (m, 1H), 1.23 & 0.96 (s, 9H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([F:34])[C:28]=2[F:35])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[CH2:36]([C@H:41]1[CH2:46][CH2:45][C@H:44]([C:47](O)=[O:48])[CH2:43][CH2:42]1)[CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[CH2:36]([C@H:41]1[CH2:42][CH2:43][C@H:44]([C:47]([O:33][C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)=[C:28]([F:35])[C:29]=2[F:34])=[O:48])[CH2:45][CH2:46]1)[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCCc1ccc(-c2ccc(O)c(F)c2F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.1 mol of dicyclohexylcarbodiimide (DCC) dissolved in CH2Cl2 is added to 0.1 mol of 4'-pentyl-2,3-difluorobiphenyl-4-ol (which can be prepared from 4'-pentyl-2,3-difluoro-4-methoxy-biphenyl by ether cleavage with HBr/glacial acetic acid), 0.1 mol of trans-4-n-pentyl-cyclohexanecarboxylic acid and a catalytic amount of 4-N,N'-dimethylaminopyridine (DMAP) in 300 ml of CH2Cl2 at 0° C., with exclusion of moisture. The mixture is then stirred at room temperature for 12 hours, the dicyclohexylurea which has precipitated is separated off and the product is worked up in the customary manner. The product is purified by crystallization. 4'-Pentyl-2,3-difluorobiphenyl-4-yl trans-4-n-Pentylcyclohexanecarboxylate is obtained, C 44° N 159.1° I.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][C:28]3[CH2:29][NH:30][CH2:31][C:24]=3[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: C1NCC2=C1CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Br
Solvent: CC#N
Product: Nc1c(F)c(N2CC3=C(CNC3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
The solution of 0.4 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.8 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide, and 0.6 ml of 1,8-diazabicyclo[5.4.0]undex-7-ene (DBU) in 40 ml of acetonitrile was refluxed at the reaction temperature of 100° C. for 7 hours. This reaction mixture was kept overnight at the room temperature, and the produced precipitate was filtered and then the residue was washed with ethanol to obtain 0.3 g of the title compound (yield 57%).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.COC([N:14]([C:29]1[C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:37]2[C:32]([CH:33]3[CH2:43][CH:34]3[CH2:35][O:36]2)=[CH:31][CH:30]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1/[CH:25]=[CH:26]\[CH2:27]O)(=[O:17])=[O:16])=O.[CH:44]([N:47](C(C)C)CC)(C)[CH3:45].C(N)C>C(Cl)Cl.O>[CH2:44]([NH:47][CH2:27]/[CH:26]=[CH:25]\[C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[S:15]([NH:14][C:29]1[C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:37]2[C:32]([CH:33]3[CH2:43][CH:34]3[CH2:35][O:36]2)=[CH:31][CH:30]=1)(=[O:17])=[O:16])[CH3:45]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: O
Solvent: ClCCl
Product: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Reaction time: 2 h
Yield: 56.5 %

Procedure:
Methane sulfonic anhydride (0.09 g) was added to a stirred, cooled mixture of methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64, 0.17 g) and N,N-di-isopropyl-N-ethylamine (0.134 g) in DCM (10 mL) at 0° C. The temperature was allowed to rise to room temperature and the mixture was stirred for 2 hours. A solution of ethylamine (2M in toluene, 2 mL) was added and the resultant mixture was stirred at room temperature for 3 hours then diluted with water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give methyl (1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.09 g) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:20][CH:19]=1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2ccc(Cl)cc2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 0.5 M 4-chlorophenylmagnesium bromide in THF (0.6 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(4-chloro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[O:13][CH3:14]>[C].[Pd].CO>[CH3:14][O:13][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:3]=1[CH3:2]
Reactant: COc1cccc(C(F)(F)F)c1CCl
Agent: [Pd]
Solvent: CO
Product: COc1cccc(C(F)(F)F)c1C
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed 2-(chloromethyl)-1-methoxy-3-(trifluoromethyl)benzene (1.09 g, 4.85 mmol, 1.00 equiv), methanol (20 mL), Palladium carbon (1.50 g). The mixture was subjected to 2 atm of H2. The resulting solution was stirred overnight at 30° C. The reaction progress was monitored by GCMS. The solids were filtered out. The 30 mL H2O was added to the solution. The resulting solution was extracted with 3×50 mL of pentane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.74 g (80%) of 1-methoxy-2-methyl-3-(trifluoromethyl)benzene as light yellow oil. The residue could be used for the next step directly. Mass spectrum (GC, m/z): Calcd. for C9H9F3O, 190.2 (M). found 190.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:10]([CH3:11])[CH2:9][CH:8]=[CH:7]C1)=[O:4].[Mn]([O-])(=O)(=O)=[O:13].[K+].S([O-])(O)(=O)=O.[Na+]>C1CCCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:10]([CH3:11])[CH2:9][C:8](=[O:13])[CH2:7]1)=[O:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COC(=O)[C@H]1CC=CC[C@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Br-]
