Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[C@H:6]([OH:28])[C@@H:7]([NH:15][C:16]([C:18]1[NH:27][C:21]2=[CH:22][N:23]=[C:24]([Cl:26])[CH:25]=[C:20]2[CH:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[Cl:26][C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([C:16]([NH:15][C@@H:7]([CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:6]([OH:28])[C:5]([OH:29])=[O:4])=[O:17])[NH:27][C:21]2=[CH:22][N:23]=1
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium hydroxide solution (0.24 mL, 2M, 0.48 mmol) was added to a solution of (S)-3-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-(R)-2-hydroxy-4-phenylbutyric acid methyl ester (EXAMPLE 43, 170 mg, 0.44 mmol) in methanol (5 mL) and the reaction stirred at rt for 24 h. The solvent was removed in vacuo and the residue partitioned between hydrochloric acid (1N, 30 mL) and ethyl acetate (3×3 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid. δH (DMSO): 2.71 (1H, dd), 2.91 (1H, dd), 3.56 (1H, d), 4.38–4.46 (1H, m), 4.77 (1H, s), 6.76 (1H, s), 7.11–7.16 (1H, m), 7.19–7.27 (4H, m), 7.45 (1H, s), 8.44–8.52 (2H, m); m/z (ES+)=374 [M+H]+.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>[C:15]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a stirred solution of 1-bromo-3-propylamine hydrobromide (5 g, 22.84 mmol) in saturated aqueous sodium carbonate (100 mL) and ethyl acetate (200 mL) at 0° C., was added benzylchloroformate (3.2 mL, 22.84 mmol) and the resulting mixture was warmed to room temperature and stirred overnight. The aqueous layer was separated and extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate and evaporated to dryness under reduced pressure. Silica gel chromatography using ethyl acetate/hexanes (1:9) provided the title compound as a colorless oil (4.7 g, 79%).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([N:29]2[CH2:33][CH2:32][C@H:31]([N:34]([CH3:36])[CH3:35])[CH2:30]2)[N:4]=1.Br.CC#N>CC(O)=O>[CH3:35][N:34]([CH3:36])[C@H:31]1[CH2:32][CH2:33][N:29]([C:5]2[NH:4][C:3](=[O:2])[C:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][N:19]=[C:18]([C:22]5[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=5)[CH:17]=4)=[C:11]([CH3:28])[N:10]=3)=[CH:7][N:6]=2)[CH2:30]1
Reactant: COc1nc(N2CC[C@H](N(C)C)C2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1nc(-c2cnc(N3CC[C@H](N(C)C)C3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 62.5 %

