Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:9])[CH2:6][CH2:7]Cl.[CH3:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:22])[C:13]2=[CH:23][S:24][CH:25]=[C:12]12>CN(C)C=O>[CH3:4][N:5]([CH3:9])[CH2:6][CH2:7][N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([CH3:10])[C:12]2=[CH:25][S:24][CH:23]=[C:13]2[C:14]1=[O:22]
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.4 g. of 55% sodium hydride-mineral oil dispersion 0.5 g. of 2-dimethylaminoethylchloride hydrochloride and 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.4 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and stirring at room temperature is continued for 18 hours. The reaction mixture is cooled, quenched with water, acidified, decolorized and filtered. The filtrate is made alkaline and extracted with chloroform. The dried chloroform extracts are concentrated to give a solid which is recrystallized from chloroform-hexane to give off-white crystals, m.p. 147°-149° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])(=O)=O.[N:36]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C.C(Cl)Cl>>[F:32][C:24]1[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:15]2[C:14]([CH3:34])=[CH:13][CH:12]=[C:11]3[C:16]=2[CH:17]=[CH:18][N:9]([C@H:7]([CH3:8])[CH2:6][N:39]2[CH2:38][CH2:37][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40]2)[C:10]3=[O:35])=[O:33])[CH:27]=[CH:26][C:25]=1[C:28]([F:30])([F:31])[F:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(=O)n([C@H](C)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A mixture of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.0002 mol), tert-butyl 1-piperazinecarboxylate (100 mg, 0.0006 mol), triethylamine (200 mg, 0.002 mol) and methylene chloride (6 mL, 0.09 mol) was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified by flash chromatography to afford the desired product as a light yellow oil (100 mg, 60%).
Reaction SMILES: Cl[CH:2]=[C:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[Na].C[O-].[Na+].N1C=CN=C1>C(#N)C.CO>[N:18]1([CH:2]=[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CC(C)(C)C(=O)C(=CCl)Oc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)C(=O)C(=Cn1ccnc1)Oc1ccc(F)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
256.7 g (1 mol) of 1-chloro-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one in 150 ml of acetonitrile were added dropwise to a suspension of 90 g (1 mol) of sodium imidazole, prepared from sodium methylate and imidazole in methanol, in 2,500 ml of acetonitrile, while stirring. Thereafter, the reaction mixture was heated to the boiling point for 6 hours. It was allowed to cool to room temperature and was concentrated by distilling off the solvent in vacuo. The residue was taken up in 1,000 ml of ethyl acetate, the mixture was washed three times with 200 ml of water each time and the organic phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. 272.4 g (94.5% of theory) of crude 1-(imidazol-1-yl)-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one were obtained as a brown oil, which was purified in the customary manner, via the nitrate, and then had a refractive index of nD20 =1.5590. ##STR52##
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]=O>C(O)=O>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:12]2[CH2:13][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)=[O:15])[CH2:17][CH2:18]1
Reactant: C=O
Reactant: Cc1ccc(C(=O)N2CC(C(=O)N3CCCNCC3)C2)cn1
Solvent: O=CO
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(C)CC3)C2)cn1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
To a stirred solution of 1-({1-[(6-methylpyridin-3-yl)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane (50 mg, 0.162 mmol) in formic acid (0.25 mL) was added formaldehyde (37% aq. sol., 0.097 mL, 1.296 mmol) and the reaction mixture was heated at 100° C. for 5 hours. Volatiles were then removed at reduced pressure to give the title compound (38 mg, 75%) after purification by silica FCC (eluting with 95:4.5:0.5 to 92.5:7.25:0.75 gradient of DCM/MeOH/NH3).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CP(=O)(O)CCCCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (2.0 g, 0.01 mole) in chloroform (40 ml) was added triethylamine (3.2 ml, 0.022 mole) and cooled in an ice bath to 0° C. Trimethyl silyl chloride (2.8 ml, 0.022 mole) was added to the above solution dropwise, followed by benzyl bromoacetate (1.6 ml, 0.011 mole). The ice bath was removed and the mixture stirred at room temperture for 5 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil (3.5 g) was dissolved in 30 ml ether; hexane was added dropwise to get a turbid solution and left at room temperature overnight to complete the crystallization. The resulting product was cooled in the freezer for 2 hours, filtered and the solid was washed very thoroughly with hexane (50 ml), ether (50 ml) and again very thoroughly with hexane (50 ml), ether (50 ml) in that order. The solid was vacuum dried to get 2.48 g (71%) of title compound, m.p. 68°-70° C. TLC: Silica gel, CH2Cl2 :MeOH:HOAc (20:1:1) shows a single spot at Rf =0.25.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C[O-].[Na+].CO.C(OC([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=O)[C:24]([NH:26][CH3:27])=[O:25])C)C.Cl.C(=O)(O)[O-].[Na+]>CO.O>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[N:4][O:3][CH3:2])[C:24]([NH:26][CH3:27])=[O:25]
Reactant: CON
Reactant: CCOC(C)OCc1ccccc1C(=O)C(=O)NC
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1CO
Yield: 97.3 %

