Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:3].[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[CH:20]1([NH:26][C:2]([O:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)C[C@H](OC(=O)Cl)C(=O)OCc1ccccc1
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](OC(=O)NC1CCCCC1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
To a solution of benzyl(2S)-2-chlorocarbonyloxy-4-methylvalerate (0.56 g) in tetrahydrofuran (11 ml) was added cyclohexylamine (0.40 g) at room temperature. After being stirred for 10 minutes, the solvent was removed by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 1N HCl, water and brine successively. The organic layer was dried over magnesium sulfate concentrated in vacuo. The residual solid was triturated with hexane to give benzyl (2S)-2-cyclohexylcarbamoyloxy-4-methylvalerate (0.45 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].IC1C=C(C=CC=1C)C(O)=O.O=S(Cl)Cl.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][C:36]=2[C:42]([F:45])([F:44])[F:43])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:39][C:38]1[CH:40]=[CH:41][C:35]([CH2:34][N:31]2[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]2)=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)=[O:6]
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(C(=O)O)cc1I
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
3-Iodo-4-methylbenzoyl chloride (0.48 g, 1.7 mmol), prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCl2 (as previously described), was added to a solution of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (0.47 g, 1.7 mmol), N,N-diisopropylethylamine (0.26 g, 2.0 mmol), and a catalytic amount of DMAP in THF (10 mL). After stirring at rt for 2 h, the reaction was quenched with water. EtOAc was added and the layers separated. The combined organic layers were concentrated to dryness and purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas), to provide 0.51 g of product as an off-white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.CCN(CC)CC.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1.C(Cl)Cl>[N:26]1([C:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:10]3[N:9]=[C:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][S:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)(=[O:47])=[O:46])[CH2:3]4)[CH:16]=[CH:15][C:11]=3[C:12]([NH2:14])=[O:13])=[CH:23][CH:22]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N2CCC[C@@H](NS(=O)(=O)c3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (30 mg, 0.071 mmol) and Et3N (0.049 mL, 0.353 mmol) in THF (2 mL) was added benzenesulfonyl chloride (18.72 mg, 0.106 mmol). The solution was stirred at rt for 10 min. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to obtain 30 mg of (R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(phenylsulfonamido)piperidin-1-yl)nicotinamide as a light yellow solid. LCMS: (M+H)+=465.40. 1H NMR (400 MHz, CDCl3) δ ppm 11.13 (1H, s), 7.84-7.90 (2 H, m), 7.58-7.63 (2H, m), 7.54-7.57 (1H, m), 7.44-7.52 (3H, m), 7.33 (2H, d, J=8.56 Hz), 5.99 (1H, d, J=8.81 Hz), 5.71-5.87 (2H, m), 3.85 (1H, d, J=10.83 Hz), 3.38-3.79 (12H, m), 1.67-1.79 (2H, m), 1.44-1.57 (2H, m).
Reaction SMILES: [O:1]=[CH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7]2.CC(=C(C)C)C.O.P([O-])(O)(O)=[O:31].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([N:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][C:2]([OH:31])=[O:1])[CH:5]=2)[CH2:9]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reactant: O=P([O-])(O)O
Agent: CC(C)=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reaction time: 0.33 h

Procedure:
To a solution of benzyl 5-(2-oxoethyl)isoindoline-2-carboxylate (290 mg, 1 mmol) in tert-butanol (10 mL) was added 2,3-dimethyl-but-2-ene (1.1 mL). To this mixture was added a solution comprising sodium dihydrogenphosphate hydrate (1.08 g, 8 mmol) and sodium chlorite (1.08 g, 9.5 mmol tech grade). This mixture was stirred for 20 min diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (25 g silica eluted with 3-20% methanol in dichloromethane) to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](I)=[C:12]([C:15]#[N:16])[C:11]([CH3:17])=[N:10]1.[CH3:18]/[C:19](/B(O)O)=[CH:20]/[CH3:21].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:18]/[C:19](/[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]([CH3:17])[C:12]=1[C:15]#[N:16])=[CH:20]/[CH3:21]
Reactant: C/C=C(/C)B(O)O
Reactant: Cc1nn(-c2ccc(O)cc2F)c(I)c1C#N
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: [K+]
Solvent: COCCOC
Solvent: O
Product: C/C=C(/C)c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Yield: 70.7 %

