Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:47])=[C:12]([C:14]3[C:15]4[CH:37]=[CH:36][C:35](=[O:38])[N:34]([C:39]5[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=5[F:46])[C:16]=4[N:17]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[N:19]=3)[CH:13]=2)=[O:7])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C1COCC1>[CH:1]1([CH2:4][NH:5][C:6](=[O:7])[C:8]2[CH:9]=[CH:10][C:11]([CH3:47])=[C:12]([C:14]3[C:15]4[CH:37]=[CH:36][C:35](=[O:38])[N:34]([C:39]5[C:40]([F:46])=[CH:41][CH:42]=[CH:43][C:44]=5[F:45])[C:16]=4[N:17]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:19]=3)[CH:13]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(NC2CCNCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 12 h

Procedure:
To a solution of 1,1-dimethylethyl 4-{[4-(5-{[(cyclopropylmethyl)-amino]carbonyl}-2-methylphenyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate in THF (2 mL) was added TFA (3.0 mL). The reaction mixture was stirred for about 12 h and concentrated. The residue was mixed with H2O (5.0 mL) and EtOAc (20.0 mL) and the resultant mixture was basified with 2.5 N NaOH aqueous (hereinafter “aq”) solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic phases were washed with saturated aq. NaCl, dried over Na2SO4, filtered, and concentrated. Purification via a CombiFlash system (DCM:MeOH=10:1) then afforded the title compound: LC-MS m/z 545 (M+H)+, 1.65 min (ret. time).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC3CC3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxybenzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (161 mg; 1.3 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 173 mg; 79%. HPLC-MS: m/z: 510.1 (M)+; Rt: 1.9 min.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 4-fluoro-phenyl isocyanate (0.065 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 54 as a colorless solid (0.055 g, 33%). LCMS m/z (%)=405 M+H+ (37Cl, 20), 404 M+H+ (35Cl, 50), 1H NMR (400 MHz, acetone-d6) δ: 8.62 (bs, 1H), 8.101 (s, 1H), 8.081 (d, J=2.3 Hz, 2H), 7.967 (t, 1H), 7.885 (d, J=2.21 Hz, 2H), 7.558 (d, J=8.91 Hz, 1H), 7.473 (t, 1H), 4.67 (m, 1H), 4.238 (s, 3H), 1.873 (d, J=6.61 Hz, 3H), 1.713 (d, J=6.61 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1)=[O:29]
Reactant: CN(C)c1ccccc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)c1ccccc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 0 °C
Yield: 58.6 %

Procedure:
2-(2-Dimethylaminobenzylthio)benzimidazole (4.8 g) was dissolved in a mixture of 40 ml of chloroform and 5 ml of methanol. After the solution was chilled to 0° C., 3.86 g of m-chloroperbenzoic acid (purity: 70%) was added portionwise. Ten minutes later, a saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The chloroform solution was washed with saturated brine and then dried over anhydrous sodium sulfate. The chloroform was distilled off under reduced pressure and the residue was recrystallized from a mixture of chloroform and ether to obtain 2.97 g of 2-(2-dimethylaminobenzylsulfinyl)benzimidazole as a colorless crystalline product (m.p. 116° C., decomposed).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:23])=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=2)=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:23][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:7][C:6]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1)=[O:9]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(N)ccc2Cl)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(NCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A solution of ethyl (4-{[(5-amino-2-chlorophenyl)carbonyl]amino}phenyl)acetate (300 mg, 0.90 mmol) in DMF (5 ml) was treated with potassium carbonate (152 mg, 1.1 mmol, 1.2 eq) and benzyl bromide (215 ul, 1.8 mmol, 2 eq) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate (150 ml) and washed with water (2×80 ml) and brine (80 ml). Organic layer dried over magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography (Biotage SP4, 40 g silica column) eluting with 0-25% ethyl acetate in hexanes to afford the title compound as a white solid (90 mg). MS (ES+) m/z 423 [M+H]+ (C24H2335ClN2O3). 1H-NMR (400 MHz, d6-DMSO) δ 1.18 (3H, t, J 7.2), 3.61 (2H, s), 4.07 (2H, q, J 7.2), 4.30 (2H, d, J 6), 6.62-7.65 (13H, m).
Reaction SMILES: [CH:1]([C:4]([CH:15]([CH3:17])[CH3:16])=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[O:6][CH3:7])([CH3:3])[CH3:2].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.C(N(CC)CC)C>[C:18]([O:14][C:10]1[CH:9]=[C:8]([C:5]([O:6][CH3:7])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:12][CH:11]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=C(C(C)C)C(C)C)c1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=C(C(C)C)C(C)C)c1cccc(OC(=O)c2ccccc2)c1
Reaction time: 1 h

