Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([OH:12])[CH:3]=1.F[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([O:12][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][C:15]=2[C:24]([F:25])([F:27])[F:26])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1O
Reactant: CS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CC(=O)O)c(C(F)(F)F)c1

Procedure:
A solution of the product from step (ii) (0.125 g), the product of example 44 step (i) (0.150 g) and cesium carbonate (0.437 g) in NMP (10 ml) was stirred at 80° C. for 10 h. The mixture was partitioned between 2M sodium hydroxide and diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic layer dried and evaporated under reduced pressure. The residue was purified using RP prep HPLC. Yield 0.025 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]([F:35])([F:34])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([C:15]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:14]([F:35])([F:13])[F:34])=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)ccc1N
Reaction time: 1 h
Yield: 112.4 %

Procedure:
4-Amino-3-methoxybenzoic acid (2.045 mmol, 0.342 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.700 g) and triethylamine (6.14 mmol, 0.853 mL, 0.621 g) were combined and stirred at room temperature in dichloro-methane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour. The reaction mixture was diluted with dichloromethane and saturated sodium hydrogen carbonate solution and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (1.13 g). MS (ESI) m/z 492.1 [M+H]+
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]1([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)[CH:32]=[O:33]>C1COCC1>[F:29][C:24]1[C:23]([O:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:28][CH:27]=[CH:26][C:25]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: Fc1ccccc1Oc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Oc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Cool a solution of 2,2,6,6-tetramethylpiperidine (5.1 mL, 30.0 mmol) in THF (40 mL) to −78° C. Add dropwise n-Butyllithium (18.7 mL, 30.0 mmol, 1.6 M in hexanes) and stir for 10 min at −78° C. Add dropwise 2-fluorophenyl phenyl ether (4.7 g, 25.0 mmol), stir 2 h at −78° C. Add N,N-dimethylformamide (2.3 mL, 30.0 mmol) dropwise over 15 min. Stir the resulting mixture for 3 h at −78° C. and allow to warm to ambient temperature over 16 h. Quench the reaction mixture with water (50 mL), extract with ethyl acetate, dry over Na2SO4, filter and concentrate under reduced pressure to give an oil. Crystallize the oil with hexanes to give a solid, collect and recrystallize from hexanes/ethyl acetate/methylene chloride to give the title compound: mp 75–77° C.; MS(m/e): 216 (M+); Calculated for C13H9FO2: Calcd: C, 72.22; H, 4.20. Found: C, 72.41; H, 4.23. Purification of the mother liquors by silica gel chromatography (2–3% ethyl acetate/hexanes) gives an additional amount of the title compound: MS(m/e): 216 (M+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[N:24][N:25]([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[N:26]=2)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[N:24][N:25]([CH2:27][C:28]([NH:30][N:31]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:29])[N:26]=2)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)Cn1nnc(-c2cccc([N+](=O)[O-])c2)n1
Solvent: CC(=O)O
Product: O=C(Cn1nnc(-c2cccc([N+](=O)[O-])c2)n1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[5-(3-nitrophenyl)-2H-tetrazol-2-yl]acetohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 80 mg of the title compound (77%) as a yellow powder in 97% purity by HPLC (Rt: 4.96, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30](C=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>C(O)C>[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(N3CCC(O)CC3)cc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A one liter three necked flask fitted with a dropping funnel, mechanical stirrer and condenser is charged with 34.35 g of 4-nitrophenylacetic acid. Piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition, 38.4 g of 4-(4-hydroxypiperidyl)benzaldehyde is added. The reaction mixture is heated at 100° C. for three hours, and at 130° C. for three hours. After cooling, the semi-solid product mass is ground in ethanol in a blender, then filtered, washed, and vacuum dried. The crude product is recrystallized from chlorobenzene, m.p. 248°-250° C.
Reaction SMILES: BrCCC1C([Cl:10])=CC(Cl)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1CCBr.Cl.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CO>[ClH:10].[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:20])[CH:16]=1)[O:12][CH2:5][CH2:6][NH:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Clc1cc(Cl)c(CCBr)c(Oc2cc(Cl)cc(Cl)c2CCBr)c1
Reactant: NC1CCCCC1
Agent: Cl
Solvent: CO
Product: Clc1cc(Cl)cc(OCCNC2CCCCC2)c1
Yield: 94.2 %

Procedure:
A solution of 27.2 g (0.1 mole) of 2-bromoethyl-3,5-dichlorophenyl ether in 300 ml of cyclohexylamine (excess) was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate stripped to dryness on a rotary evaporator. The residue was partitioned between chloroform and water and between chloroform and 10% sodium hydroxide. The chloroform layer was evaporated to dryness leaving an oil (free base). The oil was dissolved in methanol and reacted with ethereal hydrogen chloride to give 25.8 g (94.2%) solid, m.p. 216.5°-220° C.
Reaction SMILES: [S:1]([OH:27])([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)=[CH:8][C@H:9]2[C:14](=[O:16])[NH2:15])(=[O:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[S:1]([OH:27])([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH2:17][CH2:18][NH2:19])=[CH:8][C@H:9]2[C:14](=[O:16])[NH2:15])(=[O:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(OS(=O)(=O)O)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(OS(=O)(=O)O)C2=O

