Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:30]=[CH:29][C:16]2[CH2:17][CH2:18][N:19]([C:22](OC(C)(C)C)=O)[CH2:20][CH2:21][C:15]=2[CH:14]=1.[C:31]1(=O)[CH2:34]C[CH2:32]1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:30]=[CH:29][C:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:34][CH2:31][CH2:32]3)[CH2:20][CH2:21][C:15]=2[CH:14]=1)[C:8]([NH:10][CH3:11])=[O:9]
Reactant: O=C1CCC1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(Cl)c1
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(Cl)c1

Procedure:
The title compound was prepared from 3-chloro-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide (E267, Step 4) and cyclobutanone using the method outlined in Example 264 Step 7 (36 mg, 57%) MS (ES+), m/e 385 & 387 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10](=[CH2:13])[CH2:11]Cl>>[Cl:9][C:10](=[CH2:11])[CH2:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1S
Reactant: C=C(Cl)CCl
Product: C=C(Cl)CSc1ccccc1O
Yield: 49 %

Procedure:
This compound was synthesized in 49% yield from 2-mercaptophenol and 2-chloroallyl chloride according to the general procedure for 16p in Example VII. Pale oil; 1H NMR (CDCl3): 3.48 (d, J=0.7 Hz, 2H), 4.91 (d, J=0.65 Hz, 1H), 5.13 (d, J=1.35 Hz, 1H), 6.69 (s, 1H), 6.87 (dt, J=1.40 Hz, J=7.42 Hz, 1H), 6.99 (dd, J=1.35, J=8.25 Hz, 1H), 7.27 (dt, J=1.65 Hz, J=7.82 Hz, 1H), 7.45 (dd, J=1.65 Hz, J=7.70 Hz, 1H); 13C NMR (CDCl3): 45.30, 115.08, 115.98, 117.31, 120.91, 131.89, 136.59, 137.25, 157.56; HRMS (FAB): 200.00626 calcd for C9H9ClOS [M]+. found 200.00598 (−1.3 ppm, −0.3 mmu).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][CH2:14][CH2:13][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:11])[CH:6]=1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCCl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-nitro-m-cresol (2.0 g, 0.013 mol), 1-bromo-2-chloroethane (1.7 mL, 0.020 mol) and potassium carbonate (4.7 g, 0.034 mol) in N,N-dimethylformamide (21 mL) was stirred at 70° C. for 18 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 4-(2-chloroethoxy)-2-methyl-1-nitrobenzene as solid (2.1 g, y. 73%).
Reaction SMILES: Br.[Cl:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:7]=2[CH:6]=[C:5]([OH:21])[C:4]=1[OH:22].[C:23]([Br:26])(=[O:25])[CH3:24]>FC(F)(F)C(O)=O>[BrH:26].[Cl:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:23](=[O:25])[CH3:24])=[CH:18][CH:19]=3)[C:7]=2[CH:6]=[C:5]([O:21][C:17](=[O:20])[CH3:16])[C:4]=1[O:22][C:5](=[O:21])[CH3:4]
Reactant: Oc1ccc(C2CNCCc3c2cc(O)c(O)c3Cl)cc1
Reactant: CC(=O)Br
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(C2CNCCc3c2cc(OC(C)=O)c(OC(C)=O)c3Cl)cc1
Reaction time: 2 h

Procedure:
6-Chloro-7,8-dihydroxyl-1-p-hydroxyphenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (Example 2, 1.0 g) was slurried in 200 ml of trifluoroacetic acid, then 1.29 ml of acetyl bromide was added. The mixture was heated at reflux for 2 hours then stirred for 2 hours. After evaporation to dryness the residue was taken up in benzene and concentrated to give a solid which was recrystallized from ethylacetatehexane to give 6-chloro-7,8-diacetoxy-1-(p-acetoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; m.p. 214.5-217°, 0.77 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][C:20]([OH:22])=[O:21])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.I[CH3:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][C:20]([OH:22])=[O:21])=[C:7]([CH3:11])[N:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccccc1CC(=O)O
Reactant: CI
Product: Cc1c(Sc2ccccc2CC(=O)O)c2ccc(Cl)cc2n1C

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: [2-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and iodomethane.
Reaction SMILES: [C:1](Br)(=[O:3])[CH3:2].C[Si](C)(C)[O:7][C:8]1[CH:13]=[C:12]([O:14][Si](C)(C)C)[C:11]([Cl:19])=[CH:10][N:9]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([Cl:19])=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Oc1cc(O[Si](C)(C)C)c(Cl)cn1
Reactant: CC(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(O)c(Cl)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 64 %

