Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:14][CH2:15][CH2:16][OH:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:14]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:15][CH2:16][O:17][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCNCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(CCc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
Methanesulfonyl chloride (4.3 g, 0.037 mol) was added dropwise at 0° C. to a well stirred solution of 2-phenethylamino-ethanol (2.5 g, 0.015 mol, from step (i) above) and triethylamine (4.6 g, 0.045 mol) in dry dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 3 h and quenched with water. The reaction mixture was extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography over silica gel using 3% methanol in dichloromethane as eluent to yield (3 g) of compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:41](O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:41]([N:10]1[C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a solution of ethyl 3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (2.0 g, 6.30 mmol) in dry THF (20 mL) was added triphenylphosphine (1.899 g, 7.24 mmol) and benzyl alcohol (0.720 mL, 6.92 mmol). DIAD (1.373 mL, 6.92 mmol) in dry THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. THF was removed in vacuo. The crude product was dissolved in EtOAc (20 mL) and saturated NaHCO3 (40 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layer was washed with brine (50 mL) and dried over Na2SO4 and the solvent was evaporated. The residue was co-evaporated with DCM (10 mL) and then stirred in Et2O (20 mL) and the solids were filtered off. The filtrate was purified by column chromatography (silica, heptane/EtOAc, 3:1) to give 2.6 g (97%) the desired product as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:10][C:11]1[CH:45]=[CH:44][C:14]([C:15]([NH:17][C:18]2[C:19]3[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[S:30][C:20]=3[N:21](C(OC(C)(C)C)=O)[N:22]=2)=[O:16])=[CH:13][CH:12]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][N:2]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]2[C:19]3[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[S:30][C:20]=3[NH:21][N:22]=2)=[O:16])=[CH:44][CH:45]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: CNc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(=O)Nc2n[nH]c3sc(C(=O)NN(C)c4ccccc4)cc23)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 360 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide and 121 μL (1.11 mmol) of N-methylaniline are successively added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 15 days, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, washed with saturated brine, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography on a cartridge of 15 g of silica gel (0.015-0.040 mm), eluting with pure dichloromethane and then with a dichloromethane/methanol/28% aqueous ammonia mixture (12/3/0.5 by volume) at a flow rate of 10 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 11 mg of 4-[(methylphenylamino)methyl]-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a beige-colored powder melting at 242° C. LC-MS-DAD-ELSD: 511(+)=(M+H)(+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 82.8 %

Procedure:
N-t-butyloxycarbonyl-L-phenylalanine (36.54 g, 137.7 mmole), L-proline benzylester hydrochloride (33.84 g, 140 mmole) and HOBT (18.91 g, 140 mmole) were dissolved in methylene chloride (500 ml), and triethylamine (14.17 g, 140 mmole) and WSC hydrochloride (26.40 g, 137.7 mmole) were added thereto at -30° C. The solution was stirred for 2 hours at less than 0° C. and then overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 ml, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The oily residue thus obtained was crystallized from ethyl acetate and n-hexane to give N-t-butyloxycarbonyl-L-phenylalanyl-L-proline benzylester (yield: 51.61 g, 82.8%).
