Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=2[F:23])[NH2:19])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=2[F:23])[NH:19][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(-c2cc(N)ccc2F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1)C(=O)OCC
Yield: 60 %

Procedure:
5.12 g (60% yield) was prepared by the method of Example 19G from 5.5 g 3-(4-t-butyldimethylsilyloxymethylphenyl)-4-fluoroaniline and 3.5 ml diethyl ethoxymethylenemalonate. A pale yellow-green oil was obtained. NMR (CDCl3, 250 MHz): 8.5 (d, 1H, J=12 Hz), 7.5 (ABq, 4H), 7.2 (m, 3H), 4.8 (s, 2H), 4.25 (m, 4H), 1.35 (m, 6H), 1.0 (s, 9H), 0.1 (s, 6H).
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O>[C:14]1([CH2:13][S:1][C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1cccnc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccnc1SCc1ccccc1
Yield: 97.1 %

Procedure:
200 parts 2-mercaptonicotinic acid, 970 parts of water, 215 parts of 50% NaOH, and 164 parts of benzyl chloride were combined and the resulting solution was refluxed for 2 hours. After dilution with 2580 parts of water, the solution was acidified with 207 parts of 36% HCl. The resulting slurry was cooled and filtered. The wet cake was washed with water and dried to give 307 parts (97.1%) of 2-(phenylmethylthio)-3-pyridinecarboxylic acid, m.p. 190°-193° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[O:7]1)=[O:5])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([OH:7])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C1OC1c1cccc2ccccc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(O)Cc1cccc2ccccc12

Procedure:
To an ethanol (400 mL) solution of 3-naphthalen-1-yl-oxirane-2-carboxylic acid ethyl ester (21.26 g, 87.8 mmol) was added 5% palladium hydroxide on carbon (1.0 g). The reaction was then pressurized to 50 psi with hydrogen for 2 h. The reaction was then filtered through a celite pad. The cake was washed with ethanol (100 mL). The reaction was then concentrated under reduced pressure to yield 2-hydroxy-3-naphthalen-1-yl-propionic acid ethyl ester as an oil. 1H NMR(300 MHz, DMSO) 8.05 (d, 1H), 7.89(d, 1H), 7.79(d, 1H), 7.34 (m, 4H), 5.58 (d, 1H), 4.32 (dd, 1H), 4.04 (q, 2H), 3.44 (dd, 1H), 3.24 (dd, 1H), 1.05 (t, 3H).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[H][H]>C(O)C.C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[S:1]1[C:5]([C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: [H][H]
Reactant: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: c1ccccc1
Product: O=C(O)CCCCCC[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1

Procedure:
(Z)-7-((1R,2R,3R)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoic acid (Example 7, 1 molar equivalent) is dissolved in a 3:2 mixture of ethanol and benzene (0.01 M) under a nitrogen atmosphere. Wilkinson's catalyst (30% by weight relative to starting material) is added and hydrogen gas is introduced. The hydrogen uptake is monitored and upon theoretical consumption, the solvents are removed under reduced pressure and the residue is dissolved in a minimal amount of ethyl acetate containing 1% acetic acid. The crude product is purified using a filtration column on silica gel, eluted with 0.4% acetic acid in ethyl acetate. A second flash silica column eluted with an isopropanol-hexanes-acetic acid solvent system affords the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:28])[CH:17](C(OC(C)(C)C)=O)[C:18](=[O:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:28])[CH2:17][C:18](=[O:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(C(=O)OC(C)(C)C)C(=O)C1CCCN1C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 95 %

Procedure:
2-(2-tert-Butoxycarbonyl-3-oxo-butyryl)-pyrrolidine-1-carboxylic acid benzyl ester (9.74 g, 25.0 mmol) was dissolved toluene (40 mL) and was washed with 1N HCl (2×50 mL). To the resulting solution was added p-toluenesulfonic acid monohydrate (1.00 g, 5.00 mmol) and the solution was heated under nitrogen to 80° C. for 4 hours. The dark mixture was allowed to cool and was washed with water (3×100 mL). The organic layer was concentrated to give 6.87 g (95%) of 2-(3-oxo-butyryl)-pyrrolidine-1-carboxylic acid benzyl ester as an amber oil. The product was used directly in the subsequent step without further purification. [M+H]+ 290.03.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([O:15][C:16]([C@:18]1([NH2:30])[CH2:23][C@H:22]([OH:24])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C@:18]1([NH:30][C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:23][C@H:22]([OH:24])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:17])[CH3:14]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@@H]2O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)CNC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2O

