Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>O.CO>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate (250 mg, 0.5 mmol) was treated with 1 M of lithium hydroxide in water (2 mL) and methanol (1 mL). The reaction was stirred at room temperature for 12 h. Acidified by 10% aqueous citric acid to pH 5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried and concentrated. The resultant 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid was used as is with no further purification steps. LC/MS (ESI+): m/z 462 (M+H). 1H NMR (500 MHz, DMSO) δ 8.44 (s, 1H), 8.36 (d, J=8.4, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.4, 1.7, 1H), 7.35 (d, J=1.7, 1H), 5.82 (dt, J=13.1, 6.6, 1H), 4.52 (s, 4H), 2.25 (s, 3H), 1.78 (s, 6H), 1.45 (t, J=13.9, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23](F)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](=[O:24])[NH:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC1OC(=O)C=C1N
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 4-amino-5-ethoxy-5H-furan-2-one (0.05 g, 0.35 mmol) and 2-fluorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.09 g, 0.42 mmol) in tetrahydrofuran (5 mL) at room temperature under nitrogen was added sodium tert-butoxide(0.05 g, 0.49 mmol). The reaction was stirred 3 h at reflux. After cooling, the mixture was diluted with ethyl acetate, was washed with 10% potassium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 4:6 ethyl acetate:hexanes afforded (R)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.075 g, 63% yield). Also recovered was starting 4-amino-5-ethoxy-5H-furan-2-one (0.016 g, 32% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH3:12])[N:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].CCN(C(C)C)C(C)C>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:15]([CH3:14])[O:16][CH3:17])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH3:12])[N:3]=1
Reactant: CCCNc1nc(N)nc(Cl)n1
Reactant: CNOC
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1nc(N)nc(N(C)OC)n1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A mixture of 6-amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII) (5 g, 26.65 mmol), N,O-dimethylhydroxylamine hydrochloride (13 g, 133.24 mmol) and DIPEA (27.5 g, 213.2 mmol) in EtOH (100 mL) was heated at 100° C. for 16 h, after which time the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (400 mL), which was washed with water (200 mL) and then with a brine solution (200 mL) and finally dried over Na2SO4. The solvent was removed under reduced pressure to yield N-(6-amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXIX) as a white solid (5 g, 89% yield). LCMS (ESI) m/z=213 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[C:15]1([CH:21](Br)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([CH:21]([S:1][C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(Br)c1ccccc1
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Sc1cccc(N)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-mercaptoaniline (1 g) and potassium carbonate (1.21 g) in N,N-dimethylformamide (20 mL) was added 1-phenylethyl bromide (1.2 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (1.78 g).
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O.O1CCOCC1>[O:16]=[C:8]1[N:7]([CH2:6][CH2:5][NH:4][C:17](=[O:19])[CH3:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCn1c(=O)[nH]c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of NaOH (0.41 g, 10 mmoles) in water (5 ml) were simultaneously added 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (0.7 g, 3.3 mmoles) and a solution of acetic anhydride (0.37 ml, 3.9 mmoles) in dioxane (10 ml). The reaction mixture was stirred for 2 hours at room temperature and then taken to dryness. The residue was dissolved in water, adjusted to pH 4 with 10% aqueous HCl, and extracted with CHCl3. The organic layer was taken to dryness and from the crude residue 0.35 g of the title compound was obtained after crystallization from diethyl ether. M.p. 153° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:28][CH3:29])[C:4]1[CH:5]=[C:6]([C:13](N2CCOCC2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C#N)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].CC(O)=[O:32]>>[CH3:1][O:2][CH:3]([O:28][CH3:29])[C:4]1[CH:5]=[C:6]([C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:32])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: COC(OC)c1cc(C(C#N)(c2ccccc2)N2CCOCC2)ccc1[N+](=O)[O-]
