Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[CH:27]=1)=[O:24].[NH2:34][C@H:35]([CH2:37][OH:38])[CH3:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:34][C@@H:35]([CH3:36])[CH2:37][OH:38])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[CH:27]=1)=[O:24]
Reactant: C[C@H](N)CO
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)C)no4)c3)c(=O)n(C)c2n1
Product: CC(C)c1cc(NC(=O)Nc2cc(-c3cc4cnc(N[C@@H](C)CO)nc4n(C)c3=O)ccc2F)on1
Yield: 42 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (0.150 g, 0.322 mmol, 1.00 eq) was oxidized and reacted with L-alaninol (41.4 μL, 0.533 mmol, 2.00 eq) to afford (S)-1-(2-fluoro-5-(2-(1-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (67 mg, 51% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 8.73 (brs, 1H), 8.65 (brs, 1H), 8.39 (dd, J=2.4 and 8.0 Hz, 1H), 7.87 (s, 1H), 7.60-7.57 (m, 1H), 7.35-7.25 (m, 2H), 6.06 (s, 1H), 4.70 (t, J=6.0 Hz, 1H), 4.09 (brs, 1H), 3.58-3.49 (m, 4H), 3.35 (brs, 1H), 2.89 (m, 1H), 1.23 (s, 9H), 1.17-1.15 (m, 9H); MS (ESI) m/z: 496.3 (M+H+).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)=O)(=O)OC.O.[NH2:26][NH2:27]>>[CH3:24][N:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]1[CH:16]=[C:3]2[C:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)=[N:27][N:26]=1
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1cccn1C)OC
Reactant: NN
Solvent: O
Product: Cn1cccc1-c1cc2c(nn1)C1CCC2C1

Procedure:
off-white solid. MS (EI): 225.29 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([NH:8][C:9]2[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[N+:22]([O-])=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:22][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])[C:9]=1[NH:8][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:26][CH:25]=1)[C:13]([OH:15])=[O:14]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccc(C(=O)O)cc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(C(=O)O)cc1

Procedure:
By substituting 4-(p-carboxyanilino)-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 262°C (decomp.) after drying in vacuo at 115°C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(COC)OC.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C

Procedure:
0.30 g of methyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate, 0.19 g of bromobenzene, 57mg of 1,1-bis(diphenylphosphino)ferrocene dichloropalladium and 0.55 g of potassium carbonate were dissolved in 15 ml dimethoxyethane, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate and water were added thereto. The mixture was filtered through Celite, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), methyl 2-chloro-4-phenylbenzoate was obtained. Then, the resulting methyl 2-chloro-4-phenylbenzoate was dissolved in 4 ml methanol, and 2 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 0.12 g of 2-chloro-4-phenylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Br[C:12]1[CH:13]=[C:14]([C:31]([NH2:33])=[O:32])[C:15]2[NH:16][C:17]3[CH:18]=[C:19]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=[CH:21][C:22]=3[C:23]=2[N:24]=1>>[Cl:1][C:2]1[CH:9]=[C:8]([C:12]2[CH:13]=[C:14]([C:31]([NH2:33])=[O:32])[C:15]3[NH:16][C:17]4[CH:18]=[C:19]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:20]=[CH:21][C:22]=4[C:23]=3[N:24]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: O=Cc1ccc(Br)cc1Cl
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12

