Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1.CS(C)=O.C(N(C(C)C)CC)(C)C.O>ClCCl>[CH:2]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:20]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1)=[O:1]
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CO
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a solution of biphenyl-2-ylcarbamic acid 1-[2-(4-hydroxymethyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (151 mg, 0.3 mmol) in dichloromethane (3 mL) at 0° C. was added dimethyl sulfoxide (128 μL, 1.8 mmol) and diisopropylethylamine (157 μL, 0.9 mmol). After 15 minutes, sulfur trioxide pyridine complex (143 mg, 0.9 mmol) was added and stirring at 0° C. was continued for 1 hour. Water was added to quench the reaction and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (150 mg, 100% yield), which was used without further purification. [M+H+] found 500.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([F:18])[C:5]2=1.C([O-])=O.[NH4+].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([F:18])[C:5]2=1
Reactant: O=[N+]([O-])c1cc(Cl)cc2c1[nH]c1cncc(F)c12
Agent: O=C([O-])O
Agent: O=C[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: CO
Product: Nc1cc(Cl)cc2c1[nH]c1cncc(F)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
Sulfated platinum (0.1 eq, 1 g) was added to a suspension of 6-chloro-4-fluoro-8-nitro-9H-β-carboline (1.0 eq, 35 mmol, 9.3 g) and ammonium formate (3.0 eq, 105 mmol, 6.6 g) in ethanol (175 mL) and the resulting mixture heated at 75° C. for 4 h. After cooling to RT the mixture was filtered through a short plug of Celite® washing with copious amounts of methanol, and then the filtrate concentrated in vacuo to afford a beige solid. The solid was suspended in the minimum volume of methanol and added dropwise to a vigorously stirred mixture of saturated sodium bicarbonate solution and saturated sodium chloride solution. After stirring for 15 min the precipitated solids were collected by suction filtration, washed with water (200 mL) and dried in vacuo to afford 6-chloro-4-fluoro-9H-β-carbolin-8-ylamine (5.8 g, 70% 2 steps) as a beige powder. 1H-NMR (300 MHz, dmso-d6): δ 5.76 (s, 2H), 6.81 (d, 1H), 7.29 (d, 1H), 8.24 (d, 1H), 8.82 (d, 1H), and 11.71 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.59 min. MS (M+H+): 236.
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].[C:5]1([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:1][CH2:2][OH:3])[CH2:17][CH2:18]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(C(CN2CCNCC2)c2ccccc2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCN(CC(c2ccccc2)c2ccccc2)CC1

Procedure:
Ethylene bromohydrin (4.03 g) was added dropwise to a mixture of 1-(2,2-diphenylethyl)piperazine (4.30 g), potassium carbonate (6.7 g) and N,N-dimethylformamide (20 ml) with stirring. The mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over Na2SO4. The solvent was then distilled off and the residue was subjected to silica gel chromatography. Elution with ethyl ether-ethyl acetate-methanol (10:2:1, v/v) gave 4-(2,2-diphenylethyl)-1-piperazineethanol as an oil. Yield 4.24 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[S:15][CH:16]=1)[C:5]([O:7]C)=[O:6].[ClH:24]>>[ClH:24].[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[S:15][CH:16]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(-c2csc(N3CCN(C)CC3)n2)c(F)c1
Agent: Cl
Product: CN1CCN(c2nc(-c3ccc(C(=O)O)cc3F)cs2)CC1
Temperature: 90 °C

