Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:27][Mg]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:27]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C

Procedure:
In a solution of 1.4 g of 2-chloro-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]benzaldehyde in 50 mL of diethyl ether under nitrogen atmosphere, 6.6 mL of a solution (0.87 mol/L) of methyl magnesium bromide in tetrahydrofuran was added dropwise with stirring at room temperature. After the completion of the addition dropwise, the mixture was continued to stir under reflux with heating further for 30 minutes. After the completion of the reaction, 5 mL of ammonium chloride aqueous solution was added in the reaction mixture under cooling with ice and with stirring, the mixture was extracted with ethyl acetate (50 mL×1), the organic phase was washed with water (30 mL×2), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and then the solvent was distilled off under reduced pressure to obtain 1.5 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: Br[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:20]=1>>[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[C:26]([CH2:2][C:3]3[NH:12][C:11](=[O:13])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)=[C:25]([OH:30])[CH2:24]2)[CH:20]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=c1[nH]c(CBr)nc2ccccc12
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ccccc4c(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 19 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(bromomethyl)-quinazolin-4(3H)-one (Example B(55), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 19%.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=[C:9]([NH2:16])[C:8]=2[N:7]=[C:6]1[CH2:17][NH:18][O:19][CH3:20])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>ClCCl.C1(C(Cl)=O)CC1>[NH2:16][C:9]1[C:8]2[N:7]=[C:6]([CH2:17][N:18]([O:19][CH3:20])[C:31]([CH:28]3[CH2:30][CH2:29]3)=[O:32])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:13]=2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: CONCc1nc2c(N)nc(C)c(C)c2n1CC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(Cc1nc2c(N)nc(C)c(C)c2n1CC(C)C)C(=O)C1CC1
Temperature: -5 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
Under a nitrogen atmosphere, 1-isobutyl-2-[(methoxyamino)methyl]-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.53 g, 1.91 mmol) was dissolved in dichloromethane (19 mL) and cooled to −5° C. Triethylamine (293 uL, 2.10 mmol) was added followed by dropwise addition of cyclopropane carbonyl chloride (173 uL, 1.91 mmol). The solution was allowed to stir at RT for 2 hours, then cooled back to −5° C. More triethylamine (38 uL, 0.27 mmol) and cyclopropane carbonyl chloride (23 uL, 0.25 mmol) were added and the reaction was allowed to stir at 0° C. for 45 minutes. More cyclopropane carbonyl chloride (5 uL, 0.06 mmol) was added and stirring continued for another 30 minutes. Dichloromethane (100 mL) was added and the solution was washed successively with saturated aqueous sodium bicarbonate (30 mL), water (3×25 mL), and brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by HPFC eluting with a gradient of 0-35% CMA in chloroform and then recrystallized from ethyl acetate/hexanes to provide 292 mg of pure product as an off-white powder, mp 135.0-137.0° C. Anal. Calcd for C18H27N5O2 C, 62.59; H, 7.88; N, 20.27. Found: C, 62.68; H, 7.82; N, 19.93.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]([OH:16])=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18].CCN=C=NCCCN(C)C.Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([NH:39][NH2:40])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(#N)C.C1COCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]3[O:16][C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)=[N:39][N:40]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: NNC(=O)c1ccccn1