Procedure:
This was similarly prepared from 2-chloro-4-bromobenzaldehyde and 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide. MS (ESI) m/z 506.35 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.30 (1H, s), 8.54 (1H, s), 8.31-8.37 (2H, m), 8.24 (1H, dd, J=8.09, 1.68 Hz), 8.08 (1H, d, J=8.85 Hz), 7.84 (1H, s), 7.64 (1H, d, J=8.24 Hz), 7.23 (1H, d, J=2.14 Hz), 7.02 (1H, dd, J=8.85, 2.14 Hz), 3.78-3.87 (4H, m), 3.65 (2H, s), 3.60-3.64 (4H, m), 3.22-3.27 (4H, m), 2.45-2.50 (4H, m).
Reaction SMILES: [Na+].[F:2][C:3]1[CH:4]=[C:5]([CH:37]=[CH:38][CH:39]=1)[CH2:6][N:7]([CH3:36])[C:8]([C:10]1[C:11]([CH:33]([CH3:35])[CH3:34])=[C:12]([CH2:22][CH2:23][CH:24]([OH:32])[CH2:25][CH:26]([OH:31])[CH2:27][C:28]([O-:30])=O)[N:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1)=[O:9].C(O)(C(F)(F)F)=O>CC#N.CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([CH:37]=[CH:38][CH:39]=1)[CH2:6][N:7]([CH3:36])[C:8]([C:10]1[C:11]([CH:33]([CH3:35])[CH3:34])=[C:12]([CH2:22][CH2:23][CH:24]2[CH2:25][CH:26]([OH:31])[CH2:27][C:28](=[O:30])[O:32]2)[N:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1)=[O:9]
Reactant: CC(C)c1c(C(=O)N(C)Cc2cccc(F)c2)nn(-c2ccc(F)cc2)c1CCC(O)CC(O)CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)c1c(C(=O)N(C)Cc2cccc(F)c2)nn(-c2ccc(F)cc2)c1CCC1CC(O)CC(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a 7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt (270 mg, 0.49 mmol) in MeCN (50 ml) was slowly added TFA (1.0 mL, 1.23 mmol). The reaction mixture was stirred at 25° C. and monitored by HPLC. After 2 hrs, the reaction was completed. The reaction mixture was diluted with EtOAc (150 ml) and washed with H2O, saturated NaHCO3, and brine. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (70% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid (3-fluoro-benzyl)-methyl-amide (210 mg, 84%): MS(APCI+) 512.2 m/z (M+H); H-NMR (CDCl3) [Mixture of rotamers at 25° C.] δ 7.40-7.21, 7.18-6.88, 4.72, 4.611, 4.58-4.48, 4.33-4.24, 2.98-2.93, 2.80-2.68, 2.63, 2.63 2.62, 2.61, 2.57, 2.56, 2.55, 2.17-2.14, 1.80-1.63, 1.61-1.58, 1.31-1.29.
Reaction SMILES: NC(N)=[S:3].[C:5]([O:9][C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:13]1[CH2:15]O1)([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([O:9][C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:13]1[CH2:15][S:3]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: NC(N)=S
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CO1)C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CS1)C(=O)OC(C)(C)C
Yield: 83.6 %

Procedure:
Methanol (4 ml) and thiourea (83 mg, 1.096 mmol) were added to (S)-2-tert-butoxycarbonylamino-3-oxiranyl-propionic acid tert-butyl ester (Compound 30) (315 mg, 1.096 mmol), and the reaction solution was heated at reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-2-tert-butoxycarbonylamino-3-thiiranyl-propionic acid tert-butyl ester (Compound 31) (278 mg, 84%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:32][C:33]1[S:37][C:36]([C:38]2[CH:39]=[N:40][N:41]([CH3:46])[C:42]=2[C:43]([OH:45])=O)=[N:35][C:34]=1[CH:47]([F:49])[F:48].[C:50]1([C:56]2[N:57]=[C:58]3[CH:63]=[C:62]([NH2:64])[CH:61]=[CH:60][N:59]3[CH:65]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C)C=O>[Cl:32][C:33]1[S:37][C:36]([C:38]2[CH:39]=[N:40][N:41]([CH3:46])[C:42]=2[C:43]([NH:64][C:62]2[CH:61]=[CH:60][N:59]3[CH:65]=[C:56]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:57]=[C:58]3[CH:63]=2)=[O:45])=[N:35][C:34]=1[CH:47]([F:49])[F:48]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2c1
Reactant: Cn1ncc(-c2nc(C(F)F)c(Cl)s2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc(-c2nc(C(F)F)c(Cl)s2)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.4 %

