Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=[CH:5]2.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Oc1cccc2cc(F)ccc12)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(F)ccc23)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A fourth intermediate compound, 1-(6-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: Trifluoro-methanesulfonic acid 6-fluoro-naphthalen-1-yl ester (1.24 g, 4.23 mmol) and 1-Boc-piperazine (946 mg, 5.08 mmol) were dissolved in toluene (15 mL) and the mixture was degassed for 30 minutes. To this was added 2-(dicyclohexylphosphino)-biphenyl (148 mg, 0.42 mmol), palladium acetate (95 mg, 0.42 mmol), and sodium tert-butoxide (569 mg, 5.92 mmol). The mixture was stirred at 80° C. for 30 minutes, then cooled to room temperature, washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude oil was filtered through a short plug of silica gel, eluting with 3:1 hexanes/ethyl acetate to yield crude 4-(6-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl ester as a brown oil. The crude oil was dissolved in a mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred at room temperature for 4 hours. The mixture was evaporated in vacuo and diethyl ether (30 mL) was added. The grey precipitate was filtered off and rinsed with diethyl ether (20 mL) to yield the fourth intermediate compound as the TFA salt (755 mg, 52%) as a grey solid. 1H NMR (400 MHz, dmso-d6) δ 8.80 (s, 1H), 8.24–8.18 (m, 1H), 7.72 (d, 1H), 7.68 (d, 1H), 7.50 (t, 1H), 7.40 (t, 1H), 7.18 (d, 1H), 3.40–3.10 (m, 8H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][C:18](=[O:21])[S:19][CH:20]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl.ClC1C=CN=CC=1>CC(C)=O.CCOCC>[N:2]1[CH:1]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:20][S:19][C:18](=[O:21])[NH:17][N:16]=3)=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: Nc1ccc(-c2csc(=O)nn2)cc1
Agent: Cl
Agent: Clc1ccncc1
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1NN=C(c2ccc(Nc3ccncc3)cc2)CS1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
To a N-methyl-2-pyrrolidone solution (3 mL) containing 5-(4-aminophenyl)-2H-1,3,4-thiadiazine-2-one (0.27 g), triethylamine (90 μL) and 4-chloropyridine hydrochloride (0.20 g) were added in this order by heating at 100° C. with stirring, followed by further stirring with the temperature maintained for four hours. The reacted mixture was cooled and diluted with acetone (10 mL) and ether (15 mL). The precipitated crystal was separated by filtration, air-dried, dissolved in warm water (50 mL), and adjusted to pH8 with saturated potassium carbonate. The precipitated solid was separated by filtration, and purified by a silica gel column chromatography to obtain the captioned compound (0.26 g). Yield was 70.3%. melting point: 222° to 225° C. (decomposition)
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9](C(O)=O)[C:8]([Cl:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CS(C)=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)c(C(=O)O)c([N+](=O)[O-])c1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl

Procedure:
0.05 moles of 2,5-dichloro-3-nitro-terephthalic acid were refluxed in 2.11 moles of dimethyl sulphoxide (DMSO) at 189° C. for 70 minutes, after which the DMSO was removed by flash evaporation. The residue was dissolved in saturated sodium bicarbonate solution, which was extracted with chloroform to remove unwanted side-products. The aqueous phase was then acidified with 10% hydrochloric acid to complete precipitation and the resulting precipitate was filtered off, washed well with water and dried to give 88.5% crude yield of 2,5-dichloro-3-nitro-benzoic acid, melting at 214°-216° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:22]([O:24]C)=[O:23])=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:5]([CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7]([F:10])([F:9])[F:8].[OH-].[K+]>O>[Br:1][C:2]1[C:3]([C:22]([OH:24])=[O:23])=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:5]([CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: CCOCn1c(-c2ccc(Cl)cc2)c(C(=O)OC)c(Br)c1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C(=O)O)c(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.9 %