Procedure:
A mixture of 1-(2-fluoro-4-hydroxyphenyl)-5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (40 mg, 0.12 mmol), (E)-but-2-en-2-ylboronic acid (23.3 mg, 0.23 mmol), K2CO3 (96.7 mg, 0.70 mmol) and Pd(PPh3)4 (13.47 mg, 0.01 mmol) in DME (1 mL) and water (1 mL) was flushed with N2 and irradiated in the microwave at 150° C. for 10 min. Water and DCM were added and the phases were separated. The organic layer was concentrated and the crude product was purified on HPLC to give (Z)-5-(but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (23.0 mg, 73%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@H:30]1[C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@H:30]1[C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and (trans)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44](/[C:46](=[CH:50]/[CH2:51][CH3:52])/[C:47](O)=[O:48])[N:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:47](=[O:48])/[C:46](/[C:44]4[N:45]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[S:42][CH:43]=4)=[CH:50]\[CH2:51][CH3:52])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC/C=C(\C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Yield: 90.4 %

Procedure:
To a suspension of 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (1.49 g: 3 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid (1.03 g: 3.45 mMol.) in dichloromethane (30 ml) is added at -30° C. N-methylmorpholine (1.1 ml : 10 mMol.) and, after 2 minutes, phenyl dichlorophosphate (0.49 ml: 3.27 mMol.), and the mixture is stirred at the same temperature for 1 hour and 20 minutes. The reaction mixture is mixed with 1N-hydrochloric acid (6 ml) and extracted with ethyl acetate. The extract is washed with water, aqueous 5% sodium hydrogen carbonate, and brine, dried over sodium sulfate, and concentrated. The residue (2.6 g) is dissolved in hot isopropanol (100 ml), cooled, and the separating pale yellow powder is collected by filtration to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (2.01 g). Yield: 91%.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[NH2:19][C:20]([CH:24]1[CH2:26][CH2:25]1)([CH3:23])[C:21]#[N:22]>ClCCl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:19][C:20]([C:21]#[N:22])([CH:24]1[CH2:26][CH2:25]1)[CH3:23])=[O:7]
Reactant: CC(N)(C#N)C1CC1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C#N)(NC(=O)c1cccc(CCl)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
3-(Chloromethyl)benzoyl chloride (9.08 mmol, 1.290 ml, 1.716 g) and triethylamine (27.2 mmol, 3.79 mL, 2.76 g) were stirred in dichloromethane (10 mL) at 0° C. 2-Amino-2-cyclopropylpropanenitrile (9.08 mmol, 1 g) was added dropwise and the reaction allowed to warm to room temperature and stir for 1 hour. The reaction mixture was washed with water and the organic phase concentrated under vacuum to afford the title compound (1.451 g). MS (ESI) m/z 263.1 [M+H]+
Reaction SMILES: C(OO)(=[O:3])C.C(O)(=O)C.[CH:10]1[C:23]2[CH:22]=[C:21]([S:24][CH2:25][N+:26]([O-:28])=[O:27])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.[OH2:29]>C(Cl)(Cl)Cl>[CH:10]1[C:23]2[CH:22]=[C:21]([S:24]([CH2:25][N+:26]([O-:28])=[O:27])(=[O:3])=[O:29])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])CSc1cc2ccccc2c2ccccc12
Reactant: O
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])CS(=O)(=O)c1cc2ccccc2c2ccccc12
Reaction time: 20 h

