Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14]([OH:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14]([O:16][C:30](=[O:32])[CH3:31])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(O)c2ccccc21
Product: CC(=O)OC1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (described above, 3.0 g) in acetic anhydride (50 ml) was heated at 80° under a dry nitrogen atmosphere for 2 hours. The acetic anhydride was evaporated. The residue was dissolved in ethyl acetate (75 ml) and washed with saturated sodium bicarbonate (50 ml), water (50 ml), and saturated sodium chloride (50 ml). The organic phase was dried (sodium sulfate), evaporated, and the residue triturated with ether (50 ml) to give 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 164°-166.5° C. [α]D =-169° (C=0.36 in DMF).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH:2]([CH3:4])[CH3:3].[CH3:13][C:14]([CH3:16])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:14]([CH3:16])([CH3:13])[O:12][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)Cc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Cc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using 4.16 g (25 mM) of 4-isobutylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 15 ml of toluene. 5-Isobutyl-2,2-dimethyl-1,3-benzodioxol was obtained in the yield of 4.69 g (23 mM) as colorless transparent liquid having a boiling point of 79°-83° C./2 mmHg.
Reaction SMILES: C([O:8][C:9](=[O:46])[CH2:10][C@@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30]1)[C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.CC(O)=O>CCO>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)=[CH:30]1)[CH2:10][C:9]([OH:46])=[O:8])[C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)C(=O)Nc1ccncc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 40.8 %

Procedure:
According to the procedure described in Example 7(a), N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester (185 mg, 0.280 mmol) was hydrogenolyzed in EtOH (10 mL) and HOAc (1 mL) and furnished a solid that was triturated with EtOAc to give 60 mg (41%) of N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow solid. 1H NMR (CD3OD): δ 8.54 (d, 2H, J=6.6 Hz), 8.33 (d, 2H, J=6.6 Hz), 7.73-7.68 (m, 4H), 7.64-7.59 (m, 4H), 7.32 (s, 1H), 6.91 (t, 1H J=2.4 Hz), 6.52 (dd, 1H, J=1.8, 2.9 Hz), 5.31 (t, 1H, J=7.5 Hz), 4.41 (s, 1H), 2.99(dd, 1H, J=6.8, 16.7 Hz), 1.03 (s, 9H). Anal. Calculated for C30H31N5O4.0.6 H2O.0.2 EtOAc: C, 66.77; H, 6.15; N, 12.64. Found: C, 66.72; H, 5.99; N, 12.62.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[O:24][C:23]([C:25](O)=[O:26])=[N:22][N:21]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[O:24][C:20]([CH3:19])=[N:21][N:22]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1nnc(C(=O)O)o1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1nnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)o1
Yield: 3.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.652 mmol) and 5-methyl-1,3,4-oxadiazole-2-carboxylic acid (100 mg, 0.782 mmol). The product was purified twice by Flash-chromatography (normal phase and reverse phase). Yield 3.7%. 1H-NMR (400 MHz; MeOD): δ 1.28 (d, 3H), 2.58 (s, 3H), 4.30-4.44 (m, 2H), 4.53-4.64 (m, 1H), 6.76-6.78 (m, 1H), 7.71 (d, 1H), 7.76-7.80 (m, 1H), 7.86-7.90 (m, 1H), 8.02-8.04 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd].[C]>[CH3:19][C:14]1([CH3:20])[CH2:13][CH:12]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15]1
Reactant: CN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O

Procedure:
7.3 g of N-[6-benzyloxy-2,2-dimethylchroman-4-yl]-N-methylmethanesulfonamide were dissolved in 100 ml of THF/methanol (1:1) and hydrogenated in a shaking duck using Pd/carbon. After absorpt ion of hydrogen was complete, the catalyst was filtered off with suction, the filtrate was concentrated and the residue was crystallized using dhsopropyl ether/petroleum ether, 5.2 g, m.p. 159-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([F:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([F:29])[CH2:26][N:25]5[CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](F)CN1
Reactant: C=O
Product: CN1C[C@H](F)C[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (Example 184) and formaldehyde following General Procedure R.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:16][CH2:17]O>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1ccccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1O
Yield: 97.25 %

