Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:20](O)[CH3:21]>>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH2:20][CH3:21])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Agent: Cl
Product: CCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 5.2 parts of p-(2-thenoyl)hydratropic acid, 40 parts of absolute denatured ethanol and 0.5 parts of hydrochloric acid solution is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is taken up in ether. The ethereal solution is shaken with alkaline water, separated and shaken twice with water. The ether phase is dried, filtered and evaporated, yielding ethyl p-(2-thenoyl)hydratropate, also named ethyl p-(2-thenoyl)-α-methyl-phenylacetate, as a residue.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:8][C:15]([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[S:16])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ncccc1Br
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ncccc1Br
Temperature: 25 °C

Procedure:
3-Bromopyridin-2-amine (30 g, 168 mmol) and ethoxycarbonyl isothiocyanate (24.8 g, 21.3 mL, 185 mmol) were dissolved in dioxane (300 mL) and stirred at room temperature. After 4 hours further ethoxycarbonyl isothiocyanate (1 mL, 8.4 mmol) was added. After 1 hour the solvent was evaporated and the residue dried in high vacuum for 12 hours. The title compound was obtained as a light yellow solid (51.2 g, 100%) and was used crude for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(C=O)cc1
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccc(C)cc1
Yield: 47 %

Procedure:
Upon heating a solution of 6 g of 4-methylbenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 6 hours, 2-amino-4-(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 119° C (ethyl acetate/petroleum ether) is obtained. Yield: 47% of theory.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.N=[C:11]([CH3:15])[CH2:12][C:13]#[N:14]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:13]([NH2:14])=[CH:12][C:11]([CH3:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=N)CC#N
Reactant: NNc1ccc(Cl)nn1
Solvent: CCO
Product: Cc1cc(N)n(-c2ccc(Cl)nn2)n1

Procedure:
A mixture of 14.5 g (0.1 moles) of 3-chloro-6-pyridazinyl-hydrazine, 8.5 g (0.1 moles) of 3-iminobutyronitrile and 150 ml of ethanol is heated to reflux for 9 hours. After cooling the separated crystals are filtered, washed with ethanol and dried. Yield: 15.6 g (74.0%); m.p.: 148°-150° C. The hydrochloride melts at 157°-159° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([F:22])[CH:15]=2)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:30]([S:33](Cl)(=O)=[O:34])([CH3:32])[CH3:31]>C(Cl)Cl>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:7]3[C:12](=[CH:11][C:10]([NH:13][S:33]([CH:30]([CH3:32])[CH3:31])=[O:34])=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[CH:15][C:16]=1[F:22])#[N:21]
Reactant: CC(C)n1cc(-c2ccc(C#N)c(F)c2)c2ccc(N)cc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1cc(-c2ccc(C#N)c(F)c2)c2ccc(NS(=O)C(C)C)cc21
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
Cool a mixture of 1-Isopropyl-3-(4-cyano-3-fluoro-phenyl)-1H-indol-6-ylamine (0.442 g, 1.51 mmol) and triethylamine (0.306 g, 3.02 mmol) in methylene chloride (10 mL) in a brine/ice bath under argon and treated with a solution of isopropyl sulfonyl chloride (0.210 g, 1.66 mmol) in methylene chloride and the resulting mixture was stirred in the cooling bath for 30 min. After this time dilute the reaction with methylene chloride (40 mL); wash with a saturated aqueous sodium bicarbonate solution (50 mL), then water (50 mL), then brine (50 mL); and dry over sodium sulfate. Remove the solids by filtration; concentrate the filtrate under reduced pressure. Triturate the residue with boiling methylene chloride (×3) then boiling acetonitrile to afford the title compound (0.212 g, 37%) as a white solid: mp 173-175° C. dec;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I>O1CCCC1.C(OCC)(=O)C>[CH3:22][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of methyl 4-[[(tert-butoxycarbonyl)amino]methyl]benzoate (compound obtained in Reference Example 81(1), 2.0 g) in tetrahydrofuran (20 mL) is added sodium hydride (60% dispersion in mineral oil, 0.9 g) under ice-cooling. The mixture is stirred at room temperature for 30 minutes and then to the reaction mixture is added dropwise methyl iodide (2.3 mL). The mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with ethyl acetate, washed with water, and concentrated in vacuo to give methyl 4-[[N-methyl-N-(tert-butoxycarbonyl)amino]-methyl]benzoate (1.9 g, yield; 94%) as a yellow oil. MS (APCI) m/z: 280 [M+H]+
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:21]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:21]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Reaction time: 12 h