Procedure:
A 2.09 ml quantity of acetyl bromide and 0.10 ml of stannic chloride were added to a solution of 5.00 g of 2,4-bis(trimethylsilyloxy)-5-chloropyridine in 250 ml of dried dichloromethane. The mixture was stirred at room temperature for 3.5 hours. The mixture was neutralized with triethylamine and the solvent was distilled off. The residue was subjected to silica gel column chromatography using 40% ethyl acetate-benzene as an eluent, giving 2.07 g of the title compound in a yield of 64%.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[F:11][C:12]([F:35])([F:34])[C:13]([N:15]1[CH2:33][CH2:32][C:18]2([C:23]3=[CH:24][CH:25]=[CH:26][N:22]3[C:21]3[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:20]=3[O:19]2)[CH2:17][CH2:16]1)=[O:14]>>[F:31][C:27]1[C:21]2[N:22]3[C:26]([CH:9]=[O:10])=[CH:25][CH:24]=[C:23]3[C:18]3([CH2:17][CH2:16][N:15]([C:13](=[O:14])[C:12]([F:11])([F:34])[F:35])[CH2:33][CH2:32]3)[O:19][C:20]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)C=O
Reactant: O=C(N1CCC2(CC1)Oc1cccc(F)c1-n1cccc12)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2n1-c1c(F)cccc1OC21CCN(C(=O)C(F)(F)F)CC1
Reaction time: 0.33 h
Yield: 100.7 %

Procedure:
POCl3 (282 μL, 3.0 mmol) was added dropwise at 0° C. under N2 to dry DMF (234 μL, 3.0 mmol). The reaction mixture was left for 20 min at this temperature, which led to the formation of a white solid. A solution of 2,2,2-trifluoro-1-(9′-fluorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)ethanone (715 mg, 2.0 mmol) dry DMF (5.4 mL) was added drop-wise and the cooling bath was removed. The reaction was poured over ice, 1M NaOH was added (5 mL), then the pH was adjusted to 7 with 2M HCl. The mixture was extracted with dichloromethane (3×10 mL). The organics were combined, dried with MgSO4, filtered and evaporated to yield a residue that was purified by silica-gel column chromatography eluting with 5-30% EtOAc in hexanes to yield 9-fluoro-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (770 mg, quant). ESI-MS m/z calc. 382.1. found 383.3 (M+1)+; Retention time 1.71 minutes (3 min run).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C1COCC1>[CH3:1][NH:2][S:18]([CH:15]1[CH2:16][CH2:17][N:13]([C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:12])[CH2:14]1)(=[O:20])=[O:19]
Reactant: CN
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)C1
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Methylamine (40 wt % in H2O, 1 mL) was added to a solution of 3-chlorosulfonyl-pyrrolidine-1-carboxylic acid benzyl ester (256 mg, 0.843 mmol) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 10 min, and then warmed to room temperature and stirred for 2 hrs. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2×), the combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on neutral alumina, eluting with CH2Cl2/MeOH (99:1 to 95:5), gave benzyl 3-[(methylamino)sulfonyl]-1-pyrrolidinecarboxylate (173 mg, 69%): 1H NMR (CDCl3) δ 7.36-7.29 (m, 5H), 5.14 (d, J=1.9 Hz, 2H), 4.27 (d, J=42.6 Hz, 1H), 3.80-3.70 (m, 4H), 3.50 (m, 1H), 2.82 (d, J=4.9 Hz, 3H), 2.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](C#N)=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([C:17]2[N:13]([CH3:12])[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][C:16]=2[CH3:18])=[O:7])=[CH:4][CH:3]=1
Reactant: N#CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Yield: 28 %

Procedure:
A 1.50 g (0.0090 mole) sample of 4-chlorobenzoylcyanide was added over a one-hour period to 1.50 g (0.0082 mole) of ethyl 1,4-dimethylpyrrole-2-acetate at 120°-130° through which nitrogen was slowly bubbled. The mixture was heated for 27 hours. The resulting oil was chromatographed on silica gel with successive elution with hexane and 1,1,1-trichloroethane. The solvent was evaporated in vacuo from compound-bearing fractions. The residue was chromatographed through a Waters Associates, Prep LC, System 500 with elution with a 2:3 mixture of hexane:1,1,1-trichloroethane. Evaporation of solvent from the second compound-bearing fraction afforded solid which was recrystallized from methanol to give 0.74 g (28 percent yield) of ethyl 5-(4-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate, mp 108°-109°, undepressed by admixture with authentic material.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=[O:5])#[N:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>CCO>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:7]([S:10][CH3:11])=[C:3]([C:1]#[N:2])[C:4]([NH2:6])=[O:5])[CH:17]=[CH:18][CH:19]=1
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: Nc1cccc(Cl)c1
Solvent: CCO
Product: CSC(Nc1cccc(Cl)c1)=C(C#N)C(N)=O
Temperature: 25 °C
Yield: 45 %

