Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][C:11]1=[O:16].C(=O)([O-])[O-].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.[Cu]I.O>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:8][C:2]=1[F:1]
Reactant: O=C1COCCN1
Reactant: Nc1ccc(I)cc1F
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(N2CCOCC2=O)cc1F
Temperature: 140 °C
Reaction time: 2 h

Procedure:
2.0 g (8.4 mmol) 2-fluoro-4-iodo-aniline, 860 mg (8.5 mmol) morpholin-3-one, 162 mg (0.86 mmol) copper(I)iodide, 2.33 g (16.86 mmol) potassium carbonate and 91 μl N,N′-dimethylethylenediamine are suspended in 18 ml of toluene under an argon atmosphere and stirred for two hours in a microwave at a power of 35 Watts at 140° C. Water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol 50:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=O)=[C:4](Cl)[N:3]=1.CCN(CC)CC.O.[NH2:20][NH2:21]>C1COCC1.O>[Cl:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]2[NH:20][N:21]=[CH:9][C:5]=12
Reactant: NN
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c2cn[nH]c2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Amino-4,6-dichloro-pyrimidine-5-carbaldehyde (5 g, 26.04 mmol) is dissolved in THF (125 ml), Et3N (4.13 ml, 29.6 mmol) is added followed by hydrazine monohydrate (1.19 g, 26.04 mmol) in water (15 ml) and the reaction mixture is stirred at room temperature for 1.5 hours. The organic solvent is removed in vacuo and a further 30 ml of water is added to the reaction mixture. The resulting precipitate is collected by filtration and dried under vacuum to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]([NH:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[N:16]=[C:15]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=2)[N:14]=1
Reactant: COC(=O)c1ccc(Nc2nc(NCCCCCCCCCCN)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NCCCCCCCCCCNc1nc(Nc2ccc(C(=O)O)cc2)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Yield: 25.7 %

Procedure:
To a suspension of methyl 4-(4-(10-aminodecylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.1 g) in acetone (6 mL) was added potassium carbonate in water (6.00 mL). The mixture was heated to reflux overnight. After cooling to r.t., the reaction solution was acidified with 1N HCl to pH=3. All solvens were removed under vacuum. The residue was purified by prep. HPLC to give 4-(4-(10-aminodecylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (25 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[C:22]1([C@@H:32]([NH2:34])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([NH:34][C@H:32]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH3:33])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: CC(C(=O)O)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C(=O)N[C@@H](C)c1cccc2ccccc12)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100.0 mg (0.325 mmol) of 2-[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-propionic acid from Example 105A are placed in 2 ml of DMF and treated with 61.2 mg (0.357 mmol) of (1S)-1-(1-naphthyl)ethanamine, 52.7 mg (0.390 mmol) of HOBt and 81.0 mg (0.422 mmol) of EDC hydrochloride. The mixture is stirred overnight at room temperature, then partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromato-graphy on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1) and then further separated by preparative HPLC on chiral phase [Method 15]. 52 mg (35% of theory) of the diastereomerically pure target compound are thus obtained (see also Example 187).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.C([Li])CCC.[C:15](=[O:17])=[O:16].C([O-])(O)=O.[Na+]>CCOCC.CCCCCC>[CH2:2]1[O:3][C:4]2[C:5](=[C:6]([C:15]([OH:17])=[O:16])[CH:7]=[CH:8][CH:9]=2)[O:1]1
Reactant: c1ccc2c(c1)OCO2
Reactant: O=C=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was treated dropwise at -10° C. with 2.5M n-butyllithium (15 mL, 35 mmol) in hexane. When the addition was complete, the mixture was stirred under reflux for one hour. After cooling to room temperature, it was added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10% aq. NaHCO3 and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated HCl, and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure (1.1 g, 20%). EI-MS m/z 167 (M+H)+
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][C:34]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:66])[F:65])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])([CH3:39])[C:35]([O:37]C)=[O:36]>>[CH3:39][C:34]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:65])[F:66])=[CH:59][CH:58]=4)=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])([CH3:33])[C:35]([OH:37])=[O:36]
Reactant: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)(C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3)cc2C1=O
Yield: 71 %

