Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1(N)[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:3]1[C:4](O)=[O:5].[CH:14]([NH2:16])=O>C(O)C>[CH3:12][O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:14][NH:16][C:4]2=[O:5]
Reactant: NC=O
Reactant: COC1=CC(C(=O)O)C(N)(N)C=C1
Solvent: CCO
Product: COc1ccc2nc[nH]c(=O)c2c1
Yield: 50 %

Procedure:
To 1.025 mmoles of 2-amino-5-methoxy anthranilic acid add 6.14 mmoles of formamide and microwave reaction mixture for 20 mins at 160° C. After cooling the solid was diluted with 10 mL ethanol, the mixture was heated to reflux and allowed to cool slowly. The solid obtained was filtered and washed with cold ethanol and vacuum dried to give the title compound in 50% yield.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=O)(C)(C)C.[OH:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH:36]=O.[BH3-]C#N.[Na+].CO>C(O)(=O)C>[NH2:8][C:9]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:33]([OH:32])[CH:34]=2)[CH2:19]1)=[O:16])=[O:12]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(OC(F)(F)F)ccc3N)C2)cc1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[N-{2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzoyl}glycyl]aminopyrrolidine (0.050 mmol), 3-hydroxy-4-methoxybenzaldehyde (0.060 mmol), NaBH3CN (0.15 mmol), and methanol (1.3 mL) was added acetic acid (0.050 mL). The reaction mixture was stirred at 60° C. for 8 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (10 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added 4 N HCl in 1,4-dioxane and the solution was stirred overnight at room temperature. Concentration and preparative TLC gave (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]-1-(3-hydroxy-4-methoxybenzyl)pyrrolidine (Compound No. 1896) (9.1 mg, 38%): The purity was determined by RPLC/MS (93%); ESI/MS m/e 483 (M++H, C22H25F3N4O5).
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:18][CH:13](OC(=O)C)[C@H:12]([O:19][C:20](=[O:22])[CH3:21])[C@@H:11]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[NH:40]1[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]1=[O:42].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:18][C@@H:13]([N:40]2[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]2=[O:42])[C@H:12]([O:19][C:20](=[O:22])[CH3:21])[C@@H:11]1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([CH2:4][CH3:5])[CH2:6][CH3:7])[CH3:2]
Reactant: CC[Si](C#C[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 6 (3.00 g, 5.43 mmol) was dissolved in 1,2-dichloroethane (100 ml), and uracil (1.52 g, 13.6 mmol) and N,O-bis(trimethylsilyl)acetamide (9.40 ml, 38.0 mmol) were added to the solution, followed by refluxing for one hour. After the reaction mixture was allowed to cool to room temperature, trimethylsilyl trifluoromethanesulfonate (1.97 ml, 10.9 mmol) was added thereto, followed by stirring overnight at 50° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and after stirring, precipitate was filtered. The organic layer was dried over anhydrous magnesium sulfate and concentrated through distillation under reduced pressure. The residue was purified by means of silica gel column chromatography (silica gel 300 ml, eluent; n-hexane:ethyl acetate=1:1), to thereby yield a colorless viscous compound (Compound 7; 2.50 g, 4.13 mmol, 76.1%).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:1]1([CH:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Into 25 ml of pyridine was dissolved 1.0 g of 4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine obtained in Example 1 (b), and 0.51 g of benzenesulfonyl chloride was added dropwise to the resultant solution at room temperature, followed by stirring for 30 minutes. The reaction solution was poured into ice water, and extracted with chloroform. The extract was washed with water, and chloroform was removed. The residue was eluted with ethyl acetate-chloroform (1:1) by silica gel column chromatography to give 0.79 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27]CC1C=CC=CC=1)[C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[OH:27])[C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1
Reactant: COc1cc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)ccc1O
Reaction time: 1 h

