Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]3[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=3)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[OH:56][C:57]1[C:66]2[C:61](=[C:62]([OH:67])[CH:63]=[CH:64][CH:65]=2)[N:60]=[C:59](C(O)=O)[CH:58]=1>>[OH:56][C:57]1[C:66]2[C:61](=[C:62]([OH:67])[CH:63]=[CH:64][CH:65]=2)[N:60]=[C:59]([C:16]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]2[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=2)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:17])[CH:58]=1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(O)c2cccc(O)c2n1
Product: O=C(C[C@H](NC(=O)c1cc(O)c2cccc(O)c2n1)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nγ-trityl-L-asparagyl]dopamine (1.34 g, 1.8 mmol, example 7, step A) as described for example 7 (step B) using 4,8-dihydroxyquinoline-2-carboxylic acid (564 mg, 2.75 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using a solvent gradient from 30% to 60% EtOAc/CH2Cl2 containing 1% AcOH. The title compound was obtained as yellow crystals (663 mg, 52%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([CH2:17][OH:18])[O:15][C@H:12]([O:13][CH3:14])[C@H:11]([O:19][CH2:20][O:21][CH3:22])[C@H:10]1[O:23][CH2:24][O:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=[O:41])C1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:8][CH2:9][C@H:16]1[O:15][C@H:12]([O:13][CH3:14])[C@H:11]([O:19][CH2:20][O:21][CH3:22])[C@@H:10]([O:23][CH2:24][O:25][CH3:26])[C@@H:17]1[OH:18])(=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCO[C@@H]1[C@@H](OCOC)[C@@H](OC)O[C@H](CO)[C@H]1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCO[C@H]1[C@@H](OC)O[C@H](COC(=O)c2ccccc2)[C@@H](O)[C@@H]1OCOC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a stirred solution of methyl 4-O-benzyl-2,3-di-O-methoxymethyl-α-D-glucopyranoside (D. B. Berkowitz et al., J. Org. Chem. 1993, vol. 58, page 6174) (1.1 g, 2.96 mmol) in methylene chloride (10 mL) was added triethyl-amine (3.4 mL, 24.5 mmol), and benzoyl chloride (1.4 mL, 12.0 mmol). The reaction was stirred at room temperature for approximately 30 min and then diluted with EtOAc (100 mL) and washed with 0.5 N aqueous HCl (100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL). The aqueous layers were reextracted with EtOAc (100 mL) and the organics were combined, dried over Na2SO4, and then concentrated in vacuo. The crude product was taken up in ethanol (7 mL) and Pd/C-Degussa type (100 mg) was added. The reaction was stirred under an atmosphere of hydrogen for 12 h and then filtered through celite and concentrated in vacuo. The product was purified by flash chromatography (gradient 33% to 50% EtOAc/petroleum ether) to afford 2 (0.70 g, 61%) as a colorless oil: Rf=0.25 (40% EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 8.06 (d, J=7.2 Hz, 2H), 7.56 (t, J=7.2 Hz, 1H), 7.44 (t, J=7.2 Hz, 2H), 4.84 (d, J=3.6 Hz, 1H), 4.7-4.8 (m, 4H), 4.65 (dd, J=2.3, 11.9 Hz, 1H), 4.57 (dd, J=5.3, 11.9 Hz, 1H), 4.23 (br s, 1H), 3.91 (ddd, J=2.3, 5.3, 9.5 Hz, 1H), 3.71 (dd, J=9.5, 9.5 Hz, 1H), 3.61 (dd, J=3.6, 9.5 Hz, 1H), 3.50 (dd, J=9.5, 9.5 Hz, 1H), 3.46 (s, 3H), 3.45 (s, 3H), 3.39 (s, 3H); 13C NMR (CD3COCD3, 67.5 MHz) δ 167.0, 134.2, 131.5, 130.5, 129.7, 100.1, 98.8, 98.1, 81.0, 79.2, 71.4, 70.7, 65.2, 56.1, 55.7, 55.5; HRFABMS calcd for C18H27O9 (M+H+) 387.1655, found 387.1656.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]([NH:9][C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:35](Cl)=[O:36]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:14][CH2:13]2)=[CH:19][CH:20]=1)=[O:4]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COC(=O)c1ccc(NC(=O)CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CN2CCN(C(=O)c3ccc(OC)c(OC)c3)CC2)cc1
Reaction time: 2 h

