Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)C.[CH:21]1[CH:22]=[CH:23]C2N(O)N=[N:27][C:25]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.N1CCCCC1.FC(F)(F)C(O)=O>C(Cl)CCl>[N:27]1([C:18]([C@@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8]2)=[O:20])[CH2:23][CH2:22][CH2:21][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: ClCCCl
Product: O=C([C@@H]1Cc2ccccc2CN1)N1CCCCC1

Procedure:
Following a procedure similar to that described for Intermediate 14, treatment of Boc-TIC-OH with EDC, HOBt, N,N-diisopropylethylamine and piperidine, followed by deprotection using trifluoroacetic acid, afforded the title compound as a white foam. LC/MS: 245.2 (M+1).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]1[C:23]2[CH:24]=[CH:25][C:26]([O:28]C(=O)C)=[CH:27][C:22]=2[O:21][CH:20]=1>CC#N>[OH:28][C:26]1[CH:25]=[CH:24][C:23]2[C:19]([CH2:18][N:8]3[CH2:9][CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]3)=[CH:20][O:21][C:22]=2[CH:27]=1
Reactant: CC(=O)Oc1ccc2c(CCl)coc2c1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NC1CCN(Cc2coc3cc(O)ccc23)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-acetamidopiperidine (429 mg, 3.00 mmol) and K2CO3 (1.14 g, 8.25 mmol) in MeCN (5 mL) was added a solution of acetic acid 3-chloromethyl-benzofuran-6-yl ester (450 mg, 2.0 mmol) in MeCN (5 mL). The reaction mixture was further diluted with MeCN (10 mL) and heated (50° C., 15 h). The solvent was removed in vacuo and the remaining residue was suspended in 5-10% CH3OH in water and enough concentrated acetic acid was added until all solids were dissolved (pH ˜7-8). The solution was slowly basified using 4 N KOH until precipitate was observed. The precipitate was filtered and rinsed with water. The pH of the mother liquor was further adjusted (4 N KOH and concentrated acetic acid) to produce additional precipitate, which was filtered and rinsed with water. This process of pH adjustment and solid filtration was repeated until no additional precipitate was observed. The precipitate was combined and dried in vacuo to provide the title compound as an off white solid (419 mg, 73%). MS (ESI): mass calcd. for C16H20N2O3, 288.15; m/z found, 289.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.44 (s, 1H), 7.69 (d, J=7.6, 1H), 7.63 (s, 1H), 7.47 (d, J=8.4, 1H), 6.86 (d, J=2.0, 1H), 6.72 (dd, J=8.4, 2.1, 1H), 3.56-3.44 (m, 3H), 2.86-2.74 (m, 2H), 1.99 (t, J=10.6, 2H), 1.76 (s, 3H), 1.74-1.62 (m, 2H), 1.43-1.27 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:14]([C:24]2[S:25][CH:26]=[C:27]([C:29](OCC)=[O:30])[N:28]=2)[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:7]([N:11]1[C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[C:14]([C:24]2[S:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=2)[CH:13]=[N:12]1)([CH3:9])([CH3:10])[CH3:8]
Reactant: CCOC(=O)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(OC)cc2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3nc(CO)cs3)cnn2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (39.4 mg, 1.04 mmol) in THF (2.0 mL) was added a solution of the compound (200 mg, 0.52 mmol) obtained in step 1 in THF (2.0 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added Na2SO4 10H2O (excess amount), and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude (2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)methanol as a white solid, which was used for the next step without purification.
Reaction SMILES: O.O.Cl[Sn]Cl.[CH3:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([C:21]#[N:22])[CH:13]=2)[CH:9]=[CH:10][N:11]=1>Cl.[OH-].[K+]>[CH3:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:21]#[N:22])[CH:13]=2)[CH:9]=[CH:10][N:11]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])c(C#N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: O
Product: Cc1nccn1-c1ccc(N)c(C#N)c1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 80.7 %

Procedure:
SnCl2.2H2O (60.0 g; 0.26 mol) was dissolved in 37% HCl (100 mL), to this solution cooled to −10° C., 4-(2-methyl-1H-imidazol-1-yl)-2-cyano-nitrobenzene (12.0 g, 50 mmol) was added in two portions over the course of 30 min. Completed the additions the stirred reaction mixture was allowed to come to r.t., and after further 45 min. stirring, it was poured in ice/water (250 g) and 3N KOH (500 mL). The resulting suspension was filtered and the cake washed with water. The residue was suspended in 2M NH3/EtOH (250 mL), stirred for a few minutes and filtered, the filtrate was concentrated to provide the titled compound as a brown solid (8 g, 78%). C11H10N4, MW: 198.23. MS: m/z 199 (M+1). 1H-NMR (300 MHz, CDCl3) ppm: 2.21 (s, 3H), 4.70 (s, 2H), 6.79 (d, 1H), 6.97 (d, 1H), 7.22 (dd, 1H), 7.29 (d, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.Cl.[NH2:13][OH:14]>N1C=CC=CC=1.C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=[N:13][OH:14])=[CH:2]1
Reactant: NO
Reactant: O=Cc1csc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=Cc1csc2ccccc12
Yield: 98.6 %

