Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[Cl-].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Zn+])=[CH:18][CH:17]=1>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.C1COCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: Ic1ccc(-c2ncco2)cc1
Reactant: COc1ccc(C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A Schlenk Flask was charged with tetrakis(triphenylphosphine)palladium(0) (0.42 g, 0.37 mmol), nitrogen, THF (20 ML), 2-(4-iodophenyl)oxazole (1 g, 3.7 mmol), and 4-methoxybenzyl zinc chloride (0.5 M in THF, 9.6 mL, 4.8 mmol). After 3 hours, the filtrate was concentrated. The resulting solid was treated with a mixture of ethyl acetate and a dilute aqueous ammonium chloride solution. The mixture was filtered and the organic layer was dried and concentrated. Purification on silica gel using a gradient of dichloromethane in hexane gave 0.8 g of 2-[4-[(4-methoxyphenyl)methyl]phenyl]oxazole, 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.68 (s, 1H), 7.27 (d, 2H), 7.22 (s, 1H), 7.13 (d, 2H), 6.82 (d, 2H), 3.96 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([NH2:22])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>O1CCCC1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][CH2:21][N:12]([CH2:11][C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=1)[CH2:13]2)=[O:32]
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1F)Nc1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
2-(Quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine (80 mg, 0.277 mmol) was suspended in tetrahydrofuran (1 mL) then added a solution of 2-fluorophenylisocyanate (38 mg, 0.277 mmol) in tetrahydrofuran (0.5 mL). The reaction mixture was stirred at room temperature for 2 days. The product had precipitated from the reaction mixture and was collected on a glass frit, washing with minimal tetrahydrofuran then dichloromethane. The solid was dried under high vacuum to give 78 mg of 1-(2-fluorophenyl)-3-(2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)urea as a white solid. MS (ESI, pos. ion) m/z: 427.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)C(C)(C)CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a solution of 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (177) (19 mg, 0.075 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (19 μl, 2 eq) followed by addition of DIEA (65 μl). The resulting solution was stirred at r.t. for 1 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (400 μl) at 60° C. for 1 h before worked up with EA/brine. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (178) (10.5 mg, yield: 35.4%, purity>95%) as off-white solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[CH3:25][N:26](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:25]([C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([OH:23])([C:19]([F:22])([F:20])[F:21])[C:4]([OH:3])=[O:24])=[C:11]([O:17][CH3:18])[CH:12]=1)#[N:26]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)cc1OC)C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)ccc1C(C)(C)CC(O)(C(=O)O)C(F)(F)F

Procedure:
From 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, zinc cyanide and tetrakis-triphenylphosphine-palladium in dimethylformamide at 140° C. After saponification, the title acid is obtained as an amorphous powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH2:22][CH2:23][CH3:24])[CH3:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:32][CH3:33])[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([N:10]2[C:11](=[O:12])[C:7](=[CH:6][NH:5][C:4]3[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=3[CH2:1][CH3:2])[C:8]([CH2:22][CH2:23][CH3:24])=[N:9]2)=[CH:14][CH:15]=1)[CH3:30]
Reactant: CCNCC
Reactant: CCCC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=CNc1ccccc1CC
Product: CCCC1=NN(c2ccc(C(=O)N(CC)CC)cc2)C(=O)C1=CNc1ccccc1CC

Procedure:
From the reaction of 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid and diluted diethylamine solution, N,N-diethyl-4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzamide is obtained, Mp 123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31](Br)[CH3:32])[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH:31]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH3:32])[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: CC(Br)c1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(C(C)c3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 52 mg (0.19 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 9 mg (0.23 mmol) of 60% sodium hydride, 60 mg (0.23 mmol) of 2-bromo-6-(1-bromo-ethyl)-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 32 mg of a white solid: LC-MSD, m/z for C25H21BrN2O2 [M+H]+=461.0, 463.0; HPLC retention time: 2.6 min.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:16]=[CH:15][C:9]([CH2:10][N:11]3[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[N:11]1([CH2:10][C:9]2[CH:15]=[CH:16][C:6]([O:5][CH:3]3[CH2:2][N:1]([C:30]([C:28]4[O:29][C:25]([C:22]5[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=5)=[N:26][N:27]=4)=[O:31])[CH2:4]3)=[CH:7][CH:8]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Reactant: c1cc(OC2CNC2)ccc1CN1CCC1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC5)cc4)C3)o2)cc1
Yield: 67.2 %