Procedure:
A mixture of methyl 4-bromo-2-(p-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)pyrrole-3-carboxylate (13.1 g) and potassium hydroxide (3.12 g, 85%, 48 mmol) is stirred at room temperature for 20 hours, stirred at reflux for 2 hours, diluted with water, washed with diethyl ether, acidified to pH 4 with 1N hydrochloric acid and filtered to obtain a solid. The solid is washed with water and petroleum ether and dried to give the title product as a white solid (6.45 g) which is identified by 1H NMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][OH:24])[O:20][C:19]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])[O:20][C:19]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CCN1CCF
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CCN(CCF)C(=O)C3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl)-5-hydroxymethyloxazolidin-2-one (0.8 g) is dissolved in pyridine (15 ml) and the mixture cooled to 0°. Triethylamine (0.38 ml) and methanesulfonyl chloride (0.19 ml) are added to the mixture, and stirring continued at 20-25° for 2 hours. The solvent is removed and the residue dissolved in dichloromethane, washed with water, saline, dried over magnesium sulfate and concentrated. The resulting residue is triturated with ether to give (5R)-3-(3-fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (0.76 g) which is used without further purification.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[H][H]>O1CCCC1.[Pd]>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C2CCN(C3CC3)CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C2CCN(C3CC3)CC2)cc1

Procedure:
0.57 g 1-cyclopropyl-4-(4-nitro-phenyl)-piperidine are dissolved in 30 mL tetrahydrofuran and combined with Pd/C. The mixture is hydrogenated for 72 h at 7 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is used in the next stage of the synthesis without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:22]1[C:23]([NH2:34])=[N:24][CH:25]=[C:26]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:27]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[NH2:34][C:23]1[C:22]([C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=2)=[N:27][C:26]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:25][N:24]=1
Reactant: Nc1ncc(C2CCOCC2)nc1Br
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F
Temperature: 120 °C
Yield: 66.5 %

Procedure:
To a solution of methyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (259 mg, 1.308 mmol), 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (225 mg, 0.872 mmol), and PdCl2(dppf) (64 mg, 0.087 mmol) was added DME (6.5 mL) and 2 M Na2CO3 solution (3.2 mL). The reaction mixture was heated at the microwave synthesizer (120° C., 10 min). The reaction mixture was worked up with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product was purified by flash chromatography (gradient EtOAc in heptane) to yield the desired product (192 mg, 67%). LCMS (m/z): 332.2 (MH+), 0.63 min.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][C:19](F)=[O:20])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][C:19](=[O:20])[NH:7][CH2:8][CH2:9][SH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (141 mg, 1.68 mmol) in 8.2 mL water was added 2-aminoethanethiol hydrochloride (102.5 mg, 0.90 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25a (145.6 mg, 0.82 mmol) in 8.2 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 132.8 mg (69% from 24a) of clean 26a as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[C:7]([NH:11][CH2:2][C:3]([O:5][CH3:6])=[O:4])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: COC(=O)CBr
Solvent: CCOCC
Product: COC(=O)CNC(C)(C)C
Temperature: 25 °C
Yield: 96.6 %

Procedure:
Methyl bromoacetate (7.1 mL, 75 mmol) is added dropwise to tert-butylamine (31.5 mL, 300 mmol) at 0° C. The reaction mixture is diluted with ether, warmed to room temperature and filtered. The filtrate is concentrated in vacuo to obtain the title product as a clear liquid (10.52 g) which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([OH:42])[CH2:41][CH2:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:13][CH:12]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([OH:42])[CH2:41][CH2:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3ccc(CN4CCCC4)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCCC6)cc5)cc34)s2)CCC1