Procedure:
Diisopropylethylamine (0.30 ml) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (276 mg) were added to an N,N-dimethylformamide (0.72 ml) solution of the 4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (42 mg) obtained in (Example 1.7) <Step 2>. The obtained mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. Thereafter, 2-phenylimidazo[1,2-a]pyridin-7-amine (30 mg) was added to the reaction solution, and the obtained mixture was then stirred at 60° C. for 1 hour. Thereafter, the reaction solution was fractionated and purified by LC/MS to obtain the title compound (1 mg) in the form of a light brown solid.
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.O.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:18]([O:17][C:15]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=2)[CH2:2]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.5 %

Procedure:
A solution of 8.00 g (49 mmol) of 6-Methoxy-1,2,3,4-tetrahydro-isoquinoline in 196 mL of 48% hydrobromic acid was refluxed for 3 h. The mixture was then concentrated and coevaporated several times with ethanol. The resulting slurry was filtered and dried under vacuum to give 7.43 g of 1,2,3,4-Tetrahydro-isoquinolin-6-ol hydrobromide as a solid. To 7.38 g of the crude hydrobromide dissolved in 117 mL each of dioxane and water was added 6.34 g (35.3 mmol) of benzyl chloroformate with ice bath cooling. A 1 M solution of potassium carbonate was slowly added until a pH of 10 was maintained. The mixture was stirred overnight at room temperature. Excess dioxane was removed by evaporation, and the resulting aqueous mixture was acidified with 1 N HCl and the product extracted with ethyl acetate. The organic portion was washed with water and brine, dried over Na2SO4 and concentrated to give 10.4 g of an oil which was crystallized from ether/hexane to give 7.05 g of 7D as a solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH3:12][C:13]([CH3:25])([C:16](=[O:24])[CH:17]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH3:18])[CH2:14][F:15]>C1COCC1>[CH3:25][C:13]([CH3:12])([C:16]([CH:17]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH3:18])([OH:24])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:14][F:15]
Reactant: CC(C(=O)C(C)(C)CF)n1cncn1
Reactant: C#CCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC#CC(O)(C(C)n1cncn1)C(C)(C)CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a stirred solution of hex-1-yne (1.23 g, 15 mmol) in dry THF (40 ml) was added n-butyl lithium (6 ml of 2.6M, 15 mmol) at -78° C. under a nitrogen atmosphere. After 15 minutes, a solution of 2,2-dimethyl-1-fluoro-4-(1H-1,2,4-triazol-1-yl)-pentan-3-one (2.5 g, 13 mmol) in dry THF (20 ml) was added dropwise. Upon complete addition the mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then poured onto ice and extracted with ether (2×250 ml). The ethereal solution was washed with saturated brine solution then dried over anhydrous magnesium sulphate and the solvent removed. The resulting yellow oil was chromatographed (silica gel, petrol/diethyl ether elution) to give a yellow gum (2.0 g, 56.5%) which was a mixture of the RS/SR and the RR/SS forms. This gum was then purified by preparative chromatography to give the pure RS/SR form as a white solid (0.24 g, 6.8%), mp. 72°-74° C. (Found: C, 63.5; H, 9.0; N, 15.0C15H24FN3O requires C, 64.1; H, 8.5; N, 14.95%); IR 3200, 2950, 2225, 1360, 1280, 1200, 1140, 1000, 870, 680 cm-1 ; NMR (90 MHz; CDCl3) 0.8 (6H, s); 0.9 (3H, t, J 7 Hz); 1.2-1.56 (4H, m); 1.72 (3H, d, J 6.3 Hz); 2.24 (2H, m); 3.8 (1H, br); 4.36 (2H, dq, J 46.8 and 6.3 Hz), 4.8 (1H, q, J 6.3 Hz); 7.95 (1H, s); 8.24 (1H, s); m/z 282 (M+H+) 206, 185, 109, 97 (100%), 82. The RR/SS component could not be isolated in a pure state thus, a 1:1 mixture of the RS/SR and RR/SS forms was obtained as a yellow oil (0.34 g, 9.6%); NMR (90 MHz; CDCl3) 0.8 (6H, s); 0.92 (3H, t, J 7 Hz); 1.2-1.56 (4H, m); 1.66 (3H, d, J 6.3 Hz); 2.13 (2H, m); 3.8 (1H, br); 4.36 (2H, dq, J 46.8 and 6.3 Hz), 4.76 (1H, q, J 6.3 Hz); 7.93 (1H, s); 8.26 (1H, s); m/z 282 (M+H+), 206, 185, 109, 97 (100%), 82.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[O:30][CH3:31])N=[CH:19][N:18]=2)=[O:15])[CH2:10]1.[CH3:32]C(O)=O.O>C(Cl)Cl>[C:1]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[O:30][CH3:31])[CH:32]=[CH:19][N:18]=2)=[O:15])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: COc1cc(F)ccc1-c1cc(NC(=O)[C@H]2CC[C@@H](N)C2)ncn1
Solvent: ClCCl
Solvent: O
Product: COc1cc(F)ccc1-c1ccnc(NC(=O)[C@H]2CC[C@@H](NC(C)=O)C2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.3 %

