Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][C:16]1[C:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[C:19]([CH3:33])[O:18][N:17]=1.N1C=CC=CC=1>ClCCl>[CH3:15][C:16]1[C:20]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([NH:8][C:7]3[C:2]([CH3:1])=[N:3][C:4]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[CH:5][CH:6]=3)(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[C:19]([CH3:33])[O:18][N:17]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc(N2CCOCC2)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CCOCC2)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 65 °C
Yield: 67.2 %

Procedure:
A mixture of 2-methyl-6-(4-morpholinyl)-3-pyridinamine (170 mg, 0.880 mmol) and 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (265 mg, 0.880 mmol) in dichloromethane (4 mL) and pyridine (0.142 mL, 1.759 mmol) was heated at 65° C. for 2 hours. The reaction mixture was allowed to cool and separated between dichloromethane and saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and evaporated in vacuo. The crude was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient) to give the title compound (271 mg) as an off-white solid. LCMS (2 min, formic) Rt 0.82 min, m/z (ES+) 459 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CC(O)=O.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:17][CH:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:7][C:6]=2[CH:16]=1
Reactant: CCOC(=O)/C=C/COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)CC1COc2cc(F)ccc2N1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Ethyl (2E)-4-(5-fluoro-2-nitrophenoxy)but-2-enoate (Intermediate 9, 310 g, 1.09 mol) dissolved in AcOH (1.4 L) was added dropwise during one h to a slurry of iron powder (325 mesh, 305 g, 5.47 mol) in AcOH (0.90 L) at 60° C. under nitrogen atmosphere. The temperature was kept at 60-75° C. during the addition. Upon complete addition the resulting mixture was stirred at 70° C. for 30 min before it was cooled to rt. The solids were filtered off and washed with AcOH (2.5 L). The filtrate was concentrated to dryness and the residue was dissolved in EtOAc (2.0 L). The solution was washed with citric acid (aq., 10% w/w, 2×1.0 L), Na2CO3 (10% w/w, 500 mL) and water (1.5 L). The solution was then concentrated to dryness and the obtained residue was dissolved in i-PrOAc (500 mL). Concentration to dryness once again yielded a residue which was purified by column chromatography on silica using heptane/EtOAc (4:1) as eluent. The title compound (236 g, 0.986 mol, 98% w/w, 88% yield) was obtained as an oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[S:24][CH:28]=[CH:27][N:26]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: c1cscn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3)c2)cn1)c1nccs1

Procedure:
This compound was prepared by method C using compound 12a and thiazole. HRMS (ESI+): m/z=332.0853 [M+H]
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH:8]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:9](O)=[O:10]>O1CCCC1>[NH2:7][CH:8]([CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:9][OH:10]
Reactant: NC(CCN1CCCC1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)CCN1CCCC1
Temperature: 22 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
a solution of 1M lithium aluminium hydride (12.2 ml, 12.2 mmol) in tetrahydrofuran is added to a cold (−20° C.) suspension of 2-amino-4-pyrrolidin-1-ylbutanoic acid (0.994 g, 4.05 mmol) in tetrahydrofuran (20 ml). The mixture is left to warm to 22° C. and is then heated for one hour at 60° C. The mixture is then cooled to 0° C. and is carefully quenched by the successive addition of water, 1 N aqueous sodium hydroxide and water. After one hour stirring at 0° C., the suspension is filtered and the solid is washed with ethyl acetate. The liquid phase is concentrated in vacuo to yield 318 mg of 2-amino-4-pyrrolidin-1-ylbutan-1-ol ax35 as a yellow oil.
Reaction SMILES: [S-2:1].[Na+].[Na+].[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH2:18][CH2:19]Br)[CH2:15][CH2:16]Br>CN(C=O)C>[Br:4][C:5]1[CH:6]=[C:7]2[C:8]3([CH2:18][CH2:19][S:1][CH2:16][CH2:15]3)[C:9](=[O:14])[NH:10][C:11]2=[CH:12][CH:13]=1
Reactant: O=C1Nc2ccc(Br)cc2C1(CCBr)CCBr
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Br)cc2C12CCSCC2
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
Sodium sulfide (292 mg, 3.75 mmol) was added to a solution of 5-bromo-3,3-bis(2-bromoethyl)-1,3-dihydro-2H-indol-2-one from Step B (532 mg, 1.25 mmol) in DMF (2 mL) and the solution heated to 50° C. After 2.5 h, the mixture was partitioned between CH2Cl2 (20 mL) and H2O (20 μL). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=300 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:6][CH:5]([OH:18])[C:4]=2[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.[Cr](O)(O)(=O)=O>COC(C)(C)C.O>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:6][C:5](=[O:18])[C:4]=2[CH:3]=1
Reactant: COCCCN1CC(O)c2cc(Cl)sc2S1(=O)=O
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)C
Solvent: O
Product: COCCCN1CC(=O)c2cc(Cl)sc2S1(=O)=O