Solvent: C1CCCCC1
Solvent: O
Product: COC(=O)[C@H]1CC(=O)C[C@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
In a stream of nitrogen gas, 3.33 g of (1S, 6R)-1-methoxycarbonyl-6-methylcyclohex-3-ene was dissolved in 100 ml of cyclohexane, and the solution was added to a aqueous solution prepared by dissolving 13.5 g of potassium permanganate and 1.39 g of tetrabutylammonium bromide in 100 ml of H2O. The mixture was vigorously stirred for 4 hours at room temperature. To the reaction mixture was added 10 g of sodium hydrogen-sulfate, and the precipitate was filtered off. After the cyclohexane layer of the filtration was separated, and the water layer was adjusted to have a pH of 3 by concentrated hydrochloric acid, the water layer was extracted by ethyl acetate-tetrahydrofuran (1:1). The cyclohexane layer and the extraction were combined, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under a reduced pressure. To the residue, 12.5 ml of acetic anhydride and 0.825 g of sodium acetate were added, and the mixture was stirred for 1 hour at 130° C. After being cooled by air, the precipitate was filtered off, and the filtrate was concentrated under a reduced pressure. The residue was taken up into ethyl acetate, and the insoluble material was filtered off, followed by concentration of the filtrate under a reduced pressure. The residue was distilled under a reduced pressure, and thus 1.35 g of (3S, 4R)-3-methoxycarbonyl-4-methylcyclopentanone was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)cc1
Yield: 26.3 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and diethylamine (0.40 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N,N-diethylbenzenesulfonamide (0.12 g) was provided after purification. MS (ESI) m/z 293. HPLC purity 99.2% at 210-370 nm, 9.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2.[F:15][C:16]([Si](C)(C)C)([F:18])[F:17].C([O-])(=O)C.[Li+].Cl>CO.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])([CH3:13])[C:16]([F:18])([F:17])[F:15])[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(O)(c1ccc2cc(Br)ccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a DMF (25 ml) solution of 1-(6-bromo-2-naphthyl)ethanone (2.5 g, 10.0 mmol, Tetrahedron Letters (2001), 42(2), 265-266), trifluoromethyltrimethylsilane (2.14 g, 15.1 mmol) and lithium acetate (33.1 mg, 0.5 mmol) were added and the mixture was stirred for 12 hrs at room temperature. Then, the reaction was partitioned with sodium acetate aqueous solution and ethylacetate. The organic layer was dried over sodium sulfate and filtered. Then, evaporation gave the crude residue which was treated with hydrogen chloride and methanol with stirring for 5 hrs. Then, evaporation gave the crude residue which was purified through silica gel column chromatography, eluting with hexane:ethyl acetate (5:1), to give the title compound as colorless oil in 83% yield. 1H NMR (300 MHz, CDCl3) 2.50 (1H, s), 7.58 (1H, d, J=8.8 Hz), 771-7.81 (3H, m), 8.04 (2H, d, J=8.9 Hz).
Reaction SMILES: C(O[C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:17][CH2:18][C@H:19]([OH:22])[CH2:20][OH:21])C1C=CC=CC=1.[OH-].[Na+]>C(O)C.[Pd].Br.CO.O>[CH3:16][O:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[O:22][C@@H:19]([CH2:20][OH:21])[CH2:18][CH2:17]2
Reactant: COc1cccc(CC[C@H](O)CO)c1OCc1ccccc1
Agent: [Pd]
Agent: Br
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: COc1cccc2c1O[C@@H](CO)CC2
Reaction time: 12 h
Yield: 69.8 %

Procedure:
To a solution of (2S)-4-[2-(benzyloxy)-3-methoxyphenyl]-1,2-butanediol (12.00 g, 39.7 mmol) in ethanol (400 mL) was added palladium on carbon (10 wt. %, 1.2 g) and the reaction mixture was shaken under an H2 atmosphere (50 psi) for 12 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a crude oil. The residue was dissolved in hydrogen bromide (30 wt. % in acetic acid, 200 mL) and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched by the addition of water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (3×200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. The residue was dissolved in methanol (100 mL) and the resulting solution was slowly added to a solution of aqueous sodium hydroxide (2.5 M, 150 mL) in water (350 mL) and the reaction mixture was allowed to stir at 0° C. for 30 min. The reaction mixture was quenched by the addition of aqueous hydrogen chloride (1.0 M, 500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (2×200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:1) gave 5.38 g (70%, 40% ee) of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methanol as a white crystalline solid. [α]D25=−60.51 (c 9.62 in chloroform, 40% ee); Rf=0.52 (silica, ethyl acetate:hexanes 1:1); mp 65-69° C.; Anal. Calcd. for C11H14O3: C, 68.02; H, 7.27. Found: C, 67.92; H, 7.30.