Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[N:13][OH:14])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:14][N:13]=2)=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1ccc(Br)c2cnccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3cnccc23)=NO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 8-bromo-5-isoquinolinecarboxaldehyde oxime (i.e. the product from Step B) (70 mg, 0.28 mmol) in N,N-dimethylformamide (2.0 mL) was added N-chlorosuccinimide (64 g, 0.48 mmol). The reaction mixture was stirred for 0.5 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (135 mg, 0.56 mmol) (i.e. the product from Example 1, Step B) and triethylamine (0.12 mL, 0.86 mmol) in N,N-dimethylformamide (1.5 mL) was added. After stirring for an additional 12 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexanes/ethyl acetate as eluent to afford the title compound (20 mg) contaminated with some impurity.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21](=[O:37])[NH:22][C:23]1[CH:24]=[C:25]2[C:35](=[O:36])[NH:34][N:33]=[CH:32][C:27]3=[CH:28][NH:29][C:30]([CH:31]=1)=[C:26]23)=O)(C)(C)C.Cl.O1CCOCC1>>[O:36]=[C:35]1[C:25]2[C:26]3[C:27](=[CH:28][NH:29][C:30]=3[CH:31]=[C:23]([NH:22][C:21]([C@@H:9]3[CH2:10][C@@H:11]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:12][NH:8]3)=[O:37])[CH:24]=2)[CH:32]=[N:33][NH:34]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NN=Cc2c[nH]c3cc(NC(=O)[C@@H]4C[C@@H](OCc5ccccc5)CN4)cc1c23

Procedure:
Preparation of the title compound from Intermediate 142(a) (0.106 g, 0.21 mmol) and 4M HCl in dioxane (1 mL, 4.2 mmol) was carried out analogously to Example 91. Isolation, also in an analogous manner, included a further trituration with CH2Cl2/diethyl ether and afforded the title compound (0.085 g) as an orange/yellow powder in 92% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]([CH2:9][O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:8][CH2:7][CH2:6][C@H:5]([O:4][CH2:3][CH2:2][O:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:9][O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: OCCO[C@@H](CCO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCO[C@@H](CCOS(C)(=O)=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
(S)-3-(2-hydroxyethoxy)-4-(tripenylmethoxy)-1-butanol (500 g, 1.27 mole) was dissolved in 4.8 L of CH2Cl2, was cooled to 0° C. under N2, and triethylamine (386.4 g, 532 mL, 3.81 mole, 3.0 eq.) was added. Methanesulfonyl chloride (396.3 g, 268 mL, 3.46 mole, 2.7 eq.) was then added dropwise over 30 minutes at <5° C. The resultant reaction mixture was stirred at 0° to 5° C. for 1-2 hours and was monitored by HPLC. The reaction mixture was diluted with additional CH2Cl2 and was washed twice with 2 L of water and 2 L of an aqueous saturated solution of ammonium chloride. The aqueous layers were back-extracted with 1 L of CH2Cl2 and the combined organic layer was dried (MgSO4) and evaporated in vacuo to give a crude solid that was recrystallized from 1/1 heptane/ethyl acetate to give 615 g (88%) of (S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate in three crops as a solid. NMR. MS.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH:33]([CH3:36])[CH2:34][NH2:35].[BH4-].[Na+]>C(Cl)Cl.CO.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:35][CH2:34][CH:33]([CH3:36])[CH3:32])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CC(C)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCC(C)C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL), MeOH (1.5 mL), and acetic acid (4 drops) was added 2-methyl-1-propanamine (137 μL, 1.37 mmol) and stirred at room temperature. After 2 h, sodium borohydride (23 mg, 0.684 mmol) was added and the reaction mixture was purified by SCX cartridge to give 47.8 mg of the title compound (85%).
Reaction SMILES: Cl[CH:2]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)[C:3]1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC#N>[CH2:10]([N:9]([CH2:12][CH3:13])[C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([CH:2]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: C1CNCCN1
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc3cccnc23)cc1
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1

