Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]([F:14])([F:15])[F:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(C(F)(F)F)c(C)cc1O
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(F)(F)F)c(C)cc1OC(C)=O
Reaction time: 2 h

Procedure:
Methyl 2-hydroxy-4-methyl-5-(trifluoromethyl)benzoate (may be prepared as described in Description 45; 1.37 g, 5.85 mmol) was dissolved in pyridine (70 ml) and acetic anhydride (1.34 ml, 14.18 mmol) was added. The solution was stirred for 2 hours then the solvent was removed in vacuo to give oil. The oil was purified by column chromatography (SiO2, 3:1 cyclohexane/ethyl acetate) to yield the title compound as a gum. 1.53 g.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([C:11]([C:21]4[CH:26]=[CH:25][N:24]=[C:23](S(C)(=O)=O)[N:22]=4)=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[NH2:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35]>C(#N)C>[CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([C:11]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[N:22]=4)=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3c(CC4CC4)nccn23)n1
Reactant: CC(C)(CN)CO
Solvent: CC#N
Product: CC(C)(CO)CNc1nccc(-c2c(-c3ccc(F)cc3)nc3c(CC4CC4)nccn23)n1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A solution of 8-cyclopropylmethyl-2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)imidazo[1,2-a]pyrazine (3.00 g, 7.08 mmol) and 3-amino-2,2-dimethylpropan-1-ol (TCI-US, 3.65 g, 35.4 mmol) in ACN (100 mL) was heated at about 85° C. for about 2 d. After cooling to ambient temperature, a precipitate formed, which was filtered off, washed with ACN, dried in vacuo and purified by silica gel chromatography with heptane/EtOAc (gradient 50-100% EtOAc, then isocratic 100% EtOAc). After concentration, the residue was three times re-dissolved in DCM and re-concentrated, resulting in a colorless foam, which was dried in a vacuum oven for about 16 h at about 55° C. and about 21 Torr to give 1.809 g (56%) of the title compound as a colorless solid: LC/MS (Table 1, Method g) Rt=3.01 min; MS m/z: 447.2 (M+H)+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]1([CH:10]([O:17][C:18](=[O:50])/[C:19](/[N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])=[C:20](\O)/[CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC.C(Cl)Cl>[C:4]1([CH:10]([O:17][C:18](=[O:50])[CH:19]([N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])[C:20](=[CH2:21])[CH3:3])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1

Procedure:
A distilled solution of diazomethane in ether (containing 1.3 mM of diazomethane) is added to a solution of crude 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester, obtained by ozonisation of 681 mg (1.0 mM) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester, in 5 ml of methylene chloride at 0° C. The mixture is stirred for one hour at 0° C. and washed with water, and the organic layer is dried over sodium sulphate. The solvents are removed in vacuo and the residue is chromatographed on 35 g of acid-washed silica gel, using toluene/ethyl acetate, 2:1. An isomer mixture consisting of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester is obtained. IR spectrum (in CH2Cl2): 5.60, 5.88, 6.67, 9.15 and 9.92 μ.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=[C:17]2[C:16]1=[O:26])(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=[C:17]2[C:16]1=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The solution of 300 mg of N-(2-acetoxymethyl-4-nitrophenyl)-4-chlorophthalimide in 35 ml of ethyl acetate is hydrogenated with 200 mg of 5% rhodium on carbon at 2.5 atmospheres of hydrogen pressure for 3 hours. After filtration from the catalyst, the residue is crystallized from ethyl acetate-hexane to give the N-(2-acetoxymethyl-4-aminophenyl)-4-chlorophthalimide melting at 136°-138°.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 21 h
Yield: 94.8 %

