Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:32])([F:20])[F:33])[CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-[3-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.79 (m, 2H), 7.57-7.70 (m, 7H), 3.84 (s, 2H); MS (ESI−) M/Z 456 (M−H)−.
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])=[N-].[I:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)N>>[I:11][C:12]1[CH:13]=[C:14]([N:1]([C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[CH:16]=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Reactant: Nc1cccc(I)c1
Product: O=C1CCCC(O)=C1N(C1=C(O)CCCC1=O)c1cccc(I)c1

Procedure:
Following the procedure described in the Example 1, using 2-diazo-cyclohexane-1,3-dione and 3-iodoaniline as starting materials to yield the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][N:6]2[N:5]=1
Reactant: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A 50-mL single-neck round-bottomed flask was purged with nitrogen and charged with 209a (492 mg, 2.34 mmol), 10% palladium on carbon (50% wet, 234 mg), and methanol (20 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 2 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 209b (380 mg, 80%). MS: [M+H]+ 181.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[C:25]([NH:27][C:28](=[N:31][CH3:32])SC)#[N:26]>C(#N)C>[C:25]([NH:27][C:28]([NH:31][CH3:32])=[N:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:26]
Reactant: NCCCCc1nccs1
Reactant: CN=C(NC#N)SC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC#N
Product: CNC(=NCCCCc1nccs1)NC#N

Procedure:
A solution of 2-(4-aminobutyl)thiazole (from the dihydrochloride 13.8 g.) and N-cyano-N', S-dimethylisothiourea (7.75 g) in acetonitrile was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was recrystallised from isopropyl alcohol-isopropyl acetate to yield N-cyano-N'-methyl-N"-[4-(2-thiazolyl)butyl]guanidine m.p. 87°-89.5°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Cl:33]N1C(=O)CCC1=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:17]([CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])=[N:18][N:19]=[C:20]2[Cl:33])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1ccccc1)c1cc(F)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Product: O=C(c1ccccc1)c1cc(F)ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 2, 5-fluoro-2-[3-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with N-chlorosuccinimide to form-5-fluoro-2-[3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[OH:10][NH:11][C:12](=N)[CH:13]([CH3:15])[CH3:14].Cl>C(OCC)(=O)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[CH:13]([C:12]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:10][N:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC(O)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)c1noc(N2CCC(O)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carbonitrile (1 g, 7.93 mmol) and N-hydroxyisobutyrimidamide (0.972 g, 9.51 mmol) in ethyl acetate (40 mL) was added zinc chloride (1 M in Et2O, 9.5 mL, 9.5 mmol) dropwise at rt under argon. Precipitate formed immediately, and the reaction mixture was stirred at rt for 30 min. The solid was collected via filtering, rinsed several times with ether. The solid was dissolved in concentrated HCl (4 mL, 132 mmol), diluted with ethanol (8 mL), and refluxed for 1 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated to approximately half of the volume, and diluted with water (15 mL). The solution was basified with solid Na2CO3, followed by extraction with CH2Cl2 (3×30 mL). The combined organic layers were washed with saturated NaHCO3 (60 mL) and brine. It was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (hexanes-EtOAc gradient 0-50% EtOAc) to afford 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol (0.59 g, 2.79 mmol, 35% yield) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (d, J=7.07 Hz, 6H) 1.55 (d, 1H) 1.60-1.70 (m, J=12.98, 8.61, 8.61, 4.17 Hz, 2H) 1.93-2.02 (m, 2H) 2.89 (spt, J=6.95 Hz, 1H) 3.38 (ddd, J=13.20, 9.03, 3.79 Hz, 2H) 3.88-4.04 (m, 3H). LCMS (m/z)=212 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.[CH2:14]([SH:16])[CH3:15]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[S:16][CH2:14][CH3:15]
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Reactant: CCS
Product: CCSc1c(Br)ccc(NC)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 11, Step 1, using 4-bromo-3-fluoro-N-methyl-2-nitroaniline and ethanethiol as the starting materials. LCMS calculated for C9H12BrN2O2S (M+H)+: m/z=291.0, 293.0. found: 290.9, 292.9.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.C(OCC)(=O)C.[CH:21]([NH2:23])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:23][CH:21]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: NC=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]cnc2cc(F)ccc12
Yield: 82 %