Reactant: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1nnc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 16.9 %

Procedure:
(4-Chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)acetic acid (0.017 g, 0.065 mmol) and EDCl (0.014 mg, 0.072 mmol) were combined in acetonitrile (3 mL) and stirred at rt for 3 min. 2-Pyridinecarbohydrazide (0.0094 g, 0.068 mmol) was added next and the resulting mixture was stirred for 60 min. To this solution was added THF (THF 3 mL) followed by tosyl chloride (0.015 g, 0.078 mmol) and P-BEMP (0.148 g, 0.325 mmol, 2.2 mmol/g resin load). The reaction vessel was sealed and heated to 100° C. in a microwave for 5 min. The resin was filtered away and washed with CH2Cl2 (×2). The concentrated filtrate was purified (SiO2, 25% EtOAc/hexanes) to afford the title compound (0.004 g): MS (APCl) m/z 365 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=[O:29])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[H-].[Na+].S(OC)(O[CH3:36])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:27])([F:28])[C:23]([F:25])([F:26])[F:24])[N:17]=[C:16]2[O:29][CH3:36])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.51 g of isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-pentafluoroethyl -1(2H)-pyrimidinyl ]-4-fluorobenzoate are added at room temperature while stirring to a suspension of 0.93 g of a 55% sodium hydride dispersion in 25 ml of dimethylformamide and the mixture is stirred at room temperature for 30 minutes. The mixture is subsequently treated with 4.04 g of dimethyl sulphate and stirred at 50° C. for 4 hours. The reaction mixture is cooled and poured into 500 ml of water, and the aqueous solution is extracted twice with 100 ml of ethyl acetate each time. The organic phase is washed twice with 100 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is separated by chromotography on a silica el column using n-hexane/diethyl ether (2:1) as the eluent. The product is recrystallized from n-hexane. There is obtained isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-pentafluoroethyl -1(6H)-pyrimidinyl]-benzoate, m.p. 82°-84° C.
Reaction SMILES: [O:1]([C:8]1[C:13]([NH2:14])=[C:12]([C:15]#[C:16][CH3:17])[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH3:17][C:16]1[NH:14][C:13]2[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][CH:10]=[N:11][C:12]=2[CH:15]=1
Reactant: CC#Cc1ncnc(Oc2ccccc2)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
4-Phenoxy-6-prop-1-yn-1-ylpyrimidin-5-amine (776.0 mg) was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. To this solution was added dropwise a 1.0 M solution (4 mL) of potassium tert-butoxide in tetrahydrofuran, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) to give the title compound (578.6 mg) as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[C:38]([OH:39])=[CH:37][CH:36]=[CH:35][C:33]=1[OH:34]>ClCCl.O>[OH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:38]([OH:39])[C:32]=1[NH:31][C:16](=[O:18])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: Nc1c(O)cccc1O
Reactant: COc1ccc(CC(=O)O)cc1OC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2c(O)cccc2O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A suspension of 3-cyclopentyloxy-4-methoxyphenylacetic acid (2.49 g) and 1,1'-carbonyldiimidazole (2.31 g) in dichloromethane (10 ml) was stirred at room temperature, under argon, for 2 hours. The resulting solution was added to a stirred suspension of 2-aminoresorcinol (1.62 g) in dichloromethane (15 ml) and the mixture stirred at room temperature, under argon, overnight. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with water (100 ml), 1N HCl (100 ml) and brine (100 ml), dried over CaSO4 and evaporated in-vacuo to yield the title compound (2.122 g, 60%) as a beige solid. δH (250MHz;d6DMSO) 1.53-1.95 (SH,m,4×CH2), 3.65 (2H, s,CH2), 3.70 (3H,s,OMe), 4.75 (1H,m, CH), 6.3 (1H,s,ArH), 6.35 (1H,s,ArH), 6.90 (4H,m,ArH), 9.40 (2H,s,ArOH), 9.6 (1H,s,CONH).
