Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.Cl[C:44]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:45]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:45])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC(C)COC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OCC(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl) phenyl)urea (0.0867 g, 0.227 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) at 0° C. was added N,N-Diisopropylethylamine (0.1190 mL, 0.6832 mmol) followed by Isobutyl chloroformate (0.0442 mL, 0.341 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 8.18 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.52 (s, 2H), 3.86 (d, J=6.5, 2H), 3.77-3.68 (m, 4 H), 3.58 (s, 2H), 3.47 (d, J=4.3, 4H), 3.17-3.06 (m, 2H), 2.73-2.62 (m, 2H), 1.92 (dp, J=13.2, 6.6, 1H), 1.06 (t, J=7.2, 3H), 0.93 (d, J=6.7, 6H). LC/MS-m/z+483.3 (M+H)+
Reaction SMILES: [Br:1][CH:2]1[CH:8]([OH:9])[CH2:7][CH:6]2[CH:3]1[CH2:4][C:5]2=[O:10].[CH3:11][CH:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>[Br:1][CH:2]1[CH:8]([O:9][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:11])[CH2:7][CH:6]2[CH:3]1[CH2:4][C:5]2=[O:10]
Reactant: CC(O)c1ccccc1
Reactant: O=C1CC2C1CC(O)C2Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(OC1CC2C(=O)CC2C1Br)c1ccccc1
Yield: 128.7 %

Procedure:
A mixture of 2-bromo-3-hydroxybicyclo[3.2.0]heptan-6-one (15 g), α-methylbenzyl alcohol (36 g) and p-toluenesulphonic acid (1 g) was heated at 90° for 6 h. The solution was poured into 8% sodium bicarbonate (300 ml) and extracted with ether (4×150 ml). The combined extracts were washed with brine (300 ml), dried (MgSO4) and evaporated to afford crude 2-bromo-3-(1-phenylethoxy)bicyclo[3.2.0]heptan-6-one as a pale yellow oil (29.1 g). The crude product (28.1 g) was dissolved in acetone (50 ml) and treated with morpholine (19 ml). The mixture was stirred for 3 h, poured into water (200 ml) and extracted with ether (4×150 ml). The combined extracts were washed with brine (200 ml), dried (MgSO4) and evaporated. The product was purified by chromatography on silica eluting with ether-petroleum ether (7:3) to give the title compound as a waxy solid (15.7 g). I.R. (CHBr3) 1745 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-])=O>[Pt].C(OCC)(=O)C.C(O)C>[NH2:21][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1

Procedure:
A mixture of 4-amino-N-(4-tert-butylphenyl)-3-nitrobenzamide from the previous step and 100 mg of 5% platinum on carbon in 50 mL of 1:1 ethyl acetate/ethanol was reduced under a hydrogen balloon. The reaction was filtered through Celite to remove catalyst and the solvent was removed under reduced pressure to afford 3,4-diamino-N-(4-tert-butylphenyl)-benzamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:28][C@H:24]3[CH2:25][CH2:26][CH2:27][O:23]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCC1CCCO1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2C[C@H]1CCCO1

