Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH:8]=[C:9](NC(=O)C3C=CN=CC=3)[C:10]([N+]([O-])=O)=[CH:11][C:6]=2[NH:5]C(=O)[O:3]1.C(OC)(=O)C1C(=CC=CC=1)N.C[Mg]I>>[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:2]([CH3:25])([CH3:1])[OH:3]
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(NC(=O)c3ccncc3)cc21
Agent: COC(=O)c1ccccc1N
Agent: C[Mg]I
Product: CC(C)(O)c1ccccc1N

Procedure:
Thus, for example, 4,4-dimethyl-6-isonicotinoylamino-7-nitro-4H-3,1-benzoxazin-2-one is obtained by reacting methyl anthranilate with methyl magnesium iodide in ethereal solution to obtain o-aminophenyl-dimethylcarbinol, which is cyclised by reacting with phosgene in a mixture of toluene and chloroform as solvent in the presence of solid potassium carbonate to obtain 4,4-dimethyl-4H-3,1-benzoxazin-2-one. By subsequent nitration with fuming nitric acid (d=1.52), 4,4-dimethyl-6-nitro-benzoxazin-2-one is obtained which is converted by catalytic hydrogenation in the presence of Raney nickel in dimethyl formamide into 6-amino-4,4-dimethyl-4H-3,1-benzoxazin-2-one. By inserting an acetyl protecting group by means of acetic anhydride, the precondition for further nitration with fuming nitric acid (d=1.52) is created in the 7- position of the molecule. The acetyl protecting group is split off again from the resulting 6-acetamido-4,4-dimethyl-7-nitro-4H-3,1-benzoxazin-2-on e by treating with concentrated hydrochloric acid in isopropanol, and the resulting 6-amino-4,4-dimethyl-7-nitro-4H-3,1-benzoxazin-2-one is converted into 4,4-dimethyl-6-isonicotinoylamido-7-nitro-4H-3,1-benzoxazin-2-one by treating with isonicotic acid chloride in pyridine as solvent.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:19]2[CH2:23][CH2:22][C@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]2)=[C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]2=[C:7]([CH:18]=1)[C:8](=[O:17])[N:9]([OH:16])[C:10]3=[O:15])#[N:2].[ClH:32]>CCO>[ClH:32].[NH2:24][C@H:21]1[CH2:22][CH2:23][N:19]([C:4]2[C:3]([C:1]#[N:2])=[CH:18][C:7]3[C:8](=[O:17])[N:9]([OH:16])[C:10](=[O:15])[C:11]4[C:6]=3[C:5]=2[CH:14]=[CH:13][CH:12]=4)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(C#N)cc3c4c(cccc24)C(=O)N(O)C3=O)C1
Agent: Cl
Solvent: CCO
Product: N#Cc1cc2c3c(cccc3c1N1CC[C@H](N)C1)C(=O)N(O)C2=O

Procedure:
The (S)-[1-(5-cyano-2-hydroxy-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoline-6-yl)-pyrrolidin-3-yl]-carbamic acid, tert-butyl ester from above was dissolved in EtOH and reacted with a stream of HCl gas forming a precipitate which was collected by filtration and dried to give 0.021 g of the title compound, mp>250° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].CC1(C)OB([C:29]2[CH:30]=[N:31][N:32](C(OC(C)(C)C)=O)[CH:33]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:29]3[CH:30]=[N:31][NH:32][CH:33]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OCC2CC2)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OCC2CC2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A 100-mL round-bottom flask was purged with nitrogen and charged with cyclopropylmethyl (3S)-4-acetyl-7-bromo-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1 g, 2.72 mmol), tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (953 mg, 3.24 mmol), sodium carbonate (573 mg, 5.41 mmol), [1,1′bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane complex (265 mg, 0.326 mmol), 1,4-dioxane (9 mL), and water (3 mL). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was poured into water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (4×40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether) to afford cyclopropylmethyl (3S)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (400 mg, 41%) of as a yellow solid. MS (ESI, pos. ion) m/z 355 [M+H]+.
Reaction SMILES: [C:1]([C@@:4]1([OH:23])[C@@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[O:7][C@@H:6]([N:14]2[CH:21]=[C:20]([I:22])[C:18](=O)[NH:17][C:15]2=[O:16])[CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=C(C)C=C(C)C=1S(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1.[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[SH:62]>CN(C1C=CN=CC=1)C>[I:22][C:20]1[C:18]([NH:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[SH:62])=[N:17][C:15](=[O:16])[N:14]([CH:21]=1)[C@@H:6]1[O:7][C@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[C@@:4]([C:1](=[O:3])[CH3:2])([OH:23])[CH2:5]1
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@]1(O)C(C)=O
Reactant: Nc1ccccc1S
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(I)c(Nc3ccccc3S)nc2=O)C[C@@]1(O)C(C)=O
Reaction time: 1 h

