Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH2:52][CH3:53])[CH:8](C)[CH2:9][NH:10][C:11]([C@:13]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:44])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:12])([OH:3])=[O:2].NCCNC([C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(OC)=O)=CC=2)=CC3)CC1)=O>>[C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH2:52][CH3:53])[CH2:8][CH2:9][NH:10][C:11]([C@:13]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:44])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:12])([OH:3])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCC(C)N(CC)CCCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CCCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((3-carboxypropyl)(ethyl)amino)propylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (example 101) using methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as amine. The product was isolated as a white solid (3 mg, 25%). LCMS: m/e 715.45 (M+H)+, 2.06 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.88 Hz, 1H), 4.78 (s, 1H), 4.65 (s, 1H), 3.88-3.68 (m, 2H), 3.49-3.34 (m, 4H), 3.34-3.27 (m, 2H), 3.19-3.06 (m, 1H), 2.67-2.49 (m, 3H), 2.23-2.15 (m, 2H), 1.74 (s, 3H), 1.38 (t, J=7.17 Hz, 3H), 2.04-1.09 (m, 21H), 1.08 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: C(OC([CH:6]1[CH2:10][N:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:8][C:7]1=[O:19])=O)C.C(=O)=O.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[CH2:10][CH2:6][C:7](=[O:19])[CH2:8]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CN(c2ccc(OC)cc2)CC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Product: COc1ccc(N2CCC(=O)C2)cc1
Yield: 74.3 %

Procedure:
A mixture of 4-ethoxycarbonyl-1-(4-methoxyphenyl)pyrrolidine-3-one (10.53 g, 0.04 mol) in 6N hydrochloric acid (120 mL) is heated at 100° C. (bath temperature) until evolution of carbon dioxide ceases (about 1 hour). The mixture is cooled in an ice-bath, neutralized with potassium carbonate, and then is extracted with diethyl ether (4×200 mL). The combined extracts are washed with water, dried over sodium sulfate, concentrated, and then the residue is crystallized from diethyl ether-n-hexane to give 1-(4-methoxyphenyl)pyrrolidine-3-one (5.68 g, 67%), mp 104°-105° C. 1H NMR (CDCl3) d 2.68 (2H, t, 5-CH2), 3.61 (2H, t, 4-CH2), 3.63 (2H, s, 2-CH2), 3.77 (3H, s, OMe), 6.63 and 6.89 (each 2H, d, Ph).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16]CC)=[O:15])=[C:7]2[NH:19][C@H:20]1[CH2:23][C@@H:22]([O:24][CH3:25])[CH2:21]1>CO.C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]2[NH:19][C@H:20]1[CH2:23][C@@H:22]([O:24][CH3:25])[CH2:21]1
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1C[C@@H](OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@H]1C[C@@H](Nc2c(C(=O)O)cnc3ccc(Br)cc23)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Sodium hydroxide (190 ml, 379.70 mmol) was added to ethyl 6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylate (36 g, 94.92 mmol) in a mixture of MeOH (120 mL) and THF (120 mL) and the resulting mixture stirred at 60° C. for 3 h. The solvent was removed under reduced pressure and the mixture adjusted to pH 3 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water (300 mL) and dried under vacuum to afford the desired material (33.0 g, 99%) as a pale yellow solid, which was used without further purification. Mass Spectrum: m/z (ES+)[M+H]+=351.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]3[C:33](=[O:34])[N:32]([CH3:35])[C:23]4[N:24]=[C:25](S(C)(=O)=O)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:14]=2)[CH2:10][CH2:9]1.CO>C1COCC1>[CH:8]1([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]3[C:33](=[O:34])[N:32]([CH3:35])[C:23]4[N:24]=[C:25]([NH:1][CH:2]5[CH2:7][CH2:6][O:5][CH2:4][CH2:3]5)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:14]=2)[CH2:10][CH2:9]1
Reactant: NC1CCOCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnc(S(C)(=O)=O)nc2n(C)c1=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnc(NC3CCOCC3)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
