Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:37][C:36]([CH3:38])=[N:35][C:34]=2[C:39](O)=[O:40])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[S:37][C:36]([CH3:38])=[N:35][C:34]=2[C:39]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]2[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:40])=[CH:31][CH:32]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: C[C@@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of rac-trans-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate (1 eq) from the previous step in DMF was added DIPEA (2 eq) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (1.5 eq) and HATU (2 eq). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give tert-butyl (((2R,3R)-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)carbamate as a light yellow oil. To a solution of this carbamate in CH2Cl2 was added TFA (1:1 v/v). The reaction was aged at rt and monitored for disappearance of starting material by analytical reverse-phase HPLC. When starting material was consumed, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHCO3, brine, dried (MgSO4), and concentrated to afford the title compound as a pale yellow oil which crystallized. MS (ESI) 348.2 (M+H).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:25](C1C=CN=C(CN)C=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:23]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:18][NH:17][C:11]2[N:10]=[C:9]([NH:8][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=2)[CH:24]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: CC(C)(C)c1ccnc(CN)c1
Agent: Cl
Product: Cc1nc(NCc2cc(C(C)(C)C)ccn2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(4-tert-butylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02-1.10 (m, 3H), 1.24 (d, J=11.01 Hz, 11H), 1.42 (d, J=10.48 Hz, 2H), 1.55 (d, J=9.94 Hz, 3H), 1.90 (s, 3H) 2.29 (s, 3H), 3.43 (s, 1H), 4.71 (d, J=5.10 Hz, 2H), 7.52 (s, 2H) 7.59 (d, J=7.52 Hz, 1H), 8.21 (s, 1H), 8.53 (d, J=6.72 Hz, 1H), 12.48 (s, 1H); MS (ESI) m/z 368.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][C:3]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:15].[ClH:23]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:23].[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:15])=[C:2]2[CH3:1]
Reactant: Cc1c(C(=O)N2CCN(C)CC2)[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)N2CCN(C)CC2)[nH]c2ccc(N)cc12
Temperature: 25 °C

Procedure:
A mixture of 0.245 g I.15 ((3-methyl-5-nitro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone), 25 mg Pd/C 10% in 25 ml ethanol and 20 ml ethyl acetate was stirred at ambient temperature under a hydrogen atmosphere. The reaction mixture was treated with 1N aqueous hydrochloric acid and stirring was continued under a hydrogen pressure of 50 psi for 16 h. The reaction mixture was filtered through a pad of Celite. The Celite pad was washed with ethanol and the solvent was evaporated to give a brown solid.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:47])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:47]=[O:16])=[CH:26][CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C)c3c2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1
Temperature: 76 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
AIBN (22.2 mg, 0.135 mmol) was added to a stirring solution of NBS (88 mg, 0.49 mmol) and methyl 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)benzoate (163 mg, 0.451 mmol) in CCl4 (40 mL) and was heated to 76° C. The mixture was allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (63 mg, 0.54 mmol) and subjected to MW irradiation (150° C.) for 10 min. The mixture was diluted with EtOAc and washed with 10% NaHSO4 2× followed by H2O and Brine. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to to give the expected product methyl 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)benzoate (34 mg, 0.091 mmol, 20% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.31 (1H, s), 8.79 (1H, d, J=2.44 Hz), 8.74 (1H, d, J=2.44 Hz), 8.28 (1H, s), 8.16-8.25 (2H, m), 8.00-8.13 (2H, m), 7.72 (1H, t, J=7.78 Hz), 7.49-7.57 (2H, m), 3.92 (3H, s). LC-MS retention time: 1.72 min; m/z (MH+): 376. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(O[CH:4]=[N:5][C:6]#[N:7])C.[NH2:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][S:11][C:10]1([CH3:20])[CH3:19]>C(O)C>[C:6]([NH:5][CH:4]=[N:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][S:11][C:10]1([CH3:20])[CH3:19])#[N:7]
Reactant: CC1(C)SCc2ccccc2C1N
Reactant: CCOC=NC#N
Solvent: CCO
Product: CC1(C)SCc2ccccc2C1N=CNC#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
10.0 g of N-cyanoimidoformic acid ethyl ester are added dropwise to 16.7 g of 4-amino-3,3-dimethylisothiochroman in 10 ml of dry ethanol. The exothermic reaction is complete after 2 hours. The mixture is cooled to 0° C., and the precipitate is filtered off and washed with a small amount of ethanol. After drying, 14.3 g of N-cyano-N'-(3,3-dimethylisothiochroman-4-yl)-formamidine are obtained in the form of colourless crystals having a melting point of 164°-166° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([OH:16])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([O:16][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCC(O)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(Oc1ccccc1[N+](=O)[O-])C(NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 2 h
Yield: 56.3 %

