Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[N:7]=1.[CH3:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>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.O.COCCOC>[CH3:29][C:30]1[CH:35]=[C:34]([C:2]2[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C@H:15]4[C@:13]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=5)([CH2:14]4)[CH2:12]3)[N:7]=2)[CH:33]=[CH:32][N:31]=1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)nc1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
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: COCCOC
Solvent: O
Product: Cc1cc(-c2nn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)ccn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
6-bromo-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (P8,100 mg, 0.218 mmol) was suspended in a degassed mixture of 1,2-Dimethoxyethane (DME) (3.629 mL)/Water (0.726 mL), then 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (143 mg, 0.653 mmol), SODIUM CARBONATE (69.2 mg, 0.653 mmol), 2-biphenylyl(dicyclohexyl)phosphane (15.26 mg, 0.044 mmol) and Tetrakis (50.3 mg, 0.044 mmol) were added. The mixture was then heated at 90° C. and stirred at that temperature for 3 hours. The reaction mixture was then cooled down to room temperature, 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (143 mg, 0.653 mmol), 2-biphenylyl(dicyclohexyl)phosphane (15.26 mg, 0.044 mmol), SODIUM CARBONATE (69.2 mg, 0.653 mmol) and Tetrakis (50.3 mg, 0.044 mmol) were added again, the mixture was stirred at 90° C. for further 2 hours, then left stirring at room temperature overnight. The mixture was concentrated under reduced pressure and partitioned between AcOEt and water. Phases were separated, organic phase was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by Preparative HPLC affording 6-(2-methyl-4-pyridinyl)-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (E3, 15.7 mg, 0.033 mmol, 15.29% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)[C@@H:11]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH2:39][C@H:40]([O:42][CH2:43][CH3:44])[CH3:41])=[CH:33][CH:32]=2)[C@H:10]([CH:45]=O)[CH2:9]1)=O)(C)(C)C.[NH:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:43]([O:42][C@H:40]([CH3:41])[CH2:39][O:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:11]2[C@H:10]([CH2:45][N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[CH2:9][NH:8][CH2:13][C@@H:12]2[O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)=[CH:32][CH:33]=1)[CH3:44]
Reactant: C1CCNC1
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](C=O)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN3CCCC3)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reaction time: 5 h

Procedure:
To a solution of 1 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-formyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester in 5 ml of THF are added 1.2 mmol of pyrrolidine, 1.1 mmol of acetic acid and 1.5 mmol of sodium triacetoxyborohydride. The reaction mixture is stirred for 5 h, and poured on an ice H2O mixture. The mixture is extracted with TBME (3×). The combined organic phases are washed with H2O and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][Br:17])[CH:3]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Yield: 84.2 %

Procedure:
A solution of 1-bromo-3,5-dimethyl-benzene (1.0 g, 5.4 mmol, 1.0 eq), NBS (1.06 g, 5.94 mmol, 1.1 mmol) and AIBN (180 mg, 1.08 mmol, 0.2 eq) in CCl4 (20 mL) was stirred at reflux overnight. The reaction was then diluted with water and extracted with CH2Cl2. The organic extracts were combined and washed with aqueous NaHCO3, dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (Petroleum ether:EtOAc, 1:0 to 10:1) to give the title compound as a light yellow oil (1.2 g, 84%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:52]([O:54][C:55](=[O:59])/[CH:56]=[CH:57]/[CH3:58])[CH3:53]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:52]([O:54][C:55](=[O:59])[CH:56]=[C:57]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH3:58])[CH3:53]
Reactant: C/C=C/C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=C(C)c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 20 %

Procedure:
N-Boc-2-bromobenzylamine (7.15 g, 25 mmol) was dissolved into tributylamine (12 mL) and degassed under vacuum. Palladium acetate (224 mg, 1 mmol) and tri-o-tolylphosphine (608 mg, 2 mmol) was then added and the mixture degassed under vacuum. Trans-ethylcrotonate (6.25 mL, 50 mmol) was then added and the mixture was degassed with nitrogen. The tube was sealed and the mixture was heated to 110° C. for 48 h. The solution was cooled to room temperature, diluted with diethyl ether (200 mL) and filtered through celite. The solution was washed with 1N HCl (2×50 mL) and brine (50 mL) dried over magnesium sulfate and concentrated to dryness. Flash chromatography (9:1 hexanes/ethyl acetate) gave the title compound as a yellow oil (1.6 g, 20%). 1H NMR 7.22-7.37 (m, 3H), 7.08 (dd, J=7.4, 1.6 Hz, 1H), 5.75 (d, J=1.3 Hz, 1H), 4.29-4.31 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 2.45 (d, J=1.3 Hz, 3H), 1.44 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C-:1]#[N:2].[K+].C(I)C.[CH2:7]([O:9][C:10](=[O:19])[CH2:11][C:12]1[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][CH:17]=1)[CH3:8].C(OCC)(=O)C>O.C(O)C.O.CCCCCC>[C:1]([C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:19])#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)Cc1ccc[n+]([O-])c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cnccc1C#N
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
KCN (2.64 g, 31.44 mmol) in water (8 mL) was added drop wise over a period of 20 minutes to a solution of 3-(2-ethoxy-2-oxoethyl)pyridine-1-oxide ethyl iodide (I-67b: 5.3 g, 15.72 mmol) in ethanol-water (7:3 ratio, 30 mL) at 50° C. and heating was further continued for another 30 minutes. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mass was quenched using ice and extracted using DCM. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 2.4 g of the product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]4[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=4)=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH:19]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cnc3cc(-c4cccnc4)ccn23)cc1
Yield: 64.9 %

