Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](I)=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.CCOCC.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.[Cu]I>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:9][C:4]2[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1cc(Cl)cnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5.63 g (22.0 mmol) sample of 5-chloro-2-iodo-3-pyridinol, from step 7a above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), CuI (0.377 g, 1.98 mmol) and triethylamine (1.90 mL, 13.6 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 2.15 g (11.0 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1c above, dissolved in 5 mL of DMF, was added carefully. The reaction was stirred at 60° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether, then washed with 10% NaOH and brine, then dried over MgSO4. The solvent was removed, and the residue was chromatographed on silica gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 2.04 g of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.3, 1.45 (2 s, 9H), 1.94-2.3 (m, 4H), 3.45-3.65 (m, 2H), 4.97-5.1 (m, 1H). 6.66 (s, 1H), 7.70 (s, 1H), 8.47 (s, 1H); MS m/z: 323 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(Cl)(Cl)Cl.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>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1
Reactant: OCc1cc(I)c(O)c(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)C#Cc1cc(CO)nc(Cl)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
C2 (13.9 g, 48.6 mmol) is combined with trimethylsilylacetylene (9.6 mL, 68 mmol), bis(triphenylphosphine)palladium dichloride (1.02 g, 1.46 mmol) and cuprous iodide (139 mg, 0.73 mmol) in 80 mL CHCl3/40 mL THF under N2. TEA (21 mL, 151 mmol) is added, and the reaction is stirred 3 h at rt and is diluted with 200 mL CHCl3. The mixture is washed with 2×150 mL 5% HCl and the combined aqueous layers are extracted with 2×50 mL CHCl3. The combined organic layer is washed with 100 mL 50% saturated NaCl, is dried over MgSO4, and concentrated in vacuo to an amber oil. The crude material is chromatographed over 350 g silica gel (230-400 mesh), eluting with 35% EtOAc/hexane to afford 2-chloro-6-(hydroxymethyl)-4-[(trimethylsilyl)ethynyl]-3-pyridinol (C3) as a golden solid (92% yield). MS (EI) for C11H14ClNO2Si, m/z: 255(M)+.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:3]1.[F:11][C:12]1[CH:43]=[CH:42][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]3[NH:30][CH2:29][C@H:28]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[NH:4]1[C:5]([CH2:7][C:8]([N:30]2[C@H:26]([C:24](=[O:25])[NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([F:11])=[CH:43][CH:42]=4)=[CH:18][CH:19]=3)[CH2:27][C@@H:28]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:29]2)=[O:10])=[CH:6][N:2]=[CH:3]1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1)OCc1ccccc1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Product: O=C(N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cc2cnc[nH]2)C1)OCc1ccccc1
Yield: 67 %