Procedure:
243 g of alcohol 5 were dissolved in 1.56 L t-butyl methyl ether and charged into a 4-L three necked flask fitted with a reflux condenser and a thermometer. With stirring and cooling with an ice bath a mixture consisting of 155 g of sodium dichromate and 206 g sulfuric acid dissolved in 546 mL of water was added. The temperature was maintained below 20° C. during the addition. After the addition of chromic acid, the biphasic mixture was stirred for further 90 min at 25° C. until the TLC indicated complete consumption of the racemic alcohol 5. Then the aqueous layer was separated and 4× extracted with 390 mL of t-butyl methyl ether. The combined etheral solutions were successively washed with 624 mL of saturated sodium bicarbonate and sodium chloride solution, respectively. After drying with sodium sulfate and filtration the solvent was evaporated. Crystallization of the residual oil was induced by addition of a few crystals of authentic ketone 6 and about 25 mL of diethyl ether. To complete the crystallization 400 mL of n-hexane were added. An analytical sample was recrystallized from diethyl ether, mp: 48°-52° C., yield: 194 g (80%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13][CH2:14][NH2:15]
Reactant: Cn1cc(-c2ccccc2)nc1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccccc2)nc1CCN
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
To a suspension of tert-butyl 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamate (831 mg, 2.76 mmol) in dioxane (5 mL) was added HCl in dioxane (4M, 6.89 mL, 27.6 mmol) dropwise. The reaction mixture was stirred at 20° C. for 1.5 h. The crude reaction mixture was concentrated in vacuo. Heptane was added and the suspension was stirred for 30 min and evaporated in vacuo to give the product as white solid (760 mg, 2.72 mmol, 98.5%). MS: M=202.3 (M−2HCl+H)+
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[C:9]([OH:24])[C:8]2[CH2:25][N:26]([C:28]([C:30]3[N:31]=[CH:32][S:33][CH:34]=3)=[O:29])[CH2:27][C:7]1=2)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[C:9]([OH:24])[C:8]2[CH2:25][N:26]([C:28]([C:30]3[N:31]=[CH:32][S:33][CH:34]=3)=[O:29])[CH2:27][C:7]1=2)#[N:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccccc3C#N)c1=O)CN(C(=O)c1cscn1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccccc1Cn1c2c(c(O)c(C(=O)NCC(=O)O)c1=O)CN(C(=O)c1cscn1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Step A (20 mg, 0.037 mmol) was dissolved in DCM (1.5 mL) and TFA (0.5 mL, 6.5 mmol) was added. The reaction was stirred at ambient temperature overnight. The reaction was concentrated and the residue was purified on a C-18 reverse phase chromatography column eluted with 0-100% MeCN in water. The desired fractions were concentrated affording the title compound. 480.0 (M+1); Rt=2.53 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:32][CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4]
Reactant: COc1ccc(CCN)cc1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(NCCc2ccc(OC)cc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.3 %