Procedure:
A mixture of 2-cyano-3,3-bis(methylthio)acrylamide I-2 (5.0 g, 59.47 mmol) and 3-chloroaniline (8.346 g, 65.42 mmol) in EtOH (25 mL) was refluxed overnight. The reaction mixture was then allowed to cool to room temperature. The resulting solid was filtered and dried to give compound 3 (6.75 g, 45% yield, 100% purity) as a white solid.
Reaction SMILES: [C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18](Br)=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2].[C:39](N(CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C=C(C)C(C)=CC1=2)(=O)C>>[C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18]([CH3:39])=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(C)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cc(C)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(C)cc(C)cc21

Procedure:
This compound prepared utilizing the same methodology described in Example 56 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl 5-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-9-bromo-7-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylate following the procedure of Example 56 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7,8-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. ESI MS 545 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](N(OC)C)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:14][Mg]Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:9])[CH3:14])[CH:5]=[CH:4][N:3]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccnc(Cl)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (75 mg, 0.372 mmol) in THF (3 mL) at −78° C. under a nitrogen atmosphere was added methyl magnesium chloride (3.0 M in THF, 0.124 mL, 0.372 mmol) dropwise. The solution was warmed to room temperature for 1 hr. The solution was diluted with EtOAc, washed with 1 N the organic layer was neutralized with saturated aqueous NaHCO3, dried with MgSO4, filtered, and concentrated to dryness. Purification on silica gel by flash chromatography (0-100% EtOAc/hexanes) afforded 1-(2-chloropyrimidin-4-yl)ethanone (45 mg, 0.29 mmol, 77% yield). 1H NMR (500 MHz, CDCl3) δ 8.86 (d, J=4.9, 1H), 7.83 (d, J=4.9, 1H), 2.71 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])[CH2:21][CH2:20]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:31]>O1CCCC1.CN(C)C=O>[CH2:3]([N:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28][CH3:31])([CH3:29])[CH3:27])[CH2:21][CH2:20]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(O)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(C)(C)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
To a suspension of sodium hydride (abt. 60% in mineral oil, 342 mg, 8.6 mmol) in a mixture of tetrahydrofuran (20 mL) and N,N-dimethylformamide (10 mL) was added a solution of 1-{4-[(dibenzylamino)methyl]piperidin-1-yl}-2-methylpropan-2-ol (EXAMPLE 4, Step 4, 3.0 g, 8.2 mmol) in tetrahydrofuran (20 ml) at 0° C. Afer being stirred at the same temperature for 30 min, 0.53 mL (8.6 mmol) of iodomethane was added to the mixture. The mixture was stirred at ambient temperature for 3 days. The mixture was partitioned between ethyl acetate and water. After extraction with ethyl acetate, the combined organic phase was dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography on amine gel eluting with hexane/ethyl acetate (100:1) to afford 0.76 g (24%) of the title compound as colorless amorphous.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]([CH3:18])[CH2:16][NH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>C1(C)C=CC=CC=1>[CH3:18][CH:15]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:17][CH2:16]1
Reactant: O=Cc1ccccc1
Reactant: CC(CN)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC1CNC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 78 %

