Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]3[C:28]=2[CH3:29])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)C1C=CC=CC=1>[Pd].CO.O1CCCC1>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]3[C:28]=2[CH3:29])=[CH:10][C:9]=1[OH:8]
Reactant: Cc1c(CCc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)nc2ccccn12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CCc2ccc(N)c(O)c2)nc2ccccn12
Reaction time: 3 h
Yield: 30.5 %

Procedure:
10% Palladium on carbon (3.0 g) was added to a mixture of 2-[2-(3-benzyloxy-4-nitrophenyl)ethyl]-3-methylimidazo[1,2-a]pyridine (6.5 g) in a mixture of methanol and tetrahydrofuran, and the mixture was subjected to catalytic reduction under. atmospheric pressure for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by a column chromatography on silica gel, and eluted with a mixture of chloroform and methanol (9:1, V/V). The eluted fast fractions containing the desired product were collected and evaporated in vacuo to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-3-methylimidazo[1,2-a]pyridine (1.37 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[CH2:7]2.[C:31]([N:50]1[CH:54]=[C:53]([CH:55]=O)[CH:52]=[N:51]1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1CCCC1>CO>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[C:7]2=[CH:55][C:53]1[CH:52]=[N:51][N:50]([C:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:54]=1
Reactant: O=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2
Solvent: C1CCNC1
Solvent: CO
Product: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 70 °C
Yield: 62.1 %

Procedure:
To a suspension of 4-(7-methyl-1-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzonitrile (300 mg, 0.773 mmol) and 1-trityl-1H-pyrazole-4-carbaldehyde (303 mg, 0.928 mmol) in methanol (5 ml) was added pyrrolidine (0.323 ml, 3.87 mmol). The reaction mixture was heated at 70° C. overnight. After cooled to room temperature, the reaction mixture formed a precipitate. The solid was collected and washed with cold methanol to give the title compound of 13B as a bright yellow solid (340 mg, 63.2% yield).
Reaction SMILES: C(OCC1C=CC=CC=1)C1C=CC=CC=1.[Li].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Li]CCCC.[O:30]=[C:31](N1[C@@H](C(C)C)COC1=O)[C@@H:32]([CH2:35][S:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:33][CH3:34]>C1COCC1>[C:38]1([CH2:37][S:36][CH2:35][C@@H:32]([CH2:33][CH3:34])[C:31]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:30])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC[C@H](CSCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: OCc1ccccc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccc(COCc2ccccc2)cc1
Product: CC[C@H](CSCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 161.2 %

Procedure:
To a magnetically stirred, cooled (-10° C.) solution of lithium benzyloxide in anhydrous THF (400 mL), prepared from freshly distilled benzyl alcohol (28.7 mL, 30.0 g, 277 mmol) and 127.5 mL (1.6M in hexane, 204 mmol) of n-BuLi, was added a solution of the product of step 7 (48.9 g, approx. 146 mmol) in anhydrous THF (170 mL) over a 0.5 h period. After 15 min. at -10° C., the reaction mixture was warmed to 0° C., stirred for 2 h and then quenched by the addition of half-saturated aq NH4Cl (300 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with H2O (3×) and brine, dried over MgSO4 and concentrated in vacuo to give 74 g of a pale yellow oil. This crude material was purified in two portions by flash chromatography on silica with toluene giving the title compound as a colorless liquid (32.8 g), containing a small amount of butanoic acid benzyl ester and an unidentified impurity. This product was used as such for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:10]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:44][C:45]1[CH:50]=[C:49]([S:51]([CH:54]([CH3:56])[CH3:55])(=[O:53])=[O:52])[CH:48]=[CH:47][C:46]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:10]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[N:11][C:12]([C:46]2[CH:47]=[CH:48][C:49]([S:51]([CH:54]([CH3:55])[CH3:56])(=[O:53])=[O:52])=[CH:50][C:45]=2[F:44])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)n2)c(F)c1
Temperature: 80 °C
Yield: 96 %