Procedure:
Compound IIj was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and R)-(tetrahydrofuran-2-yl)methanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [S:1](=[O:4])(=O)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].P(Cl)(Cl)([Cl:14])=O.C(OC)(C)(C)C>ClCCCl>[CH:6]([N:5]([CH2:10][CH2:9][CH3:8])[S:1]([Cl:14])(=[O:4])=[O:2])([CH3:11])[CH3:7]
Reactant: O=S(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccn1
Solvent: COC(C)(C)C
Solvent: ClCCCl
Product: CCCN(C(C)C)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
52.6 g (0.356 mol) of sulfur trioxide as a 60% solution in 1,2-dichloroethane were added with stirring at from 0 to 5° C. within 25 min to a solution of 60.75 g (0.652 mol) of α-picoline in 400 ml of 1,2-dichloroethane, followed by washing with 80 ml of 1,2-dichloroethane and stirring for 15 min until the temperature rose to 22° C. 30 g (0.296 mol). of N-isopropyl-N-(n-propyl)amine were then added within 20 min with stirring and external cooling at from 20 to 30° C., followed by washing with 80 ml of 1,2-dichloroethane and stirring at 50° C. for 15 min. After cooling to 25° C., 54.6 g (0.356 mol) of phosphorus oxychloride were added with stirring and cooling to 25-30° C. within 15 min, followed by washing with 200 ml of 1,2-dichloroethane and heating to 75° C. After stirring at this temperature for 1 h, the reaction mixture was cooled and concentrated under reduced pressure, and the residue obtained was stirred 3 times with 200 ml each time of methyl tert-butyl ether. The methyl tert-butyl ether phases were decanted off and extracted twice with dilute hydrochloric acid. The organic phase was dried over magnesium sulfate, the drying agent was filtered off and the organic phase was concentrated. 55.1 g (91.3% of theory) of the title compound having a refractive index nD23=1.4605 were obtained. A gas chromatography analysis (column: Macherey and Nagel 25 m Optima 17 GC 9; pressure 14.5 psi; helium; column flow 0.6 ml/min; split, 30 ml/min; injector 280° C., detector 320° C.) showed a degree of purity of 96% (RT=11.87 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[BH4-].[Na+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([OH:14])[CH:11]([CH3:12])[CH3:13])=[C:7]([CH3:15])[C:6]=2[CH:16]=1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(Br)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C(C)C)oc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
1-(5-Bromo-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (6.2 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (100 mL) and methanol (10 mL), and sodium borohydride (90%, 1.8 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (10 mL) and 1N hydrochloric acid (50 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 1-(5-bromo-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol (6.1 g, quantitative) as a pale-yellow oil. The obtained oil was dissolved in tetrahydrofuran (50 mL), and thionyl chloride (2.3 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min then ice-cooled, and saturated aqueous sodium hydrogen carbonate solution (30 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (100 mL), sodium iodide (3.9 g), sodium carbonate (2.7 g) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (4.4 g) synthesized in Example 2(2) were added to the solution, and the mixture was stirred at 70° C. for 4 hr. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (1.12 g, 12%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([CH2:24]O)[CH:17]=[N:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].S(Cl)([Cl:28])=O>ClCCl>[Cl:28][CH2:24][C:18]1[CH:17]=[N:16][N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[C:19]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CCc1cnc(N2CCC(n3ncc(CO)c3C(F)(F)F)CC2)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1cnc(N2CCC(n3ncc(CCl)c3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution (1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.13 g, 0.366 mmol) in dichloromethane (3 mL) was added thionyl chloride (1.2 mL) and the solution was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and the crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6]([Cl:27])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1C1CCC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(C#N)cc(C(=O)Cl)cc1C1CCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 3-cyano-5-cyclobutyl-4-methoxybenzoic acid (190 mg), toluene (2.0 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.07 mL) were added, and the mixture was stirred at 60° C. for 3 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (204 mg) as a brown oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH3:10][NH2:11].C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C1COCC1>[CH3:10][NH:11][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: CN
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CNc1cc(C#N)ccn1
Temperature: 120 °C

Procedure:
To a solution of 2-chloroisonicotinonitrile (22.0 g, 159 mmole) in pyridine (500 mL) was added methylamine in THF (2N, 160 mL), and NaHCO3 (54 g). The mixture was heated to 120° C. in a sealed vessel for 40 h. After cooled to RT, the mixture was filtered and the filter cake was washed with CH2Cl2. The combined filtrated was concentrated in vacuo to give a yellow solid (21 g) as the desired compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=O.[NH3:21]>CO>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:11]2[NH:21][C:3](=[O:2])[C:5]3[S:6][CH:7]=[CH:8][C:9]=3[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: N
Reactant: COC(=O)c1sccc1NC(=O)c1cccc(OC)c1
Solvent: CO
Product: COc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1

