Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:12])=[CH:10][CH2:9][CH2:8][N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1>CO.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([CH3:12])[CH2:10][CH2:9][CH2:8][N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1
Reactant: CCN1CCC=C(C)c2ccc(O)cc21
Agent: [Pd]
Solvent: CO
Product: CCN1CCCC(C)c2ccc(O)cc21
Reaction time: 3 h
Yield: 63.7 %

Procedure:
A suspension of 8-hydroxy-5-methyl-2,3-dihydro-1-ethylbenzo[b]azepine (0.14 g) and Pd/C (10 mg) in MeOH (10 mL) was purged with H2 and then stirred under 1 atm H2 for 3 hours. The reaction was then filtered over Celite, the eluent concentrated, and the crude reaction purified over silica gel (gradient of EtOAc in heptane) to provide the title compound (0.09 g) as a clear oil: 1H NMR (CDCl3) δ 7.26 (s, 1H), 6.97 (d, 1H), 6.46-6.33 (m, 2H), 3.23-3.02 (m, 4H), 2.79-2.67 (m, 2H), 1.81-1.53 (m, 3H), 1.29 (d, 3H), 1.19 (t, 3H); MS expected 206 (C13H20NO, M+1), found 206.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:27])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([O:25]C)[CH:18]=2)=[N:10][C:9]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:27])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:25])[CH:18]=2)=[N:10][C:9]=1[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(NC(=O)CCc3ccc(OC)c(OC)c3)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Product: O=C(CCc1ccc(O)c(O)c1)Nc1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1
Yield: 60.3 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-3-(3,4-dimethoxy-phenyl)-propanamide prepared in Example 68 and boron tribromide were used as starting materials, and the crude product was recrystallized with ethyl acetate to obtain a product as a white solid in a yield of 60.3%, mp: 94-95 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 2.61 (2H, t, J=7.00 Hz, CH2), 2.68 (2H, t, J=7.00 Hz, CH2), 4.17 (2H, s, CH2), 6.43 (1H, d, J=7.84 Hz, ArH), 6.59 (2H, t, J=7.84 Hz, CH2), 6.80 (2H, d, J=7.84 Hz, ArH), 7.18˜7.24 (3H, m, ArH), 7.32 (2H, t, J=7.28 Hz, CH2), 7.41 (2H, d, J=7.84 Hz, ArH), 8.65 (1H, s, OH), 8.74 (1H, s, OH), 9.59 (1H, s, OH), 12.06 (1H, s, CONH); EI-MS m/e (%): 446.1 (M+, 18), 282.1 (100), 205.1 (17); HREI-MS Calcd. for C25H22N2O4S: 446.1300. found: 446.1299.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH2:3][NH:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16]CC3C=CC=CC=3)[CH:13]=2)[N:8]1[C:24](=[O:36])[C@@H:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH3:27])=[O:6]>C(OCC)(=O)C.[Pd]>[F:38][C:2]([F:1])([F:37])[CH2:3][NH:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=2)[N:8]1[C:24](=[O:36])[C@@H:25]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:26][CH3:27])=[O:6]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)NCC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(O)cc2CC1C(=O)NCC(F)(F)F

Procedure:
1-[N-t-butoxycarbonyl-2(S)-aminobutyryl]-5-benzyloxyindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide (1.27 g, 5.39 mmol) in ethyl acetate (28 ml) was hydrogenated under an atmosphere of hydrogen in the prescence of palladium on activated carbon at room temperature for 24 hours. The catalyst was filtered through celite with ethyl acetate washing. The filtrate was concentrated and directly chromatographed on silica gel using 2:3 petroleum spirit:ethyl acetate as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:10]([OH:27])[CH2:11][CH:12]([NH:19][C:20](=[O:26])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:10]([OH:27])[CH2:11][CH:12]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[NH:19][C:20](=[O:26])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CCC(=O)NC(CC(O)C(CC(C)C)NC(=O)OC(C)(C)C)c1ccccc1
Solvent: CC(=O)O
Product: CC(C)CCC(=O)NC(CC(O)C(CC(C)C)NC(=O)OC(C)(C)C)C1CCCCC1
Yield: 76.1 %

Procedure:
The resultant compound of Example 41 (70.0 mg, 0.161 mmol) in glacial acetic acid (15 mL) was hydrogenated over Pt black (70 mg) for 22 hours. The mixture was filtered, diluted with H2O (50 mL) and brine (50 mL), and extracted with ether (50 mL). The organic phase was washed with water (2×50 mL), saturated K2CO3 (25 mL), and brine (10 mL). Drying (MgSO4) and evaporating gave 54 mg of the desired material. Mass spectrum: (M+H)+ =441.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[C:12]12([CH2:22][OH:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[C:12]12([CH:22]=[O:23])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: O=CC12CC3CC(CC(C3)C1)C2
Yield: 89 %

