Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:13]2([CH3:30])[CH:14]([OH:29])[CH2:15][CH:16]3[C:21]4([CH3:27])[CH2:22][CH2:23][CH:24](O)[CH2:25][CH:20]4[CH2:19][CH:18]([OH:28])[CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH3:8][O:7][C:5](=[O:6])[CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:30])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][C@@H:14]2[OH:29])[C@:21]2([CH3:27])[C@@H:20]([CH2:25][C@@H:24]([N:64]=[N+:65]=[N-:66])[CH2:23][CH2:22]2)[CH2:19][C@H:18]3[OH:28])[CH2:11][CH2:10]1)[CH3:1]
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
A solution of 2.06 g of cholic acid methyl ester (marketed product) (4.87 mmol), 1.28 g of triphenylphosphine (4.88 mmol) and 1.70 g of diethylazadicarboxylate (0.76 mL, 4.88 mmol) in 50 ml of THF, at room temperature and under inert atmosphere, was added to a solution of 1.4 g of diphenylphosphorylazide (1.1 mL, 5.11 mmol) in 5 ml of THF during 15 minutes. After 24 hours at room temperature, 1 equivalent of diethylazadicarboxylate (0.76 mL, 4.88 mmol) and 1 equivalent of triphenylphosphine (1.28 g, 4.88 mmol) were added. After a further 24 hours the solvent was evaporated off under reduced pressure and the resulting crude was purified by flash chromatography. 1.6 g of the desired product (3.57 mmol) was obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.BrC1C=C[C:15]([OH:18])=CC=1.C(OC(OCC)CBr)C>>[O:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([CH:15]=[O:18])[CH:10]=[CH:9][C:5]1=2
Reactant: Oc1ccc(Br)cc1
Reactant: Brc1ccc2occc2c1
Agent: CCOC(CBr)OCC
Product: O=Cc1ccc2occc2c1

Procedure:
benzo[b]furan-5-carboxaldehyde was prepared from 5-bromobenzo[b]furan (prepared from 4-bromophenol and bromoacetaldehyde diethyl acetal by the general method described in J. Chem. Soc. Perkin 1, 1972, 556) following essentially the same procedure as that described in (b) above. Benzo[b]furan-5-carboxaldehyde was obtained as an oil. Pmr spectrum (CDCl3 ; δ in ppm): 6.90 (1H, d); 7.55-7.93 (3H, m); 8.15 (1H, d); 10.08 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.FC1C=CC=CC=1C([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([CH3:55])=[CH:48][C:49]3[S:53][CH:52]=[N:51][C:50]=3[CH:54]=2)=[CH:42][N:41]=1)=O.C([O-])(O)=O.[Na+].CC(=O)OCC>C(Cl)Cl>[F:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([CH3:55])=[CH:48][C:49]3[S:53][CH:52]=[N:51][C:50]=3[CH:54]=2)=[CH:42][N:41]=1)=[O:6]
Reactant: O=C(O)c1c(F)cncc1F
Reactant: Cc1cc2scnc2cc1-c1ccc(NC(=O)c2ccccc2F)nc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc2scnc2cc1-c1ccc(NC(=O)c2c(F)cncc2F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A suspension of 3,5-difluoroisonicotinic acid (24 mg, 0.15 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)(35 mg, 0.2 mmol) and 45 μl N-methyl morpholine in 2 ml DCM was stirred at r.t. for 1 h before addition of 5-(6-methylbenzothiazol-5-yl)-2-pyridylamine (55) (24 mg, 0.1 mmol). The resulting reaction mixture was stirred at r.t. for overnight then at 50° C. for 3 h. The reaction mixture was worked up with aq. NaHCO3/EA. Org. phase was washed with brine, concentrated, subjected to silica flash column chromatography to furnish 8.9 mg (3,5-difluoro(4-pyridyl))-N-[5-(6-methylbenzothiazol-5-yl)(2-pyridyl)]carboxamide (58) as yellow semi-solid. (yield: 23.3%, purity>90%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:5]2[S:1][C:2]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[CH:19][CH:20]=3)=[N:3][CH:4]=2)=[CH:24][CH:23]=1
Reactant: Clc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2nccs2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(-c2ncc(-c3ccc(Cl)cc3)s2)cc1
Temperature: 60 °C
Yield: 65.2 %

