Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[C:15]([C:17](=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (25.25 g, 127 mmol), ethyl cyanoacetate (13.8 ml, 130 mmol), ammonium acetate (2.73 g, 35.4 mmol), glacial acetic acid (6.3 ml) and benzene (250 ml) was heated for 4 hours at reflux under Dean Stark conditions. The reaction mixture was cooled to room temperature and washed successively with water, sodium bicarbonate solution and brine. Drying, filtration and evaporation of the organic phase provided tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate as an oil that crystallized on standing (37 g, 99%). 1H NMR (400 MHz, CDCl3): δ 4.28 (q, 2H, J=7 Hz), 3.60 (br t, 2H, J=6 Hz), 3.54 (br t, 2H, J=6 Hz), 3.12 (t, 2H, J=6 Hz), 2.76 (t, 2H, J=6 Hz), 1.47 (s, 9H), and 1.35 (t, 3H, J=7 Hz). ES-LCMS m/z 293 (M−1).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[C:21]([F:24])[C:22]=1O.C(N(CC)CC)C>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[C:21]([F:24])[C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: COC(=O)Cc1cc(F)c(O)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
Trifluoromethanesulphonic anhydride (0.854 mL, 5.21 mmol) was added dropwise to a stirred solution of methyl 2-(3,5-difluoro-4-hydroxyphenyl)acetate (Intermediate 24-3; 0.702 g, 3.47 mmol) in DCM (15.06 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. Triethylamine (1.452 mL, 10.42 mmol) was added dropwise over 5 minutes (keeping internal temperature between 5-10° C.) and the resulting solution stirred at room temperature for 4 hours under nitrogen. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (100 mL), saturated NaHCO3 (100 mL), and water (100 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (0.930 g, 80%) as a straw yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24](Cl)=[O:25].OS([O-])(=O)=O.[K+]>CN(C)C=O.C(OCC)(=O)C>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:25]
Reactant: COC(=O)CCN
Reactant: O=C(Cl)Cc1cccs1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice-bath-cooled solution of 0.45 g (3.2 mmol) of methyl β-alaninate hydrochloride and 1.14 mL of N,N-diisopropylethylamine (DlEA) in 10 mL of dimethylformamide (DMF) was added dropwise a 2 mL DMF solution of 0.51 g (3.2 mmol) of 2-thiopheneacetyl chloride. After 16 hours of stirring at room temperature, the reaction mixture was added to 50 mL of ethyl acetate (EtOAc) and 50 mL of 1 M KHSO4, and the resulting layers were separated. The organic layer was washed with 2×50 mL of 1 M KHSO4, 2×50 mL of a saturated KHCO3 solution, and 2×50 mL of H2O. The organic layer was then dried over Na2SO4 (anhydrous), filtered, and then concentrated under reduced pressure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH2:16])=[S:15])[CH2:3][S:2]1.[CH3:17]I>CC(C)=O>[CH3:17][S:15][C:14](=[NH:16])[NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][O:1][S:2][CH2:3]1
Reactant: CI
Reactant: NC(=S)Nc1ccccc1N1CCOSC1
Solvent: CC(C)=O
Product: CSC(=N)Nc1ccccc1N1CCOSC1

Procedure:
A mixture of 1-(2-thiamorpholinophenyl)thiourea (12.6 g), methyl iodide (7.1 g) and acetone (60 ml) was heated at 90°-95° C. for 21/2 hours. The solvent was removed by evaporation and the residue dried under vacuum (5 mm/Hg) to give 2-methyl-1-(2-thiamorpholinophenyl)-2-thiopseudourea hydroidide (m.p. 176°-177° C.).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][N:23]2[NH:27][CH:26]=[CH:25][S:24]2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([C:20](=[O:21])[NH:22][N:23]4[NH:27][CH:26]=[CH:25][S:24]4)[CH:28]=[CH:29][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[5-(thiadiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.79 min, MH+ 394. NMR: δH [2H6]-DMSO 13.14,(1H, b), 9.24, (1H, s), 9.14,(1H, s), 8.86,(1H, t), 8.35,(1H, d), 8.25,(1H, s), 8.10,(1H, d), 7.82,(1H, d), 7.54,(1H, d), 3.21,(2H, t), 2.46,(3H, s), 1.07,(1H, m), 0.47,(2H, m), 0.27, (2H, m).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH:14]1[C:19]2([CH3:23])[CH:20]([CH3:22])[CH2:21][CH:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18]2)[N:15]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>C1COCC1>[CH3:13][CH:14]1[C:19]2([CH3:23])[CH:20]([CH3:22])[CH2:21][CH:16]([C:17]([C:37]([O:39][CH2:40][CH3:41])=[O:38])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18]2)[N:15]1[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(Cc1ccccc1)C2C