Procedure:
tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (100 mg, 0.1512 mmol) was dissolved in DMF (1 mL) and 2-(2-fluoro-4-isopropylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (74.44 mg, 0.2268 mmol) and Pd(PPh3)2Cl2 (6.254 mg, 0.01512 mmol) were added. Na2CO3 (226.84 of 2 M, 0.4536 mmol) was added and the reaction heated at 80° C. under an atmosphere of nitrogen for 1 h in a sealed tube. The reaction mixture was partitioned between EtOAc (5 mL) and water (5 mL) and the aqueous layer extracted with EtOAc (2×5 mL). The combined organic extracts were washed with water (3×5 mL), brine (2×5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 24 g column, eluting with 0 to 50% EtOAc/Petroleum Ether, loaded in CH2Cl2) to give the product as an off-white solid that was used without further purification (114.4 mg, 96% yield)
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:7]([NH2:6])[N:8]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[CH:18]=[CH:19]3)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CC(C)(C)c1cc(N)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1ccc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a mixed solvent of dimethylformamide (8 mL) and pyridine (0.47 mL) were added 3-amino-5-tert-butylpyrazole (810 mg), N-methylindol-5-boronic acid (780 mg), copper (II) acetate (790 mg) and molecular sieves (400 mg). The reaction mixture was stirred overnight at room temperature. The reaction mixture was added with 10% aqueous ammonia and filtered through Celite®. The filtrate was added with ethyl acetate and separated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=7:3→1:1→1:4) to give the titled compound (577 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([N+:17]([O-])=O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([NH2:17])=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CNc1nc(Nc2ccc(Cl)cc2)ncc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1nc(Nc2ccc(Cl)cc2)ncc1N
Reaction time: 0.5 h

Procedure:
3.0 g of 2-(4-chlorophenylamino)-4-methylamino-5-nitro-pyrimidine are hydrogenated in 300 ml of methanol and 150 ml of dimethylformamide in the presence of 1 g of platinum on charcoal (5% platinum) for one hour at a hydrogen pressure of 50 psi. The reaction mixture is filtered and the filtrate is evaporated to dryness in vacuo. The residue is combined with 40 ml water and stirred for 30 minutes. The solid is suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[CH3:8][C:9](=O)[CH2:10][CH3:11].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:9]([CH3:8])[CH2:10][CH3:11])=[N:5][N:6]=1
Reactant: Cc1nnc(N)[nH]1
Reactant: CCC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(C)Nc1nnc(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (5 g) and butan-2-one (5.5 g) in acetic acid was added sodium cyanoborohydride (16 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (4.8 g, 61%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[Br:8].[C:9]([O-:12])(=[O:11])[CH3:10].[K+].O>CC(C)=O>[C:9]([O:12][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[Br:8])(=[O:11])[CH3:10]
Reactant: BrCc1ccsc1Br
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCc1ccsc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