Procedure:
Prepare according to General Procedure A using Boc-Glycine (458 mg, 2.62 mmol, Aldrich) and (1S,2S,4S,5R,6R)-2-amino-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (450 mg, 1.75 mmol, Preparation 22). Purify on 35 g of silica eluting with a gradient from 50/50 to 20/80 hexanes/ethyl acetate. Yield: 560 mg (77%).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[N:11]1([C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: O=C(O)CCC(=O)C(=O)O
Product: O=C(O)CCC(=O)C(=O)N1CCCC1
Yield: 51.8 %

Procedure:
Using 584 mg of 2-oxoglutaric acid and 284 mg of pyrrolidine, there was obtained 412 mg of the subject compound (84), by conducting a reaction and treatment analogous to Example 83, as colorless crystals, m.p. 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7]Br.[CH2:14]([NH2:17])[C:15]#[CH:16]>CC#N.O>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH:17][CH2:14][C:15]#[CH:16]
Reactant: Clc1ccc(OCCCBr)c(Cl)c1
Reactant: C#CCN
Solvent: O
Solvent: CC#N
Product: C#CCNCCCOc1ccc(Cl)cc1Cl

Procedure:
2.3 ml of 87% pure 3-(2,4-dichlorophenoxyl) propylbromide (2.99 g; 0.011 mole) and 1.6 ml propargylamine (1.38 g; 0.025 mole) in 30 ml CH3CN and 1.65 g k2CO3 in 3 ml H2O were stirred at room temperature for 5 days.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][N:12]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>O>[CH3:11][N:12]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:9]=[O:10])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(c1ccccc1)c1cccc2ccccc12
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(c1ccccc1)c1ccc(C=O)c2ccccc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Phosphorus oxychloride (POCl3, MW 153, 0.06M, 9.18 g) was added dropwise to DMF (MW 73, 0.36M, 26.3 g), maintaining the temperature at <10° C. with external cooling. 1-(N-Methyl-N-phenylamino)-naphthalene (MW 233, 0.06M, 14 g) was added and the reaction stirred at 100° C. for 3 hours. After cooling to room temperature and pouring into water (140 ml) the mixture was neutralised to pH 6 using saturated sodium acetate solution. The aqueous mixture was extracted using dichloromethane (2×50 ml), the combined extracts washed with water (3×100 ml) before drying over MgSO4. The solvent was evaporated under reduced pressure to give 10.4 g of 1-(N-methyl-N-phenylamino)-4-formyl naphthalene as an oil (66% yield).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]2[CH2:20][CH2:19][C@:18]([CH2:28][CH:29]=[CH2:30])([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH3:14])=[CH:9][CH:8]=1)(=O)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34]>C1(C)C=CC=CC=1.N1C=CC=CC=1.CCOC(C)=O>[CH2:28]([C@@:18]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:17][C:16](=[O:31])[N:15]([C@H:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]3[S:34][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:8][CH:9]=2)[CH3:14])[CH2:20][CH2:19]1)[CH:29]=[CH2:30]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C(=O)NNC(C)=O)cc2)C(=O)O1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3nnc(C)s3)cc2)C(=O)O1
Temperature: 130 °C
Yield: 61 %

Procedure:
N′-acetyl-4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzohydrazide (4 mg, 0.009 mmol) was dissolved in 5:1 toluene/pyridine (1.5 mL). Phosphorus pentasulfide (8.1 mg, 2 equiv.) was added and the mixture was heated in Microwave Oven for 25 min at 130° C. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with 5% HCl (2×5 mL), satd aq NaHCO3 solution (4 mL), brine (4 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified by prep HPLC to afford 2.43 mg (61% yield). LC-MS Method 1 tR=1.7, min, m/z=438; 1H NMR (CDCl3) 7.66 (d, 2H), 7.26 (t, 2H), 7.02 (t, 2H), 6.97 (d, 2H), 5.69 (m, 2H), 5.07 (dd, 2H), 2.98 (m, 1H), 2.83 (s, 3H), 1.56 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:8](=[N:12][O:13][CH3:14])[C:9](Cl)=[O:10])=[C:4]([F:23])[CH:3]=1.[NH3:24]>C1COCC1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:8](=[N:12][O:13][CH3:14])[C:9]([NH2:24])=[O:10])=[C:4]([F:23])[CH:3]=1
Reactant: N
Reactant: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(=O)Cl
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(N)=O