Procedure:
Proceeding as in Example 1, but substituting 4-imidazoleacetic acid hydrochloride and benzyl (3R,5S)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate gave Compound 253, benzyl (3R,5S)-1-(2-(1H-imidazol-5-yl)acetyl)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate (1.01 g, 1.80 mmol, 67% yield). 1H-NMR (400 MHz, DMSO-d6): 11.92 (s, 1H), 10.06 (s, 1H), 7.92-7.42 (m, 4H), 7.40-7.28 (m, 5H), 7.23-7.17 (m, 2H), 7.06-6.94 (m, 5H), 5.02 (s, 2H), 4.50 (m, 1H), 4.28-4.13 (m, 1H), 3.85-3.41 (m, 4H), 2.38-2.02 (m, 2H). MS (EI) for C30H28FN5O5. found 557.9 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[CH:4]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[C:25](=[O:28])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:13][C:9]1[C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH2:2][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][C:7]([O:28][CH3:25])=[C:8]([O:15][CH3:16])[C:9]=4[O:13][CH3:14])[CH:4]=3)[CH2:21][CH2:20]1)=[CH:4]2
Reactant: O=C([O-])[O-]
Reactant: COc1cc2cc(CCl)ccc2c(OC)c1OC
Reactant: C1CNCCN1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2cc(CN3CCN(Cc4ccc5c(OC)c(OC)c(OC)cc5c4)CC3)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Chloromethyl-5,6,7-trimethoxynaphthalene (418 mg) and piperazine (63 mg) were dissolved in DMF (10 mL), potassium carbonate (207 mL) was added to the solution, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction mixture under reduced pressure, chloroform was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1) to obtain the title compound as a free base.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]3[N:27]([C:28]([NH2:30])=[O:29])[CH2:26][CH2:25][S:24]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].[O:42]1CC[CH2:44][CH2:43]1>>[C:38]([N:30]=[C:28]([N:27]1[CH2:26][CH2:25][S:24][CH:23]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:9][CH2:10]1)[O:29][C:43](=[O:42])[CH3:44])(=[O:40])[CH3:39]
Reactant: NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N=C(OC(C)=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
1.08 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are dissolved in 20 ml of tetrahydrofuran, and 0.76 g of triethylamine is added thereto. A solution of 0.59 g of acetyl chloride in one ml of tetrahydrofuran is added to the mixture under ice-cooling, and the mixture is stirred at room temperature for 3 days. 0.59 g of acetyl chloride and 0.76 g of triethylamine are added to the mixture, and the mixture is stirred at room temperature for 24 hours. The mixture is concentrated under reduced pressure to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with a saturated sodium chloride solution, an aqueous sodium bicarbonate solution and a sodium chloride solution, successively. The ethyl acetate solution is dried and concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:ethyl acetate=2:1). The eluate is concentrated under reduced pressure to remove solvent, and the residue is recrystallized from a mixture of chloroform and ether. 0.72 g of N,O-diacetyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboximidic acid is obtained. Yield: 56%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:6]=[C:7]([S:10][CH3:11])[C:8]=1[OH:9].[N+](=[CH2:23])=[N-]>C(Cl)(Cl)Cl.CCOCC.C(O)(=O)C>[CH3:11][S:10][C:7]1[CH:6]=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:4]=[C:3]([S:2][CH3:1])[C:8]=1[O:9][CH3:23]
Reactant: C=[N+]=[N-]
Reactant: CSc1cc(CCCCCCCCO)cc(SC)c1O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1c(SC)cc(CCCCCCCCO)cc1SC
Temperature: 0 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
320 mg of compound 1 was dissolved in chloroform and 10 ml of a solution of diazomethane in ether (about 0.5M) was added thereto dropwise at 0° C. After stirring at 0° C. for 6 hours, several drops of acetic acid were added thereto. After the completion of the reaction, the mixture was extracted with ether. The extract was concentrated and subjected to column chyromatography (silica gel, ethyl acetate: hexane=1:5-1:4). As a result, 206 mg of the desired compound was obtained (yield: 62%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[C:9]2=[O:15])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:21][CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:21]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]1=[O:15])[CH3:22]
Reactant: CCI
Reactant: N#CC1CCN(C(=O)c2ccc(F)cc2)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O

Procedure:
To a solution of 1-(4-fluorobenzoyl)-2-oxopyrrolidine-3-carbonitrile (25 g) in DMF (215 mL) was added a sodium hydride 60% dispersion in mineral oil (6.5 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, and iodoethane (17 mL) was added slowly thereto. The reaction mixture was stirred under ice-cooling for 2 hr, and poured into 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (23 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O)(=O)C.[Na].C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:22])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:17][CH2:16]3)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3)cc1
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(CN2CCc3cc(OC(=O)Nc4ccc(C(C)C)cc4)ccc32)cc1
Reaction time: 0.03 h
Yield: 81.6 %

Procedure:
To a solution of indolin-5-yl 4-isopropylphenylcarbamate (15.0 mg, 50.6 μmol) in 0.75 mL of dry dichloromethane was added 4-methoxybenzaldehyde (12.3 μL, 0.101 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 2 min, acetic acid (29 μL, 0.51 mmol) and sodium triacetoxyhydroborate (38 mg, 0.18 mmol) was added, successively. After the reaction mixture was stirred at the same temperature for 30 min, the reaction mixture was diluted with diethyl ether (2 mL). After the reaction mixture was neutralized by saturated NaHCO3 aqueous solution (1 mL), the organic layer was separated. The separated organic layer was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50) to obtain the title compound as a white solid (17.2 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([S:9]C)=S)=[CH:4][CH:3]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C.Br[CH2:22][CH2:23]Br>CO.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:9][CH2:23][CH2:22][O:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: CSC(=S)c1ccc(Cl)s1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: Clc1ccc(C2=NOCCS2)s1
Temperature: 5 °C

