Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\C(C2C=CC3C=CSC=3C=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[C:43]([C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=1)(=[O:45])[NH2:44]>>[CH:1]([NH:4][C:5]([C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:50](=[O:51])[C:49]2[CH:53]=[CH:54][C:46]([C:43]([NH2:44])=[O:45])=[CH:47][CH:48]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(C(N)=O)cc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 11.9 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 4-carbamoylbenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-N1-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)terephthalamide (11.9% yield). MS m/z=576.2 [M+H], calc 575.71 for C31H41N7O4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[S:16][C:15]([C:17]([O:19]CC)=[O:18])=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]#[N:30])[CH:23]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[N:14][C:13]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]#[N:30])[CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2nc(C(=O)O)sc2-c2cccc(Cl)c2)ccc1F

Procedure:
At room temperature, 231 mg (1.48 mmol) of (3-chlorophenyl)boronic acid are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under reflux for 1 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 353 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cccc2c(O)ccnc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
4-Hydroxyquinoline (1.45 g, 10 mmol) was dissolved in 3 ml of concentrated sulfuric acid and the solution was cooled -10° C. or less. The solution was gradually added with mixed acid (0.8 ml of concentrated nitric acid with 1.2 ml of concentrated sulfuric acid) such that the reaction solution was not elevated in temperature up to 0° C. or more, and stirred at 0° C. for 3 hours. The reaction mixture was poured into crashed ice and neutralized with 2N aqueous solution of sodium hydroxide. The resulting precipitates were filtered off and washed with water. The filtrate was combined with the washing solution and extracted with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was developed by silica gel column chromatography (Wako Gel™ C-200, methylene chloride : methanol=20 : 1). Firstly eluted yellow fractions were collected and the solvent was removed to obtain 380 mg (20%) of 4-hydroxy-8-nitroquinoline.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]#[CH:20])=[CH:11][CH:10]=1>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]#[C:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: Ic1ccccn1
Reactant: C#CCCC#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1ccc(C#CCCC#Cc2ccccn2)cc1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (11 mg, 0.06 mmol) and triethylamine (3.4 mL), were added 2-iodopyridine (246 mg, 1.2 mmol) and Pd(PPh3)2Cl2 (42 mg, 0.06 mmol) under N2. A yellow suspension was obtained after 5 min of stirring at room temperature. A solution of 1-fluoro-4-(hexa-1,5-diynyl)benzene (210 mg, 1.2 mmol) in triethylamine (0.5 mL) was then added under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated. The crude product was dissolved in DCM and the organic phase was washed with saturated NH4Cl, water and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by Flash chromatography (prepacked 25 g silicagel column, Cyclohexane/ethyl acetate from 90/10 to 80/20 as eluent) to afford 87 mg of 2-(6-(4-fluorophenyl)hexa-1,5-diynyl)pyridine (Yield: 29%) as a brown powder (M.P.=68-69° C.).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[NH:18][NH2:19]>CO.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11](/[C:14](=[N:19]/[NH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])/[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: CCOC(=O)NN
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOC(=O)N/N=C(\C)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (150 mg, 0.65 mmol) was suspended in methanol (3 ml) and water (1 ml). Ethyl carbazate (78 mg, 0.75 mmol, 1.2 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 18 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with acetone. The resulting white precipitate was collected and washed with acetone to yield the product, one apparent isomer, as a white solid: 96 mg (47%).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[Br-].[Na+]>C(O)C>[C:2]([NH:5][C:6]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)(NC(C)=O)C(=O)OCC

Procedure:
To a solution of sodium metal (2.9 g; 0.125 mol) in absolute ethanol (500 mL) was added diethyl acetamidomalonate (LX) (27.2 g, 0.125 mol) followed by 4-(trifluoromethyl)benzyl bromide (LXI) (29.9 g, 0.125 mol). The reaction mixture was stirred at reflux overnight, during which time substantial amount of sodium bromide precipitated. The reaction mixture was concentrated to ca. 30% of its initial volume under reduced pressure and poured into cold water (400 mL). The precipitate was filtered and washed with water (3×250 mL), hexanes (3×150 mL) and then air dried to yield diethyl 2-acetamido-2-(4-(trifluoromethyl)benzyl)malonate (LXII) as a white solid used directly for the next step.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3([CH2:25][NH:26]C(=O)C)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:6][N:5]=1)([CH3:3])[CH3:2].[ClH:30]>>[ClH:30].[NH2:26][CH2:25][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([S:10]([NH:9][C:7]3[S:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=3)(=[O:12])=[O:11])=[CH:18][CH:17]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(=O)NCC1(c2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2)CCCCC1
Agent: Cl
Product: CC(C)c1nnc(NS(=O)(=O)c2ccc(C3(CN)CCCCC3)cc2)s1

