Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][CH:20]([CH3:22])[CH3:21])[N:12]=3)=[CH:9][N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:20]([NH:19][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([NH:1][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:3]=3)[N:8]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=3)(=[O:24])=[O:25])[CH:9]=2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1)([CH3:21])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(N)cnc32)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(Nc4ccccc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
4-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(isopropylamino)pyrimidine-5-carbonitrile (0.204 g, 0.455 mmol) in DCM (12 mL) was treated with phenylboronic acid (0.111 g, 0.910 mmol, 2.0 Eq), copper acetate (0.124 g, 0.682 mmol, 1.5 Eq), pyridine (0.074 mL, 0.910 mmol, 2.0 Eq) and 4 Angstrom molecular sieves (0.600 g) and the reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with 4M Ammonia in MeOH (12 mL) and filtered through a plug of celite whilst washing through with further DCM/MeOH. The combined washes were evaporated to dryness and purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petroleum Ether) to give the title compound as a yellow solid (85 mg, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:36]3[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH2:34][CH2:35]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: COCCN1CCNCC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: COCCN1CCN(c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N)cc4F)c23)CC1

Procedure:
Prepared from 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (20 mg, 0.0408 mmol, prepared according to Example 7, Step B) and 1-(2-methoxyethyl)-piperazine (17.6 mg, 0.122 mmol) according to the procedure described for Example 138, Step C. Yield: 12 mg (51%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:10]([C:27]2[O:31][C:30]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[N:29][N:28]=2)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:13][N:14]=1>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:27]2[O:31][C:30]([CH2:32][C:33]([OH:35])=[O:34])=[N:29][N:28]=2)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(CC(=O)OC(C)(C)C)o3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(CC(=O)O)o3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
TFA (500 μL, 6.490 mmol) was added to a stirred solution of tert-butyl 2-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)acetate (45 mg, 0.083 mmol) in CH2Cl2 (5 mL) and the reaction stirred at ambient temperature for 18 h. The solvent was removed in vacuo and the residue azeotroped with CH2Cl2 (2×5 mL) and ether (2×5 mL). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (16.7 mg, 49%); 1H NMR (400 MHz, DMSO) d 1.19 (d, 6H), 3.45 (m, 1H), 4.27 (s, 2H), 7.85 (br s, 2H), 7.96 (d, 2H), 8.30 (d, 2H), 9.04 (s, 1H) and 13.30 (s, 1H) ppm; MS (ES+) 404.2
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2.CN([CH:22]=[O:23])C.C(O)CC>C1COCC1>[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[CH:22]=[O:23])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2
Reactant: CN(C)C=O
Reactant: COc1ccc2ncc(F)cc2c1
Agent: [Li]CCCC
Solvent: CCCO
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of DIPA (15.5 mL) in THF (300 mL), cooled to −78° C., was added n-BuLi (2.35N in hexanes, 44 mL). The reaction mixture was stirred 5 min at this temperature before warming to 0° C. The reaction mixture was stirred 15 min before cooling to −78° C. 3-fluoro-6-methoxy-quinoline (prepared as described in FR 2004/01105, 15 g) in THF (50 mL+10 mL rinse) was added and the mixture was stirred 3 h at −78° C. DMF (3 mL) was added quickly. After 45 min., 1-propanol (8 mL) was added and the mixture was warmed to rt. The mixture was partitioned between water (100 mL) and EA (200 mL). The aq. layer was extracted with EA (200 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue triturated in Hept to give an orange solid (9.0 g, 51% yield).
