Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([OH:31])[C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:18][CH:17]=2)=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]=1[OH:35])(=[O:7])[CH3:6].O>CN1CCCC1=O.[Br-].[Zn+2].[Br-]>[OH:35][C:9]1[C:10]([CH2:32][CH2:33][CH3:34])=[C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([OH:31])[C:23]3[CH:30]=[CH:29][CH:28]=[C:25]([C:26]4[NH:27][N:3]=[N:2][N:1]=4)[CH:24]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:8]=1[C:5](=[O:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(SCc2ccc([C@H](O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1c(SCc2ccc([C@H](O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 140 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
Add sodium azide (66 mg, 0.25 mmol) and zinc bromide (131 mg, 0.50 mmol) to a solution of (S)-3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-hydroxy-methyl}-benzonitrile (110 mg, 0.25 mmol) in N-methylpyrrolidinone (2.0 ml). Heat the mixture at 140° C. for 12 hours, then cool to room temperature and stir for 18 hours. Pour the mixture into water (25 ml) and stir the solid suspension for 20 minutes. Filter and wash the filtered solid with water. Dissolve the solid in a 1N HCl (25 ml) and ethyl acetate (20 ml) mixture. Extract the aqueous layer with ethyl acetate (25 ml), combine the organic extracts, then wash with water, brine, dry over sodium sulfate and concentrate. Purify the crude product via reverse phase HPLC using a gradient of 90:10 to 20:80 (water/0.1% TFA):acetonitrile as eluent to give the title compound (37 mg, 31%). MS (m/z) 473 (M−H), 1H NMR (400 MHz, DMSO-d6) 12.83 (s, 1H), 8.13-8.11 (m, 1H), 7.89-7.86 (m, 1H), 7.72 (d, 1H), 7.59-7.51 (m, 2H), 7.41-7.37 (m, 4H), 6.96 (d, 1H), 5.60 (s, 1H), 4.30 (s, 2H), 2.65-2.60 (m, 5H), 1.45 (sextet, 2H), 0.90 (t, 3H).
Reaction SMILES: C[O:2][CH:3]1[CH:8]2[C:9](=[O:14])[CH:10]=[CH:11][C:12](=[O:13])[CH:7]2[CH2:6][CH:5]([C:15]([CH3:17])=[O:16])[O:4]1.C(O[CH:22]=[CH:23][CH:24]=[CH2:25])(=O)C>C1C=CC=CC=1>[OH:2][CH:3]1[C:8]2[C:9](=[O:14])[C:10]3[C:11]([C:12](=[O:13])[C:7]=2[CH2:6][CH:5]([C:15]([CH3:17])=[O:16])[O:4]1)=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: COC1OC(C(C)=O)CC2C(=O)C=CC(=O)C12
Reactant: C=CC=COC(C)=O
Solvent: c1ccccc1
Product: CC(=O)C1CC2=C(C(=O)c3ccccc3C2=O)C(O)O1
Temperature: 60 °C
Yield: 30.2 %

Procedure:
A mixture of methyl (1-methoxy-5,8 dioxo-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (100 mg, 0.450 mmol) and acetoxy butadiene (80 μg, 0.675 mmol) in dry benzene (5 mL) was heated for 3 hours at 60° C. under argon atmosphere. The solvent was then removed in vacuo and the resultting adduct was dissolved in 10 mL of toluene and then aromatized on silica gel by flash chromatography (toluene:ethyl acetate; 90%:10% followed by 70%:30%). Evaporation of the solvents gave 37 mg (31% yield) of pure titled compound.
Reaction SMILES: CS([O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)=[O:26])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:5][CH:6]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]3)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)c3ccc(O)cc3)cc2)C1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
A mixture of tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (0.6 g, 2.26 mmol), bis(4-hydroxyphenyl)methanone (2.15 g, 10.0 mmol) and K2CO3 (313 mg, 2.26 mmol) in 12 mL DMF was heated at 100° C. for 3.5 h, then quenched with water, and extracted with EtOAc. The extract was washed with water, dried, and concentrated to give a residue, to which was added CH2Cl2 and the white suspension thus formed removed and filtration. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether/CH2Cl2/acetone=4/2/1) to give the desired product (400 mg, 46% yield).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>O1CCCC1>[CH:1]1([NH:6][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC1CCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(NC1CCCC1)Oc1ccccc1
Yield: 81 %