Procedure:
Combine 4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (10 mmol) and lithium aluminum hydride (10 mmol) in tetrahydrofuran. Heat to reflux. After 12 hour, cool and carefully quench the reaction mixture with water (0.4 mL), 15% aqueous sodium hydroxide solution (0.4 mL) and water (1.2 mL). Filter and extract the filtrate with ethyl acetate. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[Br:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[Br:20][C:21]1[CH:26]=[C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=3)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1F
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1F

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example A.46) (1.50 g, 5.1 mmol) and commercially available 3-bromo-benzene-boronic acid (1.23 g, 6.12 mmol) according to the general procedure IVb. Obtained as a white solid (1.23 g, 58%). MS (EI) 416.0 [(M)+]; mp 103° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:27]>[OH-].[Na+]>[C:1]([NH:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Reaction time: 0.08 h
Yield: 39.1 %

Procedure:
140 mg of benzoyl chloride were added tc a solution of 255 mg of 5'-amino-2',5'-dideoxy-5-ethyluridine in 3 ml of 0.33M sodium hydroxide solution and the mixture was shaken vigorously for 5 minutes. The mixture was filtered and the solid was washed with 5 ml of water and 5 ml of diethyl ether, and recrystallized from ethanol to give 140 mg of 5'-benzamido-2',5'-dideoxy-5-ethyluridine of melting point 246°-247° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:17])=[N:3]1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][N:2]1[C:6]([O:7][C:21]2[CH:22]=[CH:23][N:24]=[C:19]([Cl:18])[N:20]=2)=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:17])=[N:3]1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1nn(C)c(O)c1Cc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(C)c(Oc2ccnc(Cl)n2)c1Cc1ccc(Cl)cc1Cl
Yield: 42.5 %

Procedure:
In 10 ml of acetonitrile were stirred 2.7 g (10 mmol) of 1,3-dimethyl-4-(2,4-dichlorobenzyl)-5-hydroxypyrazole, 1.5 g (10 mmol) of 2,4-dichloropyrimidine and 1.5 g (11 mmol) of potassium carbonate with refluxing for 3 hours. After completing the reaction, the reaction mixture was purified as the same manner as described in Example 4 to give 1.63 g of 1,3-dimethyl-4-(2,4-dichlorobenzyl)-5-(2-chloropyrimidine-4-yloxy)pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH2:17]([N:24]([CH2:28][Si](C)(C)C)[CH2:25]OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([CH:4]1[CH:5]([CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[CH2:28][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25]1)=[O:16]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)/C=C/CCO[Si](C)(C)C(C)(C)C
Product: COC(=O)C1CN(Cc2ccccc2)CC1CCO[Si](C)(C)C(C)(C)C

Procedure:
105.1 In analogy to example 101.1 ((E)-5-(tert-butyl-dimethyl-silanyloxy)-pent-2-enoic acid methyl ester (CAS 688801-64-1) and N-benzyl-N-(methoxymethyl)tri-methylsilylmethylamine (CAS 93102-05-7) were reacted to give (3RS,4RS)-1-benzyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-pyrrolidine-3-carboxylic acid methyl ester. Light yellow oil. MS 378.3 ([M+H]+)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[F:17].[NH3:18].CO>ClCCl>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH2:18])=[C:4]([F:17])[C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: NCc1ccc(Cl)c(Oc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 1-(bromomethyl)-4-chloro-2-fluoro-3-(phenyloxy)benzene (0.058 g, 0.184 mmol) and 7M ammonia in methanol (3 mL, 21.00 mmol) in dichloromethane (1 mL) was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with dichloromethane to give the desired product (0.023 g, 47% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 7.93 (br. s., 2H), 7.52-7.60 (m, 1H), 7.46 (t, 1H), 7.26-7.38 (m, 2H), 7.01-7.12 (m, 1H), 6.86 (d, 2H), 4.07 (s, 2 H). ES MS: m/z 252 (M+1).
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17](Cl)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CCCCC=CCC=CCCCCCCCCC(=O)Cl
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CCCCC=CCC=CCCCCCCCCC(=O)Oc1ccc(C(=O)CNC(C)C)cc1O

