Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16][CH3:17])[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=O)C=1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S@@:16]([CH3:17])=[O:26])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(N2CCOC[C@H]2C)nc(Cl)n1
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1cc(C[S@@](C)=O)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
(R)-4-(2-Chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (12.63 g, 46.13 mmol) was dissolved in DCM (100 ml), to this was added mCPBA (7.96 g, 46.13 mmol) in one portion and the reaction mixture was stirred for 10 minutes at 25° C. An additional portion of mCPBA (0.180 g) was added. The reaction mixture was quenched with saturated Na2CO3 solution (50 ml) and extracted with DCM (3×50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was dissolved in DCM (80 ml) in a 150 ml conical flask which was placed into a beaker containing Et2O (200 ml) and the system covered with laboratory film and then left for 3 days. The obtained crystals were filtered, crushed and sonicated with Et2O. The crystallisation procedure was repeated to afford (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine as white needles (3.87 g, 29%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 2.62 (3H, s), 3.30 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 4.00 (1H, dd), 4.02 (1H, s), 4.32 (1H, s), 6.42 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1B(O)O>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:21]1[CH:20]=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[NH2:15]
Reactant: Nc1ccc(F)cc1B(O)O
Reactant: Brc1ccn2c(n1)nc1ccccc12
Product: Nc1ccc(F)cc1-c1ccn2c(n1)nc1ccccc12

Procedure:
The title compound was prepared using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (2-amino-5-fluorophenyl)boronic acid. 2-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-4-fluoroaniline was obtained as a orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (d, J=7.6 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.26 (d, J=7.6 Hz, 1H), 7.99 (dd, J=11.2, 3.2 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.29 (m, 1H), 6.95 (dd, J=9.2, 5.2 Hz, 1H); MS (ESI) m/z [M+H]+279.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH3:7])[O:5][C:4](=[O:8])[CH:3]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O>>[C:9]([C:3]1[C:4](=[O:8])[O:5][CH:6]([CH3:7])[C:2]=1[OH:1])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)O
Reactant: CC1OC(=O)C=C1O
Agent: O=S(=O)(O)O
Product: CC1OC(=O)C(C(C)(C)C)=C1O
Temperature: 40 °C
Yield: 13 %

Procedure:
4-Hydroxy-5-methyl-5H-furan-2-one (15.9 g, 0.14 mol) was dissolved in tert-butanol (13.9 ml, 0.147 mol) with concentrated sulfuric acid (7.8 ml, 0.147 mol) and heated at 40° C. for 4 days. The reaction mixture was allowed to cool and was partitioned between water (75 ml) and diethyl ether (75 ml). The organic layer was separated and dried (Na2SO4), filtered and concentrated under vacuum. Chromatography on silica gel with diethyl ether as eluent gave a crude product which was further purified by chromatography on silica gel with dichloromethane as eluent then triturated with diethyl ether to give 3-tert-butyl-4-hydroxy-5-methyl-5H-furan-2-one (3.1 g) as a white solid. 1H NMR (360 MHz, CDCl3) δ 1.34 (9H, s), 1.46 (3H, d, J=6.7 Hz), 4.69 (1H, q, J=6.7 Hz).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[C:10]([CH3:13])=[CH:9][N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:7]=1)=[O:5].[CH3:25][Mg]Br>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[C:10]([CH3:13])=[CH:9][N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[N:7]=1)(=[O:5])[CH3:25]
Reactant: CON(C)C(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of N-methoxy-N,5-dimethyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.535 g, 1.6 mmol) in THF (10 mL) at −78° C. was added methylmagnesium bromide (1.1 mL, 3.2 mmol, 3 M in diethyl ether). The reaction was stirred at that temperature for 1 h then quenched with saturated ammonium chloride aqueous solution (5 mL) then water (2 mL) with slow warming to room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic extracts are washed with 1 N HCl aqueous solution (15 mL), brine (15 mL), dried (Na2SO4), filtered and concentrated to provide 3-acetyl-5-methyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.463 g, 98%) as a light yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[I-].[Na+].[NH3:15]>CO>[NH:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[C:4]([CH2:3][CH2:2][NH2:15])=[CH:5]1
Reactant: N
Reactant: ClCCc1c[nH]c2ncccc12
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: NCCc1c[nH]c2ncccc12
Temperature: 60 °C

