Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([NH:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=[N:4][NH:3]1.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.FC(F)(F)C1C=CC=CC=1OC1CCNCC1>>[F:29][C:14]([F:13])([F:28])[C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:10](=[O:12])[CH2:9][NH:8][C:7]2[C:2](=[O:1])[NH:3][N:4]=[CH:5][CH:6]=2)[CH2:23][CH2:24]1
Reactant: FC(F)(F)c1cccc(OC2CCNCC2)c1
Reactant: O=C(O)CNc1ccn[nH]c1=O
Agent: Cl
Agent: FC(F)(F)c1ccccc1OC1CCNCC1
Product: O=C(CNc1ccn[nH]c1=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Yield: 36 %

Procedure:
Compound 44 is prepared from intermediate 7a and from 4-(3-trifluoromethyl-phenoxy)-piperidine (obtained following the method described for 1a) applying synthesis method 2 (yield: 36%).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[CH2:4]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:28](OC)=[O:29])[CH:25]=3)[CH2:20]2)=[O:18])=[CH:12][CH:11]=1)=[O:9])[CH2:5][CH3:6].[BH4-].[Na+]>C(O)C.O1CCCC1>[OH:29][CH2:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19]([C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[NH:7][CH2:4][CH2:5][CH3:6])=[CH:11][CH:12]=1)=[O:18])[CH2:27]2
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(=O)OC)cc3C2)cc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(CO)cc3C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of calcium chloride (0.031 g, 0.277 mmol) in ethanol (0.8 mL) was added to a suspension of methyl 2-(4-(propylcarbamoyl)phenylcarbamoyl)isoindoline-5-carboxylate (0.04 g, 0.105 mmol) in tetrahydrofuran (1 mL). Sodium borohydride (0.02 g, 0.524 mmol) was then added in one portion and the suspension stirred at room temperature. After 18 hours, the mixture was concentrated to remove tetrahydrofuran then saturated aqueous sodium bicarbonate and water was added. The suspension was filtered and the solid was flash chromatographed to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.55 (s, 1H), 8.25 (t, J=5.6 Hz, 1H), 7.74-7.78 (m, 2H), 7.64-7.67 (m, 2H), 7.31 (d, J=4.0 Hz, 1H), 7.30 (d, J=2.3 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 5.19 (t, J=5.6 Hz, 1H), 4.71-4.78 (m, 4H), 4.52 (d, J=5.4 Hz, 2H), 3.15-3.25 (m, 2H), 1.46-1.59 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 354 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C(=O)C>[C:13]1([S:19]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[CH2:10][CH2:9]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cnc2c(c1)CCN2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1ccccc1)N1CCc2cc(Br)cnc21
Temperature: 25 °C
Yield: 8.3 %

Procedure:
To a 0° C. stirred solution of 5-bromo-azaindoline 5 (150 mg, 0.75 mmol) in N,N-dimethylacetamide (7 mL) was added in one portion 60% dispersion of NaH in mineral oil (38 mg, 0.94 mmol). After 0.5 h benzenesulfonyl chloride (0.12 mL, 0.94 mmol) in N,N-dimethylacetamide (1 mL) was added dropwise, and the mixture allowed to slowly warm to r.t. After 2 days the mixture was partitioned between AcOEt-brine. The aqueous layer was extracted with AcOEt (2×). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residue was purified by preparative TLC (PTLC) with CH2Cl2 as eluent to afford the azaindoline 6 (21 mg, 8%) as a solid. 1H NMR (400 MHz; CDCl3) δ 3.04 (t, J=8.6 Hz, 2H), 4.08 (t, J=8.6 Hz, 2H), 7.45-7.51 (m, 3H), 7.56-7.60 (m, 1H), 8.08 (m, 2H), 8.18 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:39][O:40][C:41](=[O:52])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1)[NH2:43]>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:14]([NH:43][C@@H:42]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=1)[C:41]([O:40][CH3:39])=[O:52])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-leucine (7 g) in acetonitrile (100 ml), under a nitrogen atmosphere, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.9 g) and 1-hydroxybenzotriazole (4.2 g). After stirring for 30 mins at 20° C. L-tyrosine methyl ester (5.5 g) was added and stirring was continued for 18 h. The mixture was concentrated in vacuo to ca. 10 ml and the residue was partitioned between 1M hydrochloric acid (200 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous phase was further extracted with ethyl acetate (100 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (100 ml), water (2×100 ml) and brine (50 ml), dried over sodium sulphate and evaporated in vacuo. The residue was co-evaporated with chloroform to give the title compound as a white foam (11.3 g, 98%). LCMS: Rt 3.11 min; m/z 409 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]=[CH:7]2
Reactant: CCCCCCCCBr
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred suspension of sodium hydride (NaH, 60% dispersion in mineral oil; 48 mg, 2 mmol) in anhydrous dimethylformamide (5 ml) in an ice bath was added dropwise a solution of 5-bromo 1H indole (1.5 mmol) in anhydrous DMF (10 mL) over a period of 10 min at 0 C. After stirring for 10 min, 1-Bromooctane (1.8 mmol) was added drop wise over 5 min and reaction mixture was allowed to warm to RT and left with stirring for overnight. The reaction was quenched by pouring over ice and extracted twice with ethyl acetate (25 ml). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash silica gel column chromatography with ethyl acetate and Hexane to get 5-bromo 1-octyl 1H-indole as an oil (Yield: 80 to 90%). Product was confirmed by NMR and LC-MS
Reaction SMILES: C(OC([N:6]1[CH:15]=[C:14]([CH:16]=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[CH:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=O)C.[OH-].[K+].C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>CO>[CH2:19]([O:18][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:26][CH3:27])[C:7]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[N:6][CH:15]=[C:14]2[CH:16]=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)N1C=C(C=O)c2cc(OCc3ccccc3)c(OC)cc2C1Cc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: COc1cccc(Cc2ncc(C=O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.7 %