Procedure:
Benzothiophene-3-carbaldehyde (4.0 g, 24.6 mmol) was dissolved in a mixture of pyridine (25 ml) and ethanol (25 ml). Hydroxylamine hydrochloride (3.4 g, 49.2 mmol) was added, while stirring. The mixture was stirred for 30 minutes at RT and then heated under reflux for eight hours. A red-brown solution formed. For working up, the solution was concentrated and the residue was freed from residual pyridine by distillation with ethanol (3×50 ml). Water (50 ml) was added to the oily residue and the mixture was stirred vigorously overnight. The pink solid present was filtered off with suction, washed with water and dried in vacuo. 4.3 g benzothiophene-3-carbaldehyde oxime were obtained (m.p. 87-89° C.).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[ClH:21].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)c1ccc(Cl)cc1
Yield: 118.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.63 ml (4.96 mmol) of 4-chlorobenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with ether and dried to obtain 1.01 g of the desired compound (free base) (79 3% pale yellow powder), mp: 95.0°-96.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=O)[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCCN1C(=O)OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC1CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester (25.0 g, 101 mmol) was dissolved in pyridine (125 mL) under an N2 atmosphere and cooled to −10° C. The phosphorus oxychloride (12.6 mL, 135 mmol) was dissolved in DCM (25 mL) and added dropwise over 40 mins to the pyridine solution. The reaction mixture's temperature was maintained at −10° C. and the solution was allowed to stir for 2 hours. The reaction was quenched by addition of water/ice (100 g) and transferred into a separatory funnel. The solution was extracted with diethyl ether (3×200 mL). The organic layers were combined and washed with saturated cupric sulfate (200 mL). The organic layer was dried over MgSO4 and concentrated under vacuo to afford 20.0 g (82%) of 2-cyano-pyrrolidine-1-carboxylic acid benzyl ester as a green oil.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[C:17]([O:22][CH3:23])(=[O:21])/[CH:18]=[CH:19]/[CH3:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:20][C@@H:19]1[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][C@H:18]1[C:17]([O:22][CH3:23])=[O:21]
Reactant: C/C=C/C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.8 %

Procedure:
To a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.8 mL, 7 mmol) and methyl crotonate (0.62 mL, 5.8 mmol) in DCM (25 mL) at 0° C. was added dropwise a solution of trifluoroacetic acid (0.045 mL, 0.58 mmol) in DCM (1 mL). The reaction was allowed to warm to room temperature and was stirred for 3 h. Saturated sodium bicarbonate solution was added and the phases were separated. The aqueous phase was extracted twice with DCM and the combined organics were dried over sodium sulfate and concentrated in vacuo. This yielded crude methyl rac-(trans)-4-methyl-1-(phenylmethyl)-3-pyrrolidinecarboxylate (1.58 g) which was used without further purification. LCMS: (M+H)+: 234.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2Cl)cc1N

Procedure:
Prepared from (2′-chloro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example C8) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white solid (180 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Cl[C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15].C(OC(CCCCCC(=O)C(OC)=O)=O)(C)(C)C>[Zn]>[C:8]([O:7][C:5]([CH2:4][CH2:3][CH2:2][C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15])=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: COC(=O)C(=O)Cl
Agent: COC(=O)C(=O)CCCCCC(=O)OC(C)(C)C
Agent: [Zn]
Product: COC(=O)C(=O)CCCC(=O)OC(C)(C)C
Yield: 85.4 %