Procedure:
A mixture of 3-(2-Chloroethyl)-1H-pyrrolo[2,3-b]pyridine (4.0 g) and sodium iodide (3.2 g, 0.95 eq.) in a solution of ammonia in methanol (7 N, 20 mL) is heated to 60° C. in a Fischer-Porter sealed pressure bottle for 48 h. The bottle is cooled, opened cautiously and the solvent removed in vacuo. The resultant residue is recrystallized from THF to give the title ethylamine compound as a tan solid, 4.8 g, identified by HPLC and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:25])[F:26])[CH:17]=2)[N:3]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2cccc(OC(F)(F)F)c2)nc(Cl)n1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A 2-dram round-bottom vial was charged with methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 0.483 mmol) and (3-(trifluoromethoxy)phenyl)boronic acid (80 mg, 0.386 mmol, 0.8 equiv) were added in THF (2 mL). Then 2M Na2CO3 (0.362 mL, 0.725 mmol, 1.5 equiv) and Pd(tetrakis)Ph3P (27.9 mg, 0.024 mmol, 0.05 equiv) were added and shaken at 85° C. overnight. The solvent was removed in the Genevac and the residue was washed with saturated NaHCO3 (1 mL). The aqueous layer was extracted with EtOAc (3×1 mL). The combined organic layers were dried on the Genevac and the crude was purified using flash purification with a gradient of 5-40% EtOAc in hexane to provide methyl 2-chloro-6-(3-(trifluoromethoxy)phenyl)pyrimidine-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:9][C:10]1NN=N[N:11]=1.[C-]#N.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:9][C:10]#[N:11])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(Cc2nnn[nH]2)cc1OCc1c(C)cccc1C
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC#N)cc1OCc1c(C)cccc1C

Procedure:
The solution of 2-((5-(bromomethyl)-2-methoxyphenoxy)methyl)-1,3-dimethylbenzene (Step D, 3.28 g, 9.7 mmol) and NaCN (0.624 g, 12.7 mmol) in dry DMF (20 ml) was heated at 120° C. for 2.5 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO2, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26](N[C@H](C#C)CC(O)=O)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.Cl.C[O:39][C:40](=[O:48])[C@H:41]([CH2:43][C:44]([O:46]C)=[O:45])[NH2:42]>>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26]([NH:42][C@H:41]([C:40]([OH:39])=[O:48])[CH2:43][C:44]([OH:46])=[O:45])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: C#C[C@H](CC(=O)O)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H](NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1)C(=O)O

Procedure:
The procedure for the preparation of the product of EXAMPLE 17 was repeated using L-aspartic acid dimethyl ester hydrochloride (Aldrich) in the place of ethyl (3S)-3-aminopent-4-ynoate hydrochloride to provide the title product. 1H (CD3OD): δ 7.88 (1H, t); 7.82 (1H, d); 7.42 (3H, m); 7.13 (1H, m); 7.05 (1H, d); 6.87 (1H, t); 4.20 (1H, t); 4.12 (2H, t); 3.44 (2H, t); 2.71 (2H, m); 1.93 (4H, m).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH:23][CH3:24].CO>>[CH3:22][N:23]([CH3:24])[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Solvent: CO
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccccc23)cn1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg, 0.23 mmol) and 2.0 M dimethylamine in methanol (4 ml, 8 mmol) by a procedure similar to example 122 (51%). 1H NMR (CDCl3): 8.02 (d, J=2.7 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.38-7.34 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.75-6.66 (m, 2H), 3.94 (s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].N12CCCN=C1CCCCC2>>[CH2:16]([O:15][C:13](=[O:14])/[C:12](/[OH:18])=[CH:8]/[C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C(O)=C/c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 133.2 %

Procedure:
A mixture of 1.5 g (8.7 mmol) 2-chloro-4-methyl-5-nitropyridine (commercially available) in 5.88 mL (43.5 mmol) diethyl oxalate was treated with 2.34 ml (15.6 mmol) 1,8-diazabicylo[5.4.0]undec-7-ene and stirred for 4 h at room temperature. After evaporation of all volatiles the residue was acidified with 1N KHSO4 aq. and extracted with DCM. The combined organic layers were dried with MgSO4 and concentrated under reduced pressure to afford 3.16 g of the title compounds which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:38][CH3:39])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13]1)[CH:8]=[C:7]2[O:21][C@@H:22]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:24]([C:34]([O:36]C)=[O:35])[CH2:23]1.[Li+].[OH-].O.Cl>C1COCC1>[C:30]([O:29][C:27]([N:25]1[CH2:26][C@@H:22]([O:21][C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[C:3]([O:38][CH3:39])=[CH:4][CH:5]=3)[N:10]=[C:9]([N:12]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[N:13]3)[CH:8]=2)[CH2:23][C@H:24]1[C:34]([OH:36])=[O:35])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a stirred solution of compound 112 (650 mg, 1.13 mmol) in THF (12 mL) was added LiOH (82 mg, 3.41 mmol) and water. The reaction mixture was stirred at room temperature for 16 hrs and was acidified with 1N HCl to pH 5-6. Aqueous layer was extracted with EtOAc. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 113 as a pink solid in 95% yield.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>CCOCC>[C:1]1([NH:7][NH:8][C:23](=[O:24])[C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NNc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60111.8 %