Procedure:
To a solution of 6-benzyloxy-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (85 mg, 0.17 mmol) in methanol (3 mL) was added powdered potassium hydroxide (97.7 mg, 1.75 mmol) at room temperature. The mixture was stirred at room temperature for 14 hrs. The solvent was evaporated and the residue was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane, 75% ethyl acetate/hexane, ethyl acetate) afforded 6-benzyloxy-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde as a colorless oil (30 mg, 42% yield).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[NH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].O>CN(C=O)C>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Triethylamine (58.2 g, 575 mmol) and 4-chloro-3-nitroquinoline (80.0 g, 384 mmol) were added to a solution of tert-butyl N-(2-aminoethyl)carbamate (67.6 g, 422 mmol) in DMF (300 mL), and the reaction was stirred overnight at ambient temperature. Water (600 mL) was added, and the resulting mixture was stirred for one hour. A precipitate formed and was isolated by filtration, washed with water (3×150 mL), and dried for two days in a vacuum oven at 45° C. to provide 125.36 g of tert-butyl 2-[(3-nitroquinolin-4-yl)amino]ethylcarbamate as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5](C(OCC)=O)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=1)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])C.C(OC(=O)C(C(OCC)=O)C(C1C=CC(OC)=C(OC)C=1)C(OCC)OCC)C>>[CH3:26][C:24]([CH3:25])([CH3:27])[CH2:23][O:22][C:16]1[CH:15]=[C:14]([CH:6]([CH:7]([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:5][C:4]([OH:33])=[O:3])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OCC(C)(C)C)c1)C(OCC)OCC
Agent: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OC)c1)C(OCC)OCC
Product: CCOC(OCC)C(CC(=O)O)c1ccc(OC)c(OCC(C)(C)C)c1
Yield: 68.7 %

Procedure:
Using the same procedure as in Example 1(3), 3-[3-(2,2-dimethylpropoxy)-4-methoxyphenyl]-4,4-diethoxy-2-ethoxycarbonylbutyric acid ethyl ester, instead of 3-(3,4-dimethoxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutyric acid ethyl ester, was used to obtain a light yellow solid of the above-referenced compound via 3-[3-(2,2-dimethylpropoxy)-4-methoxyphenyl]-4,4-diethoxybutyric acid (yield 68.7%).
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13]Br.[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:17].NC1C=CC=CC=1>>[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:13][C:5]3[C:4](=[CH:9][CH:8]=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=3)[C:3]2=[O:15])=[CH:27][CH:28]=1)[CH3:17]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Reactant: CCOC(=O)CCCc1ccc(N)cc1
Solvent: Nc1ccccc1
Product: CCOC(=O)CCCc1ccc(N2Cc3cc([N+](=O)[O-])ccc3C2=O)cc1