Procedure:
To a solution of 3′,5′-diacetyl-5-iodo-2′-deoxyuridine (2.19 g, 5.00 mmol) acetonitrile (ACN, 75 ml), triethylamine (TEA, 6.96 ml, 50.0 mmol) and DMAP (0.15 g, 1.25 mmol) was added mesitylsulfonyl chloride (2.19 g, 10.0 mmol). After stirring at ambient temperature for 18h, DBU (2.14 ml, 10.0 mmol) and 2-aminothiophenol was added (2.14 g, 20.0 mmol) and the solution was stirred for 1 h. The reaction mixture was concentrated and the crude product was partitioned between ethyl acetate (EA, 200 ml) and saturated aqueous sodium bicarbonate (SASB, 200 ml). The organic layer was dried (Na2SO4) and concentrated on the rotary evaporator. The crude product was purified by flash chromatography on silica gel [1-5% 2-propanol/dichloromethane (DCM)] to deliver the product 1H NMR (CDCl3) δ2.10 (s, 3H), 2.15 (m, 1H, 2.17 (s, 3H 2.77 (ddd, 1H, J=2.2, 5.2,15.1 Hz), 4.14 (bs, 1H), 4.35 (m, 3H), 5.20 (m, 1H), 6.13 (t, 1H, J=6.5 Hz), 6.78 (m, 2H), 7.30 (m, 2H), 8.05 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[BH4-].[Na+].O>C(O)C>[I:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([OH:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(I)ccc2Sc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1Cc2cc(I)ccc2Sc2ccccc21
Reaction time: 8 h

Procedure:
12.0 g of 10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-one are suspended in 100 ml of ethanol and the mixture is treated with 6 g of sodium borohydride. The mixture is stirred overnight, then treated with water and extracted with ether. The organic phase is washed with water until neutral, dried over magnesium sulphate and evaporated. The 10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-ol obtained is recrystallised from ether; melting point 131°-133° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][CH:6]1[CH:11](OS(C)(=O)=O)[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7]1>CN(C=O)C.O.C(Cl)Cl>[N:1]([CH:11]1[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:7][CH:6]1[F:5])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C(F)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])C(F)C1
Temperature: 100 °C

Procedure:
Sodium azide (68.2 g, 1.050 mol) was added to a solution of tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate, 2.5 (78 g, 0.262 mol) in DMF (620 mL). The reaction mixture was heated at 100° C. for overnight. The mixture was cooled and diluted with 500 mL) water and methylene chloride (500 mL). After separation, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to provide the desired product tert-butyl 4-azido-3-fluoropiperidine-1-carboxylate, 2.6 (62 g, 96% yield), which was used for the next reaction without any purification.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:18])[NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7].[CH3:19][C:20]1[N:21]=[C:22]([CH2:25]Br)[S:23][CH:24]=1>C1COCC1>[CH3:18][N:4]([CH3:3])[N:5]([CH2:25][C:22]1[S:23][CH:24]=[C:20]([CH3:19])[N:21]=1)[C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7]
Reactant: Cc1csc(CBr)n1
Reactant: COC(=O)c1cccc(C(=O)NN(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C(=O)N(Cc2nc(C)cs2)N(C)C)c1
Temperature: 3.5 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To the sodium hydride (16 mg, 0.68 mmol) in THF (3 ml) at 0° C., methyl 3-(2,2-dimethylhydrazinecarbonyl)benzoate (100 mg, 0.45 nmol) was added. After 10 min, 4-methyl-2-bromo methyl thiazole (103 mg, 0.54 mmol) was added and reaction mixture was stirred at 3-4° C. overnight. Reaction mixture was quenched with MeOH and diluted with ethylacetate. Organic layer was washed with water, brine and dried. Crude residue was purified by column chromatography to yield 70% of methyl 3-(2,2-dimethyl-1-((4-methylthiazol-2-yl)methyl)hydrazinecarbonyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].NC1C=[C:16]([O:18]C)[CH:15]=CC=1C(=O)C>>[NH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=1[C:16](=[O:18])[CH3:15]
Reactant: COc1ccc(N)cc1Cl
Reactant: COc1ccc(C(C)=O)c(N)c1
Product: COc1cc(C(C)=O)c(N)cc1Cl
Yield: 50 %