Procedure:
3.3 Grams of p-methoxycarbonyl-α-(1-piperazinyl)acetanilide and 1.7 g of potassium carbonate were dissolved in 50 ml of DMF, then a methylene chloride solution containing 2.7 g of 3,4-dimethoxybenzoyl chloride was added dropwise thereto under ice-cooled condition with stirring. The reaction was continued at the same temperature for 2 hours, then to the reaction mixture was added 100 ml of methylene chloride, and the methylene chloride layer was washed with water, 5%-sodium bicarbonate aqueous solution, next with potassium carbonate aqueous solution, and was dried. Methylene chloride was removed by distillation, the residue obtained was purified by a silica gel column chromatography to obtain 3.3 g of p-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of oily substance.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)O)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(N(S(F)(F)[F:48])CC)C>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[F:48])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCCOc1ccc(CN2CCC(C(F)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.1 %

Procedure:
A stirred solution of 0.6 gram (0.001 mole) of N-(4-propoxyphenylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (prepared in Example 10) in 15 mL of methylene chloride was cooled to -78° C., and 0.15 mL (0.001 mole) of diethylaminosulphur trifluoride (DAST) was added via a syringe. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time, the reaction mixture was poured into ice-water. The mixture was then extracted with two 50 mL portions of methylene chloride. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with mixtures of 5-15% acetone in methylene chloride as the eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.1 gram of N-(4-propoxyphenylmethyl)-4-[bis(4-trifluoromethoxyphenyl)fluoromethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[OH:14]O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][S:2]([CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])=[O:14]
Reactant: OO
Reactant: CSCCOc1cccc(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CS(=O)CCOc1cccc(C=O)c1

Procedure:
A solution of 1.6 g (8.15 mmol) 3-(2-methylsulphanyl-ethoxy)-benzaldehyde and 1 ml (9.78 mmol) hydrogen peroxide solution in 30 ml acetic acid is stirred for 2 h at room temperature. Then the reaction mixture is poured onto 4N NaOH and extracted with ethyl acetate. The combined organic layers are washed with sodium bisulphite solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a colorless solid, sufficiently pure for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: Fc1ccc(Br)cn1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(F)nc2)cc1

Procedure:
According to the same method as in Example 1-2) but using 2-fluoro-5-bromopyridine and 4-cyanophenylboronic acid, the entitled compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:17]=3[O:28][CH2:29][CH2:30][CH3:31])[C:9]=2[CH:8]=1)C.C1COCC1.[Li+].[OH-]>CO>[CH2:29]([O:28][C:17]1[C:18]([CH:25]([CH3:27])[CH3:26])=[CH:19][C:20]([CH:22]([CH3:23])[CH3:24])=[CH:21][C:16]=1[C:15]1[C:9]2[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:32])=[O:3])[S:11][C:10]=2[CH:12]=[CH:13][CH:14]=1)[CH2:30][CH3:31]
Reactant: CCCOc1c(-c2cccc3sc(C=CC(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1c(-c2cccc3sc(C=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. (E) 3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:16]=1>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18]([C:19](=[O:21])[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[C:12](=[O:13])[N:24]2[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(Cl)cc1NCc1ccccn1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: O=c1c2ccc(Cl)cc2n(Cc2ccccn2)c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 36 %