Procedure:
A solution of peracetic acid in acetic acid (32 wt%, 4 ml, 19 mmol) was added dropwise to an efficiently stirred solution of (9-phenanthrylthio)nitromethane (A) (1 g, 3.7 mmol) in chloroform (50 ml). The mixture was stirred for 20 hours and then diluted with water (20 ml). The organic phase was separated and washed with an aqueous solution of sodium metabisulphite, then with brine, and dried (N2SO4). The solvent was removed by evaporation to give a yellow solid. This was purified by flash chromatography on silica (Merck Kieselgel Art. 7736) eluting with toluene to give (9-phenanthrylsulphonyl)nitromethane, as a white crystalline solid (180 mg, 16% yield) m.p. 165°-166° C., (after recrystallisation from toluene); microanalysis, found: C, 59.7; H, 3.7; N, 4.6%; C15H11NO4S requires: C, 59.8; H, 3.7; N, 4.7%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:13]=1)=[CH:8]2
Reactant: CC#CC(=O)OCC
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (10.7 g), ethyl 2-butynoate (8.2 mL), tributylphosphine (7.0 mL) and tetrahydrofuran (400 mL) was stirred at 60° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95 to 100/0, volume ratio) to give the title compound (11.06 g, 80%) as an orange amorphous solid. MS 490 (MH+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17](NCCC3C=CC=CC=3O)[N:16]=2)[CH:12]=[N:13][CH:14]=1.[Cl:31]C1N=C(C2C=C(CN3CCN(C(OC(C)(C)C)=O)C[C@@H]3C)C=NC=2)C=CN=1.[NH2:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=1>>[Cl:31][C:64]1[CH:63]=[C:62]([CH2:61][CH2:60][NH:59][C:17]2[N:16]=[C:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][NH:6][CH2:7][C@@H:2]4[CH3:1])[CH:10]=3)[CH:20]=[CH:19][N:18]=2)[CH:67]=[CH:66][C:65]=1[OH:68]
Reactant: NCCc1ccc(O)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cncc(-c2ccnc(Cl)n2)c1
Reactant: C[C@H]1CNCCN1Cc1cncc(-c2ccnc(NCCc3ccccc3O)n2)c1
Product: C[C@H]1CNCCN1Cc1cncc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1

Procedure:
4-(2-(4-(5-(((S)-2-methylpiperazin-1-yl)methyl)pyridine-3-yl)pyrimidin-2-ylamino)ethylphenol: Intermediate 148 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 405. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.4 (s, 1H) 9.0 (m, 2H) 8.5 (d, 1H) 7.5 (s, 1H), 7.0 (d, 2H), 6.6 (d, 2H), 3.7-3.5 (m, 5H) 3.4-3.3 (m, 6H), 2.8 (t, 2H), 1.6 (d, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]1=[O:25])=[O:4].[Cl:28]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:28][C:13]1[NH:12][C:11]2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[C:8](=[O:25])[N:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:27])([CH3:26])[CH3:1])[C:15]=2[N:14]=1
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1c(=O)c2[nH]c(Cl)nc2n(COC(=O)C(C)(C)C)c1=O
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
2,2-Dimethylpropionic acid [3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (2.31 g) was dissolved in N,N-dimethylformamide (18 ml), and N-chlorosuccinimide (973 mg) was added to the solution while cooling on ice. Then, the mixture was stirred for 10 minutes on ice, and then at room temperature for 20 hours. The obtained reaction mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After removing the solvent by distillation from the organic layer, the residue was purified by silica gel column chromatography to give 1.61 g of the title compound from the elution fraction of hexane-ethyl acetate (1:1).
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]2[C:8](F)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][S:4][CH:3]=1.[CH2:14]([NH2:16])[CH3:15]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([C:7]2[C:8]([NH:16][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][S:4][CH:3]=1
Reactant: Fc1ncccc1-c1cscc1Br
Reactant: CCN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCNc1ncccc1-c1cscc1Br
Yield: 83.7 %