Procedure:
The PCC-based oxidation of 1-adamantanemethanol will furnish 1-adamantanecarboxaldehyde in an 89% yield, as described in the literature [20]. The Schiff base condensation between 1-adamantanecarboxaldehyde and DFOB will yield the imine-based adamantane-DFOB conjugate which will be reduced by sodium cyanoborohydride (NaCNBH3) to give the secondary amine-based adamantane-DFOB conjugate. Sodium cyanoborohydride does not reduce the hydroxamate groups of DFOB to amides [21].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:31]4[C:22](=[C:23]5[C:28](=[CH:29][CH:30]=4)[CH:27]=[N:26][CH:25]=[CH:24]5)[NH:21][C:20](=[O:32])[CH2:19][C:18]3=[O:33])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:31]4[C:22](=[C:23]5[C:28](=[CH:29][CH:30]=4)[CH2:27][NH:26][CH2:25][CH2:24]5)[NH:21][C:20](=[O:32])[CH2:19][C:18]3=[O:33])=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CC(=O)N(c2ccc(NC(=O)c3cccnc3Cl)cc2)c2ccc3cnccc3c2N1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccnc3Cl)cc2)c2ccc3c(c2N1)CCNC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
5-[4-[(2-Chloropyridin-3-yl)carbonylamino]phenyl]-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione (10 mg, 0.022 mmol) was dissolved in acetic acid (0.4 mL), the solution was added with sodium borohydride (64 mg, 0.11 mmol), the mixture was stirred at room temperature for 2 hours, and then further added with sodium borohydride (64 mg, 0.11 mmol), and the mixture was stirred at room temperature for 2 hours. This reaction mixture was added with water, made basic with sodium carbonate, and extracted three times with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (7 mg, yield 68%) as pale brown crystals.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[I-].[K+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl.[Ag]=O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:4][CH2:3][CH2:2][CH2:1][OH:5])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=[Ag]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
1.45 mL (corresponding to 20.0 mmol) of 1,3-propanediol was dissolved in 200 mL of methylene chloride. To this solution under an ice bath, 6.96 g (corresponding to 30.0 mmol) of silver oxide, 666 mg (corresponding to 4.0 mmol) of potassium iodide and 4.21 g (corresponding to 22.0 mmol) of p-toluenesulfonyl chloride were added. The resulting mixture was stirred at room temperature for 3 hours. Insoluble matters were filtered out of the reaction mixture, and were washed with ethyl acetate. The washings were combined with the filtrate, and the mixture was concentrated. The resulting crude product was purified with flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/2 to 1/1) to obtain 2.47 g (corresponding to 10.7 mmol) of 1,3-propanediol mono-p-toluenesulfonate (FIG. 1, Step 6).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>O>[F:13][C:2]([F:1])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:15])=[O:11])=[N:8][CH:9]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1ccc(OC(F)(F)F)cn1
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(OC(F)(F)F)cn1
Reaction time: 0.5 h

Procedure:
A mixture of 3 g 5-trifluoromethoxy-2-pyridinemethanol is vigorously stirred in 120 mL water at 5° C. To this mixture is added in several portions 3.0 g potassium permanganate during which time the temperature rises to 25° C. After a further 30 minutes at 25° C., the mixture is filtered, the solid washed several times with water, the filtrate and washings combined and the pH adjusted to 5. The solution is concentrated to a small volume and extracted with ethyl acetate several times. The extract is washed, dried and concentrated to give 5-trifluoromethoxy-2-pyridinecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([Cl:14])=[CH:16][CH:17]=4)[CH:22]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(Cl)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(Cl)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 46 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Chloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[O:35][N:34]=[C:33](C2C=CC(N)=CC=2)[N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:33]3[N:32]=[C:31]([CH3:30])[O:35][N:34]=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Product: Cc1nc(-c2ccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)cc2)no1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(5-methyl-1,2,4-oxadiazol-3-yl)aniline in step 1. MS: 409.5 (M+H).
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)C.[NH2:31][NH2:32].Cl>CCO>[N:17]1([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15][C:14]2([C:5]3[CH:4]=[N:32][NH:31][C:6]=3[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13]2)[CH2:19][CH2:18]1
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-c1[nH]ncc12
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (15.1 g, 35.9 mmol) and hydrazine (1.35 mL, 43.1 mmol) in EtOH (120 mL) was added hydrochloric acid (900 μL of 4.0 M in dioxanes, 3.6 mmol). The mixture was heated at 60° C. for 2 h before it was cooled and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to give tert-butyl spiro[1H-chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (8.76 g, 71%). ESI-MS m/z calc. 341.2. found 342.3 (M+1)+; Retention time: 1.69 minutes (3 min run).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].II.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24].[Cl-].[NH4+]>C(OCC)C.C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([OH:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: COc1ccccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 21 °C
Yield: 89.2 %