Reaction SMILES: [CH3:1][C:2](=O)[C:3]([CH3:6])([CH3:5])[CH3:4].[C:8]([NH:12][NH2:13])([CH3:11])([CH3:10])[CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:8]([NH:12][N:13]=[C:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)C(C)(C)C
Reactant: CC(C)(C)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(=NNC(C)(C)C)C(C)(C)C

Procedure:
To a solution of 5 g. (0.05 m.) pinacolone in 50 ml. benzene was added 5 g. (0.057 m) tert.-butylhydrazine and a spatula tip of para-toluenesulfonic acid. The flask was fitted with a Dean Stark trap and the reaction refluxed until 0.9 ml. (0.05 m.) of water was azeotroped off. The solution was cooled down and the benzene stripped off leaving 8.5 g. (100%) of a white fluffy solid. The infra-red spectrum of the solid was consistent with the structure of the proposed compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH3:22])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][N:21]([CH3:22])[C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCc1ccc(Br)cc1)C(=O)OCc1ccccc1
Yield: 64.8 %

Procedure:
Benzyl chloroformate (0.97 mL, 6.7 mmol) was added dropwise to a solution of 23B (1.1 g, 5.1 mmol)in CH2Cl2 (26 mL) and triethylamine (1 mL, 7.5 mmol). The reaction mixture washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (0% to 50% EtOAc in hexanes) afforded 28C (1.15 g, 65%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.70-2.94 (m, 5 H) 3.47 (m, 2 H) 5.08 (m, 2 H) 6.90-7.12 (m, 2 H) 7.26-7.44 (m, 7 H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:32]1([C:38](=[O:44])[CH2:39][C:40](=O)[CH2:41][CH3:42])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:41](/[C:40](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:39]/[C:38](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:42]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Product: CC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.177 mmol) of Intermediate 51 and 34 mg (0.194 mmol) of Intermediate 16 to yield 30 mg of Example 17: TLC (DCM/MeOH (4:1): Rf=0.63; 1H NMR (DMSO-d6, 400 MHz) δ11.49 (d, 1H, J=9.6), 7.77 (m, 4H), 7.37 (m, 3H), 7.10 (d, 2H, J=8.8), 6.97 (d, 2H, J=9.2), 6.79 (d, 2H, J=9.2), 5.54 (s, 1H), 4.66 (septuplet, 1H, J=6.0), 4.12 (t, 2H, J=6.8), 4.04 (m, 1H), 3.35 (m, 1H), 3.11 (m, 1H), 2.84 (t, 2H, J=6.8), 2.72 (dd, 1H, J=13.9, 9.2), 2.28 (s, 3H), 1.99 (m, 2H), 1.26 (d, 6H, J=6.0), 0.91 (m 3H, J=7.6); low resolution MS (ES+)m/e 583.1 (MH+).
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=[O:3])[CH3:2].[NH2:18]O.Cl.O>CCO>[CH3:2][C:1]1[O:3][N:18]=[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=12
Reactant: NO
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1onc2c1CNCC2
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A mixture of tert-butyl 3-acetyl-4-oxopiperidine-1-carboxylate (1.50 g) and NH2OH.HCl (0.50 g) in anhydrous EtOH was heated to reflux for 0.5 h. The reaction mixture was cooled to rt, and then poured into 20 mL of water. The resulted mixture was extracted with CH2Cl2 (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo, the residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (0.45 g, 52.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 139.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.31 (s, 3H), 2.86 (t, J=8.0 Hz, 2H), 3.15 (t, J=8.0 Hz, 2H), 3.92 (s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH2:15]([O:18][NH2:19])[CH:16]=[CH2:17]>>[CH2:15]([O:18][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])[CH:16]=[CH2:17]
Reactant: C=CCON
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Agent: Cl
Product: C=CCON=C(C(=O)O)c1ccc(O)c(Cl)c1