Procedure:
Methyl 5-chloro-2-thiophenecarbodithioate (61.4 g, 0.29 mol) was suspended in methanol (400 ml) with finely powdered hydroxylamine hydrochloride (25 g). With stirring, triethylamine (50 ml) in methanol (50 ml) was added dropwise to the suspension, to produce a reaction mixture. During this addition, the reaction mixture was cooled to 5° C. Stirring of the reaction mixture was continued until an orange (from red) color developed in the reaction mixture. Additional triethylamine (100 ml) was then added at once, followed by 1,2-dibromoethane (20 ml). The resultant reaction mixture was then stirred overnight at ambient temperature. The reaction mixture was then refluxed with removal of solvent until a precipitate appeared. The reaction mixture was then cooled and water was added. The reaction mixture was then filtered and the solid collected on the filter was recrystallized from ethanol to produce 3-(5-chloro-2-thienyl)-5,6-dihydro-1,4,2-oxathiazine (mp 74°-77° C., 21.4 g. Found C 38.5, H 2.94, N 6.45, C7 H6CINOS2 requires C 38.27, H 2.73, N 6.38).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Ni].O>[CH2:1]([O:3][C:4]([C:6]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(C#N)CCC1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(CN)CCC1
Temperature: 40 °C
Yield: 71.9 %

Procedure:
1-Cyano-cyclobutanecarboxylic acid ethyl ester (2.00 g, 13.0 mmol) was dissolved in ethanol (30 ml) and treated with Raney Nickel (1 ml as a slurry in water) and hydrogen gas at 4 bar and heating at 40° C. for 18 h. The reaction mixture was filtered through Dicalite and washed through with ethanol (50 ml). The solvent was removed under reduced pressure to give 1-aminomethyl-cyclobutanecarboxylic acid ethyl ester as a yellow oil (1.47 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1(C)C=CC=CC=1>[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
2-(4-Bromophenyl)acetic acid (7.85 g, 36.5 mmol) and (R)-4-benzyloxazolidin-2-one (3.23 g, 18.3 mmol) were combined in toluene (30 mL) and triethylamine (10.2 mL, 73.0 mmol). The solution was then heated to 80° C., and a solution of pivaloyl chloride (4.49 mL, 36.5 mmol) in toluene (7.5 mL) was added slowly. The reaction was heated to 110° C. and stirred overnight. The reaction was then cooled, and the toluene solution was washed with 2N HCl, water, 5% Na2CO3, brine and then dried over Na3SO4. After removal of the solvent, the residue was purified by column chromatography to give (R)-4-benzyl-3-(2-(4-bromophenyl)acetyl)oxazolidin-2-one (5.65 g, 83%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[CH3:77][N:78]1[C:82]([CH3:83])=[C:81](B2OC(C)(C)C(C)(C)O2)[CH:80]=[N:79]1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:81]5[CH:80]=[N:79][N:78]([CH3:77])[C:82]=5[CH3:83])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Product: Cc1c(-c2cccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc23)cnn1C
Yield: 78 %

Procedure:
Following the procedure of (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester to give the title compound (40 mg, 78%). LCMS (Method G): RT=4.12 min, [M+H]+=562.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[NH2:12])[CH2:3]1.CN1CCOCC1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1>ClCCl>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([NH:12][S:36]([C:34]3[S:35][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[CH:32][CH:33]=3)(=[O:37])=[O:38])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: COc1ccc(N)cc1N1C[C@@H](C)N[C@@H](C)C1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)cc1N1C[C@@H](C)N[C@@H](C)C1
Reaction time: 18 h

