Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([CH:26]=[O:27])[C:24]=1F)[C:20]#[N:21].O>C(#N)C>[CH3:1][C@@H:2]1[CH2:3][N:4]([C:24]2[C:23]([CH:26]=[O:27])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[F:16])[CH2:5][C@@H:6]([CH3:8])[O:7]1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: N#Cc1cc(F)c(F)c(C=O)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H]1CN(c2c(F)cc(C#N)cc2C=O)C[C@@H](C)O1
Temperature: 80 °C
Yield: 103.5 %

Procedure:
(2R,6R)-2,6-dimethylmorpholine (8.0 g, 70.0 mmol) followed by triethylamine (13.7 mL, 98.0 mmol) is added slowly to a solution of commercially available 3,4-difluoro-5-formylbenzonitrile (11.1 g, 66.7 mmol) in acetonitrile (500 mL) at room temperature. The mixture is warmed to 80° C. for 16 hours. After allowing to cool to room temperature, water (500 mL) is added and the mixture extracted twice with ethylacetate (250 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound (18.1 g): LCMS (M+H) 262.3.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH:43][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 43.3 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 26 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 601 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4]>N.[Ni]>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:15])[F:14])=[CH:8][CH:7]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(C#N)c1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: N
Product: CC(C)(CN)c1ccc(C(F)(F)F)cc1
Yield: 106.2 %

Procedure:
Using analogous reaction conditions as described in Example 16, step 1, 2-methyl-2-(4-trifluoromethyl-phenyl)-propionitrile (I-20a: 1.2 g, 5.6338 mmol) in methanolic ammonia (10 mL) was reacted with to Raney nickel (200 mg) to afford 1.3 g of the crude product which was used in the next step without further purification.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCCC.C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[C:22]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH:17]=[CH:18][C:19]=1[F:24]
Reactant: Fc1ccc(Cl)cc1F
Reactant: COc1ccc([Mg]Br)cc1
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccc(-c2ccc(F)c(F)c2)cc1
Reaction time: 24 h
Yield: 92 %

Procedure:
Using a THF solution of p-methoxyphenylmagnesium bromide (2.34 mL, 0.64 M, 1.5 mmol), 4-chloro-1,2-difluorobenzene (148.6 mg, 1.0 mmol), FeF3.3H2O (8.34 mg, 0.05 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (64.1 mg, 0.15 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours, and then at 80° C. for 12 hours, in the same manner as in Example 2. After performing silica gel column chromatography (toluene=15, 30 and 50% in hexane), the above compound was obtained as a white solid (0.215 g, yield=92%, purity=>99% (GC analysis)).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[F:31])=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19]>>[F:31][C:22]1[CH:23]=[C:24]([C:27]([OH:30])([CH3:28])[CH3:29])[CH:25]=[CH:26][C:21]=1[C:15]1[S:14][C:13]([NH:12][C:2]2[N:7]=[N:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)=[C:17]([C:18]([NH2:20])=[O:19])[CH:16]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(O)c1ccc(Cl)nn1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(C(C)(C)O)nn3)s2)c(F)c1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with starting materials 2-(6-chloropyridazin-3-yl)propan-2-ol (Intermediate 45) (117 mg, 0.68 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (200 mg, 0.68 mmol).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[C:19]([N:26]1[CH2:34][CH2:33][CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:30]([CH:29]2[CH2:33][CH2:34][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:27][CH2:28]2)=[O:31])[CH:6]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 73.9 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)pyridin-2-ylamine (400 mg, 1.61 mmol) in N,N-dimethylformamide (16 ml) were added Boc-isonipecotic acid (554 mg, 2.42 mmol), triethylamine (0.673 ml, 4.83 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.42 mmol), followed by stirring at room temperature for 6.5 hrs. Boc-isonipecotic acid (554 mg, 2.42 mmol), triethylamine (0.673 ml, 4.83 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.42 mmol) were further added thereto, followed by stirring at room temperature for 3 hrs. Furthermore, Boc-isonipecotic acid (554 mg, 2.42 mmol), triethylamine (0.673 ml, 4.83 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.42 mmol) were added thereto, followed by stirring at room temperature for 3 days. To the reaction mixture was added ethyl acetate (150 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then subjected to silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1, then ethyl acetate) to provide a crude product of the titled compound (548 mg) as a yellow oil.
Reaction SMILES: [F-:1].[F-].[F-].C(N(S([O-])([O-])=O)CC)C.[Cl:13][C:14]1[C:15]2[CH2:22][CH2:21][CH:20](O)[C:16]=2[N:17]=[CH:18][N:19]=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[C:15]2[CH2:22][CH2:21][CH:20]([F:1])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: [F-]
Reactant: OC1CCc2c(Cl)ncnc21
Agent: CCN(CC)[SH](=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Product: FC1CCc2c(Cl)ncnc21
Reaction time: 0.17 h