Procedure:
Acetic anhydride (0.035 ml, 0.304 mmol) was added to a solution of (1S,3R)-3-Amino-N-(6-(4-fluoro-2-methoxyphenyl)pyrimidin-4-yl)cyclopentanecarboxamide (100 mg, 0.30 mmol) in DCM (5 ml) and catalytic amount of AcOH (0.1 ml) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2.5 h. Water was added to the reaction mixture and extracted with DCM (3×25 ml). The combined organic layer was washed with water, brine and dried over anhydrous sodium sulfate and concentrated in vacuo to afford 90 mg (80.3%) of (1S,3R)-3-acetamido-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclopentanecarboxamide as an off white solid. 1H-NMR (400 MHz, DMSO-d6): δ=10.52 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.92 (t, 1H), 7.39-7.36 (m, 1H), 7.19-7.02 (m, 2H), 6.92 (q, 1H), 4.02 (t, 1H), 3.90 (s, 3H), 2.98 (t, 1H), 2.17-2.10 (m, 1H), 1.91-1.62 (m, 6H), 1.59-1.42 (m, 2H), HPLC (λ=214 nm, [A]): rt 10.4 min (100%), Chiral HPLC: 98.52%, mp: 125-129° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:10]=[C:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:8]=[C:7]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[C:4]=1[C:5]#[N:6].C=O.[C:31]([BH3-])#N.[Na+]>CO>[NH2:2][C:3]1[N:10]=[C:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH:20]2[CH2:21][CH2:22]2)[CH:8]=[C:7]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:31])[CH2:24]2)[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(C2CCCNC2)cc(-c2c(O)cccc2OCC2CC2)nc1N
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a stirred solution of 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinonitrile hydrochloride (200.0 mg, 0.50 mmol) in MeOH were added formaldehyde (0.5 mL) and sodium cyanoborohydride (40.8 mg, 0.65 mmol) and stirred for 2 hrs at room temperature. The reaction was quenched by an addition of water, extracted with ethyl acetate, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and dried. The crude product was purified by preparative silica gel TLC (5% MeOH in dichloromethane) to give 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)nicotinonitrile as a yellow solid. (28.5 mg, yield 15%)
Reaction SMILES: [C:1]1(=[O:15])[C:14]2[N:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH2:5][CH2:4][CH2:3][NH:2]1.CS(O[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)(=O)=O>>[O:15]=[C:1]1[C:14]2[N:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH2:5][CH2:4][CH2:3][N:2]1[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23]1
Reactant: O=C1NCCCn2nc3ccccc3c21
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Product: CC(C)(C)OC(=O)N1CCCC(CN2CCCn3nc4ccccc4c3C2=O)C1

