Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.Cl.[F:24][C:25]1[C:34]2[C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:31]=[CH:30][C:29]=2[CH:28]=[N:27][CH:26]=1>C(#N)C>[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[S:35]([N:8]2[CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3][C@@H:2]2[CH3:1])(=[O:36])=[O:37])[CH:28]=[N:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1cccc2cncc(F)c12
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1cccc2cncc(F)c12
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate (2.76 kg, 12.9 mol) and triethylamine (2.97 kg, 29.3 mol) in acetonitrile (45.2 kg) was added 4-fluoroisoquinoline-5-sulfonyl chloride hydrochloride (3.30 kg, 11.7 mol) and washed well with acetonitrile (6.45 kg) while ice cooling under an argon atmosphere. The resulting mixture was stirred for two hours while ice cooling. After confirming the disappearance of the starting materials by high-performance liquid chromatography (HPLC), the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate (74.3 kg) and a 5% sodium bicarbonate solution (66.0 kg) for extraction. The resulting organic layer was washed with water (66.0 kg) and a 20% aqueous solution of sodium chloride (33.0 kg), and then dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to give the target product as a yellow amorphous product (5.18 kg, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C@@H:8]([OH:10])[CH3:9])[CH:7]=1.FC1C=CC(OC)=C(C(=O)C)C=1.B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C@H:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: COc1ccc(F)cc1[C@H](C)O
Agent: COc1ccc(F)cc1C(C)=O
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Product: COc1ccc(F)cc1[C@@H](C)O

Procedure:
The title compound was prepared, according to the method used to make (S)-1-(5-fluoro-2-methoxy-phenyl)-ethanol from 1-(5-fluoro-2-methoxy-phenyl)-ethanone (see H. C. Brown, Tet. Letts., 35 (14), 2141-4, 1994) except that (+)-DIP-Chloride™ was used instead of (−)-DIP-Chloride™, as a white crystalline solid (63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][C:15]2([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[C:15]([CH3:22])([CH3:21])[CH2:16]2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CC1(C)CNc2ccc(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2ccnc(Cl)c2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.17 g (1.1 mmol) 2-chloroisonicotinic acid, 0.18 g (1.1 mmol) 5-fluoro-3,3-dimethyl-2,3-di-hydro-1H-indole, 0.28 mL (2.0 mmol) TEA and 3.0 mL DMF were combined with 0.39 g (1.2 mmol) TBTU and stirred overnight at RT. The reaction mixture was purified by HPLC.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1Cl
Yield: 76.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2-chlorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (2.9 g, 76%) as crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:10][C:9]=1[N+:21]([O-])=O)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:10][C:9]=1[NH2:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1ccc(OCCOC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCCOc1ccc(OCCOC(C)=O)c(N)c1
Reaction time: 20 h

Procedure:
A mixture of 2,5-bis(acetoxyethyloxy)nitrobenzene (7.5 g; 0.023 moles), methanol (200 ml) and 1% palladium on charcoal catalyst (1.0 g) was hydrogenated at room temperature and 10 atmospheres pressure for 20 hours. The reaction mixture was filtered and the residue was washed with methanol and water. The filtrate was evaporated to dryness to leave a solid residue which was used without further purification (6.24 g) m.p. 67.5°-69.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[O:15][CH:14]([C:20]([F:23])([F:22])[F:21])[C:13]([C:24]([O:26]CC)=[O:25])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[O:15][CH:14]([C:20]([F:23])([F:21])[F:22])[C:13]([C:24]([OH:26])=[O:25])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=Cc2cc(OCc3ccccc3)cc(Cl)c2OC1C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1=Cc2cc(OCc3ccccc3)cc(Cl)c2OC1C(F)(F)F