Procedure:
Using a similar protocol as described in Example 36 employing 41A (0.10 g, 0.46 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.13 g, 0.52 mmol) as starting materials afforded 130 mg (68%) of 41 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.08 (m, 2H), 3.19 (t, 4H), 3.51 (s, 2H), 3.89 (s, 3H), 4.32 (d, 1H), 4.64 (dd, 1H), 4.74 (d, 1H), 5.06 (m, 1H), 5.11 (m, 1H), 6.72 (d, 2H), 7.02 (d, 2H), 7.21 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 421 [M+H]+, LC purity: 95%.
Reaction SMILES: CN(C=O)C.[NH:6]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:7]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:32][C@H:33]([C:36]([OH:38])=[O:37])[CH2:34][OH:35].CCN(CC)CC>>[NH:6]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:7]([C:15]([NH:32][C@H:33]([C:36]([OH:38])=[O:37])[CH2:34][OH:35])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)O
Yield: 31 %

Procedure:
In a 10 ml solution of DMF containing 500 mg (1.38 mmol) of Boc-Phe-OSu was added 5 ml of an aqueous solution of H-Ser-OH.Et3N [preparation from 290 mg (2.76 mmol) of H-Ser-OH and 384 μl (2.76 mmol) of Et3N] and the mixture was stirred for 14 hr. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate and washed with 1N-HCl and saturated sodium chloride aqueous solution, successively, together with salting out. The resultant solution was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the resulting residue was purified with a silica gel column chromatography (CHCl3:MeOH). The eluate was mixed with ether and n-hexane to give crystals of 150 mg of the title compound with yield of 31%.
Reaction SMILES: [OH:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]([NH2:35])([CH3:34])[CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[N:24]=1.Br>>[OH:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:18])[F:19])=[CH:8][C:9]([C:12]([NH:35][C:28]([CH3:34])([C:25]3[N:24]=[C:23]([CH3:22])[O:27][N:26]=3)[CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:14])=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(O)CCC1)C(F)(F)F
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(O)CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-hydroxycyclobutyl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (Example 126c) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b) as starting materials and isolated (13 mg, 40%); MS (ESI, m/z): 507.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:22])[C:18](C(O)=O)=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:23].C([N:26](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:22])[C:18]([NH2:26])=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:23]
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2c(C)ccc3c(C(=O)O)c(C)nn23)c(Cl)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C)ccc3c(N)c(C)nn23)c(Cl)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 8.5 %

Procedure:
A 0° C. solution of 7-(2-chloro-4-methoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.58 g, 1.8 mmol) and triethylamine (0.30 mL, 2.2 mmol) in toluene (10 mL) was treated with diphenylphosphoryl azide (0.40 mL, 1.8 mmol) and stirred for 2.5 hours at 0° C. The reaction mixture was poured into H2O, extracted with Et2O, washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to remove the Et2O. Toluene (20 mL) was added and the reaction was heated to reflux for 3 hours. The reaction was treated with 2N HCl (5 mL) and stirred at reflux for 1 hour then cooled to room temperature. The layers were separated and the aqueous layer was basified with solid K2CO3. The residue was extracted with CH2Cl2, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to give 0.046 g (9%) of a yellow oily solid as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.1 Hz, 1H), 7.35 (d, J=9.3 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.5, 2.5 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 2.38 (s, 3H), 2.08 (s, 3H); MS (EI) m/z 302.18 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[C:16](O)(=[O:19])[C:17]#[CH:18]>C1CCCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:16](=[O:19])[C:17]#[CH:18])=[C:10]([F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1F
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1F