Procedure:
To a solution of tert-butyl 2-(4-(thiazol-2-yl)phenoxy)acetate (360 mg, 1.23 mmol) and 1-chloro-4-iodobenzene (412.5 mg, 1.73 mmol) in anhydrous acetonitrile (ACN) (5.2 mL) was added PPh3 (32.74 mg, 124 μmol) and Ag2CO3 (685.2 mg, 2.46 mmol). The flask was evacuated and re-filled with nitrogen three times and then PdCl2dppf was added (50.5 mg, 0.062 mmol). The reaction mixture was heated under Ar atmosphere for 72 h at 60° C. When the reaction was completed, the reaction mixture was filtered through Celite® (inorganic solids were removed) and the precipitate was washed with several portions of dichloromethane(3×20 mL). The filtrate was evaporated, and the residue was absorbed onto silica then subjected to flash chromatography (SiO2, hexane: ethyl acetate (AcOEt), 9:1) to afford 322.5 mg of tert-butyl 2-(4-(5-(4-chlorophenyl)thiazol-2-yl)phenoxy)acetate as a yellow solid (76% yield). RMN1H (CDCl3, 400 MHz): δ 7.94; (s, 1H), 7.92-7.87; (m, 2H), 7.56-7.46; (m, 2H), 7.42-7.35; (m, 2H), 7.01-6.93; (m, 2H), 4.57; (d, J=3.6 Hz, 2H), 1.50; (s, 9H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.[CH3:24][N:25]([CH:32]([CH3:34])[CH3:33])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH:32]([CH3:34])[CH3:33])[CH3:24])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3oc4c(c23)CCNC4)c1
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3oc4c(c23)CCN(C(=O)/C=C/CN(C)C(C)C)C4)c1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-ethynylphenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 43A (100 mg, 0.344 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (93 mg, 0.48 mmol) to yield 82 mg (55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15](O)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.3 %

Procedure:
To a solution of 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)-methyl]-2-pyridinecarboxylic acid (81 mg) in dichloromethane (2 ml) and tetrahydrofuran (2 ml) was added benzenesulphonamide (50 mg), 4-dimethyl-aminopyridine (3.5 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (61 mg) and the mixture stirred at ambient temperature for 5 hours. Solvent was removed in vacuo and water (5 ml) added. The mixture was extracted with ether (2×5 ml) and the combined extracts dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (46 mg, 42%) as a white solid. LC/MS [MH+]=545/547, Rt=3.89 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:14])O[C:11](=[O:13])[CH:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH2:17]([NH:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C>[CH2:17]([N:24]1[C:11](=[O:13])[CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([OH:14])=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc(Cl)cc2)c(O)nn1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 3-(4-chlorophenyl)-2,5-furandione (10.24 g, 66.9 mmol) in acetic acid (300 mL) was added benzylhydrazine dihydrochloride in one portion (19.6 g, 100 mmol). The reaction mixture was stirred at reflux for 14 h. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the resulting white suspension was filtered. The collected solid was washed with EtOAc (20 mL×2), and dried in a 50° C. vacuum oven for 16 h to yield 6.5 g of the desired product as a white solid. The filtrate was concentrated under reduced pressure, and the obtained residue was crystallized in EtOAc to afford additional 1.6 g of the title compound (8.1 g in total, 39% yield). HPLC/MS (method A): retention time=3.29 min, (M+H)+=313.1. 1H NMR (DMSO-d6, 500 MHz): δ 11.62 (s, 1H), 7.65 (d, J=10 Hz, , 2H), 7.51 (d, J=10 Hz, 2H), 7.23-7.38 (m, 5H), 7.04 (s, 1H), 5.11 (s, 2H).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([O:16][C:17]2[C:18]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:13]([NH:29][C:30](=[O:32])[CH3:31])=[C:12]([F:33])[CH:11]=1.[ClH:34]>C(#N)C.[Cu]Cl.[Cu](Cl)Cl>[Cl:34][C:10]1[C:15]([O:16][C:17]2[C:18]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:13]([NH:29][C:30](=[O:32])[CH3:31])=[C:12]([F:33])[CH:11]=1
Reactant: Cl
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
A solution of 2.01 g of isoamyl nitrite in 1 ml of acetonitrile was added dropwise to a mixture of 2.0 g of N-[4-amino-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide, 1.13 g of copper(I) chloride, 2.31 g of copper(II) chloride, and 20 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 1.04 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.[Cl-].[NH4+]>[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1[S:28]([NH:14][CH:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([F:1])([F:15])[F:16])(=[O:29])=[O:30]
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3ccccc23)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 53.2 %