Procedure:
Magnesium turnings (40 g, 1.65 mol) are introduced into diethyl ether (100 ml) and, while stirring, a solution of 2-bromoanisole (206 ml, 1.65 mol) in diethyl ether (450 ml) is added dropwise. The reaction can be initiated, if necessary, by adding iodine crystals. During the addition, the reaction mixture should boil gently. After the addition, the mixture was stirred at room temperature for 1 hour. A slurry of 5-chloroisatin (75 g, 0.41 mol) in THF (750 ml) was added to the Grignard solution while cooling slightly (temperature 18-24° C.), and the mixture was stirred at room temperature for 30 min. The reaction mixture was stirred into ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phase was washed four times with water, dried over magnesium sulfate and concentrated under reduced pressure. The remaining residue was stirred with 2-propanol. The resulting precipitate was filtered off, washed with 2-propanol and diethyl ether and dried. 106 g of the desired intermediate were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][NH:12]C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][NH2:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)CN)NS(=O)(=O)c1ccccc1
Temperature: -15 °C

Procedure:
Protected amide 1-6 (576 mg, 1.26 mmol) was dissolved in 6.3 mL CH2Cl2, cooled to -15° C., and TFA (6.3 mL) was added. After 25 min the reaction was concentrated, providing amine 1-7.
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>CC(O)C>[ClH:13].[Br:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: Cc1c(Br)ccc2c1NCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(N3CCc4ccc(Br)c(C)c43)ncnc2c1
Yield: 49 %

Procedure:
Utilizing a procedure analogous to that described in Example 1 (with conversion to the HCl salt as outlined for Example 2), this product was prepared in 49% yield from 6-bromo-7-methyl-indoline (1.1 eq.), and 4-chloro-7-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 200°-205° C. (dec); LC-MS: 370, 372 (MH+); anal. RP18-HPLC RT: 5.76 min.).
Reaction SMILES: C[Li].[OH:3][C@H:4]1[CH2:30][C@@:29]2([CH3:31])[C@@H:15]([CH2:16][CH2:17][C@:18]2([OH:32])[C:19](=[O:28])[CH2:20][O:21]C(=O)CCCC)[C@H:14]2[C@H:5]1[C@:6]1([CH3:35])[C:11]([C@@H:12]([CH3:33])[CH2:13]2)=[CH:10][C:9](=[O:34])[CH2:8][CH2:7]1.[Cl-].[NH4+]>CCOCC.O1CCCC1.[Cu]I>[OH:3][C@H:4]1[CH2:30][C@@:29]2([CH3:31])[C@@H:15]([CH2:16][CH2:17][C@:18]2([O:32][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH3:8])[C:19](=[O:28])[CH2:20][OH:21])[C@H:14]2[C@H:5]1[C@:6]1([CH3:35])[C:11]([C@@H:12]([CH3:33])[CH2:13]2)=[CH:10][C:9](=[O:34])[CH2:8][CH2:7]1
Reactant: CCCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 124.3 %

Procedure:
At 0° C. under argon, 40 ml of a 5% solution of methyllithium in ether is added dropwise to a suspension of 9.3 g of copper(I) iodide in 186 ml of anhydrous tetrahydrofuran. The yellow solution is cooled to -30° C., and a solution of 7.4 g of 11β,17-dihydroxy-6α-methyl-21-valeryloxy-4-pregnene-3,20-dione in 186 ml of anhydrous tetrahydrofuran is added thereto. The mixture is agitated for 10 minutes at -25° C. and poured on an aqueous ammonium chloride solution. After extraction with methylene chloride, the organic solution is washed, dried over sodium sulfate, and evaporated under vacuum. The crude product is purified on 600 g of silica gel with a methylene chloride-acetone gradient (0-20% acetone), thus isolating 4.6 g of 11β,21-dihydroxy-6α-methyl-17-valeryloxy-4-pregnene-3,20-dione, mp 160° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: O=C(O)c1oc(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c1OCc1ccccc1
Product: Cn1c(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Yield: 78.57 %

