Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH:22]([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>C(Cl)Cl>[Br:44][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(CO)c(C(C)C)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C#Cc2ccc(CBr)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 123, 180.0 mg, 0.56 mmol) and triphenylphosphine (190.0 mg, 0.73 mmol) in 5 mL CH2Cl2 was cooled to 0° C. and N-bromosuccinimide (130.0 mg, 0.73 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 212.0 mg (98%), was isolated by column chromatography (5-10% EtOAc-hexanes) as a pale-yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[H-].[Na+].Br[C:10]1[C:11]2[N:12]([C:17]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:29])=[O:21])=[CH:18][N:19]=2)[N:13]=[C:14]([Cl:16])[CH:15]=1.CN(C=O)C>C1COCC1>[Cl:16][C:14]1[CH:15]=[C:10]([NH:6][C:3]2[CH:4]=[CH:5][O:1][N:2]=2)[C:11]2[N:12]([C:17]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:29])=[O:21])=[CH:18][N:19]=2)[N:13]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: Nc1ccon1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccon3)cc(Cl)nn12
Reaction time: 0.17 h

Procedure:
To a solution of isoxazol-3-amine (25.8 mg, 0.307 mmol) in THF (0.5 mL) was added 60% NaH (12.26 mg, 0.307 mmol). The mixture was stirred for 10 min and 5A (40 mg, 0.123 mmol) was added followed by DMF (0.5 mL). The mixture was stirred overnight. The solvent was removed under a stream of nitrogen and water was added. The resulting solid was collected by filtration, rinsed with water, and dried on vacuum to give the title compound as a yellow solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[N:58]=[C:57]([Cl:59])[CH:56]=[C:55]([CH3:60])[C:34]=1[C:35]([NH:37][CH2:38][CH2:39][C@H:40]([N:42]1[CH2:47][CH2:46][CH:45]([NH:48][CH2:49][C:50]2[CH:54]=[CH:53][S:52][CH:51]=2)[CH2:44][CH2:43]1)[CH3:41])=[O:36]>CC#N>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:16]([N:48]([CH:45]1[CH2:46][CH2:47][N:42]([C@H:40]([CH3:41])[CH2:39][CH2:38][NH:37][C:35]([C:34]2[C:33]([Cl:32])=[N:58][C:57]([Cl:59])=[CH:56][C:55]=2[CH3:60])=[O:36])[CH2:43][CH2:44]1)[CH2:49][C:50]1[CH:54]=[CH:53][S:52][CH:51]=1)=[O:17])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)nc(Cl)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)C(=O)NCC(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 141 %

Procedure:
To a solution of glycine t-butyl ester hydrochloride (74 mg, 0.44 mmol) in CH3CN (5 ml) was added CDI (71 mg, 0.44 mmol), followed by DIPEA (0.077 mL, 0.44 mmol), and the mixture was stirred at 60° C. for 2 h. A solution of 2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (50 mg, 0.11 mmol) in CH3CN (5 ml) was then added to the previous mixture. After stirring at 60° C. overnight, the mixture was concentrated in vacuo and diluted with CH2Cl2 (15 ml) and saturated NaHCO3 (20 ml). The aqueous layer was extracted with CH2Cl2 (3×10 ml), then the combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (CH2Cl2, 5% MeOH, 1% NH4OH) to afford [3-(1-{(R)-3-[(2,6-dichloro-4-methyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-acetic acid tert-butyl ester as a clear oil (95 mg). 1H NMR (CDCl3) δ 0.96-0.98 (d, 3H, J=6 Hz), 1.11-1.38 (m, 2H), 1.42 (s, 9H), 1.48-1.57 (m, 1H), 1.61-1.79 (m, 3H), 2.10-2.23 (m, 1H), 2.34 (s, 3H), 2.50-2.58 (m, 1H), 2.73-2.93 (m, 3H), 3.24-3.38 (m, 1H), 3.81-3.85 (d, 2H, J=12 Hz), 3.89 (s, 2H), 4.11-4.23 (m, 1H), 4.76-4.82 (m, 1H), 7.04-7.06 (d, 1H, J=6 Hz), 7.09 (s, 1H), 7.20 (s, 1H), 7.33-7.35 (d, 1H, J=6 Hz), 7.66 (br s, 1H), 8.90 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[CH3:14][O:15][C:16](Cl)=[O:17]>O>[CH3:14][O:15][C:16](=[O:17])[NH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](=[O:5])[NH:6][CH:7]1[CH2:8][CH2:9]1
Reactant: Nc1ccccc1C(=O)NC1CC1
Reactant: COC(=O)Cl
Solvent: O
Product: COC(=O)Nc1ccccc1C(=O)NC1CC1
Reaction time: 12 h
Yield: 99.7 %

