Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=[N:3]1>[C].[Pd].CO>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C#Cc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: Cn1nccc1CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
10% Palladium carbon (1.00 g) was added to a methanol (150 mL) solution of 1-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}-1H-pyrazole (2.33 g), and the obtained solution was then stirred under a hydrogen atmosphere at a room temperature overnight. Thereafter, the reaction solution was filtrated with Celite, and the filtrate was then concentrated under a reduced pressure, so as to obtain the title compound (1.90 g) in the form of a colorless oily substance.
Reaction SMILES: [OH-:1].[Na+:2].[O:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10](=[O:21])[O:11][C:12](=[O:20])[C:13]=2[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:5][CH2:4]1>O1CCOCC1>[O:3]1[CH2:8][CH2:7][CH:6](/[C:9](=[C:13](\[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)/[C:12]([O-:11])=[O:20])/[C:10]([O-:21])=[O:1])[CH2:5][CH2:4]1.[Na+:2].[Na+:2]
Reactant: O=C1OC(=O)C(C2CCOCC2)=C1C1CCOCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C([O-])/C(=C(\C(=O)[O-])C1CCOCC1)C1CCOCC1
Reaction time: 24 h
Yield: 94.8 %

Procedure:
A 1 M NaOH (4.5 ml, 4.5 mmol) was added to a solution of 3,4-bis(tetrahydro-2H-pyran-4-yl)furan-2,5-dione (600 mg, 2.25 mmol) in 1,4-dioxane (4.5 ml) at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was concentrated, and the residue was dried in vacuo to give the title compound as a colorless solid (0.7 g, quantitative).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Cl[C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)=[O:22]
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)c1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 450 mg, 1.40 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 306 mg, 1.68 mmol) and DIPEA (733 μl, 4.20 mmol) in dry DMSO (4.7 ml). The reaction was subjected to microwave irradiation at 140° C. for 2 hours and then partitioned between ethyl acetate and water, washed with water, brine and concentrated in vacuo. The crude product was then purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to give a cream solid which was then recrystallised from a mixture of ethyl acetate and pentane to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([O:31][C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(-c3cccc4[nH]ncc34)nc21
Temperature: 155 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.1 g, 0.352 m moles) was dissolved in 2 mL DMF. 4-Methylsulfonylphenol 8a (0.12 g, 0.704 mmol) and potassium carbonate (0.24 g, 1.76 mmol) were added. After bubbling nitrogen gas through the reaction mixture, it was heated by microwave at 155° C. for 1.5-2 hours. Solvent was removed, excess potassium carbonate was filtered and partitioned and extracted with ethyl acetate. The organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous Na2SO4, solvent removed and purified to obtain 101. 1H NMR (400 MHz, DMSO) δ 13.26 (s, 1H), 8.77 (s, 1H), 8.06 (d, J=8.8, 2H), 7.92-7.51 (m, 6H), 7.51-7.27 (m, 2H), 4.13 (s, 3H), 3.28 (s, 3H) MS (ESI) m/z 420.1 (M+1)+
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19](O)[CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[CH:17][CH:18]=1.O=S(Cl)Cl.[SH:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(N(CC)CC)C>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]([S:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCS
Reactant: CCOC(=O)COc1cccc(CC(O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCSC(Cc1cccc(OCC(=O)OCC)c1)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product obtained from Step C in 50 mL of CH2Cl2 is treated with 2 mL of SOCl2. The reaction mixture is stirred at room temperature for 2 hr. and then evaporated to dryness. The crude product thus obtained in 20 mL of CH2Cl2 is treated with ethyl 3-mercaptopropionate and triethylamine (1:1) for 16 hr. at room temperature. After evaporation of solvent, the crude product is purified by flash column chromatography to obtain ethyl 2-(3-(2-(3-(2-quinolinylmethyloxy)phenyl)-2-(carbethoxyethylthio)ethyl)phenoxy)acetate.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=[CH:8][CH:9]1[NH:15][C:14](=[NH:16])[CH2:13][CH2:12][CH2:11][CH2:10]1>CCO.[Pd]>[ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][CH2:8][CH:9]1[NH:15][C:14](=[NH:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N=C1CCCCC(C=Cc2nccs2)N1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(CCc2nccs2)N1

