Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16](O)=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:33][O:34][CH:35]([O:38][CH3:39])[CH2:36][NH2:37]>C(Cl)Cl.CN(C=O)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16]([NH:37][CH2:36][CH:35]([O:38][CH3:39])[O:34][CH3:33])=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: CC(=O)Nc1cc(-c2nc(C(=O)O)c(-c3ccccc3Cl)o2)c(C)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(CNC(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl)OC
Temperature: 0 °C
Yield: 36.8 %

Procedure:
A solution of 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylic acid (0.50 g, 1.34 mmol) in DCM (15 mL) and DMF (0.05 mL) was allowed to stir at 0° C. To this solution was added oxalyl chloride (0.23 mL, 2.69 mmol) dropwise. The reaction mixture was allowed to stir at 0° C. for 15 minutes and then allowed to warm to rt and stir for 2 hr. The reaction mixture was concentrated, and then DCM (15 mL) and TEA (0.38 mL, 2.69 mmol) were added. The reaction mixture was allowed to stir at 0° C. and a solution of 2,2-dimethoxyethanamine (0.29 mL, 2.69 mmol) in DCM (5 mL) was added dropwise. The reaction mixture was allowed to warm to rt and to stir overnight and then concentrated. The residue was redissolved in water and EtOAc. The organic solution was separated and the aqueous solution was further extracted with EtOAc. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-N-(2,2-dimethoxyethyl)-1,3-oxazole-4-carboxamide (0.226 g, 37%). LCMS (FA): m/z=459 (M+H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH3:9][CH:10]([NH:18][CH3:19])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[CH:12]1([CH2:11][CH:10]([N:18]([CH3:19])[C:5](=[O:6])[CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])[CH3:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CNC(C)CC1CCCCC1
Reactant: O=C1COCC(=O)O1
Solvent: ClCCl
Product: CC(CC1CCCCC1)N(C)C(=O)COCC(=O)O
Reaction time: 0.67 h

Procedure:
A solution of 11.63 grams (0.100 mole) of diglycolic anhydride in 1 liter of dichloromethane (prepared by heating the anhydride and dichloromethane on a steam bath) was added to a solution of 15.55 grams (0.100 mole) of propylhexedrine in 700 milliliters of dichloromethane at temperatures in the range of from about 21° to about 30° during an interval of about 10 minutes. After the addition, the mixture was stirred at a temperature range of 25° to 30° C. for about 40 minutes whereupon a reaction took place with the formation of a product in the reaction mixture. The mixture was then concentrated on a rotary evaporator to recover the {2-[(2-cyclohexyl-1-methylethyl)methylamino]-2-oxoethoxy}-acetic acid product as a partially crystalline residue which after recrystallization from an ethyl acetate-hexane mixture was in the form of white plates, m.p. 90°-91° C.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[CH:15]2[CH2:16][C:17](=[O:19])[CH2:18][CH:11]1[CH2:12][O:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:22])C>CO>[CH2:3]([N:10]1[CH:11]2[CH:18]([OH:22])[C:17](=[O:19])[CH2:16][CH:15]1[CH2:14][O:13][CH2:12]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CC2COCC(C1)N2Cc1ccccc1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC2COCC(C1O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a stirred solution of potassium hydroxide (730 mg, 13 mmol) in dry MeOH (50 mL) at 0° C. under nitrogen was added a solution of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (CAS: 81514-40-1, 1 g, 4.3 mmol) in dry MeOH (20 mL) dropwise over 10 min. The reaction mixture was stirred at 0° C. for another 10 min, and PhI(OAc)2 (1.83 g, 5.5 mmol) was added portion wise over 10 min. The reaction mixture was warmed to room temperature, with stirring, overnight. After the starting material disappeared as monitored by TLC, MeOH was removed under reduced pressure and the residue was cooled to 0° C. and 10 ml of 6N HCl was added carefully. The mixture was stirred at room temperature for 2 hours, and then ethyl acetate and water (50 mL, 1:1) were added. The aqueous layer was separated and was added into K2CO3 till the solution was saturated. The mixture was extracted with ethyl acetate (20 mL) three times, dried and concentrated, the residue was purified by silica gel (EA/PE=1:2) to give 9-benzyl-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-one 106b as colorless oil, 270 mg, yield: 25%. MS: calc'd (MH+) 248, measured (MH+) 248.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29]([NH:33][CH3:34])[CH:30]=[CH:31][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]([CH3:34])[C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=3)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1cccc(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cccc(Cl)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (3-chloro-phenyl)-methyl-amine (50 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (3-chloro-phenyl)-methyl-amide: MS m/z: (M+H) 537.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1.ClS([N:17]=[C:18]=O)(=O)=O.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]#[N:17])=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc2cc(C)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc2c(C#N)c(C)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 6-methoxy-2-methyl-1H-indole (3.9 g, 24 mmol) in acetonitrile (200 mL) and DMF (20 mL) is added dropwise a solution of ClSO2NCO (4 mL, 1.3 eq.) in acetonitrile (31 mL) at 0° C. After the addition, the mixture is stirred at room temperature for 3 h. Then it is poured into ice water and saturated NaHCO3 is added to it until it becomes basic. The aqueous phase is extracted with CH2Cl2 and then evaporated. The residue is purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 81% of 6-methoxy-2-methyl-1H-indole-3-carbonitrile.
Reaction SMILES: [Cl-].[NH4+:2].[CH3:3][S:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Zn]>[CH3:3][S:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:2])=[CH:10][CH:9]=1
Reactant: CSCCNc1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Zn]
Product: CSCCNc1ccc(N)cc1