Procedure:
Methoxyamine hydrochloride (7.52 g, 0.09 mol) was dissolved in methanol (60 ml), and a 28% sodium methoxide-methanol solution (19.68 g, 0.102 mol) was added to the solution under ice-cooling to obtain a suspension. A solution of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (15.92 g, 0.06 mol) in methanol (60 ml) was added to the suspension. The mixture was stirred under reflux for 2 hours. After completion of the reaction, about half of the methanol was evaporated under reduced pressure, water (400 ml) was added, and the mixture was extracted with dichloromethane (200 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in methanol (30 ml), a 36% aqueous hydrochloric acid solution (0.61 g, 0.006 mol) was added under ice-cooling, and the mixture was stirred for 0.5 hours. After completion of the reaction, water (370 ml) and saturated sodium bicarbonate (30 ml) were added, and the mixture was extracted with dichloromethane (200 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (12.98 g, Yield: 97.3%, E/Z=96/4) as colorless crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:45](OC1C(C(O)=O)=NC(CC2(N3C4=NC=CC=C4C=C3)CCCC2)=NC=1O)[C:46]1C=CC=CC=1.[Si](OCCNC1CC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:44]1[CH2:46][CH2:45]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1CC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)C1CC1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (417) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (404) (150 mg, 0.34 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amine (94 mg, 0.44 mmol) (8d) to get a white sticky solid (96 mg, 44%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[O:8][C:9]([CH3:14])=[C:10]([CH2:12][OH:13])[CH:11]=1)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:35]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:40]=[CH:39][C:38]([O:13][CH2:12][C:10]2[CH:11]=[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:15])[O:8][C:9]=2[CH3:14])=[CH:37][CH:36]=1
Reactant: CCOC(=O)CCc1cc(CO)c(C)o1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(CCC(=O)O)cc1COc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 3.9 %

Procedure:
To a stirred, cooled 0° C. solution, in tetrahydrofuran (2.5 mL), a solution of 3-(4-hydroxymethyl-5-methyl-furan-2-yl)-propionic acid ethyl ester (36) (400 mg) in tetrahydrofuran (2.5 mL) was cooled to 0° C. and treated successively with triphenylphosphine (542 mg), biphenyl-4-ol (353 mg) and diisopropylazodicarboxylate (0.41 mL). After stirring for 10 mins at 0° C. the reaction mixture was allowed to warm to room temperature and then stirred for a further 16 hours. The reaction mixture was concentrated in-vacuo then re-dissolved in dichloromethane (15 mL) and treated with triethylamine (1.50 mL) and a scavenger resin PS-TsCl (2.5 g) and the mixture was shaken for 6 hours at room temperature. The reaction mixture was purified by flash chromatography, eluting with a mixture of diethyl ether in petroleum ether (40-60° C.) (7:93 by volume). The purified product (320 mg) was dissolved in methanol/tetrahydrofuran (2:1 by volume) (18 mL), treated with 1.0 M aqueous lithium hydroxide solution (9 mL) and allowed to stir at room temperature for 6 hours. The pH of the reaction mixture was adjusted to between pH4 and pH5 by the addition of 1.0 M hydrochloric acid (˜5.0 mL), then treated with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were further washed with brine (35 mL), then dried (sodium sulphate) and concentrated in vacuo. A sample of the crude product (50 mg) was purified by HPLC to give compound 37 as white solid (25 mg). LC/MS System C: Rt=5.33 mins, m/z (ES−)=335 (M− for C21H20O4).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:30]=1[CH3:47]>CCOC(C)=O>[F:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:47])[C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:32]2)=[CH:37][CH:36]=1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 140 °C