Procedure:
To a round bottomed flask add 4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenylamine (0.5 g, 2.1 mmol), pyridine-3-boronic acid (0.38 g, 1.5 equiv.), potassium phosphate (0.87 g, 2 equiv.), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (also called S-Phos, 0.105 g, 0.125 equiv.), 1,4-dioxane (10 mL), and water (5 mL). Deoxygenate this mixture thoroughly with N2 then add palladium (II) acetate (23 mg, 0.05 equiv.) and reflux the reaction overnight. Concentrate the reaction to dryness and slurry in DCM. Filter this slurry thru Celite® and wash with DCM. Concentrate the filtrate then purify by silica plug (EtOAc to 5% MeOH: DCM to 10% MeOH: DCM) to give a yellow solid (0.39 g, 66%). MS (ES), m/z 287 (M+1).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[CH:20]=[N:19][C:18]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])=[N:17][C:16]=3[CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C1COCC1>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:18]1[N:19]=[CH:20][C:21]2[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: CCOC(=O)C1CCN(c2nccc3nc(NCc4ccccc4Cl)ncc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2nccc3nc(NCc4ccccc4Cl)ncc23)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1-[2-(2-Chloro-benzylamino)-pyrido[4,3-d]pyrimidin-5-yl]-piperidine-4-carboxylic acid ethyl ester 13 (583 mg, 1.37 mmol) was dissolved in THF (10 mL), 2 N NaOH solution (5 mL) were added and the mixture was stirred for 3 h at 50° C. The mixture was evaporated to dryness, water was added and the pH was adjusted to 7 adding 2 N HCl solution. The aqueous layer was extracted twice with ethyl acetate and DCM. The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness. The obtained colorless solid (447 mg, 1.12 mmol, 82%) was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5]N1C(=O)C2N(C)C=NC=2N(C)C1=O.[Mg].II.C(Br)C[C@@H](CCC=C(C)C)C.C=[O:40].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C@H:2]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5][OH:40]
Reactant: CC(C)=CCC[C@@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C=O
Agent: CC(C)=CCC[C@@H](C)CCBr
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)=CCC[C@@H](C)CCCO
Reaction time: 0.5 h
Yield: 84 %

Procedure:
This example illustrates the synthesis of 1-(4-(R)-Methyl-8-methylnon-7-enyl)-3,7-dimethylxanthine (CT2536R). To a suspension of magnesium (2.74 g, 140 mmol) and a crystal of iodine in tetrahydrofuran (15 ml) was added (R)-citronellyl bromide (5.0 g, 22.8 mmol) in tetrahydrofuran (10 ml) over 30 min and the reaction stirred for a further 30 min after the addition was complete. The solution was added via a canula over 5 min to a suspension of paraformaldehyde (1.80 g, 60.0 mmol) in tetrahydrofuran (15 ml) and stirred at 25° C. for 6 hr. Saturated ammonium chloride (40 ml) was added and extracted with diethyl ether (2×30 ml). The combined organic extracts were dried (magnesium sulfate) and evaporated to give 4-(R)-methyl-8-methylnon-7-enyl alcohol as a clear liquid (3.25 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:21])[CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.B.CSC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:21])[CH2:15][S:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSC(C)(C)C
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-tert-butylsulfanyl-ethanone (1 eq.) was dissolved in THF and cooled to 0° C. Borane-dimethylsulfide (2 eq.) was added and the reaction was allowed to slowly warm to room temperature. After stirring for 2 hours the reaction mixture was concentrated then purified on silica gel to afford the title compound.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:20]([F:23])([F:22])[F:21])[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2C(F)(F)F)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccccc2C(F)(F)F)nc1-c1ccnn1-c1ccccc1
Yield: 12 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[2-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (crude 785 mg, 2.33 mmol) in 20 mL of methanol was added phenylhydrazine (377 mg, 3.50 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-[2-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (105 mg, 12% for two steps) as a yellow solid.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.[C:11]([NH:34][CH2:35][CH2:36][NH:37]C(=O)/C=C/C(OC)=O)(=[O:33])[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32]>>[C:11]([NH:34][CH2:35][CH2:36][NH:37][C:4](=[O:6])/[CH:3]=[CH:2]/[C:1]([O:8][CH2:9][CH3:10])=[O:7])(=[O:33])[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)/C=C/C(=O)OC
Reactant: CCOC(=O)/C=C/C(=O)[O-]
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)/C=C/C(=O)OCC

