Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][NH:3]1.O=S(Cl)[Cl:21].[ClH:23]>CN(C=O)C>[ClH:21].[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc3ncnc(Cl)c3c2)o1

Procedure:
A mixture of the compound of formula (IX) (0.6 g, 2 5 mmol), SOCl2 (15 mL) and one drop of DMF was heated under reflux until the reaction was complete (TLC analysis). The volatile components were evaporated (including SOCl2) to provide crude (Xa).HCl (0.9 g) that could be used directly in the next step.
Reaction SMILES: Br[C:2]1[N:7]2[C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:26]1
Reactant: C1COCCN1
Reactant: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(Br)n12
Product: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(N3CCOCC3)n12
Temperature: 120 °C
Yield: 84.9 %

Procedure:
In a 5 mL microwave vial was placed 2-4 (221 mg, 0.599 mmol) and morpholine (2.0 g, 2.0 mL, 23 mmol). The mixture was heated at 120° C. under microwave irradiation for 20 min. After cooling, the reaction mixture was purified by reversed phase HPLC to give 191 mg (85%) of 6-1. 1H NMR (500 MHz, DMSO-d6): δ 8.51 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.69-7.60 (m, 2H), 7.00 (t, J=8.1 Hz, 1H), 6.67 (d, J=9.3 Hz, 1H), 5.72 (d, J=7.0 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.63 (m, 4H), 3.10 (s, 1H), 2.99 (s, 1H), 2.93 (s, 4H). HRMS (ES) 376.1765 (M+H) found, 376.1771 required.
Reaction SMILES: F[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[F:12][CH:13]([F:16])[CH2:14][O:15][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC(F)F
Reactant: Cc1cc(C(=O)O)cnc1F
Product: Cc1cc(C(=O)O)cnc1OCC(F)F
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (1.02 g, an off-white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol (1.06 g, 12.9 mmol) in a similar manner to Step-1 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.[OH-].[K+].Cl>CS(C)=O.O>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of the product from Example 49A (3.55 g, 10 mmol), 4-aminophenol (1.09 g, 10 mmol), and potassium hydroxide (1.12 g, 20 mmol) were dissolved in dimethyl sulfoxide (15 mL) and heated at 100° C. in a CEM Discover microwave for 25 minutes. The mixture was then cooled to room temperature, poured into water (300 mL), the pH of the solution adjusted to 6 with 1N aqueous hydrochloric acid, the resultant solution stirred for 30 minutes and the resultant solid collected and dried to provide the title compound as a yellow solid (4.2 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:26][NH:27][CH3:28]>>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][N:27]([CH3:28])[CH3:26])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(C)Cc1c(F)cc(Br)cc1F
Yield: 80 %

Procedure:
According to procedure for the synthesis of Example A211A, by using 4-bromo-2,6-difluorobenzaldehyde (500 mg, 2.26 mmol), sodium triacetoxyborohydride (959 mg, 4.52 mmol) and 2M dimethylamine solution (2.626 mL, 4.52 mmol) to give the title compound as a colorless oil (452 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J=6.8 Hz, 2H), 3.54 (s, 2H), 2.26 (s, 6H); MS ESI 249.9 [M+H]+, calcd for [C9H10BrF2N+H]+ 249.0.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:15]([CH:17]=O)=[CH:16][C:9]=23)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[N:4]1)[CH3:2].[CH2:37]([NH:39][CH2:40][CH2:41][OH:42])[CH3:38]>>[CH2:37]([N:39]([CH2:17][C:15]1[N:14]([S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])[C:10]2=[N:11][CH:12]=[CH:13][C:8]([C:6]3[C:5]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=3)=[C:9]2[CH:16]=1)[CH2:40][CH2:41][OH:42])[CH3:38]
Reactant: CCNCCO
Reactant: CCn1cc(-c2ccnc3c2cc(C=O)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCN(CCO)Cc1cc2c(-c3cn(CC)nc3-c3ccc([N+](=O)[O-])cc3)ccnc2n1S(=O)(=O)c1ccccc1