Procedure:
(S)-1-(4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylpyrrolidin-3-amine (0.10 g, 0.21 mmol) was dissolved in AcOH (3 mL) and then 48% hydrobromic acid (0.1 mL) was added. The mixture was heated at 90° C. for 3.5 hours. The mixture was concentrated and the residue was treated with NaHCO3 solution. The solution was extracted with EtOAc (3×) and the organic was washed with NaHCO3, dried over Na2SO4, filtered and concentrated to obtain the crude. The crude was treated with hot MeCN and kept at RT. The solid was filtered, washed with MeCN, and dried under vacuum to obtain (S)-2-(3-(dimethylamino)pyrrolidin-1-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (62 mg, 62.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.29 (m, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.62 (dd, J=5.7, 2.4 Hz, 1H), 3.85 (s, 3H), 3.74 (m, 2H), 3.44 (m, 1H), 3.31 (s, 3H), 3.22 (m, 1H), 2.75 (m, 1H), 2.35 (s, 3H), 2.18 (s, 6H), 2.11 (m, 1H), 1.77 (m, 1H) one proton is missing; MS (ESI) m/z: 473.3 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.CN(C=O)C>[CH2:21]([O:28][NH:29][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([I:1])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CCCOc1cccc(I)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCCOc1cccc(I)c1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution in dichloromethane (20 mL) containing a few drops of DMF of 4-(3-iodophenoxy)butanoic acid (2.26 g, 7.38 mmol) was added oxalyl chloride (0.60 mL, 6.9 mmol) slowly via syringe. The reaction mixture was stirred for 30 minutes at ambient temperature, and then was decanted into a dichloromethane solution of O-benzylhydroxylamine (3.5 g, 22 mmol; prepared by shaking O-benzylhydroxylamine in a mixture of dichloromethane and saturated aqueous Na2CO3, separating the layers, and drying the organic phase over MgSO4). The reaction mixture was stirred for 3.5 hours at ambient temperature and then was extracted with water and saturated aqueous Na2CO3. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a white solid. The solid was dissolved in dichloromethane and the organic solution was washed with aqueous 1M HCl, dried over MgSO4, filtered, and concentrated in vacuo to give O-benzyl-4-(3-iodophenoxy)butanohydroxamic acid (3.12 g) as a fluffy white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[N:18][C:19]([CH3:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][S:60]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)(=[O:62])=[O:61]>CN(C=O)C>[CH3:59][S:60]([N:63]1[CH2:68][CH2:67][N:66]([C:21]([C:20]2[C:19]([CH3:25])=[N:18][CH:17]=[C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][N:11]=3)[CH:24]=2)=[O:22])[CH2:65][CH2:64]1)(=[O:62])=[O:61]
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(C(=O)O)c3)nc2)cc1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(C(=O)N4CCN(S(C)(=O)=O)CC4)c3)nc2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid 10 (0.05 mmol) in DMF (1 mL) is added HATU (0.06 mmol) and DIEA (0.14 mmol) at rt. The resulting mixture is stirred for 2 min then 1-methanesulfonyl-piperazine (0.05 mmol) is added. The reaction mixture is stirred at rt for 4 h and then directly purified by preparative LCMS to give (4-methanesulfonyl-piperazin-1-yl)-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-yl}-methanone B1. 1H NMR (400 MHz, d4-CH3OH) δ 9.30 (d, J=4.0 Hz, 1H), 8.81 (s, 2H), 8.50 (d, J=4.0 Hz, 1H), 7.60-7.758 (m, 2H), 7.07-7.05 (m, 2H), 3.96-3.94 (m, 2H), 3.85 (s, 3H), 3.54-352 (m, 2H), 3.42-3.39 (m, 2H), 3.27 (bs, 2H), 2.91 (s, 3H), 2.62 (s, 3H). MS (m/z) (M+1)+: 483.1.
Reaction SMILES: I[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH2:16])[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]=2[O:4]1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH:12]([C:11]1[C:5]2[O:4][C:3]([CH3:18])([CH2:2][N:28]3[CH2:29][CH2:30][CH:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[CH2:7][C:6]=2[C:8]([CH3:17])=[C:9]([NH2:16])[C:10]=1[CH3:15])([CH3:14])[CH3:13]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CI)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CN1CCC(c3ccccc3)CC1)O2
Yield: 45.8 %

Procedure:
A suspension of 2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethyl-5-benzofuranamine (1.1 g), 4-phenylpiperidine (0.87 g) and potassium carbonate (0.83 g) in N,N-dimethylacetamide (6 mL) was refluxed for 4.5 hours. The mixture was diluted with water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtrated and evaporated in vacuo. The residue was purified with basic silica gel column chromatography (hexane:ethyl acetate=30:1 to 10:1) and recrystallized from hexane/ethyl acetate to afford 0.55 g of the title compound. Yield 47%.
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([N:20]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][N:22]=[C:21]2S)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1>O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([N:20]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][N:22]=[CH:21]2)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1
Reactant: CCCC(c1ccc(C)cc1)n1c(C(=O)OC)cnc1S
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCCC(c1ccc(C)cc1)n1cncc1C(=O)OC
Yield: 86 %

Procedure:
0.07 Parts of sodium nitrite and 0.6 parts of nitric acid were solved in 2 parts of deionisized water. 1.0 Part of methyl 1-[1-(4-methylphenyl)butyl]-2-mercapto-1H-imidazole-5-carboxylate was added portionwise at a temperature between 25° C. and 30° C. The precipitate was isolated, yielding 0.94 parts (86% ) of methyl 1-[1-(4-methylphenyl)butyl]-1H-imidazole-5-carboxylate mononitriate. This colourless salt has a melting point of 141°-143° C. (compound 1.15).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][CH:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:24](=O)[NH:23][CH:22]=[N:21][C:20]1=2)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)[Cl:35]>>[Cl:35][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@@H:6]1[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:5]1[O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(n2cnc3c(=O)[nH]cnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 55 °C