Procedure:
To a solution of 150 mg (0.66 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine in 2 mL of pyridine was added 165 mg (0.66 mmol) of 2,4-dimethyl-6-nitrobenzenesulfonyl chloride. The mixture stirred at 80° C. in a sealed tube. After 6 hours, the mixture was diluted with 10 mL of saturated aqueous ammonium chloride solution and extracted with three 10 mL portions of ethyl acetate. The combined ethyl acetate layers were washed with five 10 mL portions of 1 N aqueous HCl, three 10 mL portions of brine, and three 10 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel using dichloromethane-hexanes (50-100% gradient). The material from the column was triturated with ether-hexanes to afford 155 mg (53%) of 2,4-dimethyl-6-nitro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide. MS: m/z 442.43 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[CH3:21][O:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccco1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: CCO
Solvent: O
Product: COc1ccc2ccc(NC(=O)c3ccco3)nc2n1
Temperature: 4 °C
Yield: 83.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-furancarboxylic acid (8.95 g), N,N'-carbonyldiimidazole (12.8 g) and 2-amino-7-methoxy-1,8-naphthyridine (10.5 g). The product produced by precipitation in water (15.5 g; m.p. 199° C.) is dissolved in boiling ethanol (500 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-(7-Methoxy-1,8-naphthyridin-2-yl)-2-furancarboxamide (13.5 g) is produced, m.p. 201° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C@@H:17]1[C@@H:21]([CH2:22][CH3:23])[CH2:20][CH2:19][NH:18]1)[N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:39][O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH2:45][S:46][CH3:47])[NH2:43]>CCOC(C)=O>[CH3:39][O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH2:45][S:46][CH3:47])[NH:43][C:11](=[O:13])[C@@H:10]1[CH2:14][CH2:15][CH2:16][N:9]1[CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C@@H:17]1[C@@H:21]([CH2:22][CH3:23])[CH2:20][CH2:19][NH:18]1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CC[C@H]1CCN[C@@H]1C(C(=O)OC(C)(C)C)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC[C@H]1CCN[C@@H]1C(C(=O)OC(C)(C)C)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)OC
Temperature: 23 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
N-[(tert-Butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-proline (0.238 mmol), HOBT (0.048 g, 0.262 mmol), EDC (0.068 g, 0.0357 mmol), and methionine methyl ester hydrochloride (0.048 g, 0.238 mmol) were dissolved in CH2CL2 (10 mL) and stirred at 23° C. for 18 h. EtOAc (100 mL) was added, and the mixture washed with satd NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave 0.085 g of title compound. 1H NMR (CD3OD) δ(major rotamer) 4.63 (t, 1H, J=7 Hz), 3.73 (s, 3H), 3.55-3.7 (m, 1H), 3.0-3.5 (m,4H), 2.3-2.7 (m, 5H), 1.9-2.2 (m, 3H), 2.08 (s, 3H), 1.6-1.9 (m, 4H), 1.46 (s, 9H), 1.3-1.45 (m, 2H), 0.92-1.02 (m, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9])=[CH:23][CH:22]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: Fc1cnccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cnccc2C(F)(F)F)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
To a solution of 3-fluoro-4-trifluoromethylpyridine (1 g, 6.1 mmol) and [2-(4-hydroxyphenyl)-ethyl]-carbamic acid tert-butyl ester (1.44 g, 6.1 mmol) in DMSO (10 mL) was added K2CO3 (5 g, 36.2 mmol), and the mixture was heated at 100° C. for 30 min. After cooling, the solids were removed by suction filtration and washed with Et2O. The pooled filtrates were diluted with Et2O (75 mL) and washed with 0.01 N HCl. The organic layer was concentrated in vacuo. The residue was dissolved in Et2O/hexane and washed with 10% NaOH. The organic layer was filtered and vacuum dried to provide 1.4 g (60% yield) of {2-[4-(4-trifluoromethyl-pyridin-3-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester as a clear, colorless oil.
Reaction SMILES: [C@H]1(C[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.[ClH:42].Cl.Cl.NC1CCN([CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH:57]([OH:60])[CH2:56][CH2:55]2)CC1>>[ClH:42].[ClH:42].[OH:60][CH:57]1[CH2:58][CH2:59][N:54]([CH2:53][CH2:52][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:55][CH2:56]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113, see example 60) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].C([O-])(=O)C.[NH4+]>CO>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of 5.0 g. of acetonine in a mixed solvent comprising 19 g. of acetone and 9.5 g. of methanol was added with 1.3 g. of ammonium acetate. The mixture was maintained at room temperature for 24 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 91.1%.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([O:17][C:18]2[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=2)[CH:11]=1>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([O:1][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:12]3[CH:13]=[CH:14][C:15]([OH:16])=[CH:10][CH:11]=3)=[CH:19][CH:20]=1)[CH2:3]2
Reactant: OC1CN2CCC1CC2
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Product: Oc1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with 4,4′-dihydroxydiphenyl ether (TCl, 202 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3 H2O, 90:10:1, Rf. 0.2) as oil (210 mg, yield, 68%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.55 (m, 1H), 1.60–1.87 (m, 2H), 1.98–2.15 (m, 1H), 2.20–2.25 (m, 1H), 2.75–2.98 (m, 5H), 3.20–3.30 (m, 1H), 4.45(m, 1H), 6.62–6.96 (m, 8(DCl/NH3) m/z 312 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:6][C:7]1[CH:14]=[C:13]([F:15])[C:10]([CH:11]=O)=[C:9]([F:16])[CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[F:15][C:13]1[CH:14]=[C:7]([OH:6])[CH:8]=[C:9]([F:16])[C:10]=1[CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=Cc1c(F)cc(O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1cc(F)c(CN2CCCC2)c(F)c1
Yield: 19.6 %