Procedure:
The methyl ester (1.76 g, 5.25 mmol) (9d) was heated at 80° C. with 6M HCl (40 mL) for 5.5 h. More 6M HCl (10 mL) was added and the mixture was heated at 90° C. for 1 h 15 min. After cooling, the mixture was then evaporated under vacuum and freeze-dried from water to give the final product as cream solids in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2(O)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:14].C([BH3-])#N.[Na+]>[Zn+2].[I-].[I-].ClCCCl>[Br:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1cc(C2(O)CCOCC2)sc1Br
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(C2CCOCC2)sc1Br
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 4-(5-bromo-4-methyl-thiophen-2-yl)-tetrahydro-pyran-4-ol (2.3 g, 8.30 mmol) and 1,2-dichloroethane (50 mL) is added ZnI2 (3.97 g, 12.45 mmol) and sodium cyanoborohydride (3.91, 62.23 mmol). The solution is stirred for 1 hour, filtered thru celite and concentrated. The residue is purified by ISCO column chromatography (5%-10% EtOAc/hexane gradient) furnish the title compound (1.53 g, 5.86 mmol, 71%). 1H NMR (CDCl3), δ 1.69-1.82 (m, 2H), 1.84-1.92 (m, 2H), 2.14 (s, 3H), 2.84-2.98 (m, 1H), 3.49 (dt, J=11.8, 2.2 Hz, 2H), 4.00-4.07 (m, 2H), 6.51 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:33](=[O:34])[C:32]2[CH:31]=[C:30]([O:29][CH3:28])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=2)[CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of methyl 4-benzyloxycarbonylpiperazine-2-carboxylate (1.2 g) obtained in Reference Example 21, triethylamine (0.9 g) and dichloromethane (15 ml) is added dropwise, taking 5 minutes while stirring at 0° C., to a solution of 3,4,5-trimethoxybenzoyl chloride (1.08 g) in dichloromethane (10 ml). The reaction mixture is stirred at room temperature for 10 minutes, and then poured into water, followed by extraction with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone=2:2:1) to give methyl 4-benzyloxycarbonyl-1-(3,4,5-trimethoxybenzoyl)-piperazine-2-carboxylate as a colorless oily product (2.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[CH:23][C:22]=2[CH:33]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])=[CH:23][C:22]=2[CH:33]=1
Reactant: Brc1ccc2oc(CC3CCCCN3)cc2c1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3cc(Br)ccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (490 mg) was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (488 mg) and (RS)-2-(5-bromo-benzofuran-2-ylmethyl)-piperidine, D70 (530 mg) by a procedure similar to that described for Example 1.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]=2[N:5]=1.CO.O.[NH2:25]N>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]=[C:4]([NH:3][NH2:25])[CH2:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[CH:17]=1
Reactant: NN
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: Cl
Solvent: O
Solvent: CO
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 0.67 h

Procedure:
To a suspension of 3.4 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine dihydrochloride in 60 parts by volume of methanol is added 1.25 parts of 80% hydrazine hydrate. The suspension is stirred for 40 minutes, diluted with water and extracted with methylene chloride. The extract is washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from a mixture of methylene chloride and benzene to give 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as colorless prisms. Melting point: around 170° C (browning), 202° C to 204° C (decomposition).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH:11]([C:14](N)=[O:15])[O:10][C:9]=2[CH:17]=1)(=[O:4])[CH3:3].[CH2:18]([OH:20])[CH3:19]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH:11]([C:14]([O:20][CH2:18][CH3:19])=[O:15])[O:10][C:9]=2[CH:17]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc2c(c1)OC(C(N)=O)CO2
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1COc2ccc(C(C)=O)cc2O1

Procedure:
150 ml of ethanol are saturated with hydrochloric acid; 6 g (27.12 mmol) of the amide obtained in Step B are then added to the medium. After 18 hours of reflux, the mixture is cooled and then filtered. The filtrate is concentrated in vacuo and the residue is taken up in water; the aqueous phase is then neutralised with solid sodium hydrogen carbonate. After extraction with dichloromethane, the organic phase is dried over magnesium sulphate, filtered and then concentrated in vacuo. The title ester is obtained in the form of a white solid after passage over a silica column (eluant:AcOEt/PE:30/70).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>>[CH2:14]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)[CH:13]=[CH2:12]
Reactant: OCc1cccc(Br)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCOCc1cccc(Br)c1

Procedure:
The desired compound is prepared by reaction of 3-bromobenzyl alcohol with NaH and allyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH3:14])=[N:10][NH:9][C:8]2=[O:15])=[CH:4][CH:3]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19].N1C=CC=CC=1>CN(C=O)C.C([O-])(O)=O.[Na+].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH3:14])=[N:10][N:9]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)[C:8]2=[O:15])=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1n[nH]c(=O)n(Cc2ccc(Cl)cc2)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-n2nc(C)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 64.6 %