Procedure:
t-Butyl 4-bromobutanoate (1.22 g, 5.49 mmol), activated zinc (0.75 g in 15 ml of THF) and methyl chlorooxoacetate (0.74 ml, 6 mmol) were reacted by the same procedure as described in Example 1 for the preparation of methyl 7-tert-butyoxycarbonyl-2-oxoheptanoate to give the crude title material (1.08 g) as a colorless liquid which is used directly in next step.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:3].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[OH:13])[CH2:8][CH:9]([CH3:10])[CH3:11])=[O:5])[CH3:3]
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.46 g of Z-Ala-Sta-OMe are dissolved in 20 ml of MeOH, 1.03 g of ammonium formate are then added at RT, the mixture is stirred until a solution forms, 400 mg of 10% Pd/C are then added and the mixture is stirred for 5 min at RT. After 5 min, checking by TLC shows that the starting material has disappeared. The pH is 8 to pH paper. The whole mixture is filtered on celite and then the methanolic solution is filtered on a column of Amberlite IR 45 resin (OH) and the methanol is evaporated off. The residue is taken up in ether, the mixture is evaporated to dryness, the residue is then dissolved in CH2Cl2, the insoluble material is filtered off and the filtrate is evaporated to dryness to give a white powder.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.II.[O:19]1[CH:21]([CH3:22])[CH2:20]1.[NH4+].[Cl-]>C1COCC1>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([CH2:20][CH:21]([OH:19])[CH3:22])=[CH:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Reactant: CC1CO1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 14.5 h

Procedure:
To a solution of (4-bromobenzyloxy)(tert-butyl)dimethylsilane (3.080 g) in THF (20 mL) were added Mg (0.288 g) and I2 (cat) at room temperature under an Ar atmosphere. The mixture was heated at 50° C. for 1 hour, and then cooled to room temperature. To the mixture was added 1,2-epoxypropane (0.77 mL) at room temperature under an Ar atmosphere, and the mixture was stirred at room temperature for 14.5 hours, and then heated at 50° C. for 1 hour, and then cooled to room temperature. To the mixture was added saturated aqueous NH4Cl, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1) to afford 1-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]propan-2-ol (1.485 g) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1(C(=O)OCC)CCCC1=O
Temperature: 56 °C
Yield: 37.8 %

Procedure:
To a solution of ethyl 2-oxocyclopentanecarboxylate (93.27 g, 597 mmol) and ethyl 2-bromoacetate (144.64 g, 866 mmol) in acetone (1.2 L) was added K2CO3 (165 g, 1194 mmol). The mixture was heated at 56° C. for 24 h. The solid was filtered off and the filter cake was washed with acetone (3×100 mL). The filtrate was concentrated and the resultant liquid was purified by a silica gel plug to give the title compound as light yellow liquid (54.7 g). LCMS m/z=243.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.14 Hz, 3H), 1.24 (t, J=7.14 Hz, 3H), 1.95-2.03 (m, 1H), 2.06-2.15 (m, 2H), 2.35-2.50 (m, 2H), 2.55-2.60 (m, 1H), 2.80 (dd, J=15.2, 2.09 Hz, 1H), 2.95 (dd, J=15.2, 2.09 Hz, 1H), 4.09 (q, J=7.14 Hz, 2H), 4.12 (q, J=7.14 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>CN(C)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=3)[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CNc1ccccc1C2=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: COc1ccc2c(c1)CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1C2=O
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 8-methoxy-11-oxo-6,11- dihydrodibenz[b,e]azepine (150 mg) in N,N-dimethylaniline (1 ml) was added 4-nitrobenzoyl chloride (140 mg) at 110° C. The mixture was stirred for 1 hour at the same temperature and diluted with ethyl acetate. The solution was washed successively with diluted hydrochloric acid and brine. The organic phase was dried over magnesium sulfate, and evaporated in vacuo to give crude 8-methoxy -5-(4-nitrobenzoyl)-11-oxo-6,11-dihydrodibenz[b,e]azepine (240 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](I)[N:8]2[CH2:11][CH3:12])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].ClCCl>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)[N:8]2[CH2:11][CH3:12])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:3]=1
Reactant: CCn1c(I)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CCn1c(-c2cncnc2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Temperature: 120 °C
Yield: 77.4 %