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(Cc1ccccc1)C2C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of diisopropylamine (13.2 mL, 94 mmol) in THF (175 mL) at -60° C. under nitrogen was added n-BuLi (36.2 mL, mmol, 2.6M hexane). The mixture was stirred for 30 minutes, cooled to -78° C. and ethyl 3,4,8-trimethyl-2-(phenylmethyl)-2azabicyclo[2.2.2]octane-6-carboxylate (26.8 g, 85 mmol) in THF (225 mL) was added. The mixture was stirred for 3 hours, then ethyl chloroformate (8.96 mL, 94 mmol) in THF (20 mL) was added dropwise. The mixture was stirred for 24 hours, quenched with saturated NH4Cl, and poured into water (1000 mL). The solution was extracted with ether (3X), and the organic layers were combined and dried over MgSO4. The ether layer was treated with charcoal and the solvent was removed in vacuo to afford 32.1 g (97%) of diethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate as a golden oil.
Reaction SMILES: [F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([NH2:16])=[CH:11][CH:12]=3)[C@@:7]3([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]3)[C:6]=2[CH:5]=[C:4]([O:23][CH3:24])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[NH2:22][C:18]1[O:19][CH2:20][CH2:21][C@@:7]2([N:17]=1)[C:6]1[CH:5]=[C:4]([O:23][CH3:24])[CH:3]=[C:2]([F:1])[C:15]=1[O:14][C:13]1[C:8]2=[CH:9][C:10]([NH:16][C:32](=[O:33])[C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N)ccc1O2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1O2
Reaction time: 0.03 h
Yield: 46.8 %

Procedure:
To a suspension of (S)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (102 mg, 0.310 mmol) and 5-chloropicolinic acid (54 mg, 0.341 mmol) in ethyl acetate (2 mL) was added triethylamine (0.13 mL, 0.929 mmol) and the mixture was stirred for 2 min, followed by addition of 1-propanephosphonic acid cyclic anhydride (T3P) (50 wt. % solution in ethyl acetate) (0.37 mL, 0.619 mmol). After 2 hr at RT, the mixture was quenched with sat NaHCO3 and diluted with 3 ml EtOAc. The organic layer was separated, concentrated in vacuo, and the residue purified by FC on 12 g RediSep Gold column using 10-80% DCM/MeOH/NH4OH (90:10:1) in DCM to afford (S)—N-(2-amino-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-7′-yl)-5-chloropicolinamide (68 mg, 0.145 mmol, 47% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(CC)C.[CH2:14]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[CH2:15][CH3:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1.C1CCCCC1.CCCCCC>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[C:20]1([OH:23])[CH2:21][CH2:22][CH:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]1
Reactant: Fc1ccccc1F
Reactant: CCCC1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCC1CCC(O)(c2cccc(F)c2F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
1,2-Difluorobenzene (29) (58.8 g) and THF (500 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −73° C. s-Butyllithium (1.03 M, in a n-hexane and cyclohexane solution; 500.0 ml) was added dropwise thereto in the temperature range of −74° C. to −65° C., and the mixture was stirred for another 2 hours. Subsequently, 4-propylcyclohexanone (30) (72.2 g) in a THF (200 ml) solution was added dropwise thereto in the temperature range of −76° C. to −65° C., and the stirring was continued for another 20 hours while the mixture was allowed to return to 25° C. Then, the reaction mixture was poured into a vessel containing ammonium chloride (55.1 g) and ice-water (1,000 ml), and mixed. Toluene (1500 ml) was added thereto and the mixture was allowed to separate into organic and aqueous phases, and then an extractive operation was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, giving 119.6 g of 1-(2,3-difluorophenyl)-4-propylcyclohexanol (31). The compound (31) was yellow oil.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:9]([NH:11][C@H:12]([C:17]([CH2:19][C:20]([NH2:28])([CH3:27])[C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[O:18])[CH2:13][C:14](=[O:16])[OH:15])=[O:10])[CH2:5][CH2:6][S:7][CH3:8].