Procedure:
To an N,N-dimethylformamide (40.0 mL) solution of 4fluorophenol (5.00 g, 44.6 mmol) and 4-fluorobenzaldehyde (4.00 mg, 32.2 mmol) was added potassium carbonate (13.4 g, 96.6 mmol), which was stirred for 21 hours at 80° C. The reaction solution was then cooled to room temperature, water was added thereto, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15→1:10) to obtain the title compound (6.60 g, 90.1%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[Cl:25][CH2:26][C:27](=O)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(CC)CC)C>C(O)C>[Cl:25][CH2:26][C:27]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:4]2[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=2)[N:2]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
2-Amino-3',4,4',5-tetramethoxybenzophenone hydrochloride (36.0 g) and ethyl 4-chloroacetoacetate (21.4 g) were stirred in ethanol (350 ml) under reflux for 7 hours. After completion of the reaction, triethylamine (10.6 g) was added dropwise at a temperature not over 20° C. and the mixture was stirred at 5° C. for 1 hour. The crystals were collected by filtration, washed twice with 50 ml each of ethanol and dried under reduced pressure to provide ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (41.0 g; yield 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:25]([F:26])=[CH:24][C:19]2[N:20]=[C:21]([NH2:23])[S:22][C:18]=2[CH:17]=1.CCN(CC)CC.[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1COCC1>C(C#N)(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:25]([F:26])=[CH:24][C:19]2[N:20]=[C:21]([NH:23][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:22][C:18]=2[CH:17]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cc2nccc(Oc3cc4sc(N)nc4cc3F)c2cc1OC
Agent: CC(=O)C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3cc4sc(NC(=O)Cc5ccccc5)nc4cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (95 mg, 0.25 mmol), Et3N (0.10 ml, 0.72 mmol), phenylacetyl chloride (0.044 ml, 0.33 mmol), and THF (1.0 ml) were combined and stirred at room temperature for 1 hr. Additional phenylacetyl chloride (0.044 ml, 0.33 mmol) was added and the mixture heated to reflux for 1-2 hrs. After cooling to room temperature, the reaction mixture was diluted with 1:1 AcCN:H2O (1.0 ml) and the resulting solids filtered, washed with 1:1 AcCN:H2O and dried under high vacuum to give N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-phenyl-acetamidc (72 mgs, 59%). 1H-NMR (400 MHz, DMSO): 12.80 (s, 1H), 8.54 (d, 1H), 8.18 (d, 1H), 7.91 (d, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.34 (m, 4H), 7.28 (m, 1H), 6.60 (d, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.86 (s, 2H). LC/MS Calcd for [M+H]+ 490.1. found 490.0.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:14])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C#N)cc1F
Yield: 1024.5 %

Procedure:
A solution of 4-cyano-2-fluorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with p-toluenesulfonic acid monohydrate (0.46 g, 2.43 mmol) and heated to reflux overnight. The solvent was removed and the reaction residue was extracted with EtOAc, washed with saturated Na2CO3, brine and dried over Na2SO4 to give Methyl 4-cyano-2-fluorobenzoate (4.46 g, 95%). This Methyl ester (1.03 g, 5.77 mmol) was combined with methanol (60 mL) and Raney Ni (2 spatula tip fulls were added after washing with methanol under argon). It was then put under Hydrogen at 50 PSI on a PARR shaker for 18 hrs. The reaction was filtered through celite and washed with methanol while being kept under N2. It was then purified by silica gel chromatography with methanol and methylene chloride to give methyl 4-(aminomethyl)-2-fluorobenzoate (247.6 mg, 23%) as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)O)cc2)=C(C)C1=O
Reactant: CC(C)N
Product: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 22.2 %

Procedure:
4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (21 mg, 0.063 mmol) obtained in Example 52 and isopropylamine (0.008 ml, 0.095 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (5.1 mg, 0.014 mmol, yield 22%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[OH:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[OH:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: OC[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCC[C@H]4CO)cc3c2)cc1