Reaction SMILES: [CH3:1][SiH:2]([Cl:4])[Cl:3].[F:5][C:6]([F:13])([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH2:8]>>[F:5][C:6]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:7][CH2:8][Si:2]([CH3:1])([Cl:4])[Cl:3]
Reactant: C[SiH](Cl)Cl
Reactant: C=CC(F)(F)C(F)(F)F
Product: C[Si](Cl)(Cl)CCC(F)(F)C(F)(F)F
Yield: 91 %

Procedure:
Into a reaction vessel were put 200 g of methyldichlorosilane and the same amount of the same binary catalyst as in Example 1, followed by the addition of 242 g of 3,3,4,4,4-pentafluorobutene. After the completion of the reaction at 70° C under 6 atmospheres, the reaction product was subjected to distillation to produce 3,3,4,4,4-pentafluorobutylmethyldichlorosilane (Boiling point: 130° C) at the yield 91% of the theoretical.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][C:24](=O)OC)=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][CH3:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl {2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbamate (115 mg, 0.303 mmol) was dissolved in 10 mL of THF at 0° C. 1M HCl/ether (0.425 mL, 0.424 mmol) was added and the solution was stirred at 0° C. for 15 min. LiAlH4 (57 mg, 1.52 mmol) was added slowly and the solution was stirred at rt overnight. The reaction was quenched at 0° C. by the addition of MeOH (1 mL) and water (2 mL). Anhydrous Na2SO4 (5.0 g) was added and the solution was stirred at rt for 30 min. The solution was filtered and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. Yield: 95 mg (93%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.41-1.51 (m, 2 H), 1.54 (s, 9 H), 1.57-1.67 (m, 2 H), 1.68-1.76 (m, 3 H), 2.07-2.17 (m, 3 H), 2.87 (s, 3 H), 4.15 (d, J=7.42 Hz, 2 H), 6.61 (dd, J=8.59, 2.34 Hz, 1 H), 7.01 (d, J=1.95 Hz, 1 H), 7.09 (d, J=8.59 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[CH2:24][OH:25])=[O:18])=[CH:10][C:9]=1[O:26][CH3:27].[H][H].CCOC(C)=O>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[CH2:24][OH:25])=[O:18])=[CH:10][C:9]=1[O:26][CH3:27]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(=O)N2CCCC2CO)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CCCOc1cc(N)c(C(=O)N2CCCC2CO)cc1OC

Procedure:
The nitro ester 14 (38.4 g, 97 mmol) was dissolved in ethanol (2 batches of 19.2 g in 200 mL ethanol per 500 mL hydrogenation flask). 10% Pd/C was added as a slurry in ethanol (1 g per batch) and the mixture was hydrogenated in a Parr hydrogenation apparatus at 40 psi until no further hydrogen uptake was observed. Reaction completion was confirmed by TLC analysis (EtOAc) and the mixture was filtered through celite. The solvent was removed in vacuo and the amine 15 was used directly in the next step. (35.4 g, quantitative yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:23])[NH:11][C:12]1[CH:17]=[C:16]([Br:18])[N:15]=[C:14]([Br:19])[C:13]=1[N+:20]([O-:22])=[O:21])[CH3:8].Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[N:30][CH:31]=1.[I-].[Na+]>CC(C)=O>[CH2:7]([O:9][C:10](=[O:23])[N:11]([C:12]1[CH:17]=[C:16]([Br:18])[N:15]=[C:14]([Br:19])[C:13]=1[N+:20]([O-:22])=[O:21])[CH2:25][C:26]1[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH3:8]
Reactant: CCOC(=O)Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: Cc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Potassium carbonate (7.95 g) was added to a stirred solution of (2,6-dibromo-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (10.62 g) in acetone (100 ml). 5-(chloromethyl)-2-methylpyridine (4.89 g) was then added, followed by sodium iodide (5.18 g). The mixture was left to stir under nitrogen for 18 hours. The reaction mixture was filtered, concentrated in vacuo, and then partitioned between ethyl acetate (100 ml) and water (100 ml). The organics were dried (MgSO4) and evaporated to a dark purple gum, which was columned on Isco Companion on a silica column (330 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 40:60 to 80:20 over 6 column volumes. This provided the title compound (8.5 g) as a green gum which solidified to a pale green solid on standing.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][C:18]([C:20]3[N:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:19][C:4]=2[CH2:3]1.[C:26]([OH:35])(=[O:34])[C@@H:27]([C@H:29]([C:31]([OH:33])=[O:32])[OH:30])[OH:28].O>CO>[C:31]([CH:29]([CH:27]([C:26]([OH:35])=[O:34])[OH:28])[OH:30])([OH:33])=[O:32].[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[CH:16]=[CH:17][C:18]([C:20]3[N:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:19][C:4]=2[CH2:3]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CN1CCC(Oc2ccccc2)c2ccc(-c3cccnn3)cc2C1