A mixture of 2-bromo-3-methylthiophene (17.7 g), N-bromosuccinimide (17.7 g), 2,2'-azobis(isobutyronitrile) (0.32 g) and carbon tetrachloride (200 ml) was stirred for 4 hours under reflux. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-bromomethyl-2-bromothiophene (12.56 g). A suspension of 3-bromomethyl-2-bromothiophene (6.30 g), potassium acetate (9.8 g) in acetone (100 ml) was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-acetoxymethyl-2-bromothiophene (5.8 g). This crude product was dissolved in tetrahydrofuran (50 ml), and 1N aqueous sodium hydroxide (50 ml) and ethanol (20 ml) were added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-hydroxymethyl-2-bromothiophene (4.6 g). This crude product of 3-hydroxymethyl-2-bromothiophene was dissolved in methylene chloride (100 ml), manganese dioxide (15 g) was added. The mixture was stirred at room temperature for 6 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-bromo-3-thiophenecarbaldehyde (3.92 g). The crude product of 2-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.0 g) in water (15 ml) and 30% aqueous hydrogen peroxide (2.5 ml) were added. Further, sodium chlorite (2.7 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide (2.7 g) and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-bromo-3-thiophenecarboxylic acid (2.89 g) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])([O-])=O.C(O)(=O)C.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13]
Reactant: C[C@@H](CO)Nc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](CO)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
A 1-L round bottomed flask containing (S)-2-(2-nitrophenylamino)propane-1-ol (6.9 g, 35.2 mmol) and equipped with a magnetic stir bar was charged with methanol (138 mL), acetic acid (6.04 mL, 106 mmol), and 10% palladium on carbon (0.700 g, 0.658 mmol). The flask was fitted with a three-way stopper with a balloon of hydrogen attached. A vacuum line was connected, and the flask was gently evacuated, then back filled with hydrogen, twice. The reaction mixture was then stirred under a hydrogen atmosphere at rt. After 4 h, the reaction mixture was filtered through a pad of Celite, and the filter cake and catalyst were rinsed with fresh methanol. The filtrate was concentrated under reduce pressure to a dark syrup. The material was redissolved in toluene (ca. 200 mL), which was then removed under reduced pressure. The residue was then dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (75 mL) followed by 5 wt % aqueous sodium chloride (50 mL). The ethyl acetate extract was then concentrated under reduced pressure to afford (S)-2-(2-aminophenylamino)propane-1-ol (5.12 g, 88%) as a dark purple solid. MS (ESI, pos. ion) m/z 167 [M+1]+.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O>C(O)C>[Br:25][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Reactant: O=C(CBr)c1cccc(Br)c1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(Br)c3)cs2)c1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To a solution (5 mL) of the compound (1.1 g, 5.16 mmol) obtained in Example 1b in ethanol was added 2-bromo-1-(3-bromophenyl)ethanone (1.6 g, 5.67 mmol), and the mixture was heated under reflux for 3 hr. The mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The obtained crude product was washed with ethyl acetate to give the title compound (1.44 g, 71%) as white crystals.
Reaction SMILES: [CH3:1][O: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[CH:13]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH3:23])([O-:22])=[O:21]>O>[N+:20]([CH:23]=[CH:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])([O-:22])=[O:21]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc2ccccc2c1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: COc1ccc2ccccc2c1C=C[N+](=O)[O-]
Yield: 95 %