Procedure:
Prepared analogously to Example 1.1.b. from 4′-chloro-3-fluorobiphenyl-4-ylamine and propynoic acid. Yield: 0.16 g (43.7% of theory); C15H9ClFNO (M=273.69); calc.: molecular ion peak (M+H)+: 274/276; found: molecular ion peak (M+H)+: 274/276; Rf value: 0.3 (silica gel, cyclohexane/ethyl acetate (3:1)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([N:12]2[C:7](=[O:9])[C:3]3[C:2](=[N:1][CH:6]=[CH:5][CH:4]=3)[C:10]2=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: O=C1c2cccnc2C(=O)N1c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2,3-pyridinedicarboxylic acid anhydride (19.4 g) in tetrahydrofuran (260 mL) was added aniline (11.8 mL) and the mixture was refluxed 2 hours. The reaction mixture was concentrated. Acetic anhydride (65 mL) was added to the reaction mixture, which was refluxed for 1.5 hours. After cooling in ice bath, the reaction mixture was poured in ice water (200 mL) and stirred for 1 hours. The precipitate was collected by filtration. It was washed with water and then washed with ethanol on heating to give the title compound (20.9 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:23])[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:23][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:26]([O:25][CH3:24])[CH:27]=3)[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)Nc2nc(-c3ccc(F)cc3)c(Cc3ccc([N+](=O)[O-])cc3)s2)cc1OC
Yield: 24 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-fluoro-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 9 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1-10:1) to obtain a product as a white solid in a yield of 24.0%, mp: 128-129└. 1H-NMR (DMSO-d6, 400 MHz) δ: 3.91 (3H, s, OCH3), 3.95 (3H, s, OCH3), 4.31 (2H, s, CH2), 6.90 (1H, d, J=9.00 Hz, ArH), 7.08 (2H, t, J=8.68 Hz, ArH), 7.38 (2H, d, J=8.68 Hz, ArH), 7.25˜7.47 (4H, m, ArH), 8.19 (2H, d, J=8.68 Hz, ArH), 10.04 (1H, br, CONH); EI-MS m/e (%): 493.2 (M+, 17), 165.3 (100); HREI-MS Calcd. for C25H20FN3O5S: 493.1108. found: 493.1105.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>C1COCC1>[C:15]([O:14][C:12](=[O:11])[NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCc1ccc(O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Temperature: 0 °C

Procedure:
Suspend tyramine (10.0 g, 73.0 mmol) in THF (200 mL). Cool to 0° C. Add a solution of (BOC)2O (31.8 g, 145 mmol) in THF (43 mL). Allow reaction mixture to warm to room temperature overnight. After 20 hours concentrate. Purification through two Waters 500A columns on a PrepLC system 500A to give the title compound: MS FAB ES+ 238.3 (M+H)+, base peak 182.2 (M+2H—C(CH3)3)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=8.5 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:27]CC1C=CC=CC=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[OH:27]
Reactant: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1O
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of [4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-[(2R)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone (2.28 g, 5.00 mmol) in methanol (25 mL) was added 10% Pd/C (100 mg). The mixture was degassed and charged with hydrogen for three times, and then stirred under hydrogen balloon overnight. The reaction was filtered through a celite pad, washed with methanol, and condensed. After high vacuum dry, [4-(6-amino-5-hydroxy-pyridin-3-yl)-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone was obtained (1.74 g, 95% yield). 1H NMR(400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.54 (m, 3H), 7.46 (m, 2H), 7.14 (s, 1H), 5.68 (s, 2H), 4.22 (m, 1H), 3.45 (m, 2H), 2.66 (m, 1H), 2.52 (m, 4H), 1.96 (m, 2H), 1.84 (m, 3H), 1.64 (m, 4H); MS m/z 367 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+].[CH2:22](O)[CH3:23]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:22][CH3:23])=[O:6]
Reactant: CCO
Reactant: Nc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cccc(N)c1
Temperature: 25 °C

