Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.[O:41]1[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:46][CH:43]4[CH2:44][CH2:45][O:41][CH2:42]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: OCC1CCOC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCOC1
Reaction time: 18 h
Yield: 30.7 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), tetrahydro-3-furanmethanol (90 mg, 0.88 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (12 ml) and the mixture stirred for 18 hours. The mixture was diluted with ether, and the resulting precipitate was removed by filtration. The solvent was removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (0.75 ml of a 1M solution, 0.75 mmol) was added. The mixture was diluted with ether and the resulting precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (a gradient from 50150/1 to 50/5012). The purified product was triturated with ether, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(tetrahydrofuran-3-ylmethoxy)quinazoline (93 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([OH:14])=O.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[O:8][CH2:7][CH2:6]2)=[O:14])=[CH:21][CH:22]=1
Reactant: O=C(O)C1CCOc2ccc(F)cc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3ccc(F)cc32)cc1
Yield: 64.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 6-fluorochroman-4-carboxylic acid (1.96 g) and [(4-dimethylaminophenyl)methyl] (4-isopropylphenyl) amine (2.68 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-6-fluoro-N-(4-isopropylphenyl)chroman-4-carboxamide (2.89 g) was obtained. melting point: 95-98° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c12
Reactant: c1cn[nH]c1
Product: Cc1csc2nc(-n3cccn3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11](O)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:30][C:31]1[CH:36]=[C:35]([NH2:37])[CH:34]=[CH:33][N:32]=1>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]([NH:37][C:35]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:30])[CH:36]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cc1cc(N)ccn1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)Nc4ccnc(C)c4)cnc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.2 %

Procedure:
6-Chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid (150 mg, 0.37 mmol) in SOCl2 (2 mL) was heated at 60° C. for 1 hour. The reaction mixture was concentrated, dried under reduced pressure and dissolved in DCM (3 mL). 2-Methylpyridin-4-amine (45 mg, 0.41 mmol), and TEA (0.16 mL, 1.11 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours, concentrated and then purified by silica gel chromatography (5% MeOH in DCM) to obtain 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-N-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (102 mg, 55% yield) as a yellow solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=3.263 minutes. [M+H]=499.06.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]1[C:16]([CH2:17][C:18]([O:20]CC)=[O:19])=[C:15]([CH3:23])[N:14]=[C:9]12.CO>O>[C:18]([CH2:17][C:16]1[N:8]2[CH:7]=[CH:6][C:5]3[C:10]([C:9]2=[N:14][C:15]=1[CH3:23])=[CH:11][CH:12]=[CH:13][C:4]=3[Cl:3])([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1c(C)nc2c3cccc(Cl)c3ccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CC(=O)O
Yield: 74.2 %