Procedure:
The title compound is prepared from 3-(4-bromo-2-fluorobenzyl)-2-methoxyimino-4-oxooctanoyl chloride (from Step G) according to the method of Example 4, Step E, except that instead of bubbling ammonia into the cold reaction mixture, it is preferable to prepare a saturated solution of ammonia in THF (at about -50° C.) and add this cold solution gradually (under protection from moisture) to a stirred solution of the acid chloride in THF at -50° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:8][N:7]([CH3:17])[N:6]=1)=[O:4].[OH-].[Na+].Cl>O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]([CH3:17])[N:8]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1nn(C)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc(C(=O)O)c(-c2ccc(F)cc2)n1
Temperature: 120 °C
Yield: 91 %

Procedure:
5-(4-Fluoro-phenyl)-2-methyl-2H-[1,2,3]triazole-4-carboxylic acid methyl ester D24 (940 mg, 4 mmol) in water (65 ml) was treated with 2N sodium hydroxide (4 ml) and the mixture was heated at 120° C. for 2 h. The volume of water was reduced to 20 ml in vacuo and the ice-cooled residue was treated with 2N HCl (4 ml). Filtration, washing with water and drying in vacuo afforded the title compound as a white solid (810 mg, 91%). Mass spectrum (API+). Found 222 (MH+) C10H8FN3O2 requires 221.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]([O:18]CC)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO>[CH2:28]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([OH:18])=[O:17])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Yield: 55 %

Procedure:
First, 12 g of ethyl 2,2-bis(6-benzyloxyhexyl)acetate, 250 ml of methanol, and 100 ml of an aqueous solution containing 16.8 g of 85% potassium hydroxide were placed in a 500 ml flask. Then, the mixture was stirred under reflux for 2 hours. The reaction mixture was poured into diluted hydrochloric acid, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from a mixed solvent of hexane and acetone to obtain 6.2 g of 2,2-bis(6-benzyloxyhexyl)acetic acid (Y: 55%).
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1B(O)O.Br[C:23]1[C:24]2[C:29]([CH:30]=[C:31]3[C:36]=1[CH:35]=[CH:34][CH:33]=[CH:32]3)=[CH:28][CH:27]=[CH:26][CH:25]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C(=CC(=CC=1)C)C)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.O.C(O)(C)(C)C>[CH:35]1[C:36]2[C:31](=[CH:30][C:29]3[C:24]([C:23]=2[C:14]2[CH:15]=[CH:16][C:17]4[C:18]5[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=5)[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:12]=4[CH:13]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:32]=[CH:33][CH:34]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: OB(O)c1ccc2c3ccccc3c3ccccc3c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(C)c(C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: c1ccc2c(-c3ccc4c5ccccc5c5ccccc5c4c3)c3ccccc3cc2c1
Yield: 59.9 %

Procedure:
Under the nitrogen atmosphere, triphenylen-2-ylboronic acid (5.6 g), 9-bromoanthracene (3.5 g), (Pd(PPh3)4) (0.5 g), potassium phosphate (5.8 g), and a mixture solvent of pseudo cumene, t-butyl alcohol, and water (48 ml) (pseudo cumene/t-butyl alcohol/water=10/1/1 (volume ratio)) were added to a flask and then refluxed for 8 hours. After adding water, the precipitates were collected by suction filtration. The obtained solid was washed with water followed by methanol and purified by silica gel column chromatography (solvent: toluene). After re-crystallization with a mixture solution of toluene/ethyl acetate, 2-(anthracen-9-yl)triphenylene (3.3 g) was obtained as an eleventh intermediate compound. The scheme is represented in the following “Reaction 21”.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1(O)Cc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Product: CC1=Cc2ccccc2C1
Yield: 67.8 %

Procedure:
25.5 g (0.17 moles) of compound 12, 3.2 g (0.017 moles) of p-toluenesulfonic acid and 500 ml of hexane were placed in a round-bottomed flask fitted with a Dean-Stark apparatus. This suspension was refluxed for 3 h. After cooling, the hexane fraction was decanted from the insoluble products and the solvent was removed under vacuum to leave an oil, which was then distilled in a short distillation column at 45° C. and 0.03 mbar to give 15 g (yield: 68%) of compound 13. 1H NMR (400 MHz, CDCl3): δ=7.33 (d, J=7.6 Hz. 1H); 7.21 (m, 2H); 7.06 pseudo dt, J=7.2, 1.4 Hz, 1H); 6.45 (bs, 1H); 3.25 (s, 2H); 2.12 (s, 3H).
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[C:31]2=[O:38])[CH:27]=[CH:28][CH:29]=1.[CH3:39][O:40][CH2:41]I>C1COCC1>[CH3:39][O:40][CH2:41][C:30]1([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)[CH2:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[C:31]1=[O:38]
Reactant: COc1cccc(C2CCCCN(C)C2=O)c1
Reactant: COCI
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC1(c2cccc(OC)c2)CCCCN(C)C1=O
Reaction time: 1 h