Procedure:
3-Benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-05) (1.62 g, 78.57%) was synthesized as a yellow solid from 3-benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-05) (2.0 g, 4.45 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[C:20]5[C:25]([C:26](=[O:29])[C:27](=[O:28])[C:17]=4[S:16][CH2:15]3)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[C:30]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C@@H:40]2[CH2:42][O:41]2)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C>>[C:30]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C@@H:40]([OH:41])[CH2:42][N:3]2[CH2:4][CH2:5][CH:6]([N:9]3[CH2:14][CH2:13][C:12]4([O:19][C:18]5[C:20]6[C:25]([C:26](=[O:29])[C:27](=[O:28])[C:17]=5[S:16][CH2:15]4)=[CH:24][CH:23]=[CH:22][CH:21]=6)[CH2:11][CH2:10]3)[CH2:7][CH2:8]2)=[CH:36][CH:35]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C3CCNCC3)CC1)O2
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC(N3CCC4(CC3)CSC3=C(O4)c4ccccc4C(=O)C3=O)CC2)cc1

Procedure:
Compound 198 was synthesized using 1′-piperidin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione bis-hydrochloride, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane, hunig's base and conditions outlined in procedure Y. M.p.=190-193° C.; 400 MHz 1H NMR (CDCl3) δ: 8.04-8.02 (m, 1 H), 7.74-7.67 (m, 2 H), 7.51-7.47 (m, 1 H), 7.30-7.28 (m, 2 H), 6.85-6.83 (m, 2 H), 4.30 (t, 1 H), 4.02-3.94 (m, 2 H), 3.46-3.1 (m, 3 H), 2.95-2.92 (m, 4 H), 2.82 (d, 2 H), 2.72 (t, 2 H), 2.65 (bs, 2 H), 2.45 (t, 1 H), 2.19 (d, 2 H), 1.98-1.93 (m, 6 H), 1.29 (s, 9 H); LCMS: 591 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].O.[N-:17]=[N+:18]=[N-].[Na+]>C(O)(C(F)(F)F)=O>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)=[N+:17]=[N-:18]
Reactant: Nc1ccc2ccncc2c1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
To a solution of 7-aminoisoquinoline (7.0 g) in TFA (35 mL) at 0° C. was added sodium nitrite (4.02 g) portionwise over a period of 30 minutes. The reaction was stirred at 0° C. to room temperature for 1.5 h. Water (3.5 mL) was added followed by portionwise addition of sodium azide (3.48 g) at 0° C. over a period of 30 minutes. After the addition, the reaction was slowly warmed up to room temperature and stirred for 1 h. Two third of TFA was evaporated and the residue was cooled to 0° C. Sodium bicarbonate (sat. in water) was added dropwisely to the residue until the pH was about 8-9. After extraction with methylene chloride (4×60 mL), the organic phase was combined, washed with water, brine, dried over sodium sulfate, filtered and concentrated to leave 7-azidoisoquinoline (7.5 g) as a dark brown solid. CI mass spectrum z (rel. intensity) 171 (M+H, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[C:17](#[N:20])[CH2:18][CH3:19].C1(C)C=CC=CC=1>C([O-])(O)=O.[Na+]>[NH2:8][C:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:18]([CH3:19])[C:17]#[N:20]
Reactant: CCC#N
Reactant: COc1ccc(C#N)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(N)=C(C)C#N)cc1
Reaction time: 72 h
Yield: 35.1 %

Procedure:
Combine 4-methoxybenzonitrile (50.0 g, 376 mmol), potassium t-butoxide (84.2 g, 752 mmol), propionitrile (62.0 g, 1.130 mmol) and toluene (1,880 mL); and stir for 72 h. Dilute with satd NaHCO3 and extract with EtOAc. Evaporate the organic solution and crystallize from hexane/EtOAc to afford 3-amino-3-(4-methoxyphenyl)-2-methylacrylonitrile. Yield: 35.1%. ES-MS: m/e 189.2 (m+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1.CCCCCC>CCOC(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Brc1cccc(Br)c1
Reactant: OB(O)c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Brc1cccc(-c2ccncc2)c1

Procedure:
Prepared according to the general procedure Coupling-1 using 4-pyridinylboronic acid and 1,3-dibromobenzene. Flash chromatography (Hexane:EtOAc, 70:30) afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:41]([S:44](Cl)(=[O:46])=[O:45])[CH2:42][CH3:43]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([S:44]([CH2:41][CH2:42][CH3:43])(=[O:46])=[O:45])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21

Procedure:
In the same manner as Example 1-D-02, using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (40 mg) and propane-1-sulfonyl chloride (0.70 ml) instead of mesyl chloride, a crude product of bis-(4-methoxy-benzyl)-[5-[2-morpholin-4-yl-7-(propane-1-sulfonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl]-amine was obtained. Using a crude product (12 mg) of this bis-(4-methoxy-benzyl)-[5-[2-morpholin-4-yl-7-(propane-1-sulfonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl]-amine, the PMB groups were removed according to the above Deprotection method 2, to obtain 5-[2-morpholin-4-yl-7-(propane-1-sulfonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-ylamine as a colorless powder (5.4 mg, 77%).