Procedure:
To a suspension of (2S,5R)-4-(2-(tert-butoxycarbonylamino)ethyl)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate (Intermediate 229, 0.060 g, 0.15 mmol) in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (0.100 mL). After 15 minutes the solvent was removed in vacuo and the residue was dried under high vacuum. Purified by reverse phase chromatography using acetonitrile/water to afford the title compound as a white solid after lyophilization (0.006 g, 13%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(Cl)nc2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 6-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=41%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([F:34])[CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:30]1([CH2:29][O:28][C:20]2[CH:21]=[CH:22][C:23]([CH:25]([F:27])[F:26])=[CH:24][C:19]=2[C:18]2[C:13]3[NH:12][C:11]([CH3:33])=[C:10]([C:8]([NH:7][C@@H:5]4[CH2:6][C@@H:2]([NH:1][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:3][C@H:4]4[F:34])=[O:9])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1F
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1C[C@@H](F)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f71) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [P:1]([Cl:12])(Cl)([O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:2].Cl.[CH2:14]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH3:15].CCN(CC)CC>C(Cl)Cl>[Cl:12][P:1]([NH:19][C@H:18]([C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])([O:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:2]
Reactant: O=P(Cl)(Cl)Oc1ccc(Cl)cc1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1ccc(Cl)cc1

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.090 M) of 4-chlorophenyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1* mixture of diastereoisomers.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].[CH2:9]=[O:10].C(N(CC)CC)C>CC(C)=O>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][OH:10])[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)c1cc[nH]n1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccn(CO)n1
Temperature: 130 °C
Reaction time: 7 h
Yield: 87.5 %

Procedure:
The mixture of 1.15 g of 3-i-propyl-1H-pyrazole, 0.94 g of paraformaldehyde and 0.14 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 1.28 g of 3-i-propyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]2[C:25]3[N:26]=[C:27]([CH2:29][O:30][CH2:31][CH2:32][OH:33])[NH:28][C:24]=3[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[C:8]1([CH2:14][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]2[C:25]3[N:26]=[C:27]([CH2:29][O:30][CH2:31][CH2:32][O:33][S:42]([CH3:41])(=[O:44])=[O:43])[NH:28][C:24]=3[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCCOCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
Triethylamine (0.17 mL, 1.25 mmole) was added to a solution of N,N-bis(phenylmethyl)-2-(2-hydroxyethoxy)methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.14 mmole) in methylene chloride (20 mL). Methanesulfonyl chloride (0.09 mL, 1.14 mmole) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide 0.6 g of N,N-bis(phenylmethyl)-2-(2-methylsulfonyloxyethoxy)methyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].C([N:31]=[C:32]=[S:33])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:32](=[S:33])[NH2:31])[N:6]=1)=[O:4]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)c1n[nH]c2ccccc12
Solvent: CCNCC
Product: COC(=O)c1nn(C(N)=S)c2ccccc12

Procedure:
1-Thiocarbamoyl-1H-indazole-3-carboxylic acid methyl ester was prepared (113 mg) following general procedure D using 1H-Indazole-3-carboxylic acid methyl ester (120 mg, 0.69 mmol), Fmoc isothiocyanate (213 mg, 0.76 mmol), and diethyl amine (0.5 mL). LCMS m/z: 236 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[S-:10][C:11]#[N:12].[NH4+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][C:11]#[N:12])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: N#C[S-]
Reactant: Oc1c(Cl)cccc1Cl
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cc(Cl)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.8 %