Procedure:
The title material Of Example 183 in EtOH is hydrogenated over 10% Pd on carbon catalyst in a standard Parr apparatus by the method of Example 35 to generate the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:16]2[C:7]([C:8]3[CH:9]=[C:10]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:11]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[N:12][C:13]=3[CH:14]=[CH:15]2)=[N:6][N:5]=1)[CH3:2].Cl.CCOC(C)=O>CO.C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:16]2[C:7]([C:8]3[CH:9]=[C:10]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:11]([C:17]4[CH:18]=[CH:19][C:20]([C:23]5([NH2:27])[CH2:24][CH2:25][CH2:26]5)=[CH:21][CH:22]=4)=[N:12][C:13]=3[CH:14]=[CH:15]2)=[N:6][N:5]=1)[CH3:2]
Reactant: CCOc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCOc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc3ccn12
Temperature: 25 °C

Procedure:
tert-Butyl {1-[4-(3-ethoxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (9-1) (0.775 g, 0.133 mmol) was dissolved in MeOH (2 mL) and DCM (2 mL), and 4N solution of HCl in EtOAc (10 mL, 40 mmol) was added. The reaction mixture was then permitted to stir at room temperature, capped but not under an atmosphere of nitrogen. After 1 hour the reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were then combined, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1-[4-(3-ethoxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine (1-100) as an off-white solid. HRMS (M+H)+: observed=436.215, calculated=436.2132.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:4]([NH:3][S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-fluorophenyl)acetate dihydrochloride (I82) (325 mg, 0.92 mmol) in DCM (10 ml), were added triethylamine (386 μl, 2.78 mmol) and benzenesulfonyl chloride (142 μl, 1.11 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with 1M Na2CO3, water and then brine, dried over Na2SO4 and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-(4-fluorophenyl)-2-(phenylsulfonamido)acetate (150 mg; 39% yield).
Reaction SMILES: [CH:1]1[C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:10]=[CH:9][C:3](=[C:4]([C:7]#[N:8])[C:5]#N)[CH:2]=1.[CH2:17]([N:21]([CH2:37][CH2:38][CH2:39][CH3:40])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]2[S:31]C=[CH:33][CH:34]=2)=[C:24]([O:35][CH3:36])[CH:23]=1)[CH2:18][CH2:19][CH3:20].O.C(OCC)(=O)C>CN(C)C=O>[C:7]([C:4]([C:5]1[S:31][C:30]([CH:29]=[CH:28][C:25]2[CH:26]=[CH:27][C:22]([N:21]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][C:24]=2[O:35][CH3:36])=[CH:34][CH:33]=1)=[C:3]1[CH:2]=[CH:1][C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:10]=[CH:9]1)#[N:8]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OC)c1
Reactant: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C(C#N)=c3ccc(=C(C#N)C#N)cc3)s2)c(OC)c1
Temperature: 50 °C
Yield: 14.5 %

Procedure:
In 8 ml of N,N-dimethylformamide, 375 mg (1.84 mmol) of 7,7,8,8-tetracyanoquinodimethane was dissolved. With stirring under ice cooling, 600 mg (1.75 mmol) of dibutyl[3-methoxy-4-[2-(thiophene-2-yl)vinyl]phenyl]amine was dissolved in 2 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 1 hour and further stirred with heating at 50° C. overnight. After the reaction mixture was poured into 80 ml of water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography and washed with chloroform to give 132 mg of a yellowish white crystal having a mp of 211-214° C. (yield: 14.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([O:13][CH2:14][CH3:15])=[CH:7][C:6]=1[CH3:16])=[O:4].C(O)C[OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]2([O:19][CH2:15][CH2:14][O:13]2)[CH2:7][C:6]=1[CH3:16])=[O:4]
Reactant: OCCO
Reactant: CCOC1=CC(C)=C(C(=O)OC)C(C)(C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C1=C(C)CC2(CC1(C)C)OCCO2

Procedure:
670 g. of crude 2,6,6-trimethyl-4-ethoxy-1,3-cyclohexadien-1-carboxylic acid methyl ester and 185 g. of ethylene glycol were heated in 3 l. of benzene in the presence of 3 g. of p-toluene sulfonic acid. The reaction was stopped after 1.5 l. of benzene had distilled over. The cold solution was washed with sodium bicarbonate solution and water, dried, and evaporated. The remaining oil was dissolved in 1 l. of petroleum ether and crystallized at -10°. A yield of 320 g. (m.p. 67°-69°) was obtained after recrystallization from petroleum ether. This product was identified as 7,9,9-trimethyl-1,4-dioxaspiro[4,5]dec-7-on-8-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)([CH3:11])[C:9](=[O:20])[NH:8][C:7]1=[O:21])[CH3:2].[NH2:23][C:24]1C=[CH:28][CH:27]=[CH:26][CH:25]=1.BrC1C=CC=CN=1.C([O-])(=O)C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1.[Cu].[Cu]Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)([CH3:11])[C:9](=[O:20])[N:8]([C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:7]1=[O:21])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)NC(=O)C1(C)c1cc(F)cc(F)c1
Reactant: Nc1ccccc1
Agent: Cl[Cu]
Agent: [Cu]
Agent: Brc1ccccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CN1C(=O)N(c2ccccn2)C(=O)C1(C)c1cc(F)cc(F)c1

