Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:23]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)=[CH:26][CH:25]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1ccc(OCCN2CCCCC2)cc1
Product: Brc1cnc2[nH]c(-c3ccc(OCCN4CCCCC4)cc3)nc2c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-[2-(1-piperidinyl)ethoxy]benzaldehyde.
Reaction SMILES: O[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.NO.S(Cl)([Cl:22])=O>C1COCC1>[Cl:22][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCCN2CCCCC2)cc1
Agent: NO
Solvent: C1CCOC1
Product: ClCc1ccc(OCCN2CCCCC2)cc1

Procedure:
This material is prepared from the amino alcohol 1-[2-(4-Hydroxymethyl-phenoxy)-ethyl]piperidine by treatment with thionyl chloride in THF at 0° C. Resulting solid is used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[C:22]([OH:34])(=[O:33])/[CH:23]=[CH:24]/[C:25]1[CH:32]=[CH:31][C:29]([OH:30])=[C:27]([OH:28])[CH:26]=1>ClCCl>[CH3:1][NH:2][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][N:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[C:22]([O-:34])(=[O:33])/[CH:23]=[CH:24]/[C:25]1[CH:32]=[CH:31][C:29]([OH:30])=[C:27]([OH:28])[CH:26]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Solvent: ClCCl
Product: O=C([O-])/C=C/c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.57 g (0.5 cmole) of ranitidine and 0.95 g (0.5 cmole) of caffeic acid were suspended in dichloromethane (15 ml). The mixture was stirred for 2 hours 30 minutes at room temperature, was filtered, washed with dichloromethane. Dry weight 2.4 g. Quantitative yield.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.C([O:15][C:16](=O)[CH:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[N:23]=[C:22]2[C:29]1[N:34]=[C:33]([O:35][C@H:36]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][CH2:40][C:37]32[CH2:39][CH2:38]3)[CH:32]=[N:31][CH:30]=1)[CH3:18])(C)C>C1COCC1>[OH:15][CH2:16][CH:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[N:23]=[C:22]2[C:29]1[N:34]=[C:33]([O:35][C@H:36]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:41][CH2:40][C:37]32[CH2:38][CH2:39]3)[CH:32]=[N:31][CH:30]=1)[CH3:18]
Reactant: CC(C)OC(=O)C(C)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CO)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C
Yield: 65.5 %

Procedure:
Lithium aluminum hydride, 1.0 M solution in Et2O (109 μl, 0.109 mmol) was added to a solution of (4R)-tert-butyl 4-((6-(5-(1-isopropoxy-1-oxopropan-2-yl)-1-methyl-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (30 mg, 0.055 mmol) in THF (546 μl) at 0° C. for 1 h. The reaction was quenched with EtOAc and triturated with NH4Cl before it was filtered and concentrated to give (4R)-tert-butyl 4-((6-(5-(1-hydroxypropan-2-yl)-1-methyl-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (18 mg, 0.036 mmol, 66.8% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 494.0 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([CH:15]=[N:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCO.[Pd]>[N:17]1[N:16]=[CH:15][N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]=12
Reactant: c1ccc(COc2cccn3cnnc23)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccn2cnnc12
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a 8-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine (8.05 g, 35.7 mmol) dissolved in EtOH 100 ml was added 300 mg 10% Pd/C (Degussa). The reaction vessel was inerted with nitrogen and then purged with hydrogen 3 times, and the reaction was stirred under double balloon pressure of hydrogen overnight. The catalyst was removed by filtration and the filtrate concentrated to give a residue of [1,2,4]triazolo[4,3-a]pyridin-8-ol (4.23 g, 87% yield) that was used in the next step without further purification.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:25])(=O)[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:27]([O:29][NH:30][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)[CH2:6][C:5]1=[O:25])[CH3:2])[CH3:28]
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(OC(F)(F)F)cc2)CC1=O
Reactant: CCON
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCONC(C)=C1C(=O)CC(CCSc2ccc(OC(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.19 Gram of 2-acetyl-5-[2-(4-trifluoromethoxyphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 10 ml of ethanol, and 0.07 g of ethoxyamine hydrochloride and 0.06 g of triethylamine were added to the resulting solution which was then stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. Chloroform was removed and the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.12 g of 2-(1-ethoxyaminoethylidene)-5-[2-(4-trifluoromethoxyphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[O:27]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[N:3]([C:37]2[CH:38]=[CH:39][C:34]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc(Oc3ccccc3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-phenoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.37 g, 92%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25](O)=[O:26])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([O:23][CH2:24][C:25](=[O:26])[CH2:2][C:1](=[O:3])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)CC(=O)c2ccncc2)CC1