Procedure:
Following the procedure described in Intermediate 101 using 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde and 2-(ethylamino)ethanol provided the title compound as a yellow solid. ESMS [M+H]+: 651.4.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][Cl:30]>>[Cl:30][CH2:29][CH2:28][CH2:27][N:20]1[C:19]([O:23][CH3:24])=[N:18][C:17]2[C:21]1=[N:22][C:14]([O:13][C@@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=2[NH2:25]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reactant: ClCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and 1-bromo-3-chloropropane.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=3)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:42]>C(O)C>[ClH:42].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)=[C:20]([C:37]([F:38])([F:39])[F:40])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc([N+](=O)[O-])c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc([N+](=O)[O-])c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Compound 95-3 (587 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (430 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([CH2:22]Br)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N#N.[NH:26]1[CH2:45][CH2:44][CH2:43][C@H:27]1[C:28]([NH:30][C@H:31]([C:36]([NH:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:29].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([CH2:22][N:26]1[CH2:45][CH2:44][CH2:43][C@H:27]1[C:28]([NH:30][C@H:31]([C:36]([NH:38][CH2:39][CH:40]([CH3:41])[CH3:42])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:29])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CBr)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)NCC(C)C
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NCC(C)C

Procedure:
A solution of 8.86 g of [N-(benzyloxycarbonyl)-L-phenylalanyl]methyl bromide 6.71 g of N2 -L-prolyl-N1 -isobutyl-L-isoleucinamide and 2.60 g of triethylamine in 400 ml of dichloromethane was stirred at room temperature overnight. The solvent was removed by evaporation and the crude product was chromatographed on silica gel using ethyl acetate for the elution. The resulting product was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate to give 8.70 g of N2 [N-[[N-(benzyloxycarbonyl)-L-phenylalanyl]methyl]-L-prolyl]-N1 -isobutyl-L-isoleucinamide as an off-white solid of m.p. 80°-81° C.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15](Br)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Temperature: 80 °C

Procedure:
A mixture of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine (20 mg, 0.044 mmol) and phenylboronic acid (6.9 mg, 0.057 mmol) in DME (1 mL) was prepared in a sealed tube and purged with N2. Tetrakis(triphenylphosphine) palladium(0) (0.002 mmol) was added, and the reaction tube sealed and heated at 80° C. overnight. After cooling, the reaction mixture was diluted with EtOAc, washed with IN NaOH and brine, dried (MgSO4), and concentrated. The residue was purified by preparative TLC (40% EtOAc/hexanes) to afford N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.77 (s, 1H), 7.52-7.36 (m, 5H), 7.10 (d, 1H, J=2.4 Hz), 7.05 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=2.4 and 8.7 Hz), 6.87 (dd, 1H, J=2.4 and 8.7 Hz), 6.73 (d, 1H, J=8.7 Hz), 6.69 (d, 1H, J=8.7 Hz), 4.23-4.20 (m, 8H); LCMS: ret. time: 25.38 min.; purity: 100%; MS (m/e): 455 (MH+).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[N:13]=[CH:14][NH:15][CH:16]=3)=[C:10]([CH2:17][O:18][CH3:19])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[CH3:19][O:18][CH2:17][C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[N:13]=[CH:14][N:15]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH:16]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COCc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: COCc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C#N)cc2)cn1
Yield: 42 %

Procedure:
As described for Example 1f, 3-phenyl-4-(1H-imidazol-4-yl)-5-methoxymethyl-isoxazole (128 mg, 0.50 mmol) was converted, using 4-fluorobenzonitrile instead of 1-(4-fluorophenyl)-ethanone, to the title compound (75 mg, 42%) which was obtained as an off-white solid. MS: m/e=357.0[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([Cl:21])[C:12]=1[C:13](Cl)=[O:14].C(N(CC)CC)C>O1CCOCC1>[Cl:10][C:11]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([Cl:21])[C:12]=1[C:13]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: Nc1ccnc(Cl)c1F
Reactant: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cc(I)cc1Cl
Temperature: 100 °C
Yield: 53.8 %