Procedure:
The crude product compound III (˜6.6 mmol) and piperazine (2.3 g, 26 mmol) was dissolved in dry MeCN (50 mL) and heated at reflux 12 h. The solvent was removed in vacuo, the residue dissolved in CH2Cl2 and washed with water and the organic phase dried (K2CO3) and evaporated in vacuo. After chromatography on silica (0-20% MeOH in CH2Cl2, 1% NH4OH), a total of 1.8 g (68%, 2 steps) compound 1 was obtained. Further purification could be achieved by reverse phase chromatograpy (LiChroprep RP-18, 10-50% MeCN in water, 0.1% TFA) to give 1.2 g colorless product. The dihydrochloride salt was made by treatment with 2 eq. HCl in ether.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[OH-].[Na+]>O>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Food-grade sucrose, 600 g, was dissolved in 600 ml of water. The pH was adjusted and maintained at 6.5 by the addition of 0.5 N sodium hyroxide solution as needed. To the sucrose solution was added 18,000 units of fructosyl transferase enzyme preparation, obtained by the method of Example 1 and 12,000 units of glucose isomerase enzyme prepared as described by Cory, U.S. Pat. No. 4,077,842. After the mixture had been stirred at 55° C. for 22 hours, it was heat treated to stop the enzyme reaction.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17]>[Pd].CO>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([C:16]([O:18][CH3:19])=[O:17])[N:4]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)oc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(N)cc2)oc1C
Yield: 66.2 %

Procedure:
The same operation as in Example (95b) was performed using methyl 5-methyl-2-(4-nitrophenyl)-1,3-oxazole-4-carboxylate obtained in Example (97c) (0.75 g, 2.86 mmol), 10% Pd/C (0.3 g) and methanol (10 mL). Purification by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 1/2, 1/4) gave 0.44 g of the title compound as a colorless solid (66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)=[N:9][N:10]=2)[CH:7]=1.Cl.Br[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:12]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: BrCCN1CCOCC1
Reactant: Oc1cccc(-c2nnc3ccc(Br)cn23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2nnc(-c3cccc(OCCN4CCOCC4)c3)n2c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of Example 10 step a (250 mg, 1.21 mmol), N-(2-bromoethyl)morpholine hydrochloride (306 mg, 1.32 mmol) and K2CO3 (500 mg, 3.62 mmol) in DMF (20 mL) was heated at 50° C. for 24 h. The reaction was then allowed to cool to RT and concentrated in vacuo. The residue was purified by FCC (DCM:MeOH, 1:0 to 9:1) to afford the title compound (479 mg, 98%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.44 (1 H, dd, J 1.7, 1), 7.74-7.69 (1 H, m), 7.50 (1 H, t, J 7.9), 7.39-7.35 (2 H, m), 7.35-7.30 (1 H, m), 7.14-7.08 (1 H, m), 4.21 (2 H, t, J 5.6), 3.74 (4 H, t, J 4.6), 2.85 (2 H, t, J 5.6), 2.63-2.56 (4 H, m).
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].O.[CH3:17]O>>[OH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]([O:15][CH3:17])=[O:14]
Reactant: CO
Reactant: O=C(O)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccccc1O
Yield: 98 %

Procedure:
H2SO4 (4.0 mL, 74.63 mmol) was added to a solution of salicylic acid (5.0 g, 36.20 mmol) in MeOH (60 mL). The reaction mixture was refluxed for 20 h, allowed to reach r.t., poured into H2O (100 mL) and extracted with CH2Cl2 (120 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 5.44 g of methyl 2-hydroxybenzoate (colourless oil, yield: 98%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[C:11](=[O:18])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH2:12].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([O:13][C:11](=[O:18])[NH:12][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(N)=O
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C#N)cn1
Temperature: 70 °C