Reactant: CC(=O)O
Product: COC(OC)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]

Procedure:
(3-Dimethoxymethyl-4-nitro-phenyl)-morpholin-4-yl-phenyl-acetonitrile (0.7 mol) in CH3CO2H (1500ml) was stirred and refluxed for 30 min. The mixture was poured on ice/water and extracted with diisopropyl ether. The organic layer was washed with alkalic water and water. The organic layer was dried (MgSO4) and evaporated to yield a residue. The aqueous layers which contained product were extracted with CH2Cl2. The organic layer was dried (MgSO4) and evaporated to yield a residue. The combined residues were purified on a glass filter over silica gel (eluent: CH2Cl2). The pure fractions were collected and evaporated to yield the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:13]([OH:19])=[C:12]([I:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](Br)[CH3:22]>CN(C=O)C>[CH2:21]([O:19][C:13]1[C:12]([I:20])=[CH:11][C:10]([O:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[C:15]([CH:16]([CH3:18])[CH3:17])[CH:14]=1)[CH3:22]
Reactant: CC(C)c1cc(O)c(I)cc1Oc1cnc(N)nc1N
Reactant: CCBr
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Yield: 78.9 %

Procedure:
To a solution of 4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenol (0.2 g, 0.52 mmol) in anhydrous DMF (2 ml) was added EtBr (57 mg, 0.52 mmol) in portions. The reaction mixture was partitioned between EtOAc and H2O. The organic extract was dried over Na2SO4, filtered and aconcentrated. Flash chromatography on silica (3% MeOH in methylene chloride with 1% NH4OH) gave 5-(4-Ethoxy-5-iodo-2-isopropyl-phenoxy)-pyrimidine-2,4-diamine (0.17 g, 28% ) as a yellow solid. (M+H)=415.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: CN(Cc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1)S(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of tert-butyl(3R)-6-cyclohexyl-3-(3-{[methyl(methylsulfonyl)amino]methyl}-1,2,4-oxadiazol-5-yl)hexanoate (preparation 6) (264 mg, 0.60 mmol) in 4M HCl in dioxan (2 ml) was stirred at room temperature for 20 hours. Further 4M HCl in dioxan (2 ml) was added and stirred for a further 3 hours. A few drops of concentrated HCl was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to afford the title compound (245 mg—contained some dioxan as impurity).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=1[F:13])C(O)=O.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=1[F:13]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Product: COC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 140 °C
Reaction time: 24 h
Yield: 86.4 %

Procedure:
Into a 100 ml three necked flask, 20 g (0.079 mol) of the 3,4,5,6-tetrafluorophthalic acid-monomethyl ester prepared in Example 14, and 2.8 g (0.0079 mol) of tri-n-octylamine were charged, and the mixture was heated and stirred at 140° C. for 24 hours. After completion of the reaction, the reaction mixture was separated by distillation to obtain 14.2 g of 2,3,4,5tetrafluorobenzoic acid methyl ester. The yield was 86.3%.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C@@H:7]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:8][N:9]([CH3:19])[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=S)#[N:2].Cl[C:28]1[CH:29]=[C:30]([C@:34]([C@@H:42]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]2)([OH:41])[CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:31]=[CH:32][CH:33]=1.C(Cl)CCl>CN(C=O)C.CCOCC>[C:1]([N:3]=[C:4]([N:44]1[CH2:45][CH2:46][CH2:47][C@@H:42]([C@:34]([OH:41])([C:30]2[CH:29]=[CH:28][CH:33]=[CH:32][CH:31]=2)[CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:43]1)[NH:6][C@@H:7]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:8][N:9]([CH3:19])[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])#[N:2]
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=S)NC#N)C(=O)OCC[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOCC
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=NC#N)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a stirred solution of 1-cyano-3-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)thiourea (230 mg, 0.58 mmol) and (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (180 mg, 0.58 mmol) in DMF (5 mL) was added EDC (0.17 g, 0.87 mmol). The mixture was stirred for 16 h at rt, diluted with ether (175 mL) and washed with 5% aq HCl (2×50 mL) and brine (50 mL). The combined aqueous washes were back extracted with ether. The combined ether extracts were concentrated to afford crude product (290 mg). The mixture was purified by prep HPLC to afford (3R)—N′-cyano-N-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine (145 mg, 37%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:15]=[C:16]([C:21]4([O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]4[OH:25])[O:22][CH3:23])[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1[CH2:40][CH2:39][O:38]CC1.C(O[C:45](=[O:47])[CH3:46])(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:21]([O:25][C@@H:24]1[C@@H:26]([O:27][C:24](=[O:25])[CH3:26])[C@H:28]([O:29][C:45](=[O:47])[CH3:46])[C@@H:30]([CH2:32][O:33][C:39](=[O:38])[CH3:40])[O:31][C:21]1([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([CH2:13][C:11]2[S:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH:15]=1)[O:22][CH3:23])(=[O:22])[CH3:16]
Reactant: CN1CCOCC1
Reactant: COC1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a stirred solution of methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucopyranoside (net weight 10.54 g) in toluene and ethyl acetate was added N-methylmorpholine (11.9 g) and 4-dimethylaminopyridine (217 mg) at room temperature. The solution was cooled to 0° C. and acetic anhydride (52.7 mL) was added dropwise below 15° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 hours. The mixture was quenched with 28% NH3 aqueous solution (ca. 31.6 mL) while maintaining pH range of 6 to 7. Water was added to the mixture and separated. The organic layer was washed with water and brine, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give methyl 2,3,4,6-tetra-O-acetyl-1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucopyranoside (17.59 g) as yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:40]=[CH:39][C:19]3[NH:20][C:21]([C:23]4[C:27]([NH:28][C:29](=[O:38])[C:30]5[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=5[F:37])=[CH:26][NH:25][N:24]=4)=[N:22][C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[C:29]([NH:28][C:27]1[C:23]([C:21]2[NH:20][C:19]3[CH:39]=[CH:40][C:16]([O:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:17][C:18]=3[N:22]=2)=[N:24][NH:25][CH:26]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(OCC3CCNCC3)ccc2[nH]1)c1c(F)cccc1F
Yield: 41.1 %

Procedure:
4-{2-[4-(2,6-Difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazol-5-yloxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (0.024 g, 0.043 mmol) (prepared in a manner analogous to Example 130) was treated with 1:1 TFA:DCM (2 ml) for 20 min. The solution was reduced in vacuo and azeotroped with toluene (×3). Purification by preparative LC/MS gave 2,6-difluoro-N-{3-[5-(piperidin-4-ylmethoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide as a white solid (8 mg, 41%). (LC/MS: Rt 1.99, [M+H]+ 453.06).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].C1N=CN([C:26](N2C=NC=C2)=[S:27])C=1>CC#N>[N:1]([C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:18])([F:19])[F:20])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[C:26]=[S:27]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c(N)c1
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c(N=C=S)c1

Procedure:
A mixture of N-(3-amino-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide (200 mg, 0.69 mmol), TCDI (133 mg, 0.746 mmol) and MeCN (3 mL) was refluxed for 1 h. Concentration and purification by column chromatography gave the sub-title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[N:41]1[CH:42]=[CH:43][CH:44]=[C:39]([CH2:38][NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH:40]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCc2cccnc2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCc2cccnc2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-pyridin-3-ylmethyl-benzenesulfonamide (example B.5) according to general procedure II. Yellow solid. MS (ISP) 619.2 [(M−H−]; mp 257° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]2>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]3)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)nc1Cl
Yield: 64 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (410 mg, 2.36 mmol), thionyl chloride (5 mL), tert-butyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate (described in Andronati, S. A.; Krys'ko, A. A.; Chugunov, B. M.; Kabanova, T. A.; Artemenko, A. G.; Russ. J. Org. Chem., 42, 8, 2006, 1174-1182, 0.94 g, 4 mmol) and pyridine (5 mL), to obtain 619 mg of the title compound as a white solid (64%).