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 10,13-octadecadienoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(10,13-octadecadienoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-hydroxy-4-(10,13-octadecadienoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate. By catalytic hydrogenation of 3-hydroxy-4-(10,13-octadienoyloxy)phenyl isopropylaminomethyl ketone methanesulfonate, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(octadecanoyloxy)-alpha-(isopropylaminomethyl)benzyl methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17]C)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1([C:15]([OH:17])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)C1(C)c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C(=O)O)c2ccccc2-c2ccccc21

Procedure:
12.6 g (0.053 mol) of methyl 9-methylfluorene-9-carboxylate and 53 mL of 2 molar, aqueous sodium hydroxide solution are stirred in 120 mL of 1,4-dioxane for 24 hours at ambient temperature. The dioxane is distilled off, made up to a total volume of 300 mL with water, and extracted with diethyl ether. The aqueous phase is acidified with 3 molar aqueous HCl, crystallized, and filtered. Yield: 11.25 g of white crystals (95% of theoretical yield); melting point: 168° C.–169° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C:15]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)=[CH:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([CH:15]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCC=C(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COCCCCC(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1

Procedure:
(S)-tert-butyl 2-(1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxypent-1-enyl)morpholine-4-carboxylate (133 mg, 0.28 mmol) was dissolved in methanol and hydrogenated under 50 psi of hydrogen in the presence of 10% Pd(OH)2/C as catalyst for 48 h. The reaction mixture was filtered and evaporated to give (2S)-tert-butyl 2-(1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxypentyl)morpholine-4-carboxylate in nearly quantitative yield. MS m/z 470 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:7][CH:8]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:9]2[CH:10]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of ethyl 3-[(2-aminoethyl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (90 mg, 0.284 mmol) and triethylamine (59 μL, 0.426 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (26 μL, 0.341 mmol) in dichloromethane (1 mL) dropwise. The reaction mixture was warmed to room temperature and stirred one hour. The reaction mixture was quenched with ice and diluted with dichloromethane. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5%, methanol in dichloromethane) provided ethyl 5-[(4-fluorophenyl)methyl]-3-({2-[(methylsulfonyl)amino]ethyl}amino)-2-pyridinecarboxylate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1 H), 7.87 (t, J=5.6 Hz, 1 H), 7.13 (dd, J=8.3, 5.5 Hz, 2 H), 6.97 (t, J=8.7 Hz, 2 H), 6.89 (s, 1 H), 4.93 (m, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 3.91 (s, 2 H), 3.38 (m, 2 H), 3.33 (m, 2 H), 2.94 (s, 3 H), 1.41 (t, J=7.1 Hz, 3 H); MS m/z 396 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17](=[N:22][OH:23])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(CCCCCOCc2ccccc2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CCCCCOCc2ccccc2)CC1

Procedure:
1-(5-Benzyloxypentyl)-4-piperidone oxime is prepared from 1-(5-benzyloxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])[CH3:4].[OH-].[K+]>C(O)(=O)C>[Br:1][C:11]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([O:5][CH2:3][CH3:4])[CH:12]=1
Reactant: CCOc1ccccc1N
Reactant: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1cc(Br)ccc1N
Reaction time: 1 h
Yield: 59.6 %