Procedure:
The compound of example 523 was prepared analogous to compound of example 98 by hydrolysis of compound of example 522.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)C=C[C:4]([S:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(S(N)(=O)=O)C2C(=CC=CC=2)C=CC=1>>[CH2:33]([C:23]1[N:22]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][NH:13][C:11]([NH:10][S:7]([C:4]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:1]=[CH:2][CH:3]=3)(=[O:8])=[O:9])=[O:12])=[CH:21][CH:20]=2)[C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1)[CH3:34]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: NS(=O)(=O)c1cccc2ccccc12
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccc3ccccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 1-naphtylsulfonamide (Arnswald, M.; Neumann, W. P. Chem. Ber., 1991, 124, 1997; Khorgami, M. H. Synthesis, 1972, 574).
Reaction SMILES: [NH2:1][CH:2]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][CH2:5][CH:6]([NH2:16])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O:27][C:28](=O)[CH2:29][O:30][CH2:31][C:32](OC)=[O:33]>CO>[CH2:19]([O:18][CH2:17][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:16][C:32](=[O:33])[CH2:31][O:30][CH2:29][C:28](=[O:27])[NH:1]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)COCC(=O)OC
Reactant: NC(CNCC(N)COCc1ccccc1)COCc1ccccc1
Solvent: CO
Product: O=C1COCC(=O)NC(COCc2ccccc2)CNCC(COCc2ccccc2)N1

Procedure:
1,5 -Diamino-1,5-dibenzyloxymethyl-3 -aza-pentane (0.250 g, 0.73 mmol) (Example 6 (d)) and diglycolic acid dimethyl ester (0.118 g, 0.73 mmol) were dissolved in methanol (20 ml). The mixture was refluxed for 6 days. The solvent was evaporated and the mixture chromatographed on a silica column. 5,9-Bis(benzyloxymethyl)-1-oxa-4,7,10-triazacyclododecane-3,11-dione was isolated as a yellow oil. Yield 0.273 g (85%). FAB MS: 442 (M+1).
Reaction SMILES: [C:1]([O:7]C(C)(C)C)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[N:14]=1>C1(C)C=CC=CC=1>[Si:21]([O:20][CH2:19][C:15]1[N:14]=[C:13]([NH:12][C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH:18]=[CH:17][CH:16]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6.6 mL of tert-butyl acetoacetate was dissolved in 10 mL of toluene and the mixture was stirred at 100° C. for 1 hour. To the reaction solution was added a solution of 1.9 g (8.1 mmol) of 2-amino-6-(tert-butyldimethylsilyloxymethyl)pyridine in 5 mL of toluene and the mixture was stirred at the same temperature for 15 hours. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography to give 2.2 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH:9](=[N:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Product: Oc1ccc(N=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
2.1 g (19.3 mmol) of 4-aminophenol was dissolved in 28 ml ethanol, and 1.9 ml (19.3 mmol) benzaldehyde was added. The mixture was heated to the reflux temperature and reacted for 1.5 h, Then, the reaction mixture was cooled to the room temperature and the solid separated out from the mixture was filtered by sucking. The filter cake was washed with a small amount of ethanol and dried to obtain 3 g of a yellow solid with the yield of 76.9%. m.p. 182-183° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]([C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.O>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[N:13][CH:14]=1)(=[O:8])[CH3:7]
Reactant: c1c[nH]nn1
Reactant: CC(=O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2ccnn2)nc1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
207 mg (corresponding to 3.00 mmol) of 1H-1,2,3-triazole was dissolved in 5 mL of dimethylformamide. Then, 200 mg (corresponding to 1.00 mmol) of 5-acetyl-2-bromopyridine and 414 mg (corresponding to 3.00 mmol) of potassium carbonate were added thereto. The resulting solution was heated at 100° C. for 3 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, supplemented with a saturated ammonium chloride aqueous solution and water, and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=4/1), to obtain 57.2 mg (corresponding to 0.304 mmol) of 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine (FIG. 1, step 1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].N12CCCN=C1CCCCC2.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26](Cl)=[O:27]>ClCCl>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[O:27]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CNC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of glycine ethyl ester hydrochloride (21.77 g, 156 mmol) in anhydrous dichloromethane (260 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (55 mL, 368 mmol) was added under nitrogen, which addition turned the suspension clear. Then 2-thiopheneacetyl chloride (19.2 mL, 156 mmol) was added dropwise. After completion of the addition, the flask was warmed to room temperature and the mixture was stirred for 1 hour. Then it was washed with water (260 mL×3), dried and concentrated. A dark brown oil was obtained (31.77 g, yield 89%), which turned into a dark brown solid upon standing. 1H NMR (CDCl3, 500 MHz), δ=7.26 (dd, J=5.0, 1.0 Hz, 1H), 7.01-6.97 (m, 2H), 6.19 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 4.00 (d, J=5.0 Hz, 2H), 3.83 (s, 2H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH2:28]([P:30](C#N)([CH2:32][CH3:33])=[O:31])[CH3:29]>CN(C)C=O>[CH2:28]([P:30]([NH:3][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)=[NH:2])([CH2:32][CH3:33])=[O:31])[CH3:29]
Reactant: COC(=O)CCc1ccc(-c2nc(-c3ccc(C(=N)N)cc3)cn2C)cc1
Reactant: CCP(=O)(C#N)CC
Solvent: CN(C)C=O
Product: CCP(=O)(CC)NC(=N)c1ccc(-c2cn(C)c(-c3ccc(CCC(=O)OC)cc3)n2)cc1

