Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[K+].[Cl:6][C:7]1[C:8]([OH:17])=[C:9]([CH:11]=[C:12]([Cl:16])[C:13]=1[CH2:14][CH3:15])[NH2:10].[CH3:18][C:19]([C:23]1[CH:35]=[C:34]([C:36]([CH3:40])([CH3:39])[CH2:37][CH3:38])[CH:33]=[CH:32][C:24]=1[O:25][CH:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])([CH3:22])[CH2:20][CH3:21]>C(O)(C)C.O.C1(C)C=CC=CC=1.CCCCCCC>[CH3:22][C:19]([C:23]1[CH:35]=[C:34]([C:36]([CH3:39])([CH3:40])[CH2:37][CH3:38])[CH:33]=[CH:32][C:24]=1[O:25][CH:26]([CH2:30][CH3:31])[C:27]([NH:10][C:9]1[CH:11]=[C:12]([Cl:16])[C:13]([CH2:14][CH3:15])=[C:7]([Cl:6])[C:8]=1[OH:17])=[O:28])([CH3:18])[CH2:20][CH3:21]
Reactant: CCc1c(Cl)cc(N)c(O)c1Cl
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCc1c(Cl)cc(NC(=O)C(CC)Oc2ccc(C(C)(C)CC)cc2C(C)(C)CC)c(O)c1Cl
Temperature: 60 °C

Procedure:
A heel was created via batch mode in Reactor 1 by first adding of 16 g (0.16 moles) of potassium bicarbonate, and 55 g of deionized water, and stirring until all of the solid had dissolved. Then, 24 g of isopropanol, 30 g (0.146 moles) of 3,5-dichloro-4-ethyl-2-hydroxyaniline (the amine), 120 g of heptane, and 20 g of toluene were added. The contents of the reactor system were heated to approximately 60° C. while agitating at 400 rpm. To this 2-phase mixture, 57.5 g (0.169 moles) of 2-[2,4-bis(1,1-dimethylpropyl)phenoxy]butyryl chloride (the acid chloride) were added over approximately 45 minutes. The analysis of the upper phase of the mixture was 94% product on a solvent free-basis. The continuous feeds were started at the following rates to provide six hours of residence time: 0.51 g/min 1.36 mmoles/min) of a 55 wt % solution of amine in isopropanol; 1.82 g/min (1.48 mmoles/min) of a solution of the acid chloride solution (27.5 wt % in a mixture of 6 parts of heptane and 1 part of toluene. A 22.5 wt % solution of potassium bicarbonate in water was added to maintain the pH between about 2 and 4. The flowrate of the potassium bicarbonate solution ranged from 0.64-0.68 g/min (1.37-1.46 mmoles/minute).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH2:16][N:1]=[C:2]1[NH:10][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[S:3]1)[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: Nc1nc2cnccc2s1
Product: CN(C)CN=c1[nH]c2cnccc2s1
Yield: 80.9 %

Procedure:
A stirred mixture of 2-aminothiazolo[4,5-c]pyridine [prepared according to the procedure of H. W. Altland and G. A. Molander, J. Heterocyclic Chem., 14, 129 (1977)] (0.5 g, 3.3 mmole) and N,N-dimethylformamide dimethyl acetal (5 ml) was stirred at an oil bath temperature of 80° C. for two hours under an atmosphere of argon. The solution was concentrated to dryness to leave the crystalline product. The solid was triturated with cold petroleum ether and dried to afford 0.55 g (80.9%) of the title compound, mp. 125°-127° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][C:26]4[C:25](=[O:35])[CH:24]([C:36]([O:38][CH3:39])=[O:37])[CH2:23][CH2:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40]C(C)([O-])C.[K+].CI>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][C:26]4[C:25](=[O:35])[C:24]([CH3:40])([C:36]([O:38][CH3:39])=[O:37])[CH2:23][CH2:22][C:21]=4[N:20]=3)=[CH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
A solution of methyl 2-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinoline-6-carboxylate (65 mg, 0.12 mmol) in anhydrous THF (1.0 mL) was cooled to 0° C. under a nitrogen atmosphere, followed by the dropwise addition of potassium tert-butoxide solution (1M in THF, 150 μL, 0.15 mmol). The mixture was stirred at 0° C. for 15 minutes followed by the addition of methyl iodide (10 μL, 0.16 mmol). The reaction mixture was allowed to warm to room temperature and stirred for a further 4 hours. The mixture was diluted with ethyl acetate (2.0 mL), washed with 1M HCl solution (2.0 mL), brine (2×2.0 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give the desired product as a brown solid (54 mg, 83% yield). LCMS (Method A) RT=7.92 min, M+H+=541.18.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.[OH2:8]>>[CH3:5][CH2:6][CH2:1][CH2:7][O:8][C@H:6]([CH2:5][OH:8])[CH2:1][CH3:7]
Reactant: O
Reactant: Cc1ccccc1
Product: CCCCO[C@@H](CC)CO
Reaction time: 1.5 h

Procedure:
200 ml of an acidic ion-exchange resin (Bio-Rad 50 W-X2) was added to the mixture and it was stirred for 1.5 hours. 200 ml of toluene was added to the mixture and water was removed by azeotropic distillation. The product was filtered to remove the resin, and the solvent was removed under reduced pressure. The resulting diol (482 g) had a hydroxyl number of 67 mg KOH/g.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1>COCCO.[Pd]>[O:1]1[CH:10]2[CH:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cnc2c(c1)OCCC2
Agent: [Pd]
Solvent: COCCO
Product: C1COC2CCCNC2C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To a solution of 3,4-dihydro-2H-pyrano[3,2-b]pyridine (0.60 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The reaction mixture was stirred at 70° C. for 3 hours under H2 (2 MPa) and filtered. The filtrate was concentrated in vacuo to give the title compound as colorless oil (0.56 g, 90.00%), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 142.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[C:32]1([C@H:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC#N>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:31])[F:30])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:40][C@@H:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:39])[N:5]=2)[CH:26]=1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: C[C@@H](N)c1ccccc1
Solvent: CC#N
Product: C[C@@H](NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.20 mmol) and (1R)-1-phenylethan-1-amine (242 mg, 2.00 mmol) in MeCN (3 mL, 57.07 mmol) was stirred at 80° C. for 12 h. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (2#-Analyse HPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBD Column, 19&#65533; 100 mm 5 um 13 nm; mobile phase, Water with 10 mM NH4CO3 and ACN (40% ACN up to 58% in 6 min); Detector, UV 254/220 nm. This resulted in 38 mg of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a off-white solid. LCMS (Method 25) [M+H]+=552.1, RT=1.16 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.72 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.34 (s, 1H), 7.60 (dd, 1H, J=2.7, 9.0 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.31-7.17 (m, 6H), 6.98 (t, 1H, J=73.2 Hz), 4.18 (t, 2H, J=6.0 Hz), 3.70 (q, 1H, J=6.6 Hz), 2.83-2.73 (m, 2H), 1.22 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH:6]1([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[N:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=O)=[O:16])[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1>>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:20]([C:19]1[CH:23]=[CH:24][N:25]=[CH:26][C:18]=1[NH:17][C:15]([C:13]1[C:12]([NH:27][C:28]2[CH:33]=[N:32][CH:31]=[N:30][CH:29]=2)=[CH:11][CH:10]=[C:9]([CH:6]2[CH2:7][CH2:8]2)[N:14]=1)=[O:16])=[O:22]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CNCCO
Product: CN(CCO)C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 32 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-methylamino-ethanol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (32%) as amorphous yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1>CO.N1CCCCC1>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1C#CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C#CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperidine-1-carboxylate (0.0503 g, 0.130 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0173 g, 0.119 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}prop-2-ynyl)piperidine-1-carboxylate (0.0293 g, 44%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a red solid (118 mg).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([NH:13][C:14](=[O:22])/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[N:9][NH:10]2)=[CH:6][CH:5]=1.Cl.C(OCC)(=O)C>C(O)C.O1CCCC1.O>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([NH:13][C:14](=[O:22])[CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[N:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C=C/C(=O)Nc1n[nH]c2cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C=CC(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 50 °C
Yield: 61.2 %

Procedure:
0.95 cm3 of 1N sodium hydroxide is added to 280 mg of ethyl (2E) 4-[(6-chloro-1H-indazol-3-yl)amino]-4-oxo-2-butenoate, described in Example 2, in 25 cm3 of ethanol. The reaction medium is then heated at 50° C. for two hours, followed by addition of a further 1 equivalent of 1N sodium hydroxide. The temperature is maintained at 50° C. for a further 30 minutes and the heating is then stopped. At about 20° C., the medium is neutralized with 1N hydrochloric acid and then concentrated under reduced pressure (2 kPa; 40° C.). The solid thus obtained is taken up in 25 cm3 of tetrahydrofuran, 50 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 30 cm3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate. The solution is filtered and evaporated under the conditions described previously. The residue is taken up in 10 cm3 of ethyl acetate and the insoluble material is then filtered off and rinsed with 5 cm3 of ethyl acetate and with 10 cm3 of diethyl ether and dried under reduced pressure (90 Pa; 50° C.). 155 mg of 4-[(6-chloro-1H-indazol-3-yl)amino]-4-oxo-2-butenoic acid (E form) are obtained in the form of a pale yellow solid melting at 260° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.I[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:44]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1I
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 2-iodotoluene according to the general procedure C. Obtained as a yellow oil (755 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([O:9][CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:5][CH:4]=1.CS(Cl)(=O)=O.[H-].[Na+].[CH3:28][CH2:29]OC(C)=O>O.CCO.C1COCC1.C(N(CC)CC)C>[NH:12]1[CH2:11][CH:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][O:1][CH2:28][CH3:29])=[N:8][CH:7]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(CO)nc2)C1
Reactant: CCOC(C)=O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOCc1ccc(OC2CNC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-{[6-(hydroxymethyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (242 mg) and THF (3 ml) were mixed, and triethylamine (182 mg) and methanesulfonyl chloride (147 mg) were added thereto, followed by stirring at room temperature for 1 hour. In another flask, THF (3 ml) and EtOH (237 mg) were mixed, and NaH was added thereto, followed by stirring at room temperature for 10 minutes. The reaction mixture prepared immediately before was added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. DCE (4 ml) and TFA (1 ml) were added to the obtained residue, followed by stirring at room temperature for 5 hours, and then concentrating under reduced pressure. CHCl3 and a 1 M aqueous NaOH solution were added to the residue, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-(ethoxymethyl)pyridine (131 mg).
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([C:20]([OH:22])=[O:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH2:23](Br)[CH:24]=[CH2:25].CN(C)C=O>O>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([C:20]([O:22][CH2:25][CH:24]=[CH2:23])=[O:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Reactant: C=CCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Reaction time: 6 h

Procedure:
To 7 grams of the potassium salt of 2-(2-chlorophenyl)-4-quinolone-8-carboxylic acid were added 2 ml of allyl bromide and 200 ml of dimethyl formamide, the mixture was stirred at 70° to 80° C. for 6 hours, and poured into water. The mixture was extracted with chloroform, the solvent was removed from the extract, and the residue was recrystallized from acetone to give 5.6 grams of the title compound, pale yellow needles, melting point 121° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[OH:10][NH:11][C:12](=N)[CH:13]([CH3:15])[CH3:14].Cl>C(OCC)(=O)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[CH:13]([C:12]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:10][N:11]=1)([CH3:15])[CH3:14]
Reactant: N#CN1CCC(O)CC1
Reactant: CC(C)C(=N)NO