Procedure:
Crude compound 2 (130 mg) was dissolved in dry CH2Cl2 (10 mL) and heated to 55° C. Dry DMF (1 mL) followed by a 2 M solution of SOCK in CH3Cl2 (2.43 mL, 0.57 mmol) were added dropwise over a period of 45 minutes. The reaction mixture was gently refluxed for an additional 75 minutes. The reaction mixture was cooled to room temperature and diluted with CH2Cl2. The organic layer was washed with saturated NaHCO3 solution (2×50 mL), brine (50 mL) and dried (anhydrous sodium sulfate). The organic phase was concentrated in vacuo and purified by preparative TLC (5% MeOH/CHCl3) to obtain pure 3 (50 mg, 26% from 1): UV (MeOH)λmax 263.0 nm, 212.5 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.O=C1CCC(=O)N1[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:36])[N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:36])[N:28]([CH3:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:22][CH:21]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: NCCc1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title product was prepared from 2-(4-chloro-phenyl)-ethylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was subjected to preparative HPLC (method C) (39%, off-white crystals). HPLC-MS m/z=409.2 (M+1), Rt: 4.27 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.S(O)(O)(=O)=O.[NH2:16]O.C(Cl)Cl.C([O-])(O)=O.[Na+]>O>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:16]
Reactant: NO
Reactant: O=Cc1c(O)cccc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,6-dihydroxybenzaldehyde (300 mg, 2.17 mmol) and hydroxylamine sulfate (758 mg, 6.51 mmol) in water (30 mL) is stirred at RT for 45 min. Methylene chloride (60 mL) is added followed by NaHCO3 (911 mg, 10.85 mmol) and the mixture is stirred at RT for 30 min. The organic phase is separated and dried over sodium sulfate and the solvent removed under reduced pressure to give the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH:21]=1
Reactant: ClCc1cccnc1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cccnc2)c(=O)[nH]c1=O
Yield: 28.7 %

Procedure:
5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (101 mg, yield: 28.7%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:19][C:20]1[CH:25]=[N:24][C:23](Cl)=[CH:22][N:21]=1>CN(C)C=O>[Cl:19][C:20]1[N:21]=[CH:22][C:23]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:24][CH:25]=1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: Clc1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (184 mg, 0.85 mmol) was dissolved in dry dimethylformamide (3 ml), cooled to 0° C. and treated with sodium hydride (60% in mineral oil, 36 mg, 0.89 mmol). The mixture was allowed to warm to room temperature over 30 minutes. A solution of 2,5-dichloropyrazine (D47) (139 mg, 0.94 mmol) in dry dimethylformamide (1 ml) was added and the mixture stirred at room temperature for 5 hours. The mixture was applied to a SCX column and washed with methanol then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (268 mg); MS (ES+) m/e 330 [M+H]+.
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13]O[C:11]=1[CH3:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:2]([O:9][CH:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:1]=[C:11]1[CH3:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: Cc1occc(=O)c1OCc1ccccc1
Solvent: CCO
Product: CC1=NC=CC(=O)C1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
28% aqueous ammonia (100 ml) and 30 ml of ethanol were added to 3-benzyloxy-2-methyl-4-pyrone (40.6 g, 0.188 mol). The mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated under the reduced pressure. The precipitate was filtered, and was then washed with a minor amount of ethyl acetate to give 32.2 g of 3-benzyloxy-2-methyl-4-pyridone as a light yellow crystal. The same compound was also obtained from the filtrate (5.6 g, yield 93%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>C1(C)C=CC=CC=1>[C:15]([C:3]1[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:20][N:21]([CH3:23])[CH3:22])#[N:16]
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1cccc(Nc2n[nH]c(N)c2C#N)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2n[nH]c(N=CN(C)C)c2C#N)c1
Temperature: 25 °C

