Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23]Br.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-:32].[K+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[O:31]([CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:32][C:3]1[CH:12]=[CH:11][CH:10]=[CH:5][CH:4]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1ccccc1
Reactant: [OH-]
Reactant: BrCc1ccc2ccccc2c1-c1c(CBr)ccc2ccccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc(OCc2ccc3ccccc3c2-c2c(COc3ccccc3)ccc3ccccc23)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A mixture of 11.0 g (25 mmol) of 2,2'-bis(bromomethyl)-1,1'-binaphthyl, 4.8 g (51.2 mmol) of phenol, 5.0 g (89.3 mmol) of pulverized potassium hydroxide and 1.14 g (5 mmol) of triethylbenzylammonium chloride is admixed with 30 ml of dichloromethane and stirred for 5 hours at 40° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cn1ccnc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cn1ccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 47.9 %

Procedure:
Using 1-methyl-1H-imidazole-2-carboxylic acid (36.7 mg, 0.29 mol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (51 μL, 0.58 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (75 mg, 0.24 mmol) and N,N-dimethylacetamide (1.5 mL) as starting materials and in the same manner as in Example 119, the title compound (48 mg, 47%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]1([O:26][CH2:27][CH:28]2[O:30][CH2:29]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(C)C.Cl>CO.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:29][CH:28]([OH:30])[CH2:27][O:26][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: COc1cc(O)ccc1N1CCNCC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc(O)ccc1N1CCN(CC(O)COc2cccc3ccccc23)CC1

Procedure:
A solution of 4.16 g. (0.02 mole) 1-(2-methoxy-4-hydroxyphenyl)-piperazine and 4.2 g. (0.021 mole) 2,3-epoxypropyl naphthyl ether in 50 ml. isopropanol is heated under reflux for 4 hours, while stirring. The solution is evaporated and the tarry residue obtained is dissolved in methanol. It is acidified with isopropanolic hydrochloric acid and diethyl ether carefully added thereto, an oily product precipitating out which is separated by decanting off. The solution is diluted with acetone. After a short time, the compound begins to crystallise out. When crystallisation is complete, the crystals are filtered off with suction and again recrystallised from methanol/diethyl either. Yield 4.8 g. (50% of theory); m.p. 230°-232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[NH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:24]
Reactant: CC(C)CCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCC(C)C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 1-amino-3-methylbutane.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[F:15][CH2:16][C:17](=O)[CH3:18]>ClCCl>[F:15][CH2:16][C:17]([CH3:18])([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:5]#[N:6]
Reactant: CC(=O)CF
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(N)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(C)(C#N)CF)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
Trimethylsilyl cyanide (0.146 ml, 1.1 mmol) was added dropwise to the mixture of p-toluidine (0.107 g, 1 mmol) and fluoroacetone (0.082 g, 1.1 mmol). The reaction mixture was stirred at room temperature for 12 h and then concentrated under vacuum to obtain a brown liquid which was subjected to chromatography (dichloromethane) to yield 19a (0.179 g, 0.93 mmol, 93%) as a yellowish solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36](B3[O:42][C:41](C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:29][CH2:28]1.[OH2:47]>>[CH:41]([OH:42])=[O:47].[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:36]4[CH:35]=[N:34][N:33]([CH:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)[CH:37]=4)[CH:3]=3)[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:23]=1
Reactant: CN1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O
Reactant: Fc1ccc(Cl)cc1-c1cc(-c2cncc(Br)c2)c2cccnc2n1
Product: CN1CCC(n2cc(-c3cncc(-c4cc(-c5cc(Cl)ccc5F)nc5ncccc45)c3)cn2)CC1
Product: O=CO
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 59.7 mg (0.144 mmol) 4-(5-bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine and 55.3 mg (0.190 mmol) 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine 67.2 mg (0.316 mmol) tri-potassiumphosphate trihydrate were added. The mixture was heated to 80° C. under nitrogen. Then 5.5 mg (0.008 mmol) bis(triphenylphosphine)palladium(II)-chloride were added. The reaction mixture was stirred for 4 hours at 80° C. The reaction mixture was cooled to room temperature and water was added. The resulting precipitate was filtered off, washed with water and air-dried. The residue was purified by preparative HPLC yielding 2-(5-chloro-2-fluoro-phenyl)-4-{5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-3-yl}-[1,8]naphthyridine formate as colourless crystals; HPLC-MS: 1.29 min, [M+H] 292.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].IC.[C:34]([O-])([O-])=O.[Cs+].[Cs+].C1C[O:43][CH2:42][CH2:41]1>>[C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[N:14]([CH3:34])[C:42](=[O:43])[CH3:41])=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Agent: [Cs+]
Solvent: CI
Product: CC(=O)c1c(N(C)C(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reaction time: 8 h