Procedure:
To a solution of 4-[1-(3-methoxy-4-benzyloxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (1.00 g) in THF (20 ml) is added palladium on carbon (10%, 0.2 g). The mixture is stirred under a hydrogen atmosphere for 1 hour. The catalyst is filtered and the filtrate is evaporated to dryness to give the title compound in pure form, m.p. 265° C. (This compound is also listed as Example 74 in Table 1.)
Reaction SMILES: [CH2:1](NC)[CH2:2][CH2:3]C.[CH3:7][O:8][C:9]([O:14][CH3:15])([N:11]([CH3:13])[CH3:12])[CH3:10]>>[CH3:7][O:8][C:9]([O:14][CH3:15])([N:11]([CH2:13][CH2:1][CH2:2][CH3:3])[CH3:12])[CH3:10]
Reactant: CCCCNC
Reactant: COC(C)(OC)N(C)C
Product: CCCCN(C)C(C)(OC)OC
Temperature: 130 °C

Procedure:
6.1 g (0.07 mol) of n-butylmethylamine are stirred with 9.3 g (0.07 mol) of N,N-dimethylacetamide dimethyl acetal for 24 hours under reflux at a bath temperature of 130° C. Subsequent vacuum distillation gives N-butyl-N-methylacetamide dimethyl acetal, bp 72°-75° C./31 mbar.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[C:17]([Cl:23])[CH:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26]>>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[N:25][OH:26])=[C:17]([Cl:23])[CH:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)c(Cl)c2)cc1
Agent: Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=NO)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 4′-{[tert-butyl(dimethyl)silyl]oxy}-3-chloro-1,1′-biphenyl-4-carbaldehyde (405 mg, 1.17 mmol) with hydroxylamine hydrochloride (154 mg, 2.22 mmol) according to Method C to yield a yellowish oil which was used in the next step without purification: MS (ESI) m/z 362/364 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:15]=1.C(Cl)Cl>N1C=CC=CC=1>[CH3:12][O:13][C:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:22][CH:21]=2)[N:15]=1
Reactant: COc1nn(-c2ccc(N)cc2)c(=O)o1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nn(-c2ccc(NC(=O)Cc3ccc(Cl)cc3)cc2)c(=O)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
201 mg of 4-chlorophenylacetyl chloride were added dropwise to a mixture consisting of 200 mg of 5-methoxy-3-(4-aminophenyl)-3H-(1,3,4)oxadiazol-2-one, 20 ml of methylene chloride and 0.1 ml of pyridine cooled in ice, and the mixture was stirred at room temperature for 5 hours. Volatiles were removed in vacuo. The residue was stirred with water and the solid was filtered off with suction and dried at 40° C. in vacuo.
Reaction SMILES: [NH2:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[OH:4].[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([NH:1][C@@H:2]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[C@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[O:34])=[CH:25][CH:24]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H](Cc1ccc(C(F)(F)F)cc1)[C@H](O)c1ccncc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (70 mg, 0.24 mmol) in acetonitrile (5 ml) were added 4-fluoronaphthalenecarboxylic acid (45 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1-hydroxy-1H-benzotriazole (36 mg, 0.24 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (55 mg, 50%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[N:4]1)[CH3:2].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[CH2:1]([N:3]1[C:7]([C:8]([O:10][CH2:16][CH3:17])=[O:9])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccnn1CC

Procedure:
To a solution of 1-ethyl-1H-pyrazole-5-carboxylic acid (950 mg) (for example, available from Fluorochem) in ethanol (50 ml) was added sulphuric acid (0.5 ml) and the mixture stirred at reflux under nitrogen for 70 h. The solvent was removed in vacuo and the residue partitioned between DCM (25 ml) and saturated sodium bicarbonate solution (25 ml) and separated using a hydrophobic frit. The aqueous layer was washed with DCM (2×20 ml) and the organic phases were combined. The solvent was removed in vacuo to give the title compound (1.09 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]([F:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 34.6 %