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([N:25]1[C:29]2=[N:30][C:31]([CH2:57][CH3:58])=[C:32]([CH2:41][NH:42][C:43](=[O:56])[C:44]3[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][OH:55])=[CH:46][CH:45]=3)[C:33]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]2[CH:27]=[N:26]1)[CH3:24]>C1COCC1.C(Cl)Cl>[CH2:23]([N:25]1[C:29]2=[N:30][C:31]([CH2:57][CH3:58])=[C:32]([CH2:41][NH:42][C:43](=[O:56])[C:44]3[CH:45]=[CH:46][C:47]([CH2:50][CH2:51][CH2:52][CH2:53][CH:54]=[O:55])=[CH:48][CH:49]=3)[C:33]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]2[CH:27]=[N:26]1)[CH3:24]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCC=O)cc1
Yield: 99.7 %

Procedure:
Dess Martin Reagent (432 mg, 1.02 mmol) was added to a solution of Intermediate 34 (250 mg, 0.51 mmol) in THF (5 mL) and DCM (5 mL). The resultant mixture was stirred at rt for 2 h. The solvent was removed in vacuo and the crude solid was purified by column chromatography on silica gel eluting with 0-10% DCM-MeOH to afford the title compound as a white solid (250 mg). ES/MS calcd. for C28H38N5O3+ 492.3. found m/z=492.3 (M+H)+.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1C=CC=CC=1>[O:12]1[CH2:13][CH2:14][N:9]([C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: O=C1CCCC(=O)C1
Solvent: c1ccccc1
Product: O=C1C=C(N2CCOCC2)CCC1
Temperature: 25 °C

Procedure:
In 700 ml benzene was dissolved 40.0 g 1,3-cyclohexanedione and 62 ml morpholine. The resulting solution was heated at reflux under nitrogen atmosphere for 1.5 hours. The water present in the reaction mixture was collected using a Dean-Stark trap. Upon cooling to room temperature, the reaction mixture was filtered through alumina and the filtrate concentrated in vacuo. Trituration of the resulting oil with ether solidified 62.4 g of 3-morpholino-2-cyclohexen-1-one crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([C:21]3[C:29]4[CH:28]=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=3)=[O:20])[CH:18]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.[F:33][CH:34]1[CH2:37][NH:36][CH2:35]1>>[F:33][CH:34]1[CH2:37][N:36]([CH2:1][C:3]2[CH:4]=[C:5]([CH2:9][C:10]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([C:19]([C:21]4[C:29]5[CH:28]=[N:27][CH:26]=[N:25][C:24]=5[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=4)=[O:20])[CH:18]=3)=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH2:35]1
Reactant: FC1CNC1
Reactant: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C=O)c3)c2)c2cncnc21
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(CN4CC(F)C4)c3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 266 using 2-(3-formylphenyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide (Preparation 192, 60 mg, 0.14 mmol) and 3-fluoroazetidine to afford the title compound in 16% yield, 11 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a stirred suspension of crude 2-tert.-butoxycarbonyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol (33.5 mmol) and caesium carbonate (25.1 g, 77.1 mmol) in dry acetone is added ethyl bromoacetate (5.6 ml, 50.3 mmol). The reaction mixture is stirred at rt overnight and then filtered over a small plug of Celite. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (hexane/EtOAc 5:1) to afford pure sub-title compound as yellow oil (8.45 g) in 70% yield (over two steps). tR (LC-2) 2.46 min; ESI-MS (positive ion): m/z 381.54 [M+Na]+ (calcd 358.43 for C20H26N2O4).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:1]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzyl bromide (2.29 mL, 19.3 mmol) was added dropwise to a cooled (0° C.) mixture of commercially available 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoic acid (4.96 g, 19.3 mmol) and K2CO3 (6.67 g, 48.3 mmol) in 40 mL of DMF. The reaction mixture was permitted to warm to rt and stir for 3 days (the reaction was likely complete after only a few h). The reaction mixture was diluted with ether and washed four times with water, then once with brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 30% ethyl acetate/hexanes) provided tert-butyl 4-[3-(benzyloxy)-3-oxopropyl]piperidine-1-carboxylate. 1HNMR (CDCl3, 500 MHz): δ 7.38 (m, 5H), 5.14 (s, 2H), 4.09 (br m, 2H), 2.65 (m, 2H), 2.41 (t, J=7.5 Hz, 2H), 1.63 (m, 4H), 1.47 (s, 9H), 1.40 (m, 1H), 1.10 (dq, J=4.0, 12 Hz, 2H).