Procedure:
A mixture of 2-chloro-3-fluoropyridin-4-ylamine (1.73 g, 11.8 mmol), 2,6-dichloro-4-iodobenzoyl chloride (5.90 g, 17.65 mmol) and triethylamine (3.1 mL, 22.4 mmol) in dioxane (35 mL) was heated to 100° C. for 18 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resultant residue was triturated with diethyl ether and dried under reduced pressure to give the desired compound as a pink solid (2.83 g, 54% yield). 1H NMR (300 MHz, CDCl3): δ 8.49-8.43 (m, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.82-7.73 (m, 2H).
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3Cl)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.C([O-])([O-])=O.[Na+].[Na+].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH:31]=[CH2:32])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CN1CCCC1=O
Product: C=Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 160 °C
Reaction time: 1 h

Procedure:
(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (3) (417 mg, 1.0 mmol) and tributyl(vinyl)tin (0.58 mL, 2.0 mmol) were dissolved in anhydrous NMP (10 mL) and the resulting solution was degassed and back-filled with argon (two cycles). To this mixture, Na2CO3 (212 mg, 2.0 mmol), Pd(OAc)2 (45 mg, 0.2 mmol) and di-(1-adamantyl)-n-butylphosphine (215 mg, 0.6 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon (two cycles) and then stirred at 160° C. under argon for 1 h. The reaction mixture was allowed to cool to RT and then partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-2-phenyl-8-vinylisoquinolin-1(2H)-one (8) as an off-while solid. ESI-MS m/z: 409.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[ClH:25]>O1CCOCC1>[ClH:25].[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
A round bottom flask was mixed with tert-butyl 1-[4-(trifluoromethyl)phenyl]piperidin-4-ylcarbamate (472 mg, 1.42 mmol) and a solution of 4.0 N HCl in 1,4-dioxane (20 mL). The reaction mixture was allowed to stir at RT for a period of 17.0 hours. After 17.0 hours the reaction mixture was concentrated to dryness to afford a crude solid. The resulting solid was triturated with ether and filtered to give a total of 377 mg of desired product (92% yield). The product was used without further purification.
Reaction SMILES: C([O:8][C:9](=[O:42])[C@@H:10]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:11][C:12](=[O:33])[C@H:13]([CH2:29][CH2:30][CH2:31][NH2:32])[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:15]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:13]([C:12]([NH:11][C@@H:10]([C:9]([OH:42])=[O:8])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:29][CH2:30][CH2:31][NH2:32])([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)N[C@H](CCc1ccccc1)C(=O)O
Yield: 104.7 %

Procedure:
A solution of NaNd-bis-Boc-L-Ornithyl-D-Homophenylalanine Benzyl ester (2.80 g, 4.80 mmol) in methanol (200 mL) was treated with 10% Pd/C catalyst (0:2 g) and stirred in the atmosphere of hydrogen at 25° C. for 3 hr. The catalyst was removed by filtration through Celite pad and the filtrate evaporated to dryness to give the title product (2.48 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]#[C:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:10]3[CH2:9][N:8]([CH3:21])[C:7](=[O:22])[C:6]=2[CH:23]=1.[CH2:24](I)[CH3:25].[OH-].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]#[C:16][C:17]([O:20][CH2:24][CH3:25])([CH3:19])[CH3:18])=[C:10]3[CH2:9][N:8]([CH3:21])[C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: CN1Cc2c(C#CC(C)(C)O)ncn2-c2ccc(F)cc2C1=O
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(C)(C)C#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reaction time: 0.08 h

Procedure:
3.0 g (9.5 mmol) of 8-fluoro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one were dissolved in 20 ml of N,N-dimethylformamide and treated at 3° with 2.97 g (19 mmol) of ethyl iodide and 2.13 g of freshly powdered potassium hydroxide (38 mmol). After stirring for 5 minutes the cooling bath was removed and the mixture was left to come to room temperature. The reaction mixture was then poured into 200 ml of water, acidified with 4N hydrochloric acid and extracted four times with methylene chloride. The combined extracts were washed five times with water, dried over magnesium sulphate and evaporated. By recrystallization of the crude product from ethyl acetate and hexane there was obtained 8-fluoro-3-(3-ethoxy-3-methyl-1-butynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 136°-138°.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]([CH2:11][CH3:12])=[C:9]([CH2:13][C:14]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)[C:8]([CH2:26][CH3:27])=[N:7]1)C.O.[NH2:30][NH2:31]>O>[CH2:26]([C:8]1[C:9]([CH2:13][C:14]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[C:10]([CH2:11][CH3:12])[N:6]([CH2:5][C:4]([NH:30][NH2:31])=[O:3])[N:7]=1)[CH3:27]
Reactant: NN
Reactant: CCOC(=O)Cn1nc(CC)c(Cc2cc(C)c(OC)c3c2CCC3)c1CC
Solvent: O
Product: CCc1nn(CC(=O)NN)c(CC)c1Cc1cc(C)c(OC)c2c1CCC2
Temperature: 62.5 °C
Yield: 91.4 %