Procedure:
In the same manner as in Example 1, step 6and using 7-(2,5-dimethylphenylamino)-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (91 mg, 0.19 mmol) obtained in step 4 and ethanesulfonamide (100 mg, 0.95 mmol), the title compound (38 mg, 35%) was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[S:26][CH:27]=[CH:28][C:24]=3[C:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:19]3[S:20][CH:21]=[CH:22][C:18]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:50][Sn:51](Cl)([CH3:53])[CH3:52].O>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[S:26][C:27]([Sn:51]([CH3:53])([CH3:52])[CH3:50])=[CH:28][C:24]=3[C:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:19]3[S:20][C:21]([Sn:51]([CH3:53])([CH3:52])[CH3:50])=[CH:22][C:18]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CCCCCCCCCCc2c3ccsc3c(CCCCCCCCCCc3ccccc3)c3ccsc23)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2c(CCCCCCCCCCc3ccccc3)c3sc([Sn](C)(C)C)cc3c(CCCCCCCCCCc3ccccc3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 4,8-bis(10-phenyldecyl)benzo[1,2-b:4,5-b′]dithiophene (466 mg, 0.75 mmol) in dry tetrahydrofuran (15 mL) was added n-butyllithium (2.5 M in hexane, 0.66 mL, 1.65 mmol) at −78° C. After 1 hour, trimethyltin chloride (349 mg, 1.75 mmol) was added in one portion. The mixture was stirred at room temperature overnight, poured into water (25 mL) and extracted with ether three times. The organic layer was washed with brine and dried over anhydrous MgSO4. Upon evaporating the solvent, a pale yellow oil was obtained (500 mg, yield 70%). 1H NMR (CDCl3, 500 MHz) δ=7.49 (s, 2H), 7.27-7.32 (m, 4H), 7.17 (d, J=7.5 Hz, 6H), 3.19 (t, J=7.5 Hz, 4H), 2.59 (t, J=8.0 Hz, 4H), 1.75-1.84 (m, 4H), 1.56-1.66 (m, 4H), 1.42-1.50 (m, 4H), 1.17-1.41 (m, 20H), 0.45 (s, 18H).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.O>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:22][C:23]2[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)o1
Reaction time: 18 h
Yield: 78.1 %

Procedure:
A mixture of 401 mg of 4-benzhydryloxypiperidine synthesized in Production Example 1, 288 mg of methyl 5-chloromethylfuran-2-carboxylate, 352 mg of potassium carbonate, and 3.5 mL of acetonitrile was stirred for 18 hours. The reaction solution was diluted with ethyl acetate and then thrown into water, and the organic layer was collected by separation. The organic layer was washed with a saturated saline solution and then dried over magnesium sulfate. The solvent was distilled off. The resulting product was subjected to a silica gel column chromatography (chloroform/acetone (volume ratio)=20:1 to 10:1) to give the title compound (475 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:12][O:13][C:14](=[O:23])[CH:15](Br)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH3:12][O:13][C:14](=[O:23])[CH:15]([N:4]1[C:3](=[O:9])[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[N:5]1)[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(Cl)c(Cl)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
A solution of 4,5-dichloropyridazin-3(2H)-one (25.5 g, 154 mmol) in tetrahydrofuran was treated with 60% sodium hydride (7.42 g, 185.5 mmol) at 0° C. The reaction was stirred at 0° C. for 10 min, and then stirred at 25° C. for 1 h. At this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 54.5 g, 185.5 mmol), and was stirred for 2 d at 50° C. The reaction solution was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Chromatography (1/15 ethyl acetate/petroleum ether) afforded 3-cyclopentyl-2-(4,5-dichloro-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (23 g, 46.8%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH2:21][OH:22])=[CH:15][N:14]=1)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH2:21][OH:22])=[CH:15][N:14]=1)[CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])(=[O:10])=[O:11]
Reactant: COc1nc(CO)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1nc(CO)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2,3-dichloro-N-[5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]-benzenesulphonamide (1.0 g) in dichloromethane (100 mL) was added diisopropylethylamine (0.57 mL) and 2-(trimethylsilyl)ethoxymethyl chloride (0.58 mL). The reaction mixture was stirred at room temperature for 0.5 h, then washed with water. The organic phase was dried (MgSO4), filtered and evaporated to give a yellow oil. This was purified by chromatography on silica gel eluting with dichloromethane/ethyl acetate mixtures to give the title compound as a colourless oil (0.8 g).
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([OH:10])[CH2:2]2.[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:10][CH:3]1[CH2:2][C@H:1]2[N:8]([CH3:9])[C@H:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CN1[C@@H]2CC[C@H]1CC(O)C2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1[C@@H]2CC[C@H]1CC(Oc1ccc([N+](=O)[O-])cc1Cl)C2
Yield: 60.6 %