Procedure:
To a solution of 2-hydroxybenzoic acid (63) (5.0 g, 36.2 mmol) in anhydrous EtOH (150 ml) was added 98% H2SO4 (4 ml). The mixture was refluxed for 4 h and concentrated. The residue was extracted with CH2Cl2 dried over MgSO4 and evaporated. The crude was purified by distillation to give 68 as colorless liquid. (5.85 g, 35.21 mmol). Yield: 97.25%; MS (EI, 70 eV): m/z 166.2 (M+); 1H-NMR (CDCl3, 200 MHz): δ 1.39 (t, J=7.2 Hz, 3H), 4.37 (q, J=7.2, 7.0 Hz, 2H), 6.81 (t, J=6.6 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.82 (dd, J1=8.0, 1.8 Hz, 1H), 10.83 (s, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 170.20, 161.64, 135.56, 129.89, 119.06, 117.53, 61.40, 14.18; Anal. Calcd for C9H10O3: C, 65.05; H, 6.07.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:41]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[NH2:41][C:10]1[CH:11]=[C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c(N)c1

Procedure:
Acetic acid (R)-1-(4-benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethyl ester in a mixture of THF and toluene is stirred under hydrogen in the presence of PtO2 at room temperature for 15 hours. The mixture is filtered through celite and the filtrate is concentrated in vacuo. ES+ MS m/e 549 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH:14]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl>COCCO.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:26][C:25]1[CH:24]=[N:23][C:22]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:3]=3)[S:8](=[O:10])(=[O:9])[NH:11][CH2:12][C:13]3[CH:14]=[C:15]([NH:19][C:20]=1[N:21]=2)[CH:16]=[CH:17][CH:18]=3
Reactant: Nc1cccc(S(=O)(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COCCO
Product: O=S1(=O)NCc2cccc(c2)Nc2nc(ncc2Cl)Nc2cccc1c2
Temperature: 150 °C

Procedure:
To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}benzenesulfonamide (38.0 mg, 0.089 mmol) in 2-methoxyethanol (0.49 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (45 μL). The resulting mixture was heated at 150° C. in the microwave for 15 min. The mixture was diluted with Na2CO3 (aq), extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the crude, which was purified by Combi-Flash column chromatography (4 g column, 0 to 50% EtOAc in Hex) to the desired product as a white powder (7 mg, 20%). LCMS for C17H14ClN5O2S (M+H)+: m/z=388.0, 390.0. 1H NMR (400 MHz, CD3OD): δ 7.62 (m, 1H), 7.54 (s, 1H), 7.28 (t, J=2.0 Hz, 1H), 7.08 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 6.78 (t, J=8.0 Hz, 1H), 6.35 (m, 1H), 6.18 (ddd, J=8.0, 1.6, 1.0 Hz, 1H), 5.98 (m, 1H), 5.82 (ddd, J=7.6, 2.0, 1.0, 1H), 4.20 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:19])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:8][C:9]=1[N+:20]([O-:22])=[O:21])[CH3:2]
Reactant: CCOc1ccc(C(=O)C(=O)c2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCOc1ccc(C(=O)C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To 0.5 gram of 1-(4-ethoxyphenyl)-2-phenylethane-1,2-dione prepared in Step 1, was add 10 milliliters of concentrated nitric acid and the resulting mixture was heated to 110° C. for 2 hours. The reaction mixture was cooled and poured into 20 milliliters of water. The precipitate was recrystallized from ethanol to give 1-(4-ethoxy-3-nitrophenyl)-2-phenylethane-1,2-dione. The synthesis is summarized by the equation:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[N:11]1([CH:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:19][CH2:18][CH2:17][CH:16]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH3:20])=[O:8])=[CH:9][CH:10]=1
Reactant: CC(CCN)n1ccnc1
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CC(CCNC(=O)c1ccc(Cl)nc1)n1ccnc1

Procedure:
When 6-chloronicotinic acid was reacted with 3-(1H-imidazol-1-yl)butanamine by the procedure of Example 20 the desired compound was obtained, mp 137°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc(I)cn1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc(-c2ccccc2)cn1
Yield: 70.5 %