Procedure:
A solution of sodium hydroxide (1.25 g) in water (5 ml) was added to a mixture of 7-chloro-3-ethoxycarbonylmethyl-2-methylimidazo[2,1-a]isoquinoline (4.75 g) and methanol (48 ml) and the mixture was refluxed for 1.5 hours. After being cooled, the mixture was evaporated in vacuo and 1N hydrochloric acid (31.4 ml) was added to the residue under ice-cooling. The resulting precipitate was collected by filtration, washed with water, dried in a desiccator and washed with a mixture of ethanol and methanol to give 3-carboxymethyl-7-chloro-2-methylimidazo[2,1-a]isoquinoline (3.2 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:29]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
Acryloyl chloride (0.100 mL, 1M in THF, 0.1 mmol) was added dropwise to a fine slurry of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile (Intermediate 99, 47 mg, 0.10 mmol) and DIPEA (0.027 mL, 0.16 mmol) in THF (2 mL) at −10° C. over a period of 2 minutes under N2. The mixture was then stirred at 0° C. for 10 minutes then allowed to warm to r.t. over 20 minutes. The mixture was then cooled again to −10° C. and further acryloyl chloride (0.06 mL, 1M in THF, 0.06 mmol) was added dropwise. The mixture was stirred at 0° C. for a further 10 minutes, then allowed to warm to r.t. over 20 minutes. The mixture was then concentrated in vacuo and the resulting reside was dissolved in CH2Cl2 (2 mL). This solution was washed with sat. NaHCO3 (1 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 7N methanolic ammonia in CH2Cl2 gave a residue that was washed with CH3OH (0.1 mL) and dried in air to give the title compound (11 mg, 20%) as a cream crystalline solid; 1H NMR: 2.28 (3H, s), 2.54-2.65 (4H, m), 2.93 (4H, s), 3.75 (3H, s), 5.71 (1H, d), 6.18 (1H, d), 6.64 (1H, dd), 6.91 (2H, m), 7.18 (1H, s), 7.47 (1H, d), 8.02 (1H, s), 8.52 (1H, s), 8.67 (1H, s), 9.04 (1H, s), 9.40 (1H, s), 11.99 (1H, s); m/z: ES+ MH+ 509.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH2:45][C:46](Cl)=[O:47]>>[N:34]1([CH2:33][CH2:32][CH2:31][O:30][C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:46](=[O:47])[CH2:45][C:41]6[S:40][CH:44]=[CH:43][CH:42]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Yield: 37 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[3-(4-morpholinyl)propyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 37% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (d, J=1.1 Hz, 2H) 2.3 (s, 6H) 3.5 (d, J=4.6 Hz, 4H) 3.9 (s, 2H) 3.9 (m, 2H) 6.5 (m, 2H) 7.0 (m, 2H) 7.1 (m, 2H) 7.3 (dt, J=7.6, 1.4 Hz, 2H) 7.4 (m, 3H) 7.5 (t, J=2.1 Hz, 1H) 7.7 (d, J=1.8 Hz, 1H) 7.9 (t, J=1.8 Hz, 1H) 8.2 (d, J=5.3 Hz, 1H) 8.5 (d, J=8.6 Hz, 1H) 8.8 (m, 1H) 9.5 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 646 [M+H]+.
Reaction SMILES: [C:1]([C:5]([CH2:7]Br)=[O:6])([F:4])([F:3])[F:2].[C:9]([C:13](OCC)=[O:14])([F:12])([F:11])[F:10].O1CCCC1>[Zn].CN(C)C=O>[C:1]([C:5]([CH2:7][C:13]([C:9]([F:12])([F:11])[F:10])=[O:14])=[O:6])([F:4])([F:3])[F:2]
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCOC(=O)C(F)(F)F
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CC(=O)C(F)(F)F)C(F)(F)F

Procedure:
CF3COCH2Br (1.91 gr, 10 mmol), CF3CO2C2H5 (1.42 gr, 10 mmol), and zinc powder (1.3 gr) were put into a flask (100 ml) together with a mixed solvent comprising tetrahydrofuran (20 ml) and dimethylformamide (10 ml), and they were subjected to the reaction for a period of one hour while being irradiated with ultrasonic waves by means of an ultrasonic cleaner (35W, 32 kHz). After the reaction, impurities contained in the mixed liquid were filtered, then water (500 ml) was added to the filtered liquid, whereby an oil layer generated was extracted by means of diethylether. After drying the extracted liquid with magnesium sulfate, the solvent was removed. The product (CF3COCH2COCF3) (bp: 70° to 72° C.) was obtained through distillation with a yield by 69%.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH2:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:24][C:25]1[N:30]=[C:29](Cl)[N:28]=[C:27]([NH:32][C@@H:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([CH3:43])([CH3:42])[CH2:34]2)[N:26]=1>C1COCC1>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([NH:23][C:29]2[N:28]=[C:27]([NH:32][C@@H:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]([CH3:42])([CH3:43])[CH2:34]3)[N:26]=[C:25]([Cl:24])[N:30]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)C[C@H](Nc2nc(Cl)nc(Cl)n2)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)C[C@H](Nc2nc(Cl)nc(N[C@@H]3C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C3)n2)c2ccccc21
Reaction time: 3.5 h
Yield: 64.8 %

