Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCO.O>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:26]([C:25]3[CH:29]=[CH:30][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(O)c3ccc(OC)c(C)c3n2)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-4-methoxy-3-methyl benzamide in dry THF (60 ml) was added pyridine (2 eq) and the mixture was cooled to 5° C. 4-Methoxybenzoic acid chloride (1.25 eq) was added slowly and the mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and then suspended in water. The compound was left in the water for some hours, filtered and washed with cold water and diethyl ether and dried under vacuum. The residue was then added to a suspension of sodium carbonate (2.5 eq) in a 1:1 mixture of water and EtOH and the mixture was refluxed for two hours. The EtOH was removed under reduced pressure, a solution of 5% citric acid was added and the mixture was allowed to stay overnight. The title compound was isolated by filtration, then washed with water and diethyl ether and dried under vacuum. (5.5 g, 92%).
Reaction SMILES: [CH2:1]([O:10][C@@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]1[N:19]1[C:29]2[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=2[N:21]=[CH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[Si](Cl)(C)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>N1C=CC=CC=1>[C:35]([NH:27][C:26]1[NH:25][C:23](=[O:24])[C:22]2[N:21]=[CH:20][N:19]([C:29]=2[N:28]=1)[C@@H:12]1[O:13][C@H:14]([CH2:17][OH:18])[C@@H:15]([OH:16])[C@H:11]1[O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21

Procedure:
2'-O-nonylguanosine (14.7 g) in pyridine (360 ml) was treated with trimethylsilyl chloride (23.4 ml) and isobutyryl chloride (30.6 ml) as per the procedure of Example 4 to yield crude product (37 g). The crude material was purified by silica gel chromatography (eluted with 90/10 CHCl3 /MeOH) to yield 14.6 g of product re-crystallized from EtOAc. m.p. 168°-169° C. 1H NMR (DMSO-d6) δ0.85 [t, 3, CH3 (nonyl)], 1.14 [m, 18, O--CH2CH2 (CH2)6, CH(CH3)2 ], 1.40 [m, 2, O--CH2CH-2 (CH2)6 ], 2.79 [m, 1, CH(CH3)2 ], 3.31-3.63 (m, 4, H5', O--CH2 (CH2)7 !; 3.96 (m, 1, H-4'), 4.27-4.37 (m, 2, H-2', H-3'); 5.10 (t, 1, 5'-OH, J=5 Hz), 5.18 (d, 1, 3'-OH, J=4 Hz), 5.91 (d, 1, H-1', J=6.6 Hz), 8.31 (s, 1, 8-H), 11.73 (s, 1, C2 amide) and 12.11 (s, 1, N1 amide). Anal. Calcd. for C23H37N5O6 : C, 57.60; H, 7.78; N, 14.60. Found: C, 57.63; H, 7.92; N, 14.62.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH:30]=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH:30]=[CH2:1])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CCCC1CCC(C=Cc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(c2ccc(C=CC3CCC(CCC)CC3)cc2)CC1

Procedure:
Potassium tert-butoxide (1.0 eq, 0.44 g, 3.62 mmol) was added slowly with stirring for 3 minutes to 32 ml of solution including methyltriphenylphosphonium bromide (1.2 eq, 1.55 g, 4.33 mmol) dissolved in THF. Then, the solution was stirred for 30 minutes at a room temperature and THF solution (35 ml) of trans-4-{4-[2-(4-propyl-cyclohexyl)ethenyl]phenyl}cyclohexane carbaldehyde (1.23 g, 3.62 mmol) obtained in Example 2-2 was added slowly dropwise for 10 minutes to reaction mixture, and then was stirred at a room temperature for 24 hours.
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].[H-].[Na+].Br[CH2:15][C:16]1[CH:43]=[CH:42][C:19]([C:20]([NH:22][C:23]2[CH:28]=[C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[CH:26]=[CH:25][C:24]=2[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:21])=[CH:18][CH:17]=1>C1COCC1.C(OCC)(=O)C>[C:37]([O:36][C:35]([NH:34][C:24]1[CH:25]=[CH:26][C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:28][C:23]=1[NH:22][C:20]([C:19]1[CH:42]=[CH:43][C:16]([CH2:15][CH:3]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[C:1]#[N:2])=[CH:17][CH:18]=1)=[O:21])=[O:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C#N)Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C