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g, 19.3 mmol) in formamide (30 ml) was heated at 150° C. for 6 hours. The reaction mixture was poured onto icetwater 1/1 (250 ml). The precipitated solid was collected by filtration, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 82%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:12]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[C:4]=3[CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Reactant: OB(O)c1cccc(Cl)c1
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-chlorophenyl boronic acid according to Procedure A. White solid: mp 150-151° C. 1H-NMR (CDCl3) δ 8.52 (s, 1H, D2O exchangeable), 7.50 (s, 1H), 7.31-7.44 (m, 4H), 7.16 (d, 1H, J=1.5 Hz), 6.89 (d, 1H, J=8.2 Hz), 2.03 (m, 4H), 0.94 (t, 6H, J=7.4 Hz); MS (EI) m/z 315(M+, 53%). Anal. Calc. For C18H18ClNO2: C, 68.46; H, 5.75; N, 4.44. Found: C, 68.16; H, 5.81; N, 4.32.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:19][C:20]#[N:21])=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:22]I.O>CN(C)C=O>[CH3:22][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:18]=2)[C:14]([CH2:19][C:20]#[N:21])=[CH:15]1
Reactant: CI
Reactant: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CC#N)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.67 h
Yield: 98.8 %

Procedure:
65.5 g (0.474 mol) of powdered potassium carbonate was added to a solution of 28.9 g (0.143 mol) of (6-nitro-1H-indol-3,yl)-acetonitrile (13) from Step C above in 230 ml of dimethylformamide at room temperature. The suspension was stirred for 40 minutes then 25.48 g (0.179 mol) of methyl iodide was added dropwise over 65 minutes. After stirring at room temperature over night the reaction mixture was cooled and poured into a total of 600 ml of water. The precipitate was filtered, washed with a little water and dried on phosphor anhydride until reaching constant weight. The procedure yielded 30.4 g (95.4%) of (1-methyl-6-nitro-1H-indol-3-yl)acetonitrile (14), which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4].[CH3:15][N:16]([CH2:24][CH2:25][C:26](=O)[CH3:27])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.[BH3-]C#N.[Na+]>CO>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]([CH2:24][CH2:25][CH:26]([NH:1][CH2:2][CH:3]([C:5]2[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=2)[OH:4])[CH3:27])[CH3:15])=[CH:18][CH:19]=1
Reactant: CC(=O)CCN(C)c1ccc(C)cc1
Reactant: NCC(O)c1ccc(O)c(C(N)=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N(C)CCC(C)NCC(O)c2ccc(O)c(C(N)=O)c2)cc1
Reaction time: 20 h

Procedure:
To a solution of 20 mmol 5-(2-amino-1-hydroxyethyl)salicylamide and 5.7 g (30 mmol) 4-(N,4-dimethylanilino)-2-butanone [b.p. 93°-6°/0.1 mm, prepared by procedure of Craig, et al, J. Org. Chem., 29, 410 (1964)] in 150 ml methanol, add 1.9 g (30 mmol) NaCNBH3. After 20 hrs., concentrate, and partition between EtOAc and 1.0 N NaHCO3 solution. Dry and concentrate. Warm the foam with EtOAc to give a white solid, m.p. 123°-6°.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[CH:9]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:3]1=[O:27].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C)C=O>[CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:9]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:3]1=[O:27]
Reactant: C1COCCN1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(N2CCOCC2)c1
Temperature: 210 °C
Reaction time: 0.83 h