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine (0.200 g, 0.556 mmol), TEA (0.21 mL, 1.50 mmol) in THF (0.80 mL) was added 4,6-dichloro-N-[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine (0.160 g, 0.500 mol). The reaction was stirred for 3.5 h then concentrated in vacuo. The residue was purified by preparative TLC (10% EtOAc/hexanes) followed by DCM. The relevant band was cut and washed using acetone, filtered, and concentrated in vacuo to afford the title compound (0.228 g, 71%). LC/MS: Rt=2.77 min, ES+ 633 (FA standard).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3S(C3C=CC=C(F)C=3)(=O)=O)=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:34](OC(=O)C1C=CC(N)=CC=1F)[CH3:35]>>[CH2:34]([O:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(F)c1)CCC2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3cccnc3c2)cc1F

Procedure:
2-Fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 473.24 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 2 was performed using 4-amino-2-fluorobenzoic acid ethyl ester and yielded 2-fluoro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester, which was reduced to 2-fluoro-4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester in step 3. Step 4 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 2-fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:10][Si:11]([CH3:26])([CH3:25])[C:12]#[C:13][CH2:14][CH2:15]N1C2C=CC=CC=2N=N1>>[CH3:10][Si:11]([CH3:26])([CH3:25])[C:12]#[C:13][CH2:14][CH2:15][N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: C[Si](C)(C)C#CCCn1nnc2ccccc21
Product: C[Si](C)(C)C#CCCn1nc2ccccc2n1
Yield: 67 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(A), from benzotriazole (116 mg, 0.97 mmol) to yield 157 mg (0.64 mmol, 67%) of 2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole and 1-(4-trimethylsilanyl-but-3-ynyl)-1H-benzo[d][1,2,3]triazole.
Reaction SMILES: C(OC([N:11]1[CH:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23]([NH2:29])=[N:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[C:13](=[O:30])[C@@H:12]1[CH3:31])=O)C1C=CC=CC=1.[H][H]>[Pd].CO.C(O)(=O)C>[NH2:29][C:23]1[C:22]2[C:27](=[CH:28][C:19]([CH2:18][N:14]3[CH2:15][CH:16]([CH3:17])[NH:11][C@@H:12]([CH3:31])[C:13]3=[O:30])=[CH:20][CH:21]=2)[N:26]=[CH:25][N:24]=1
Reactant: [H][H]
Reactant: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1
Yield: 153.9 %