Procedure:
Diethyl cyanomethylphosphonate (0.19 ml, 1.175 mmol) was dissolved in THF (7 ml). The solution was cooled to 0° C. Sodium hydride (0.0818 g, 2.045 mmol) was added to the reaction. The reaction was allowed to stir for several minutes. Tert-butyl [2-{[4-(bromomethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate (0.5047 g, 1.035 mmol) was added in a solution of THF. The reaction was allowed to slowly warm to room temperature and stir overnight. The reaction was diluted with ethyl acetate and quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was partially purified by column chromatography on silica gel. MS: cal'd 484 (MH+-Boc), exp 484 (MH+-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:17][C:4]1[C:5]2[C:6](=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:8][N:9]=2)[CH:16]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)c2noc(-c3ccccc3)c2c1

Procedure:
A mixture of 16.2 g (0.067 mole) of 5-chloro-7-methyl-3-phenyl-2,1-benzisoxazole, 11.9 g (0.067 mole) of N-bromosuccinimide, 275 ml of carbon tetrachloride and 0.1 g of dibenzoylperoxide was heated at reflux under illumination of a flood lamp for 2 hr. The mixture was filtered and the filtrate was washed once with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to give a yellow solid as residue. An NMR analysis of the residue showed it was a mixture containing 8% of starting methyl compound, 83% of monobromo compound and 9% of dibromo compound. An analytical sample, m.p. 142°-144° C., was obtained by recrystallizing twice from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:10][C:5]=2[S:4][C:3]=1[C:21]([OH:23])=O.CC[N:26]=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C.C([O-])(O)=O.[Na+].O>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:10][C:5]=2[S:4][C:3]=1[C:21]([NH2:26])=[O:23]
Reactant: O=C(O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
To a solution of 3-chloro-6-((2,4-dichlorobenzyl)oxy)-1-benzothiophene-2-carboxylic acid (190.4 mg) in DMF (dry) (4.9 mL) were added HOBt ammonia complex (112 mg), EDCI (141 mg) and triethylamine (0.205 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NaHCO3 and water. The precipitate was collected by filtration, and washed with water and hexane to give the title compound (195 mg).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:25]=2[F:24])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(C[C@H]2CCCO2)n1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)n(C[C@H]2CCCO2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of the product of Example 1C (7.8 g) and triethylamine (14.6 mL, 105 mmol) in THF (60 mL) at ambient temperature was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.3 mL, 35.0 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 3 h. The mixture was quenched with saturated, aqueous NaHCO3 (20 mL) and diluted with EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 40% hexanes/EtOAc) gave the title compound (11.0 g, 26.6 mmol). MS (DCI/NH3) m/z 414 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[O:8]2.C[N+]1([O-])CC[O:29]CC1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH2:5][C:6](=[O:29])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[O:8]2
Reactant: C[N+]1([O-])CCOCC1
Reactant: COc1cc(OC)c2c(c1)OC(c1ccc(OC)c(OC)c1)C=C2
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(c1)OC(c1ccc(OC)c(OC)c1)C(=O)C2
Temperature: 25 °C
Reaction time: 36 h
Yield: 30 %