Solvent: CO
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
To a solution of the aryloxybenzazepine (52 mg, 0.16 mmol) from Step B above in methanol (1 mL) was added L-tartaric acid (23.5 mg, 0.16 mmol) followed by slow addition of water (5 mL). The resultant solution was lyophilized overnight to give (−)-2-methyl-5-phenoxy-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, tartrate salt (70 mg, 93%, AUC HPLC>99%) as a white solid: mp 98-100° C.; 1H NMR (CD3OD, 500 MHz) δ 9.17 (d, J=5.0 Hz, 1H), 8.21-8.18 (m, 2H), 8.08 (d, J=8.0 Hz, 1H), 7.82-7.79 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.28-7.25 (m, 2H), 7.06 (d, J=7.9 Hz, 2H), 6.95 (t, J=7.4 Hz, 1H), 5.75 (d, J=8.0 Hz, 1H), 4.92-4.84 (m, 1H), 4.51-4.48 (m, 1H), 4.41 (s, 2H), 3.95-3.85 (m, 1H), 3.57-3.55 (m, 1H), 2.88 (s, 3H), 2.46-2.38 (m, 2H); ESI MS m/z 332 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@@H](Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
In analogous manner to that described in example 5a), the reaction of (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-butyric acid and 1-fluoro-2-nitro-4-trifluoromethyl-benzene yielded quantitatively the title compound as a brown oil, MS m/e (%): 426.4(M+NH4+, 85).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:28]=[C:29]([C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[NH2:30]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:30]=[C:29]([C:31]4[N:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1ncccn1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ncccn4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 46 mg (0.33 mmol) of N′-hydroxypyrimidine-2-carboximidamide were reacted according to the General Method 2. Yield: 66 mg (64% of theory)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:25]2[CH:24]=[C:23]([C:22]3[CH2:21][C:20](=[O:36])[NH:19][C:9]4[CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(OC(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethoxy-phenyl}-carbamic acid tert-butyl ester (Example M167) (238 mg, 0.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (137 mg, 75%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19](Cl)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1.C([O-])(O)=O.[Na+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19]([C:43]4[CH:42]=[CH:41][CH:40]=[C:39]([C:38]([F:49])([F:48])[F:37])[CH:44]=4)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 85 °C
Reaction time: 28 h
Yield: 11.2 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (50.0 mg, 0.96 mmol), 3-Trifluoromethyl phenyl boronic acid (31.0 mg, 1.4 mmol) were taken in THF (5 ml) and degassed for 10 minutes. To above degassed solution NaHCO3 (20.0 mg, 0.24 mmol) in water (1 ml) and Pd(PPh3)4 were added and degassed for another 20 minutes. The reaction mixture was stirred for 28 hours at 80-90° C. The mixture was cooled to 25-27° C. and diluted with water (5 ml). The aqueous layer was extracted with DCM (3×5 ml). The organic layer was washed with brine (2×10 ml), dried over Na2SO4, and the solvent was evaporated. The residue obtained was purified by preparative TLC (35% Ethyl acetate in hexane) to obtain pure 8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (68 mg, quantitative) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:8])[CH2:6][SH:7].C([O:12][CH:13]([CH3:22])[C:14](Cl)=[C:15]1[CH2:19][CH2:18][CH2:17][C:16]1=O)(=O)C.C(OC(C)C(C1CCCC=1Cl)=O)(=O)C.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.O.CO>[CH3:3][O:4][C:5]([C:6]1[S:7][C:14]([CH:13]([OH:12])[CH3:22])=[C:15]2[CH2:19][CH2:18][CH2:17][C:16]=12)=[O:8]
Reactant: CC(=O)OC(C)C(Cl)=C1CCCC1=O
Reactant: COC(=O)CS
Agent: CC(=O)OC(C)C(=O)C1=C(Cl)CCC1
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc(C(C)O)c2c1CCC2
Reaction time: 1 h
Yield: 35.6 %

Procedure:
Add sodium hydride (60% in mineral oil, 2.12 g, 0.053 mol) to a solution of mercapto-acetic acid methyl ester (2.8 g, 0.026 mol) in tetrahydrofuran (100 mL) at −10° C.˜0° C. and stirred the mixture at −10° C.˜0° C. for 1 hour. Then add a mixture of 1-chloro-1-(2-oxocyclopentylidene)propan-2-yl acetate and 1-(2-chlorocyclopent-1-enyl)-1-oxopropan-2-yl acetate (5.47 g, 0.025 mol, 6:1) in tetrahydrofuran (15 mL) at 0° C. After stirring at 0° C. for overnight, dilute the reaction mixture with water and extract with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue and K2CO3 (6.9 g, 0.05 mol) in MeOH (20 mL) is heated at 50° C. overnight. The solvent is removed. The residue is purified by silica gel chromatograph (eluting with 2.5% to 10% ethyl acetate in petroleum ether) to give 3-(1-hydroxy-ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester (3.2 g, 14.1 mmol, 35.6% for 2 steps) as yellow oil. 1H NMR (CDCl3, 400 MHz): δ 5.03 (m, 1H), 3.83 (m, 3H), 2.88 (m, 2H), 2.66 (m, 2H), 2.38 (m, 2H), 2.12 (s, 1H), 1.54 (d, J=7.2, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[C:12]#[CH:13])[CH3:9].[Br:17][C:18]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:21](I)=[CH:20][N:19]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[Br:17][C:18]1[N:19]=[CH:20][C:21]2[CH:13]=[C:12]([CH:11]([O:14][CH2:15][CH3:16])[O:10][CH2:8][CH3:9])[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]=2[CH:23]=1