Procedure:
Prepared by reacting 4-(4-amidino-phenyl)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-1-methyl-imidazole with diethylphosphorylcyanide in dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].O>C1COCC1>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([NH:8][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:21]
Reactant: CC1(N)CCCCC1
Reactant: O=C(Cl)CCCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(NC(=O)CCCCl)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Dissolve 1-methylcyclohexanamine (0.78 g, 6.89 mmol) in anhydrous THF (100 mL) and cool to 0° C. Add Et3N (3.49 g, 34.45 mmol) and 4-chlorobutanoyl chloride (1.94 g, 13.78 mmol) with stirring under N2. Stir the reaction mixture for 2 hours at room temperature and add water (100 mL). Extract the aqueous with EtOAc (3×200 mL) and then combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 30-80% of EtOAc-Hexane) to give 1.35 g (90%) of 4-chloro-N-(1-methylcyclohexyl)butanamide as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11]Cl)=[CH:6][CH:5]=1.SC1C=CC(C(OC)=O)=CC=1.[Na].[I:26][C:27]1[CH:28]=[N:29][C:30](=[O:33])[NH:31][CH:32]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][N:31]2[CH:32]=[C:27]([I:26])[CH:28]=[N:29][C:30]2=[O:33])=[CH:6][CH:5]=1)=[O:13]
Reactant: O=c1ncc(I)c[nH]1
Reactant: COC(=O)c1ccc(SCCl)cc1
Agent: COC(=O)c1ccc(S)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCn2cc(I)cnc2=O)cc1
Yield: 92 %

Procedure:
A solution of methyl4-(chloromethylthio)benzoate [The methyl 4-(chloromethylthio)benzoate reagent was made in the conventional manner as previously described for its analogues in Preparations 1 and 4 by chloromethylation of methyl 4-mercaptobenzoate; yield 92%](8.2 mmol) in DMF (10 ml) was added dropwise to a stirred suspension of the sodium salt of 5-iodopyrimidin-2-one (8.2 mmol) in DMF (50 ml) and the final mixture heated at 60° C. for 3h. The solvent was then distilled off, the residue triturated with water and with a little ether. The product was a mixture of the N- and O-isomers in the ratio 4:1; yield 1.50 g (45%). The title compound, the N-isomer, was obtained after fractional crystallisation from ethyl acetate and methanol, m.p. 210° C. NMR
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[N:27][CH:28]=1
Reactant: OCc1ccc(Cl)cn1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 13.8 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (200 mg), (5-chloropyridin-2-yl)-methanol (152 mg) and tributylphosphine (437 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (536 mg). The mixture was stirred under sonication at 50° C. for 3 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine (30 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to give the title compound (40 mg) as a white solid.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=CC=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.ClC1C=C(C)N=CN=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:11]4[CH:16]=[C:15]([CH3:14])[N:8]=[CH:9][N:10]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Cc1cc(Cl)ncn1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)ncn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-chloro-6-methylpyrimidine. MS (ESI) mass calcd. for C20H20FN7O, 393.4; m/z found, 394.2 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[CH2:25]([O:27][CH2:28][C:29](O)=[O:30])[CH3:26]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:29](=[O:30])[CH2:28][O:27][CH2:25][CH3:26])[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: CCOCC(=O)O
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Product: CCOCC(=O)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1

