Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([C:13]1[C:14]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:15](B(O)O)[CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:12]>>[CH2:24]([O:23][C:14]1[C:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH:11]=[O:12])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOc1c(C=O)cc(C)cc1B(O)O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CCCCOc1c(C=O)cc(C)cc1-c1ccc([N+](=O)[O-])cn1

Procedure:
The title compound was synthesized in a manner analogous to Example 52(i), except for replacing 2-chloro-5-nitropyridin with 2-chloro-5-nitropyridine, and replacing 3-formyl-2-isopropoxy-5-methylphenylboronic acid with 3-formyl-2-butoxy-5-methylphenylboronic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]2[CH2:28][CH2:27][P:26]([O:30]C)(=[O:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.C[Si](Br)(C)C>C(Cl)Cl>[CH3:32][C:2]([CH3:1])([CH3:33])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]2[CH2:24][CH2:25][P:26]([OH:30])(=[O:29])[CH2:27][CH2:28]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: COP1(=O)CCC(N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)C2CCP(=O)(O)CC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(1-methoxy-1-oxo-1λ5-phosphinan-4-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (10 mg, 0.02 mmol) was dissolved in 1 mL of CH2Cl2, and to the solution was added TMSBr (26 μL, 0.2 mmol). The reaction mixture was stirred at room temperature for 40 minutes. Another portion of TMSBr (26 μL, 0.2 mmol) was added and the mixture was stirred at room temperature for 5 hours before cooling to 0° C. and quenching through the addition of methanol (0.5 ml). The solvent was removed under vacuum and the residue was purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid). This resulted in 6 mg (62%) of the title compound. MS (m/z): 480.2 [M+H]+; HPLC retention time: 3.831 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH:13]=[CH2:14]>>[CH2:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=2[CH3:1])=[CH:22][CH:23]=1)[CH:13]=[CH2:14]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: C=CCOc1ccc(C=O)cc1
Product: C=CCOc1ccc(CNc2cccc([N+](=O)[O-])c2C)cc1

Procedure:
2-Methyl-3-nitroaniline and 4-allyloxybenzaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH2:10][CH:11](OS(C)(=O)=O)[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O-:33])(=[S:32])[CH3:31].[K+].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:29])[CH2:10][CH:11]([S:32][C:30](=[O:33])[CH3:31])[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC(CNC(=O)OCc1ccccc1)CC(=O)OCc1ccccc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC(CNC(=O)OCc1ccccc1)CC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 250 mg (0.59 mmol) 4-benzyloxycarbonylamino-3-methanesulfonyloxy-butyric acid benzyl ester in 5 ml DMF were added sequentially 68 mg (1.0 equiv.) potassium thioacetate and 101 μl (1.0 equiv.) DIPEA. The reaction mixture was stirred for 2 h at 80° C. under argon and light protection. Further 68 mg (1.0 equiv.) potassium thioacetate and 101 μl (1.0 equiv.) DIPEA were added. After stirring for another 2 h at 80° C., the mixture was poured into 10 ml water and extracted three times with 15 ml ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate) gave pure 3-acetylsulfanyl-4-benzyloxycarbonylamino-butyric acid benzyl ester as yellow oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].Cl.[CH:20]1(OC2C=C(C=C(OC)C=2)C=O)CCCC1>C[Mg]Cl.C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]([OH:11])[CH3:20])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C=O)cc(OC2CCCC2)c1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: C[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To the 3-cyclopentyloxy-4-methoxybenzaldehyde in THF solution from Example 1, 3 M methyl magnesium chloride in THF (240 mL) was added dropwise at −10 to -4° C. over 5 hours. After stirring an additional 1 hour at 0° C., HPLC showed 0.07% aldehyde remaining. The reaction mixture was slowly treated with 20% ammonium chloride (340 g) and then acidified with 10% hydrochloric acid (270 g) to a pH of 8. The layers were separated, the aqueous layer extracted with THF, and the combined extracts washed with brine. The organic solution was concentrated to give 1-(3-cyclopentyloxy-4-methoxyphenyl) ethanol as an oil (115.05 g, 81% yield, purity 94.4% by HPLC area). 1H-NMR: 6.93 (d, J=1.8 Hz, 1H), 6.88 (dd, J=8.2 Hz, J=1.8 Hz, 1H), 6.83 (d, J=8.2, 1H), 4.80 (m, 2H), 3.84 (s, 3H), 1.99–1.80 (m, 6H), 1.61 (m, 2H), and 1.48 (d, J=6.4 Hz, 3H). 13C-NMR: 149.2, 147.6, 138.5, 117.5, 112.3, 111.7, 80.3, 70.0, 56.0, 32.7, 25.0, and 24.0.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCOCC>CN(C=O)C>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@:4]1([OH:16])[CH3:17])(=[O:28])=[O:27]
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a mixture of (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (4.66 g, 19.4 mmol)) and Et3N (7.01 mL, 50.4 mmol)) in DMF (40 mL) was added methanesulfonyl chloride (2.66 g, 23.3 mmol) dropwise at 0° C. After stirring at room temperature for 3 h, ether (400 mL) was added. The organics were washed with 1N HCl (20 mL), saturated aqueous sodium bicarbonate (20 mL), brine (2×20 mL), dried (Na2SO4), and concentrated to give ((1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)methyl methanesulfonate (12) (5.90 g, 96%) as a light yellow sticky mass.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])=[C:2]=[S:3].O.[NH2:15][NH2:16]>C1COCC1>[NH2:15][N:16]1[C:6](=[O:7])[C:5]2[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1][C:2]1=[S:3]
Reactant: NN
Reactant: COC(=O)c1ccccc1N=C=S
Solvent: C1CCOC1
Solvent: O
Product: Nn1c(=S)[nH]c2ccccc2c1=O
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Methyl 2-isothiocyanatobenzoate (5.00 g, 25.9 mmol) was dissolved in THF (125 mL), followed by addition of hydrazine monohydrate (2.51 mL, 51.8 mmol). The reaction mixture was refluxed for 1 h, cooled to RT and the precipitate was collected by filtration. The precipitate was washed with water and dried in vacuo to give pure title compound (4.78 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[NH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=O)[C:6]=2[S:5][CH:4]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:22])=O>>[CH3:1][O:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([Cl:22])=[C:6]2[S:5][CH:4]=1
Reactant: CCOC(=O)c1c[nH]c2c(OC)csc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnc2c(OC)csc2c1Cl
Reaction time: 0.5 h