Procedure:
A solution of 3-bromo-4-(2-fluoropyridin-3-yl)thiophene (0.344 g) and ethylamine (0.2 g) in dioxane (1 mL), in a sealed tube, was heated at 100° C. for four days. The mixture was cooled, diluted with ethyl acetate, washed with water, dried, filtered, and evaporated. The residue was fractionated by chromatography to give 3-bromo-4-(2-ethylaminopyridin-3-yl)thiophene (0.316 g) as an oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:37])([F:36])[F:38])[CH:22]=2)=[O:19])=[CH:39][C:40]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)CC1
Reactant: C#Cc1ccc(NC2CC2)nn1
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CC5)nn4)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The intermediate compound 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide was made as for Example 12 (Step 1 to 4) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 10.66 (1H, s), 8.53 (1H, s), 8.19 (1H, s), 8.02-8.05 (1H, d, J=6.0 Hz), 7.98-8.01 (1H, d, J=6.0 Hz), 7.77 (1H, s), 7.70-7.73 (1H, d, J=6.0 Hz), 3.62 (2H, s), 3.33 (2H, m), 2.82 (2H, m), 2.54 (4H, m), 2.50 (3H, s).
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[C:8]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:7]([CH3:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]1([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:24][CH:23]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=1.[OH-:34].[Na+]>CC(C)=O.O>[CH2:15]([N:14]([CH2:13][C:8]1[C:9]([CH3:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[C:6]([OH:34])[C:7]=1[CH3:19])[S:30]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][C:8]2[C:7]([CH3:19])=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[C:10]([OH:11])[C:9]=2[CH3:12])(=[O:28])=[O:27])[CH:21]=1)(=[O:32])=[O:31])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCNCc1c(C)cc(C(C)(C)C)c(O)c1C
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCN(Cc1c(C)cc(C(C)(C)C)c(O)c1C)S(=O)(=O)c1cccc(S(=O)(=O)N(CCCC)Cc2c(C)cc(C(C)(C)C)c(O)c2C)c1
Reaction time: 15 h
Yield: 100.1 %

Procedure:
To a stirred solution of 6-t-butyl-3-(butylaminomethyl)-2,4-dimethylphenol (5.26 grams; 0.02 mole) in acetone (40 mls) is slowly added 1,3-benzenedisulfonyl chloride (2.75 grams; 0.01 mole) while maintaining the temperature at 25°-30° C. by cooling. To this mixture is slowly added a solution of 50% caustic soda (1.6 grams; 0.02 mole) in water (22 mls) while maintaining the temperature at 25°-30° C. by cooling. The mixture is allowed to come to room temperature and stirred for 15 hours. The mixture is then allowed to settle, and the upper layer is separated and slowly treated with ice water (100 mls). The resulting oil which separates solidifies upon standing for 2.5 hours. The solid is then recovered by filtration to obtain the crude product (7.3 grams; 100% of theoretical). Recrystallization of the crude product from glacial acetic acid affords the pure product (2.5 grams; m.p. 143°-144.5° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([NH2:17])[N:4]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([NH:17][C:26](=[O:27])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Nc2cc(N(C)C)nc(NC(=O)Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
A mixture of N4,N4-dimethyl-N6-(4-methylphenyl)-2,4,6-pyrimidinetriamine (122 mg, 0.50 mmol), phenylacetyl chloride (84 mg, 0.55 mmol), and triethylamine (100 mg, 1.00 mmol) in CH2Cl2 was stirred at room temperature for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC using hexane/EtOAc (1:3), giving the desired product (60 mg, 33%).
Reaction SMILES: FC(F)(F)[O:3][C:4]1C=CC(N2C=NC(C3C=CC(C(CC)CC(N=[N+]=[N-])=O)=CC=3)=N2)=C[CH:5]=1.[N:32]([CH2:35][CH:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]=[CH:48][N:47]([C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57]([F:60])([F:59])[F:58])=[CH:52][CH:51]=3)[N:46]=2)=[CH:41][CH:40]=1)[CH2:37][CH3:38])=[C:33]=[O:34].[CH:61]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[NH:70][C:71]([NH2:73])=[S:72])([CH3:63])[CH3:62]>>[CH:61]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[N:70]1[C:4](=[O:3])[CH2:5][S:72]/[C:71]/1=[N:73]\[C:33]([NH:32][CH2:35][CH:36]([C:39]1[CH:40]=[CH:41][C:42]([C:45]2[N:49]=[CH:48][N:47]([C:50]3[CH:51]=[CH:52][C:53]([O:56][C:57]([F:59])([F:58])[F:60])=[CH:54][CH:55]=3)[N:46]=2)=[CH:43][CH:44]=1)[CH2:37][CH3:38])=[O:34])([CH3:63])[CH3:62]
Reactant: CCC(CN=C=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CCC(CC(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1NC(N)=S
Product: CCC(CNC(=O)/N=C1\SCC(=O)N1c1ccccc1C(C)C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared from 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1 H-1,2,4-triazol-3-yl)phenyl)pentanoyl azide/3-(4-(1-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C42a) and 1-(2-isopropylphenyl)thiourea and isolated as a brown foam (0.041 g, 30%).