Procedure:
Over approximately 1 hour, 3 ml (58.4 mmol) of bromine dissolved in 20 ml of acetic acid is added dropwise to 7.8 ml (60 mmol, 1.03 eq) of 2-ethoxyaniline diluted in 20 ml of acetic acid. When all the bromine has been added, the precipitate formed is filtered on a Buchner funnel and rinsed with acetic acid. The hydrobromide is taken up in H2O, 5 g (90 mmol, 1.5 eq) of KOH pellets is added and extracted with CH2Cl2. The organic phase is dried on MgSO4 and the solvent is evaporated. The residue is purified by column chromatography (eluent CH2Cl2/pentane 9:1) to produce 7.52 g of the expected product as a brown oil (yield: 58%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:11])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[C:17](/[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=1[F:11])\[CH3:18])[CH3:13]
Reactant: CCOc1cccc(O)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(OCC)c1F

Procedure:
To a stirred mixture of 3-ethoxy-2-fluoro-phenol (6.00 g, 0.038 mol) and ethyl-2-butynoate (8.60 g, 0.077 mol) in tetrahydrofuran (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (5.80 g, 0.038 mol) slowly. After addition was complete the mixture was stirred at reflux for 7 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product, (E)-3-(3-ethoxy-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester, was obtained as a brown oil (6.00 g, 58%) and used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][C:32](Cl)=[O:33].Cl>ClCCl>[Br:30][CH2:31][C:32]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1)=[O:33]
Reactant: O=C(Cl)CBr
Reactant: CCCCCCCCCCCCCCCc1ccc(NC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1ccc(N(C)C(=O)CBr)cc1
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
Compound 8 (1.5 g) was dissolved in dichloromethane (10 mL). Potassium carbonate (980 mg) and the solution of bromoacetyl chloride (890 mg) in dichloromethane (5 mL) was added thereto at 0° C., followed by stirring for 1.5 hours. The reaction solution cooled with ice was poured into 1N hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (1.7 g) having the following physical property values.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27].[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C>ClCCl.Cl>[C:28]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1N(C[C@@H]2CCCN2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@H]1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Yield: 83.7 %

Procedure:
A solution of 1′-[(2S)-pyrrolidin-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.23 g, 0.62 mmol), acetic anhydride (0.09 mL, 0.95 mmol) and triethylamine (0.17 mL, 1.2 mmol) in dichloromethane (4 mL) was stirred at ambient temperature for 40 min. The reaction was diluted with 0.2 M hydrochloric acid (50 mL) and extracted with dichloromethane (3×25 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/diethyl ether (4:1) afforded 1′-{[(2S)-1-acetylpyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.21 g, 84%) as an off-white solid: mp 103-108° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.54, 7.53 (d, J=7.8 Hz, 1H), 7.35, 7.34 (dd, J=8.1, 7.7 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.06 (dd, J=7.5 Hz, 1H), 6.49, 6.46 (s, 1H), 6.42, 6.41 (s, 1H), 4.91, 4.90 (d, J=9.0 Hz, 1H), 4.68, 4.67 (d, J=9.0 Hz, 1H), 4.54, 4.53 (t, J=8.7 Hz, 2H), 4.49-4.42 (m, 1H), 3.95-3.80 (m, 2H), 3.61-3.54 (m, 1H), 3.46-3.36 (m, 1H), 3.00, 2.99 (t, J=8.6 Hz, 2H), 2.26-1.76 (m, 4H), 2.11-2.08 (s, 3H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ 178.49, 178.47, 170.2, 161.9, 161.8, 161.5, 161.4, 142.6, 142.4, 132.5, 132.3, 129.36, 129.33, 123.8, 123.7, 123.6, 123.5, 120.4, 120.2, 120.0, 119.9, 119.2, 118.7, 110.01, 109.96, 93.4, 93.2, 80.9, 80.8, 72.5, 57.9, 55.0, 54.8, 47.9, 41.5, 41.2, 29.2, 29.1, 28.0, 27.8, 23.9, 22.92, 22.90; MS (ES+) m/z 405.1 (M+1).