Procedure:
3-(cis-3,5-Dimethyl-1-piperazinyl)-4-(methyloxy)aniline (D2) (100 mg, 0.42 mmol) in dichloromethane (10 ml) was stirred with morpholinomethyl-polystyrene HL resin (320 mg, 4 mmol/g loading, 1.28 mmol) at ambient temperature. 5-(2-Pyridinyl)-2-thiophenesulfonyl chloride (110 mg, 0.4 mmol) was added and the mixture stirred for 18 hours. Argopore-trisamine scavenger resin (100 mg, 4 mmol/g loading, 0.4 mmol) was then added and the mixture stirred for a further 30 minutes. The resin was removed by filtration, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography (1:19 2M ammonia in methanol: dichloromethane) to afford the title product (El). MS (ES+) 459 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][CH2:11][O:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[C:5]2[OH:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][CH2:11][O:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:5]2[OH:29]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCOC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCOC2)C1=O
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl N-((6-chloro-4-hydroxy-2-oxo-5′,6′-dihydro-spiro[naphthalene-1,3′-pyran]-3-yl)carbonyl)glycinate (106 mg, 252 μmol) was mixed with TFA (6300 μL, 252 μmol) and stirred for 30 minutes. The product was co-evaporated with DCM (5×) to give the title compound. MS m/e=366.0 (M+H)+. Calculated for C17H16ClNO6 365.07.
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.S(=O)(O)[O-].[Na+].S(=O)(O)[O-:18].[C:21](=O)([O-:23])[O-:22].[Na+].[Na+]>>[CH2:21]1[O:23][C:7]2[CH:6]=[C:5]3[C:10]([CH2:1][CH2:2][C:3](=[O:18])[CH2:4]3)=[CH:9][C:8]=2[O:22]1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCc2ccccc21
Reactant: O=S([O-])O
Agent: [Na+]
Product: O=C1CCc2cc3c(cc2C1)OCO3

Procedure:
A solution of 21 (669 mg, 2.83 mmol) in 10 mL glacial acetic acid was placed in a hydrogenation flask. To this mixture 460 mg of 10% Pd-C was added and the resulting mixture was shaken in a Parr apparatus at 40 psig of hydrogen for 40 h. The reaction mixture was filtered through a celite bed, which was washed thrice with 5 mL portions of glacial acetic acid. The glacial acetic acid was rotaevaporated to give the crude tetralone, 9. The crude tetralone was then treated with sodium bisulfite to convert it to the more stable bisulfite adduct. Pure tetralone was generated as required from its bisulfite adduct by treatment with 10% sodium carbonate solution followed by extraction with dichloromethane; mp=91-92° C. (lit144=88-91° C.); IR (Nujol) 1727; 1H NMR δ2.51 (2H, t), 2.97(2H, t), 3.48 (2H, s), 5.92 (2H, s), 6.58 (1H, s), 6.69 (1H, s); 13C NMR δ21.5, 37.7, 45.1, 101.4, 107.5, 118.5, 121.0, 127.8, 144.2, 146.4, 211.5; Anal. calcd for C11H10O3: C, 69.46; H, 5.30; Found: C, 69.40; H, 5.29.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[CH:10]1[C:15]([O:16][C:17](Cl)=[O:18])=[CH:14][CH:13]=[C:12]([Cl:20])[CH:11]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:18])[N:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]2)[CH3:1])=[CH:10][CH:11]=1
Reactant: CN[C@H]1CC[C@H](O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](O)CC1
Temperature: 25 °C

Procedure:
To a solution of 16.1 g (124.7 mmol) trans-4-methylamino-cyclohexanol in 40 ml CH2Cl2, 18.3 ml (130.9 mmol, 1.05 eq) 4-chlorophenylchloroformate and 22.4 ml (130.9 mmol, 1.05 eq) Huenigs base were added at 0° C. The solution was stirred at RT over night, diluted, and washed with 1M HCl, sat. aqueous NaHCO3 solution. The organic phase was dried over MgSO4. Column chromatography on silica gel with EtOAc:hexane 1:1 yielded 32.2 g (91%) trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester as white solid, MS: 283 (M, 1Cl).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=1)#[N:9]>ClCCl>[C:8]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:23]([F:24])([F:25])[F:26])[CH:11]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
Trifluoroacetic acid (0.55 ml) was added to a solution of tert-butyl 4-cyano-2-(trifluoromethyl)benzoate (194 mg) in dichloromethane (2 ml) under ice cooling, followed by stirring at the temperature for one hour. It was warmed to room temperature and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, a 1M aqueous sodium hydroxide solution (2 ml) was added thereto, followed by washing with diethyl ether. 1M hydrochloric acid (2 ml) was added to the aqueous layer, followed by extraction with ethyl acetate-methanol mixed solution (4:1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 4-cyano-2-(trifluoromethyl)benzoic acid (136 mg) as a colorless solid.