4-Amino-tetrahydropyran (11 mg, 0.106 mmol) was dissolved in 2 mL THF, and N-cyclopropyl-3-(2-methanesulfonyl-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-4-methyl-benzamide (21 mg, 0.051 mmol) was added. The reaction mixture was stirred for 6.5 hours at room temperature, and then 1 mL MeOH was added. The resulting mixture was loaded directly onto a preparative TLC plate and eluted with 5% MeOH in methylene chloride to give N-cyclopropyl-4-methyl-3-[8-methyl-7-oxo-2-(tetrahydro-pyran-4-ylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-benzamide: MS (M+H)=434; MP=239.3-241.0° C.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(C1C=C(C2C=CC=C(N)C=2)C=CC=1)=O)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CCOC(=O)c1cccc(-c2cccc(N)c2)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that 3′-amino-biphenyl-3-carboxylic acid ethyl ester (prepared in two steps from 3-nitrophenylboronic acid) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.40 (1H, s), 8.29 (1H, t), 8.12-8.08 (1H, m), 7.85-7.81 (1H, m), 7.64-7.61 (1H, m), 7.57-7.47 (4H, m), 7.41-7.27 (3H, m), 7.06 (1H, d), 4.80 (1H, d), 4.65 (1H, d), 4.39 (1H, d), 4.25 (1H, d), 2.84-2.77 (1H, m), 2.02-1.70 (6H, m), 1.44-1.16 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 61.19; H, 7.07; N, 8.48%; C35H38N4O5.C7H17NO5.1.9H2O requires: C, 61.21; H, 7.19; N, 8.50%.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[C:12]([CH3:29])=[C:13]([CH:22]2[CH2:27][NH:26][C:25](=[O:28])[CH2:24][O:23]2)[C:14]([O:20][CH3:21])=[C:15]([CH:17](O)[CH3:18])[CH:16]=1>C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH3:29])=[C:13]([CH:22]2[CH2:27][NH:26][C:25](=[O:28])[CH2:24][O:23]2)[C:14]([O:20][CH3:21])=[C:15]([CH:17]([Cl:3])[CH3:18])[CH:16]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1C1CNC(=O)CO1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CNC(=O)CO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of thionyl chloride (15 μL, 0.21 mmol) and N,N-dimethylformamide (10.0 μL) was stirred at room temperature for 10 minutes. A solution of 6-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]morpholin-3-one (19.0 mg, 0.0634 mmol) (racemic mixture of two diastereomers from step 5) in methylene chloride (1.0 mL) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired compound as a racemic mixture of two diastereomers, 19 mg, 94%. LCMS calculated for C14H17ClNO3 (M-Cl)+: m/z=282.1; found: 282.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[O:20]([C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccsc1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1ccsc1
Temperature: 4 °C
Yield: 67.5 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-thiophenecarboxylic acid (5 g), N,N'-carbonyldiimidazole (6.3 g) and 2-amino-7-phenoxy-1,8-naphthyridine (8.3 g). The product produced by precipitation in water (11.6 g; m.p. 110° C.) is dissolved in boiling acetonitrile (50 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with diisopropyl ether (3×10 cc) and dried at 35° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-thiophenecarboxamide (8.2 g) is produced, m.p. 95° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[N:10][CH:9]=[CH:8][C:5]=1[C:6]#N.C([O-])(O)=[O:13].[Na+]>Cl>[C:6]1(=[O:13])[C:5]2[CH:8]=[CH:9][N:10]=[CH:11][C:4]=2[CH2:3][CH2:2][O:1]1
Reactant: N#Cc1ccncc1CCO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=C1OCCc2cnccc21
Yield: 15.29 %

Procedure:
3-(2-Hydroxyethyl) isonicotinonitrile (I-67d: 650 mg, 4.362 mmol) was heated with concentrated HCl (10 mL) at 100° C. overnight. The reaction mass was neutralized with NaHCO3 solution, extracted using DCM and the organic layer was concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 100 mg of the product (15.29% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Si]([O:15][C@H:16]1[C@H:20]2[O:21][CH2:22][C@@H:23]([O:24][C:25]3[N:26]([CH2:56][CH:57]=[CH2:58])[C:27]4[C:28]([N:55]=3)=[N:29][C:30]([C:34]3[CH:39]=[CH:38][C:37]([N:40]5[CH:44]=[C:43]6[CH2:45][N:46](C(OC(C)(C)C)=O)[CH2:47][C:42]6=[N:41]5)=[CH:36][CH:35]=3)=[C:31]([Cl:33])[CH:32]=4)[C@H:19]2[O:18][CH2:17]1)(C(C)(C)C)(C)C.[NH4+].[OH-].CO.C(O)C>C(Cl)Cl.C1C=CC=CC=1>[CH2:56]([N:26]1[C:27]2[C:28](=[N:29][C:30]([C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH:44]=[C:43]5[CH2:45][NH:46][CH2:47][C:42]5=[N:41]4)=[CH:38][CH:39]=3)=[C:31]([Cl:33])[CH:32]=2)[N:55]=[C:25]1[O:24][C@H:23]1[C@H:19]2[O:18][CH2:17][C@@H:16]([OH:15])[C@H:20]2[O:21][CH2:22]1)[CH:57]=[CH2:58]
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-c3ccc(-n4cc5c(n4)CN(C(=O)OC(C)(C)C)C5)cc3)c(Cl)cc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CNC5)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