Procedure:
A mixture of 2,4-dichloro-5-cyanopyridine (10g, 57.8 mmol), tert-butyl carbamate (8.2 g, 70.5 mmol), Pd(OAc)2 (0.26 g, 1.1 mmol), Xantphos (1.34 g, 2.3 mmol) and K2CO3 (12 g, 87 mmol) in THF (150 ml) was degassed 3× with nitrogen. The mixture was then heated at 70° C. for 4-5 h and monitored by chromatography until complete conversion. Following completion of the reaction, additional THF (100 ml) was added and heated the mixture at 70° C. for additional 1 h and then cooled to room temperature. The suspension was then filtered through a pad of celite to remove the solid. The filtrate was then concentrated and azeotropically distilled with ethyl acetate before filtering to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 10.82 (s, 1H), 8.79 (s, 1H), 8.09 (s, 1H), 1.49 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:16])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:5]C(=O)C>Cl>[NH2:5][C@H:4]([C:3]([OH:16])=[O:2])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: Cl
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 105 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
There was dissolved 1.40 g (6.0 mmol) of the phenylalanine methyl ester (31) in 50 ml of a 1N HCl solution and then the resulting solution was stirred at 105° C. for 12 hours. After cooling, the resulting mixture was concentrated and then ion-exchanged using Dowex-50w-X8 to thus give 1.10 mg (5.97 mmol, 99%) of the title compound: phenylalanine (1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][C:13]=3[CH:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:36][NH2:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:37][CH3:36])[CH2:14][C:13]=3[CH:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cc(-c3ccccc3)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3cccc(OC)c3)c2O1

Procedure:
The title compound was prepared (0.053 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 206-209° C.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[BH4-].[Na+]>CCO>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:9][CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccnc1Cl

Procedure:
To a solution of ethyl 2-chloronicotinate (1 g, 5.39 mmol) in 10 ml EtOH at room temperature is added 2.04 g (53.9 mmol) NaBH4 over 30 minutes in several portions. The solution is stirred for. The excess borohydride is quenched by the addition of methanol. The solvents are evaporated and the residue partitioned between dichloromethane and water. The aqueous Phase is extracted 3× with 10 ml of dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, filtered and evaporated in vacuo to yield a light yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([OH:23])[C@H:5]([C:10](=[O:22])[C@H:11]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH:12]([CH3:14])[CH3:13])[C:6]([O:8]C)=[O:7].COCCOC.Cl>O>[OH:23][C@H:4]([C@H:5]([C:10](=[O:22])[C@H:11]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH:12]([CH3:14])[CH3:13])[C:6]([OH:8])=[O:7])[C:3]([OH:24])=[O:2]
Reactant: COC(=O)[C@@H](C(=O)[C@H](c1ccc(Cl)cc1)C(C)C)[C@@H](O)C(=O)OC
Agent: Cl
Solvent: COCCOC
Solvent: O
Product: CC(C)[C@H](C(=O)[C@H](C(=O)O)[C@@H](O)C(=O)O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 2(R)-hydroxy-3(R)-[2(S)-(4-chlorophenyl)-3-methylbutanoyl]-butanedioic acid dimethyl ester (diastereoisomer K) (1 g, 2.6 mmol), 1,2-dimethoxyethane (18.3 ml) and of conc HCl (18.3 ml) was heated, under stirring, at 70° C. for 1 hour. The reaction mixture was cooled at room temperature, poured into water (50 ml) and extracted with dichloromethane (2×50 ml). The organic phase was extracted with a 10% aqueous solution of sodium bicarbonate (4×50 ml). The aqueous phase was acidified with conc HCl to pH 1 and extracted with dichloromethane (3×50 ml). The combined organic phase was washed with water, anhydrified over sodium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:30][C:31](=[O:33])[CH3:32])[C@@H:12]([O:26][C:27](=[O:29])[CH3:28])[C@@H:13](OS(C4C=CC(C)=CC=4)(=O)=O)[O:14][C@H:8]3[N:7]([CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[C:6]=2[CH:41]=1.[C:42]([O-:45])(=[S:44])[CH3:43].[K+]>CC(C)=O>[C:42]([S:44][C@H:13]1[O:14][C@@H:8]2[C@@H:9]([S:10][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:41][C:6]=3[N:7]2[CH2:34][CH2:35][N:36]([CH2:37][CH3:38])[CH2:39][CH3:40])[C@@H:11]([O:30][C:31](=[O:33])[CH3:32])[C@H:12]1[O:26][C:27](=[O:29])[CH3:28])(=[O:45])[CH3:43]
Reactant: CC([O-])=S
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)c3ccc(C)cc3)O[C@H]21
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](SC(C)=O)O[C@H]21
Yield: 97.4 %