Procedure:
A suspension of 10.71 g (50.22 mmol) of 5-amino-4-cyano-3-(3-methyl-phenylamino)-pyrazole [for preparation see: Arch. Pharm. (Weinheim) 326, 245 (1993)], 9.9 ml (57.8 mmol) of N,N-dimethylformamide diethyl acetal and 150 ml of toluene is heated under reflux for 4 hours. The reaction mixture is then cooled to RT and filtered and the filter residue is washed with toluene and diethyl ether, yielding the title compound; m.p. 260-261° C.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[C:3]#[CH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]#[N:21]>C(C(C)=O)C>[CH3:5][C:2]([N:6]1[CH2:7][CH2:8][N:9]([CH2:19][C:20]#[N:21])[CH2:10][CH2:11]1)([CH3:1])[C:3]#[CH:4]
Reactant: N#CCBr
Reactant: C#CC(C)(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CC(C)(C)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a suspension (10 mL) of 1-(1,1-dimethyl-2-propynyl)piperazine (350 mg, 2.3 mmol) and potassium carbonate (480 mg, 3.45 mmol) in methyl ethyl ketone (MEK) was added bromoacetonitrile (0.176 mL, 2.53 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with MEK and filtered. The filtrate was concentrated to give the title compound (0.439 g, quantitative) as a white solid.
Reaction SMILES: [OH-:1].[K+].O.[CH2:4]([C:6]([C:25]1[CH:38]=[CH:37][C:28]([O:29][CH2:30][C@@H:31]2[O:35][C:34](=[O:36])[CH2:33][CH2:32]2)=[C:27]([CH3:39])[CH:26]=1)([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[C:11]([CH3:24])[CH:10]=1)[CH2:7][CH3:8])[CH3:5]>CO>[CH2:4]([C:6]([C:25]1[CH:38]=[CH:37][C:28]([O:29][CH2:30][C@H:31]([OH:35])[CH2:32][CH2:33][C:34]([OH:36])=[O:1])=[C:27]([CH3:39])[CH:26]=1)([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[C:11]([CH3:24])[CH:10]=1)[CH2:7][CH3:8])[CH3:5]
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2ccc(C(C)(C)O)o2)c(C)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(CC)(c1ccc(OC[C@H](O)CCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(C)(C)O)o2)c(C)c1
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A 1 N potassium hydroxide aqueous solution (0.1 mL, 0.1 mmol) and water (0.1 mL) were added to a solution of 5(R)-[4-(1-ethyl-1-{4-[5-(1-hydroxy-1-methyl-ethyl)-furan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (Example 19-(3); 2.8 mg, 0.006 mmol) in methanol (1 mL) at room temperature, and the mixture was stirred at the same temperature for one hour. The reaction solution was directly purified by silica gel chromatography (dichloromethane/methanol=8/3, saturated with water) to give the title compound (0.9 mg, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.CCN(CC)CC.[CH:19]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20]1>CCO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:25]3[CH2:26][CH2:27][N:22]([CH:19]4[CH2:21][CH2:20]4)[CH2:23][CH2:24]3)[S:8][C:4]=2[CH:3]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: Clc1nc2ccc(Br)cc2s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Brc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Yield: 31 %

Procedure:
To a solution of 6-bromo-2-chlorobenzothiazole (8.2 g, 33 mmol) in EtOH (115 mL) was added Et3N (16.7 g, 165 mmol), followed by 1-cyclopropylpiperazine (5 g, 39.6 mmol). The mixture was heated at reflux for 12 h. Then the mixture was evaporated to remove EtOH. Water (120 mL) was added to the residue and the mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with a mixture of EtOAc/petroleum ether (1:10 with 0.1% NH4OH added) to give 3.46 g (31%) 6-bromo-2-(4-cyclopropylpiperazin-1-yl)benzothiazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:16]1[CH2:20][N:19]([C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[C:18](=O)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C@@H:16]1[CH2:17][CH2:18][N:19]([C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(NC(=O)OC(C)(C)C)c2ccccc2)CC1=O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC[C@@H](C(NC(=O)OC(C)(C)C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 88.2 %

Procedure:
In an atmosphere of nitrogen 1Mborane-tetrahydrofuran complex (4.6 ml) was added dropwise to tetrahydrofuran (10 ml) solution of 4-(R)-[1-tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (600 mg, 1.52 mmol) under ice-cooling, and then the mixture was stirred at room temperature for 13 hours. After evaporation of the solvent under a reduced pressure, the resulting residue was mixed with 80% hydrous ethanol (15 ml) and triethylamine (3 ml) and heated under reflux for 5 hours. After spontaneous cooling, the solvent was evaporated under a reduced pressure, and chloroform (30 ml) was added to the resulting residue. This was washed with water (10 ml) and saturated brine (10 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with chloroform:methanol (20:1), 510 mg (88%) of the title compound was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19].[OH-].[Na+]>CCO.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of methyl 2-methyl-2′-(trifluoromethyl)biphenyl-4-carboxylate, prepared in step 1 (3 g; 10.19 mmol; 1 eq.) in EtOH (90 mL), was added at RT an aqueous solution of sodium hydroxide (6.12 mL; 5 M; 30.58 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under vacuum to give a brown solid. It was taken up in water (400 mL) and the aqueous phase was washed twice with EtOAc (200 mL). Aqueous phase was acidified with concentrated HCl (2 mL) to pH 2. Then it was concentrated under vacuum until a precipitate was formed (⅓ of volume). The suspension was filtered off and dried under vacuum, affording the title compound as a beige solid (2.41 g, 84%). 1H NMR: (DMSO-d6, 300 MHz) δ 13.03 (s, 1H), 7.91-7.68 (m, 5H), 7.38-7.36 (d, J=8.27 Hz, 1H), 7.27-7.25 (d, J=8.24 Hz, 1H), 2.05 (s, 3H). LC/MS (Method A): 279.0 (M−H)−. HPLC (Method A) Rt 4.49 min (Purity: 95.7%).