Procedure:
Condensation of 4-acetylpyridine with 4-carboxymethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 1), employing the protocol described in Preparation 22, afforded the title compound: m/z (ES+)=263.2 [M-Boc+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4cc(C)cc(C)c4)CC3)c(OC)nc2c1
Yield: 90 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.26 (s, 4H), 3.75 (s, 4H), 3.90 (s, 3H), 4.14 (s, 3H), 6.59 (s, 3H), 6.99-7.20 (m, 3H), 7.73-7.75 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-:27])=[O:26])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][C:18]1[CH:17]=[C:16]([C:13]2[N:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:24]=[C:2]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:3]=[CH:4][C:5]=3[N+:25]([O-:27])=[O:26])=[N:11][CH:12]=2)[CH:21]=[CH:20][C:19]=1[CH3:22]
Reactant: C1CCNCC1
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])cn2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3[N+](=O)[O-])cn2)cc1C
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 5-chloro-N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-2-nitrobenzamide (3.66 g, 9.56 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL), piperidine (3.8 g, 44.71 mmol, 4.70 equiv), and potassium carbonate (3.96 g, 28.70 mmol, 3.00 equiv). The resulting solution was stirred for about 8 h at 85° C. in an oil bath. The reaction was then quenched with 450 mL of water. The resulting solution was extracted with 3×300 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 3.86 g (crude) of N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-2-nitro-5-(piperidin-1-yl)benzamide as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]3[O:15][C@H:9]3[C:8]=2[CH:16]=1)(=[O:3])[CH3:2].[OH-].[NH4+:18]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[C@@H:9]([NH2:18])[C:8]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(=O)c1ccc2c(c1)[C@@H]1O[C@H]1C(C)(C)O2
Agent: [OH-]
Product: CC(=O)c1ccc2c(c1)[C@H](N)[C@@H](O)C(C)(C)O2

Procedure:
From (3R,4S)-6-acetyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (Example 1 of GB-A-1511187) by stirring in ethanolic ammonium hydroxide solution.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[Br:17]N1C(C)(C)C(=O)N(Br)C1=O>C(O)(=O)C.S(=O)(=O)(O)O>[Br:17][C:9]1[CH:10]=[C:5]([C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])[CH:6]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:8]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(c1cc(Br)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 35 °C
Reaction time: 3.5 h
Yield: 163.5 %