Procedure:
To a slurry of 2-amino-N-cyclopropyl-benzamide (6.7 g, 38.1 mmol) in water was added KHCO3 (9.5 g, 95.1 mmol) followed by careful addition of methylchloroformate (5.88 ml, 76.2 mmol). The mixture was stirred for 12 h then the aqueous layer was extracted with EtOAc. The EtOAc extract was washed with 1N HCl then dried over MgSO4 and concentrated to give 8.9 g (99%) of (2-cyclopropylcarbamoyl-phenyl)-carbamic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][C:38]1=[O:42]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:33][CH2:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 56 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (15 mg, 0.0344 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.05 mL) was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (10 mg, 56% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.03 (t, J=5.6 Hz, 1 H), 8.50 (s, 1 H), 7.29-7.17 (m, 2 H), 7.20-7.16 (m, 2 H), 7.01-6.91 (m, 4 H), 6.69 (s, 1 H), 3.93 (s, 2 H), 3.44-3.32 (m, 6 H), 2.35 (t, J=8 Hz, 2 H), 2.04-1.96 (m, 2 H), 1.89-1.78 (m, 2 H); MS m/z 533 (M+1).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][CH2:25][C:26](Cl)=[N:27]O>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][CH2:25][C:26]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:27]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: ON=C(Cl)CCc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(CCc2c(Cl)cccc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A solution of methyl isobutyrylacetate (0.662 g, 5.8 mmol) in tetrahydrofuran (1.16 mL) was stirred at 0° C. as 0.5 N sodium methoxide in methanol solution (11.6 mL, 5.8 mmol) was added. A solution of 3-(2,6-dichlorophenyl)-N-hydroxypropanimidoyl chloride (1.04 g, 4.82 mmol) in tetrahydrofuran (3.8 mL) was added and the solution was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated and the residue triturated with water and filtered to yield a white solid which was dried in a 45° C. oven with P2O5 under reduced pressure to yield the title compound (0.926 g, 56%). 1H NMR (DMSO-d6): 7.43 (d, J=8 Hz, 2H), 7.25 (t, J=8 Hz, 1H), 3.73 (s, 3H), 3.67 (septet, J=7 Hz, 1H), 3.24-3.20 (m, 2H), 3.07-3.03 (m, 2H), 1.23 (d, J=7 Hz, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[N:22]=[C:21]([OH:23])[CH:20]=[C:19]([CH3:24])[N:18]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[N:22]=[C:21]([OH:23])[CH:20]=[C:19]([CH3:24])[N:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1cc(O)nc(N)n1
Solvent: c1ccncc1
Product: Cc1cc(O)nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 2-amino-6-methylpyrimidin-4-ol (25 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 313.1, found 314.1 (M+1)+. Retention time 2.31 minutes.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].[C:24](Cl)(=[O:28])[C:25](Cl)=[O:26]>C(OCC)C>[CH2:1]([N:3]1[C:4]2[C:9](=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C:25](=[O:26])[C:24]1=[O:28])[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CCN1C(=O)C(=O)c2c(OC)ccc(C3CCc4cc(OC)ccc4C3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (260 mg) in diethyl ether (30 ml) was added dropwise oxalyl chloride (0.21 ml) on an ice bath, and the solution was stirred for 30 minutes at room temperature. The reaction solution was concentrated in vacuo, the total amount of the resulting {ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}oxoacetyl chloride (crude product) was stirred in dichloromethane (5 ml), a solution of aluminum chloride (220 mg) in dichloromethane (20 ml) was added dropwise thereto on an ice bath, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with ice water, extracted with chloroform, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (160 mg).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[CH:5][CH:4]=1)#[N:2].C(OC(=O)C)(=O)C.[N+:28]([O-])([OH:30])=[O:29]>C(O)(=O)C>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[C:5]([N+:28]([O-:30])=[O:29])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(C#N)c2ccccc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 4.2 g (15.7 mmol) 4-cyano-1-ethoxalylaminonaphthalene in 125 ml glacial acetic acid was added 125 ml acetic anhydride. At 15° C. a solution of 12 ml 100% nitric acid in 60 ml glacial acetic acid was added dropwise. Stirring was continued at 25° C. for 24 h and then at 50° C. for 1.5 h. The reaction mixture was poured into 500 ml ice-water to give 3.5 g (72%). M.p. 178.0° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=[O:8])[CH:4]=[N:3][CH:2]=1.C1(C)C=C[C:12]([S:15](O)(=O)=O)=[CH:11]C=1.SCCO>>[O:8]1[CH2:11][CH2:12][S:15][CH:7]1[C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1cncnc1
Agent: OCCS
Product: c1ncc(C2OCCS2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrimidine-5-carboxaldehyde (1 g, 9.25 mmol), p-toluene sulfonic acid (0.176 g, 0.95 mmol) and 2-mercaptoethanol (0.65 ml, 9.25 mmol) were all put in a 50 ml round bottomed flask, fitted with a condenser, drying tube and a Dean-stark trap. Toluene (30 ml) was added and the mixture refluxed with stirring overnight, cooled to room temperature and excess toluene evaporated in vacuo. Saturated sodium carbonate 10 ml was added and extracted with chloroform (7×10 ml). The extract was dried over MgSO4, filtered and the solvent evaporated in vacuo to 1.73 g (115%) crude yellow oil. TLC (silica; chloroform/methanol 9.8:0.2) indicated the product and some impurities.
Reaction SMILES: OCC(CO)O.[OH-:7].[K+].[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[CH:16]=[CH:17][NH:18]2)=[CH:13][C:12]=1[C:22]#N.Cl.[OH2:25]>>[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[CH:16]=[CH:17][NH:18]2)=[CH:13][C:12]=1[C:22]([OH:25])=[O:7]
Reactant: COc1cc2[nH]ccc(=O)c2cc1C#N
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: OCC(O)CO
Product: COc1cc2[nH]ccc(=O)c2cc1C(=O)O
Temperature: 160 °C
Reaction time: 3 h

