Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:24])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[F:1][C:2]1[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:24])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Reaction time: 7 h
Yield: 79.9 %

Procedure:
To a mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.05 mmol) in anhydrous methanol (1 mL) and anhydrous THF (1 mL) at ambient temperature under nitrogen atmosphere was added zinc dust (33 mg, 50 mmol) and ammonium chloride (27 mg, 50 mmol). The reaction mixture was stirred for 7 h before the catalyst was filtered off and the filtrate was concentrated in vacuo to give a solid which was partitioned between chloroform and water. The aqueous phase was extracted twice with chloroform. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the desired compound (16 mg, 87%) as a solid. 1H NMR (CDCl3) δ 7.86-7.83 (m, 1H), 7.50-7.38 (m, 2H), 7.09-7.00 (m, 1H), 6.56-6.45 (m, 1H), 4.14 (t, 2H, J=5.5 Hz), 2.99-2.38 (m, 18H); MS(ESI+) m/z 401.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].[CH3:22][S:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:30][C:29]2[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:33][CH:32]=2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Product: CS(=O)(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C from (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-methylsulfonylbenzyl chloride. MS (ES+) 461.2
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9](OCC)=[O:10])[CH:5]=[N:4][N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.O1CCOCC1>[OH:10][CH2:9][C:8]1[CH:7]=[C:6]([N:1]2[CH:2]=[N:3][N:4]=[CH:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cccc(-n2cnnc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: OCc1cccc(-n2cnnc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
430 mg of ethyl 3-(1,3,4-triazol-1-yl)benzoate [synthesized substantially in accordance with the method described in J. Med. Chem., 5, 383 (1962)] was dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of dioxane, and 100 mg of lithium aluminium hydride was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate. The desiccant was separated by filtration, and the solvent evaporated. The residue was purified by silica gel column chromatography [Wakogel C-200, 20 g; eluting solvent: chloroform/methanol=20/1] to give 240 mg (yield 69%) of 1(3-hydroxymethylphenyl)-1,3,4-triazole.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@@H:10]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([NH:30][C:31]([CH3:37])([CH3:36])[CH2:32][C:33](O)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([O:8][C:9](=[O:22])[C@H:10]([NH:11][C:33](=[O:34])[CH2:32][C:31]([NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])([CH3:37])[CH3:36])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Product: CC(C)(CC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Prepared from D-tryptophan benzyl ester (1 g; 3.40 mmol) and 3-t-butoxycarbonylamino-3-methylbutanoic acid (0.91 g; 4.19 mmol) by the procedure described in Example 6, Step C. The yield was 0.981 g (58%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:24]([C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=4)=[O:25])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: Cn1ccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (30 mg, 1.1 eq, 0.13 mmol) was added to a solution 1-methyl-1H-imidazole-2-carboxylic acid (15 mg, 1.0 eq, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 1.1 eq, 0.13 mmol), 1-hydroxybenzotriazole (16 mg, 1.0 eq, 0.12 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was then triturated with methanol and the resultant solid was isolated by filtration to yield the title compound as a yellow solid (3 mg, 0.01 mmol, 8%). LCMS: [M+H]+=335, Rt=1.48 min, 94% purity.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@:16]1([CH2:20][C:21]#[CH:22])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@:16]1([CH2:20][C:21]#[CH:22])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: c1ccncc1
Product: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reaction time: 16 h