Procedure:
7.05 g (30.2 mmol) 2-tert-Butoxycarbonylamino-3-hydroxy-pentanoic acid in 7 ml dimethylformamide were added at 0° C. to 2.80 g (64.1 mmol) sodium hydride (55%) in 56 ml dimethylformamide. The suspension was stirred for 2 hours and then 3.54 ml (33.2 mmol) 1-fluoro-2-nitrobenzene were added. After stirring for 2 days the mixture was poured on ice/water and extracted with diethylether. The pH was adjusted to 1 by adding aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1/1 yielded 6.03 g (56%) 2-tert-butoxycarbonylamino-3-(2-nitro-phenoxy)-pentanoic acid as orange oil, MS m/e (%): 353.4 (M−H, 100).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[C@@H:5]([CH3:36])[CH2:4]1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[CH2:4][C@@H:5]4[CH3:36])=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@@H]1C
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@@H](C)C1

Procedure:
Starting from N-[(1S*,2S*,4S*)-4-amino-2-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f63) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Cl.CCN(CC)CC>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:13][C:14]1[N:18]=[CH:17][N:16]([CH2:23][C:22]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:21]=2[Cl:20])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Reactant: ClCc1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(Cc2ccc(Cl)cc2Cl)cn1)NC(=O)OC(C)(C)C

Procedure:
N-(tert-butoxycarbonyl)-L-histidine methyl ester (1.0 g) was added to a solution of 2,4-dichlorobenzyl chloride (0.73 g) and Et3N (0.27 g) in benzene (10 ml) and the mixture was heated under reflux for 1 hr. The mixture was cooled and the precipitate was removed by filtration. The filtrate was washed with H2O, dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent; 95:5, CHCl3/MeOH) to give N-(tert-butoxycarbonyl)-1-[(2,4-dichlorophenyl)methyl]-L-histidine methyl ester. The obtained compound was treated in a similar manner as described in R. Example 4 to give 1-[(2,4-Dichlorophenyl)methyl]-L-histidine methyl ester, dihydrochloride salt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1OC)([O-:3])=[O:2].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>>[CH:19]([NH:23][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH2:21][CH3:22])[CH3:20]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CCC(C)N
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
More specifically, the process for producing N-sec-butyl-4-tert-butyl-2,6-dinitroaniline comprises reacting 4-tert-butylphenol with dimethyl sulfate to produce 4-tert-butylanisole. The 4-tert-butylanisole is then reacted with a nitrating agent including a mixture of nitric acid, sulfuric acid and oleum to produce 2,6-dinitro-4-tert-butylanisole. The 2,6-dinitro-4-tert-butylanisole is then reacted with sec-butylamine to produce N-sec-butyl-4-tert-butyl-2,6-dinitroaniline.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br[CH2:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[CH3:32][C:31](=[CH2:30])[CH2:33][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)[C:20]([OH:22])=[O:21]
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: C=C(C)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(C)CC(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to -78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and cooling to -78° C., 3-bromo-2-methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at -78° C. for 1h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)-.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][OH:25])=[CH:21][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: OCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, phenylethanol and DBU in dioxane. ES-MS m/e (%): 362 (M{81Br}+H+, 96), 360 (M{79Br}+H+, 100), 258 ([M{81Br}+H-PhCH═CH2]+, 55), 256 ([M{81Br}+H-PhCH═CH2]+, 52).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:28])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(=[O:31])[CH3:30].O>C1COCC1>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:28])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: CCOc1ccccc1NC(=O)OCCN1CCN(c2cccc(N)c2)CC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1NC(=O)OCCN1CCN(c2cccc(NC(C)=O)c2)CC1
Reaction time: 20 h
Yield: 42.2 %