Reaction SMILES: [Br:1][C:2]1[C:6]2=[CH:7][C:8]([Cl:30])=[C:9]3[C:14]([C:13](=[O:15])[O:12][C:11]([C:16]4[N:17]([C:23]5[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=5)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=4)=[N:10]3)=[C:5]2[NH:4][N:3]=1.Cl.[C:32]1([NH2:38])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C)C=O>[C:32]1([NH:38][C:13]([C:14]2[C:9]([NH:10][C:11]([C:16]3[N:17]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:12])=[C:8]([Cl:30])[CH:7]=[C:6]3[C:5]=2[NH:4][N:3]=[C:2]3[Br:1])=[O:15])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2nc3c(Cl)cc4c(Br)n[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2c(Cl)cc3c(Br)n[nH]c3c2C(=O)NC2(C3CC3)CC2)n(-c2ncccc2Cl)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
To a solution of 120 mg (0.24 mmol) of the above 3-bromo-5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 2.4 mL of N,N-dimethylformamide is added 95 mg (0.71 mmol) of bicyclopropyl-1-ylamine hydrochloride and 99 μL (0.71 mmol) of triethylamine. The reaction is stirred at 50° C. for 24 hours and then concentrated in vacuo. The residue is taken-up with acetone and after filtration the filtrate is evaporated. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 1:1) affords 80 mg (56%) of a solid; LC/MS:606/608 (M+H)+, m.p.: 190-194° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[O:17]=[C:18]1[NH:23][C:22]([C:24]([O:26]CC)=O)=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:19]1=2.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:80]2[CH:84]=[N:83][C:82]([O:85][CH2:86][CH2:87][O:88][C:89]3[CH:90]=[C:91]([CH2:95][NH2:96])[CH:92]=[CH:93][CH:94]=3)=[N:81]2)C=CC=CC=1>>[O:17]=[C:18]1[NH:23][C:22]([C:24]([NH:96][CH2:95][C:91]2[CH:92]=[CH:93][CH:94]=[C:89]([O:88][CH2:87][CH2:86][O:85][C:82]3[N:83]=[CH:84][NH:80][N:81]=3)[CH:90]=2)=[O:26])=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:19]1=2
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3cccs3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3cccs3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 4-oxo-5-(2-thienyl)-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 39 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (149 mg, 46%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[H-].[Na+].O>CN(C=O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[C:2](=[O:3])[O:4][C:5]1=[O:12]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccccn2)c2ccccc12
Temperature: 25 °C
Reaction time: 42 h
Yield: 33.8 %

Procedure:
To a solution of isatoic anhydride (25.4 g, 0.156 mol) in DMF (300 mL) were added 2-(chloromethyl)pyridine hydrochloride (28.1 g, 0.171 mol) and sodium hydride (66% in oil, 12.5 g, 0.34 mol) under ice-cooling. The obtained mixture was stirred at room temperature for 42 hr. Water (750 mL) was added to the reaction mixture and the mixture was ice-cooled. The precipitated solid was collected by filtration, and recrystallized from acetone-diisopropyl ether to give the title compound (13.4 g, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]([CH2:38][C:39]([O:41]C)=[O:40])[CH2:33][C:34]([O:36]C)=[O:35])=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]([CH2:33][C:34]([OH:36])=[O:35])[CH2:38][C:39]([OH:41])=[O:40])=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)CC(CC(=O)OC)c1ccc2c(c1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(CC(=O)N2CCc3cc(C(CC(=O)O)CC(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Yield: 23.4 %

Procedure:
A stirred suspension of dimethyl 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioate [270 mg, Reference Example 4(c)] in ethanol (10 ml) was treated with a solution of sodium hydroxide (190 mg) in water (2 ml) and the mixture stirred at reflux for 3 hours. After cooling to room temperature the mixture was treated with water (10 ml) and then carefully acidified to pH1 by the addition of hydrochloric acid (3M) with ice cooling. the resultant precipitate was collected by filtration, then dried and then recrystallised from ethyl acetate to give the title compound (60 mg) as a white crystalline solid. LC-MS: RT=2.44 minutes (100% total area by ELS); MS (ES+) 568 (MNa+).