TFA (3.2 ml, 41.5 mmol) was added to a stirred solution of tert-butyl 2-[4-[2-[[(3R,3aR,6R,6aS)-6-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy]-1-allyl-6-chloro-imidazo[4,5-b]pyridin-5-yl]phenyl]-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate (477.4 mg, 0.649 mmol) in DCM (3.2 ml). The reaction mixture was a pale yellow solution that was stirred at room temperature for 3 days. The reaction mixture was evaporated under reduced pressure to give a light yellow oil. Flash chromatography of the oil utilizing a 40 g silica RediSep Rf® column and employing a 0-10% (10% NH4OH/MeOH)/DCM gradient followed by 10% (10% NH4OH/MeOH)/DCM afforded the title compound as an off-white solid following lyophilization from ethanol and benzene. LC-MS: calculated for C26H25ClN6O4 520.16 observed m/e: 521.15 (M+H)+ (Rt 1.00/2 min)
Reaction SMILES: [CH3:1][S:2]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:17]>CN(C=O)C>[CH3:1][S:2]([C:5]1[N:6]([CH3:17])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1nc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(S(C)(=O)=O)nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a cooled (0° C.), stirred solution of 2-(methylsulfonyl)-1H-benzimidazole (4.60 g, 0.023 mol) in DMF (25 mL) was added NaH (60% dispersion in mineral oil; 0.94 g, 0.023 mol) in several portions. After 1 hour, iodomethane (3.33 g, 0.023 mol) was added. The cooling bath was removed and stirring was continued for 18 hours. The mixture was recooled to 0° C., H2O (75 mL) was added, and the off-white precipitate was collected by filtration to give 4.30 g (88%) of product m.p. 131°-132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH:15]1[CH2:23][C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]2[CH:17]([CH2:18][N:19]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:20]2)[C:16]1=[O:43])(=O)C.[Cl-].[NH4+].C(OCC)C>O1CCCC1>[CH2:36]([N:19]1[CH2:18][CH:17]2[CH:21]([C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:23][CH:15]([OH:14])[C:16]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:43])[CH2:20]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(=O)OC1CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Temperature: 0 °C
Yield: 64.8 %

Procedure:
To a suspension of 84.4 g of 2-methoxyphenylmagnesium bromide in 1000 cm3 of tetrahydrofuran is added dropwise, at room temperature and with stirring, a solution of 22 g of (3aRS,5RS,7aRS)-5-acetoxy-2-benzyl-7,7-diphenylperhydro-4-isoindolone in 220 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 18 hours, treated with 200 cm3 of saturated aqueous ammonium chloride solution, and taken up with 200 cm3 of diethyl ether and 200 g of ice. The organic phase is separated off after settling, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 250 cm3 of petroleum ether and then recrystallized in 200 cm3 of methanol; the crystals are washed with 200 cm3 of isopropyl ether. 16.4 g of (3aRS,4RS,5RS,7aRS)-2-benzyl-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol are obtained, melting at 236° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=O)[O:16]CC)=[C:4]([F:20])[CH:3]=1.[OH:21][CH:22]([C:27]([CH3:29])=[CH2:28])[C:23]([O:25]C)=O.Cl>C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:23](=[O:25])[C:22](=[C:27]([CH3:29])[CH3:28])[O:21][C:15]2=[O:16])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: C=C(C)C(O)C(=O)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (3.01 g, 10 mmol), methyl 2-hydroxy-3-methyl-3-butenoate (3.09 g, 30 mmol), ferric chloride (162 mg, 1.0 mmol) and tributylamine (92.7 mg, 0.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 3 hours. After the reaction solution was cooled to room temperature, toluene (30 mL) was added, and then the reaction solution was washed with 1N sodium hydroxide (20 mL×2) and 1N hydrochloric acid (20 mL×2). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, acidic methanol (5.0 mL) was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.25 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, washed with a 20:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (2.36 g, yield 66.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][NH:19][C:20]3[C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][N:23]=[C:22]4[N:31]([CH3:35])[N:32]=[C:33]([CH3:34])[C:21]=34)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][NH:19][C:20]3[C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=[C:22]4[N:31]([CH3:35])[N:32]=[C:33]([CH3:34])[C:21]=34)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1NCS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nn(C)c2ncc(C(=O)O)c(NCS(=O)(=O)c3ccc(Oc4ccc(Cl)cc4)cc3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