Procedure:
A mixture of 2-chloro-5-iodopyridine (5.0 g, 20.9 mmol), phenylboronic acid (2.6 g, 20.9 mmol), Pd(Ph3P)4 (1.45 g 1.25 mmol), sodium carbonate (6.64 g, 62.6 mmol), DME (20 mL) and water (5 mL) was degassed with nitrogen and then refluxed overnight. The mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then vacuum distilled to give 2-chloro-5-phenylpyridine (2.79 g, 14.71 mmol (70.5% yield).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](O)=[O:26]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:21]3[NH:20][CH:24]=[CH:23][CH:22]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1ccc[nH]1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1ccc[nH]1
Yield: 80 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless prisms, melting at 136°-137° C., in an 80% yield.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](=[O:23])N(OC)C)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18](=[O:23])[CH3:25])[CH2:16][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 500 mL flask was charged with 15.2 g (45.4 mmol) trans-[4-(methoxy-methyl-carbamoyl)-cyclohexylmethyl]-carbamic acid benzyl ester and 350 mL anhydrous THF. The soluton was cooled to 0° C. then 33.3 mL (99.9 mmol) 3M CH3MgCl was added dropwise over 10 minutes. The reaction mixture was then stirred for 1 hour at 0° C. then quenched with 20 mL 2N acetic acid and poured into 300 mL water. The aqueous was extracted with ethyl acetate (3×200 mL) and the combined organics were washed with 0.5M HCl (1×100 mL), water (1×100 mL), brine (1×100 mL), dried over Na2SO4 and concentrated to a solid. The solid was recrystalized from IPE and filtered to give 5.5 g of a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[CH2:39][C:40](OC)=[O:41]>CN(C=O)C>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]2[N:6]3[N:5]=[C:4]([C:7]4[CH:8]=[CH:9][C:10]([O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[CH:11][CH:12]=4)[C:3]([C:20]([NH2:22])=[O:21])=[C:2]3[NH:1][C:40](=[O:41])[CH2:39][C:31]=2[CH:32]=1)([O-:38])=[O:37]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)Cc1cc([N+](=O)[O-])ccc1-2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (30 mg, 0.10 mmol) in DMF (5 mL) was added K2CO3 (28 mg, 0.20 mmol) and methyl 2-(2-fluoro-5-nitrophenyl)acetate (21 mg, 0.10 mmol). The mixture was warmed to 80° C. stirred for about 16 hr. After cooling down to RT, the mixture was concentrated under reduced pressure to remove solvent. The residue was portioned with DCM (10 mL) and water (10 mL), the aqueous was extracted with DCM (2×10 mL), the combined organic phases were washed sat. Sodium chloride (10 mL), dried over anhydrous Sodium sulfate, filtered, concentrated and purified by pre-TLC (DCM/CH3OH=20/1) got the product about 10 mg (21.9%). 1H NMR (400 MHz, DMSO-d6) δ 10.66 (br s, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.37 (dd, J=2.6, 9.2 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.65-7.53 (br s, 2H), 7.45-7.40 (m, 2H), 7.22-7.16 (m, 1H), 7.12-7.05 (m, 4H), 3.92 (s, 2H). MS (ESI) m/e [M+1]+ 456.1.
Reaction SMILES: [Na].[C:2]([C:4]([C:11]#[N:12])=[C:5]([NH:8][C:9]#[N:10])[S:6][CH3:7])#[N:3].[ClH:13]>C(OCC)C>[NH2:10][C:9]1[N:3]=[C:2]([Cl:13])[C:4]([C:11]#[N:12])=[C:5]([S:6][CH3:7])[N:8]=1
Reactant: Cl
Reactant: CSC(NC#N)=C(C#N)C#N
Agent: [Na]
Solvent: CCOCC
Product: CSc1nc(N)nc(Cl)c1C#N
Temperature: 25 °C