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O.[F:48][C:49]([F:76])([F:75])[C:50]([C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][CH:69](O)[CH3:70])=[C:61]([CH2:72][CH2:73][CH3:74])[CH:60]=1)([O:55]COC)[C:51]([F:54])([F:53])[F:52]>C1(C)C=CC=CC=1.O1CCCC1>[F:48][C:49]([F:75])([F:76])[C:50]([C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][CH:69]([N:4]2[C:3](=[O:8])[C:2]([CH3:1])([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=3)[NH:6][C:5]2=[O:7])[CH3:70])=[C:61]([CH2:72][CH2:73][CH3:74])[CH:60]=1)([OH:55])[C:51]([F:52])([F:54])[F:53]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCC(C)O
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OCCCC(C)N1C(=O)NC(C)(c2ccc(OC(C)C)cc2)C1=O
Yield: 88.5 %

Procedure:
5-Methyl-5-[4-(1-methylethoxy)phenyl]imidazolidine-2,4-dione (25.8 mg), triphenylphosphine (22.8 mg) and a solution of ethyl azodicarboxylate in toluene (2.2 mol/L, 34.7 μL) were added to a mixed solution of 5-[4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenyloxy]pentan-2-ol (15.0 mg, 34.7 μmol) in tetrahydrofuran (1 mL) at room temperature. After completion of the reaction, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 19.0 mg of the title compound (yield: 89%) as a colorless oil.
Reaction SMILES: Cl.O1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:22][CH2:23][N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][N:28]([C:32]([C:34]4[C:35]([CH3:41])=[N:36][CH:37]=[N:38][C:39]=4[CH3:40])=[O:33])[CH2:29]3)[CH2:25]2)[CH2:17][CH2:16]1)=[O:14])(C)(C)C.ClC(OC)=O>C(Cl)Cl>[CH3:8][O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:22][CH2:23][N:24]2[CH2:25][CH:26]3[CH:30]([CH2:29][N:28]([C:32]([C:34]4[C:35]([CH3:41])=[N:36][CH:37]=[N:38][C:39]=4[CH3:40])=[O:33])[CH2:27]3)[CH2:31]2)[CH2:17][CH2:16]1)=[O:14]
Reactant: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCN(C(=O)OC(C)(C)C)CC3)CC2C1
Agent: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)N1CCC(C(CCN2CC3CN(C(=O)c4c(C)ncnc4C)CC3C2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
HCl-dioxane (1 mL, 4.0 M) was added to 78a (Ar1=Ph, Ar2=4,6-dimethyl-pyrimidin-5-yl, 40 mg, 0.073 mmol). The mixture was stirred at RT for 90 min. The solvent was removed, and the residue was dried in vacuo. Methyl chloroformate (8 μL, 0.10 mmol) was added to a solution of the residue from the deprotection, TEA (16 μL, 0.11 mmol) in DCM (0.5 mL) maintained at 0° C. The reaction mixture was stirred and warmed to RT. The crude product was purified on a preparative TLC plate developed with a 45:55 mixture of DCM and DCM/MeOH/NH4OH (60/10/1) to afford 0.004 g (11%) of V-7.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].COC(C)=C.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2.[H-].[Na+]>C1COCC1.CN(C=O)C>[OH:4][CH2:3][CH2:2][N:16]1[C:17]2[C:13](=[CH:12][C:11]([Br:10])=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: OCCBr
Reactant: Brc1ccc2[nH]ccc2c1
Agent: C=C(C)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCCn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
Under a N2 atmosphere, 2-bromoethanol (17.6 g, 141 mmol) and 2-methoxypropene (10.1 g, 141 mmol) were stirred in 71 mL of THF at 0° C. for 30 minutes The resulting solution was added to a stirring mixture of 5-bromoindole (22.83 g, 116 mmol) and 60% NaH (4.62 g, 193 mmol) in 40 mL of DMF and 60 mL of THF. The solution was stirred at ambient temperature for 4 hours. The reaction mixture was worked up by quenching the excess of NaH with water and removing the aqueous layer. The organic layer was vigorously stirred with 200 mL of 2% aqueous phosphoric acid for 5 hours when the layers were separated. The organic layer was washed with water (2×200 mL) and the solvent removed. The residue was purified by column chromatography (30:70 EtOAc-Hex) to give 17 g of 1-(2-hydroxylethyl)-5-bromoindole.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([O:22][CH:23]([O:32][CH2:33][CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:13][C:14]1[C:19]([CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]([O:22][CH2:20][CH3:21])[O:32][CH2:33][CH3:34])[OH:31])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Fc1ccccn1