Procedure:
(2R)-3-[(2R,3S)-5,7,3′,4′-tetrakis(methyloxy)-3-hydroxyflavan)]-5,7,3′,4′-tetramethoxyflavan-3-ene (6) (20 mg, 0.030 mmol) was dissolved in THF (5 mL) and OsO4 (0.9 mg, 0.004 mmol) and N-methylmorpholine-N-oxide (16.3 mg, 0.139 mmol) was added. The reaction mixture is stirred 1-2 days at r.t. under argon (TLC monitoring of consumption of starting material). Solution of sodium metabisulfite (10% aq.) was added and reaction mixture was stirred for 30 minutes. Then was made the extraction 3× with dichloromethane, washed with NaHCO3 (sat. aq.), NaCl (sat. aq.) and dried over MgSO4. Evaporation left crude material which was purified on preparative TLC plates (toluene acetone 6:4) to afford (2S,3S)-3-[(2R,3S)-5,7,3′,4′-tetrakis(methyloxy)-3-hydroxyflavan)]-5,7,3′,4′-tetramethoxyflavan-3-one (7) (Rf 0.19, 6 mg, 0.009 mmol, 30%).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH:54]=[CH:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]1=[O:62]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:48][C@H:49]1[CH2:55][CH:54]=[CH:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]1=[O:62])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CC=CCN(c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=CCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S,Z)-2-oxo-1-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (30 mg, 0.053 mmol) and Intermediate 52 (20 mg, 0.064 mmol) to give a white solid (26 mg, 65% yield). Anal. Calcd. for C43H50N4O6S m/z 750.4. found: 751.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (dd, J=36.0, 7.3 Hz, 2H), 7.34 (t, J=7.8 Hz, 2H), 7.26-7.06 (m, 11H), 6.02-5.84 (m, 1H), 5.79-5.66 (m, 1H), 5.65-5.56 (m, 1H), 5.28-5.12 (m, 1H), 5.01 (d, J=4.4 Hz, 2H), 4.82 (d, J=17.7 Hz, 1H), 3.78 (dd, J=17.8, 7.9 Hz, 1H), 3.17-2.93 (m, 2H), 2.93-2.36 (m, 11H), 2.25-2.04 (m, 2H), 2.04-1.87 (m, 2H), 1.87-1.73 (m, 1H), 1.72-1.38 (m, 7H), 1.32 (d, J=6.2 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4([C:21]#N)[CH2:20][CH2:19]4)[CH:14]=3)[C:9]2=[O:23])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.C1C[O:38]CC1>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4([CH:21]=[O:38])[CH2:20][CH2:19]4)[CH:14]=3)[C:9]2=[O:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCc3cc(C4(C#N)CC4)ccc3C2=O)cc1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CCc3cc(C4(C=O)CC4)ccc3C2=O)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of 722 mg of 1-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-cyclopropanecarbonitrile in 3 ml of dichloromethane and 9 ml toluene, cooled at −50° C. was added dropwise 4.8 mL of 1.0 M DIBAL in THF. After stirring 1 hour at −50° C., the reaction was quenched with 5 ml of 1N HCl, left to warm to room temperature and stirred 0.5 hour. Next the mixture was extracted with ethyl acetate and the organic layer was washed with 0.5 N HCl, sodium carbonate 5% solution, and brine. After drying over sodium sulfate and removal of solvent in vacuo, the residue was purified by silica gel column chromatography using 30%-60% ethylacetate in hexane to provide 0.075 g of 1-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-cyclopropanecarbaldehyde.
Reaction SMILES: [Br-].[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)=O>C1COCC1>[CH2:2]([O:9][CH2:10][CH2:11]/[CH:12]=[CH:42]\[CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[CH2:46][CH2:45]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(/C=C\CCOCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(3-Benzyloxypropyl)triphenylphosphonium bromide (2.88 g, 5.86 mmol) was suspended in 15 mL THF and cooled to 0° C. Sodium bis(trimethylsily)amide (1M in THF, 5.63 mL, 5.63 mmol) was added dropwise. The mixture turned deep orange. tert-Butyl 4-formylpiperidine-1-carboxylate (1 g, 4.69 mmol) in 3 mL THF was added after 5 minutes. Color faded to slight yellow. The reaction was stirred at RT for 1.5 hours, before quenching with saturated aqueous ammonium chloride solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, concentrated and purified by passing through a 40 gram Biotage silica gel cartridge using 20% EtOAc/hexanes to afford the product as colorless oil. NMR integration indicated >20:1 Z/E selectivity. LRMS calc: 345.2; obs: 346.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[N:3]=1.O.[NH2:22][NH2:23]>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:5]=3)=[CH:15][CH:14]=2)[NH:23][N:22]=1
Reactant: NN
Reactant: CC(C)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
In a 25 mL sealable tube were combined 4-{2-amino-6-[(1-methylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (0.21 g, 0.54 mmol), hydrazine monohydrate (1.06 mL, 21.6 mmol), and EtOH (10 mL). The tube was sealed and the reaction mixture was stirred overnight at 95° C. The mixture was concentrated and to the resulting solid was added to EtOH (2 mL) followed by hexanes (15 mL). The mixture was sonicated and filtered. The solid was washed with hexanes to afford the title compound (167 mg, 99%) as an off-white solid. LC-MS (ES) m/z=284 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (d, J=6.6 Hz, 6H), 4.12 (bs, 1H), 5.36 (s, 2H), 5.94 (s, 2H), 6.24 (s, 1H), 6.71 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.82 (s, 1H), 11.50 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.Br[C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2ccco2)cc1
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution (25 ml) of 2-(4-trifluoromethylphenyl)furan (3.18 g) in tetrahydrofuran was added dropwise n-butyl lithium (1.6 M solution in hexane, 10.0 ml) under an argon atmosphere at −78° C. This mixed solution was heated to room temperature, and a solution (30 ml) of zinc chloride (2.25 g) in tetrahydrofuran was added. This mixture was stirred for 1 hr., and then ethyl 3-bromobenzoate (2.38 ml) and tetrakis (triphenylphosphine)palladium (0.433 g) were added. This mixture was stirred overnight under an argon atmosphere, and then poured into 0.5 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, volume ratio) and recrystallized from hexane-ethyl acetate to give ethyl 3-[5-(4-trifluoromethylphenyl)-2-furyl]benzoate (1.89 g, yield 35%) as pale-brown needle crystals. melting point: 93–94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([NH:17][CH2:18][CH3:19])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:17][CH2:18][CH3:19])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:20].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:17][CH2:18][CH3:19])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCNC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Agent: Cl
Product: CCNCC1(c2ccc(Cl)c(Cl)c2)CCCCC1