Procedure:
The compound of formula (56), the sodium salt of 2,2-dicyano-1-methylsulfanyl-vinyl-cyanamide, is reacted by addition to a large excess of anhydrous hydrogen chloride in an ethereal solvent, preferably diethyl ether, at 0° C. and the mixture is allowed to warm slowly to room temperature for over 1-36 hours, preferably 18 hours. The product of formula (57), 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile, is isolated by conventional means, and preferably purified by means of recrystallisation or chromatography. Alternatively, the compound of formula (56), the sodium salt of 2,2-dicyano-1-methylsulfanyl-vinyl-cyanamide, is reacted with hydrogen bromide in a protic solvent, preferably acetic acid, at 5° C. and the mixture is allowed to warm slowly to room temperature for over 1-36 hours, preferably 1 hour. The product of formula (57), 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, is isolated by conventional means, and preferably purified by means of recrystallisation or chromatography.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:22](=[CH:23][CH:24]=[C:15]3[O:14][CH2:13]2)[N:21]=[C:20]([CH3:25])[CH:19]=[CH:18]4)(=O)=O)=CC=1.[S:28]1[C:32]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:31][C:30]2[CH:39]=[CH:40][CH:41]=[CH:42][C:29]1=2>CS(C)=O>[S:28]1[C:32]([C:33]2[CH2:34][CH2:35][N:36]([CH2:11][CH:12]3[O:26][C:16]4=[C:17]5[C:22](=[CH:23][CH:24]=[C:15]4[O:14][CH2:13]3)[N:21]=[C:20]([CH3:25])[CH:19]=[CH:18]5)[CH2:37][CH:38]=2)=[CH:31][C:30]2[CH:39]=[CH:40][CH:41]=[CH:42][C:29]1=2
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC=C(c2cc4ccccc4s2)CC1)O3
Temperature: 90 °C
Reaction time: 18 h
Yield: 137.8 %

Procedure:
To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-toluenesulfonate (0.638 g, 1.66 mmol) and 4-benzo[b]thiophen-2-yl-1,2,3,6-tetrahydro-pyridine (0.46 g, 2.1 mmol) was added 12 mL of dimethylsulfoxide. The mixture was stirred at 90° C. for 18 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between 500 mL each of methylene chloride and saturated aqueous sodium bicarbonate. The methylene chloride layer was washed with water twice and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.98 g of oil. This was chromatographed on silica gel with a gradient of ethyl acetate and hexane. The product fractions were collected and concentrated in vacuum to give 0.39 g of the title compound as nearly pure, light yellow oil. This was triturated with ethanol to give 0.2563 g of the S enantiomer of the title compound as a light yellow solid, m.p. 174-176° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C@@H:8]2[O:25][C@H:24]([CH2:26][O:27]C(=O)C)[C@@H:19]([O:20]C(=O)C)[C@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[C:3]=1[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.[OH-].[Na+]>C(O)C>[C@@H:8]1([O:7][C:4]2[C:3]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([CH:38]4[CH2:40][CH2:39]4)=[CH:36][CH:37]=3)=[C:2]([CH3:1])[NH:6][N:5]=2)[O:25][C@H:24]([CH2:26][OH:27])[C@@H:19]([OH:20])[C@H:14]([OH:15])[C@H:9]1[OH:10]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(C3CC3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of 5-methyl-4-[(4-cyclopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.14 g) in ethanol (8.4 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.63 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (0.087 g).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:40]([C:52](=[O:54])[NH2:53])[CH:39]=1)[CH2:15][CH:16]([OH:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=2)=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CI>CN(C)C=O>[CH2:7]([N:14]([CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:40]([C:52](=[O:54])[NH2:53])[CH:39]=1)[CH2:15][CH:16]([OH:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]([CH3:1])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=2)=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3nc(C(F)(F)F)c[nH]3)cc2)ccc1OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CN(CCOc2ccc(OCc3ccccc3)c(C(N)=O)c2)Cc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
At 0°, 0.18 g of potassium tert.-butoxide is added to a solution of 1.0 g of 1-[N-benzyl-2-(3-carbamoyl-4-benzyloxyphenoxy)-ethylamino]-3-[4-[4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol in 5 ml of dimethylformamide and the mixture is stirred for 20 minutes in an ice bath. At 0°-5°, a solution of 0.12 ml of methyl iodide in 3 ml of dimethylformamide is added and the mixture is then stirred for 4 hours at room temperature. The reaction solution is concentrated by evaporation, the residue is dissolved in water and the solution is extracted with ethyl acetate. After drying the organic phase over sodium sulphate, this is concentrated to dryness by evaporation, yielding the crude 1-[N-benzyl-2-(3-carbamoyl-4-benzyloxyphenoxy)-ethylamino]-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol which is further processed in that form.