Procedure:
To 3-aminobenzoic acid (7.00 g, 0.52 mol) dissolved in 300 mL of absolute ethanol was added ~3.5 mL of concentrated sulfuric acid. The reaction mixture was heated at reflux for 2 days and then cooled to ambient temperature. Potassium carbonate (8.9 g) was added and then most of the ethanol was removed under reduced pressure. The solution was partitioned between chloroform and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was filtered through silica gel eluting with ethyl acetate to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.40 (t, 3H), 3.85 (bs, 2H), 4.35 (q, 2H), 6.90 (m, 1H), 7.25 (m, 1H), 7.45 (m, 2H). MS (DCl/NH3) m/e 166 (M+H)+, 183 (M+H+NH3)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH2:10][OH:11])=[CH:4][CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:11][CH2:10][C:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]=1)(=[O:14])[CH3:13]
Reactant: CC1CC=C(CO)C(C)(C)C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC1=CCC(C)CC1(C)C
Yield: 85.4 %

Procedure:
A mixture of 4,6,6-trimethyl-1-cyclohexene-1-methanol (3 g, 19.5 mmole) and acetic anhydride (2.4 g, 24 mmole) was heated to 70° during 3 h, then distilled at a bath temperature of 70°/0.5 hPa, to obtain 3.27 g (86%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH:13](I)([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:5]([O:8][CH:13]([CH3:15])[CH3:14])=[N:6][CH:7]=1
Reactant: CC(C)I
Reactant: COC(=O)c1cc(O)ncc1Br
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC(C)C)ncc1Br
Yield: 99 %

Procedure:
A solution of methyl 5-bromo-2-hydroxypyridine-4-carboxylate (3.00 g, 12.9 mmol), isopropyl iodide (3.30 g, 19.4 mmol) and Ag2CO3 (4.66 g, 16.8 mmol) in toluene (40 mL) was heated at 100° C. for 2 hours. The solid was filtered through CELITE® and the filtrate was concentrated under vacuum and purified by column chromatography (0-20% ethyl acetate/heptanes) to give methyl 5-bromo-2-(propan-2-yloxy)pyridine-4-carboxylate (112a, 3.5 g, 99%) as a colorless oil.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[C:38]1([CH:48]=O)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1.Cl>C1COCC1>[C:38]1([CH:48]=[C:11]([CH2:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)C(CCCOC1CCCCO1)P(=O)(OCC)OCC
Reactant: O=Cc1cccc2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=Cc1cccc2ccccc12)CCCOC1CCCCO1
Yield: 84 %

Procedure:
579 mg of lithium chloride was suspended in 20 ml of dry THF under an argon stream, and 5.0 g of ethyl 2-diethylphosphono-5-(2-tetrahydropyranyloxy)pentanoate was added under stirring. After stirring the mixture for 5 minutes at room temperature, 2.6 g of DBU was added, and the mixture was stirred at room temperature for 10 minutes. Then, 1.7 g of α-naphthoaldehyde was added, and the mixture was stirred at room temperature overnight. Then, the reaction solution was neutralized with 1N hydrochloric acid under cooling with ice and extracted with ethyl acetate. The ethyl acetate layer thereby obtained was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 3.37 g of ethyl 3-(1-naphthyl)-2-[3-(2-tetrahydropyranyloxy)propyl]-2-propenoate as slightly yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]=[CH:26][O:25]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][CH2:23][CH:24]2[CH2:29][CH2:28][CH:27]=[CH:26][O:25]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: SCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CSCC2CCC=CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A solution of 260 mg of 4-chlorobenzyl mercaptan in 3 ml of dimethylformamide was mixed with 72 mg of 55% sodium hydride, and the mixture was stirred at room temperature for 30 minutes. 2 ml of a dimethylformamide solution containing 400 mg of 2-tosyloxymethyl-3,4-dihydro-2H-pyran were then added, and the mixture was stirred at 80°-90° C. for 4 hours. The mixture was then treated and the product purified essentially as described in Example 34(a) to give 224 mg of 2-(4-chlorobenzylthiomethyl)-3,4-dihydro-2H-pyran, as a colourless oil.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:28]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Product: COc1cccc(S(=O)(=O)NC2CCN(CCc3c[nH]c4ccccc34)CC2)c1

Procedure:
Using an analogous procedure to Example 1 3-[2-(4-amino-1-piperidyl)ethyl]indole monohydrate may be reacted with m-methoxybenzenesulphonyl chloride to give the title compound.