Procedure:
Under ice cooling, 3.9 ml of diethylaminosulfite trifluoride (DAST) was added dropwise to 5.00 g of 4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine obtained above dissolved in 40 ml of chloroform, and the mixture was stirred at the same temperature for 10 minutes. After the solvent was removed under reduced pressure, water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and condensed. The obtained residue was applied to silica gel column chromatography to obtain 3.09 g of the title compound as a yellow oily product.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[C:23]1([CH2:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)Cc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)c1ccc(OC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.9 %

Procedure:
To the product from step 1 (5 mg, 0.129 mmol) was added 4M HCl in dioxane (6 mL) and the resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo to obtain the title product as a yellow solid (43 mg, 99%): MS; m/z 296 (M+H): LCMS (UV) 99%. 1H NMR (400 MHz, DMSO-d6) δ 1.72-1.77 (m, 1H), 1.87-2.01 (m, 2H), 2.11-2.15 (m, 1H), 3.21-3.23 (m, 2H), 3.91-3.93 (m, 1H), 4.22-4.27 (dd, 1H J1=8, J2=10.8 Hz), 4.33-4.37 (dd, 1H J1=4 Hz, J2=10.8 Hz), 4.33 (s, 2H), 7.09 (d, 2H, J=9.2 Hz), 7.20-7.33 (m, 4H); 8.05 (d, 2H, J=9.2 Hz), 9.1 (s, 1H), 9.6 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:36][C:35]1=[O:48]>>[Si:41]([O:40][CH2:39][C@@H:38]1[CH2:37][CH2:36][C:35](=[O:48])[N:34]1[C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:20])[CH3:21])=[O:23])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1c1cc(F)ccc1CN
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one, derived from reduction of intermediate 121, (R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile. 1HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.52-7.33 (7H, m), 7.02 (1H, broad s), 5.60 (2H, s), 4.60-4.20 (2H, m), 4.02 (3H, t, J=5.0 Hz), 3.89 (3H, t, 5.0 Hz), 3.53 (2H, broad s), 2.51 (2H, s), 2.44-2.26 (2H, m), 1.94 (1H, broad s), 1.57 (3H, s), 1.55 (3H, s), 0.82 (9H, broad s), −0.02 (6H, s). LCMS (M+H)+ m/z 665.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13].[S:34](N)([NH2:37])(=[O:36])=[O:35].CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:37][S:34]([NH:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13])(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCN)c2cccc(Cl)c2)C1
Reactant: NS(N)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCNS(N)(=O)=O)c2cccc(Cl)c2)C1
Temperature: 110 °C
Reaction time: 0.03 h
Yield: 59.3 %

Procedure:
To a 50 mL round bottom flask were added the TFA salt of (R)-tert-butyl 3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.0803 g, 0.16 mmol, 1.0 equiv), sulfamide (0.2368 g, 2.46 mmol, 15 equiv), 1,4-dioxane (5 mL) and DIEA (1 mL). The resulting mixture was heated at 110° C. for 2 h. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 1.5 min, flow rate 25 mL/min) to give 0.0438 g (59%) of (R)-tert-butyl 3-((S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate. LC-MS (3 min) tR=1.74 min, m/z 486, 484 (MNa+), 362.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[NH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>CO.O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1n[nH]c2ccc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNC(=O)c1n[nH]c2ccc(C(=O)O)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of methyl 3-(methylcarbamoyl)-1H-indazole-5-carboxylate (400 mg, 1.7 mmol) in methanol (10 mL) and water (10 mL), was added lithium hydroxide monohydrate (0.36 g, 8.5 mmol). The reaction was heated to 60° C. and was stirred overnight. The methanol was removed under reduced pressure and the remaining residue was acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (350 mg, 94%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ): 13.99 (s, 1 H), 8.85 (s, 1 H), 8.47-8.48 (m, 1 H), 7.94-7.96 (m, 1 H), 7.65-7.68 (m, 1 H), 2.82 (d, J=4.4 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:29])[CH:16]([CH:21](O)[CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH2:17][C:18]=3[O:19]C)[CH:9]=2)=[CH:4][CH:3]=1.Cl>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([CH:14]3[C:15](=[O:29])/[C:16](=[CH:21]/[CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)/[CH2:17][C:18]3=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)C(C(O)C2CCOCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Temperature: 120 °C
Yield: 33.8 %