Reaction SMILES: O[C:2]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[C:13]([OH:15])=[CH:12][CH:11]=[CH:10]2)([CH3:4])[CH3:3].[OH2:16].N1[CH:22]=[CH:21]C=CC=1>C(O)(=O)C>[C:21]([O:15][C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:2]([CH3:4])=[CH2:3])[CH:10]=[CH:11][CH:12]=1)(=[O:16])[CH3:22]
Reactant: c1ccncc1
Reactant: CC(C)(O)c1cccc2cccc(O)c12
Reactant: O
Solvent: CC(=O)O
Product: C=C(C)c1cccc2cccc(OC(C)=O)c12
Temperature: 60 °C

Procedure:
11.3 g of 8-(1-hydroxy-1-methyl-1-ethyl)-1-naphthol was dissolved in 24 ml of pyridine, to which 12 ml of anhydrous acetic acid was added. The solution was raised in temperature to 60° C. and heated for 6 hours under agitation. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic phase was washed with a 2N hydrochloric acid aqueous solution, water and a saturated saline solution in this order, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 3.6 g of the captioned compound as an oily substance.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:32]1[CH2:33][CH2:34][C@@H:29]([NH:28][C:26]([C:22]2[C:18]3=[N:19][CH:20]=[CH:21][C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:17]3[NH:24][C:23]=2[CH3:25])=[O:27])[C@H:30]([OH:35])[CH2:31]1)(=[O:38])[CH3:37]
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f25) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]1[C:5]([Cl:6])=[N:4][O:3][C@@H:2]1[C@H:7]([NH2:11])[C:8]([OH:10])=[O:9].[C:12](=[O:15])(O)[O-:13].[Na+].O[CH2:18][CH:19]1[C:31]2[C:30](C(Cl)=O)=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2.Cl>C(OCC)(=O)C.O>[Cl:6][C:5]1[CH2:1][CH:2]([CH:7]([NH:11][C:12]([O:13][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:15])[C:8]([OH:10])=[O:9])[O:3][N:4]=1
Reactant: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1cccc2c1C(CO)c1ccccc1-2
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(C(=O)O)C1CC(Cl)=NO1)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
To 178 mg. of AT-125 in 4 ml. of water is added 300 mg. of sodium bicarbonate. After cooling the mixture to 0°-5° C., 300 mg. of 9-hydroxymethyl fluorenylcarbonyl chloride is added and it is stirred for two hours and allowed to stand overnight at room temperature. The resulting semi solid is taken up in ethyl acetate and 1N hydrochloric acid is added until a pH of 3 is attained. The organic phase is separated, dried over sodium sulfate, concentrated and chromatographed on 20 g. of CC-4 silica gel employing 40% ethyl acetate/Hexane. Those fractions containing the desired product are evaporated and the residue recrystallized from ethyl acetate to yield 3-chloro-α-[[(9H-fluoren-9-yl-methoxy)carbonyl]amino]-4,5-dihydro-5-isoxazole acetic acid. m.p. 182°-183° C. The NMR fits the desired structure.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][C:5]3([OH:12])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH2:13]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][C@H:24]1[C:30](O)=[O:31])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:13]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][C@H:24]1[C:30](=[O:31])[NH:1][CH:2]1[CH:3]2[CH2:11][CH:7]3[CH2:6][C:5]([OH:12])([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
To a solution of 4-amino-adamantan-1-ol (0.58 g, g, 0.0035 mol) in DMF (12 mL) was added (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (1.0 g, CAS: 72180-27-9, Journal of Medicinal Chemistry, 2007, 50(20), 4953-4975), NMM (0.9 mL) and HOBT (0.644 g), and the reaction was stirred for 10 minutes. EDCI (0.80 g) was then added and the reaction mixture was stirred at room temperature for 5 h. The reaction was diluted with water (30 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The organic layer was separated and dried over anhydrous Na2SO4. Concentration of the organic layer under reduced pressure using rotary evaporator gave sticky crude material, which was purified through column chromatography (10-20% ethyl acetate:hexane, silica 100-200, Diameter of column—2.5 cm, Height of silica—approx. 7 inch) to give the desired (S)-4,4-difluoro-2-(5-hydroxy-adamantan-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (1.2 g, 78%) as a white solid.