Procedure:
To a solution of 3-tropanol (6.7 g), 2-chloro-4-nitrophenol (8.2 g) and triphenylphosphine (16.1 g) in a mixture of dichloromethane (200 ml) and tetrahydrofuran (50 ml), diethyl azodicarboxylate (9.7 ml) was added dropwise with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (19:1) as the eluent to afford the title compound (8.5 g, yield: 60%) as a pale yellow amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>CC(N(C)C)=O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:18][CH:19]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Oc2ccc(Br)cn2)cc1

Procedure:
As shown in scheme 7, 4-Hydroxybenzaldehyde is treated with potassium carbonate and 2,5-dibromopyridine in DMAC to afford 4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 is combined with isoamylamine, sodium triacetoxyborohydride, acectic acid, and dichloromethane to yield the reductive amination product [4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). The resulting aryl bromide 36 is treated with acetamide, copper iodide, and 1,2 diaminocyclohexane in dioxane to yield the target compound 37.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(Cl)(Cl)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]=[N:22][CH:21]=[CH:20]2)=[O:13].C1CCN2C(=NCCC2)CC1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[CH:23]=[N:22][CH:21]=[CH:20]3)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Reactant: NCc1ccc(Br)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-bromobenzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 356 (M+H)+; 1H NMR (DMSO-d6) δ 9.52 (s, 1H), 9.15 (s, 1H), 8.49 (d, 1H), 8.11 (d, 1H), 7.77 (d, 1H), 7.67 (t, 1H), 7.55 (m, 3H) 7.32 (d, 2H), 7.25 (t, 1H), 4.34 (d, 2H); Anal. Calcd for C17H14BrN3O.0.25H2O.0.16MeOH: C, 56.34; H, 4.17; N, 11.49. Found C, 56.32; H, 4.45; N, 11.70.
Reaction SMILES: [CH3:1][C:2](=[CH2:19])[CH2:3][N:4]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH3:16])=[C:10]([CH3:17])[C:9]=1Br)[C:5](=[O:7])[CH3:6]>[Pd]>[C:5]([N:4]1[C:8]2[C:13](=[C:12]([CH3:14])[C:11]([O:15][CH3:16])=[C:10]([CH3:17])[CH:9]=2)[C:2]([CH3:19])([CH3:1])[CH2:3]1)(=[O:7])[CH3:6]
Reactant: C=C(C)CN(C(C)=O)c1cc(C)c(OC)c(C)c1Br
Agent: [Pd]
Product: COc1c(C)cc2c(c1C)C(C)(C)CN2C(C)=O
Yield: 83.3 %

Procedure:
Treatment of 14 (1.9 g, 5.8 mmoI) according to the general procedure used for Pd-catalyzed cyclization afforded 15 (1.2 g, 85% yield) as a viscous liquid. 13C NMR: δ 11.6, 16.4, 24.1, 26.9, 41.1, 59.9, 64.7, 116.7, 126.5, 129.7, 135.7, 137.8, 153.4, 168.0; HRMS: calcd. for C15H21NO2 247.1572, fnd. 247.1581.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>O>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:17]2[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]2=[O:9])=[CH:14][CH:13]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: COc1ccc(CN)cc1
Solvent: O
Product: COc1ccc(Cn2c(C)cc(O)cc2=O)cc1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
4-Hydroxy-6-methyl-2-pyrone (4.60 g, 36.45 mmol) and 4-methoxybenzylamine (5.00 g, 36.45 mmol) in H2O (100 mL) were heated to reflux. After 15 hours at reflux the reaction was allowed to cool to room temperature. The precipitate was collected by filtration washing with H2O to give a pale yellow solid (8.00 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 7.2 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 5.74 (d, J=2.0 Hz, 1H), 5.56 (d, J=2.5 Hz, 1H), 5.08 (s, 2H), 3.68 (s, 3H), 2.14 (s, 3H).