Procedure:
3-Methoxy-6-ethoxycarbonylthieno[3,2-b]pyridin-7-(4H)-one (3 g, 0.0118 mol) and phosphorus oxychloride (10 ml) was heated under reflux for one hour. The reaction mixture was poured onto ice (200 g) and stirred for 30 minutes. The mixture was then basified with 40% sodium hydroxide solution and extracted with chloroform (3×100 ml). The chloroform extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound as a buff-colour solid, 3.2 g, m.p. 135°-137°.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])[C:20]([F:36])=[CH:19][C:18]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:36][C:20]1[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:22][C:17]([O:1][C:2]2[C:3]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)=[C:18]([N+:37]([O-:39])=[O:38])[CH:19]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)COc1nc(OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-hydroxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine, 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide is added potassium carbonate, and the mixture is stirred for 2 hours at 70° C. The reaction solution is cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([CH3:12])[C:3]=1[I:13].C([Mg]Cl)(C)C.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.[NH4+].[Cl-]>CCOCC.C1COCC1>[I:13][C:3]1[C:4]([CH3:12])=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[B:19]([OH:24])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(I)c(I)c(C)c1OC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)c(I)c(C)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of 1,2-diiodo-4,5-dimethoxy-3-methylbenzene (Example 5(b), 2.0 g, 4.95 mmol) in 120 mL of a mixture of THF and Et2O (1:1) was added dropwise at −78° C., isopropylmagnesium chloride (2 M in THF, 2.72 mL, 5.44 mmol). After the mixture was stirred for 2 h at that temperature, B(OiPr)3 (10.50 ml, 14.84 mmol) was added. The solution was warmed to room temperature overnight; then a saturated solution of NH4Cl was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times), dried over Na2SO4 and concentrated. To the concentrated sample, hexane was added and the resulting precipitate was isolated to give 0.90 g of the pure product (56%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[C:30](O)=[O:31].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:30]([C:22]2[O:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)=[O:31])[N:8]=1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (80 mg, 0.297 mmol), benzofuran-2-carboxylic acid (48 mg, 0.297 mmol), and EDC (56.9 mg, 0.297 mmol) were combined in CH2Cl2 (3 ml) and the pH adjusted to 9.5 with triethylamine (41 μl, 0.297 mmol). After stirring 30 minutes at 25° C., the reaction was concentrated and chromatographed on silica gel (3% MeOH in CH2Cl2) to give the title compound as a white solid from CH2Cl2 /Et2O: (m.p. 289°-291°).
Reaction SMILES: [SH2:1].[CH3:2][N:3]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:5]2[CH2:4]1>N1C=CC=CC=1.C(N(CC)CC)C>[CH3:2][N:3]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[N:16][C:17]([C:18](=[S:1])[NH2:19])=[C:5]2[CH2:4]1
Reactant: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1Cc2c(C(N)=S)ncn2-c2ccccc2C1=O
Reaction time: 48 h
Yield: 87 %