Reactant: C#CC(OCC)OCC
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1cc2cnc(Br)cc2n1S(C)(=O)=O
Temperature: 60 °C
Yield: 51 %

Procedure:
To DMF (3.4 mL) containing triethylamine (0.64 mL, 0.46 g 4.5 mmole) was added propargylaldehyde diethyl acetal (183 uL, 163 mg, 1.27 mmole) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide, (Preparation 8, 400 mg 1.06 mmole) followed by copper(I) iodide (7.1 mg, 0.037 mmole). The reaction was placed under nitrogen. Bis(triphenylphosphine)palladium dichloride (26.1 mg, 0.037 mmole) was added and the reaction was flushed again with nitrogen, then heated at 60° C. for 2 hours. The reaction was cooled and added to water (35 mL) containing a sodium bicarbonate solution (3 mL). The reaction was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water containing sodium bicarbonate solution (3×10 mL), brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 100% dichloromethane to 5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane to give the title compound (207 mg, 51%). 1H-NMR (CDCl3, 500 MHz): δ 1.32 (t, J=6.94 Hz, 6H), 3.38 (s, 3H), 3.75 (m, 2H), 3.84 (m, 2H), 5.86 (d, J=0.95 Hz, 1H), 6.94 (t, J=0.95 Hz, 1H), 8.14 (t, J=0.95 Hz, 1H), 8.67 (d, J=0.95 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:23])[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].[BH4-].[Li+].C(O)(=O)C.CO>C1COCC1.C(O)C>[O:22]=[C:18]1[CH2:19][CH2:20][CH2:21][N:17]1[CH2:16][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[CH2:3][OH:2])=[O:24])=[O:23]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1CCCN1CC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
N-[(2-Oxo-1-pyrrolidinyl)acetyl]-L-prolyl-L-proline methyl ester (Compound 1) (2.56 g) as obtained in Example 1 was dissolved in a mixture of THF (30 ml) and ethanol (6 ml), to which was added a THF solution of 2 M lithium borohydride (7.3 ml) under ice-cooling. After 3 hours' stirring at room temperature, a 50% acetic acid-methanol solution was added to adjust the pH of the mixture to 6. The residue obtained by concentration was purified by silica gel column chromatography (chloroform-methanol) to give 2.02 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl-L-prolinol.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:28][NH2:29])[CH:20]=[N:21][C:22]=1[N:23]1[CH:27]=[CH:26][CH:25]=[N:24]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH2:28][C:19]3[CH:20]=[N:21][C:22]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[C:17]([CH3:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)cnc1-n1cccn1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1-n1cccn1
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (520 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (600 mg, 2.2 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine hydrochloride (480 mg, 2.2 mmol, Amine-53) in a similar manner to Intermediate-2.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O>CS(C)=O>[O:1]([CH2:8][CH2:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH:14]=[O:15])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCOc1ccccc1)N1CCC[C@H]1CO
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C[C@@H]1CCCN1C(=O)CCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
A mixture of N-(3-phenoxy)propionyl-prolinol (1.4 g) and triethylamine (1.7 g) was dissolved in anhydrous dimethyl sulfoxide (16 ml), and to the stirred solution, a solution (16 ml) of sulfur trioxide-pyridine complex (2.6 g) in dimethyl sulfoxide was added. After stirring the mixture at room temperature for 10 minutes, the reaction solution was poured into iced water (150 ml) and subjected to extraction with ethyl acetate. The extract was washed successively with 10% aqueous citric acid, water, saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under vacuum, the resulting crude product was purified by medium-pressure liquid column chromatography on silica gel (solvent: chloroform) to obtain the end compound as an oil (1.2 g).