[C:29]([O:33][C:34]([NH:36][C@H:37]([C:48](N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC)=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:36][C@H:37]([C:48]([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:17]([CH2:19][C:20]([NH2:28])([CH3:27])[C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[O:18])[CH2:13][C:14](=[O:15])[OH:16])=[O:10])[CH2:5][CH2:6][S:7][CH3:8])=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Reactant: CCCNC(=O)C(C)(N)CC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: O
Product: CCCNC(=O)C(C)(N)CC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
When an equivalent quantity of L-methionyl-L-aspartyl-N1 -propyl-2-amino-2-methylpropionamide hydrochloride hydrate is substituted for the L-methionyl-L-aspartyl-D-alanine amide hydrochloride of Example 6, and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-N1 -propyl-2-amino-2-methylpropionamide hydrated with 2/3 mole of water per mole. Actual elemental analysis shows C: 55.82%; H: 7.21%; N: 12.37% and S: 4.72%. Theoretical elemental analysis is C: 55.79%; H: 7.22%; N: 12.20% and S: 4.66%. This compound is represented by the following formula. ##STR17##
Reaction SMILES: CC([NH:4][C@H:5]1[C@H:10]([O:11][C@@H:12]([C@H:17]([OH:25])[C@@H:18]([NH:21][C:22]([CH3:24])=[O:23])[CH:19]=[O:20])[C@H:13]([OH:16])[CH2:14][OH:15])[O:9][C@H:8]([CH2:26][OH:27])[C@@H:7]([OH:28])[C@@H:6]1[OH:29])=O.C(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O)(=O)C>>[C:22]([NH:21][C@H:18]([C@H:17]([C@@H:12]([C@@H:13]([CH2:14][OH:15])[OH:16])[O:11][C@@H:10]1[O:9][C@H:8]([CH2:26][OH:27])[C@@H:7]([OH:28])[C@H:6]([OH:29])[C@H:5]1[NH2:4])[OH:25])[CH:19]=[O:20])(=[O:23])[CH3:24]
Reactant: CC(=O)N[C@H]1[C@H](O[C@@H]([C@H](O)[C@H](C=O)NC(C)=O)[C@H](O)CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N)[C@H](O)CO

Procedure:
This enzyme is reacted with the starting compound, di-N-acetylchitobiose, whereby only the acetyl group of the N-acetylglucosamine residue positioned at the non-reducing terminal of said di-N-acetylchitobiose is removed to convert said residue to a glucosamine residue, thereby obtaining the intended product, 2-acetylamino-4-O-(2-amino-2-deoxy-β-D-glucopyranosyl)-2-deoxy-D-glucose.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[S:35][CH:34]=[N:33][C:32]=1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:32]4[N:33]=[CH:34][S:35][C:31]=4[CH3:30])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1scnc1C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ncsc2C)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-methylthiazole-4-carboxylic acid (21 mg, 0.15 mmol).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([NH:17][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and butylamine as starting materials to give the aimed compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH2:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:17]3)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClCCl.Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH2:23][CH2:24][CH2:25][NH2:26])=[CH:17]3)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2ccc3[nH]c(CCCNC(=O)OC(C)(C)C)cc3c2)cc1OC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc3[nH]c(CCCN)cc3c2)cc1OC
Reaction time: 2 h

Procedure:
A 250 round bottom flask was charged with tert-butyl 3-(5-(3,4-dimethoxyphenylcarbamoyl)-1H-indol-2-yl)propylcarbamate (3.0 g, 6.62 mmol), dichloromethane (33 mL), and 1M hydrochloric acid in diethyl ether (33 mL) and the resulting mixture stirred for 2 h. The resulting mixture was then concentrated in vacuo, the residue triturated with diethyl ether, and placed under high vacuum to yield 2-(3-amino-propyl)-1H-indole-5-carboxylic acid (3,4-dimethoxy-phenyl)-amide. MS (ES+) 354 (M+1); HPLC: Kromasil C18 column (50×2 mm; 3.5μ), gradient 10-90% (MeCN+0.16% TFA) in (water+0.2% TFA) over 4 min, tR=2.46 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(N)cc2)cn1
Reaction time: 4 h