Procedure:
950 mg (4.35 mmol) of 4-chlorobenzenesulfonylisocyanate and 950 mg (3.61 mmol) of 4-chloro-2-(2-pyridylmethyl)aminobenzoic acid were treated in the same way as in Example 1 to obtain 600 mg of the above-identified compound (yield 36.0%). Properties: colorless crystal, Melting point: >180° C. (decomposition), PMR (δppm, DMSO-d6):5.29 (2H,s), 7.3-7.5 (4H,rn), 7.7-7.8 (3H,m), 7.97 (1H,d), 8.17 (2H,d), 8.48 (1H,d)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:24][C:23]3([CH2:26][CH2:25]3)[C:15]3[C:16]4[C:17](=[N:22][C:14]=3[CH:13]2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[NH:18][CH:19]=[CH:20][CH:21]=4)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:34]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[C:4]([NH:9][C:10]([N:12]2[CH2:24][C:23]3([CH2:26][CH2:25]3)[C:15]3[C:16]4[C:17](=[N:22][C:14]=3[CH:13]2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[N:18]([CH3:34])[CH:19]=[CH:20][CH:21]=4)=[O:11])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(NC(=O)N2CC3(CC3)c3c4ccc[nH]c-4nc3C2c2cccc(F)c2)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(NC(=O)N2CC3(CC3)c3c4cccn(C)c-4nc3C2c2cccc(F)c2)c1

Procedure:
The compound (188 mg) prepared in Example 15 was suspended in toluene (8 mL) and methyl p-toluenesulfonate (0.32 mL) was added, followed by refluxing for 2 hours. After the reaction solution was air-cooled, an aqueous saturated sodium carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→methylene chloride:methanol=85:15) to obtain the titled compound having the following physical properties (122 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].O.[OH-].[Na+]>C(OCC)C>[C:13]1([CH:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCC(O)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirring suspension of 1.20 g of lithium aluminum hydride in 100 mL of diethyl ether under an argon atmosphere at 0° C. is slowly added a solution of 4.40 mL of commercially available valerophenone in 5.0 mL of diethyl ether over 10 minutes. After 0.5 hours the grey suspension is warmed to room temperature. After 1 hour the reaction mixture is re-cooled to 0° C. and slowly treated with 1.25 mL of water followed by 5.50 mL of 1N sodium hydroxide. After 1 hour the resulting white precipitant is filtered through a pad of magnesium sulfate with diethyl ether washings. The filtrate is concentrated under reduced pressure to afford 4.5 g of 1-phenyl-1-pentanol as a clear, colorless oil. This product may be used directly in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9]O)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:17]2[CH:16]=[CH:15][C:14]([NH2:19])=[C:13]([O:12][CH3:11])[CH:18]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: COc1ccccc1N
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(Cc2cnc(N)nc2N)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A solution of 6.30 g (0.045 mol) of 2,4-diamino-5-hydroxymethylpyrimidine, 6.15 g (0.05 mol) of o-anisidine and 3.75 ml of concentrated hydrochloric acid in 55 ml of glacial acetic acid was heated to reflux for 6 hours. The mixture was stirred at room temperature overnight. The solvent was removed under vaccum and the residue was taken up in water, made basic with ammonium hydroxide, and the aqueous solution was extracted with dichloromethane:methanol/3:1. The organic layers were combined, dried and concentrated to a purple glass. This was purified on a silica gel column to give 7.81 g of the 4-N-acetylated product.
Reaction SMILES: [C:1]([NH:5][CH2:6][C@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])=[CH:11][CH:10]=1)[OH:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:17][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([C@H:7]([OH:8])[CH2:6][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:11]=1)[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@H](O)CNC(C)(C)C)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1ccc([C@H](O)CNC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
15.8 g of the compound [5-5] was dissolved in 50 mL of chloroform, 45 mL of trifluoroacetic acid was added thereto under an ice-cold condition, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0 to 90/10) to obtain 10.7 g of (1S)-1-{4-[(1S)-1-aminoethyl]phenyl}-2-(tert-butylamino)ethanol [67-3] (hereinafter, referred to as the compound [67-3]) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][CH:8]=[C:9]([C:15](=[O:27])[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([O:24][CH3:25])[C:17]=1F)[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:6])([CH3:5])[CH3:4]>CN(C=O)C>[C:3]([N:7]1[C:17]2[C:16](=[CH:21][C:20]([F:22])=[C:19]([F:23])[C:18]=2[O:24][CH3:25])[C:15](=[O:27])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)C(=CNC(C)(C)C)C(=O)c1cc(F)c(F)c(OC)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(C)(C)C)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of NaH (5.61 g, 140 mmol, 60% in oil) in DMF (300 mL) was cooled to 0° C. and treated dropwise with ethyl 3-(tert-butylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylate (42.02 g, 117 mmol) in DMF (100 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with water and then dried to yield ethyl 1-tert-butyl-6,7-difluoro-1,4-dihydro-8-methoxy4-oxoquinoline-3-carboxylate (38.9 g, 98%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH3:11])=[C:7]([OH:9])[CH:8]=1.C(=O)([O-])O.[Na+].[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([CH3:21])[CH3:20])#[N:18]>O1CCCC1>[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH3:11])=[C:7]([OH:9])[CH:8]=1)=[O:26])([CH3:21])[CH3:20])#[N:18]
Reactant: CCc1ccc(N)cc1O
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a two-layer solution of 5-amino-2-ethylphenol hydrochloride (2.2 g, 12.6 mmol) in tetrahydrofuran (20 mL)/1N aqueous sodium hydrogen carbonate solution (38 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 12 hr. The aqueous layer was separated, and extracted with ethyl acetate (80 mL). The combined organic layer was washed with water (40 mL) and saturated brine (40 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (45 mL)/hexane (25 mL) was added to the obtained residue, and the obtained solid was collected by filtration to give the title compound (3.48 g, 90%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:15][C:4]3[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(O)c(-c2ccccn2)nc1C
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
5,6-Dimethyl-3-hydroxy-[2,2′]bipyridine (241 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.08 g), 4-dimethylaminopyridine (441 mg), and cesium carbonate (1.18 g) were suspended in dimethyl sulfoxide (6 ml), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (408 mg, yield 73%).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Br:1][C:2]1[N:10]([CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH3:17])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cc1ccccc1CBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Product: Cc1ccccc1Cn1c(Br)nc2c1c(=O)[nH]c(=O)n2C