Procedure:
Cyclopentylamine (9.9 ml, 100 mmol) was dissolved in tetrahydrofuran (400 ml); pyridine (8.9 ml, 110 mmol) was added thereto; and the reaction mixture was stirred. The reaction mixture was cooled with ice; phenyl chloroformate (13.8 ml, 110 mmol) was added dropwise for 5 minutes while stirring; and the reaction mixture was stirred at room temperature for 24.5 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in a solvent mixture of hexane:ethyl acetate=5:1, filtered off, washed with hexane, and dried under aeration to yield the title compound as colorless crystals (16.6 g, 81 mmol, 81%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:11][CH2:12][OH:13].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=1>O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:22][CH2:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)[N:6]2[CH2:11][CH2:12][OH:13]
Reactant: Nc1ncnc2c1nc(Br)n2CCO
Reactant: NCc1cccnc1
Solvent: O
Product: Nc1ncnc2c1nc(NCc1cccnc1)n2CCO
Temperature: 150 °C
Yield: 86.9 %

Procedure:
A mixture of 0.387 g (1.5 mmol) 6-amino-8-bromo-9-(2-hydroxyethyl)-9H-purine and 0.456 3-picolylamine (4.2 mmol) was heated to 150° C. under an argon atmosphere. After completion of the reaction (˜5 hours) the reaction mixture was diluted with water leading to the precipitation of the product. The precipitate was isolated, washed with water and diethylether to give 0.372 g (87%) of the desired product.
Reaction SMILES: FC1C=C(C2C=C([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])C(=O)N(CC(C)C)N=2)C=CC=1C.O[C:27]1[C:28](=[O:48])[N:29]([CH2:44][CH:45]([CH3:47])[CH3:46])[N:30]=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[C:32]=1C>>[CH2:44]([N:29]1[C:28](=[O:48])[C:27]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:32][C:31]([C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=2)=[N:30]1)[CH:45]([CH3:46])[CH3:47]
Reactant: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(CC(C)C)c(=O)c1O
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Product: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(COS(C)(=O)=O)c1=O
Yield: 89.9 %

Procedure:
Following the procedure of Example 1 (9), 4-hydroxy-methyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as colorless fine-needles (yield: 89.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1>C(O)(=O)C.Cl.O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c3cc(N)ccc3c(C)cn2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cn2c(=O)c(C(=O)O)cnc2c2cc(N)ccc12
Yield: 74.5 %

Procedure:
A suspension of ethyl 10-amino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (400 mg) in a mixture of acetic acid (6 ml) and 36% hydrochloric acid (3 ml) was refluxed for 55 minutes. The mixture was cooled and diluted with water. The precipitated solid obtained was collected and dissolved into 6 ml of 1N aqueous sodium hydroxide. The resulting solution was filtered for removal of insoluble materials. The filtrate obtained was cooled and adjusted to pH 6 with 1N hydrochloric acid and neutralized with acetic acid to give 10-amino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (270 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Cl:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Cl:31]
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.25 g, 0.75 mmol) in dry CHCl3 (20 mL), NCS (0.08 g, 0.6 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.15 g) as thick syrup.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[CH:13][C:12]([C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=1.CN(C)C=O>CO>[C:9]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:14]=[CH:13][C:12]([C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([OH:18])[CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:11][CH:10]=1
Reactant: OC(CCl)(c1ccc(F)cc1)c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: OC(Cn1ccnc1)(c1ccc(F)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Yield: 27.9 %