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-N-ethylcyclohexanecarboxamide (86 mg, 0.286 mmol) using General Procedure E followed by HCl salt formation. The crude HCl salt was recrystallized from CH3CN (4.5 mL) to give pure (±) N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine hydrochloride as colorless crystals. HPLC Rt=8.90 min; 1H NMR (400 mHz, McOH-d4) 7.57 (d, J=2.2 Hz, 1H), 7.54 (d, J=8.43 Hz, 1H), 7.34 (dd, J=2.2, 8.43 Hz, 1H), 3.11 (s, 3H), 2.94-2.88 (q, 2H), 2.18-2.15 (m, 2H), 1.68-1.58 (m, 5H), 1.51-1.30 (m, 3H), 1.17 (t, 3H); LC-MS 8.45 min, (M+1)+286 @ 8.7 min.
Reaction SMILES: [CH3:1][N:2]([O:23][CH3:24])[C:3](=[O:22])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]([O:23][CH3:24])[C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH3:27])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CON(C)C(=O)c1cc(O)ccc1NC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)OCc2ccccc2)c(C(=O)N(C)OC)c1
Temperature: 0 °C

Procedure:
An N,N-dimethylformamide (8 ml) solution of N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide (0.8 g), methyl iodide (0.2 g) and potassium carbonate (0.5 g) was stirred for 3 hours at 60° C. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The organic layer was washed with water, which was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give N-methyl-N-methyloxy 2-benzyloxycarbonylamino-5-methyloxy-benzamide as a yellow oily product (0.55 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:9][CH:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C:4]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12].C.C(=O)(O)[O-].[Na+:26]>[Pd].O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH2:9][CH:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C:4]=1[C:11]([O-:13])=[O:12].[Na+:26]
Reactant: COC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC1=C(C(=O)[O-])N2C(=O)CC2C1
Reaction time: 0.5 h

Procedure:
A mixture of benzyl 3-methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (50 mg) and 10% palladium on powdered charcoal (50 mg) in 1:1 dioxane-H2O (5 ml) containing sodium bicarbonate (12.5 ml) is hydrogenated at 40 psi for 30 mins. The mixture is filtered and the catalyst is washed with more water (5 ml). The combined filtrate is extracted with ethyl acetate, concentrated in vacuo to ca. 2 ml, and lyophilized to yield sodium 3-methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH2:1]([C:8]1([OH:22])[CH2:14][O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23].O1CCOCC1>O1CCOCC1>[ClH:23].[CH2:1]([C:8]1([OH:22])[CH2:14][O:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(Cc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: OC1(Cc2ccccc2)CNCCOC1
Reaction time: 24 h
Yield: 91.7 %

Procedure:
tert-Butyl 6-benzyl-6-hydroxy-1,4-oxazepane-4-carboxylate (Preparation 81, 37.15 g, 0.12 mol, 1 eq) was dissolved in dioxane (200 mL), and 4M hydrogen chloride/dioxane (60.4 mL, 0.24 mol, 2 eq) was added. The mixture was stirred for 24 h, evaporated, and coevaporated with ether. The formed precipitate was washed with ether and dried to title compound (27.3 g, 0.11 mol, 93%).