Procedure:
Using a procedure similar to that described in Example 1 except starting with 4-amino-1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and 2-ethoxyacetic acid, the title compound was obtained as a white glassy solid (68%), mp 112.5°-4.0° C.; MS(CI): 425 (M+H); NMR (300 MHz,DMSO-d6): 1.12(t, 3H, J=7 Hz), 1.49(br m, 2H), 1.61(br m, 2H), 2.26(m, 2H)), 2.45(br m, 2H), 2.93(br m, 2H), 3.45(q, 2H, J=7 Hz), 3.62(br s, 1H), 3.78(s, 2H), 4.34(s, 1H), 6.94(m, 3H), 7.23(m, 4H), 7.48(d, 1H, J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:13]=[N:14][N:15]=[C:7]1[CH:6]=[CH:5]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc2c(ccc3nnnn32)c1
Temperature: 130 °C

Procedure:
To 6-Bromo-2-chloro-quinoline (223 mg, 1.0 mmol) in DMF (10 mL) was added sodium azide (65 mg, 1.0 mmol). The reaction was heated at 130° C. for 1 hour, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (50% EtOAc in hexanes) to give the desired product, 9d.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:33][C:34]2[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=2)[CH2:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>Cl>[CH3:39][N:35]1[CH:36]=[CH:37][N:38]=[C:34]1[CH2:33][N:25]([CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:5]([CH2:4][C:3]([OH:40])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:19][CH:20]=1)[CH2:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: CCCN(CCC)CCCCN(CC(=O)OC)Cc1ccc(CN(Cc2nccn2C)Cc2nccn2C)cc1
Agent: Cl
Product: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2nccn2C)Cc2nccn2C)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 130.5 %

Procedure:
The compound (36.8 mg) obtained in Example 81-1 was dissolved in concentrated hydrochloric acid (1.0 ml) and the whole was stirred at 100° C. for 1 hour. After completion of the reaction, the solution was concentrated and dried under vacuum, thereby obtaining a hydrochloride (46.8 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[OH:10]O>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N+:3]=1[O-:10]
Reactant: OO
Reactant: Cc1cnc(C)c(C)c1
Solvent: CC(=O)O
Product: Cc1cc(C)c(C)[n+]([O-])c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 243.6 %

Procedure:
To a 100 liters reaction vessel was added 2,3,5-trimethyl-pyridine (10.9 kg, 89.2 moles) and acetic acid (30 liters). The temperature was raised to 90° C. The mixture was stirred for 3 hours and thereafter cooled to 60° C., whereafter H2O2 (35% solution, 3122 ml, 35.67 moles) was added during 1 hour. The temperature was then raised to 90° C. The reaction mixture was stirred overnight. After cooling to 40° C. an additional amount of H2O2 solution (936 ml, 10.7 moles) was added during 1 hour. The temperature was then raised to 90° C. The reaction mixture was stirred for 3 hours and was allowed to stand without heating overnight. Excess of acetic acid was distilled off under vaccum. To the remainder was added NaOH (10M) until pH 10. CH2Cl2 (10 liters) was added and the resulting mixture was stirred vigorously. The CH2Cl2 phase was separated and the water phase was extracted twice with CH2Cl2 (10 liters). The combined CH2Cl2 -phases were dried over MgSO4 and filtrated. The filtrate was evaporated yielding 2,3,5-trimethyl-pyridine-N-oxide (11920 g, 94% purity). The identity of the product was confirmed with 1H and 13C NMR.