Procedure:
To a solution of 500 mg of 17β-hydroxy-10-(2-propynyl)estr-4-en-3-one in 4 ml of pyridine at 25° C. is added 4 ml of acetic anhydride and the mixture is allowed to stand at room temperature for 16 hours. It is then concentrated under reduced pressure, the residue is diluted with ether and the ether solution is washed with 1 N hydrochloric acid and with aqueous sodium bicarbonate and then dried and concentrated. The resultant residue is recrystallized from ethyl acetate-hexane to give 17β-acetoxy-10-(2-propynyl)estr-4-en-3-one. This compound has the following structural formula ##STR10##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:21]Cl.C[Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:21])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred suspension of the 1-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.22 g, 0.81 mmol) in methanol (5 mL), THF (5 mL), and dichloromethane (5 mL) was added (trimethylsilyl)diazomethane solution (2M in diethyl ether, 1 mL, 2 mmol) dropwise at rt. The reaction mixture was stirred at rt for 1 hr and carefully quenched by the slow addition of acetic acid. Concentration under reduced pressure and titration with methanol gave methyl 1-(4-fluorophenyl)-1H-indazole-5-carboxylate (0.16 g, 0.59 mmol, 73% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:11]([OH:13])=O)[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].Cl.[NH2:16][C@@H:17]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:32]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=[CH:34][C:29]([CH2:28][C@H:17]([NH:16][C:11]([C:6]2([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10]2)=[O:13])[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:30][CH:31]=1
Reactant: N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC1(C(=O)O)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A solution of 1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxylic acid (672 mg, 3.36 mmol), (S)-benzyl 2-amino-3-(biphenyl-4-yl)propanoate hydrochloride (957 mg, 2.60 mmol), WSC.HCl (833 mg, 4.34 mmol), 1-hydroxy-7-azabenzotriazole (591 mg, 4.34 mmol) and DIPEA (0.759 ml, 4.34 mmol) in DMF (15 ml) was allowed to stir at room temperature for 2 hours. The reaction was quenched with H2O (10 ml) and 35% NH4OH aqueous (2 ml). The mixture was stirred for 30 minutes. The product was extracted with EtOAc, washed twice with 1 M HCl aqueous, once with H2O, and then once with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 60:40) to give (S)-benzyl 3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoate (1.143 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:26])[NH:15][CH2:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[N:20][NH:21]3)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[NH:21]1[C:22]2[C:18](=[C:17]([CH2:16][NH:15][C:14]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=3)=[O:26])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccc2[nH]ncc12)c1cc(C(F)(F)F)c(C(=O)O)s1
Reaction time: 15 h

Procedure:
A mixture of 5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (200 mg, 0.52 mmol), lithium hydroxide monohydrate (220 mg, 5.22 mmol), THF (4 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 160 mg (83%). MS m/e 370.0 (M+H+).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:4]
Reactant: O=C(CNC(=O)c1ccccc1)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CNC(=O)c1ccccc1)c1ccccc1
Yield: 109.6 %

Procedure:
Thiosemicarbazide (1.33 g, 14.6 mmol) was added to a solution of N-(2-oxo-2-phenyl-ethyl)-benzamide (3.5 g, 14.6 mmol), prepared in the previous step, in 53 ml of methanol plus 4 ml of 1N HCl plus 3.75 ml of water and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure to give 5.0 g of an off-white solid. Recrystallization of this solid from isopropyl alcohol gave the title compound (3.64 g, 80%) as a white solid, mp 171-172° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][CH:15]1[C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)[CH:3]=2)=[CH:19][CH:18]=[CH:17][NH:16]1
Reactant: COc1ncccc1B(O)O
Reactant: Brc1cccc(-c2cnco2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC1NC=CC=C1c1cccc(-c2cnco2)c1