Procedure:
0.8 g of ammonium chloride and 20 g of powdered zinc are added to 44 ml of aqueous-alcoholic solution (10% of water, 90% of alcohol). This mixture is brought to reflux with stirring, and 0.04 mole (8.5 g) of 4-nitro-N-[[β-(methylthio)ethyl]aniline is added, the addition being regulated so as to maintain the reflux without heating. The decolorized reaction medium is filtered while boiling into a flask containing 8.5 ml of strength hydrochloric acid. The expected product precipitates in the form of a dihydrochloride. It is dried under vacuum at 55° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][CH:25]=[C:26]([CH3:27])[C:19]=34)=[C:12]([F:28])[CH:11]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:16][C:14]1[CH:15]=[C:10]([NH:9][C:4]2[CH:3]=[CH:2][N:7]=[C:6]([NH2:8])[N:5]=2)[CH:11]=[C:12]([F:28])[C:13]=1[O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[NH:24][CH:25]=[C:26]([CH3:27])[C:19]=12
Reactant: [H][H]
Reactant: Cc1c[nH]c2nccc(Oc3c(F)cc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c[nH]c2nccc(Oc3c(F)cc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
50 mg (0.12 mmol) of 6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine are dissolved in 10 ml of ethanol. 35 μl (0.25 mmol) of triethylamine and 26 mg (0.02 mmol) of 10% palladium-on-carbon are added, and the mixture is hydrogenated under atmospheric pressure in a hydrogen atmosphere overnight. The mixture is then filtered through Celite®, and the celite is washed with methanol. The solvent is removed under reduced pressure and the crude product is purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[C:16]([OH:18])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:1][C:2]1[N:17]=[C:16]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(O)c2c(n1)-c1ccccc1CCCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 20B (950 mg, 2.4 mmol) in CH2Cl2 (30 mL) was added para-toluenesulfonyl chloride (1.09 g, 5.7 mmol), 4-dimethylaminopyridine (50 mg, 0.41 mmol) and triethylamine (1.1 mL. 7.9 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 (100 mL), washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with EtOAc:hexanes (25:75) to provide the title compound.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.C1C=CC=CC=1.[Cl:49][CH2:50][CH2:51][CH2:52]O>>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[Cl:49][CH2:50][CH2:51][CH2:52][O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: OCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: c1ccccc1
Product: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)OCCCCl)cccc12
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydrate in 10 ml of 3-chloro-1-propanol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 5 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine 3-chloropropyl ester di(p-toluenesulfonate) in 88% yield; mp. 140°-145° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH2:27]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc(NCc2ccccc2)cc1