Procedure:
Mono ethyl fumarate (commercially available) was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-ethyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z) -docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C30H40N2O4: 496.33; found 497 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:44])[F:43])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][O:35][C:36]([F:39])([F:38])[F:37])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:43])[F:44])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][O:35][C:36]([F:39])([F:38])[F:37])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCOC(F)(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CCOC(F)(F)F)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
195 mg (0.29 mmol) of tert-butyl 4-{[2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoyl]amino}benzoate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 84 mg (50% of theory)
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH2:20]([O:22][C:23](=[O:35])[CH2:24][NH:25][CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)[CH3:21].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:20]([O:22][C:23](=[O:35])[CH2:24][N:25]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)[CH3:21]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNC1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1Cc2ccccc2C1
Reaction time: 8 h

Procedure:
To a solution of CBZ-L-valine (5.0 g, 0.02 mol)in CH2Cl2 (50 mL) were added 4-dimethylaminopyridine (2.44 g, 0.02 mol), N-(2-indanyl)glycine ethyl ester hydrochloride (5.6 g, 0.02 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCDI) (3.83 g, 0.02 mol). Approximately 20 mL CH2Cl2 was used to wash the reagents into the reaction flask. After the mixture was stirred overnight the solvent was removed under vacuo and the residue treated with ethyl acetate: 1N HCl (3:1). The separated organic layer was washed with 1N HCl, 5% aqueous Na2CO3 and saturated aqueous NaCl-solution followed by drying over magnesium sulfate and filtration. After removal of the solvent under reduced pressure an oil (4.3 g) remained, which was purified over silica gel using CH2Cl2 as eluent. 3.4 g of a colorless oil was collected (Rf: 0.7, silica gel, CH2Cl2 :CH2OH 97:3 ) and used as is for saponification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:46][C:47]([CH3:61])([CH2:50][N:51]1[CH:60]=[C:54]2[N:55]=[CH:56][C:57]([Br:59])=[CH:58][C:53]2=[N:52]1)[C:48]#[N:49]>CN(C=O)C>[Br:59][C:57]1[CH:56]=[N:55][C:54]2=[CH:60][N:51]([CH2:50][C:47]([NH:46][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:10][C:2]=3[F:1])([C:48]#[N:49])[CH3:61])[N:52]=[C:53]2[CH:58]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
2-Fluoro-4-trifluoromethoxybenzoic acid (80 mg, 0.357 mmole), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC.HCl, 78 mg, 0.4 mmole), 1-hydroxybenzotriazole monohydrate (HOBt.H2O, 69 mg, 0.45 mmole) and N-methylmorpholine (71 μL) were stirred in DMF (2 mL) for 20 minutes at room temperature prior to adding 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (100 mg, 0.357 mmole, described in Example 182). The mixture was stirred overnight at room temperature, quenched with a saturated solution of ammonium chloride and extracted with EA. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (17 mg, 9%). MS (ES): M/Z [M+H]=486. 1H NMR: (400 MHz, CHLOROFORM-d): 1.91 (s, 3H), 4.90 (d, J=14.1 Hz, 1H), 5.08 (d, J=14.1 Hz, 1H), 7.07 (d, J=12.1 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 8.02 (d, J=12.1 Hz, 1H), 8.15-8.28 (m, 2H), 8.38 (s, 1H) and 8.62 (d, J=2.0 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −108.6 (td, J=11.9, 9.2 Hz, 1F) and −58.3 (s, 3F). 2-fluoro-4-trifluoromethoxybenzoic acid was prepared as follows:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:3]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown powder; MS: [M+H]+=449.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[NH2:36])[CH2:27][CH2:26]1>CC(O)C.Cl>[CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[O:33][CH2:32][CH2:31][N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CN1CCN(CCOc2ccccc2N)CC1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Agent: Cl
Solvent: CC(C)O
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccccc4OCCN4CCN(C)CC4)sc3c2)ccn1
Temperature: 80 °C

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (25 mg, 0.072 mmol, 1.0 eq) in 1 mL of IPA and 1 mL conc. HCl was added 2-(2-(4-methylpiperazin-1-yl)ethoxy) aniline (25 mg, 0.108 mmol, 1.5 eq) and reaction mixture heated at 80° C. in oil bath for 2 hours. Thereafter, the product was purified via reverse phase HPLC. This procedure was generalized for other analogues for which progress of the reaction was monitored by LC-MS and amount of aniline and reaction time adjusted as needed. LC/MS (m/z) [519.1] (MH+)