A mixture of 1.90 g (3.69 mmol) of the preceding ester and 4.05 ml (4.06 mmol) of 1 N KOH in 15 ml of tetrahydrofuran was stirred at room temperature for 2 days and then 0.75 ml of 1 N KOH was added and the mixture was refluxed overnight. The solvent was removed under vacuum and the toluene (25 ml) added to the residue and removed under vacuum. The residue was triturated with ethyl acetate and the solid filtered and dried under vacuum to give 1.6 g of 4-{[4-(4-chlorophenyloxy) benzenesulfonyl]methylamino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, potassium salt. Following the procedure of Example 52, 1.60 g of the preceding potassium salt was converted to the title compound to obtain 1.82 g of solid. This solid was purified on thick layer silica gel plates with 4% CH30H in ethyl acetate as solvent to give 0.59 g of light yellow solid, m.p. 120° C. dec.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1)([CH3:3])[CH3:2].[Br:10][C:11]1[N:12]=[C:13](Br)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:10][C:11]1[N:12]=[C:13]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=2)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: CC(C)n1cc(N)cn1
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(Nc2nc(Br)cn3ccnc23)cn1
Temperature: 25 °C
Yield: 144.8 %

Procedure:
A mixture of impure 1-isopropyl-1H-pyrazole-4-amine (2) (1.00 g), from above, 6,8-dibromoimidazo[1,2-a]pyrazine (3) (750 mg, 2.71 mmol), and N,N-diisopropylethylamine (526 mg, 4.16 mmol) in DMF (20 mL) was stirred at 100° C. for 3 h. After this time, the reaction was cooled to room temperature and poured into ice water (200 mL). The resulting suspension was filtered and the filter cake dried to a constant weight under vacuum to afford impure 6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4) (1.26 g) as an off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 4.49 (m, 1H), 1.40 (d, 6H); ESI MS m/z 323.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](O)=[O:41])=[CH:31]1.ON1C2C=CC=CC=2N=N1.[ClH:53].CN(C)CCCN=C=NCC.Cl>C(#N)C.C(O)C.CC(O)C>[ClH:53].[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:40](=[O:41])[CH2:39][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([CH3:29])[CH:31]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCc3cccnc3)ccc21
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CC(C)O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)Cc3cn(C)c4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.6 %

Procedure:
To a solution of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridine 3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.5 g), 1-methyl-3-indoleacetic acid(0.27 g), and 1-hydroxybenzotriazole (HOBT) (0.24 g) in acetonitrile (10 ml), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC) (0.30 g) was added and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→0:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (1.1 ml) was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound(0.26 g) as a pale orange white amorphous.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[C:20]([CH:23]=1)[C:21]#[N:22].[H-].[Na+]>CN(C)C=O>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=[C:2]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=4)=[C:20]([CH:23]=3)[C:21]#[N:22])[CH:12]=[C:6]12
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cn1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)cn3)c(C#N)c1)nc2=O
Reaction time: 0.17 h

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and 5-(hydroxymethyl)-2-5 ((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile. An exemplary process is shown as below: To a solution of 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (0.108 mL, 0.601 mmol) in N,N-dimethylformamide (DMF) (5 mL) was added NaH (48.1 mg, 1.202 mmol) and stirred for 10 mins. Then 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (80 mg, 0.401 mmol) was charged and stirred for 45 mins at rt. The resulting solution was 10 quenched by addition of 1 mL aq. NH4Cl and the solution was filtered. The resulting solution was submitted for MDAP to afford the desired product as a white solid.