Procedure:
40 g. Compound 40 g was synthesized from 3-chlor-4-methoxy-aniline 39 g as a brown solid in 50% yield, according to the procedure as described for compound 40a.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[CH3:30][S:31]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:38][C:37]1[CH:36]=[CH:35][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:41][CH:40]=1)[CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCN3CCOCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCN3CCOCC3)Cc3ccc(S(C)(=O)=O)cc3)c2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The product from example 1 step (viii) (0.1 g), 4-methylsulphonylbenzyl bromide (0.0673 g) and potassium carbonate (0.0373 g) were combined in DMF (1.5 mL) and stirred at RT for 15 hrs. The reaction mixture was diluted with methanol filtered and purified by RPHPLC to give title compound, 0.039 g
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([NH2:11])[S:10][C:4]=2[CH2:3]1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=1>>[Br:19][C:17]1[CH:18]=[C:13]([NH:11][C:9]2[S:10][C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][C:5]=3[N:8]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN1CCc2nc(N)sc2C1
Product: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)sc2C1
Yield: 52.6 %

Procedure:
Following Example 110c, 3 g of 141a and 4 g of 3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 141b as a yellow solid (2.8 g, 52%). LCMS: [M+H]+ 357
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[Br:39]C1C=CC=CC=1CC(=O)C(OCC)=O.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Br:39])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccccc1Br
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1ccccc1Br)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 24 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(2-bromophenyl)-2-oxopropanoate B8 (100 mg, 0.369 mmol), sodium hydride (9.74 mg, 0.406 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (152 mg, 0.369 mmol). The resulting compound was isolated in the form of white solid in 24% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc(O)cc2)C1

Procedure:
A solution of 82 mg (0.2 mmol) of (RS)-[1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester in 2 ml of THF is hydrogenated in presence of 7 mg palladium on carbon (10%) at ambient pressure and RT during 18 h. For the working-up, the reaction mixture is filtered over Dicalit, then evaporated under reduced pressure. The crude (RS)-[1-(4-hydroxy-phenyl)-5-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester is obtained as a colorless oil, which is directly engaged in the next step without further purification and characterisation.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[O:18])[NH:6][C:7]1[S:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:17])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:17][C:9]1[CH:8]=[C:7]([N:6]2[CH2:2][CH2:3][NH:4][C:5]2=[O:18])[S:11][C:10]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1sc(NC(=O)NCCCl)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
A mixture of ethyl 5-(3-(2-chloroethyl)ureido)-3-methylthiophene-2-carboxylate (6.11 g, 21.02 mmol) and potassium carbonate (2.91 g, 21.0 mmol) in anhydrous acetonitrile (60 mL) was stirred under nitrogen atmosphere at 70° C. for 5 h, and then was allowed to cool to ambient temperature and was partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was extracted with 10% methanol in dichloromethane (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with 20% ethyl acetate in hexanes to afford the title compound as a cream solid in 88% yield (4.70 g): 1H NMR (300 MHz, CDCl3) δ 6.16 (s, 1H), 5.15 (br s, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.97-3.89 (m, 2H), 3.71-3.64 (m, 2H), 2.50 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 255.2 (M+1).
Reaction SMILES: C[C:2]1[C:9](F)=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][NH2:15]>CN(C=O)C>[CH3:14][NH:15][C:9]1[CH:2]=[C:3]([CH:6]=[CH:7][C:8]=1[N+:11]([O-:13])=[O:12])[C:4]#[N:5]
Reactant: Cc1c(C#N)ccc([N+](=O)[O-])c1F
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1cc(C#N)ccc1[N+](=O)[O-]