Procedure:
1.52 g of 2-methoxynaphthaldehyde (8.16 mmol), 0.4 g of ammonium acetate (5.19 mmol) and 20 cm3 of nitromethane (96%) are introduced into a 50-cm3 two-necked round-bottomed flask equipped with a condenser. The reaction mixture is heated to reflux for 1 h 30 min while stirring. It becomes yellow. The nitromethane is evaporated off in a rotary evaporator and the residue is then taken up with dichloromethane. Hydrolysis of the ammonium acetate is carried out by pouring the above mixture into water. The aqueous phase is washed twice with CH2Cl2, the organic phase once with water. The latter phase is dried with MgSO4 and the solvent is removed in a rotary evaporator. 1.77 g of yellow crystals (equivalent to 7.73 mmol of the expected product) are then obtained, corresponding to a 95% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])#[CH:15]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:14]#[C:15][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1
Reactant: CC(C)c1nnc2ccc(Cl)nn12
Reactant: C#Cc1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Temperature: 60 °C
Yield: 64.1 %

Procedure:
A solution of 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (20.0 g, 102 mmol, Preparation #G.1) in DMF (300 mL) was evacuated and purged with nitrogen 3 times. To the reaction mixture was added 1-ethynyl-2,4-difluorobenzene (21.1 g, 153 mmol), CuI (0.969 g, 5.09 mmol), TEA (42.5 mL, 305 mmol) and bis(triphenylphosphine)palladium(II) chloride (3.57 g, 5.09 mmol). The reaction mixture was evacuated and purged with nitrogen 3 times. The reaction mixture was heated to about 60° C. for about 6 h, cooled to ambient temperature, and diluted with EtOAc (500 mL). The organic solution was washed with water (3×500 mL), brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was dissolved in a minimal amount of hot DCM and allowed to cool to ambient temperature. The solid 1,2-bis(2,4-difluorophenyl)ethyne (6.7 g, 26.3%) was filtered off and the filtrate was purified by silica gel chromatography using heptane/EtOAc (gradient, 1:1 to 0:1) to give product. The product was then precipitated by dissolving in EtOAc (500 mL) and adding heptane (100 mL portions) while concentrating in vacuo. The solid was collected by vacuum filtration and dried under vacuum to give the title compound (19.5 g, 64%) as an off white solid. LC/MS (Table 1, Method a) Rt=2.72 min; MS m/z: 299.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.C[Si]([N:26]=[C:27]=[O:28])(C)C>C(Cl)Cl.C(O)(C)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:13]([C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:27]([NH2:26])=[O:28])=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: CC(C)O
Product: NC(=O)N(Cc1ccc(Cl)cc1)[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(R)-3-(4-Chloro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butylester (0.690 g, 2.2 mmol) was dissolved in CH2Cl2 with a few drops of isopropanol and trimethylsilylisocyanate (0.365 mL, 2.6 mmol) were added. The solution was allowed to stir at room temperature for 12 h, the reaction was concentrated down and used directly in the next reaction. ESI-MS m/z: 354 (M+1), retention time 2.15.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:1]1[CH:2]=[CH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of 150 g of methyl p-toluate and 195.5 g of NBS in CCl4 (1.67 L) under N2 at 50° C. was added portion wise over 30 min, solid benzoyl peroxide (5.0 g). There was no exothermic reaction observed. After heating for 2 hours at 50° C., the yellow solution was heated at 65° C. for 6 hrs. There was still some unreacted starting material. The suspension was stirred overnight at 65° C. After cooling to room temperature (r.t), the precipitate formed was filtered off and washed with 150 mL of CCl4 and the filtrate was concentrated to afford a yellow oil that solidified on standing. The title compound, containing a small fraction of starting material was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:2]=1.[NH2:16][OH:17]>C(O)C>[OH:17]/[N:16]=[C:12](\[NH2:13])/[C:11]1[CH:10]=[CH:9][C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(Oc2cccnc2)cc1
Reactant: NO
Solvent: CCO
Product: N/C(=N\O)c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-(Pyridin-3-yloxy)benzonitrile (486 mg, 2.48 mmol) was dissolved in ethanol (10.0 mL) then hydroxylamine (1.0 mL, 9.9 mmol) was added and the mixture was refluxed for 4 hours. The reaction was cooled to room temperature and concentrated in vacuo to give the product which immediately formed yellow solid (565 mg, 100%) which was taken to the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ(ppm): 5.83 (2H, bs), 7.05 (2H, d, J=9.0 Hz), 7.43 (1H, ddd, J=8.4, 4.4, 0.8 Hz), 7.46 (1H, ddd, J=8.4, 2.7, 1.6 Hz), 7.72 (2H, d, J=8.8 Hz), 8.39 (1H, dd, J=4.5, 1.5 Hz), 8.41 (1H, d, J=2.8 Hz), 9.64 (1H, bs). 13C NMR (125 MHz, DMSO-d6) δ(ppm): 118.1 (CH), 124.8 (CH), 126.1 (CH), 127.4 (CH), 129.2, 134.5 (CH), 141.2 (CH), 144.9 (CH), 150.3, 153.0, 156.7. MS (FAB+): 230 (MH+). HRMS for C12H11N3O2 (MH+): calculated: 230.0930; found 230.0941.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:34][CH2:35][CH2:36][NH:37][C:38]1[N:46]=[C:45]([Cl:47])[N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:34][CH2:35][CH2:36][NH:37][C:38]1[N:46]=[C:45]([Cl:47])[N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
190 mg of 3-chlorobenzoic acid, 205 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 280 mg of the product obtained in Stage 1 of Example 7 is added and the reaction medium is agitated for 5 hours and 30 minutes at ambient temperature. Water is added, followed by extracting with methylene chloride, drying, evaporating the solvents, recrystallizing from ether, separating, drying and 334 mg of expected product is collected.