Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15](=[O:23])[CH:14]=1>>[Br:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:1]([O-:4])=[O:2])[CH:21]=2)[NH:16][C:15](=[O:23])[CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(CCBr)c2ccccc2[nH]1
Agent: O=S(=O)(O)O
Product: O=c1cc(CCBr)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
To a mixture of nitric acid (60%) (21 ml) and concentrated sulfuric acid (14 ml) was added 4-(2-bromoethyl)-2(1H)-quinolinone (II-2) (3.5 g, 13.9 mmol) under ice-cooling and then the mixture was stirred at 45 ° C. (bath temperature) for 45 minutes.
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27](F)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27]([N:5]3[CH2:6][C:3]([F:7])([F:2])[CH2:4]3)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[O:15]
Reactant: FC1(F)CNC1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(N3CC(F)(F)C3)c(Cl)c2)cc1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 24.6 %

Procedure:
3,3-Difluoroazetidine hydrochloride (98 mg, 0.76 mmol) was added to a suspension of 5-chloro-4-(5-chloro-6-fluoropyridin-3-yloxy)-2-fluoro-N-(methylsulfonyl)benzamide (Example 19, 150 mg, 0.38 mmol) and potassium carbonate (74 mg, 0.53 mmol) in dimethylsulfoxide (1 mL). The reaction mixture was stirred at 90° C. in the microwave for 15 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude compound was purified by reverse phase preparative HPLC eluting with acetonitrile:water (from 5:95 to 95:5) to give the title compound as a colourless solid (44 mg, 25%).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[C:10](=[O:35])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[C:42]([O:46][CH3:47])(=[O:45])[CH:43]=[CH2:44].O>CN(C)C=O>[O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)[C:10](=[O:35])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:44][CH2:43][C:42]([O:46][CH3:47])=[O:45]
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCn1c(=O)n(CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 20 h
Yield: 42 %

Procedure:
2,4-Dioxo-3-[3-(4-diphenylmethoxypiperidino)propyl]-1,2,3,4-tetrahydroquinazoline (3.50 g) obtained in Example 79 and potassium carbonate (1.24 g) were suspended in N,N-dimethylformamide (50.0 ml), and then methyl acrylate (1.01 ml) was added. The reaction mixture was stirred at 120° C. for 20 hours, poured onto an iced water, and then extracted with ethyl acetate. After the extract was washed with water and dried (Na2SO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (3:1, v/v) to give the title compound (1.73 g, 42%) as a crystal. This product was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH2:21])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Product: O=C(COCc1ccccc1)NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)—C-(7-Benzenesulfonyl-chroman-2-yl)-methylamine (130 mg, 0.43 mmol) triethylamine (0.3 mL) and benzyloxy acetyl chloride 77 uL) were added to 3 mL methylene chloride at 0° C. The reaction mixture was stirred at room temperature for three hours and then quenched by addition of water. The mixture was extracted with methylene chloride and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography gave 4.34 mg of (R)—N-(7-benzenesulfonyl-chroman-2-ylmethyl)-2-benzyloxy-acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([N+:13]([O-])=O)=[CH:6][C:5]=1[CH:16]([C:32]1[CH:37]=[C:36]([N+:38]([O-])=O)[CH:35]=[C:34]([CH:41]([CH3:43])[CH3:42])[C:33]=1[O:44][CH2:45][CH3:46])[C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[O:29][CH2:30][CH3:31])[CH3:2]>CCO.C1COCC1.[Ni]>[CH:16]([C:17]1[C:18]([O:29][CH2:30][CH3:31])=[C:19]([CH:26]([CH3:28])[CH3:27])[CH:20]=[C:21]([CH:22]=1)[NH2:23])([C:32]1[C:33]([O:44][CH2:45][CH3:46])=[C:34]([CH:41]([CH3:43])[CH3:42])[CH:35]=[C:36]([CH:37]=1)[NH2:38])[C:5]1[C:4]([O:3][CH2:1][CH3:2])=[C:9]([CH:10]([CH3:11])[CH3:12])[CH:8]=[C:7]([CH:6]=1)[NH2:13]
Reactant: CCOc1c(C(C)C)cc([N+](=O)[O-])cc1C(c1cc([N+](=O)[O-])cc(C(C)C)c1OCC)c1cc([N+](=O)[O-])cc(C(C)C)c1OCC