Procedure:
The ester from Step 1 was hydrolyzed via a method similar to that described in Example 9z, Step 3 to give the crude product as a tacky solid. Brine was added and the mixture was extracted with EtOAc (20 mL). The EtOAc solution was dried over MgSO4, filtered and concentrated in vacuo to give the product as a yellow crystalline solid in quantitative yield: ESHRMS m/z 383.0311 (M−H, C18H11ClF3O4, Calc'd 383.0292). 1H NMR (dmso-d6/300 MHz) 13.49 (brs, 1H), 7.90 (s, 1H), 7.34-7.50 (m, 5H), 7.27 (s, 2H), 6.05 (q, 1H, J=7.2 Hz), 5.12 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:20]C(=O)C(F)(F)F)[CH2:14]2)[C:9]([CH3:27])=[C:8]2[C:3]=1[C:4](=[O:34])[C:5]([C:31]([OH:33])=[O:32])=[CH:6][N:7]2[CH:28]1[CH2:30][CH2:29]1.[OH-].[K+].Cl>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH2:20])[CH2:14]2)[C:9]([CH3:27])=[C:8]2[C:3]=1[C:4](=[O:34])[C:5]([C:31]([OH:33])=[O:32])=[CH:6][N:7]2[CH:28]1[CH2:30][CH2:29]1
Reactant: Cc1c(N2C[C@@H](NC(=O)C(F)(F)F)C(C)(C)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N2C[C@@H](N)C(C)(C)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A mixture of 0.47 g of 5-amino-1-cyclopropyl-7-((S)-4,4-dimethyl-3-trifluoroacetylamino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, 0.32 g of potassium hydroxide and 3.2 ml of water was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 10% hydrochloric acid to pH 8 and extracted with methylene chloride. The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. The residue was triturated with a mixture of acetone and diethyl ether to give 0.30 g of the desired compound as yellow crystals. The crystals were subsequently recrystallized from acetonitrile and 0.18 g of yellow needles, m.p. 191.5°-193° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: CNc1ccccc1F
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccccc3F)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2-fluoroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2/hexanes:ethylacetate) provided 169bp. 1H NMR (500 MHz, CDCl3) δ 7.40 (m, 1 H), 7.31 (m, 1 H), 7.18-7.22 (m, 2 H), 6.80 (s, 1 H), 6.94 (d, J=8.3 Hz, 1 H), 6.77 (d, J=8.2 Hz, 1 H), 6.60 (s, 1 H), 5.00 (s, 2 H), 3.42 (s, 3 H), 2.26 (s, 3 H). LCMS (ESI) m/z: 354.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClC(Cl)C>[Cl:15][CH2:16][C:17]([C:7]1[C:2]([F:1])=[CH:3][C:4]([F:9])=[CH:5][C:6]=1[F:8])=[O:18]
Reactant: Fc1cc(F)cc(F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(CCl)c1c(F)cc(F)cc1F
Temperature: 0 °C
Yield: 43.6 %