Procedure:
A stirred suspension of [3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic acid ethyl ester (3.3 gm, 0.0085 mole) and 99% Hydrazine hydrate (33 ml) was heated at 60-65° C. for 3 hours. The reaction mixture was poured into water (200 ml), stirred for an hour and then filtered. The obtained solid was stirred in Methanol (10 ml), filtered and dried to give 2.9 gm of desired product as a solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([OH:40])[CH2:20][CH:19]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][CH:17]2[CH:13]1[CH2:14][N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:16]2>CS(C)=O.O>[C:1]([CH2:21][CH:19]1[CH2:18][CH:17]2[CH:13]([CH2:14][N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:16]2)[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH3:4])([OH:40])[CH2:20]1)#[N:2]
Reactant: [C-]#N
Reactant: COc1ccccc1C1(O)CC(COS(=O)(=O)c2ccc(C)cc2)CC2CN(C(=O)OC(C)(C)C)CC21
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C1(O)CC(CC#N)CC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 50 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
40 g of potassium cyanide are added carefully to a solution of 215 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-tert-butyloxycarbonyl-6-tosyloxymethylperhydroisoindol-4-ol in 800 cm3 of dimethyl sulphoxide. The reaction mixture is stirred at 50° C. for 20 hours, diluted with 1 liter of water and extracted with twice 200 cm3 and then 100 cm3 of ethyl acetate. The combined organic extracts are washed with twice 500 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is recrystallized from 200 cm3 of ethyl ether, and the crystals are washed with the same solvent, drained and then dried under reduced pressure (2.7 kPa). 142 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-(2-methoxyphenyl)-2-tert-butyloxycarbonylperhydroisoindol-4-ol are obtained in the form of a white solid. M.p.K =149° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[CH2:17][CH3:18])[CH3:2].[H-].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[C:7]=1[CH2:17][CH3:18])[CH3:2]
Reactant: ClCc1cccc(Cl)c1
Reactant: CCOC(=O)Cc1c(CC)[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1c(CC)n(Cc2cccc(Cl)c2)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
2-Ethyl-5-methoxy-1H-indole-3-acetic acid ethyl ester (1.82 g, 7.4 mmol) was added to 296 mg (7.4 mmol) of NaH/mineral oil (previously washed with hexane), the mixture stirred for 0.5 hours and 0.93 mL (7.4 mmol) of 3-chlorobenzyl chloride added. After 21 hours, water was added and the mixture extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 2.13 g (75% yield) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-methoxy-1H-indole-3-acetic acid ethyl ester as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=O.O[C@@H](C1C=CC=C(O)C=1)[CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C>C(#N)C>[O:13]=[C:11]([C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[CH2:21][C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: CCOC(=O)c1cccc(OCc2cccs2)c1
Solvent: CC#N
Product: N#CCC(=O)c1cccc(OCc2cccs2)c1

Procedure:
Condensation between ethyl 3-(thiophen-2-ylmethoxy)benzoate and acetonitrile following the method used in the preparation of phenol (Intermediate I) gave after flash column chromatography 3-oxo-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH:19]=O)[CH:3]=1.[C:21]1([CH2:27][CH2:28][NH2:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH2:19][NH:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CNCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid (0.4 g, 1.23 mmol), 2-phenylethylamine (0.16 mL, 1.23 mmol), sodium cyanoborohydride (0.189 g, 3.0 mmol), and acetic acid (2 drops) were combined in CH2Cl2 and stirred at room temperature for 10 minutes. Aqueous work-up yielded the title compound.