Reactant: CCOC(OCC)c1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccccc1C(O)c1cccnc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2.5 ml of diisopropylamine in 20 ml of dry tetrahydrofuran at -78° C. was added 11 ml of a 1.6 M solution of butyllithium in hexanes. The solution was stirred for 20 min. then a solution of 1.15 g of 2-fluoropyridine in 3 ml of tetrahydrofuran was added. The solution was stirred at -78° C. for 30 min then a solution of 2-formylbenzaldehyde diethylacetal in 3 ml of tetrahydrofuran was added dropwise. This solution was stirred for 1 h then warmed to room temperature overnight. The reaction was poured into a 5% solution of sodium carbonate and extracted with two 300 ml portions of ether. The combined organic layers were washed with 300 ml of water then the same volume of brine and dried over sodium sulfate. Evaporation of the solvent afforded (2-fluoropyridin-3-yl)-2-(diethoxymethyl)-phenyl methanol as a viscous oil; 1H-NMR (200 MHz, CDCl3) d 5.60 (CHOEt).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15]C(O)[CH2:13][CH2:12]1.C(OC(C)C)(C)C.O1CCOCC1>>[C:1]([O:9][CH:10]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: O=C(OC1CCNCC1)c1ccccc1
Yield: 65 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), piperidin-4-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and diisopropyl ether/1,4-dioxane (3/1) (5.0 ml) was heated to reflux for 46 hours, and as a result, piperidin-4-yl benzoate was obtained at a yield of 65%. The yield of N-benzoylpiperidin-4-yl benzoate was 30%.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[C:24]([NH2:27])=[N:25][CH:26]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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>[NH2:27][C:24]1[N:25]=[CH:26][C:21]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:29])[F:30]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: Cn1nc(Br)c2cnc(N)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2cnc(N)c(C(F)(F)F)c2)c2cnc(N)nc21
Temperature: 25 °C

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (0.1 g, 0.438 mmol), tetrakis(triphenylphosphine)palladium (0.031 g, 0.027 mmol), 5-(4,4,5,5-tetra methyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (Intermediate 10) (0.135 g, 0.669 mmol), cesium carbonate (0.290 g, 0.892 mmol) and water (1 ml) are suspended in 1,4-dioxane (4 ml) and heated using microwave radiation at 150° C. for 45 minutes. The reaction mixture is cooled to room temperature, filtered through Celite® (filter agent) and washed with EtOAc. The solvents are removed in vacuo and purification of the crude residue by flash chromatography on silica eluting with iso-hexanes:EtOAc (2:1) results in an off white solid. The solid is further purified by recrystallisation from 1:1 MeOH/EtOAc resulting in a white solid which is collected by filtration and dried under vacuum to afford the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2](C)[CH3:3].C([Li])CCC.Br[C:13]1[CH:14]=[CH:15][C:16]([Cl:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Cu]C#N.C(Br)C=C>C1COCC1>[CH2:3]([C:13]1[CH:14]=[CH:15][C:16]([Cl:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:1]
Reactant: CC(C)(C)OC(=O)c1cc(Br)ccc1Cl
Reactant: CC(C)C[Mg]Br
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1ccc(Cl)c(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., isobutylmagnesium bromide (2.0 M ether solution, 1.2 eq.) and n-butyl lithium (2.5 M hexane solution, 2.4 eq.) were added to anhydrous THF (0.3 M). After stirring at 0° C. for 30 min, the reaction mixture was cooled to −40° C. and tert-butyl 5-bromo-2-chlorobenzoate from the previous step (1 eq.) was added over 15 min. The now red solution was stirred at −40° C. for 1 h before copper (I) cyanide (30% loading) was added. The resulting suspension was stirred at −40° C. for 15 min and then added allyl bromide (3 eq.). After stirring at −40° C. for another 2 h, the reaction mixture was quenched with sat. aq. NH4Cl and warmed to RT. The biphasic mixture was poured into more sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→19:1 (v/v) Hex:ether) afforded the title compound as a light yellow oil.