Procedure:
A mixture of phenylhydrazine (25 ml, 0.25 mmole) and triethylamine (35 ml, 0.25 mmole) in anhydrous ether (500 ml) was cooled down to -5° to -10° C. (ice-salt bath) under nitrogen and treated dropwise, over a 30 minute period, with 4-fluorobenzene carbonyl chloride (30 ml, 0.25 mole). The reaction mixture was warmed to room temperature, stirred for 3.0 hours, then filtered, washing the solids well with ether (200 ml). The solids were dissolved in dichloromethane (600 ml), stripped to near dryness, suspended in hexane (600 ml) and filtered. The clear filtrate was evaporated to dryness, triturated with tetrahydrofuran (700 ml) and filtered, washing the solids well with tetrahydrofuran (100 ml). The filtrate was evaporated to dryness and dried in vacuo to give a crude product (34.6 g) contaminated with two other components.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5].Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32]>>[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH:36][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:4](=[O:5])[C:3]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:2]=2[Cl:1])=[CH:24][CH:23]=1)[CH3:32]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d. MS (EI) 536.1 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12](#[N:14])[CH3:13].[Sn](Cl)(Cl)(Cl)Cl>ClCCCl>[NH2:14][C:12](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C(C(=O)OCC)=C(C)N
Temperature: 125 °C
Yield: 96.8 %

Procedure:
To a solution of diethyl malonate (19.05 mL, 124 mmol) and acetonitrile (6.46 mL, 124 mmol) in 1,2-dichloroethane (DCE) (80 mL) under nitrogen atmosphere was slowly added tin(IV) chloride (31.9 mL, 272 mmol) in 30 min and then the mixture was heated to 125° C. for 2.5 h. The mixture was concentrated to a paste and then dissolved in acetone (350 mL), transferred to a beaker vigorously stirred and saturated Na2CO3/water (250 mL) was added dropwise to pH˜9-10. The slush was filtered through a bed of celite stirring the surface of the Celite™ to facilitate filtering. The filter cake was washed with dichloromethane (4×200 mL). The aqueous phase was separated from the filtrate and the organic phase was dried (Na2SO4), concentrated and dried in vacuo to provide diethyl 2-(1-aminoethylidene)malonate (25.51 g, 120 mmol, 97% yield) as a pale amber oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (m, 6 H), 2.15 (s, 3 H), 4.06-4.32 (m, 4 H), 4.81-5.20 (m, 1 H), 8.72-9.18 (m, 1 H); LCMS (m/z) ES+=202 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][CH2:9][NH2:10])[N:7]=1.C=O.[C:14](O)(=O)C>O.CO>[CH3:11][N:2]([CH3:1])[C:3]1[S:4][C:5]2[CH2:14][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(=O)O
Reactant: CN(C)c1nc(CCN)cs1
Agent: C=O
Solvent: O
Solvent: CO
Product: CN(C)c1nc2c(s1)CNCC2
Reaction time: 2.5 h
Yield: 219.2 %

Procedure:
2-Dimethylamino-4-(2-aminoethyl)thiazole (1.7 g, see preceding preparation), formaldehyde (0.78 ml of a 37% solution in water, 9.6 mmol) and acetic acid (0.15 ml, 2.6 mmol) were combined in methanol (100 ml). After 2.5 hours at room temperature, the reaction mixture was treated with additional formaldehyde (0.15 ml, 1.8 mmol) and allowed to stir for an additional 16 hours. The reaction was then filtered, and the filtrate was concentrated in vacuo and purified by column chromatography (eluant: 89:10:1 of chloroform:methanol:concentrated ammonium hydroxide), providing the title product as a white solid (1.04 g, 5.7 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C([O-])([O-])=O.[Na+].[Na+]>CC1C=CC=CC=1C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3F)Oc3ccc(Br)cc32)N=C1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN1C(=O)C2(CC(c3ccccc3F)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 90 °C
Yield: 5.2 %