Procedure:
A stirred solution of ethyl[5-(3,5-difluorophenyl)-5-methyl-2,4-dioxoimidazolidin-1-yl]acetate, isomer A (100 mg, 0.320 mmol, described in Intermediate 7), 2-bromopyridine (0.156 mL, 1.60 mmol), copper powder (71.2 mg, 1.12 mmol), copper (I) chloride (6.34 mg, 0.064 mmol), and potassium acetate (94.0 mg, 0.961 mmol) in pyridine (1.8 mL) was heated at 100° C. for 18 h. The cooled reaction mixture was poured onto 10% citric acid (20 mL) and with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to provide the title compound. MS: m/z=390 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH2:17])(=[O:5])=[O:4].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>N1C=CC=CC=1.ClCCl>[F:19][C:2]([F:18])([F:1])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])(=[O:4])=[O:5]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(N)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 4.5 h

Procedure:
To a solution of 2-amino-4-methoxycarbonylphenyl trifluoromethanesulfonate (2.6 g) in a mixture of pyridine (5.6 ml) and dichloromethane (20 ml) was added benzyl chloroformate (2.08 ml) at 0° C., and the mixture was stirred at 20° C. for 4.5 hours. The mixture was diluted with dichloromethane and washed successively with diluted hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane to give 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (2.61 g) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[C:12](Cl)[CH:11]=2)[C:7]([CH3:20])=[N:6][C:5]=1[CH3:21])(=[O:3])[NH2:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:31]1[CH:43]=[CH:42][C:34]([CH2:35][C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:33][C:32]=1[Cl:44]>COCCOC.CO.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:44][C:32]1[CH:33]=[C:34]([CH2:35][C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)[CH:42]=[CH:43][C:31]=1[C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[C:5]([CH3:21])=[N:6][C:7]=2[CH3:20])=[CH:11][CH:12]=1
Reactant: O=c1[nH]c(Cc2ccc(Br)c(Cl)c2)no1
Reactant: Cc1nc(C)c(-c2ccc(B(O)O)c(Cl)c2)nc1C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(Cc4noc(=O)[nH]4)cc3Cl)cc2)nc1C(N)=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 29.8 %

Procedure:
To a degassed solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (Intermediate 5-1; 562 mg, 2.07 mmol) in DME (60 mL), methanol (15 mL) and water (15 mL) was added tripotassium phosphate (660 mg, 3.11 mmol), 3-(4-bromo-3-chlorobenzyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate 23-1; 600 mg, 2.07 mmol) followed by (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (341 mg, 0.41 mmol). The resulting mixture was stirred at 80° C. under nitrogen for 90 minutes. The reaction mixture was allowed to cool to ambient temperature evaporated and partitioned between DCM (100 mL) and 0.5M HCl (100 mL), the suspension was filtered (difficult as most of the material was a sticky gum) and the resultant material retained. Organic phase separated off, dried by passing through a phase seperating cartridge. Removal of the solvent under reduced pressure gave crude product which was combined with previously filtered material for chromatography. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% formic acid) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(2′-chloro-4′-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)biphenyl-4-yl)-3,5-dimethylpyrazine-2-carboxamide (269 mg, 29.8%) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.Cl.[N:12]([O-])=O.[Na+]>O>[Br:1][C:2]1[C:3]2[N:4]([N:12]=[N:10][N:9]=2)[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NNc1nc(Cl)ncc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Clc1ncc(Br)c2nnnn12
Temperature: 10 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-2-chloro-4-hydrazinylpyrimidine (17 g, crude, 59.2 mmol) and 3 M HCl (600 mL). To the above was added dropwise a solution of NaNO2 (8 g, 0.1 mol) in water (15 mL) at 10° C. The resulting mixture was stirred at 10° C. for 1 h. Work-up: the resulting crystalline solid was collected by filtration. The solid was washed with ethanol (20 mL), and dried to afford 10 g (72%) of the product as a red solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[CH:8][CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=2[O:4][C:3]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu].C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[CH:8][CH:9]=[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:5]=2[O:4][CH:3]=1
Reactant: Cc1c(C(=O)O)oc2c(C(C)(C)C)ccc(O)c12
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1coc2c(C(C)(C)C)ccc(O)c12
Temperature: 210 °C