Procedure:
Alkene 1b (4.5 g, 1.9 mmol) was dissolved in 50 mL of dry CH2Cl2 with 5.3 mL of anhydrous triethylamine. The flask was purged with argon and cooled in an ice bath. Benzoyl chloride (4.05 g, 2.9 mmol) was added dropwise. The cooling bath was removed and stirring continued for 1 hour at room temperature. The mixture was filtered and the solution was washed with water, dried over MgSO4 and evaporated. The residue was suspended in hexane, the solid filtered away and the solution evaporated. The residue was purified by column chromatography on silica gel, eluting with 1% ethyl acetate in hexane yielding 3.7 g of dioxetane 1d: 1H NMR (CDCl3) δ 8.25-7.05 (m, 9H), 3.25 (s, 1H), 2.54 (sept, 1H, J=6.9 Hz), 2.40 (sept, 1H, J=6.9 Hz), 2.29 (s, 3H), 1.26 (d, 6H, J=6.9 Hz), 0.95 (d, 6H, J=6.9 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[H][H]>[Pd].CO.C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])[C:12]([OH:14])=[O:13]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(F)(F)F)c(O)c1
Yield: 86 %

Procedure:
10% Pd/C (590 mg) was added to 3-benzyloxy-4-trifluoromethyl-benzoic acid in a methanol-ethyl acetate mixed solvent (1:1), and the mixture was stirred at room temperature for two days in a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give 3-hydroxy-4-trifluoromethyl-benzoic acid (582 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccc(Br)cc1
Product: O=C(NCc1ccc(Br)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 4-bromo-benzylamine (91 mg, 0.49 mmol). The title compound was obtained as a yellow solid (19 mg, 35% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.41 (1H, m), 8.99 (2H, s), 8.46 (1H, s), 7.53 (2H, dd), 7.24 (2H, dd), 4.43 (2H, m). MS m/z: 515.93, 517.96, 519.92 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[C:15]([CH3:24])=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[OH:25].Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:25][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[CH:9][CH:8]=[C:7]2[O:13][C:14]1[C:15]([CH3:24])=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
7-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (25 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. 1-Bromo-2-chloroethane (54 mg) and potassium carbonate (52 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give 6-(2-chloroethoxy)-7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (24 mg, yield 79%).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:11][C:4]1[CH:5]=[C:6]([C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:10])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: CN1CCNCC1
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O

Procedure:
5-Formyl-4-methyl-1H-pyrrole-2-carboxylic acid was amidated with 1-methylpiperazine using General Amidation Procedure 1 to give 3-Methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde. MS m/z 236 [M+1].
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:11]([CH3:15])[O:12]2)=[CH:7][CH:6]=1>C(O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:14][C:13]=3[OH:12])=[N:2][NH:3][C:11]=2[CH3:15])=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2c(C)oc3cc(O)ccc3c2=O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(-c3ccc(O)cc3O)n[nH]c2C)cc1

Procedure:
Hydrazine hydrate (2 ml, ˜55%) was added to a suspension of 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one (0.57 g, 2 mmol) in ethanol (15 ml) and the mixture heated under reflux for ˜5 hrs., to give a pale brown solution. The solution was allowed to cool and concentrated to a pale yellow solid, the solids were washed with water, to give the pyrazole as an off-white solid, dried in vacuo, (0.45 g). Sample was recrystallised from boiling toluene, to give the 4-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol as a pale brown crystalline solid, washed with hexane, dried in vacuo.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].N1C=CC=CC=1>ClCCl>[C:1]([O:12][CH:11]([C:10]1[S:9][CH:8]=[N:7][C:6]=1[CH3:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: Cc1ncsc1C(O)c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccccc1)c1scnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (0.6 ml) was added to a solution of 1-(4-methyl-5-thiazolyl) -1-phenylmethanol (800 mg) and pyridine (0.5 ml) in dichloromethane (30 ml) at 0° C. under an atmosphere of dry nitrogen. The mixture was allowed to warm room temperature and was then stirred overnight. Evaporation and purification of the residue by flash chromatography gave the title compound.
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].O>N1C=CC=CC=1>[C:10]1(=[N:15][OH:16])[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: ON=C1CCCc2ccccc21