Procedure:
A stream of hydrogen sulphide was passed for 1 hr. through a solution of 10.2 g (0.429 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 250 ml of pyridine and 2.5 ml of triethylamine. The green solution was left to stand for 48 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and the suspension obtained was suction filtered. There were obtained 9.0 g (87%) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide as yellow crystals. A sample was recrystallized from methanol and gave pale yellow crystals; m.p. 295-297°.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][N:51]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:50]1=[O:64]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:48][C@H:49]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][N:51]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:50]1=[O:64])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCCCN(Cc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCCN(Cc4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-benzyl-2-oxoazocan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 45 (6.3 mg, 0.027 mmol) to give a white solid (9.5 mg, 62% yield). Anal. Calcd. for C45H56N4O6S m/z 780.7. found: 781.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.03 (m, 16H), 6.81 (d, J=7.4 Hz, 1H), 5.34 (t, J=4.6 Hz, 1H), 5.13 (d, J=6.1 Hz, 1H), 5.07 (d, J=14.7 Hz, 1H), 5.03-4.93 (m, 1H), 4.92-4.80 (m, 1H), 4.06 (d, J=14.7 Hz, 1H), 3.77 (t, J=13.2 Hz, 1H), 3.68 (s, 3H), 3.25-3.04 (m, 2H), 2.92-2.64 (m, 5H), 2.47-2.29 (m, 2H), 2.12-1.95 (m, 2H), 1.90-1.09 (m, 18H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]([NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[O:26])=[C:20]2[N:19]=[CH:18][C:17]=1[C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)=[O:34])C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]([NH:27][S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])=[O:26])=[C:20]2[N:19]=[CH:18][C:17]=1[C:33]([N:35]1[CH2:36][CH2:37][CH:38]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:39][CH2:40]1)=[O:34]
Reactant: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3OCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3O)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 81.5 %

Procedure:
N-[7-(2-Benzyloxyphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]ethanesulfonamide (120 mg, 0.19 mmol) obtained in Example 48, step 3 was dissolved in THF (5 mL), 10 wt % palladium-activated carbon (12 mg) was added, and the mixture was stirred at room temperature for 7 hr under a hydrogen atmosphere, and at 60° C. for 1 hr. The mixture was allowed to cool, and the reaction mixture was filtered. The obtained solvent was evaporated under reduced pressure to give the title compound (85 mg, 88%).
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][Cl:22])=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Triethylamine (2.98 mL; 21.20 mmol) was added at 0° C. to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (2.0 g; 8.48 mmol) and 4-(chloromethyl)benzoyl chloride (1.74 g; 8.90 mmol) in dichloromethane (75 mL). The mixture was stirred for 1 hour at room temperature and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to furnish 2.60 g (88%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[NH2:32][C:33]1[N:34]=[C:35]([Cl:42])[C:36]2[CH:41]=[CH:40][NH:39][C:37]=2[N:38]=1.[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC>C(Cl)Cl.C(#N)C>[NH2:32][C:33]1[N:34]=[C:35]([Cl:42])[C:36]2[CH:41]=[CH:40][N:39]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:37]=2[N:38]=1
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Agent: Br
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To an ice-cold solution of product from Step C of Example 62 (1.27 g, 2.57 mmol) in CH2Cl2 (30 mL) was added HBr (5.7 M in acetic acid; 3 mL) dropwise. The reaction mixture was stirred at room temperature for 2 h, concentrated in vacuo and co-evaporated with toluene (2×15 mL). The resulting oil was dissolved in MeCN (15 mL) and added dropwise into a well-stirred mixture of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine [for preparation see Heterocycles 35: 825 (1993)] (433 mg, 2.57 mmol), KOH (85%, powdered) (0.51 g, 7.7 mmol), tris-[2-(2-methoxyethoxy)ethyl]amine (165 L, 0.51 mmol) in acetonitrile (30 mL). The resulting mixture was stirred at rt for 1 h, filtered and evaporated. The residue was purified on a silica gel column using hexanes/EtOAc, 5/1, 3/1 and 2/1 as eluent to give the title compound as a colorless foam (0.65 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15]>C(O)(C)C>[OH:16][CH:13]([CH2:14][OH:15])[CH2:12][NH:11][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: NCC(O)CO
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnccc1NCC(O)CO
Yield: 33.8 %

Procedure:
A solution of 4-chloro-3-nitropyridine (1.1 g, 6.94 mmol) and 3-amino-1,2-propanediol (1.22 g, 13.4 mmol) in isopropanol (50 ml) was stirred at 20°-25° C. for 20 hours and then concentrated under reduced pressure. Flash chromatography of the residue over silica gel and elution with 10% MeOH-90% CHCl3 gave pure 4-(2,3-dihydroxy-1-propylamino)-3-nitropyridine (500 mg, 33.8%). An analytically pure sample, m.p. 131°-35° C., was obtained upon recrystallization from MeOH-EtOAc-hexane.
Reaction SMILES: [CH2:1]1[CH2:15][O:14][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:4][CH2:5][CH2:6]O)[O:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:31])C=C.O>C(#N)C>[CH2:1]1[CH2:15][O:14][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:4][CH2:5][CH2:6][Br:31])[O:2]1
Reactant: OCCCC1(c2ccccc2)OCCO1
Reactant: C=CCBr
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O
Product: BrCCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.2 g of the alcohol compound obtained in 20 ml of acetonitrile were added 1.2 g of 1,1'-carbonyldiimidazole and 2.5 ml of allyl bromide. The mixture was stirred for 2 hours at room temperature and then heated under reflux for 1.5 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.1 g of 4,4-ethylenedioxy-4-phenylbutyl bromide as colorless crystals.