Procedure:
2,6-Dichlorophenol (100 g, 0.613 mole) and ammonium thiocyanate (102.73 g, 1.350 mole) were mixed in methanol and the solution cooled to 0° C. Chlorine gas was bubbled through the reaction, maintaining the temperature below 10° C. The solution turned a pale yellow color. The reaction was stirred for a total of 3 hours until acidic, at which time ammonia gas was bubbled through and the solution stirred for an additional three hours at 0° to 10° C. The reaction was poured into iced distilled water, and filtered, yielding approximately 20 g of a yellow solid which was dried overnight in vacuo. The filtrate was extracted with ethyl acetate, dried over magnesium sulfate and stripped to yield approximately 100 g of crude product. Following purification by chromatography, the material was taken up to 1 liter of toluene, charcoal added, filtered and recrystallized from hexane to yield 55.03 g of prioduct as a yellow solid. The structure was confirmed by NMR.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH:11]=[CH:10]1.[Cl-].[NH4+].C(OCC)C>C1COCC1>[C:1]1([C:10]2[CH2:11][CH2:12][CH2:13][C:9]=2[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CCC1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1=C(c2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 160 ml (120 mmol) of a THF solution of phenylmagnesium chloride, a solution of 8.38 ml (100 mmol) of-2-cyclopentenone in 70 ml of THF was dropwise added with ice cooling. The mixture was stirred at 0° C. for 1 hour and then further stirred at room temperature for 1 hour. Then, 200 ml of an ammonium chloride saturated aqueous solution was added. To the reaction solution, diethyl ether was added to perform extraction. The resulting ether solution was dried over magnesium sulfate, and the solvent was distilled off to obtain of a crude product of phenylcyclopentenol as a gold liquid (17.5 g). In a glass tube oven, 6 g of the crude product was placed, and the product was heated at 180 to 190° C. for 1 hour at atmospheric pressure, then cooled to room temperature and slowly heated (finally) to 195° C. under reduced pressure (1 to 4 mmHg). As a result, 2.5 g of a white crystal was sublimed (51.3%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][CH:8]=1)(=O)=O.[N:23]1[CH:28]=[CH:27][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:25][CH:24]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.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.C1(C)C(C)=CC=CC=1>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][CH:8]=[C:7]([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=S(=O)(Oc1ccc(Br)c(Cc2ccccc2)n1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Brc1ccc(-c2ccncc2)nc1Cc1ccccc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A mixture of 298 mg of 2-benzyl-3-bromo-6-pyridyl trifluoromethanesulfonate, 277 mg of (4-pyridyl)tributyltin, 87 mg of tetrakis(triphenylphosphine)palladium(0), 209 mg of tetrabutylammonium chloride and 5.0 ml of xylene was heated under stirring in an oil bath kept at 140° C. for one hour in a nitrogen atmosphere. After cooling as it was, the solvent was removed, and the residue was subjected to NH-silica gel column chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (3:1), to give 196 mg of the target compound.
Reaction SMILES: [CH:1]([N:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH3:6])([CH3:3])[CH3:2].C(N(P(OC)[Cl:18])C(C)C)(C)C>C1COCC1>[CH3:6][CH2:5][N:4]([CH:7]([CH3:9])[CH3:8])[CH:1]([CH3:3])[CH3:2].[ClH:18]
Reactant: COP(Cl)N(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
344 mg (0.5 mmole) of N6 -benzoyl-5'-O-dimethoxy-trityl-2'-O-methyl-adenosine (compound IIa) were dissolved in 2 ml of anhydrous THF, and the resulting solution was admixed with 362 μl (2 mmoles) of diisopropyl ethyl amine (DIPEA) with stirring under an argon atmosphere at room temperature. Then 300 μl (1.5 mmoles) of N,N-diisopropyl-amino-methoxy-chlorophosphine was added over 1 minute. After 5 minutes, DIPEA hydrochloride was formed as a white precipitate. Stirring was continued at room temperature and, after 45 minutes, the reaction mixture was analysed by a chromatography using silica gel 60 TLC (the mobile phase: n-hexane/acetone (1:1) containing 5% of triethyl amine) to confirm whether the spot of the starting material (Rf =0.52) had disappeared and the spot of the product (IIb2) (Rf =0.76) had appeared. After the confirmation of the latter spot, 20 ml of ethyl acetate was added to the reaction mixture under cooling with ice. Then the reaction mixture was washed twice with 15 ml of an ice-cooled saturated aqueous sodium bicarbonate solution, and then washed once with 15 ml of an ice-cooled saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate. After the sodium sulfate had been separated by a filtration, the filtrate was evaporated to dryness. The oily residue thus obtained was dried under reduced pressure, and dissolved in 2 ml of dichloromethane, and added dropwise with stirring to 200 ml of n-hexane which had been cooled to a temperature of -50° C., whereby a white precipitate was formed
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=O)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
To a solution of vanillin (500 mg), phenylboronic acid (1.60 g) and copper(II) acetate (712 mg) in methylene chloride (10 mL) were added molecular sieve 4A (750 mg) and triethylamine (665 mg), and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The solution was washed successively with 0.5M aqueous hydrochloric acid solution, 1M aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-methoxy-4-phenoxybenzaldehyde (440 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)#[CH:42].C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:42]#[C:41][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: C#Cc1ccccc1
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc2nc(C#Cc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reaction time: 12 h

Procedure:
The solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (35 mg, 0.06 mmol), ethynylbenzene (8 μL, 0.08 mmol), and triethylamine (1 mL) in ethyl acetate (0.5 mL) was degassed with nitrogen. Copper(I) iodide (1 mg) and bis(triphenylphosphine)palladium (II) dichloride (7 mg) were added, and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (silica gel, ethyl acetate/hexanes) gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H37ClNO3: 554.2. Found: 554.3.