Procedure:
To 1.6 M n-BuLi in hexane (3.38 mL, 5.42 mmol) at 0° C. was added a solution of 2,2,6,6-tetramethyl piperidine (0.91 mL, 5.42 mmol) in anh. THF (10 mL) over 5 min. A solution of 3-(3-methoxy-phenyl)-1-methyl-azepan-2-one (as described in Example 4, Step A) (0.632 g, 2.71 mmol) in anhydrous THF (10 mL) was added and stirred OC for 1 h. Iodomethyl methyl ether (0.275 mL, 3.25 mmol) was added. After stirring for 30 min, the reaction was quenched with H2O, concentrated in vacuo, diluted with EtOAc, washed with 5N HCl (100 mL), water and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH:5]=[CH:4][NH:3]1.[C:15]12([CH2:25][NH2:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.CN(C)C=O>>[C:15]12([CH2:25][NH:26][C:12]([C:7]3[C:6]4[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)=[O:14])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: O=C(O)c1cccc2c(=O)[nH]ccc12
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc2c(=O)[nH]ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,2-dihydro-1-oxoisoquinoline-5-carboxylic acid (0.107 g, 0.000566 mol), 1-adamantanemethylamine (0.120 mL, 0.000679 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.141 g, 0.000735 mol), 1-hydroxybenzotriazole (0.099 g, 0.00074 mol) and triethylamine (0.12 mL, 0.00085 mol) in N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at room temperature for 18 hours. The mixture was poured onto water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were dried over sodium sulfate and reduced in vacuo to afford the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[C:15]1([S:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][S:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: NCCSc1ccccc1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Solvent: CO
Product: N#CNC(=NCCSc1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and 2-phenylthioethylamine (0.49 g, 3.2 mmol) was added. The mixture was stirred at room temperature for 2 hours After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 10 g) eluting with chloroform-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from diethyl ether to give the title compound (0.49 g, 1.7 mmol, yield: 66%) as colorless crystals.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]([C:18]#[CH:19])([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:4][CH2:3]1.Cl.[C:21]1([O:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(Cl)Cl>[O:27]([C:28]([N:2]1[CH2:3][CH2:4][C:5]([C:18]#[CH:19])([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:7]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-4-ethynyl-4-(2-nitrophenoxy)piperidine (liberated from 10.0 g of the hydrochloride) in 45 ml of methylene chloride was added dropwise a solution of 5.8 g of phenylchloroformate in 45 ml of methylene chloride. The mixture was stirred at room temperature for 1 hr and at reflux, under nitrogen, for 16 hrs. The solution was allowed to cool to room temperature, poured into water, extracted with methylene chloride, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of solvent provided an oil (13.9 g). A 2.2 g sample of the oil was chromatographed on 150 g of alumina. The column was eluted with three 150 ml volumes of ether. Evaporation of the solvent from the second fraction provided 1.36 g (65%) of product. Recrystallization from isopropyl alcohol provided the analytical sample, mp 76°-80°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[CH:8][C:7]=1I)[CH3:2].[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O>[CH2:1]([O:3][C:4](=[O:21])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[CH:8][C:7]=1[C:24]1[CH:23]=[N:22][C:31]2[C:26]([CH:25]=1)=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:2]
Reactant: CCOC(=O)Nc1ccc(NCc2ccc(Cl)s2)cc1I
Reactant: OB(O)c1cnc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)Nc1ccc(NCc2ccc(Cl)s2)cc1-c1cnc2ccccc2c1
Temperature: 125 °C
Yield: 33.2 %

Procedure:
{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-iodophenyl}-carbamic acid ethyl ester (15 mg), 3-quinolineboronic acid (29.7 mg), palladium(II) acetate (ca. 1 mg), potassium carbonate (0.035 mL, 5M aqueous solution), and acetone (2 mL) were mixed and heated in heated in a sealed glass tube in a microwave synthesizer for 10 minutes at 125° C. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (4 mL), the organic phase washed with water (2×2 mL), and brine (2×2 mL), dried over magnesium sulfate, and filtered. The solvent was removed in vacuo, and the crude product was purified by preparative LC-MS. The collected fraction was evaporated in: vacuo, redissolved in ethyl acetate (5 mL), and the organic phase was washed with saturated aqueous sodium bicarbonate (3 mL), water (3 mL), and brine (2×2 mL). The organic phase was dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to furnish the title compound (5 mg, 33%).