Procedure:
Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.19 g, 0.69 mmol) was dissolved in DMF (2.00 mL, 26 mmol) and sodium hydride (0.018 g, 0.76 mmol) was added and the reaction was treated with 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (0.100 g, 0.35 mmol) and heated to 140° C. for 6 h. The reaction was then diluted with EtOAc and washed with 2% sodium bicarbonate then brine. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The reaction was then purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane and then purified by preparative reverse phase HPLC to afford 1-(7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=528.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.99 (1H, m), 7.83 (1H, dd, J=10.2, 2.3 Hz), 7.50-7.62 (3H, m), 7.35-7.42 (2H, m), 7.10 (1H, d, J=8.2 Hz), 6.29 (1H, dd, J=8.2, 2.3 Hz), 5.56 (1H, d, J=2.3 Hz), 4.07 (1H, d, J=9.8 Hz), 3.80-3.91 (3H, m), 3.56-3.63 (4H, m), 3.41-3.54 (2H, m), 2.82-2.89 (4H, m), 2.05 (3H, d, J=1.2 Hz), 1.90-2.02 (2H, m), 1.81-1.88 (1H, m), 1.62-1.72 (1H, m)
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.C([Li])CCC.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CCCCCC.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[NH:5][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: COC(=O)CBr
Reactant: COc1ccc2[nH]c(C3CC3)cc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)Cc1c(C2CC2)[nH]c2ccc(OC)cc12

Procedure:
As in Example 1, Part C, 4.46 g (0.024 mole) of 2-cyclopropyl-5-methoxy-1H-indole was treated with 15 mL (0.024 mol) of a 1.6M solution of n-butyl lithum in hexane, 24 ml (0.024 mol) of a 1M solution of ZnCl2 in ether, and 12.27 mL (0.024 mol) of methyl 2-bromoacetate to give after chromatography on silica gel (5% EtOAc/toluene→15% EtOAc/toluene) 3.81 g (61%) of 2-cyclopropyl-5-methoxy-1H-indole-3-acetic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[C:3]=1[NH2:10].[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>O=P(Cl)(Cl)Cl>[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]2[NH:10][C:3]3[C:4]([CH3:9])=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Cc1ccc(N)c(N)c1C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1C

Procedure:
2-(4-Nitrophenyl)-4,5-dimethyl benzimidazole was prepared by mixing 1,2-diamino-3,4-dimethylbenzene (1.36 g, 9.8 mmole with 4-nitrobenzoic acid (1.67 g, 9.8 mmole) and dissolved in POCl3 (10 ml) and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice. The resulting solid was filtered, washed with NaHCO3 and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(C(=O)O)c(N)c1
Agent: [BH4-]
Solvent: C1CCOC1
Product: COc1ccc(CO)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-methoxybenzoic acid (15.0 g, 89.8 mmol) in THF (300 mL) was added borohydride in THF (450 mL, 450 mmol) at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (500 mL×3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound. MS (ES+) C8H11NO2 requires: 153, found: 154 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1F)[C:5]([O:7]CC)=[O:6].[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:16]1[CH:17]=[CH:18][N:19]=[C:15]1[CH3:14])[C:5]([OH:7])=[O:6]
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nccn1-c1ccc(C(=O)O)cc1F
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3,4-difluorobenzoate (1.5 g) in N,N-dimethylformamide (12 mL) is added 2-methylimidazole (1.3 g) and K2CO3 (2.2 g) and the mixture is heated at 140° C. in a microwave oven for 1 h. After cooling to room temperature, water and ethyl acetate are added and the organic layer is dried (MgSO4) and concentrated. The residue is purified by chromatography (ethyl acetate/hexane 0:1→1:0). The ester is dissolved in methanol (30 mL) and 4 M aqueous NaOH (3 mL) is added and the mixture is stirred at room temperature for 1 h. The mixture is neutralized with 6 M aqueous HCl, concentrated and then acidified with 6 M aqueous HCl. The precipitate is filtered off washing with a small amount of water and dried by suction to give the title compound.
Reaction SMILES: C([N:8]1[C:12]2[CH2:13][CH:14]([F:16])[CH2:15][C:11]=2[C:10]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[N:9]1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[F:16][CH:14]1[CH2:15][C:11]2=[C:10]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[NH:9][N:8]=[C:12]2[CH2:13]1
Reactant: FC1Cc2c(-c3nnn[nH]3)nn(Cc3ccccc3)c2C1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: FC1Cc2n[nH]c(-c3nnn[nH]3)c2C1
Reaction time: 96 h
Yield: 63.1 %