Procedure:
20.2 g (0.297 mol) of imidazole are added to a solution of 9.5 g (0.175 mol) of sodium methylate in 49 ml of methyl alcohol. A slution of 44.3 g (0.135 mol) of 1-(4-biphenylyl)-2-chloro-1-(4-fluorophenyl)-ethanol in 103 mol of dimethylformamide is then added dropwise, and the reaction mixture is heated to 60° C. for 90 minutes. It is concentrated by distilling off the solvent in vacuo, and the residue is stirred with water. The crystals which remain are washed with acetonitrile and recrystallised from ethyl alcohol. 13.5 g (28% of theory) of 1-(4-biphenylyl)-1-(4-fluorophenyl)-2-(imidazol-1-yl)-ethanol of melting point 220° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C:6]1[N:7]=[C:2]([N:1]=[CH:28][N:29]([CH3:31])[CH3:30])[N:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)[N:5]=1
Reactant: N#Cc1ccc(Nc2nc(N)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (1) (0.0016 mol) and 1,1-dimethoxy-N,N-dimethylmethanamine (21 ml) were combined and stirred vigorously at ambient temperature for 8 hours. The reaction mixture was filtered and the collected solid was washed with ether (Fraction A). Additional compound was obtained by concentration of the filtrate (Fraction B). Fractions A and B were combined and recrystallized from ethanol, yielding 0.15 g of 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[(dimethylamino)methylene]amino]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 62).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>CCCCCC>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([N:5]=[CH:13][N:14]([CH3:16])[CH3:15])=[C:3]([C:1]#[N:2])[CH:9]=1
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cc(Br)ccc1N
Solvent: CCCCCC
Product: CN(C)C=Nc1ccc(Br)cc1C#N
Yield: 85.3 %

Procedure:
59 g (300 mmol) of 2-cyano-4-bromoaniline are suspended in 35 ml of dimethylformamide dimethyl acetal (780 mmol) and heated under reflux for 1.5 h. The resulting mixture is cooled and then 300 ml of hexane are added. The resulting solid is filtered off and washed with hexane. 64.5 g (85%) of the desired product are obtained.
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)C.[F:16][C:17]([Si](C)(C)C)([F:19])[F:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:16][C:17]([F:19])([F:18])[CH:4]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[OH:13]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=Cc1ccc(C(O)C(F)(F)F)cc1
Yield: 76.5 %

Procedure:
According to Reference Example 8-12, by use of 4-(diethoxymethyl)benzaldehyde (400 mg, 1.92 mmol), (trifluoromethyl)trimethylsilane (0.34 mL, 2.3 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 0.19 mL, 0.19 mmol) and tetrahydrofuran (8 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Then, purification by silica gel column chromatography (chloroform/methanol=1/0 to 3/1) was performed to give 4-(2,2,2-trifluoro-1-hydroxyethyl)benzaldehyde (300 mg, yield: 77%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1>>[O:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: BrCC1CCCCO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC3CCCCO3)CC1)O2

Procedure:
Compound 119 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(bromomethyl)tetrahydro-2H-pyran and conditions outlined in procedure V. M.p.=135-137° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.8 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 4.0 (d, 1H), 3.5 (dt, 2H), 2.9 (m, 3H), 2.65-2.3 (m, 4H), 2.1 (m, 2H), 1.9 (m, 3H), 1.5 (m, 4H), 1.3 (m, 2H); LCMS: 400 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH:7]([CH3:17])[CH2:8][NH:9]C(=O)OC(C)(C)C)=[O:5]>Cl.CO>[NH2:9][CH2:8][CH:7]([NH:6][C:4](=[O:5])[C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[OH:1])[CH3:17]
Reactant: CC(CNC(=O)OC(C)(C)C)NC(=O)c1ccccc1O
Agent: Cl
Solvent: CO
Product: CC(CN)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.6 %

Procedure:
A mixture of tert-butyl 2-(2-hydroxybenzamido)propylcarbamate (2.4 g, 8.16 mmol) in saturated HCl-MeOH (50 mL) was stirred (RT, 2 h) and concentrated under reduced pressure to afford N-(1-aminopropan-2-yl)-2-hydroxybenzamide (1.8 g, 96%) as a white solid. Mass calculated for C10H14N2O2=194.23. found: [M+H]+=195.2.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](SC)=[C:18]([C:21]#[N:22])[C:19]#[N:20])[CH:13]=[CH:14][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[NH2:26][NH2:27]>CO>[NH2:20][C:19]1[NH:27][N:26]=[C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:11]=2)[C:18]=1[C:21]#[N:22]
Reactant: CSC(Nc1cccc(CNC(=O)OC(C)(C)C)c1)=C(C#N)C#N
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(Nc2n[nH]c(N)c2C#N)c1