Procedure:
To a mechanically stirred solution of 1,3,5-trifluorobenzene (6.0 mL, 58 mmol) in dichloroethane (14.0 mL) was added gradually AlCl3 (15.5 g, 116 mmol) in a period of 15 min with caution. Violent bumping and HCl gas evolution was observed. The mixture was carefully heated to reflux, and chloroacetyl chloride (5.5 mL, 69 mmol) was added drop wisely in a period of 45 min. The reaction mixture was heated at reflux for an additional 6.0 h. The solution was cooled, carefully poured onto an ice/water slush (200 mL) and the aqueous solution was extracted with ether (3×50 mL). The combined ethereal layers were washed with 10% aqueous HCl (2×30 mL), 1.0 N aqueous NaOH (3×30 mL), and brine (25 mL). The solution was dried over MgSO4(s) and concentrated under reduced pressure to give 2-chloro-1-(2,4,6-trifluorophenyl)ethanone (5.28 g) as yellow solids in 51% yield: 1H NMR (500 MHz, CDCl3) δ 6.79-6.76 (m, 2 H), 4.50 (s, 2 H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([C:46]2[NH:47][C:48]([CH3:51])=[N:49][N:50]=2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([C:46]5[NH:47][C:48]([CH3:51])=[N:49][N:50]=5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cnc(-c2nnc(C)[nH]2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: Cc1nnc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)o1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(-c2nnc(C)[nH]2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4nnc(C)o4)CC3)c12
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)methylene]-piperidine-1-carboxylic acid tert-butyl ester (0.0348 g, 0.098 mmol) in CH2Cl2 (1 mL) was added TFA (0.5 mL) and the reaction mixture was stirred for 30 min. The solvent was then removed in vacuo and the residual material was dissolved in CHCl3 (1 mL). To this solution was then added 4-methoxy-7-(5-methyl-1,3,4-triazol-2-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0621 g, 0.206 mmol) and iPrNEt2 (0.18 mL, 1.03 mmol), followed by BOP—Cl (0.0670 g, 0.263 mmol). The mixture was stirred at rt for 2 h and then the solvent was removed in vacuo. The residue was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated, and the residue was purified by preparative HPLC (NH4OAc) to give the title compound (0.0093 g, 18%) as a colorless solid:
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[CH3:3][CH:2]([CH3:4])[C:1](=[O:5])[C:6](=[CH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=Cc1ccccn1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccn1)C(=O)C(C)C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of ethyl isobutyrylacetate (15.78 g, 99.7 mmol) and pyridine-2-carboxaldehyde (10.7 g, 99.9 mmol) in dry benzene (100 mL) at room temperature under argon was added acetic acid (0.30 mL, 5.2 mmol) and piperidine (0.80 mL, 8.1 mmol). After stirring at room tempertaure for 1 hour and at reflux for 3 hours, the cooled mixture was washed with water, saturated NaHCO3 and saturated NaCl solutions, dried (Na2SO4) ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate (EtOAc)-hexane (1:9) to give title compound (20.61 g, 83%) as an orange, viscous oil which crystallized on standing to a semi-solid mass, mp 53°-55° C.
Reaction SMILES: [NH4+].O[N:3]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:24][C:25]1[CH:34]=[C:33]([C:35]([O-:37])=O)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C>[NH2:24][C:25]1[CH:34]=[C:33]([C:35]([NH2:3])=[O:37])[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1N
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(N)=O)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Under ice cooling, 1-hydroxy-1H-benzotriazole ammonium salt (6.86 g, 45.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.64 g, 45.1 mmol) were added to DMF solution (40 mL) of 1-methyl 2-aminoterephthalate (8.0 g, 41.0 mmol). The mixture was stirred at the same temperature for 1.5 hours and at room temperature for 30 minutes. After ice water was added to the reaction mixture, the precipitated crystals were taken by filtration and washed with water and diethyl ether. The filtrate was neutralized with sodium hydrogencarbonate, which was extracted 4 times with a tetrahydrofuran-ethyl acetate mixture. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from water-ethyl acetate to give the title compound (7.32 g, 92%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:5][C:6]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])[C:3]#[CH:4]>C(N(CC)C1C=CC=CC=1)C>[CH3:1][C:2]1([CH3:17])[CH:3]=[CH:4][C:13]2[C:6](=[C:7]([C:8]#[N:9])[CH:10]=[CH:11][C:12]=2[N+:14]([O-:16])=[O:15])[O:5]1
Reactant: C#CC(C)(C)Oc1cc([N+](=O)[O-])ccc1C#N
Solvent: CCN(CC)c1ccccc1
Product: CC1(C)C=Cc2c([N+](=O)[O-])ccc(C#N)c2O1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A solution of compound 6A (270 mg, 1.17 mmol) in N,N-diethylaniline (1 mL) was heated to 185° C. for 3 h. After cooling to rt, the reaction mixture was chromatographed (silica gel) eluting with 0-50% EtOAc/hexane to afford the title compound (230 mg).
Reaction SMILES: [Na+].[NH2:2][C@H:3]([C:7]([O-:9])=[O:8])[CH2:4][CH2:5][SH:6].Cl.Cl.ClC[CH:14](O)[C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31].[I-].[K+]>>[C@@H:18]1([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[O:19][C@H:15]([CH2:14][S:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[NH2:2])[C@@H:16]([OH:31])[C@H:17]1[OH:30]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)CCl)[C@@H](O)[C@H]1O
Reactant: N[C@@H](CCS)C(=O)[O-]
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CSCC[C@H](N)C(=O)O)[C@@H](O)[C@H]1O
Temperature: 10 °C
Reaction time: 5 h