Procedure:
Glycerol (20 ml) and potassium hydroxide (KOH, 3.0 g) were added to the 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carbonitrile (2 g) of Production Example 24, and after heating and stirring at 160° C. for 3 hours, water (40 ml) was added and the mixture was heated at 80° C. for 30 minutes. After cooling, 2N hydrochloric acid was added to acidity and the precipitated insoluble portion was filtered out, washed with water and then dried under reduced pressure to obtain the title compound (1.6 g).
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][NH:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][Si:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: C[Si](C)(C)CCSCCNC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CNCCSCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
A solution of 400 mg (2.00 mmol) of N-formyl-2-[[2-(trimethylsilyl)ethyl]thio]ethyl amine in 5 ml of absolute diethyl ether is added under argon at 0° C. to a stirred slurry of 152 mg (4.00 mmol) of lithium aluminum hydride in 5 ml of the same solvent. After 1 hr at 20° C., the stirred reaction mixture is quenched by addition of 0.6 ml of water and 0.15 ml of 15% sodium hydroxide solution, the resulting precipitate is filtered off, washed with diethyl ether. The combined organic layers is evaporated in vacuo, and the residue is distilled to N-methyl-2-[[2-(trimethylsilyl)ethyl]thio]ethyl amine (350 mg, 93.5%).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].Cl.[O:38]([NH2:40])[CH3:39].C(P(=O)(OCC)OCC)#N>>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([NH:40][O:38][CH3:39])=[O:22])[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Reactant: CON
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(C)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{7-isobutyl-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent. Mass: 518.28 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[C:9]([N+]([O-])=O)[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].C(O)(=[O:20])C>[Fe]>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:20])[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CC(=Cc1ccc(S(C)(=O)=O)c(F)c1)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Temperature: 100 °C

Procedure:
Freshly prepared 2-fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene (Example 68b) (20 g, 77 mmol) in glacial acetic acid (150 ml) is added slowly in 15×10 ml portions to a stirred slurry of iron powder (46 g, 833 mmol) in glacial acetic acid (150 ml) at 60° C. The reaction mixture is heated at 100° C. for an additional 2 hours, allowed to cool to room temperature and poured on to ice water (600 ml). The mixture is filtered through celite to remove iron residues, washing with dichloromethane (300 ml). The organic layer is removed and the aqueous solution is extracted with more DCM (3×200 ml). The combined organic extracts are dried (MgSO4), filtered and concentrated to a red solution. The titled product crystallises from this solution on standing.
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([CH2:15][C:16]([NH2:18])=O)[CH:13]=[CH:14][C:8]=2[S:7](=[O:20])(=[O:19])[N:6]=1)([CH3:3])[CH3:2].C(O)=O.C=O>C(#N)C>[CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([CH2:15][C:16]#[N:18])[CH:13]=[CH:14][C:8]=2[S:7](=[O:19])(=[O:20])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC1=NS(=O)(=O)c2ccc(CC(N)=O)cc2N1
Agent: C=O
Solvent: CC#N
Solvent: O=CO
Product: CC(C)NC1=NS(=O)(=O)c2ccc(CC#N)cc2N1