Procedure:
By using 2-bromomethyl-4-nitrobenzoic acid methyl ester and 4-(4-aminophenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]([OH:26])[CH3:25])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:39].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:39][C:17]([C:19]4[S:20][C:21]([CH:24]([OH:26])[CH3:25])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.36 g), ammonium acetate (1.33 g) and acetic acid (15 mL) was stirred at 100° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, 2M aqueous sodium hydroxide solution (4 mL), tetrahydrofuran (8 mL) and methanol (8 mL) were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.43 g, yield 33%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 487 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH:15]=O.Cl.[O:18]([NH2:20])[CH3:19].N1C=CC=CC=1>CCO.CCOC(C)=O>[CH3:19][O:18][N:20]=[CH:15][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: CON
Reactant: O=Cc1cc(-c2ccccc2)ccc1CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CON=Cc1cc(-c2ccccc2)ccc1CO
Reaction time: 24 h

Procedure:
A solution of the aldehyde from step A (0.13 g, 0.61 mmol), methoxylamine hydrochloride (61 mg, 0.735 mmol) and pyridine (2 mL) in EtOH (10 mL) was heated at reflux for 16 h. Further portions of methoxylamine hydrochloride (61 mg, 0.735 mmol) and pyridine (2 mL) were added and heating was continued for 24 h. The solution was cooled, diluted with EtOAc, extracted with water (2×) then brine, dried and concentrated to give the title compound as an oil. This was used as such in the next step.
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[N:4]=[C:5]2[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][N:6]2[CH:14]=1.[H][H]>CO.[Pd]>[BrH:1].[NH2:11][C:10]1[C:5]2[N:6]([CH:14]=[C:3]([CH3:2])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cn2cccc([N+](=O)[O-])c2n1
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: CO
Product: Cc1cn2cccc(N)c2n1

Procedure:
A solution of 16.5 g 2-methyl-8-nitro-imidazo[1,2-a]pyridine-hydrobromide in 800 ml methanol is saturated with hydrogen at room temperature at low pressure for 8 hours after addition of a catalytic amount of commercial Pd/C-catalyst. The catalyst is then filtered off and the filtrate evaporated until dry. After recrystallization from acetronitrile 11.9 g of the title compound of m.p. 237°-238° C. is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:5][CH:6]([NH:10][C:11](=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=O)[C:7](O)=[O:8].CN1CCOCC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH2:25]([O:24][C:22]([N:4]1[CH2:5][CH:6]([N:10]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[C:7](=[O:8])[NH:1][CH2:2][CH2:3]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)N(CCN)CC(NC(=O)c1ccccc1C(=O)O)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)N1CCNC(=O)C(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
To a solution of 150.00 g (208.00 mmol) of N-{2-[(2-amino-ethyl)-ethoxycarbonyl-amino]-1-carboxy-ethyl}-phthalamic acid dissolved in 3 L of anhydrous dimethylformamide was added 75.50 mL (686.40 mmol) of N-methylmorpholine. The resulting mixture was stirred at room temperature for 10 min and 143.00 g (520.00 mmol) of diphenylphosphoryl azide was added. The mixture was stirred at room temperature for 36 h and evaporated to dryness. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous solution of sodium chloride, saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 96/4/0.6 led to afford 23.00 g (33%) of the desired compound.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[C:16]([Br:20])=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[C:16]([Br:20])=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2c(Br)cccc2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Brc1cccc2c1CN(Cc1ccccc1)CCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 9.5 %

Procedure:
To a solution of 4-benzyl-6-bromo-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (4.94 g, 14.9 mmol) in tetrahydrofuran (60 ml) was added 1M borane-tetrahydrofuran solution (61.5 ml, 61.5 mmol), and the mixture was stirred at 80° C. for 2 hr. Under ice-cooling, methanol (140 ml) and sodium hydroxide (13.2 g, 331 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure. The residue was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the desired product (450 mg, 9.5%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([NH:16][CH:17]=O)[CH2:3]1.CO.Cl.O>O1CCCC1>[CH3:17][NH:16][C:4]1[CH2:3][C:2](=[O:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=1
Reactant: O=CNC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Temperature: 10 °C

Procedure:
4,5-Dihydro-5-oxo-1-(2,4,6-trichlorophenyl)-1H-pyrazol-3-yl formamide (39.6 g, 129.2 mmole) was dissolved in dry tetrahydrofuran (500 ml) with warming and then cooled to 10° C. with stirring. Borane dimethylsulfide complex (10M, 80 ml, 800 mmole) was added dropwise by syringe through a septum cap. The reaction mixture was heated on a steam bath for ca 12 hrs (overnight), cooled in an ice bath, methanol (150 ml) added dropwise and the mixture stirred for 1 hr until the effervescence had subsided. Concentrated hydrochloric acid (30 ml) was then added to give a clear solution. This was poured into water (51) and extracted with ethyl acetate (×2) and the extract washed and dried (MgSO4). Evaporation of the solvent left a white glass which was dried under vacuum for 2 hrs. The yield of product was 33.4 g, 88%.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C@@H:6]([CH2:11][N+:12]([O-])=O)[CH2:7][CH:8]([CH3:10])[CH3:9])C.[OH-].[K+].[H][H]>O.[Ni]>[CH3:10][CH:8]([CH2:7][C@H:6]([CH2:11][NH2:12])[CH2:5][C:4]([OH:15])=[O:3])[CH3:9]
Reactant: CCOC(=O)C[C@H](CC(C)C)C[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Yield: 80 %