Procedure:
To a mixture of 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester [1 g, 4.83 mmol, Intermediate (54)] and N,N-diisopropylethylamine (1.27 mL, 7.25 mmol) in THF (16 mL) is added 2-(4-methoxyphenyl)-ethylamine (707 μL, 4.83 mmol). The resulting mixture is stirred at ambient temperature for 20 hours and poured into 50 mL water and extracted three times with 40 mL ethyl acetate. The organic extracts are combined and washed with 20 mL brine, dried over magnesium sulfate, filtered and concentrated to afford a solid which is purified via flash column chromatography on silica gel (35 g) eluting with 5 to 50% EtOAc in heptane gradient to afford 2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid methyl ester [1 g, 64.5%, Intermediate (55)]. LCMS: RT=2.9 minutes, MS: 322 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1
Reactant: CNC(=O)COC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNC(=O)COC(=O)N1CCCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cn2)CC1
Temperature: 150 °C
Yield: 57.5 %

Procedure:
0.12 g (0.3 mmol) of 2-(methylamino)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1,4-diazepane-1-carboxylate, prepared in step 11.3., 0.25 g (1.2 mmol) of 4-(trifluoromethoxy)-phenylboronic acid and 0.9 ml (1.8 mmol) of aqueous sodium carbonate solution (2M), suspended in 3.5 ml of toluene and 0.8 ml of ethanol are introduced into a Pyrex reactor. 0.07 g (0.06 mmol) of tetrakis-(triphenylphosphine)palladium is then added and, after sealing the reactor, it is maintained at 150° C. for 15 minutes under microwave irradiation. The organic phase is recovered after separation of the phases by settling, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 30/70/5 mixture of ethyl acetate, cyclohexane and methanol. After crystallization from diisopropyl ether, 0.078 g of product is obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.C(OC(=O)C)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[NH:4][N:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2[nH]nc(N3CCOCC3)c2c1

Procedure:
3-Bromo-5-nitro-1H-indazole (0.5 gm, 2 mmol) was dissolved in 3.5 ml of morpholine and heated in a sealed tube for 40 hrs. The mixture was then cooled and added to ethylacetate, washed with brine and dried over magnesium sulfate. After chromatography on silica gel using 20-50% ethylacetate/hexanes as eluent the title compound was obtained (210 mg, 0.85 mmol).
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=2)=[O:12])[CH2:28][CH2:29]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
To tetrahydrofuran (120 mL) were added 4-bromobenzoyl chloride (25 g), 1-(2,4-dimethylphenyl)piperazine (22 g) and 1N aqueous sodium hydroxide solution (120 mL), and the mixture was stirred at room temperature for 6 hr. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The title compound (31 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17]([C:19]1[O:20][C:21]([CH2:24]Cl)=[CH:22][CH:23]=1)=[O:18]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:21]3[O:20][C:19]([C:17]([OH:18])=[O:16])=[CH:23][CH:22]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)c1ccc(CCl)o1
Product: Cc1ccc(-c2ccc(OCc3ccc(C(=O)O)o3)cc2)cc1

Procedure:
5-(4′-Methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 4′-methyl-biphenyl-4-ol (purchased from Maybridge plc, Tintagel, Cornwall, UK or from Intermediate 5) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 47 mg. Mass spectrum (ES) MH+=309.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])[N:11]([CH3:20])[N:10]=1.[Br:21]Br>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16]([Br:21])=[CH:17][C:18]=2[CH3:19])[N:11]([CH3:20])[N:10]=1
Reactant: Cc1ccsc1-c1nc(-c2c(F)cccc2Cl)nn1C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)sc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 81.1 %

Procedure:
3-(2-fluoro-6-chlorophenyl)-5-(3-methyl-2-thienyl)-1-methyl-1,2,4-triazole (1.18 mmol., 364 mg) was dissolved in glacial acetic acid (4 ml). Bromine (2.36 mmol, 0.124 ml) was added in two portions and the reaction allowed to stir 5 days at room temperature. Diluted with water and extracted into diethyl ether, washed with saturated NaHCO3 and brine, dried over MgSO4. Concentrated to a white solid. Wgt. 0.51 g, recrystallized from hexane ethyl acetate to afford the product as a white solid (0.37 g, 81%) MP 117-118° C.; Anal. Calcd. For C14H10BrClFN3S; C, 43.44; H, 2.60; N, 10.86. Found; C, 43.46; H, 2.71; N, 10.81.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14](O)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(#N)C.[C:20]1(=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[CH:22]=C1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([C:14]3[C:20](=[O:31])[C:29]4[C:24]([C:23](=[O:30])[CH:22]=3)=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=C(O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C1C=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 31 °C
Yield: 101.4 %