Procedure:
A solution of 1-(5-(5-chloro-2-(4-(pyrrolidin-1-ylmethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 8C) (1.81 g, 2.92 mmol) in methanol (19.49 mL) and aqueous 2N sodium hydroxide (5.85 ml, 11.69 mmol) was heated to 70° C. for 1 hour. The methanol was removed under reduced pressure, and the remaining aqueous layer was diluted with 20 mL water. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with a 2:1 methanol:water solution to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 7.98-7.91 (m, 2H), 7.43-7.36 (m, 2H), 7.03 (s, 1H), 6.67 (s, 1H), 3.60 (s, 2H), 2.69-2.55 (m, 2H), 2.47-2.33 (m, 6H), 2.04-1.89 (m, 2H), 1.75-1.66 (m, 4H); MS ESI(+) m/z 465.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:15]([Cl:16])=[N:14][C:13]([Cl:17])=[CH:12][N:11]=1)[OH:9]>[O-2].[Mn+4].[O-2].ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:15]([Cl:16])=[N:14][C:13]([Cl:17])=[CH:12][N:11]=1)=[O:9]
Reactant: OC(c1ccccc1Cl)c1ncc(Cl)nc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)c1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a dichloromethane solution of (2-chlorophenyl)-(3,5-dichloropyrazin-2-yl)methanol (7.1 g, 24.5 mmol) was added portion wise solid manganese (IV) oxide (25 g, 245 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give (2-chlorophenyl)-(3,5-dichloropyrazin-2-yl)methanone (6.02 g, 21 mmol, 85% yield). Mass spec., M+1=288.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](OC)=[O:13]>>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:13]
Reactant: COC(=O)c1ccco1
Reactant: C1CNCCN1
Product: O=C(c1ccco1)N1CCNCC1
Yield: 65.8 %