Procedure:
A mixture of 145.4 g (422 mmol) of 3-[3-(N-Boc-aminomethyl)-phenylamino]-2-cyano-3-methylmercapto-acrylonitrile, 21.96 ml (443 mmol) of hydrazine hydrate and 1000 ml of methanol is heated under reflux for 2 hours and then concentrated by evaporation in vacuo, yielding 5-amino-[3(N-Boc-aminomethyl)-phenylamino]4-cyano-pyrazole; TLC-Rf=0.28 (methylene chloride/methanol [9:1]).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+]>C1COCC1.O>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(C2CCCN2C(=O)OC(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 34B (2.7 g) in THF (50 mL) was added lithium hydroxide (0.2 g) in water (5 mL). The mixture was stirred at ambient temperature overnight and partitioned between ethyl acetate and 0.5 M hydrochloric acid. The extract was washed with water, dried over magnesium sulfate, filtered and concentrated. The concentrate was flash chromatographed on silica gel with ethyl acetate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:35]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:42])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)c1cccnc1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(C(=O)c4cccnc4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A24 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (16 mg, 0.037 mmol), triethylamine (50 μl), nicotinoyl chloride (10 mg, 0.046 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 1.95 (m, 2H), 2.14 (m,2H), 3.07 (s, 3H), 3.55 (m, 1H), 3.65 (m, 2H), 4.13 (m, 1H), 5.72 (m, 1H), 7.40 (m, 1H), 7.79 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.41 (s, 1H), 8.70 (m, 2H), 10.20 (s, 1H). Exact mass calculated for C22H22N6O6S 498.13, found 499.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]Br>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH:16]([Br:24])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(c1ccc(OCc2ccccc2)cc1)C(Br)c1ccncc1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 1-(4-(benzyloxy)phenyl)-2-(pyridin-4-yl)ethanone (1.39 g, 4.58 mmol) in acetic acid was added a solution of bromine (0.72 g, 4.58 mmol) in acetic acid (3 mL). After stirring 2 h, the solid was collected via filtration and washed with acetic acid to provide 1.67 g (96%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO) δ: 5.21 (s, 1H), 7.15 (d, 2H), 7.42 (m, 3H), 7.87 (m, 1H), 8.06 (d, 2H), 8.77 (m, 1H). MS m/z: 382 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=S)[NH:10][NH2:11].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=1
Reactant: NNC(=S)Nc1ccccc1Cl
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccccc2Cl)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of 10.05 g (0.05 mole) of 4-(2-chlorophenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was treated with 8.48 g (0.05 mole) of ethyl 2-choroacetoacetate and stirred under nitrogen atmosphere at room temperature for 1 hr. The reaction mixture was treated with 40 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1 hr, during which time the yellow slurry became a clear, deep orange solution. The characteristic insoluble amorphous sulfur was removed by filtration. The filtrate began to solidify. It was allowed to cool for approximately 16 hr to yield 10.1 g of yellow crystalline product. The filtrate was concentrated in vacuo to yield an additional 3 g of yellow product. The 2 solids were combined and recrystallized from benzene to give 10.4 g of white crystalline product, mp 188°-189° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][N:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][N:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1cncnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a suspension of 2-(4-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyrimidin-5-yl)acetamide (29) (0.029 g, 0.060 mmol) in anhydrous methanol (2 mL) was added a 37% aq. solution of formaldehyde (0.018 mL, 0.24 mmol) under an atmosphere of nitrogen, followed by sodium triacetoxyborohydride (0.063 g, 0.30 mmol). The reaction was stirred at room temperature for 2.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL), the combined organic layers were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice. The resulting off-white solid was suspended in DCM (5 mL) and cyclohexane was added (˜10 mL). The suspension was sonicated and the product was collected by filtration. The solid was washed with petroleum benzine 40-60° C. (5×10 mL), air-dried and subsequently dried under high-vacuum to give the title compound (30) (0.017 g, 57% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.01 (s, 1H), 8.94 (s, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 7.64 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.11 (s, 1H), 3.57 (s, 2H), 3.28-3.22 (m, 4H), 2.87 (d, J=11.2 Hz, 2H), 2.46-2.36 (m, 1H), 2.20 (s, 3H), 1.98 (t, J=10.6 Hz, 2H), 1.76-1.58 (m, 4H). LCMS Method C: it 4.52 min; m/z 500.1 [M+H]+.