Procedure:
A solution of the product from Example 2 (60 mg) in THF (1 mL), under nitrogen, was treated with iodomethane (73 uL) and Cs2CO3 (58 mg). The suspension was stirred overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification on a preparative silica TLC plate eluted with 25% EtOAc in hexane afforded the title compound. HPLC/MS: 528.1 (M+1), 530.1 (M+3); Rt=4.08 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][OH:14].Cl.C([O-])(O)=O.[Na+].CO>O>[OH:14][NH:13][C:11](=[NH:12])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N=C(Cc1ccc([N+](=O)[O-])cc1)NO
Temperature: 25 °C

Procedure:
A 250-mL round bottomed flask was charged with 2-(4-nitrophenyl)acetonitrile (2.5 g, 15.4 mmol, 1 eq.), NH2OH/HCl (2.12 g, 31 mmol, 2 eq), NaHCO3 (2.82 g, 2.3 mol, 7 eq.), MeOH (100 ml) and water (16 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure. The residue was treated with water (100 ml). Solid was collected by filtration and washed with water (3×20 ml) followed by dichloromethane (3×10 ml). After drying, the title compound was obtained as yellowish solid (2.46 g, 84% yield).
Reaction SMILES: [Si](O[C:9]1[N:10]([CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[C:13](C)[C:12]=2[N:18]=1)(C(C)(C)C)(C)C.[O:20]1CCC[CH2:21]1.C(O)(=O)C>O>[OH:20][CH2:21][C:9]1[N:10]([CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:18]=1
Reactant: Cc1nccc2c1nc(O[Si](C)(C)C(C)(C)C)n2C
Reactant: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(CO)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.00 g of 2-t-butyldimethylsilyloxy-methyl-1-methylimidazo[4,5-c]pyridine (prepared as described in Preparation 72) in 60 ml of a 1:1:1 by volume mixture of tetrahydrofuran, acetic acid and water was stirred at room temperature for 1 hour and then at 60° C. for 5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate and then concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.97 g of the title compound, melting at 285°-290° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([Br:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Cl:11])[C:3]=1[CH3:12].BrC1C(C)=C(Br)C(Br)=C(Br)C=1Br.C1C[NH2+]CC1.C1[O:34]C2OC1C2(C(I)I)CCC1(C(I)I)C2OC1CO2>>[Br:1][C:2]1[C:7]([Br:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Cl:11])[C:3]=1[CH:12]=[O:34]
Reactant: Cc1c(Cl)c(Br)c(Br)c(Br)c1Br
Reactant: IC(I)C1(CCC2(C(I)I)C3COC2O3)C2COC1O2
Agent: C1CC[NH2+]C1
Agent: Cc1c(Br)c(Br)c(Br)c(Br)c1Br
Product: O=Cc1c(Cl)c(Br)c(Br)c(Br)c1Br

Procedure:
When 2,3,4,5-tetrabromo-6-chlorotoluene, mp 268°-269°, was substituted for pentabromotoluene in Example 7 and the resultant dioxonium compound was hydrolyzed according to the procedure of Example 35 an essentially quantitative yield of the title compound was obtained. The structure of the novel high melting compound was confirmed by infrared and nuclear magnetic resonance spectroscopy as well as by elemental analysis.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1)([O-:3])=[O:2].[N:18]([C:21](OCC)=O)=C=S.[Cl-].O[NH3+].C([N:32](CC)C(C)C)(C)C>CO.C(O)C.CS(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:32]=[C:21]([NH2:18])[N:14]=2)[CH:13]=1)([O-:3])=[O:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Solvent: CS(C)=O
Product: Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2n1
Yield: 96.3 %