Yield: 86.6 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (1.7 g, 12 mmol) in DMF (100 mL) was added 4-methyl-1H-imidazole (0.82 g, 10 mmol) and K2CO3 (11 g, 80 mmol). The mixture was heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with brine (100 mL×2). The organic layer was dried and concentrated. The solid was dissolved in MeOH and bubbled with Ar for 2 min. before adding 10% Pd—C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacuo to afford title compound (1.5 g, 87%) as brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]2.[C:29](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:29])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
A mixture of ethyl 5-(2-methoxyethoxy)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.50 g), potassium carbonate (480 mg) and N,N-dimethylformamide (20 mL) was stirred at 0° C. for 30 min. Methyl iodide (550 mg) was added at 0° C. to the reaction mixture, and the mixture was stirred at room temperature for 15 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 over magnesium sulfate, and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate-hexane (4:1-2:1) to give the title compound (1.30 g, yield 85%) as a colorless 25 oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[C:17]([O:21][C:22](=[O:30])[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.C(O)(=O)C.ClCCl>[C:17]([O:21][C:22](=[O:30])[NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:16])[CH2:26][CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 0.17 h

Procedure:
To 10 mL of a dichloromethane solution containing 0.23 g of (7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.21 g of tert-butyl(piperidin-4-yl)carbamate and 60 μL of acetic acid were added, and the mixture was stirred for 10 minutes. Thereto was added 0.34 g of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction mixture was added with water and ethyl acetate, and the reaction solution was neutralized with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.43 g of a colorless oily substance, tert-butyl(1-(2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C)C1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:22]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)CCCCCO
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOC(=O)OCC
Temperature: 0 °C
Yield: 48.3 %

Procedure:
160 g of ethyl 6-hydroxy-hexanoate, 145.4 g of N,N-dimethylaniline and 200 ml of anhydrous toluene are placed in a round flask which is provided with a dropping funnel, a thermometer and a stirrer. 119.4 g of ethyl chloroformate are added dropwise at 25° C. within a half hour while stirring. The reaction mixture is held under reflux for 3 hours. After cooling the reaction mixture is poured on to ice-water, the organic phase is washed twice with water, with 100 ml of a 5% hydrochloric acid solution and then neutral with water. After drying over sodium sulphate the solvent is distilled off. 173 g of crude product are obtained. Fractional distillation gives 112 g (yield 48.3% of theory) of chemically pure ethyl 6-ethoxycarbonyloxy-hexanoate; 75 g thereof can be used as an olfactorily pure product without further treatment.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:28][CH:29]=4)[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(CNC(=O)c3ccc(OC(F)(F)F)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.4 mmol) in acetonitrile (10 mL), was added 4-trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.63 mL, 3.6 mmol). The mixture was stirred at room temperature for one hour. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethoxy-benzamide as an off-white solid (500 mg, 71% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.40 min (99.5%); mp, 165-167° C.; 1HNMR (DMSO-d6) 2.15-2.20 (m, 1H, CHH), 2.56-2.88 (m, 6H, CHCH2, CH3), 4.60 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.458-8.04 (m, 7H, Ar), 9.28 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.90, 23.40, 30.60, 42.35, 56.53, 119.93 (q, JC-F=257 Hz), 120.01, 120.67, 123.87, 126.62, 129.56, 133.19, 134.17, 134.07, 137.97, 145.83, 150.35, 154.61, 160.43, 165.06, 169.45, 172.59. LCMS MH=489; Anal Calcd For C23H19N4O5F3+1.1H2O: C, 54.36; H. 4.20; N, 11.02; F, 11.21. Found: C, 54.40; H, 3.89; N, 10.67; F, 11.06.