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1c(C(C)C)cc(N)cc1C(c1cc(N)cc(C(C)C)c1OCC)c1cc(N)cc(C(C)C)c1OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a three-neck round-bottom flask, a sample of 4 (3.63 g, 5.69 mmol) was dissolved in a solution of EtOH/THF (25/180 mL). Rainey nickel (˜100 mg) was added to the mixture, which was then degassed by the freeze-pump-thaw method and the flask was backfilled with anhydrous H2 gas. The reaction was stirred at room temperature under a constant H2 stream for two days and then filtered to remove the Rainey nickel The solvent was removed under reduced pressure. The residue was dissolved in diethyl ether and extracted with a 10% HCl solution (3×, 50 mL). The aqueous phase was washed with hexanes (3×50 mL) followed by addition of 2 M NaOH to a final pH of 10. The precipitated solid was extracted into dichloromethane (3×50 mL). The combined organics were dried with sodium sulfate and the volatiles removed under reduced pressure. The residue was then recrystallized from methanol yielding 2.53 g (81%) of 5 as a colorless crystalline solid. 1H NMR (CDCl3-d) δ ppm 1.14 (18 H, d, J=6.9 Hz), 1.19 (9 H, t, J=7.0 Hz), 3.09 (6 H, br. s.), 3.21 (3 H, spt, J=6.9 Hz), 3.38 (6 H, q, J=6.9 Hz), 6.26 (3 H, d, J=2.9 Hz), 6.37 (3 H, d, J=2.7 Hz), 6.51 (1 H, s). 13C-{1H} NMR, δ 15.5, 24.0, 26.3, 38.4, 69.4, 111.1, 115.2, 138.9, 141.6, 142.9, 147.3. Anal. calcd. for C34H49N3O3: C, 74.55; H, 9.02; N, 7.67. Found: C, 74.26; H, 9.24; N, 7.59.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)[CH:22]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2cccnc2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.15 mmol) and 3-pyridylboronic acid (20 mg, 0.16 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.89 (d, 1H), 8.87 (dd, 1H), 8.65 (m, 1H), 8.26 (dd, 1H), 8.17 (dd, 1H), 8.14 (d, 1H), 8.09 (d, 2H), 7.96 (m, 1H), 7.88 (d, 1H), 7.74 (d, 2H), 7.45 (dd, 1H), 7.38 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Mg]([CH2:15][CH2:16][CH2:17][CH2:18][Mg]Br)Br>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]1([OH:6])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C)cc1Br
Reactant: Br[Mg]CCCC[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of methyl 2-bromo-4-methylbenzoate (5.0 g, 21.3 mmol) in THF (20 mL) was added dropwise BrMg(CH2)4MgBr (50 mL, 25.5 mmol) at 0° C. under nitrogen and then stirred at rt overnight. The reaction mixture was quenched with aqueous NH4Cl and extracted with EA. The combined organic layer was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4. The solution was concentrated and the residue was purified by column chromatography over silica gel eluted with PE-EA (20:110:1) to provide 1-(2-bromo-4-methylphenyl)-cyclopentanol (4.2 g; yield 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1 H), 7.39 (s, 1 H), 7.10 (d, 1 H), 4.84 (s, 1 H), 2.33 (s, 3 H), 1.89-1.74 (m, 8 H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([C:21](N(OC)C)=[O:22])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>C1COCC1>[CH3:1][N:2]1[C:6]([C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:12](=[O:14])[CH3:13])[CH2:20][CH2:19]2)=[O:22])=[CH:5][N:4]=[N:3]1
Reactant: CON(C)C(=O)C1CCN(C(C)=O)CC1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)c2cnnn2C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-1H-1,2,3-triazole (0.28 g, 3.37 mmol) in dry THF (3 mL) was cooled in a −78° C. bath and n-butyllithium (2.5 M in hexanes, 1.26 mL, 3.15 mmol) was added dropwise over a 20 minute period. The suspension was stirred in the cold bath for 30 minutes and then 1-acetyl-N-methoxy-N-methylpiperidine-4-carboxamide (0.74 g, 3.45 mmol, Intermediate 52: step a) dissolved in THF (3 mL) was added dropwise. The resulting suspension was stirred at −78° C. for 5 minutes then warmed to 0° C. and stirred for an additional 30 minutes. The mixture was warmed to room temperature and stirred for 2.5 hours then quenched with saturated aqueous NH4Cl. The aqueous mixture was extracted with EtOAc (2×). The combined EtOAc extracts were dried over Na2SO4, filtered, concentrated to dryness and chromatographed (EtOAc/DCM) to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([O:13]C(=O)C)[CH2:7]2)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[OH:13][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=2)[CH2:9]1
Reactant: CC(=O)OC1Cc2ccc(C(C)=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc2c(c1)CC(O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A solution of acetic acid 5-acetyl-indan-2-yl ester (Compound E-24; 1.50 g, 6.87 mmol) in dioxane (7 mL) was treated with 1.0 N sodium hydroxide (NaOH; 7.7 mL), and the solution was stirred at room temperature overnight. The solution was diluted with H2O (25 mL) and was extracted with CH2Cl2 (2×). The combined extracts were dried (MgSO4) and concentrated to give the title compound (1.06 g, 88%): 1H NMR δ 7.85 (s, 1H), 7.79 (m, 1H), 7.33 (d, J=7.7 Hz, 1H), 4.76 (m, 1H), 3.29-3.21 (m, 2H), 3.00-2.94 (m, 2H), 2.59 (s, 3H), 1.73 (d, J=5.3 Hz, 1H); ELMS m/z 176 (M+, 76), 161 (100).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.[CH3:46][N:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][N:50]=1)[NH2:48]>C(Cl)Cl>[CH3:46][N:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:51][N:50]=1)[NH:48][C:13]([C:10]1[CH:11]=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1)=[O:15]