Procedure:
Pd(PPh3)4 (3.84 mg, 0.1 mmol) was added to the solution of 2′-amino-6-bromo-2-(2-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 0.1 mmol) and 3-cyanophenylboronic acid (18.3 mg, 0.12 mmol) in dimethyl-benzene (6.6 mL) and an aqueous solution of Na2CO3 (2 M, 0.23 mL). The mixture was heated at 90° C. in an oil bath overnight. The mixture was concentrated to give the crude product which was purified by prepared HPLC to give the desired product 3-(2′-amino-2-(2-fluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (2.2 mg, 0.5%). 1H-NMR (MeOD): 2.5 (d, 1H), 3.30 (t, 1H), 3.5 (s, 3H), 6.35 (d, 1H), 7.2 (t, 2H), 7.3 (d, 2H), 7.65 (t, 3H), 7.75 (s, 2H), 7.85 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[N+:14]([O-])([OH:16])=[O:15]>>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: CC1(C)C(=O)Nc2cc(O)ccc21
Reactant: O=[N+]([O-])O
Product: CC1(C)C(=O)Nc2cc(O)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.5 g. 1,3-Dihydro-3,3-dimethyl-6-hydroxy-2H-indol-2-one were added portionwise, with vigorous stirring, to 35 ml. 65% nitric acid which was cooled with a mixture of ice and salt. The reaction mixture was further stirred in the cold for 10 minutes, diluted with ice/water to 150 ml. and the crystalline precipitate filtered off with suction and subsequently washed with water to give 4.1 g. (73% of theory) of the title compound in the form of yellow crystals; m.p. 244°-247° C.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)[CH2:6]CCC[CH2:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[S:28])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(O)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[S:28])=[CH:22][C:18]=1[C:19]([O:21][CH:1]([CH3:6])[CH3:2])=[O:20]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)OC(=S)Nc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(NC(=S)OC(C)C)ccc1Cl

Procedure:
This is the preparation of compound 32 using 1,3-dicyclohexylcarbodiimide. A mixture of 2-chloro-5-[[(1-methylethoxy)thioxomethyl]amino]benzoic acid (2 g, 0.007 mol), isopropyl alcohol (1.3 g, 0.02 mol), 4-dimethylaminopyridine (0.85 g, 0.007 mol) in 25 ml methylene chloride was stirred in an ice bath and 1,3-dicyclohexylcarbodiimide (1.7 g 0.008 mol) added. The mixture was allowed to come to ambient temperature and stirred overnight. The precipitated solid was filtered off and the filtrate washed with dilute hydrochloric acid and aqueous 5% sodium bicarbonate. After drying over magnesium sulfate, filtering and removing the methylene chloride, the product was crystallized from toluene/petroleum ether. Yield 1.2 g m.p. 89° C. A mixed m.p. with authentic compound 32 also gave m.p. 89°-90° C. The N.M.R. spectrum was identical with that of authentic compound 32.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[N:39]([CH3:43])[C:38](=[O:44])[CH:37]=[CH:36]3)[CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:43][N:39]1[C:40]2[C:35](=[CH:34][C:33]([O:32][CH2:31][CH2:30][CH2:29][N:21]([CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[CH2:22][C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[CH:42][CH:41]=2)[CH:36]=[CH:37][C:38]1=[O:44]
Reactant: Cn1c(=O)ccc2cc(OCCCN(Cc3ccncc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)ccc2cc(OCCCN(Cc3ccncc3)C3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Trifluoroacetic acid (30 ml) was added to a dichloromethane solution (10 ml) of 4-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.08 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. PL-HCO3 (40 g) was added to the dichloromethane solution of the residue and followed by celite filtration. The filtrate was condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=4:1). The purified product was condensed under reduced pressure to give the title compound (758 mg) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([N+:10]([O-])=O)[C:3]=1[OH:13]>CCOC(C)=O.[Ni]>[NH2:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([Br:1])[C:3]=1[OH:13]
Reactant: COc1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COc1cc(N)c(O)c(Br)c1
Reaction time: 2.5 h
Yield: 96 %

Procedure:
Raney/Ni (2.5 g) was added into a solution of 2-bromo-4-methoxy-6-nitrophenol (8.8 g, 35.5 mmol) in EtOAc (100 mL). The mixture was shaken in a Parr apparatus under hydrogen at 25 psi for 2.5 h. The reaction mixture was filtered through celite and concentrated under vacuum to give a gray solid (7.4 g, 96% yield; 95-97° C.); MS m/e 218 (M+H)+.