Procedure:
A mixture of 5-(3-bromo-phenyl)-oxazole VI-a (1.33 g, 5.94 mmol), 2-methoxy-3-pyridinylboronic acid (1.00 g, 6.53 mmol), Pd(PPh3)4 and K2CO3 (1.81 g, 13.1 mmol) in THF (20 mL) and water (10 mL) was heated to reflux for 4 h. The mixture was cooled, then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4), filtered and the residue purified by column chromatography (SiO2; eluting with 30% EtOAc in cyclohexane) to afford the desired product VI-b as brown oil which crystallized on standing (1.37 g, 91%). 1H NMR (300 MHz, CDCl3) δ 8.18 (dd, J=1.8, 5.0 Hz, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.64 (d, J=6.9 Hz, 2H), 7.53-7.44 (m, 2H), 7.37 (s, 1H), 6.99 (dd, J=5.0, 7.2 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: C(C1C=C2C(=CC=1)C(NC(=O)C1C=CC=CC=1)=NC=C2)=O.C([NH:29][C:30]1[C:39]2[C:34](=[CH:35][C:36]([CH:40]=[CH:41][C:42]([OH:44])=O)=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1)C1C=CC=CC=1.NC1C2C(=CC(C=CC(O)=O)=CC=2)C=CN=1.Cl.[CH3:62][O:63][C:64](=[O:76])[CH2:65][C:66]([N:68]1[CH2:73][CH2:72][CH:71]([NH:74][CH3:75])[CH2:70][CH2:69]1)=[O:67]>>[CH3:62][O:63][C:64](=[O:76])[CH2:65][C:66]([N:68]1[CH2:69][CH2:70][CH:71]([N:74]([C:42](=[O:44])[CH:41]=[CH:40][C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[C:30]([NH2:29])=[N:31][CH:32]=[CH:33]3)[CH3:75])[CH2:72][CH2:73]1)=[O:67]
Reactant: CNC1CCN(C(=O)CC(=O)OC)CC1
Reactant: O=C(O)C=Cc1ccc2c(NCc3ccccc3)nccc2c1
Agent: Cl
Agent: Nc1nccc2cc(C=CC(=O)O)ccc12
Agent: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Product: COC(=O)CC(=O)N1CCC(N(C)C(=O)C=Cc2ccc3c(N)nccc3c2)CC1

Procedure:
Using the method described in example 81a N-(6-formyl-1-isoquinolinyl)benzamide (1f) was transformed into 3-(1-(benzylamino)-6-isoquinolinyl)acrylic acid. This compound was used to prepare 3-(1-amino-6-isoquinolinyl)acrylic acid according to the procedure described in example 81b. Reaction of 3-(1-amino-6-isoquinolinyl)acrylic acid with 3-(4-(methylamino)piperidin-1-yl)-3-oxopropionic acid methyl ester hydrochloride according to the procedures described in example 81e yielded the title compound. NMR (CDCl3) δ:1.8 (4H, m), 2.7 (1H, m), 3.0 (3H, s), 3.2 (1H, m), 3.5 (2H, d), 3.7 (3H, s), 3.9 (1H, br d), 4.8 (2H, m), 4.9 (2H, br s), 7.0 (1H, d), 7.5 (1H, d), 7.65 (1H, d), 7.8 (3H, m), 8.0 (1H, d).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11]O)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH3:1][N:2]([CH2:10][CH2:11][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: c1nc[nH]n1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(CCn1cncn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution (ice bath) of 2-[N-methyl-N-(t-butoxycarbonyl)amino]ethanol (J. Med. Chem., 1999, 42(11), 2007-2020; 5 g, 28 mmol), triphenyl phosphine (9.35 g, 36 mmol) and 1,2,4-triazole (1.64 g, 24 mmol) in DCM (30 ml) was added diethylazodicarboxylate (5.64 ml, 35.7 mmol) dropwise. The ice bath was removed and the reaction mixture allowed to stir at room temperature for 1 hour. The precipitate was discarded and the filtrate was concentrated and purified by flash chromatography, eluting with a 50% EtOAc/DCM and then 100% EtOAc to give a pale yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH2:2][CH3:3].Br[C:20]1(C=CC=[C:26]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[C:35]([CH2:43][CH3:44])=[N:36][O:37][C:38]=3[C:39]=2[CH2:40][CH2:41][CH3:42])[CH2:25]1)OCCC>>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:20][CH2:25][CH2:26][O:30][C:31]1[CH:32]=[CH:33][C:34]2[C:35]([CH2:43][CH3:44])=[N:36][O:37][C:38]=2[C:39]=1[CH2:40][CH2:41][CH3:42])[CH2:2][CH3:3]
Reactant: CCCOC1(Br)C=CC=C(Oc2ccc3c(CC)noc3c2CCC)C1
Reactant: CCCc1cc(CC(=O)OC)cc(CCC)c1O
Product: CCCc1cc(CC(=O)OC)cc(CCC)c1OCCCOc1ccc2c(CC)noc2c1CCC