Procedure:
8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and 2-methylbenzyl bromide were reacted and purified as described in the General procedure G, step A, to afford 82A as white crystals in 79%.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[CH2:20][N:14]4[CH2:15][CH2:16][NH:17][C:18](=[O:19])[CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][CH2:16][N:17]([CH2:24][C:25]5[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=5)[C:18](=[O:19])[C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1NCCN2CC(Oc3cnc(C4CC4)cn3)CC12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN2CCN1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 18.6 %

Procedure:
To a solution of 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]-pyrazin-1(2H)-one [3:1 (7R,8aS: 7R,8aR) diastereomer ratio](112 mg, 0.408 mmol) from Example 163 Step 3 in N,N-dimethylformamide (1 mL) under nitrogen was added sodium hydride (60% weight suspension in mineral oil) (19.60 mg, 0.490 mmol), and the resulting suspension was stirred at room temperature. After 20 minutes, the suspension was treated with 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.076 mL, 0.490 mmol). The resulting solution was stirred at room temperature for 3 hours, and it was then partitioned between water and ethyl acetate (3×). The combined organic extracts were dried over sodium sulfate and then filtered. The filtrate was concentrated under a stream of nitrogen, and the crude material was purified with a 12 g silica gel cartridge eluted with a gradient 0-5% methanol/dichloromethane over 17 minutes to give an oil. The oil (54 mg) was loaded onto 2×0.25 mm silica gel prep plates and eluted with 5% methanol/ethyl acetate to give the title compound (33 mg, 0.076 mmol, 18.69% yield) as the first eluting diastereomer as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (d, J=1.4 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 5.49-5.39 (m, 1H), 4.71 (d, J=14.9 Hz, 1H), 4.60 (d, J=14.9 Hz, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.46 (ddd, J=12.1, 7.9, 6.6 Hz, 1H), 3.38 (dd, J=10.9, 5.7 Hz, 1H), 3.20 (dt, J=12.1, 4.0 Hz, 1H), 3.07-2.99 (m, 2H), 2.88 (dd, J=10.8, 3.0 Hz, 1H), 2.53 (ddd, J=15.1, 8.0, 7.3 Hz, 1H), 2.44 (ddd, J=14.6, 7.9, 1.7 Hz, 1H), 1.99 (tt, J=7.8, 5.3 Hz, 1H), 1.01-0.90 (m, 4H); MS (ESI+) m/z 433 (M+H)+.