Procedure:
A sealed 2.5 ml tube containing 0.05 g of 5,5-dimethyl-1-(2-chloropyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione, 0.5 ml of dimethylformamide, 0.034 g of potassium carbonate and 0.021 ml of morpholine is placed in a Personal Chemistry Emrys Optimiser microwave oven. The mixture is irradiated with magnetic stirring at 210° C. for about 50 minutes. The reaction mixture is placed on a Bond Elut Varian cartridge of reference 1225-6053 containing 2 g of SCX phase conditioned with dimethylformamide. The cartridge is washed with methanol and then eluted with 2M ammoniacal methanol. The ammoniacal fractions are concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 16 mm in diameter packed with 2 g of conditioned 15-35 μm silica, and then eluted with a mixture (cyclohexane/ethyl acetate) (8/2) (v/v) at a flow rate of 10 ml/minute. The fractions between 160 and 260 ml are concentrated to dryness under reduced pressure. 0.01 g of 5,5-dimethyl-1-(2-morpholinopyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained in the form of a powder, the characteristics of which product are as follows:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2CNC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1Cc2ccc(OCCCN)cc2CNC1=O
Yield: 100 %

Procedure:
A solution of methyl (±)-8-[3-(tert-butoxycarbonylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.70 g) in CH2Cl2 (7 mL) and TFA (2 mL) was stirred under argon at 0° C. for 1 hr, then was concentrated to give the title compound (0.75 g, 100%) as a colorless glass: MS (ES) m/e 321.4 (M+H)+.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([O-:23])=[CH:21][CH:20]=1.[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([O:23][C:4]2[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:21][CH:20]=1
Reactant: Cc1ccc([O-])cc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(C)cc2)cc1C(=O)OC

Procedure:
Dimethyl 4-nitrophthalate was reacted in DMF with sodium 4-methylphenoxide to give dimethyl 4-(4-methylphenoxy)phthalate in analogy to a process known from the literature (J. Org. Chem. Vol. 42, No. 21, 1977, 3419-3425). After standard working up and chromatography using hexane/EA, the diester was isolated as a yellowish oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](Br)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cu][C:20]#[N:21]>CN1CCCC1=O>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([C:20]#[N:21])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(C(C)C)cc1OCC
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc(C#N)c(C(C)C)cc1OCC
Yield: 40.3 %

Procedure:
Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (12 g, 3.8 mmol) was treated with copper (I) cyanide (682 mg, 7.6 mmol) in N-methyl-2-pyrrolidinone (40 ml) as described in Procedure 5 to give the title compound as an oil (400 mg).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[CH3:19][NH2:20]>>[N+:1]([CH:4]=[C:5]([NH:20][CH3:19])[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCCCc1ccccn1
Reactant: CN
Product: CNC(=C[N+](=O)[O-])NCCCCc1ccccn1

Procedure:
A mixture of 1-nitro-2-methylthio-2-[4-(2-pyridyl)butylamino]ethylene and 33% ethanolic methylamine were heated on a steam bath for 15 minutes. Concentration, followed by crystallisation from ethyl acetate yielded the title compound m.p. 90°-91°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.O=S(Cl)[Cl:13]>O1CCOCC1>[Cl:13][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1
Solvent: C1COCCO1
Product: COc1ccc(CCl)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
110 mmol 4-methoxybenzyl alcohol was dissolved in 60 ml dioxane and 150 mmol SOCl2 was slowly dropped into the solution. The solution was stirred for 3 h at 60° C. and evaporated under reduced pressure. EtOAc was added and the resulted solution was washed with water. The separated organic layer was dried and evaporated to give 107 mmol 1-(chloromethyl)-4-methoxybenzene.
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:3].C(O)C.[OH-].[K+].Cl>CCOCC>[ClH:1].[ClH:1].[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH:5]([NH:4][CH2:2][CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCNC(Cc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCNC(Cc1ccccc1N)c1ccccc1
Reaction time: 3 h