Procedure:
To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-cyclopent-2-enone (280 mg, 0.65 mmol) in acetone (2 ml) was added 2N hydrochloric acid (2 ml) and the reaction heated to 120° C. for 60 minutes by microwave irradiation. The crude reaction was diluted with ethyl acetate (25 ml) and washed with saturated aqueous ammonium chloride solution (25 ml), brine (25 ml) and the organic layer dry loaded onto silica and purified by flash chromatography to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (88 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][S:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[O:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:30].[Na+]>CO.CC#N.O>[O:30]=[S:16]1[CH2:15][CH2:14][N:13]([C:11]2[CH:10]=[CH:9][C:8]([NH:19][C:20]([C:22]3[O:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=3)=[O:21])=[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:12]=2)[CH2:18][CH2:17]1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(N3CCSCC3)cc2N2CCCCC2)o1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2ccc(N3CCS(=O)CC3)cc2N2CCCCC2)o1
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
To a solution of 25.3 mg (0.0638 mmol) 5-cyano-furan-2-carboxylic acid (2-piperidin-1-yl-4-thiomorpholin-4-yl-phenyl)-amide (as prepared in Example 6, step (b)) in 2 mL of MeOH-MeCN (1:1) was added 15.0 mg (0.0702 mmol) of sodium periodate in 0.20 mL of water. After stirring for 1.5 h, an additional 4.1 mg (0.019 mmol) of sodium periodate was added. After stirring for 1.5 h, a final 9.5 mg (0.11 mmol) of sodium periodate was added and the mixture stirred for 24 h. The mixture was concentrated to near dryness, extracted with EtOAc (10 mL) and dried (Na2SO4). Concentration and chromatography on a 5-g silica SPE column with a gradient of 60-100% EtOAc-dichloromethane afforded 13.3 mg (51%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.51 (br s, 1H), 8.35 (d, 1H, J=8.9 Hz), ca. 7.2 (d, 1H, obscured by CHCl3 peak), 7.23 (d, 1H, J=3.7 Hz), 6.81 (d, 1H, J=2.6 Hz), 6.77 (dd, 1H, J=8.9, 2.6 Hz), 3.94 (m, 2H), 3.51 (m, 2H), 2.91 (m, 4H), 2.85 (m, 4H), 1.81 (m, 4H), and 1.66 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H24N4O3S, 413.2 (M+H), found 413.1.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([SH:21])([CH3:20])[CH3:19].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:21][C:18]([CH3:20])([CH3:19])[CH3:17])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)(C)S
Reactant: O=Cc1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Sc1c(Br)cccc1C=O
Temperature: 110 °C
Yield: 98.1 %

Procedure:
A mixture of 3-bromo-2-fluorobenzaldehyde (5.0 g, 25 mmol), potassium carbonate (4.0 g, 30 mmol) and 2-methyl-2-propanethiol (5.5 mL, 49 mmol) in dry DMF (25 mL) was heated to 110° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, added to water (100 mL) and extracted with DCM (3×50 mL). The combined organic fractions were washed with water (50 mL), dried, and evaporated to afford 6.7 g (98%) of the crude title compound which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 1.31 (s, 9H), 7.26-7.41 (m, 1H), 7.93-7.99 (m, 2H), 10.73 (s, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][S:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29]C=3C(OC)=O)[C@@H:18]([OH:33])[C@H:17]2[OH:34])[CH2:2]1.SC1C=CC=C[N:37]=1.C(C1C=CC=CC=1S)(OC)=O>>[O:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:17]([OH:34])[C@H:18]([OH:33])[C@@H:19]([CH2:21][S:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][N:37]=3)[O:20]2)[CH2:2]1
Reactant: Sc1ccccn1
Reactant: COC(=O)c1ccccc1SC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Agent: COC(=O)c1ccccc1S
Product: O[C@@H]1[C@H](O)[C@@H](CSc2ccccn2)O[C@H]1n1cnc2c(N[C@H]3CCOC3)ncnc21