Procedure:
To a mixture of 77 mg (0.2 mmol) of 2-[4-(3-aminophenyl)piperazino]ethyl-N-(2-ethoxyphenyl)carbamate derivative and 44.6 μl (0.32 mmol, 1.6 eq) of TEA in 5 ml of THF, 71 μl (0.3 mmol, 1.5 eq) of acetyl chloride is added. Shaking is carried out at room temperature for about 20 hours. Then H2O is added and the aqueous phase is extracted with CH2Cl2. After drying on Na2SO4 and concentration under vacuum, a white solid is obtained which is purified by column chromatography (eluent CH2Cl2/iPrOH 9:1) to produce 36 mg of the expected product as a brown oil (yield: 43%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][O:29][C:30]2[CH:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:33]1[N:32]=[CH:31][C:30]([O:29][CH2:28][CH:25]3[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]3)=[CH:35][CH:34]=1)[CH:9]=[CH:8]2)=[O:4]
Reactant: CN(C)C(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Product: CN(C)C(=O)c1ccc2c(ccn2-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using N,N-dimethyl-1H-indole-5-carboxamide (intermediate-12) and tert-butyl-4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Intermediate 29).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.CN.C=O.[CH3:21][N:22]1[CH2:27]COC[CH2:23]1>O.C(O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:23][N:22]([CH3:27])[CH2:21][N:12]([CH2:13][CH3:14])[C:10]3=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: CN1CCOCC1
Agent: C=O
Agent: CN
Solvent: CCO
Solvent: O
Product: CCN1CN(C)CN(c2nc3ccc(Br)cc3s2)C1=O
Yield: 88 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, methylamine, formaldehyde, and N-methyl morpholine in a mixed solvent of ethanol and water was reacted to give the desired compound 1.56 g (88%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][CH2:13][CH3:14])[CH:11]=1)[CH:7]=O)[CH3:2].[C:15](#[N:19])[CH2:16][C:17]#[N:18]>C(O)CC.[OH-].[K+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][CH2:13][CH3:14])[CH:11]=1)[CH:7]=[C:16]([C:15]#[N:19])[C:17]#[N:18])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1
Reactant: N#CCC#N
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: CCOc1cc(C=C(C#N)C#N)cc(OCC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an amount of 56c (1.0 g, 5.15 mmole) of 3,5-diethoxybenzaldehyde dissolved in 10 mL of propanol, was added malononitrile (375 mg, 5.67 mmole) and 2 drops of sat. KOH. The mixture was stirred at r.t. for 10 mins. Precipitates was filtered to yield 1.0 g of 2-(3,5-diethoxybenzylidene)malononitrile (56d). MS [m+H] calc'd for C14H14N2O2, 243.11; found 243.11.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]([CH2:30][C:31]1[CH2:35][CH2:34][CH2:33][CH:32]=1)[C:24]([C@@:26]1([CH3:29])[CH2:28][O:27]1)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]1([CH2:30][C@H:23]([NH:22][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:24]([C@@:26]2([CH3:29])[CH2:28][O:27]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH:32]=1
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCC2)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (2.00 g, 6.78 mmol) and (S)-2-amino-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (1.98 g, 6.78 mmol) in DMF (10 mL) at 0° C. was added HATU (3.00 g, 8.36 mmol) followed by DIEA (5.90 mL, 33.9 mmol) and the mixture was stirred for 15 min then quenched with NaHCO3 (sat., aq.), extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (1:1 hexanes/EtOAc) provided tert-butyl ((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (2.62 g, 82%) as a colorless oil. MS(EI) for C26H36N2O6, found 473.3 (MH)+.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]([F:56])([F:55])[C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:44]=[CH:43][C:42]([C:41]([F:40])([F:55])[F:56])=[CH:47][CH:46]=2)[CH2:53][CH2:52]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: FC(F)(F)c1ccc(C2CCC(=CCC3OCCCO3)CC2)cc1
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.2 g, 27 mmols), followed by adding tetrahydrofuran (100 ml), suspending, and stirring under ice cooling till the liquid temperature reached 10° C. The resulting reaction mixture was added potassium t-butoxide (3.0 g, 27 mmols), followed by elevating the temperature up to room temperature under ice cooling, stirring for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(4-trifluoromethylphenyl) cyclohexanone (6.0 g, 25 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)-ethylidene)-4-(4-trifluoromethylphenyl)cyclohexane.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:23])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12](Cl)=[CH:11][CH:10]=2)=[O:5])C.Cl.[O:25]1[CH2:30]COCC1>O>[CH3:14][C:9]1[CH:10]=[C:4]([C:6]2[C:7](=[O:23])[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][C:12]([CH:30]=[O:25])=[CH:11][CH:10]=3)[O:5][N:8]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(C=O)ccc3[nH]c2=O)on1
Yield: 78 %

Procedure:
A mixture of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (200 mg, 0.61 mmol), 10% HCl (1 mL) and dioxane (3 mL) was heated to reflux for 48 h. After cooling, water was added and the resulting precipitate was collected by filtration, washed with water and dried to afford 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (a) (143 mg, 78%). MS: 300.5 (M+H).