Procedure:
3.00 g of N-Ethyl-2-nitro-α-phenylphenethylamine hydrochloride is treated with 100 ml of hot 95% ethanol containing 1.10 g of potassium hydroxide for 15 minutes, after which the mixture is filtered and placed in a Paar flask. 0.15 g of 10% palladium on charcoal is added and the mixture is hydrogenated at room temperature and 50 psia for 3 hours, after which the catalyst is removed. The ethanol is evaporated from the filtrate and the resulting yellow oil is poured onto 100 ml of water. The biphasic aqueous mixture is extracted with methylene chloride (2×100 ml). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride evaporated to afford a colorless oil. The oil is dissolved in 50 ml of ether. Ethereal hydrogen chloride (100 ml) is added precipitating the hydrochloride acid salt as an oil. The ethanol is evaporated and the oil is dissolved in 20 ml of i-propanol with heating. Upon cooling, white crystals, mp>248° C. dec, fell from solution providing 2-amino-N-ethylα-phenylphenethylamine dihydrochloride.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:30][OH:31])[CH:14]=[C:15]([O:26][CH2:27][O:28][CH3:29])[C:16]=1[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:29][O:28][CH2:27][O:26][C:15]1[CH:14]=[C:13]([CH:12]=[C:11]([O:10][CH2:9][O:8][CH3:7])[C:16]=1[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:30]=[O:31]
Reactant: COCOc1cc(CO)cc(OCOC)c1C/C=C/c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCOc1cc(C=O)cc(OCOC)c1C/C=C/c1ccccc1
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
To a solution of pyridine (62 g, 0.78 mol) in CH2Cl2 (500 mL) were added CrO3 (39 g, 0.39 mol) and Silica gel (40 g) in several portions at 0° C. After stirring for 10 min, [3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-phenyl]-methanol (220e) (45 g, 0.13 mol) was added in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) indicated that the reaction was complete. The reaction mixture was filtered and the filter cake was washed with Et2O. The combined filtrates were concentrated. The residue was suspended in Et2O and filtered again. The filtrate was concentrated under vacuum to give the crude title compound (45 g, 100% yield) as a yellow oil, which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 9.89 (s, 1H), 7.16-7.41 (m, 5H), 6.25˜6.44 (m, 2H), 5.36 (s, 4H), 3.66 (d, 2H), 3.47 (s, 6H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:29])=[C:4]([C:21]([OH:28])=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[O:16][C:17]([F:20])([F:19])[F:18])=[O:6].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[C:3]([CH3:29])=[C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]=2[OH:28])=[O:6])=[C:9]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)#[N:15]
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1OC(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1OC(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 3-Bromo-5-tert-butyl-N-(2-trifluoromethoxy-4-cyano-phenyl)-6-hydroxy-2-methyl-benzamide (0.141 g, 0.3 mmole) in dioxane (5 ml) under nitrogen, phenylboronic acid (37.0 mg, 0.3 mmole), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmole) and sodiumcarbonate (1.05 ml, 2 M solution in water) were added. The reaction mixture was heated at 100° C. for 48 hours. The reaction mixture was evaporated, diluted with ethyl acetate and the organic phase was washed with citric acid solution (10%). The organic phase was dried over sodium sulphate and evaporated. The crude compound was purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH:15]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH2:15])[CH2:9]1)=[O:44]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2N)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: Nc1sc(-c2ccccc2F)nc1C(=O)Nc1cnccc1N1C[C@@H](N)C[C@@H](F)C1

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with tert-butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-fluoropiperidin-3-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid. Obtained the desired product as a white solid (50 mg). ESIMS m/z=431.1 (M+1).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]([CH3:57])[CH2:47][CH2:48][O:49][C:50]1[CH:56]=CC(N)=[CH:52][CH:51]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:52]=[CH:51][C:50]([O:49][CH2:48][CH2:47][N:46]([CH3:57])[CH3:45])=[CH:56][CH:30]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(OCCN(C)C)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(2-(dimethylamino)ethoxy)aniline as the aniline component. (23%, MS=557.3 (M+H))