Procedure:
Compound 28 was prepared in the manner of compound 23 substituting 2-mercaptopyridine for 2-carbomethoxythiophenol [MS 431.4 (M+1)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.Cl[CH2:13][CH2:14][N:15]([CH2:23][CH2:24]Cl)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[CH2:16]([N:15]1[CH2:23][CH2:24][N:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cc(F)cc2c1OCC2
Reactant: ClCCN(CCCl)Cc1ccccc1
Solvent: CCCCO
Product: Fc1cc2c(c(N3CCN(Cc4ccccc4)CC3)c1)OCC2
Yield: 73.3 %

Procedure:
A solution of 5-fluoro-7-amino-2,3-dihydrobenzofuran (1.38 g, 9 mmol) and bis(2-chloroethyl)-benzylamine (3.14 g, 14 mmol) in butanol (20 ml) was stirred at 100° C. for 10 hours. The salt was filtered off, washed with ethyl ether (30 ml) and dried under vacuum: mp 232-233.5° C. The salt was converted to the free base to afford 2.06 g (73%) of the title compound.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][CH:10]([OH:13])[CH2:11][Cl:12])[O:3]1.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[Cl:12][CH2:11][CH:10]1[O:13][C:6](=[O:8])[CH2:5][C:4](=[O:3])[CH2:9]1
Reactant: CC1(C)OC(=O)C=C(CC(O)CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CC(=O)OC(CCl)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
A mixture of 940 mg (4.26 mmol) of (-)-2,2-dimethyl-6-(3-chloro-2-hydroxypropyl)-1,3-dioxin-4-one (98% ee), 882 mg (6.39 mmol) of potassium carbonate and 10 ml of methanol was stirred at room temperature for 12 hours. After completion of the reaction, methanol was distilled off, and the resultant residue was neutralized with 10% HCl and then extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography (an eluent of hexane:ethyl acetate=3:1), thereby obtaining 510 mg (yield 74%) of (-)-6-chloromethyltetrahydropyran-2,4-dione.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1C=CC=CC=1.[CH3:22][CH:23]([N:25]1[C:29]([NH2:30])=[CH:28][CH:27]=[N:26]1)[CH3:24]>C(O)(=O)C>[CH3:22][CH:23]([N:25]1[C:29]2[N:30]=[C:9]([C:10]3[CH:14]=[CH:13][S:12][CH:11]=3)[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:28]=2[CH:27]=[N:26]1)[CH3:24]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccsc1
Reactant: CC(C)n1nccc1N
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccsc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 2,4-dioxo-4-(3-thienyl)butanoate (542 mg, 2.397 mmol), benzene (5 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and acetic acid (5 ml). The crude product was purified using column chromatography (silica gel, eluent: 0 to 100% EtOAc/hexanes) to afford the product as 590 mg (78%). LCMS E-S (M+H)=315.8. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53 (t, J=6.8 Hz, 3 H), 1.66 (d, J=6.8 Hz, 6 H), 4.56 (q, J=7.1 Hz, 2 H), 5.43 (spt, J=6.7 Hz, 1 H), 7.47 (dd, J=5.1, 3.0 Hz, 1 H), 7.84-7.95 (m, 1 H), 8.08-8.18 (m, 2 H), 8.32-8.43 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[NH3:10]>>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH2:10])[C:2]=1[NH2:1]
Reactant: N
Reactant: Nc1c(Cl)ncnc1Cl
Product: Nc1ncnc(Cl)c1N
Temperature: 118 °C

Procedure:
A suspension of 5-Amino-4,6-dichloropyrimidine (3 g, 0.02 mol) in ammonia (25 mL, 7N/MeOH, 0.175 mole) was heated at 118° C. overnight(under pressure). The reaction was cooled to 23° C., filtered and washed with ethanol to obtain 1.92 g (70%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:33][CH3:34])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:31]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C23H22ClN5O2, 435.9