Procedure:
To a solution of the intermediate from step B (13 mg, 0.04 mmol) in MeOH (1 mL) was added formic acid (0.1 mL) followed by palladium black (10 mg). After stirring the reaction mixture under nitrogen atmosphere for 96 hours, it was filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (Gilson) to give the title compound (4.9 mg). 1H NMR (CD3OD, 500 MHz) δ 5.8 (d, J=51.9 Hz, 1H), 3.31-3.17 (m, 2H), 3.14-2.92 (m, 2H). LC-MS: 0.99 min; (M+H)=195.17.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]=[C:27]([C:2]2[N:3]=[C:4]([NH2:16])[C:5]3[N:6]([N:8]=[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH:7]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cn3nc(-c4ccco4)nc3c(N)n2)CC1
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A mixture of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (112 mg, 0.4 mmol; see Examples 1 and 2), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (185 mg, 0.6 mmol; see Eastwood, P. Tetrahedron Letters 41:3705-3708 (2000) for its preparation), Pd(PPh3)3 (28 mg, 0.024 mmol), and aqueous Na2CO3 (2 M, 1 mL) in DMF (4 mL) was heated (at approximately 80° C.) for 16 hours. The reaction was filtered and then purified by HPLC (C18, H2O:MeCN gradient) to afford 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (72 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 2.47 (br. s, 2H), 3.54 (t, j=6.2 Hz, 2H), 4.05 (br. s, 2H), 6.7 (br. s, 1H), 6.7 (dd, J=3.3, 1.7 Hz, 1H), 7.12 (dd, J=3.5, 0.7 Hz, 1H), 7.91 (dd, J=1.7, 0.7 Hz, 1H), 8.18 (s, 1H). MS. m/z 383 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[C:16]([O:23][CH3:24])[N:15]=2)[CH:3]=1.[NH3:25].CO>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:25])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[C:16]([O:23][CH3:24])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C(C)C)c(OC)n1
Solvent: CO
Product: COc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1C(C)C
Temperature: 40 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of ethyl 6-chloro-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxylate (500 mg, 1.43 mmol) was added 7N ammonia in MeOH (20.5 mL, 143 mmol). The mixture was stirred at 40° C. for 18 h, after which the solvent was removed to give 6-chloro-4-(5-isopropyl-6-methoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (450 mg, 98%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d6) 8 ppm 11.47 (s, 1H), 9.10 (s, 1H), 8.17 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 6.53 (d, J=7.7 Hz, 1H), 5.71 (s, 1H), 4.04 (s, 3H), 3.18 (m, 1H), 1.23 (d, J=7.1 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O>C(O)(=O)C>[C:14]([O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:4]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: BrCc1cccc(-c2ccsc2)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1cccc(-c2ccsc2)c1
Yield: 41.8 %

Procedure:
A stirred solution of 8.7 g (0.034 mol) of 3-(3-bromomethylphenyl)thiophene and 5.1 g (0.051 mol) of potassium acetate in 65 mL of glacial acetic acid was heated under reflux for three hours. The reaction mixture was cooled and transferred to a separatory funnel, and 150 mL of water was added. The mixture was extracted with two portions of 120 mL each of methylene chloride. The combined extracts were washed with 150 mL of a saturated solution of sodium chloride, two portions of 150 mL each of a saturated aqueous solution of sodium bicarbonate, and finally 100 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give an oil residue. The residue was subjected to column chromatography on silica gel, eluting with hexane:methylene chloride (3:2). The appropriate fractions were combined to give 3.3 g of 3-(3-thienyl)phenylmethyl acetate.