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: CN(N)c1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(NC(=O)c1cnc(-c2ccccc2)nc1)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid (100 mg, 0.52 mmol), 1-hydroxybenzotriazole (77 mg, 0.57 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (111 mg, 0.57 mmol) and DIPEA (0.57 mmol) in DCM (5 mL) is added N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-hydrazine (109 mg, 0.57 mmol). The reaction mixture is stirred at rt for 18 hours and then concentrated. The residue is purified by silica gel chromatography eluting with 10-75% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic acid N′-methyl-N′-[5-trifluoromethyl-pyridin-2-yl]-hydrazide as a solid (189 mg). MS: 374 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.54 (s, 3H), 6.82 (d, 1H), 7.53-7.59 (m, 3H), 7.74 (d, 1H), 8.45 (d, 2H), 8.53 (d, 2H), 9.25 (s, 2H). IC50=100 nM.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][CH2:20][CH2:21][C:22](O)=[O:23].Br.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][NH:32][CH2:31]2.C(N=C=NCCCN(C)C)C>ClCCl>[O:23]=[C:22]([N:32]1[CH2:31][C:30]2[C:34](=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=2)[CH2:33]1)[CH2:21][CH2:20][CH2:19][N:3]1[CH2:4][CH2:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]1=[O:1]
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Reactant: O=C(O)CCCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(CCCN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Reaction time: 18 h

Procedure:
To 4-(2-oxo-3,3-diphenylpyrrolidin-1-yl)butanoic acid (Example 155A, 0.039 g, 0.121 mmol) and 5-(trifluoromethyl)isoindoline hydrobromide (0.036 g, 0.133 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.032 mL, 0.181 mmol) and the reaction stirred for 18 hours. The reaction was loaded onto a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.0, 1H), 7.45 (d, J=14.3, 1H), 7.36-7.13 (m, 11H), 4.67 (d, J=9.6, 2H), 4.57 (d, J=5.5, 2H), 3.50 (t, J=6.5, 2H), 3.41 (t, J=6.5, 2H), 2.74 (t, J=6.5, 2H), 2.26 (t, J=6.9, 2H), 2.01 (p, J=6.6, 2H); MS (ESI+) m/z 493.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[N:13]1([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[N:3]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: Clc1cncc(-c2ccsc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1cc(-c2cncc(N3CCNCC3)n2)cs1
Temperature: 85 °C

Procedure:
A mixture of the product from step 1 above (1.04 g, 5.29 mmol), piperazine (1.32 g, 15.3 mmol), and K2CO3 (0.81 g, 5.82 mmol) in acetonitrile (6 mL) was heated in a sealed pyrex flask at 85° C. for 8.5 h. The reaction mixture was diluted with dichloromethane, filtered, and concentated in vacuo. The semi-solid residue was purified by column chromatography on silica gel (18×5 cm) using CHCl3/MeOH (9:1)
Reaction SMILES: C=O.[NH2:3][C:4]1[N:5]=[C:6]([NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[S:7][C:8]=1[C:9]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[F:20])=[O:10].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>>[NH2:3][C:4]1[N:5]=[C:6]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:24][CH2:23]2)[S:7][C:8]=1[C:9]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[F:20])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)c(F)c1C(=O)c1sc(NC2CCNCC2)nc1N
Agent: C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)c(F)c1C(=O)c1sc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Yield: 90 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(2,3-difluoro-6-methoxy-phenyl)methanone methanone (0.05 g, 0.14 mmol) (Example 8) was treated with methanesulfonyl chloride in a manner similar to Example 9 except that diisopropylethyl amine was additionally used as a catalyst to give 50 mg (90% yield) of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)thiazol-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone. 1H NMR (DMSO−d6, 300 MHz) δ1.57 (m, 2H, CH2), 1.92 (m, 2H, CH2), 2.85 (m, 5H, SCH3 & NCH2), 3.53 (m, 2H, NCH2), 3.6-4.0 (broad,1H, CH), 3.88(s, 3H, OCH3), 6.72 (m,1H, Aromatic), 7.42 (m,1H, Aromatic), 7.6 (2× brd, 1H, NH), 7.8 (brd, 1H, NH), 7.99 (m, 1H, Aromatic), 9.0 (brd, 1H, NH). LR/LC/MS: (M+H): compatible with 446. Ki CDK1=0.001 μM; Ki CDK2=0.001 μM; Ki CDK4=0.002 μM.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([NH:20][CH2:21][C:22](=O)[CH3:23])=O)=[CH:16][C:15]=3[S:27]([CH3:30])(=[O:29])=[O:28])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34]>O1CCOCC1>[F:1][C:2]1[CH:32]=[CH:31][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]4[S:34][C:22]([CH3:23])=[CH:21][N:20]=4)=[CH:16][C:15]=3[S:27]([CH3:30])(=[O:29])=[O:28])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CC(=O)CNC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(F)cc3c2C)c(S(C)(=O)=O)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: Cc1cnc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)s1