Procedure:
Pyrrolidine (6.6 mL, 80 mmol) was added to a solution of intermediate 20, 4-hydroxy-2,6-difluorobenzaldehyde (9.7 g, 61.3 mmol) in dichloromethane (100 mL). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (19.5 g, 925 mmol) was added in portions under stirring. The reaction mixture was intensively stirred for 24 h at RT. Water (100 mL) and concentrated HCl were added to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×100 mL), then with EtOAc (100 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, the obtained crystals were separated by filtration, dried in vacuo, dissolved in small amount of water, HCl was added to attain pH˜7, and water layer was extracted with CHCl3 (2×100 mL). The organic layer was separated, washed with brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (2.6 g, 20%, 12 mmol). LCMS data: 215 and 214 (M+H)+ (calculated for C11H13F2NO 213.23). 1H NMR data (DMSO-d6): 10.26 (br.s, 1H, OH), 6.38-6.46 (m, 2H, H—Ar), 3.52 (s, 2H, Ar—CH2); 2.35-2.44 (m, 4H), 1.58-1.68 (m, 4H).
Reaction SMILES: [Cl-].C[Zn+].Cl[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1.[CH2:13](N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:13])[CH:10]=1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: COc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn+]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COc1ccnc(C)c1
Yield: 49.7 %

Procedure:
Methylzinc chloride in THF (2 M, 10.489 mL, 21 mmol) was added to a solution of 2-chloro-4-methoxypyridine (0.500 g, 3.48 mmol) and Pd(PPh3)4 (0.161 g, 0.14 mmol) in THF (10 mL). The mixture was refluxed for 40 h and then poured into an aqueous solution (10 mL) containing ethylenediaminetetraacetic acid (1.5 g). The resulting mixture was neutralized with K2CO3 and extracted with Et2O. The organic layer was concentrated to give a residue, which was purified on a silica gel column eluting with MeOH:EtOAc (1:10) to give 4-methoxy-2-methylpyridine (0.213 g, 50.0%).
Reaction SMILES: [CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]3=[O:20])=[CH:10][C:9]=2[F:21])=[C:5]([O:24][CH3:25])[CH:4]=1)[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:18](=[O:19])[CH2:17][CH2:16][C:15]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:20])=[CH:10][C:9]=2[F:21])=[C:5]([O:24][CH3:25])[CH:4]=1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCc1ccc(Oc2ccc(N3C(=O)CCC3=O)cc2F)c(OC)c1
Solvent: CC#N
Product: CCc1ccc(Oc2ccc(NC(=O)CCC(=O)N3CCOCC3)cc2F)c(OC)c1
Temperature: 30 °C
Reaction time: 72 h
Yield: 87.3 %

Procedure:
To 1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-dione (40.4 mg, 0.12 mmol) were added acetonitrile (120 μL) and morpholine (20 μL, 0.24 mmol). The reaction mixture was stirred at 30° C. for 3 days under argon, then concentrated, dissolved in ethyl acetate, washed with saturated NH4Cl and extracted with ethyl acetate. Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give the title product (45.1 mg; 87%) after purification by preparative TLC (dichloromethane/methanol: 9/1).