Procedure:
To a stirred solution of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanone (5.00 g) in glacial acetic acid (1.0 mL) and concentrated sulfuric acid (6.0 mL) at 0° C. was added 1,3-dibromo-5,5-dimethylhydantoin (3.54 g). After stirring at 35° C. for 3.5 hours, the reaction mixture was poured into ice-water (60 mL) and extracted with chloroform (30 mL×2). The organic extracts were combined, washed with saturated aqueous sodium hydrogencarbonate solution (50 mL×1) and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in hexane (20 mL) and filtered, and the filtrate was concentrated under reduced pressure to provide the title compound as a yellow oil (6.50 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([C:17]([O:19][Si](C)(C)C)=[CH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.BrBr.S(=O)(O)[O-].[Na+]>C1COCC1.C(#N)C.C1CCCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:18][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Agent: BrBr
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: CC#N
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C(Cc1cc(F)ccc1[N+](=O)[O-])c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 2.12 mL (20 mmol) of 4-fluoronitrobenzene and 4.12 mL (21 mmol) of [(1-phenyl-1-ethenyl)oxy]trimethylsilane in 30 mL of THF at -78° C. was added 5.502 g (20 mmol) of TASF dissolved in 6 mL of acetonitrile and 5 mL of THF. After stirring for 3 hrs at -78° C., 1.00 mL (19.50 mmol) of bromine in 5 mL of cyclohexane was added dropwise. After being stirred for 15 min at -78° C., the mixture was warmed to room temperature and stirred further for 30 min. Thirty mL of saturated sodium bisulfite was added, and the product was extracted into four 60 mL portions of ether. The organic phase was washed with saturated sodium chloride, dried, and concentrated. Chromatography on silica using 30% ether/hexanes yielded the expected product. The yield was 1.660 g (38%) of product, which was an oil. The product material was analyzed by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:25]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29](=[O:36])[NH:30]2)[CH2:10][NH:11][C@@H:12]([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O-]S(C(F)(F)F)(=O)=O.C(N(CC)C(C)C)(C)C.[NH2:54][CH2:55][CH2:56][CH2:57][N:58]([CH3:85])[C:59]([CH2:61][CH2:62][N:63]1[CH2:68][CH2:67][CH:66]([O:69][C:70](=[O:84])[NH:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[CH2:65][CH2:64]1)=[O:60]>CN(C=O)C>[Si:1]([O:8][C@H:9]([C:25]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29](=[O:36])[NH:30]2)[CH2:10][NH:11][C@@H:12]([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:54][CH2:55][CH2:56][CH2:57][N:58]([CH3:85])[C:59]([CH2:61][CH2:62][N:63]2[CH2:64][CH2:65][CH:66]([O:69][C:70](=[O:84])[NH:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=3[C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)[CH2:67][CH2:68]2)=[O:60])=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CN(CCCN)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: C[C@@H](Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cc1cccc(CC(=O)NCCCN(C)C(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A mixture of (3-{(S)-2-[(R)-2-(tert-butyldimethylsilanyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}phenyl)acetic acid (135 mg, 0.264 mmol); 2-chloropyridium triflate on Wang resin (polymer-supported Mukaiyama reagent) (1.19 mmol/g loading; 635 mg, 0.775 mmol) and N,N-diisopropylethylamine (132 μL, 0.755 mmol) in DMF (4.78 mL) was stirred at room temperature for 30 min. Biphenyl-2-ylcarbamic acid 1-{2-[(3-aminopropyl)methylcarbamoyl]ethyl}piperidin-4-yl ester (122 mg, 0.278 mmol) was added and this mixture was stirred at room temperature overnight. The mixture was filtered and the resin was washed with DCM (4 mL), MeOH (4 mL) and THF (4 mL). The filtrate was concentrated under reduced pressure and the residue was dissolved in DCM. This solution was washed with water (2×10 mL), saturated aqueous sodium bicarbonate (2×10 mL) and brine (1×10 mL); and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% MeOH in DCM) to give the title compound (59 mg, 24% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C(=O)C>[C:7]1([N:6]2[C:2]([NH:1][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:34])=[CH:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(NC(=O)c2ccccc2)n(-c2ccccc2)n1
Reaction time: 18 h
Yield: 76.2 %

Procedure:
To a solution of ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (498 mg) synthesized according to the method described in WO2004/98589 in N,N-dimethylacetamide (10 mL) were added N-ethyldiisopropylamine (417 mg) and benzoyl chloride (453 mg) at room temperature. After stirring at the same temperature for 18 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→3:1) to give the title compound as colorless crystals (yield 550 mg, yield 76%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCOCC1.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[C:4]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:3]=[C:2]2[NH2:1]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2nc(N3CCOCC3)nc(N)c2cc1OC
Temperature: 85 °C
Yield: 94.7 %