Procedure:
According to Scheme 4 Step 2: A mixture of compound 8(A) (100 mg, 0.39 mmol), 3-acetamidophenylboronic acid (107 mg, 0.59 mmol), copper acetate (79 mg, 0.44 mmol) and pyridine (65 μl, 0.79 mmol) in DMF (3 mL) was stirred at 65° C. during 15 hours. The reaction mixture was diluted with 100 mL of a saturated solution of NaHCO3 and the aqueous layer was extracted twice with DCM (100 mL). The organic layers were combined and successively dried over MgSO4, filtered and concentrated under reduce pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 20 g, C18) using Water/CH3CN 6/4 as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 8(B) (97 mg, 63%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:3]([O:2][CH3:1])=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=1
Reactant: COc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of crude 4-methoxy-3,5-dinitro-benzoic acid (D24) (4.43 g, 17.3 mmol, 1 equiv) in MeOH (60 ml) was added concentrated H2SO4 (4 ml). The resulting mixture was refluxed for 3 h, cooled to room temperature and concentrated in vacuo. The residue was partitioned between H2O and AcOEt. The two layers were separated and the organic phase was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (iso-hexane/AcOEt: 85/15) gave 4-methoxy-3,5-dinitro-benzoic acid methyl ester (D25) (2.84 g, 65%) as an off white solid.
Reaction SMILES: [F:1][CH:2]([F:27])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][N:12]2[C:20](=[O:21])[C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:22]C(=O)C)[C:14]=3[CH2:13]2)=[CH:7][C:6]=1[CH3:26].[ClH:28]>C1COCC1>[ClH:28].[NH2:22][C:15]1[C:14]2[CH2:13][N:12]([CH2:11][C:8]3[CH:9]=[N:10][C:5]([O:4][CH2:3][CH:2]([F:1])[F:27])=[C:6]([CH3:26])[CH:7]=3)[C:20](=[O:21])[C:19]=2[CH:18]=[CH:17][N:16]=1
Reactant: CC(=O)Nc1nccc2c1CN(Cc1cnc(OCC(F)F)c(C)c1)C2=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(CN2Cc3c(ccnc3N)C2=O)cnc1OCC(F)F
Temperature: 90 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (200 mg, 0.54 mmol, Step-1) in THF (5.0 mL) is added aqueous hydrochloric acid (3.0 mL) at rt. The reaction mixture is stirred at 90° C. for 16 hours. The reaction mixture is concentrated to give 220 mg (>99% yield) of the title compound as pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([CH:16]3[CH2:22][CH:21]4[N:23]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Cu](C#N)[C:31]#[N:32].[I-].[K+]>CN(C=O)C>[F:27][C:25]([F:26])([F:28])[C:24]([N:23]1[CH:21]2[CH2:20][CH2:19][CH:18]1[CH2:17][CH:16]([CH:6]1[C:5]3[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[CH:15][C:14]=3[O:13][C:12]3[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22]2)=[O:29]
Reactant: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(Br)ccc31)C2)C(F)(F)F
Reactant: N#C[Cu]C#N
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F
Yield: 60 %

Procedure:
To a solution of 1-[3-(3-bromo-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 2j (1.8 g, 3.86 mmol) in DMF (40 mL) was added copper cyanide (0.69 g, 7.72 mmol) and potassium iodide (50 mg), and the mixture was heated to reflux for 18 h. More copper cyanide (0.43 g) was added, and the mixture was heated to reflux for 30 h. The mixture was filtered and poured in ice-water. The solid was separated via filtration, washed with water, and air-dried. The crude product was purified via flash column chromatography (eluent gradient: 5% to 30% ethyl acetate in heptane) to yield 0.956 g (60%) of title compound 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-9H-xanthene-3-carbonitrile, 3j. MS m/z (MH+) 412.8.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[C:24][C:25]([OH:27])=O)[CH2:18][CH2:17]1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Br:48])[CH:43]=1>O1CCCC1.N1C=CC=CC=1>[Br:48][C:44]1[CH:43]=[C:42]([NH:41][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([NH:28][C:25](=[O:27])[C:24]#[C:23][CH2:22][N:19]4[CH2:18][CH2:17][O:16][CH2:21][CH2:20]4)[CH:30]=3)[N:35]=[CH:34][C:33]=2[C:39]#[N:40])[CH:47]=[CH:46][CH:45]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: O=C(O)C#CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cnc2ccc(NC(=O)C#CCN3CCOCC3)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
Isobutyl chloroformate(0.161 g, 1.18 mmol) and N-methylmorpholine(0.150 g, 1.48 mmol) were added to an ice cold solution of 0.250 g (1.48 mmol) of 4-morpholino-2-butynoic acid in 10 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.250 g (0.74 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 mL of pyridine was added and the mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice water and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate, and dried in vacuo to give 0.096 g (27%) of yellow solid; ESMS m/z 490.1 (M+H+); mp 112-115° C.
Reaction SMILES: [BH4-].[Na+].B(O)(O)O.[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([CH:24]=1)[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:16])(=[O:9])[CH3:8]>C(O)C>[OH:9][CH:7]([C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:14]([CH:24]=1)[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:16])[CH3:8]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: OB(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 1 h