Procedure:
150 g of (S)-5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl; assay: 97.2%) were suspended in 300 mL of H2O. KOH (90.1.g, assay 86.1%, 2.05 eq.) was added. The initially turbid reaction mixture became clear which indicated that the reaction was nearly completed. After complete conversion (as determined by HPLC) the reaction mixture was transferred to a hydrogenation reactor. 90.0 g of an aqueous slurry of Raney Nickel were added. At a hydrogen pressure of 12 bar and a temperature of 45° C. the mixture was stirred until complete conversion was detected by HPLC giving 88.0 g of pregabalin in an aqueous solution.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=[O:14].OO.CSC>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:14]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: CSC
Product: O=[N+]([O-])c1ccc[n+]([O-])c1Cl
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-3-nitropyridine (0.69 g, 4.35 mmol) was chilled to 0° C. and trifluoroacetic acid (9 mL) was slowly added followed by 30% hydrogen peroxide (1 mL). The solution was warmed to 70° C. for 1.5 hours, cooled to 0° C. and excess peroxide was decomposed by dropwise addition of dimethylsulfide (1 mL) and stirring 0.5 hours. The reaction was concentrated at reduced pressure onto silica gel and flash chromatographed (1×3 inches). Elution proceeded as follows: 50% ethyl acetate/hexane (175 mL), nil; 75% ethyl acetate/hexane (175 mL), 0.589 g (77%) of 2-chloro-3-nitropyridine-N-oxide as an orange solid suitable for use without further purification. A sample recrystallized from ethyl acetate/hexane had mp 98°-100° C. Analysis calculated for C5H3ClN2O3 : C, 34.41; H, 1.73; N, 16.05. Found: C, 34.75; H, 1.67; N, 15.80.
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH3:12])(=[O:11])[O:6][CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH3:12])(=[O:11])[O:6][CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)COP(C)(=O)CCC#N
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)CCCN

Procedure:
A solution of 20.0 g of isobutyl P-(2-cyanoethyl)-P-methyl-phosphinate in 200 ml of ethanol is added to 230.0 g of an 8% solution of ammonia in ethanol. To this are added 15 ml of Raney nickel slurry and the resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate is concentrated under reduced pressure. The crude product is distilled under reduced pressure to give isobutyl P-(3-aminopropyl)-P-methyl-phosphinate, b.p. 130°/0.01 mbar, 31P-NMR spectrum: δ=+57.6 ppm (CDCl3).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(O[C:28]1(O[Si](C)(C)C)[CH2:30][CH2:29]1)C.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH:28]1[CH2:30][CH2:29]1
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)C1CC1
Yield: 15.4 %

Procedure:
A mixture of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine (115 mg, 0.35 mmol), (1-Ethoxy-cyclopropoxy)-trimethylsilane (360 mg, 2.0 mmol), AcOH (0.2 ml, 3.5 mmol), NaCNBH3 (110 mg, 1.75 mmol) and 4 Å molecular sieves (100 mg) in MeOH (5 ml) was heated to reflux for 18 hours. The mixture was cooled, concentrated in vacuo and partitioned between 2M NaOH (10 ml) and DCM (10 ml). The organic phase was separated and the aqueous phase extracted with DCM (2×10 ml). The combined organic phases were concentrated in vacuo and purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:1) to provide the title compound as a clear colourless oil (20 mg, 0.054 mmol, 15%). 1H NMR (400 MHz, CDCl3) δ 0.15 (m, 2H), 0.29 (m, 2H), 1.68 (m, 1H), 1.70-1.90 (m, 6H), 1.85 (s, 3H), 2.00-2.10 (m, 4H), 2.60 (m, 4H), 2.65 (s, 2H), 2.68 (m, 2H), 3.50 (t, 2H), 3.76 (m, 2H), 4.01 (t, 2H), 6.85 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 373.2844 [MH]+.