Procedure:
To the solution of 2.0 g of the compound (36) obtained in Example 35 in 100 ml of acetone, 1.0 g of potassium thioacetate was added, and the mixture was heated with refluxing for 6.5 hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 1.65 g (yield 96.8% ) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[O:35][CH3:36].Cl.[CH3:38][O:39][CH:40]1[CH2:43][NH:42][CH2:41]1.CCN(C(C)C)C(C)C>C1COCC1>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:42]2[CH2:43][CH:40]([O:39][CH3:38])[CH2:41]2)=[O:32])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: COC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CC(OC)C2)ccc1N
Yield: 58.6 %

Procedure:
HATU (2.70 g, 7.10 mmol) was added to a solution of 4-amino-3-methoxybenzoic acid (880 mg, 5.26 mmol), 3-methoxyazetidine hydrochloride (0.971 g, 7.86 mmol) and DIPEA (2.85 mL, 16.32 mmol) in THF (15 mL) at room temperature. THF was removed under reduced pressure, and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 100% EtOAc in cyclohexane followed by a second chromatography eluting with 0 to 4% MeOH in DCM to afford the title compound (728 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
First, 0.15 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61) was dissolved in 0.50 ml of N,N-dimethylformamide, to which 97 mg of potassium carbonate and 48 μl of methyl bromoacetate were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 97 mg (yield, 53%) of 3-{4-chloro-2-fluoro-5-[(methoxycarbonyl)methoxy]phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-165; m.p., 116.6° C.).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][Si](C(C)C)(C(C)C)C(C)C)=[CH:20][N:19]=1)[OH:17].O>C1(C)C=CC=CC=1.[Cu]Cl>[CH:12]1([CH2:11][O:10][C:8]2[CH:7]=[CH:6][C:5]3[CH2:15][CH:16]([C:18]4[N:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=4)[O:17][C:4]=3[CH:9]=2)[CH2:14][CH2:13]1
Reactant: CC(C)[Si](Oc1ccc(C(O)Cc2ccc(OCC3CC3)cc2Br)nc1)(C(C)C)C(C)C
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(C2Cc3ccc(OCC4CC4)cc3O2)nc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 55.1 %

Procedure:
Sodium hydride (27.7 mg) was added to a suspension of 2-[2-bromo-4-(cyclopropylmethoxy)phenyl]-1-(5-{[tris(1-methylethyl)silyl]oxy}pyridin-2-yl)ethanol (600 mg) and copper(I) chloride (5.71 mg) in toluene (10 mL) at room temperature. The reaction mixture was stirred at 120° C. for 3 hr, and allowed to cool to room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (10 mL), and a THF solution (1.0 M, 5.76 mL) of tetrabutylammonium fluoride was added thereto. The reaction mixture was stirred at room temperature for 30 min, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (180 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2([CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[C:5]1=[O:20])([CH3:3])[CH3:2].[C:21]([O:25][C:26]([NH:28][C:29]([CH3:48])([CH3:47])[C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1)[C:34](O)=[O:35])=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.O>[NH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[C:29]([NH:28][C:26](=[O:27])[O:25][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:48])[CH3:47])[C:34]([N:16]2[CH2:17][CH2:18][CH2:19][C:6]3([C:5](=[O:20])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH:7]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:15]2)=[O:35])=[CH:39]1
Reactant: CC(C)N1CC(c2ccccc2)C2(CCCNC2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture comprising 2-isopropyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (ASW MedChem) (278 mg, 0.899 mmol), (R)-2-(2-(tert-butoxycarbonylamino)-2-methylpropanamido)-3-(1H-indol-3-yl)propanoic acid (Intermediate 3C) (350 mg, 0.899 mmol) and DIPEA (0.628 ml, 3.59 mmol) in DMF (4 ml) was treated with ®T3P (50% in DMF, 0.525 ml, 1.797 mmol) and stirred at RT for 2 h 20 min. The reaction mixture was diluted with water (5 ml) and extracted with EtOAc. The organic portion was dried (MgSO4) and concentrated in vacuo Purification of the crude product by chromatography on silica eluting with 1% MeOH in DCM afforded the title compound;