Procedure:
Palladium on carbon (10%, 700 mg) is added to a solution of (2S,6RS)-4-(4-amino-quinazolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.62 g, 3.87 mmol) in 20 mL of methanol and 2 mL of acetic acid. The reaction mixture is left to stir in an atmosphere of hydrogen for eight hours. The palladium is filtered off, and the volitale solvents are removed on the rotovap. The crude product (1.7 g, 95%) is isolated as a white solid. The two epimers are separated on silica gel (1% triethylamine/15% methanol/methylene chloride). The minor epimer is assigned as (3S,5R)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one and the major epimer is assigned as (3S,5S)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH:3]([CH2:11][CH:12]([S:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH3:30])[CH:3]([CH2:11][CH:12]([S:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)C(CC(Cc1ccccc1)SNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(CC(Cc1ccccc1)SNC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 21.1 mm t-butyl 3-methyl-2-(3-phenyl-2-benzamidothiopropyl)butyrate in 5 ml of methylene chloride is added 15 ml of trifluoroacetic acid. The solution is stirred at room temperature for approximately 21/2 hours. The solvent is then evaporated, yielding 3-methyl-2-(3-phenyl-2-benzamidothiopropyl)butyric acid.
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17].[OH-].[K+]>CN(C=O)C>[CH3:1][N:8]1[C:4]([CH3:3])=[C:5]([CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17])[N:6]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1[nH]c(-c2ccccc2)nc1CC(C)(C)[N+](=O)[O-]
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1c(CC(C)(C)[N+](=O)[O-])nc(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
Methyliodide (1.4 g) was added dropwise to a stirred mixture of 5-methyl-4-(2-methyl-2-nitro-propyl)-2-phenyl-1H-imidazole (2.0 g) and fine powdered potassium hydroxide (2.0 g) in DMF (30 ml) at 10-20° C. The reaction mixture was stirred at RT for 2 h, quenched with ice/water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate and concentrated. The residue was purified on silica gel using methylene chloride/methanol 2 and 5% as eluent, to obtain the desired product (0.98 g) as a light yellow amorphous compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(=O)Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(Cc1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Bromophenyl)propan-2-one (2.03 g) was dissolved in CHCl3 (40 mL), and morpholine (1.24 mL) was added thereto, followed by stirring at room temperature overnight and then at 60° C. for 4 hours. NaBH(OAc)3 (4.03 g) and acetic acid (1.1 mL) were sequentially added thereto, followed by stirring overnight. The reaction was terminated by addition of water, and the reaction solution was separated between CHCl3 and a saturated aqueous NaHCO3 solution. The residue was purified by silica gel column chromatography (mobile phase: CHCl3/EtOAc=80/20 to 60/40 (v/v)) to yield the title compound (1.67 g, colorless oil).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccc(F)cc1
Yield: 96 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 2-(4-fluorophenoxy)-3-(4-hydroxyphenyl)propionate (2.75 g), which is the product of Reference example 37(b), 2-(2-bromoethyoxy)tetrahydropyran (2.08 g)and potassium carbonate (3.75 g) and the reaction mixture was treated to afford the desired compound (3.75 g) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[O:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[OH-].[Na+].Cl>CO.O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:23])=[O:2])=[C:7]([O:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CCc1ccc(C(C)(C)C)cc1OC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(CCC(=O)O)c(OC2CCOCC2)c1
Reaction time: 12 h
Yield: 100.1 %

Procedure:
3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]propionic acid methyl ester (14.1 mg, 0.044 mmol, 1 eq) and sodium hydroxide (8.8 mg, 0.220 mmole, 5 eq) were added in methanol and H2O. The reaction mixture was stirred for 12 hrs. The reaction mixture was acidified with 5% HCl solution. The reaction mixture was concentrated in vacuo to yield 3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]propionic acid (13.5 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH:17]1([C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:27]2[CH2:28][CH2:29][N:24]([C:22]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:23])[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)C2CCCC2)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(C1CCCC1)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-cyclopentanecarbonylpiperidin-4-one (83.5 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}cyclopentylmethanone (144 mg, 81%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.42 min, m/z 415.36 (36), 413.40 (M++H, 100). HPLC tr=6.82 min (98.32%) 1H NMR (270 MHz, CDCl3) δ 1.23 (2H, m, CH2), 1.52 (2H, m, CH2), 1.60-1.90 (9H, m, 4CH2+NH), 2.66 (2H, m, CH2), 2.85 (1H, quin, J=7.9 Hz, CHCO), 3.00 (1H, m, CHNH), 3.79 (2H, m, CH2), 3.85 (1H, m, ½CH2), 4.40 (1H, m, ½CH2), 6.83 (2H, AA′BB′, ArH), 6.87 (1H, m, ArH), 7.12 (1H, td, ArH), 7.23 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.38 (1H, dd, J=7.4, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 26.12, 30.09, 32.29, 32.24, 40.55 (CH2), 41.19 (CH), 44.04, 45.65 (CH2), 54.00 (CH), 118.93, 119.62, 124.54, 127.95, 128.70, 129.84, 130.58, 131.83, 154.34, 156.38 (ArC), and 174.37 (C═O).