Procedure:
Using the method of Example 17, Step D, methyl 3,5-dipropyl-4-hydroxyphenylacetate and 1-bromo-3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)phenoxypropane as the starting material, the title compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(#N)C.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C([O-])(O)=O.[Na+]>[C:10]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:12])[CH3:11]
Reactant: NCCC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of β-alanine (2.25 g, 25 mmol) in aq. NaHCO3 (15 mL) was added acetonitrile (15 mL) and acetic anhydride (2.55 g, 25 mmol). The reaction mixture was stirred at room temperature for 3 h. Acetic anhydride (2.55 g, 25 mmol) was added and after 2 h and pH was adjusted to 4-5 by addition of NaH2PO4.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](N)[CH2:27][CH3:28].S>C(O)C>[CH2:26]([NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25])[CH2:27][CH3:28]
Reactant: CCCN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 100 °C

Procedure:
A solution of 10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, D series (2.5 g) and propylamine (8.3 cc) in absolute ethanol (50 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After cooling, the orange solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual brown oil is purified by chromatography on a column (height: 25 cm; diameter: 2 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (80:20 by volume) (1 liter) of ethyl acetate and cyclohexane and collecting 40-cc fractions. The combined fractions 8 to 18 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-Propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, D series (2.4 g) is thereby obtained in the form of a yellow oil {[α]D20 =22±0.5° (0.06%; methanol)}. This oil is dissolved in 2-propanol (7.5 cc) at a temperature in the region of 50° C., and this solution is poured with stirring into a solution of fumaric acid (0.68 g) in 2-propanol (7.5 cc) at a temperature in the region of 60° C. Stirring is continued for 2 hours at a temperature in the region of 5° C. The solid formed is drained, washed with 2-propanol (2×2 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. N-Propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide acid fumarate, D series (2 g) is thereby obtained in the form of a yellow solid, m.p. 206° C., the NMR characteristics of which are identical to those described in Example 13.
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][CH2:7][N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]1=[O:21])C.N#C[Br:26]>C(OCC)C>[Br:26][CH2:4][C:5]#[C:6][CH2:7][N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]1=[O:21]
Reactant: CCN(CC)CC#CCN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O
Reactant: N#CBr
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCBr)C1=O
Yield: 81.5 %

Procedure:
A solution of 2.4 g of (S)-1-[4-diethylamino-2-butynyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone and 0.8 g of cyanogen bromide in 40 ml of diethyl ether is stirred at room temperature for 18 hours. The solution is washed with 30 ml of 1N hydrochloric acid and saturated sodium bicarbonate, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, methylene chloride) to give 2.0 g of the desired product as a colorless oil. [α]D26 =-31° (methylene chloride).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][C@@H:16]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCN(CC)CC>C(Cl)Cl>[Cl:34][C:28]1[CH:27]=[C:26]([NH:25][C@H:16]([CH2:15][NH:14][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:31]=[CH:30][C:29]=1[C:32]#[N:33]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-nitrobenzenesulfonyl chloride (14.15 g, 64 mmol) in CH2Cl2 (50 mL) was added dropwise over 20 min to an ice cold solution of 1,1-dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (19.8 g, 64 mmol) and Et3N (6.5 g, 64 mmol) in CH2Cl2 (150 mL) and the reaction was stirred at room temperature for 30 min. The reaction was washed with H2O and cold 0.1 N HCl. The organic layer was dried over CaCl2, filtered, and concentrated. The crude product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[NH:36][C:35](=[O:37])[S:34][N:33]=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[NH:36][C:35](=[O:37])[S:34][N:33]=4)=[CH:30][CH:31]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2nsc(=O)[nH]2)cc1
Product: CCC(C(=O)Nc1ccc(-c2nsc(=O)[nH]2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
65 mg (0.19 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 54 mg (0.28 mmol, 1.5 eq.) of 3-(4-aminophenyl)-1,2,4-thiadiazol-5(4H)-one were reacted according to General Method 7. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 45 mg (46% of theory)