Procedure:
In the same manner as in Example 17-1 and using 5-(3-nitrophenoxy)pyridin-2-amine (3.10 g, 13.4 mmol), ethyl isothiocyanatoformate (2.29 g, 17.4 mmol), hydroxylammonium chloride (4.00 g, 57.6 mmol), N,N-diisopropylethylamine (7.20 mL, 41.3 mmol), DMSO (20 mL), ethanol (25 mL) and methanol (25 mL) as starting materials, the title compound (3.50 g, 96%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([OH:10])=[C:5]([O:11][CH3:12])[CH:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[C:17]#[N:18].[OH-].[K+]>C(#N)C>[CH2:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([O:10][C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[F:13])=[C:5]([O:11][CH3:12])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(OC)c(O)cc1F
Reactant: N#Cc1ccc(F)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCc1cc(OC)c(Oc2ccc(C#N)cc2F)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A suspension of 4-ethyl-5-fluoro-2-methoxyphenol (1 g, 5.87 mmol), 3,4-difluorobenzonitrile (899 mg, 6.46 mmol) and potassium hydroxide (395 mg, 7.04 mmol) in anhydrous acetonitrile (35 mL) under argon was stirred at 80° C. overnight. The reaction mixture was concentrated under vacuum and diluted with ethyl acetate and a saturated aqueous solution of ammonium chloride. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and concentrated in vacuo to give a brown oil (1.6 g). The crude product was purified by flash chromatography on silica gel, using cyclohexane/ethyl acetate (9:1) as eluent. The title product was obtained as a colourless oil that crystallized slowly (1.42 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][C:20]1[C:25](=[O:26])[N:24]2[CH2:27][CH2:28][CH2:29][C:30](=[O:31])[C:23]2=[N:22][C:21]=1[CH3:32].C(N(C(C)C)CC)(C)C>CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][C:20]4[C:25](=[O:26])[N:24]5[CH2:27][CH2:28][CH2:29][C:30](=[O:31])[C:23]5=[N:22][C:21]=4[CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2=O
Temperature: 26 °C
Reaction time: 0.25 h