Yield: 98.1 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2 g.) and O-allylhydroxylamine hydrochloride (1.1 g.) were reacted according to a similar manner to that of Preparation (5-2)(a) to give oil of 2-allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.5 g.).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([NH2:16])[N:10]=1.CCN(CC)CC>CC#N>[Cl:8][C:9]1[CH:14]=[C:13]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[CH2:1][CH3:2])[N:12]=[C:11]([NH2:16])[N:10]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC[C@@H]1CCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@@H]1CCCN1c1cc(Cl)nc(N)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A mixture of (2R)-2-ethylpyrrolidine (80 mg, 0.59 mmol), 4,6-dichloro-2-pyrimidinamine (119 mg, 0.726 mmol) and Et3N (0.25 mL, 1.77 mmol) in CH3CN (6 mL) was stirred overnight at 80° C. The mixture was poured onto water (˜150 mL), sonicated and filtered to afford the title compound (94 mg, 70%) as a white solid. LC-MS (ES) m/z=227, 229 [M+H]+.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.[C:29]([CH2:31][C:32](ON1C(=O)CCC1=O)=[O:33])#[N:30]>CN(C=O)C>[C:29]([CH2:31][C:32]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([N:4]2[C:3](=[O:2])[NH:11][C:10]3[C:5]2=[N:6][C:7]([C:12]2[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=24)=[N:8][CH:9]=3)[CH2:24]1)=[O:33])#[N:30]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
To a solution of the compound obtained in example 6 (45 mg, 0.095 mmol) in anhydrous DMF (3 mL), 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (69 mg, 0.38 mmol) and anhydrous TEA (0.09 mL, 0.665 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO2 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 11.7 mg of the desired compound (29% yield).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][N:24]=1>>[CH3:30][O:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[N:28]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: COc1ccnc(Cl)n1
Product: COc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-methoxy-pyrimidine. MS (ESI) mass calcd. for C22H22N4O2S, 406.50; m/z found, 407.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])=[O:30])=[CH:24][CH:23]=1
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(C(=O)C(C)(C)OC(=O)Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 72 mg (0.34 mmol) 2-hydroxy-4'-(methylthio)isobutyrophenone in 1.7 mL of CH2Cl2 were added 0.2 mL of pyridine and 140 mg (0.81 mmol) of 4-fluorophenylacetyl chloride. The mixture was stirred at room temperature overnight and then quenched with NH4OAc buffer. The product was extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography eluting with 8:1 hexane/EtOAc to give 95 mg of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:32][CH2:33][CH2:34][NH2:35])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:35][CH2:34][CH2:33][NH:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Reactant: COc1ccc(NCCN)cc1OC
Product: COc1ccc(NCCNCCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-propyl chloride and 2-(3,4-dimethoxyphenylamino)-ethylamine analogously to Example 6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:18]([O-])=O.[Na+]>Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-[(4-fluorophenyl)sulfonyl]phenylamine (IV, Step II, 3.10 g, 12.3 mmol) in concentrated hydrochloric acid (30 mL) at 0° is treated with sodium nitrite (934 mg, 13.5 mmol) in H2O (15 mL). After 30 min, the mixture is treated with stannous chloride (5.57 g, 24.7 mmol) in concentrated hydrochloric acid (15 mL). The mixture is stirred at 0° for 1 hr, and then at 20-25° for 1 hr. The precipitate is collected and slurried in H2O. The mixture is made basic (sodium hydroxide, 50%) and the solid isolated. The material is partitioned between methylene chloride and saline. The organic layer is dried, filtered, and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 7.85-7.95, 7.74, 7.13, 6.85, 5.64 and 3.65 δ.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:20](O)=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:14][C:15]1[C:20]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1ncccc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Product: Cc1ncccc1OC[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 55.1 %

Procedure:
An ice-cooled solution of 1-t-butoxycarbonyl-2-(S)-azetidinemethanol (from Example 7b, 0.623 g, 3.33 mmol) was allowed to react with 2-methyl-3-hydroxypyridine (0.399 g, 3.66 mmol) under the conditions of Example 2a to yield the title compound (0.511 g, 55%). MS (DCI/NH3) m/e: 279 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.10 (dd, J=4.4, 1.5 Hz, 1H), 7.15-7.06 (m, 2H), 4.54-4.53 (m, 1H), 4.35-4.34 (m, 1H), 4.07 (dd, J=10.3, 2.6 Hz, 1H), 3.96-3.88 (m, 2H), 2.51 (s, 3H), 2.42-2.31 (m, 2H), 1.40 (s, 9H).