Procedure:
To solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (0.240 g, 1 mmol) in 10 ml dioxane was added morpholine (0.350 ml, 4 mmol). The mixture was heated at 85° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with water and solid was precipitated. The resulting precipitate was collected by filtration and washed with water and little amount of methanol and to give A 6,7-dimethoxy-2-morpholin-4-yl-quinazolin-4-ylamine (0.275 g) in 94% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 1 was prepared from bis(4-fluorophenyl) acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.39–7.31 (m, 3H), 7.29–7.21 (m, 5H), 7.02–6.96 (m, 4H), 4.80 (s, 1H), 3.40 (q, 2H, J=4.5 Hz), 2.94 (d, 2H, J=10.2 Hz), 2.51–2.38 (m, 4H), 1.97 (dt, 2H, J=1.8, 10.4 Hz), 1.81 (m, 2H), 1.68 (quintet, 2H, J=6.8 Hz,), 1.59 (m, 3H), 1.23 (d, 6H, J=6.9 Hz); ESMS m/e: 534.3 (M+H)+; Anal. Calc. For (HCl salt) C32H37F2N3O2.HCl.0.20 CHCl3: C, 65.11; H, 6.48; N, 7.07. Found: C, 65.30; H, 6.50; N, 6.96.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:14][CH2:13]1)=O)C.O>C1COCC1.O.[OH-].[Na+]>[CH3:25][O:24][C:21]1[N:20]=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([CH2:10][OH:9])[CH2:13][CH2:14]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1CCN(c2ccc(OC)nc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCC(CO)CC2)cn1
Temperature: 0 °C

Procedure:
A round bottom flask is charged with anhydrous THF (8 mL) and LAH (122 mg, 3.17 mmol) is added. The contents are placed under N2 and cooled to 0° C. To this is added a solution of 6′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-carboxylic acid ethyl ester (400 mg, 1.51 mmol) in THF (2 ml) over 5 min. The reaction is allowed to come to r.t. and continue to stir for an additional hour. 4 drops of H2O are added, followed by 4 drops of 15% NaOH(aq) and allowed to stir at r.t. for 20 min. 0.5 mL of H2O are added, and the contents are filtered through a pad of celite and washed with THF. The solution is reduced to an oil under vacuum, and purified by flash chromatography on silica gel using 3% methanol/methylene chloride as the eluent to provide (6′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanol. 1H NMR (300 MHz, CDCl3) δ 7.95 (d, 1H), 7.29 (dd, 1H), 6.66 (d, 1H), 3.88 (s, 3H), 3.53 (m, 4H), 2.65 (dt, 2H), 1.85 (m, 2H), 1.65 (m, 1H), 1.42 (m, 2H); MS (EI) 222 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[N+:5]([O-])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.C(Cl)(=[O:17])C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]([CH2:7][OH:17])=[N:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccc2)[n+]([O-])c1C
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nn(-c2ccccc2)nc1CO
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
7.1 g of 4,5-dimethyl-2-phenyl-1,2,3-triazol-1-oxide was dissolved in 25 ml of toluene, and heated to 80° C. 4.8 g of acetyl chloride diluted with 13 ml of toluene and 9.1 ml of triethylamine diluted with 13 ml of toluene were simultaneouly added dropwise thereto, keeping the temperature below 85° C. After stirring for 1 hour at 80° C., 2.5 ml of acetyl chloride diluted with 5 ml of toluene and 4.5 ml of triethylamine diluted with 5 ml of toluene were simultaneously added. After stirring for 1 hour at 80° C., the solution was left overnight at room temperature. 7 ml of 30% aqueous solution of sodium hydroxide was added, then toluene and triethylamine were distilled off under reduced pressure. 5 ml of ethanol and 30% aqueous solution of sodium hydroxide were added, and refluxed with heating for 1 hour. After ethanol was distilled off under reduced pressure, 50 ml of 10% saline solution was added, and left for some time at room temperature. The deposited crystals was dissolved in ethyl acetate, washed with water and a saturated salt solution, then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified through silica gel column chromatography (hexan/ethyl acetate=1/2), then washed with hexan/diisopropyl ether (=10/1) to obtain 5.7 g of the aimed compound.