Procedure:
4 Å molecular sieve (10 g) was added to a solution of 1.06 g (10.0 mmol) of benzaldehyde and 1.35 g (10.0 mmol) of 2-phenylpropylamine in toluene (45 ml) and the mixture was refluxed for 4 h. After cooling to RT the mixture was filtered through diatomaceous earth and the filtrate was concentrated to small volume under vacuum. The residue was dissolved in TFA (90 ml) and the solution was heated at 120° C. for 20 h. Then it was concentrated to small volume under vacuum and made alkaline with a 2N aqueous NaOH solution. It was then extracted with EE. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 7:3) of the residue produced 1.74 g (7.8 mmol, 78%) of 4-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]1[C:10]2(CCC(=O)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:4]=[C:3]1[CH2:12][CH2:11][C:10]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To solution of methyltriphenylphosphonium bromide (17 g, 1.5 eq.) in THF (100 mL) at 0° C. was added dropwise n-butyllithium (2.5 M in hexanes, 18 mL, 1.4 eq.) and the resulting mixture was stirred for 1 h. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.0 g, 32 mmol, 1.0 eq.) in THF (10 mL) was then introduced dropwise and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by addition of sat. NaHCO3 and the separated aqueous layer was extracted with 4×EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (5% to 10% EtOAc/hexanes) to give 8-methyene-1,4-dioxa-spiro[4.5]decane (3.92 g, 79%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([C:30](=[O:38])[CH2:31][CH2:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O[Li].O>O1CCOCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:30](=[O:38])[CH2:31][CH2:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=3)=[CH:39][CH:40]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc(C(=O)OCC)cc3)cc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc(C(=O)O)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using ethyl 4-[{4-[(4-butylphenyl)ethynyl]benzyl}(3-cyclopentylpropanoyl)amino]benzoate and LiOH.H2O in the presence of dioxane as a yellow powder (79%). 1H NMR (CDCl3, 300 MHz) δ 8.08 (m, 2H), 7.49-7.35 (m, 4H), 7.23-7.02 (m, 6H), 4.91 (br s, 2H), 2.66-2.53 (m, 2H), 2.18-2.05 (m, 2H), 1.70-1.20 (m, 13H), 1.30-0.82 (m, 5H). M− (ESI): 506.4; M+ (ESI): 508.4. HPLC, Rt: 5.67 min (Purity: 98.5%).
Reaction SMILES: C([C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:5][CH:4]=1)=O.OO.[OH:32]S(O)(=O)=O.C([O-])(O)=O.[Na+]>CO>[OH:32][C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)c1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(O)cc2)c1

Procedure:
2.3 g (6 mmol) of 1-(4-formylphenoxy)-2-(3-methoxyphenyl)-6-methoxynaphthalene was suspended in 15 mL of MeOH and 1.7 mL (9 mmol) of 30% H2O2 was added. To the stirring mixture, 0.76 mL of conc. H2SO4 was slowly added. An additional 30 mL of MeOH was added and the reaction was allowed to proceed for forty-eight hours. The reaction was neutralized with NaHCO3 solution and extracted with CHCl3. The CHCl3 was washed with brine, dried with Na2SO4, and chromatographed on a silica gel column eluted with CHCl3. This yielded 1.6 g of the title compound as a tan amorphous powder, mp 125-126° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][NH:9][CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[NH2:16].[CH:17](=O)[CH2:18][CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][N:9]([CH2:17][CH2:18][CH3:19])[CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[NH2:16]
Reactant: CCC=O
Reactant: Nc1c(Cl)cc2c(c1Cl)CCC1CNCC21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN1CC2CCc3c(cc(Cl)c(N)c3Cl)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
6,8-Dichloro-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-7-ylamine (275 mg, 1.07 mmol) and propionaldehyde (81 μl, 1.12 mmol) were dissolved in tetrahydrofuran (25 ml). Acetic acid (90 μl, 1.6 mmol) and sodium trisacetoxyborohydride (340 mg, 1.6 mmol) were sequentially added to the reaction mixture and stirred for 1 hour at room temperature. The reaction mixture was concentrated and the residue was dissolved in a 1 M NaOH solution (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted once more with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield the pure product (295 mg, 92%).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:8]([N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1C=CC(=O)N1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1C=CC(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Maleimide (20.0 g, 206 mmol) and trityl chloride (57.4 g, 206 mmol) were mixed together in 200 ml of chloroform and triethylamine (31.3, 309 mmol) was added dropwise to the reaction over a period of 20 minutes. After stirring for one hour at room temperature, the reaction was washed with 10% aqueous hydrogen chloride (HCl) solution and dried over magnesium sulfate (MgSO4). The crude product was slurried in 20 ml of ethylacetate. A total of 18.4 g of a solid material was filtered and dried (60% yield). 1H NMR (CDCl3): 7.31 (m, 15H, aromatics), 6.25 (s, 2H, vinyl).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:23]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:18]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]2[CH2:21][CH2:20][C:19]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:18]=3[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:23]=2[CH:24]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3cc(Cl)ccc3CCc3ccc(Cl)cc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCN2c3cc(Cl)ccc3CCc3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above ester (1.5 g, 3.1 mmol) was dissolved in ethanol (20 ml). A 4 N aqueous sodium hydroxide solution (2.3 ml) was added and the mixture was stirred at ambient temperature for 3 h. A concentrated aqueous hydrochloric acid solution (3 ml) was added until pH 1 and the mixture was extracted with dichloromethane (300 ml). The phases were separated and the organic phase was washed with water (10 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue re-evaporated with acetone. The foamy residue was dissolved in acetone (20 ml) and left for crystallization. This afforded 1.25 g of the title compound as a solid.