Reaction time: 4.5 h
Yield: 77 %

Procedure:
Into 5 mL of 1,4-dioxane solution of 150 mg of 4-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)sulfonamido-3-methanesulfonyl-N-(2-oxopropyl)benzamide was added 135 mg of diphosphorus pentasulfide, followed by 4.5 hours of heating under refluxing. The reaction was terminated by adding water to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, successively and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1 to 1/1) to obtain 115 mg of the title compound as amorphous.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([OH:12])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].CCCCCC>CN(C)C=O>[C:3]1([CH:9]([O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#CC(O)c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CC(OCC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a stirred suspension of NaH (60%, 76 mg, 1.89 mmol) in 5 mL of anhydrous N,N-dimethylformamide was added 1-phenylprop-2-yn-1-ol (250 mg, 1.89 mmol). After 15 min at room temperature, methyl bromoacetate (179 μL, 1.89 mmol) was added. The resulting mixture was stirred at room temperature for 90 min before it was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×15 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate:hexane (1.9), to provide the title compound as a colorless oil (160 mg, 41% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:28]=[O:29]>C1COCC1>[CH:28]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1)=[O:29]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(C=O)cc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-(4-bromophenyl)morpholine-4-carboxylate (684 mg, 2 mmol, CAS 1131220-82-0) in THF (6 ml) was cooled to −78° C., treated dropwise with n-butyllithium (1.88 ml, 3 mmol, 1.6 M solution in hexane) and stirred 30 min at −78° C. Dimethylformamide (1 ml, 2 mmol) was added dropwise and the mixture was stirred for 2 h at −78° C., and then allowed to warm up to −10° C. The reaction mixture was quenched by addition of saturated ammonium chloride solution (4 ml) and water (4 ml) and the resulting mixture was partitioned between water and ethyl acetate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]2[CH:8]=[N:9][N:10]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:11]=2[CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cc(Br)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To sodium hydride (1.886 g, 47.2 mmol) in DMF (10 ml) stirring at 0° C. was added a solution of 6-bromo-1H-indazol-4-amine (10 g, 47.2 mmol, available from Sinova) in DMF (30 ml) dropwise. NOTE-gas evolution. Upon complete addition the mixture was treated with benzene sulphonyl chloride (6.08 ml, 47.2 mmol) dropwise. The resulting mixture was stirred for 2 hrs at room temperature then the mixture was poured onto ice water (300 ml). The mixture was then extracted with ethyl acetate and the layers separated. The aqueous was re-extracted with ethyl acetate. The organics were then combined and washed with brine, dried over magnesium sulfate then filtered and evaporated to yield a brown gum that was triturated using DCM to yield the title compound as a peachy solid (8.72 g).
Reaction SMILES: [I-].[CH3:2][NH+:3]1[CH2:8][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1>C(O)(C(F)(F)F)=O>[CH3:2][N:3]1[CH2:8][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][N:5]=[CH:4]1
Reactant: COC(=O)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C[NH+](C)C1
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN=CN(C)C1
Temperature: 25 °C

Procedure:
1-Methyl-3-triphenylmethyl-5-methoxycarbonyl-1,4,5,6-tetrahydropyrimidinium iodide (395 mg, 0.75 mmol) is dissolved in TFA (1 ml) with stirring in a stoppered round bottom flask at room temperature. After 18 hours stirring the excess TFA is evaporated in vacuo, and the dark residue triturated with ether. The ether is decanted leaving an oily residue that is taken up in ice cold sat. Na2CO3 and then extracted with chloroform. After drying and evaporation the chloroform fraction gave the free base which is recrystallized (chloroform/hexane) to yellow crystals 88 mg (74%) identified by 300 MHz nmr, ms m/z=156.