Procedure:
L-Homocysteine sodium salt solution (850 Kg), prepared as described above, was cooled to 10° C. and dil.hydrochloric acid (1:1; 100 Lit) was added til the pH became 11.3 to 11.5. To this solution, 5′-Chloromethyl adenosine hydrochloride (135 Kg) and potassium iodide (13.5 Kg) were added and stirred at 70-80° C. for 5 h. The reaction was monitored by HPLC and cooled to 15° C. Dil.hydrochloric acid (1:1; 200 Lit) was added to bring down the pH to 2.0. Activated carbon (10 Kg) was added, stirred for 30 min and filtered. To the mother liquor, ammonia solution (15%) was added to set the pH to 6.0-6.2. The precipitate was stirred at 20° C. for 24 h and filtered. The solid was washed two times with water (200 Lit). The wet cake was dried at 40° C. under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:21]2)=[O:19])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1.[C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][CH2:53][F:54])[CH:46]=1)#[CH:44]>CN(C=O)C.C(N)CCC.CS(C)=O.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:13]([O:12][C:10](=[O:11])[CH2:9][C@H:8]([NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31][CH2:30]2)[CH2:21]1)=[O:19])[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:44]#[C:43][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][CH2:53][F:54])[CH:46]=2)[CH:3]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: C#Cc1cccc(OCCF)c1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2cccc(OCCF)c2)c1
Yield: 39.5 %

Procedure:
To a degassed solution of tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate (example 27c, 100 mg, 15 mmol), copper iodide (4.4 mg, 23 μmol) and tetrakis(triphenylphosphine) palladium(0) (18 mg, 15 μmol) in DMF (0.4 mL) and n-butyl amine (0.23 mL) was added a solution of 1-ethynyl-3-(2-fluoroethoxy)benzene (50 mg, 0.31 mmol) in DMF (0.6 mL) over 60 minutes at 100° C. After additional 20 minutes at 100° C. the mixture was diluted with DMSO and purified by preparative HPLC to yield 90 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[3-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15]S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O.[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>CN(C)C=O.C(OC)(=O)C1C(=CC=CC=1)O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:28]=2[C:27]([O:30][CH3:31])=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COC(=O)c1ccccc1O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
After dissolving 300 mg of 1-(tert-butoxycarbonyl)-4-(methanesulfonyloxymethyl)piperidine in 3 ml of N,N-dimethylformamide, 0.16 ml of methyl salicylate, 180 mg of anhydrous potassium carbonate and tetra n-butylammonium iodide (catalytic amount) were added and the mixture was stirred at 100° C. for 1.5 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (226 mg, 65% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH:10](OC(=O)C)[CH:9]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:2][CH2:3][CH3:4].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:16])([CH3:17])[CH:10]=[C:9]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1)C(N(C)S(C)(=O)=O)C(OC(C)=O)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1ccc2c(c1)C(N(C)S(C)(=O)=O)=CC(C)(C)O2

Procedure:
A solution of 0.5 g (1.3 mmol) of N-(6-butoxy-3-acetoxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide (Example 6) and 1.1 g (7.5 mmol) of DBU in 2.5 ml of toluene was heated at 105° C. for 60 h. The reaction mixture was diluted with EA and washed with hydrochloric acid until the aqueous phase gave an acidic reaction. The mixture was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated i. vac., giving 0.3 9 of N-(6-butoxy-2,2-dimethyl-2H-chromen-4-yl)-N-methyl-methanesulfonamide; m.p. 114-116° C.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(OC)c(-c2cccs2)cc1C=O
Yield: 90.8 %

Procedure:
Ex-1A: A solution of 5-bromo-2,4-dimethoxy-benzaldehyde (10.0 g, 40.80 mmol) and thiophene-2-boronic acid (7.8 g, 60.96 mmol) in ethylene glycol dimethyl ether (250 mL) was stirred at room temperature under nitrogen for 15 min. Tetrakis(triphenylphosphine)-palladium(0) (4.85 g, 4.19 mmol) and a sodium carbonate solution (2 M, 70 mL) were then added, and the resulting mixture was refluxed under nitrogen overnight. Upon codling to room temperature the reaction was poured into water (250 mL) and extracted with dichloromethane (2×250 mL). The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 3:1) gave 9.2 g (91%) of the desired 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde product as a pale yellow solid, m.p. 125–126° C. 1H-NMR (300 MHz, CDCl3) δ 10.34 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.5 and 1.5 Hz), 7.31 (dd, 1H, J=5.2 and 1.5 Hz), 7.07 (dd, 1H, J=5.2 and 3.5 Hz), 6.51 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H)