Procedure:
3-(3-Methoxy-benzoylamino)-thiophene-2-carboxylic acid methyl ester, 24, (12.78 g) was added to methanol (200 mL) previously saturated with ammonia. The mixture was placed in a bomb reactor, and heated to 100° for 2 days. The solvent was then removed in vacuo and the resulting residue was suspended in isopropanol (250 mL); 2M sodium hydroxide solution was then added (83 mL), and the mixture was heated to reflux for 5 hours. The reaction mixture was then cooled and acidified to pH 1. 2-(3-methoxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one, 25, (12.16 g) was collected as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][CH:27]([NH:33][CH3:34])[CH2:28]2>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[CH:32][C:23]=4[O:22][CH3:21])[CH2:28]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNC1CCc2c(cccc2OC)C1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3c(cccc3OC)C1)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 5-methoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene. Mp: 149°-150° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].CCN(C(C)C)C(C)C.[CH2:23]([S:27](Cl)(=[O:29])=[O:28])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][S:27]([CH2:23][CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[C:4]=2[CH:3]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCS(=O)(=O)Oc1cc(=O)oc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
6-Chloro-4-hydroxycoumarin (0.455 mmol, 0.090 g) is suspended in 5 mL DCM. DIEA (1.37 mmol, 0.237 mL) is added and the reaction is cooled to 0° C. 1-Butanesulfonyl chloride (0.5 mmol, 64.8 μL) is dissolved in DCM is added and and the reaction is stirred at ambient temperature for 2 hrs. The DCM is removed under reduced pressure and the residue is redissolved in MeOH/H2O then is purified by HPLC to afford the title compound (36.2 mg, 25%) 1H NMR (DMSO-d6, 300 MHz) δ 7.81 (2H, m), 7.56 (1H, d, J=8.75 Hz), 6.59 (1H, s), 3.99 (2H, m), 1.83 (2H, m), 1.46 (2H, m), 0.92 (3H, t, J=7.25 Hz); MS (ESI, Pos.) calcd for C13H13ClO5S m/z [M+H]=317.0, found 317.1.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23].[OH-].[K+].Cl.[C:31](OCC)(=[O:33])C>CO>[F:11][C:12]1[C:17]([CH:18]([OH:19])[C:10]2[C:3]3[C:2]([O:33][CH3:31])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23]
Reactant: CCOC(C)=O
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(OC)c23)c1F
Reaction time: 0.17 h

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.200 g, 1.30 mmol) and propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (9, 0.401 g, 1.52 mmol), 3.83 mL of methanol was added and this suspension was allowed to stir for 10 minutes, followed by the addition of potassium hydroxide (0.238 g, 4.24 mmol). The reaction was allowed to stir at room temperature over the weekend. The reaction was poured into 25 mL of 1N hydrochloric acid and 25 mL of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting residue was purified by silica gel column chromatography eluting with a gradient of 20-100% ethyl acetate in hexanes. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-0057, 176 mg). 1N NMR was consistent with the compound structure. MS(ESI) [M+H+]−=413.1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[N:13]=[CH:12][CH:20]=[CH:19][C:15]=2[C:16]([NH2:18])=[O:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Oc2ncccc2C(N)=O)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
4-Hydroxyacetophenone (1 equiv), 6-chloronicotinamide (1 equiv) and K2CO3 (1.4 equiv) in anhydrous DMF (0.4 M) was heated at 150° C. under nitrogen during 2.5 days. After cooling down to room temperature, toluene was added and solvents were evaporated. The residue was partitioned in water/EtOAc. The aqueous layer was thoroughly extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum (toluene was added to aid DMF evaporation). The crude mixture was purified by flash chromatography using EtOAc/CH2Cl2/2 M NH3 in MeOH (12:7:1) as eluent in 20% yield.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].O=[C:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O.[Pd]>[CH3:18][CH2:17][CH2:16][C@H:10]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCC(=O)C(=O)OCC
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reaction time: 0.5 h