Procedure:
Sodium borohydride (32.8 mg, 0.87 mmol) and boric acid (53.6 mg, 0.87 mmol) were added to a suspension of 5-acetyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 72; 100 mg, 0.29 mmol) in ethanol (5 ml). The mixture was stirred for one hour and then it was quenched using saturated NaHCO3 solution (5 ml). The mixture was extracted with dichloromethane (3×5 ml). The organic layers were dried (MgSO4) and the solvent removed in vacuo. The residue was purified by MDAP to yield the title compound as a golden solid. 62 mg.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[C:22]([F:27])=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:28].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[C:22]([F:27])=[C:23]([F:26])[CH:24]=[CH:25][C:20]=4[O:19][CH2:18][C:17]3=[O:28])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: C1CC(OCC2CC2)CCN1
Reactant: O=C1COc2ccc(F)c(F)c2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2ccc(F)c(F)c2N1CCCN1CCC(OCC2CC2)CC1
Yield: 53.7 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.037 g, 0.24 mmol), 4-(3-chloropropyl)-5,6-difluoro-4H-benzo[1,4]oxazin-3-one (0.065 g, 0.25 mmol), K2CO3 (0.06 g, 0.48 mmol), and KI (0.072 g, 0.48 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; heptanes/EtOAc 1:1) to give the title compound (0.049 g, 54%). Rf=0.21 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 6.84-6.70 (m, 2H), 4.48 (s, 2H), 4.48 (s, 2H), 4.08-4.02 (m, 2H), 3.34-3.26 (m, 1H), 3.24 (d, J=6.8 Hz, 2H), 2.75-2.68 (m 2H), 2.38 (t, J=7.2 Hz, 2H), 2.18-2.06 (m, 2H), 1.92-1.81 (m, 4H), 1.63-1.52 (m, 2H), 1.06-0.96 (m, 2H), 0.52-0.47 (m, 2H), 0.18-0.14 (m, 2H); 13C NMR (CDCl3) d 165.0, 147.5 (dd, J=242.3 Hz, J=13.2 Hz), 143.9, 140.7 (dd, J=250.2 Hz, J=17.3 Hz), 119.9, 111.7 (dd, J=7.3 Hz, J=3.5 Hz), 110.9 (d, J=18.9 Hz), 74.5, 72.7, 68.5, 55.5, 51.2, 42.7 (d, J=10.4 Hz), 31.1, 25.5, (d, J=2.6 Hz), 11.1, 3.2.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43]>C1COCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:16])[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)O
Yield: 76.7 %

Procedure:
The suspension of mixed anhydride in THF is prepared by using 1.78 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 0.51 g of N-methylmorpholine and 0.68 g of isobutyl chlorocarbonate. To the suspension the aqueous solution of 1.31 g of L-leucine and 1.0 g of triethylamine is added, and treated in the same manner as Example 1 to give 1.8 g (77%) of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][NH:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:5]=1
Reactant: C1CNCCN1
Reactant: CC(C)(C)CNc1cc(Cl)nc(N2CCCC2)n1
Product: CC(C)(C)CNc1cc(N2CCNCC2)nc(N2CCCC2)n1
Yield: 76 %

Procedure:
The reaction of 4-chloro-6-(2,2-dimethylpropylamino)-2-pyrrolidinopyrimidine with piperazine as described in Example 4 gives the title compound in a yield of 76.0%, m.p.: 140°-145° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:19][NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([O:31]C)=[O:30])[CH2:25][CH2:24]3)=[S:22])[CH3:18])[C:13]([CH3:33])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:19][NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]3)=[S:22])[CH3:18])[C:13]([CH3:33])=[N:12]2)=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C1CCN(C(=S)NNC(C)=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=NN(c2ccc(C(C)(C)C)cc2)C(=O)C1=C(C)NNC(=S)N1CCC(C(=O)O)CC1
Yield: 54.9 %

Procedure:
Methyl 1-(N′-{1-[1-(4-t-butylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-ethyl}-hydrazinothiocarbonyl)-piperidine-4-carboxylate (89.6 mg, 0.190 mmol) in methanol (3.0 mL) was stirred with 1 M aqueous sodium hydroxide (570 μL, 0.570 mmol) at room temperature for 11 hours, with 1 M aqueous sodium hydroxide (380 μL, 0.380 mmol) at room temperature for 3 hours and then with 1 M hydrochloric acid (950 μL, 0.950 mmol) and water at room temperature for another 30 minutes. The resulting precipitate was collected by filtration, washed with water and methanol and dried under reduced pressure to give 47.7 mg of the desired product (55% yield).