Procedure:
1 g of N-{1-[4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-cyclohexylmethyl}-acetamide was suspended in 25 ml five molar hydrochloric acid and heated under reflux for 20 hours. The cooled reaction mixture was evaporated in vacuo. The residue was purified by chromatography on silica gel with the eluents dichloromethane:methanol=95:5 to obtain 0.78 g of a with solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:21][N:20]([CH3:22])[C:18]1[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=[CH:16][N:17]=1
Reactant: CN(C)c1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ncnc(N2CCNCC2)n1
Temperature: 40 °C

Procedure:
A solution of 1 mmol of 4-(4-Dimethylamino-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml dichloromethane was chilled and treated with 14 mmol of trifluoroacetic acid. The reaction mixture was heated to 40° C. for 30 min. After cooling, 50 ml of 2M aqueous sodium hydroxide was added. The organic layer was separated, dried and concentrated to yield the title compound as a yellowish oil. MS (m/e): 267.0 (M+CH3COO+, 100%)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5][N:4]=1>C1COCC1.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NC1(c2ccccc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc(C(=O)O)c(NC2(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxylate (crude from step 2) in THF (4 mL) was added LiOHH2O (150 mg, 3.57 mmol) in H2O (2 mL). The mixture was stirred at room temperature overnight. THF was removed under vacuum and the residue was acidified with 1N HCl, white solids precipitated out, which were collected by filtration, dried on vacuum to give 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxylic acid (646 mg). MS 302.3 (M+H).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[OH:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>>[CH3:3][CH:2]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)CCCC(C)Br
Product: CC(C)CCCC(C)Oc1ccc(C#N)cc1

Procedure:
2-bromo-6-methyl-heptane was reacted with p-hydroxy-benzonitrile to obtain p-[(1,5-dimethyl-hexyl)-oxy]-benzonitrile (boiling point = 165°-168° C/1.0 mmHg);
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1>[CH3:14][S:15]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:17])=[O:16]
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCOS(C)(=O)=O

Procedure:
The N,N-dimethylethanolamine (Aldrich, 0.11 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH3:13]N(C)C=O>S(Cl)(Cl)=O>[OH:9][CH2:7][C:6]1[N:1]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:4][CH:5]=1
Reactant: O=C(O)c1cccc(C(=O)O)n1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(CO)n1

Procedure:
A mixture of 2,6-pyridinedicarboxylic acid (10 g) in thionyl chloride (40 ml) with catalytic dimethylformamide was heated at reflux for 4 hours. The mixture was evaporated to dryness and azeotroped with toluene. Toluene (20 ml) was added to the residue followed by methanol (20 ml). The solvent was evaporated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in methanol and sodium borohydride (0.96 g) was added. The mixture was heated at reflux for 2 hours and evaporated. The residue was partitioned between chloroform and water. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% methanol in chloroform. Yield 2.76 g.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].C([O-])(O)=O.[Na+].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:21][CH2:20]1
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(C=O)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-formylbenzenesulfonyl chloride (1.0 g) in DCM (10 mL) was added NaHCO3 (sat'd aq, 10 mL) followed by 1-methyl-piperazine (0.6 mL). The reaction mixture was vigorously stirred for 1 h, the organic layer separated, and the aqueous layer extracted with DCM (2×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give 4-(4-methyl-piperazine-1-sulfonyl)-benzaldehyde (1.28 g) without further purification.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:20]3)=[C:15]([CH3:26])[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:23]([O:22][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:6][CH:7]=3)=[CH:14][C:15]=2[CH3:26])[CH2:21][CH2:20]1)([CH3:25])[CH3:24]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
Using General Procedure I; a solution of methyl{4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 84, 100.0 mg, 0.28 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 60.0 mg (62%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][C:8]([O:10][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (13.20 g, 75.8 mmol) in N,N-dimethylformamide (25 ml) was treated at 22° C. with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The reaction mixture was then diluted with toluene (500 ml), washed with water (3 times), saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the solvent was evaporated under reduced pressure to give an oil. Distillation under vacuum gave 20.9 g (96% yield) of the title material as a clear oil: Bp 80-90° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1H NMR (400 MHz, CDCl3) δ: 0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2), 4.35 (dd, 1, J=4, 6).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH2:12][CH3:13].Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[C:12]2[CH3:13]
Reactant: NNc1ccc(Cl)cc1
Reactant: CCC(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Product: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Temperature: 25 °C