Procedure:
The product from Example 1C and 2-(S)-(hydroxymethyl)pyrrolidine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 347 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[C:11]1([CH:18]=CC(O)=[CH:14][CH:13]=1)O.CCOCC>C1(C)C=CC=CC=1.C=CC=C>[CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]2[CH:6]([C:7](=[O:9])[CH:8]=1)[CH2:14][CH:13]=[CH:11][CH2:18]2
Reactant: COC1=CC(=O)C=CC1=O
Reactant: Oc1ccc(O)cc1
Agent: C=CC=C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC1=CC(=O)C2CC=CCC2C1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 2-methoxybenzoquinone (17, 750 mg, 5.43 mmol, TCI, used as received), hydroquinone (38 mg, Matheson, used as received) in toluene (7.5 mL) and butadiene (54, 7.5 mL, Matheson, used as received; Note: condensed butadiene into the toluene with ice bath cooling) contained in a screw top, sealed robe (Ace) was stirred overnight in a 60° C. oil bath. The resulting solution was allowed to cool to rt, then was further cooled in an ice bath. A precipitate formed. The sealed tube was opened. The solid was collected by filtration, washed with hexanes and allowed to air dry (930 mg). The solid was crystallized from hexanes (dissolved in 350 mL, hot filtered, concd to 200 mL, re-filtered, allowed to cool to rt) to yield a yellow powder (703 mg, 68%, >95% pure by 1H NMR analysis); mp 120°-122° C. (hexanes), lit. (Cavill et al., Aust. J. Chem. 26:595-601 (1993)) 126.5°-128° C. (ether); 1H NMR (CDCl3) δ2.21 (m, 2H), 2.51 (m, 2H), 3.16 (m, 1H), 3.26 (m, 1H), 3.79 (s, 3H), 5.69 (m, 2H), 5.90 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][S:18]([CH3:17])(=[O:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CCOS(C)(=O)=O

Procedure:
To a solution of (S)-2-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.300 g, 1.30 mmol) in dichloromethane (5 mL) was added methane sulfonylchloride 0.304 mL, 3.9 mmol) and triethylamine (0.547 mL, 3.9 mmol) at rt for 1-16 h. The reaction mixture was diluted with dichloromethane and washed with NaHCO3 (10%, W/V), followed by water. The dichloromethane layer was dried (Na2SO4), filtered and the solvent was evaporated to dryness. The product was sufficiently pure for the next step and was used without any further purification. LC-MS [M+Na] 329.9
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OC(C(=O)OC(C)(C)C)c1ccccc1
Yield: 77.9 %