Procedure:
A slurry of 2-(3-isopropylamino-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-6-yl)acetamide (50 mg) in a mixture of 0.8 ml of acetonitrile, 0.2 ml of formic acid and 25 mg of paraformaldehyde was heated at reflux for 16 h, and then evaporated to dryness. The residue was purified on a silica column eluted with dichloromethane-methanol (95:5) to give the title compound; m.p. 195-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[BH4-].[Na+].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>C(O)C.CCOCC>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: NCCCn1ccnc1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCC(NCCCn1ccnc1)c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
In a similar manner to Example 1, a mixture of 4'-chloropropiophenone (8.4 g) and 1-(3-aminopropyl)imidazole (6.3 g) was heated at 120° C. for 9 hours. The cooled mixture was dissolved in absolute ethanol (100 ml), treated with sodium borohydride (3.9 g) and boiled under reflux for 16 hours. The oil obtained after work-up was dissolved in ether and treated with ethereal oxalic acid until the mixture was just acidic. The solid was filtered off and recrystallised from ethanol to give N-[1-(4-chlorophenyl)propyl]-3-(imidazol-1-yl)propylamine oxalate, m.p. 189°-190° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]([CH2:12][C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=3)[C:9](=[O:37])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38]I>CC#N>[CH3:38][N:14]1[C:13]([CH2:12][N:10]2[CH2:11][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][C:9]2=[O:37])=[CH:17][N:16]=[CH:15]1
Reactant: O=C1CC(c2ccccc2)CN1Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CI
Solvent: CC#N
Product: Cn1cncc1CN1CC(c2ccccc2)CC1=O
Temperature: 25 °C

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, 4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x44 (2 g, 4.1 mmol) is dissolved in CH3CN (20 ml) and MeI (283 μL, 4.5 mmol) is added. The mixture is stirred at room temperature and two additional portions of MeI (283 μl and 500 μl) are added after 40 h and 46 h. After stirring for 16 h at room temperature, the mixture is concentrated and dissolved in a 1/1 mixture of AcOH and water. After stirring at room temperature for 48 h, the mixture is filtered and evaporated to dryness (by azeotropic distillation with toluene). The residue is dissolved in a solution of HCl at pH 1 (25 ml) and extracted with CH2Cl2 (3×50 ml). The aqueous phase is brought at pH 10 by adding solid K2CO3 and extracted again with CH2Cl2 (3×50 ml). Combined organic phases are dried over MgSO4, filtered and concentrated to give 1 g of crude product which is purified by chromatography on silicagel (60 g of SiO2, CH2Cl2/EtOH/NH4OH: 94/5.4/0.6 (v/v/v)) to give 0.5 g of 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one. This free base is treated with a 3.6 M solution of HCl (5 ml), and the resulting solid is recrystallized in CH3CN to lead to 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one hydrochloride 119.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.Cl>O1CCCC1.C(O)C>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2NCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Aqueous 1 N sodium hydroxide solution (15 ml, 15 mmols) was added to a solution of ethyl 4-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminobutyrate (4.6 g, 10 mmols) in tetrahydrofuran (15 ml) and ethanol (15 ml). The resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was acidified with 1 N hydrochloric acid added thereto, and then extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an amorphous solid of 4-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminobutyric acid (4.1 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:32]C(=O)OC(C)(C)C)[C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:31])[CH3:30])[CH:21]=3)=[O:19])[CH:17]=2)=[O:10])=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[NH2:32][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]2[C:28]3[CH:27]=[N:26][CH:25]=[N:24][C:23]=3[N:22]([CH:29]([CH3:31])[CH3:30])[CH:21]=2)=[O:19])[CH:17]=1)=[O:10]
Reactant: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)cc3)c2)c2cncnc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(N)c3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
To tert-butyl (1-(4-chlorophenyl)-2-((5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl)amino)-2-oxoethyl)carbamate (Preparation 299, 64 mg, 0.11 mmol) was added 4M HCl/dioxane (5 mL) and the reaction stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and purified by preparative reverse phase HPLC to give the title compound as a beige solid in 8% yield, 4 mg.