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)c1noc(N2CCC(O)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carbonitrile (1 g, 7.93 mmol) and N-hydroxyisobutyrimidamide (0.972 g, 9.51 mmol) in ethyl acetate (40 mL) was added zinc chloride (1 M in Et2O, 9.5 mL, 9.5 mmol) dropwise at rt under argon. Precipitate formed immediately, and the reaction mixture was stirred at rt for 30 min. The solid was collected via filtering, rinsed several times with ether. The solid was dissolved in concentrated HCl (4 mL, 132 mmol), diluted with ethanol (8 mL), and refluxed for 1 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated to approximately half of the volume, and diluted with water (15 mL). The solution was basified with solid Na2CO3, followed by extraction with CH2Cl2 (3×30 mL). The combined organic layers were washed with saturated NaHCO3 (60 mL) and brine. It was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (hexanes-EtOAc gradient 0-50% EtOAc) to afford 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol (0.59 g, 2.79 mmol, 35% yield) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (d, J=7.07 Hz, 6H) 1.55 (d, 1H) 1.60-1.70 (m, J=12.98, 8.61, 8.61, 4.17 Hz, 2H) 1.93-2.02 (m, 2H) 2.89 (spt, J=6.95 Hz, 1H) 3.38 (ddd, J=13.20, 9.03, 3.79 Hz, 2H) 3.88-4.04 (m, 3H). LCMS (m/z)=212 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C>C1(C)C=CC=CC=1>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[NH:21][CH2:20][CH:19]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(C(CN)c2ccccc2)CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=C1NCC(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A solution of rac-4-(2-amino-1-phenyl-ethyl)-1-benzyl-piperidine-4-carboxylic acid ethyl ester (2.9 g, 8 mmol) in toluene (30 mL) was heated under reflux for 4 h. After cooling to room temperature and evaporation the mixture was purified by chromatography on silica gel eluting with DCM:MeOH:NH4OH (95:4.5:0.5) to afford the title compound (1.47 g, 58%) as a white solid. MS: m/e=321.4 (M+H).
Reaction SMILES: [C:1]([S:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1>COCCOC.[Cl-].[NH4+]>[C:1]([S:5][C:6](=[O:11])[CH:7]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1)[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)SC(C)(C)C
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A solution of 3-oxothiobutyric acid S-tert-butyl ester (7.5 g) in 1,2-dimethoxyethane (10 mL) was added to a stirred suspension of sodium hydride (60% in oil, 1.9 g) in 1,2-dimethoxyethane (100 mL) at −20° C. The mixture was warmed to 0° C. for 10 minutes and then a solution of 1-bromomethyl-4-methanesulfonylbenzene (12.9 g) in 1,2-dimethoxyethane (30 mL) was added dropwise over a period of 10 minutes. The resulting mixture was warmed to room temperature over 30 minutes and then stirred at this temperature for 17 hours. The mixture was diluted with saturated aqueous ammonium chloride solution (70 mL) and the phases separated. The aqueous phase was extracted with diethyl ether and the combined organic phases were dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 4:1 by volume) gave title compound, 7.1 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[C:7]2[CH3:15].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:15][C:7]1[C:6]2[C:10](=[C:2]([NH:1][S:21]([C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)(=[O:23])=[O:22])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:11](=[O:14])[CH2:12][CH3:13]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCC(=O)c1[nH]c2c(N)cccc2c1C
Solvent: c1ccncc1
Product: CCC(=O)c1[nH]c2c(NS(=O)(=O)c3cccs3)cccc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a mixture of 1-(7-amino-3-methyl-1H-indol-2-yl)propan-1-one (0.17 g) and pyridine (6 mL) was added thiophene-2-sulfonyl chloride (0.18 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (0.19 g, yield 65%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point >185° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][OH:37])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH:32]([CH2:36][OH:37])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CCNC(CO)C1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)OCc4ccccc4)CC3CO)nc(-c3ccccc3O)nc2c1
Temperature: 40 °C
Yield: 49 %

Procedure:
To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (245 mg, 0.91 mmol) in 3.0 mL of CH2Cl2 was added sequentially 3-hydroxymethyl-piperazine-1-carboxylic acid benzyl ester (336.3 mg, 1.34 mmol) and triethylamine (190 mL, 1.37 mmol), and the reaction mixture was heated at 40° C. for 6 h. The reaction mixture was cooled and extracted with water (2×10 mL) and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure to give an oil. The residue was purified by normal phase LC (20-85% EtOAc-hexanes) to give 3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester (216 mg, 64% yield). LC/MS: m/z 485.4 (M+H)+ at 3.02 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).