Procedure:
A solution of 7-methoxy-1-tetralone (10 g; 56.8 mmol) in pyridine (28 ml) and hydroxylamine hyrochloride (9 g; 130.6 mmol) was refluxed for 12 hours. The mixture was poured into water and extracted with CH2Cl2. The organic phase was washed with 1N HCl and 0.5N NaHC3, dried over MgSO4 and evaporated to give 7-methoxy-,1,2,3,4-tetrahydronaphthalen-1-one oxime as a brown solid (10 g; 92.5%).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:69][C:70]1[S:71][CH:72]=[CH:73][N:74]=1>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:69][C:70]3[S:71][CH:72]=[CH:73][N:74]=3)=[O:33])=[CH:34][CH:35]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: Nc1nccs1
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)Nc3nccs3)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2-aminothiazole (8.26 mg, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (5.8 mg, 18%). LC-MS m/z 590 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:30][CH:31]=2)O1>>[OH:17][CH2:16][C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[N:12][CH:11]=[C:10]([C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)=[N:30][CH:31]=3)[N:9]2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: OCc1cn2ccnc(N3CCOCC3)c2n1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(CO)cn34)cn2)CC1

Procedure:
Compound 1d was subjected to Suzuki coupling reaction conditions with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate using the method described in Example 1, Step G to obtain compound 30a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H33N7O4: 496.2 (M+H). Found 496.3.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)=[C:15]([CH3:31])[CH:14]=2)[N:3]=1.[CH3:32][C:33]1[NH:37][N:36]=[C:35]([NH2:38])[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:18]1[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:38][C:35]3[CH:34]=[C:33]([CH3:32])[NH:37][N:36]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][C:15]([CH3:31])=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)[CH:17]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(C(F)(F)F)c(Nc4cc(C)[nH]n4)n3)cc2C)cc1
Temperature: 150 °C

Procedure:
The mixture of 4′-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide (Step 1, 20 mg, 0.044 mmol), 5-methyl-1H-pyrazol-3-amine (4.3 mg, 0.044 mmol), Xantophos (5.0 mg, 0.009 mmol), paladium acetate (II) (1.0 mg, 0.004 mmol), and cesium carbonate (28.6 mg, 0.088 mmol) in 2.0 mL of THF is heated at 150° C. in a microwave reactor for 25 min. The reaction mixture is filtered, the filtrate is concentrated in vacuo, and purified by preparative RP-HPLC to afford 5′-Methoxy-N,2′-dimethyl-4′-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)biphenyl-4-carboxamide; ESMS m/z 512.2 (M+H+).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[F:29])=O.[CH:30]([NH2:32])=[S:31].[OH-].[Na+]>O1CCOCC1>[F:29][C:23]1[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:32]=[CH:30][S:31][CH:19]=1
Reactant: O=C(CBr)c1ccc(O)cc1F
Reactant: NC=S
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: NC=O
Product: Oc1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirred solution of phosphorus pentasulfide (4.0 g, 9.0 mmol) in dioxane (40 ml) was added formamide (4.8 g, 106 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (1.2 g, 5.15 mmol) in dioxane (14 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (864 mg, 86% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O1CCOCC1.O>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: C1COCCN1
Reactant: Cc1ccc(OCCCBr)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(OCCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A solution of the 4-(3-bromo-propoxy)-1-methyl-2-nitro-benzene V-h (500 mg, 1.82 mmol) in dry dioxane (30 mL) was treated with K2CO3 (1.01 g, 7.28 mmol) and morpholine (319 μl, 3.65 mmol) and heated to 100° C. for 6 h. The cooled mixture was diluted with water and extracted with DCM. The combined organics were dried (MgSO4), filtered and evaporated before purification by column chromatography (SiO2; eluting with 2% EtOH in DCM) to afford the desired product as a yellow-orange oil V-i (356 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=2.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.05 (dd, J=8.5, 2.7 Hz, 1H), 4.06 (t, J=6.3 Hz, 2H), 3.79-3.66 (m, 4H), 2.49 (dt, J=9.0, 5.1 Hz, 9H), 2.07-1.88 (m, 2H).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.O(C)[Na].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.C1COCC1>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH2:2][CH2:1][OH:12])[CH:11]=[CH:10][C:8]=1[O:9][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCCc1ccccc1
Reactant: COc1cc(CCO)ccc1O
Agent: CO[Na]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CCO)ccc1OCCCCc1ccccc1

Procedure:
To a solution of homovanillyl alcohol (10 g, 59.3 mmol) in dry methanol (140 ml), there is added 12 ml of 1N NaOCH3 in methanol. After addition of a solution of 1-bromo-4-phenylbutane (12.6 g, 59.3 mmol) in THF (10 ml) the reaction mixture is kept at reflux for 3 hours. After cooling the reaction is quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate (2 times, 500 ml each). The organic layer is dried over MgSO4 and the solvent is removed by evaporation. The crude residue is then purified on silica gel using ethyl acetate/n-hexane (1/1) as mobile phase.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 97.8 %

Procedure:
Beginning with 6.0 gm (37.0 mMol) 6-nitro-1H-indole and 11.4 gm (74.0 mMol) 4-piperidone hydrochloride monohydrate, 8.8 gm (97%) of the title compound were recovered as an orange solid.