Procedure:
To a solution of silver nitrate (14.17 g, 0.0838 moles) dissolved in 200 ml water, 100 gm (0.419 moles) trans-4-(4-chlorophenyl)cyclohexane carboxylic acid and acetonitrile (500 ml) was added. The solution was heated to reflux followed by addition of 1,4-naphthoquinone (80 gm, 0.506 moles). A solution of ammonium persulfate (239 g; 1.048 moles) in water (600 ml) was added dropwise to the above solution and continued reflux for half an hour. The reaction mass was then cooled to 30-32° C. and extracted with methylene chloride. The organic layer was first washed with water, followed with 10% sodium carbonate aqueous solution, and further with water until neutral pH. The organic layer was concentrated to afford the compound of Formula II (2-[4-(4-chlorophenyl)cyclohexyl]-1,4-naphthoquinone, 149 gm).
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[C:22]([O:24]CC)=[O:23])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[C@H:10]([C:22]([OH:24])=[O:23])[CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](C(=O)O)C1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Excess sodium metal was added to a stirred solution of the product of step E (0.651 g, 1.85 mmol) in methanol (5.0 mL) at ambient temperature, and the resulting solution was heated to 75° C. After approximately 1 h, 5 M sodium hydroxide (3.0 mL) was added and the reaction mixture heated to 100° C. for an additional 1 h. After cooling to room temperature, the reaction mixture was acidified to pH 5 with 2 N hydrochloric acid and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was used without further purification in the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.Cl.[CH2:13]([NH2:15])[CH3:14]>C(N(CC)CC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH2:13][CH3:14])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CCN
Agent: Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid, ethylamine hydrochloride and triethylamine.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[S:12][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2Cl)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(2-chlorophenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 8, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:37]=[CH:36][CH:35]=[CH:34][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[O:11][CH2:12][CH2:13][N:14]3[C:15](=[C:16]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:17]4[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:22]=43)[C:34]=2[CH:35]=[CH:36][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCOc3ccccc3OCc3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OCc2ccccc2)cccc1-3
Temperature: 130 °C
Reaction time: 41 h
Yield: 33.3 %

Procedure:
To a solution of methyl 1-[2-(2-benzyloxyphenoxy)ethyl]-2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.61 g) in N,N-dimethylacetamide (100 ml) were added potassium acetate (905 mg, 9.22 mmol) and tetrakis(triphenylphosphine)palladium (800 mg, 0.69 mmol), and the mixture was stirred at 130° C. for 41 hr. The mixture was allowed to cool to room temperature, and filtered through celite. Saturated aqueous ammonium chloride solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=6:1) to give methyl 4-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (745 mg, yield 34%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17](=[O:18])[NH:35][C:34]2[CH:36]=[CH:37][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3.78 g (10 mmol) 4-tert-Butoxycarbonylamino-piperidine-1,4-dicarboxylic acid monobenzyl ester (commercially available), 1.76 g (13 mmol) 4-isopropyl-aniline (commercially available), 2.1 g (11 mmol) EDCI and 1.36 g (11 mmol) DMAP in 50 mL THF was stirred at room temperature over night. After concentration of the mixture ethyl acetate and water was added. The mixture was extracted with ethyl acetate and the combined organic fractions were dried with MgSO4 and evaporated. The residue was purified over silica eluting with a gradient formed from ethyl acetate and hexane to afford after evaporation of the product containing fractions 2.85 g (57%) of the title compound as white solid. MS (m/e): 496.3 [(M+H)+].