Procedure:
The title compound is prepared from N-(4-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-acetamide dihydrochloride (Example 174) and benzaldehyde according to the method described in Example 177. Melting Point: 147° C. (dec.) (diethylether-ethyl acetate)
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13](=[O:26])[CH2:14][O:15][C:16](=[O:25])[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=O)C1C=CC=CC=1>CCO.Cl.[Pd]>[NH2:11][CH:12]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13](=[O:26])[CH2:14][O:15][C:16](=[O:25])[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24]
Reactant: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(N)CC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
2,6-Dimethyl-benzoic acid 3-benzyloxycarbonylamino-4-tert-butoxycarbonyl-2-oxo-butyl ester, 110, (11.3 g, 24.1 mmol) is dissolved in a solution of EtOH (400 mL) and 1N HCl (29 mL), treated with 10% Pd/C (500 mg) and stirred under a hydrogen atmosphere for 4 h. The solution is filtered and concentrated to yield 7.6 g of the desired product as an HCl salt that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH2:12](Br)[CH2:13][CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: OCc1c(F)cc(O)cc1Cl
Reactant: CCCBr
Product: CCCOc1cc(F)c(CO)c(Cl)c1
Yield: 69 %

Procedure:
This compound was prepared from 3-Chloro-5-fluoro-4-hydroxymethyl-phenol and propylbromide according to the procedure described in Example 179 to give the product as a yellowish oil (259 mg, 69%); MS (EI): 218.1 (M)+.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:20][C:15]1[CH:14]=[C:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(F)c1
Temperature: 100 °C
Yield: 85.4 %

Procedure:
To a solution of 6-{(S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile—66 mg (0.16 mmol) dissolved in toluene (2 mL) were added 67 mg (0.47 mmol) of 1-chloroethyl chloroformate and 61 mg (0.47 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 45 mg (85%) of the title compound as a light yellow oil. ES-MS m/e: 330.3 (M+H+).
Reaction SMILES: O=[C:2]([CH3:21])[CH2:3][O:4][C:5]([CH:7]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:8]1)=O.C([NH2:25])(=O)C.B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH2:14]([O:13][C:11]([N:9]1[CH2:10][CH:7]([C:5]2[O:4][CH:3]=[C:2]([CH3:21])[N:25]=2)[CH2:8]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)=O
Reactant: CC(=O)COC(=O)C1CN(C(=O)OCc2ccccc2)C1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: Cc1coc(C2CN(C(=O)OCc3ccccc3)C2)n1
Temperature: 130 °C

Procedure:
To 130 mg (0.45 mmol) azetidine-1,3-dicarboxylic acid 1-benzyl ester 3-(2-oxo-propyl)ester in 4 mL xylene were added 132 mg (2.25 mmol) acetamide, 39 μL (0.31 mmol) boron trifluoride etherate and the mixture was heated at 130° C. for 24 hours. After cooling to room temperature and evaporation of the solvent the product was purified by chromatography (silica, hexane-EtOAc 6:4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1cccc(S)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(Sc2ccnc(Cl)c2)c1
Yield: 95.1 %

Procedure:
Using the method of Example 3, Step A, 3-methoxybenzenethiol (884 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(3-methoxyphenylthio)pyridine (1.51 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.12 (d, 1H), 7.39 (t, 1H), 7.13 (d, 1H), 7.08 (s, 1H), 7.03 (d, 1H), 6.93 (s, 1H), 6.88 (d, 1H), 3.83 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].P([O-])([O-])(O)=O.[Na+].[Na+]>CN(C)C(=O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=2)[N:4]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(I)nn1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cn2nc(I)ccc2n1
Yield: 41.8 %