Procedure:
3-Methylamino-4-nitro-benzonitrile (1.58 mg) was prepared by following General Procedure A starting from methyl 3-fluoro-4-nitrobenzonitrile (1.66 g) and methylamine (2 M in THF, 10.0 mL) in DMF. The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:14])[CH:2]([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:44][CH2:45][C:46]1[N:51]=[CH:50][C:49]([C:52](=[N:54]O)[NH2:53])=[CH:48][CH:47]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:54]=[C:52]([C:49]3[CH:48]=[CH:47][C:46]([CH2:45][OH:44])=[N:51][CH:50]=3)[N:53]=2)=[CH:7][C:6]=1[CH3:14])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)O)ccc1CC(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(-c3ccc(CO)nc3)no2)ccc1CC(C)C

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 12 (12a) using 4-isobutyl-3-methylbenzoic acid (0.12 g, 0.61 mmol) that was obtained in Example 27 (27d), 1-hydroxybenzotriazole (86 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g, 0.64 mmol), 6-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxypyridine-3-carboximidamide (0.16 g, 0.58 mmol) that was obtained in Example 23 (23c), and tetrabutylammonium fluoride (a 1.0 M solution in tetrahydrofuran, 1.2 ml, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:3 to 1:1) as the eluent to afford the title compound (0.19 g) in a yield of 99% as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[OH:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][OH:33]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:30]([CH2:31][CH2:32][OH:33])[CH2:29][CH2:28][OH:27])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: OCCNCCO
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN(CCO)CCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with bis-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at 50° C. for 3 hours to yield trans-(4-{4-[bis-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 471 (MH+, 1Cl).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](Br)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCCCCCCCCBr
Agent: Cl
Product: CCCCCCCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.96 g) and nonyl bromide (0.57 mL) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.20 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.81 g) was obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][CH2:15]O)(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[Br:19]CCCS(C)(=O)=O>>[Br:19][CH2:15][CH2:14][CH2:13][S:10]([CH2:9][CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:18])[CH3:17])(=[O:12])=[O:11]
Reactant: CC(C)(C)[Si](C)(C)OCCCS(=O)(=O)CCCO
Reactant: CS(=O)(=O)CCCBr
Product: CC(C)(C)[Si](C)(C)OCCCS(=O)(=O)CCCBr

Procedure:
Intermediate 24 (485 mg) was prepared from Intermediate 20 (1.18 g, 4 mmol)) according to an analogous procedure to that described for Intermediate 14.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:22])[CH2:20][CH3:21])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nc(-c2ccccc2)c(-c2nc(C)no2)s1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and propionyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[OH:12].CCOC(C)=O>C(OC)(C)(C)C.P([O-])([O-])([O-])=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18]1)[OH:12]
Reactant: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Agent: O=P([O-])([O-])[O-]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: COc1cccc([C@H](O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Silica gel (EM Sciences, 230-400 mesh, 215 g) was added to a solution of (R)-enriched α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, butyrate ester (5a) (72 g, 0.16 mol, 82% ee) in t-BuOMe (320 mL). The resulting slurry was concentrated (35° C./20 torr) to give a light yellow powder. A mixture of the powder, partially purified Candida cylindracea lipase (17.1 g, equivalent to 522 g of crude enzyme from Sigma) in phosphate buffer (0.1 M, pH 7, 5.2 L) was stirred at 45° C. for 4 days. EtOAc (4 L) was added and the mixture was stirred at room temperature for 1 hour. Solid material was removed by filtration, and the two phases in the filtrate were separated. Both the solid and aqueous layer were extracted with EtOAc (2 L). The combined organic solutions were concentrated (35° C./20 torr) to a residue which was purified by flash chromatography (SiO2, 10 cm×15 cm, eluted with 1:1 EtOAc; hexane (8 L) and 1:19 EtOAc: MeOH (8 L)). The desired fractions (TLC, Rf 0.16, acetone) were combined and concentrated (35° C./20 torr) to a residue which was dissolved in methylene chloride (800 mL). The solution was washed with 0.5N NaOH (2×600 mL), brine (600 mL) and dried (MgSO4). The mixture was filtered and the filtrate was concentrated (30° C./20 torr) to give a solid which was recrystallized from cyclohexane (2 L) to give (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a white solid (31 g, 52% yield, 99.9% ee); m.p. 113-114° C., [α]D20+14.0° (c 0.49, CHCl3).