Procedure:
To a suspension of piperazine (69.68 g, 0.8091 mol) in xylenes (100 mL) was added (50.00 g, 0.3965 mol) of methyl 2-furoate. The formed reaction mixture was refluxed for 18 hours. The unreacted piperazine was filtered and the filtrate was concentrated under vacuum to give 47.0 g (0.2608 mol) of required product (64% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:13])/[CH:10]=[CH:11]/[CH3:12].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH:11]([CH3:12])[CH2:10][C:9]2=[O:13]
Reactant: C/C=C/C(=O)O
Reactant: Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(=O)c2cc(F)ccc2O1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
11.2 G (0.1 mol) of para-fluorophenol and 17.2 g (0.2 mol) of crotonic acid were dissolved in 100 ml of polyphosphoric acid, and the solution was reacted with vigorously stirring at 120° C. for 8 hours. After cooling, the reaction solution was poured into 450 ml of iced 2N-sodium hydroxide solution, and the mixture was extracted with 500 ml of chloroform. The chloroform layer was washed with 2N-sodium hydroxide solution and with water, followed by drying over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from n-hexane in the amount of about ten times. There were thus obtained 5.8 g (yield : 32%) of the subject material, 6-fluoro-2-methyl-4- chromanone.
Reaction SMILES: [ClH:1].C([NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[ClH:1].[NH2:9][C:10]([CH3:21])([CH3:20])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)(CCc1ccc(O)cc1)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(N)CCc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
4-(3-Benzylamino-3-methylbutyl)phenol hydrochloride (3.84 g, 12.6 mmol) and 10% palladium on carbon (0.8g) were suspended in methanol (95 ml) in a hydrogenation apparatus. The vessel was sealed and shaken for 16 hours at 50° C. and a 60 psi hydrogen atmosphere. The resulting suspension was filtered through Celite and concentrated in vacuo to yield a white solid (1.46 g, 54%). NMR, MS.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:37]=[CH:36][C:25]3[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:31])([CH3:32])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc21
Yield: 56.1 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (77 mg, 0.244 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (60 mg, 0.258 mmol), DL-10-Camphorsulfonic acid (70 mg, 0.301 mmol) and isopropanol (4 mL) in a microwave tube. Microwaved reaction at 120° C. for 30 minutes. Evaporated off solvent, dissolved residue in methylene chloride and washed with saturated sodium bicarbonate solution, then brine. Dried with magnesium sulfate, filtered and purified with normal phase chromatography eluting with hexane/ethyl acetate to yield a yellow solid, 2-[5-Chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (70 mg, 56%). LCMS: m/z=511.11 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.07 (s, 1H), 7.59 (d, 1H, J=8.6 Hz), 7.52 (s, 1H), 7.37 (d, 1H, J=6.8 Hz), 7.24 (m, 1H), 7.10 (s, 1H), 6.97 (d, 1H, J=8.8 Hz), 6.80 (d, 1H, J=3.8 Hz), 3.72 (m, 2H), 2.91 (d, 3H, J=4.3 Hz), 2.14 (m, 2H), 1.87 (m, 2H), 1.25 (m, 3H), 1.18 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22]>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])[C:11]=1[CH3:12]
Reactant: O=C1CCCCN1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure I using 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.01 mmol) and piperidin-2-one to give 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one. Mass Spectrum (ESI) m/e=311.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:20][NH2:21])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH3:2].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]([I:32])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH2:20][NH:21][C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]([I:32])=[CH:25][N:24]=1)[CH3:2]
Reactant: CCOc1cc(CN)ccc1OCc1ccc(OC)nc1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a stirred solution of (3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (2.75 g, 9.54 mmol) in acetonitrile (50 mL) was added 2-chloro-5-iodo-3-nitropyridine (2.85 g, 10.01 mmol) and N,N-diisopropylethylamine (1.85 g, 14.31 mmol). The resulting yellow mixture was heated to reflux. After 3 h, the red-brown solution was allowed to cool to room temperature, resulting in the formation of a precipitate. The solids were isolated by filtration and washed with water (200 mL). The moist solids were dissolved in dichloromethane (100 mL), and a small amount of water separated and was removed. The solution was dried over magnesium sulfate, filtered, and concentrated to provide 4.34 g (85%) of N-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3-nitropyridin-2-amine as an orange solid.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([NH:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[CH3:7].Cl.Cl[CH2:23][C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH3:35])=[CH:29][CH:28]=2>C(O)C>[CH3:35][O:34][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]([CH2:23][CH2:7][C:6]([NH:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])=[CH:33]2
Reactant: COc1ccc2ncc(CCl)cc2c1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)CCc1cnc2ccc(OC)cc2c1)C(=O)OCC
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of sodium ethoxide prepared from 0.3 g (13.1 mmol) of sodium and 30 mL of ethanol were added, in one portion, 2.85 g (13.1 mmol) of diethyl acetamidomalonate. After 30 minutes, 1.52 g (6.24 mmol) of 3-chloromethyl-6-methoxyquinoline hydrochloride were added and the resultant mixture was refluxed overnight. The reaction mixture was evaporated and the residue was dissolved in 25 mL of 1N hydrochloric acid and extracted twice with ethyl ether. The aqueous layer was neutralized with solid sodium bicarbonate and extracted twice with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, using first 4:1 methylene chloride/ethyl acetate and the 1:1 methylene chloride/ethyl acetate as eluents, to give 1.82 g (75.2%) of the desired product as a white solid, which melted at 151°-152° C. after crystallization from a mixture of ethyl acetate and isopropyl ether. TLC Rf =0.34 (ethyl acetate); NMR (CDCl3) δ 8.4 (1H, d), 7.9 (1H, d), 7.7 (1H, bs), 7.35 (1H, d), 7.0 (1H, d), 6.6 (1H, bs), 4.3 (4H, q), 3.9 (3H, s), 3.85 (2H, s), 2.05 (3H, s), 1.3 (6H, t); IR (KBr) ν 3400, 3230, 1740, 1640, 1300 cm-1. The product has the formula: ##STR101##
Reaction SMILES: OC[C:3]1([C:10]2[CH:15]=[N:14]C=CN=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH:16]1(N)CC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:16]1[C@@H:15]([NH2:14])[C@@H:10]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(CO)(c2cnccn2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
A solution of 4-(hydroxymethyl)-4-(pyrazin-2-yl)cyclohexanone (360 mg, 2.0 mmol, 1.0 equiv) in acetonitrile (4 mL) was treated with cyclopropylamine (280 μL, 4.0 mmol, 2.0 equiv), acetic acid (0.1 mL) and NaBH(OAc)3 (848 mg, 4.0 mmol, 2.0 equiv) successively. After being stirred at 25° C. for 12 h, the reaction mixture was carefully diluted (sat.NaHCO3) and extracted (10% MeOH/CH2Cl2). The organics were washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, EtOAc containing 2.5% NH4OH then EtOAc/5% MeOH containing 2.5% NH4OH, the second spot was collected) to provide 180 mg of trans amine as a white solid (0.70 mmol, 42%).