Procedure:
Into a tank, fitted with a stirrer, introduce 25 kg of L-alanine dissolved in water, 1.1 kg of sodium hydroxide and 36 kg of ethyl 2-oxopentanoate. Stir the reaction mixture for 30 minutes. Into a hydrogenation apparatus introduce 5% palladium-on-carbon suspended in water, then the mixture obtained above. Hydrogenate at ambient temperature at a pressure of 1 bar until the theoretical amount of hydrogen has been absorbed. Remove the catalyst by filtration, then add concentrated hydrochloric acid to the filtrate until a pH of 3 is obtained. Harvest the resulting solid by means of filtration, take up the cake in acetonitrile at reflux, filter while hot and then allow to crystallize.
Reaction SMILES: C(Cl)([Cl:3])=O.C(=O)([O-])[O-].[K+].[K+].[C:11]1([CH:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)N2CC(OC3C=CC(Cl)=C(Cl)C=3)C2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[C:11]1([CH:17]([Cl:3])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1Cl
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: ClC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 14 g (0.144 mole) of phosgene weighed into 200 mL of methylene chloride was treated with 19.9 g (0.144 mole) of anhydrous potassium carbonate and stirred for 1 h then 45.9 g (0.12 mole) of 1-(diphenylmethyl)-3-(3,4-dichlorophenoxy)azetidine in 100 mL of methylene chloride was added dropwise and stirring was continued for 72 h. The reaction mixture was filtered to remove the inorganic salts and then concentrated in vacuo to a pale yellow oil (67 g). Trituration of the residue with cyclohexane yielded a crude pale yellow solid (23.6 g). The filtrate was treated with ligroin and upon standing an additional 13.3 g of tacky material was obtained (contaminated with diphenylmethyl chloride). After several recrystallizations from cyclohexane to remove traces of diphenylmethyl chloride a portion was obtained as fine white crystals, mp 96°-99° C.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[F:20][CH2:21][CH:22]([NH2:26])[CH2:23][CH:24]=[CH2:25].C(N(CC)CC)C.O>O1CCCC1>[F:20][CH2:21][CH:22]([NH:26][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:8])[CH2:23][CH:24]=[CH2:25]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: C=CCC(N)CF
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCC(CF)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Tert-Butyloxycarbonyloxyimino-2-phenylacetonitrile (3.35 g, 13.6 mmoles) in dry tetrahydrofuran (40 ml) is slowly added with ice cooling to a stirred mixture of 1-fluoro-2-amino-4-pentene hydrochloride (1.9 g, 13.6 mmoles) and triethylamine (2.78 g, 27.2 mmoles) in tetrahydrofuran (30 ml). After standing overnight at room temperature, water is added, the tetrahydrofuran is removed under reduced pressure, and the residue is extracted twice with ether. After washing with 1 N sodium hydroxide, then with water until neutral, the organic layer is dried and stripped to give 1-fluoro-2-tert-butoxycarbonylamino-4-pentene (2.33 g, 85%) as an oil which is used without further purification.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[CH:3]\[C:4]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[O:5].[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>CC(O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:13]([C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:14]([CH3:16])[NH:1][C:2]([CH3:11])=[C:3]2[C:4]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[O:5])[CH:32]=[CH:33][CH:34]=1
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCc2ccccc2)=C(C)N1

Procedure:
3.53 g (22.9 mmol) of 2-cyanoethyl 3-aminocrotonate, 4.40 g (22.9 mmol) of benzyl acetoacetate and 2.60 ml (23.0 mmol) of 3-chlorobenzaldehyde were heated at 80° C. under stirring in 100 ml of 2-propanol for 3 days. 2-Propanol was evaporated under reduced pressure to obtain 5-benzyl 3-(cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. 100 ml of ethyl acetate and 10% palladium/carbon were added to the reaction mixture, and they were stirred at room temperature in hydrogen atmosphere under atmospheric pressure for 7 days. The reaction liquid was filtered. The filtrate was evaporated under reduced pressure. The residue was washed with chloroform to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:15])[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[CH3:16].[BH4-].[Na+]>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]([OH:15])[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(C(=O)CS(C)(=O)=O)cc(C)c1N
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(C(O)CS(C)(=O)=O)cc(C)c1N

Procedure:
A suspension of 16.5 g. of 4'-amino-3',5'-dimethyl-2-(methylsulfonyl)-acetophenone and 10.6 g. of sodium borohydride in 500 ml. of alcohol was stirred at room temperature for 20 hours, resulting in a solution. After the addition of 500 ml. of water, the alcohol was evaporated under vacuum and the mixture was extracted with two 1 liter portions of ethyl acetate. The ethyl acetate extract was washed with two 500 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. After crystallization of the residue from ether, there was obtained 4-amino-3,5-dimethyl-α-[(methylsulfonyl)-methyl]-benzyl alcohol having a melting point of 146°-148° C.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[CH3:19][CH:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[CH2:22][CH2:21]1
Reactant: CC1CCNCC1
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2)CC1
Yield: 88.4 %

Procedure:
Proceeding as indicated in example 2, with 0.03 mole (7.8 g) of 2-chloro-5-nitro-benzophenone, 0.05 mole (5.7 cm3) of 4-methylpiperidine and 0.03 mole (4.1 g) of calcium carbonate in 80 cm3 of ethanol, 8.6 g (Yield: 88%) of the expected product are obtained. M.P. 81° C.