Procedure:
Using 3-amino-6-iodopyridazine (2.0 g, 9.05 mmol), N,N-dimethylacetamide (20 mL), ethyl 3-bromo-2-oxopropanate (1.82 mL, 14.5 mmol) and disodium hydrogenphosphate (3.21 g, 22.6 mmol), and in the same manner as in Reference Example 3, the title compound (1.2 g, 44%) was obtained as a green powder.
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CO>[C:22]([NH:26][CH2:21][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: O=C1CCC(c2ccc(OCC3CO3)c([N+](=O)[O-])c2)=NN1
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]
Yield: 70.4 %

Procedure:
A stirred mixture of crude 6-[4-(2,3-epoxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone (3.3 g, 0.011 mole), methanol (70 ml), and t-butylamine (7.2 ml, 0.068 mole), was gently heated under reflux for 105 minutes. The filtered solution was evaporated under reduced pressure to an orange coloured foam (4 g, 97%). The crude base (3.77 g) was digested with water (200 ml) and glacial acetic acid added to pH 4, then the solution filtered and washed with dichloromethane (3 × 100 ml). The aqueous phase was treated with potassium carbonate solution to pH 9, then extracted with dichloromethane and the combined organic extracts washed with a little water. Evaporation of the dried solution gave crude 6-[4-(3-t-butylamino-2-hydroxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone (2.82 g, m.p. about 92°-105°C). After two recrystallisations from ethyl acetate the free base (m.p. about 124°C) was converted into its hydrochloride m.p. 260°-262°C. The pure hydrochloride recrystallised from methanol-ether, had m.p. 263°-265°C (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:16]1[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=[CH:14][CH:15]=1)=[O:19])[CH2:24]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2nc(-c3ccc(F)cc3)oc12
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3nc(-c4ccc(F)cc4)oc13)C2
Yield: 15 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamide was prepared from 2-(4-fluorophenyl)benzoxazole-7-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 15% yield as an off-white solid: mp 229-231° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.26 (m, 2H), 8.20 (d, J=8.3 Hz, 1H), 7.94 (dd, J=1.0, 7.9 Hz, 1H), 7.71 (dd, J=1.0, 7.6 Hz, 1H), 7.50 (m, 3H), 4.39 (m, 1H), 3.02 (m, 2H), 2.43 (s, 3H), 2.32 (m, 2H), 2.08 (m, 1H), 1.93 (m, 2H), 1.48 (m, 3H), 0.96 (m, 2H); MS (ESI) m/z 394 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10](C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 527 mg (2.22 mmol) of 1-isopropyl-3-methyl-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2-one in DCE (15 mL) was added 611 mg (2.22 mmol) of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester in DCE (10 mL) and stirred for 2 hours at room temperature. Sodium triacetoxyborohydride (706 mg, 3.33 mmol) was then added and the reaction mixture stirred overnight at room temperature. The reaction mixture was diluted with DCM, the organic layer washed with sodium bicarbonate, and then dried over sodium sulfate. The organic layer was concentrated and purified by flash silica gel chromatography eluting with methanol:DCM (0-10%) to give 612 mg (56%) of (3S,4S)-3-[1-isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19]N2CCSCC2)=[C:12]([NH2:26])[CH:11]=1)=[O:5].Cl>C(Cl)Cl.CO>[ClH:1].[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][C:4]([O:3][CH3:2])=[O:5])=[C:12]([NH2:26])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCNc1ccc(C(=O)NCCC(=O)OC)cc1N

Procedure:
The same procedure is used as in (2) with the addition of ethereal hydrochloric acid. Rf value: 0.65 (silica gel; methylene chloride/Methanol=9:1)