Procedure:
To the solution of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (formula-8) (0.62 grams) taken in methanol added 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-9) (0.94 grams), diisopropyl ethyl amine (0.75 grams) and refluxed the reaction for 23 hrs. Cooled the reaction mixture to 26° C. and stirred for 15 minutes. Filtered the precipitated solid. Washed the solid with chilled methanol and dried. Separated the compound with column chromatography using chloroform/methanol as an eluent.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:14])[C:10]=2[O:9]1
Reactant: Cc1ccccc1B(O)O
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.055 g, 24%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.20 g, 0.826 mmol) and 2-methylphenylboronic acid (0.168 g, 1.24 mmol). mp 166-169° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].CO.ClCCl>ClCCCl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:29]([N:18]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:9]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=2)[CH:8]=1)=[O:36])[CH3:35]
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1Nc1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)CC(=O)N(c1ccc(F)cc1)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of ethyl 5-(4-fluorobenzyl)-3-[(4-fluorophenyl)amino]pyridine-2-carboxylate (456 mg, 1.24 mmol) in 1,2-dichloroethane was added ethyl 3-chloro-3-oxopropanoate (0.18 mL, 2.36 mmol) and the resulting yellow solution was refluxed for 1 hour or until determined complete by TLC (5% methanol/dichloromethane). The mixture was cooled to ambient temperature, quenched with water and extracted with dichloromethane. The organics were washed with saturated aqueous sodium bicarbonate, brine, and dried over sodium sulfate to yield ethyl 3-[[3-(ethyloxy)-3-oxopropanoyl](4-fluorophenyl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (477 mg, 80% yield) as mixture of rotamers. The yellow oil can be carried on without further purification or purified by silica gel chromatography (0-12% methanol/dichloromethane gradient elution). Spectral data was consistent with the expected product as mixture of rotamers. MS m/z 505 (M+23).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][CH2:13][C:14]([NH2:16])=[NH:15].[Cl:17][C:18]1[C:19]([C:24](O)=[O:25])=[N:20][CH:21]=[CH:22][N:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][CH2:13][C:14]([NH:16][C:24]([C:19]1[C:18]([Cl:17])=[N:23][CH:22]=[CH:21][N:20]=1)=[O:25])=[NH:15]
Reactant: O=C(O)c1nccnc1Cl
Reactant: N=C(N)COCCc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1cc(F)ccc1F)NC(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
2-[2-(2,5-Difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (158 mg, 0.631 mmol) was dissolved in DMF (3 ml) and 3-chloro-2-pyrazine-carboxylic acid (100 mg, 0.631 mmol), TBTU (213 mg, 0.662 mmol) and DIPEA (565 μl, 3.15 mmol) were added. The reaction mixture was stirred at ambient temperature for 4.5 h. Then water was added and the mixture was extracted three times with CH2Cl2. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated. The crude title compound (195 mg, brown gum) was used for the next reaction step without further purification. MS: m/e=355.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][CH:14]=2)[N:7]=1>C1COCC1.CO.[Pt]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][CH:14]=2)[N:7]=1
Reactant: COC(=O)/C=C/c1cc(C)n(C(OCc2ccc(Cl)cc2)c2cccc(Cl)c2)n1
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(C)n(C(OCc2ccc(Cl)cc2)c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of unsaturated ester 6 (0.31 g, 0.65 mmol) and 5 Pt/C (0.01 g) in THF (6 mL) and MeOH (12 mL), previously purged with nitrogen, was stirred under a hydrogen atmosphere (balloon) at RT overnight. The platinum was removed by filtration through Hyflo and the filtrate was evaporated to dryness to afford the saturated ester 7, 0.31 g (99%).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[C:11]([NH2:28])=[N:12][CH:13]=[C:14]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=3)[N:15]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[OH:38][C@H:39]([CH3:44])[CH2:40][C:41](O)=[O:42]>CN(C)C=O.C(#N)C>[NH2:28][C:11]1[N:12]=[CH:13][C:14]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([CH:22]3[CH2:23][CH2:24][N:25]([C:41](=[O:42])[CH2:40][C@H:39]([OH:38])[CH3:44])[CH2:26][CH2:27]3)[N:17]=2)=[N:15][C:10]=1[C:8]1[O:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1
Reactant: C[C@@H](O)CC(=O)O
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(C)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (201 mg, 0.63 mmol) was added to a stirred suspension of 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (200 mg, 0.52 mmol, described in Example 1), N-ethyl-N-isopropylpropan-2-amine (0.273 mL, 1.56 mmol) and (R)-3-hydroxybutanoic acid (65.2 mg, 0.63 mmol) in N,N-dimethylformamide (3 mL). The resulting suspension was stirred at room temperature for 2 hours. The resulting mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml/minute) using an isocratic mixture of 31% acetonitrile in water (containing ammonium carbonate (2 g/L). The fractions containing the desired compound were evaporated to dryness to afford a pale yellow solid. This solid was stirred in acetonitrile (3 mL) at room temperature. The resulting solid was filtered, washed with cold acetonitrile and dried to afford the title compound (125 mg, 51.0%) as a pale yellow solid.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][NH:3]1.P(Br)(Br)(Br)(Br)[Br:17]>ClCCCl.CC(O)=O>[Br:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][N:3]=1
Reactant: BrP(Br)(Br)(Br)Br
Reactant: O=C(O)c1ccc2c(=O)[nH][nH]c(=O)c2c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(Br)n[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
1,4-Dioxo-1,2,3,4-tetrahydro-phthalazine-6-carboxylic acid (91.0 g, 0.44 mol) was suspended in DCE (1.0 L) and phosphorus pentabromide (761.0 g, 1.77 mol) was added in three portions and the reaction heated to reflux for 24 hours. The reaction was cooled to RT and poured onto ice (2.5 kg) and the resulting precipitate filtered and washed with water to give the crude product (130.0 g). This crude material was suspended in HOAc (1.6 L) and heated to 125° C. for 2 h. The reaction was cooled to RT and poured onto ice (1.5 kg) and the resulting precipitate filtered. The solid was washed with water and dried to give the title compound (85 g, 73% yield) as a yellow solid. Tr=0.94 min, m/z (ES+) (M+H)+ 310 & 312