Procedure:
This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (1.97 g; 8.5 mmol), the product of 6a (2.35 g; 8.7 mmol), and triethylamine (0.88 g; 8.7 mmol) in ethyl acetate (30 mL) as described in Example 1a. The crude product was purified by flash chromatography on a 65×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2) (1100 mL) collecting 18×50 mL fractions. After evaporation of fractions 3-8, 2.79 g (78%) product was obtained (amber oil).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](I)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25](C)[CH:26]=O>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([N:25]([CH3:26])[CH3:24])[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccccc1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(-c2cncc(N(C)C)n2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a sealed tube was added 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (See Example 2, 50 mg, 0.11 mmol, 1.0 equiv) and dimethyl formamide (1 mL). The reaction mixture was stirred at 100° C. After 18 hr, the reaction mixture was cooled to room temperature and diluted with dichloromethane washed with saturated NaHCO3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 2-(6-dimethylamino-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (32 mg, 80%). 1H NMR (400 MHz, CD2Cl2) δ 8.51 (s, 1H), 8.06 (s, 1H), 7.29-7.36 (m, 5H), 6.21 (bs, 1H), 4.59 (d, J=8.0 Hz, 2H), 3.17 (s, 6H), 2.71 (s, 3H); HRMS (M+H)+=354.13.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[CH:27]=O.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([N:21]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]([C:32]([F:33])([F:34])[F:35])=[C:24]([F:23])[CH:25]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (340 mg, 1.06 mmol) in MeOH (6 ml) was added 3-fluoro-4-trifluoromethyl-benzaldehyde (230 mg, 1.20 mmol). Then a solution of NaBH3CN (85 mg, 1.3 mol) in MeOH (1.5 ml) and AcOH (0.01 ml) were added. The reaction mixture was stirred overnight at RT, concentrated under vacuo, diluted with EtOAc, washed with H2O. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, EtOAc/Heptane 1:4) to afford 145 mg (28%) of the title compound as a colorless oil.
Reaction SMILES: [F-].[K+].Br[CH2:4][C:5](OCC)=[O:6].[NH2:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[OH:20]>CN(C)C=O>[N+:17]([C:15]1[CH:14]=[CH:13][C:12]2[O:20][CH2:4][C:5](=[O:6])[NH:10][C:11]=2[CH:16]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
To a mixture of 10.6 g (182 mmol) of potassium fluoride and 55 ml of anhydrous dimethylformamide was added 7.76 ml (72 mmol) of ethyl bromoacetate and the reaction mixture was stirred at room temperature for 15 minutes. Then 10.79 g (70.0 mmol) of 2-amino-4-nitrophenol was added and the reaction mixture was heated to 55° C. for 6 hours. The reaction mixture was cooled slowly to room temperature, stirred for 12 hours and poured onto 300 ml ice. The solid which formed was filtered off, washed with water and dried (20-50 Torr, 50° C., 16 hrs). The resulting orange solid was taken up in 100 ml EtOAc and 100 ml H2O. The aqueous layer was extracted with EtOAc (2×100 ml). The organic layers were then combined and washed with water (3×150 ml) and 10% HCl and dried (MgSO4). The solvent was removed in vacuo and the resulting solid was recrystallized from ethylene dichloride to yield 3.6 g (27% yield) of 6-nitro-2H-1,4-benzoxazin-3(4H)-one as an orange solid, m.p. 221°-223° C.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]2)[N:8]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[Br:30][C:31]1C(Cl)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1>C(Cl)Cl>[Br:30][C:31]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:7]3[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[S:5][CH:6]=3)[CH2:15][CH2:14]2)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1
Reactant: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
tert-Butyl 4-((2-isopropylthiazol-4-yl)methyl)piperazine-1-carboxylate (0.380 g, 1.15 mmol, 1.0 eq) was dissolved in DCM (3.6 mL) and the mixture cooled in an ice-water bath before the dropwise addition of TFA (3.6 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 2-isopropyl-4-(piperazin-1-ylmethyl)thiazole (supposedly 0.260 g, 1.15 mmol, 1.1 eq) was suspended in iPrOH (3.5 mL) and DIPEA (0.9 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.270 g, 1.05 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.300 g, 59%); 1H-NMR (500 MHz, DMSO-d6): δ 1.31 (d, J=7.0 Hz, 6H, iPr—CH3), 2.53-2.65 (br s, 4H, piperazine N(CH2)2), 3.06 (m, 4H, piperazine N(CH2)2), 3.20-3.33 (m, 1H, iPr—CH), 3.61 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.31 (s, 1H, thiazole 5-H), 8.15 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.81 min—4411443 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: FC1C=C(C2C(=O)C3C(=CC=C(F)C=3)NC=2[C@@H](N2C(=O)C3C(=CC=CC=3)C2=O)C)C=C(F)C=1.[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39]([NH:43][CH:44]([C:46]2[N:47](C)[C:48]3[C:53]([C:54](=[O:64])[C:55]=2[C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:52][C:51]([F:65])=[CH:50][CH:49]=3)[CH3:45])[N:38]=[CH:37][N:36]=1>>[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39]([NH:43][C@H:44]([C:46]2[NH:47][C:48]3[C:53]([C:54](=[O:64])[C:55]=2[C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:52][C:51]([F:65])=[CH:50][CH:49]=3)[CH3:45])[N:38]=[CH:37][N:36]=1
Reactant: CC(Nc1ncnc(N)c1C#N)c1c(-c2cc(F)cc(F)c2)c(=O)c2cc(F)ccc2n1C
Agent: C[C@@H](c1[nH]c2ccc(F)cc2c(=O)c1-c1cc(F)cc(F)c1)N1C(=O)c2ccccc2C1=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1[nH]c2ccc(F)cc2c(=O)c1-c1cc(F)cc(F)c1

Procedure:
4-amino-6-(((1S)-1-(3-(3,5-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile was synthesized from (S)-2-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-2-yl)ethyl)-isoindoline-1,3-dione in a similar manner as the above compound 4-amino-6-(1-(3-(3,5-difluorophenyl)-6-fluoro-1-methyl-4-oxo-1,4-dihydroquinolin-2-yl)-ethylamino)pyrimidine-5-carbonitrile. 1H-NMR (400 Hz, DMSO-d6) δ 11.50 (s, 1H), 7.97 (s, 1H), 7.69-7.73 (m, 2H), 7.59 (td, J=8.0, 4.0 Hz, 1H), 7.46 (s, br, 1H), 7.17-7.22 (m, 2H), 7.05 (s, br, 1H), 5.01-5.06 (m, 1H), 1.48 (t, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=437 (M+1).