Procedure:
5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride is synthesized based on the method described in U.S. Pat. No. 3,468,894. (4-Chloro-phenyl)-hydrazine hydrochloride (3.0 g, 16.8 mmol) and 3-propionylpyridine (2.4 g, 17.6 mmol) in ethanol (45 mL) is heated to reflux for 6 h. The mixture is then cooled to room temperature and added to HCl (4M in 1,4-dioxane, 17.6 mL). The resulting mixture is heated to reflux for 24 h. The mixture is then cooled to room temperature and the yellow precipitate is filtered and washed with methanol (10 mL) three times to give 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride as a yellow solid. MS (ESI) m/z 243.0 and 244.9 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12]2[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(OC)cc2)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.2 %

Procedure:
A mixture of (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.38 g, 1.16 mmol) in tetrahydrofuran (8.75 mL) and water (2.9 mL) was treated with lithium hydroxide monohydrate (59 mg, 1.40 mmol). The reaction was stirred at 25° C. for 2.5 h. At this time, the reaction was diluted with water (50 mL), acidified with a 2N aqueous hydrochloric acid solution and then was extracted with 10% methanol/dichloromethane (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.36 g, 99%) as a white solid: HR-ES-MS m/z calculated for C17H21NO5 [M+H]+ 320.1493, observed 320.1493. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H), 1.34-1.54 (m, 1H), 1.54-1.68 (m, 1H), 1.68-1.86 (m, 1H), 3.77 (s, 3H), 4.10 (d, J=18.1 Hz, 1H), 4.22 (d, J=18.1 Hz, 1H), 4.62 (dd, J=11.5, 4.2 Hz, 1H), 4.75 (s, 1H), 7.00 (d, J=9.1 Hz, 2H), 7.23 (d, J=9.1 Hz, 2H), 12.89 (br. s., 1H).
Reaction SMILES: [C:1]([O:18][CH2:19][C:20](=[CH2:23])[CH2:21][OH:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[C:1]([O:18][CH2:19][C:20](=[CH2:23])[CH2:21][O:22][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(CO)COC(=O)CCCCCCCCCCCCCCC
Reactant: O=C(O)CCCCCCCBr
Product: C=C(COC(=O)CCCCCCCBr)COC(=O)CCCCCCCCCCCCCCC

Procedure:
Following the procedure described in Preparation 9, but replacing 3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with 3-hexadecanoyloxy-2-methylenepropan-1-ol (from Preparation 2), and replacing 6-bromohexanoic acid with 8-bromooctanoic acid, the desired product was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:33]([O:37][C:38]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[CH:53]=[CH:52][C:51]([CH2:54]O)=[CH:50][CH:49]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:54][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[CH2:41][NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])=[CH:53][CH:52]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
To a solution of 60 mg (0.15 mmol) of 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]butanamide (Step D) in 0.5 mL of dry dimethylformamide under nitrogen was added 6.4 mg (0.16 mmol) of 60% sodium hydride/oil dispersion. After stirring for 15 minutes, a solution of 60 mg (0.15 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step I) in 0.5 mL of dimethylformamide was aded by cannula. The flask which originally contained the methanesulfonate ester was rinsed with 0.5 mL of dimethylformamide which was added to the reaction mixture. After stirring at room temperature for two hours, the reaction mixture was diluted with 75 mL of ethyl acetate, washed with 20 mL of water and 20 mL of saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (60:40) to afford 89 mg (96%) of the product as a white foam. FAB-MS: calculated for C42H48N4O6 704; found 705 (M+H). 1H NMR (200 MHz, CDCl3); 1.31 (s, 3H), 1.32 (s, 3H), 1.37 (s, 9H), 1.76 (s, 1H), 2.30-2.62 (m, 5H), 4.15 (d, 5 Hz, 2H), 4.40-4.60 (m, 2H), 4.85 (d, 14 Hz, 1H), 4.95 (d, 10 Hz, 1H), 5.04 (d, 10 Hz, 1H), 5.18 (d, 14 Hz, 1H), 5.65 (s, 1H), 6.70 (d, 6 Hz, 1H), 7.10-7.42 (m, 17H).