Procedure:
In a 5-mL microwave vessel equipped with a stirbar was placed (S)-4-(2-chloro-9-ethyl-8-iodo-9H-purin-6-yl)-3-methyl-morpholine (30 mg, 0.074 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (22.7 mg, 0.110 mmol, 1.5 eq.), potassium phosphate (46.9 mg, 0.22 mmol, 3.0 eq.), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (3.0 mg, 0.0037 mmol, 0.05 eq.), and degassed 1,4-dioxane (3.0 mL). The microwave tube was capped, and the reaction mixture was heated under microwave irradiation (300 watts, 120° C.) for 15 minutes. The reaction mixture was diluted with ethyl acetate (10 mL) and filtered through a pad of Celite. The organic layer was washed with water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in heptane) to give the desired compound (k-1) as a foam (20.6 mg, 77.8%). 1H NMR (CDCl3, 400 MHz) δ ppm 9.34 (s, 1H), 9.13 (s, 2H), 6.00 to 4.60 (broad s, 2H), 4.42 to 4.28 (m, 2H), 4.11 to 3.97 (m, 1H), 3.87 to 3.72 (m, 2H), 3.71 to 3.59 (m, 1H), 3.59 to 3.40 (broad s, 1H), 1.51 to 39 (m, 6H); LC-MS m/z (method A): RT=2.21 min, [M+H]+=360.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]([OH:26])[N:8]([C:17]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[C:9]2=[O:16].CN(CCN(C)C)C.[I:35]I>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([I:35])=[C:10]2[C:6]=1[CH:7]([OH:26])[N:8]([C:17]([CH3:18])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:25])[C:9]2=[O:16]
Reactant: II
Reactant: COCOc1c(OC)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(OC)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 76.9 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-methoxymethoxy-5-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.00 g, 5.60 mmol) was dissolved in THF (60 mL), and the solution was treated with TMEDA (2.70 mL, 17.9 mmol), sec-butyl lithium-hexane solution (0.95 mol/L, 18.9 mL, 18.0 mmol) and iodine (2.13 g, 8.39 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20 to 70/30) to obtain 4-methoxymethoxy-5-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenyl ethyl)isoindolinone (2.08 g, yield 77%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C@@H:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:9][C@@:8]([CH2:27][C:28]([O:30][CH3:31])=[O:29])([CH3:26])[C:7]1=[O:32])[CH2:4][CH3:5].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>N1C=CC=CC=1>[Cl:25][C:21]1[CH:20]=[C:19]([C@@H:10]2[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[N:6]([C@@H:3]([CH2:4][CH3:5])[CH2:2][NH:1][S:39]([C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)(=[O:41])=[O:40])[C:7](=[O:32])[C@:8]([CH2:27][C:28]([O:30][CH3:31])=[O:29])([CH3:26])[CH2:9]2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC[C@@H](CN)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC[C@@H](CNS(=O)(=O)c1cccnc1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of methyl 2-((3R,5R,6S)-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (13 mg, 0.027 mmol; Example 196, Step A) and pyridine-3-sulfonyl chloride (4.84 mg, 0.027 mmol) in pyridine (0.3 mL) was stirred at 110° C. for 4 h. Chromatography on silica gel (0 to 60% EtOAc in hexanes) gave methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetate. This was hydrolyzed with LiOH (1N solution in water, 0.3 mL) in ethanol (0.5 mL) for 3 h at rt. HPLC purification (C18 column, eluted with 10 to 95% CH3CN in water, with 0.1% TFA) gave the title compound as a 1:1 complex with 2,2,2-trifluoroacetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[H-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CN(C=O)C>[O:18]1[CH2:17][CH:16]1[CH2:14][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: ClCC1CO1
Reactant: Oc1cccc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OCC2CO2)c2cccnc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
In 20 ml of dried DMF was dissolved 1 g of 5-hydroxyquinoline, and 0.28 g of sodium hydride (60% content) was then added thereto, followed by heating with stirring at 50° C. for 30 minutes. Afterward, 1.92 g of epichlorohydrin was further added to the reaction liquid and the latter was then heated with stirring at 90° C. for 3 hours, and the solvent was distilled off under reduced pressure. Water was then added to the residue, and the liquid was extracted with chloroform. The chloroform extract was then decolored and purified with active carbon, then was dried with anhydrous sodium sulfate, and was distilled off. The residue was then purified through a silica gel column chromatograph by the use of an effluent solvent of chloroform:methanol=100:1, so that 0.88 g of 5-(2,3-epoxypropoxy)quinoline was obtained in an oily state.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16](=[O:18])[CH3:17])[CH2:12]2)=O)(C)(C)C.[ClH:19].O1CCOCC1>C(Cl)Cl>[ClH:19].[CH:13]12[NH:8][CH:9]([CH2:15][CH2:14]1)[CH2:10][N:11]([C:16](=[O:18])[CH3:17])[CH2:12]2
Reactant: CC(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-acetyl-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.20 g, 4.49 mmol) in DCM (25 mL) is added 4M HCl in 1,4-dioxane (20.0 mL, 80.0 mmol) and the reaction stirred at about 25° C. for 18 hours. The reaction is concentrated, suspended in Et2O, and filtered to afford the title compound (U) as a hydroscopic solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:15](=[O:16])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(Br)cc2[nH]1
Yield: 128 %

Procedure:
The mixture of 4-bromobenzene-1,2-diamine (200 mg, 1.1 mmol), CDI (174 mg, 1.1 mmol) in dioxane was reacted at 50° C. for 16 hours. The mixture was concentrated and the residue was dissolved in DCM and extracted with water with the combined organic phases dried by Na2SO4 and concentrated to give 300 mg of crude product which was used without further purification. LCMS (m/z): 213.1/214.1 [M+H]+/[M+2H]+