Procedure:
A mixture of 3-methyl-4-hydroxy-7-tert-butylbenzofuran-2-carboxylic acid (0.250 g, 1.0 mmol), quinoline (0.75 mL), and copper powder (0.064 g, 1.0 mmol) was heated to 210° C. until gas evolution ceased (about 10 minutes) and then poured into 2N HCl (15 mL). Carbon tetrachloride (15 mL) was added and the biphasic mixture was filtered through celite. The layers were separated and the aqueous layer extracted with an additional portion of carbon tetrachloride (15 mL). The combined extracts were dried (Na2SO4) and concentrated. Flash chromatography using 10% ethyl acetate in hexane as eluant afforded 3-methyl-4-hydroxy-7-tert-butylbenzofuran, compound 10a. Recrystallization from hexane provided analytically pure material. 1H NMR d 1.46 (9H, s), 2.43 (3H, s), 6.49 (1H, d, J=8 Hz), 6.98 (1H, d, J=8 Hz), 7.36 (1H, s).
Reaction SMILES: O[CH:2]1[CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Cl:14][CH:2]1[CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1
Reactant: OC1CCC2CCCCN2C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClC1CCC2CCCCN2C1

Procedure:
A solution of 14 g. (0.11 mole) of 3-hydroxyquinolizidine in 75 ml. of thionyl chloride and 50 ml. of benzene was refluxed for one hour. The solvent was completely evaporated, and the residue dissolved in chloroform. The solution was passed through an alumina column and evaporation of the chloroform gave crude 3-chloroquinolizidine. The crude material was chromatographed on an alumina column eluting with ether-petroleum ether, 1:19 to yield pure 3-chloroquinolizidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccccc1CCN
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1CCNC(=O)c1ccc(Cl)cc1
Yield: 70.2 %

Procedure:
1-Amino-2-(2-methylphenyl)ethane (13.5 g) was dissolved in 80 ml of pyridine. While the solution was cooled with stirring, 18 g of 4-chlorobenzoyl chloride was added dropwise. They were reacted at room temperature for 5 hours. Pouring of the reaction mixture into cold water gave a precipitate of crystals. The crystals were washed in water, dried, and recrystallized from cyclohexane to afford 19.2 g of 1-(4-chlorobenzoylamino)-2-(2-methylphenyl)ethane having a melting point of 95° to 96° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=4[S:29]([NH:32]C(C)(C)C)(=[O:31])=[O:30])=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:37])[CH:3]=1.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=4[S:29]([NH2:32])(=[O:31])=[O:30])=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:37])[CH:3]=1
Reactant: CCCCc1cc(-c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1cc(-c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)cc2)c(S(N)(=O)=O)s1
Reaction time: 8 h

Procedure:
To a mixture of the product of step D (215 mg, 0.40 mmol) and anisole (3 drops) was added TFA (3 mL). After standing at room temperature overnight, the solvent was removed and the residue was dissolved in EtOAc and washed with 2N Na2CO3 and brine. The organic was dried over MgSO4 and concentrated in vacuo to provide the titled compound, Rf=0.31 (20:1 CH2Cl2 /MeOH).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:18])=[CH:9][C:10]=1[NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)=O.[NH3:19]>CO>[Cl:18][C:8]1[N:7]=[N:6][C:5]([C:3]([NH2:19])=[O:2])=[C:10]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:9]=1
Reactant: COC(=O)c1nnc(Cl)cc1Nc1ccn(C)n1
Reactant: N
Solvent: CO
Product: Cn1ccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reaction time: 16 h
Yield: 100 %

Procedure:
6-Chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid methyl ester (75 mg, 0.28 mmol) was suspended in 7M ammonia in methanol (3 mL). After 16 h, the reaction mixture was concentrated in vacuo to give 6-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amide (70 mg, 100%) as an off-white solid which was used directly in the next step without purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.39 (s, 1H) 8.77 (br. s., 1H) 8.24 (s, 1H) 8.13 (br. s., 1H) 7.72 (d, J=2.3 Hz, 1H) 6.18 (d, J=2.3 Hz, 1H) 3.84 (s, 3H); LCMS (EI/CI) m/z: 253 [M+H].