Procedure:
The product was prepared using the method described in example 1d), using 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-b]indazol-1-one and tert-butyl 3-{[(metylsulphonyl)oxy]methyl}piperidine-1-carboxylate as reagents. Thus, 3.6 g of tert-butyl 3-[(1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-b]indazol-2(3H)-yl)methyl]piperidine-1-carboxylate were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([Cl:10])=[C:4](Cl)[C:3]=1[Cl:12].[NH2:13][NH2:14].C(N(CC)CC)C>C(O)C>[Cl:10][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([Cl:1])=[C:3]([Cl:12])[C:4]=1[NH:13][NH2:14]
Reactant: NN
Reactant: N#Cc1nc(Cl)c(Cl)c(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1nc(Cl)c(Cl)c(NN)c1Cl
Temperature: 45 °C

Procedure:
To a reaction flask was added 400 milliliters of 95 percent ethanol and 24.2 grams (0.10 mole) of tetrachloropicolinonitrile. The mixture was heated to 45°C. with stirring and 3.7 grams (0.11 mole) of 95 percent hydrazine and 10.1 grams (0.10 mole) of triethylamine was added thereto. The mixture was heated under reflux for 1 hour and the reaction mixture thereafter cooled to 40°C. To this mixture was added 400 grams of an ice-water mixture and the solid 3,5,6-trichloro-4-hydrazinopicolinonitrile product which precipitated was recovered by filtration, water washed and dried. The product was recovered in a yield of 20.6 grams (87 percent of theoretical) melting at 178°-181°C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(CCCF)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(CCCF)cc3)cc2)C1
Yield: 19.7 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-(3-fluoro-propyl)-benzenesulfonyl chloride (161 mg, 0.68 mmol). Purification of the crude product by chromatography on reversed phase silica gel (H2O+0.1% acetic acid:CH3CN+0.1% acetic acid, 75:25) provided the title compound (40 mg, 20%) as a colourless gum.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(OC([N:29]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[CH3:38])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH2:39]([N:29]1[C:10]2[C@:9]3([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:18](=[O:19])[N:30]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[CH3:38])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1cccc(NN(Cc2ccccc2)C(=O)OC(C)(C)C)c1C
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cccc(-n2c(=O)c3c(n2Cc2ccccc2)[C@@]2(C)CC[C@@H]3C2(C)C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
Triethylamine (440 μL, 3.2 mmol) was added to solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 329 mg, 1.5 mmol) in 1,2-dichloroethane (6 mL) over 1 min. Then a solution of N-benzyl-N′-(2,3-dimethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (450 mg, 1.38 mmol) in 1,2-dichloroethane (12 mL) was added over 2 min. The reaction mixture was stirred at room temperature for 15 min and then heated in an oil bath at 50° C. for 2 h and then at 60° C. for 1 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 1 h. The reaction mixture was allowed to cool, silica gel was added, the solvent was evaporated and the mixture was purified using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes and then 5% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, and then treated with methanol and charcoal. This mixture was stirred for 20 min, filtered through Celite and evaporated to give an orange gum. The gum was purified for a second time using an ISCO 40 g column, eluting with 2-4% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, co-evaporated with diethyl ether and petroleum ether, and then dried under high vacuum at room temperature to give (4R,7S)-1-benzyl-2-(2,3-dimethyl-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (57 mg, 11%) as an off-white foam. ES(+)-MS (M+H) 387.
Reaction SMILES: N1C=CN=C1.C1CCN2C(=NCCC2)CC1.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:27][C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:29]=1[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][N:41]=1>C1COCC1>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[C:29]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][N:41]=3)=[C:28]([NH:27][C:24](=[O:25])[CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:32][N:31]=2)=[CH:34][CH:35]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Agent: c1c[nH]cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.9 %

Procedure:
Imidazole 0.43 g and DBU 1.9 g were dissolved in 40 mL of THF. Under cooling with ice, 0.97 g of phenylacetyl chloride was dropped into the solution, followed by 20 minutes' stirring at room temperature. Then 40 mL of a THF solution containing 0.8 g of 5-amino-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole was dropped into the system and stirred at room temperature for 6 hours. From the reaction solution the solvent was distilled off under reduced pressure and water was added to the residue, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. Thus obtained residue was purified on 40 g silica gel column chromatography (eluent, chloroform:methanol=100:1) and washed with ether to provide 0.77 g of the title compound (yield: 66%) in the form of colorless crystal.