Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[C:4]([C:6]1[C:7]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]([O:20]C)[C:9]([F:19])=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]=1[CH3:12])#[N:5].BrB(Br)Br.O>[Cl-].[Na+].O>[C:4]([C:6]1[C:7]([NH:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:25])[CH3:27])=[C:8]([OH:20])[C:9]([F:19])=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]=1[CH3:12])#[N:5]
Reactant: COc1c(F)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(F)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
A dichloromethane (60 ml) solution of N-(5-cyano-2-fluoro-3-methoxy-6-methylbiphenyl-4-yl)-2,2-dimethylpropionamide (I-70) (2.02 g, 5.93 mmol) was cooled at −78° C., a dichloromethane solution of 1 N tribromoborane (17.8 ml, 17.8 mmol) was dropwise added, followed by stirring at −78° C. for 15 minutes. Afterwards, this was heated up to −12° C., and stirred for 30 minutes. The reaction liquid was put into cold water (100 ml), saturated brine (50 ml) was added, the intended product was extracted with ethyl acetate (300 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the entitled compound (1.70 g, 88%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15](O)=[O:16])[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15]([N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)=[O:16])[N:7]=1
Reactant: C1COCCN1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)O)N2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)N3CCOCC3)N2)n1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
To a solution of (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetic acid (105d, 0.05 mmol, 22.6 mg) in DMF (0.5 mL) was added HBTU (0.075 mmol, 28 mg), Et3N (0.125 mmol, 17 μL) and morpholine (0.1 mmol, 8.3 μL). The reaction mixture was stirred over night at r.t. and LCMS shows completion of the reaction. Purified by prep LCMS to afford the title compound (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-morpholinoethanone (102, 5.7 mg, 22%) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.83 (s, 3H) 3.15 (dd, J=17.31, 10.23 Hz, 2H) 3.43-3.51 (m, 2H) 3.63 (d, J=5.31 Hz, 2H) 3.65-3.71 (m, 4H) 3.89 (s, 3H) 4.71 (s, 2H) 4.97 (dd, J=10.36, 3.79 Hz, 1H) 5.96 (br. s., 1H) 6.77 (d, J=8.34 Hz, 1H) 7.03 (d, J=7.07 Hz, 1H) 7.14 (dd, J=9.35, 2.78 Hz, 1H) 7.19 (td, J=8.40, 2.65 Hz, 1H) 7.63 (dd, J=8.84, 5.56 Hz, 1H) 7.68 (dd, J=8.34, 7.33 Hz, 1H). MS (ES) [M+H] calculated for C26H28FN7O4, 522.22. found 522.00.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21](=[N:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1)[C:22]1[CH:23]=[C:24]([O:32][CH3:33])[C:25]2[O:29][CH2:28][CH2:27][C:26]=2[C:30]=1[F:31]>CN(C=O)C>[F:31][C:30]1[C:26]2[CH2:27][CH2:28][O:29][C:25]=2[C:24]([O:32][CH3:33])=[CH:23][C:22]=1[CH:21]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]#[N:42])=[CH:39][CH:40]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)c2c(c1F)CCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
After adding 144 mg of 2-hydrazinopyrimidine and 900 μl of triethylamine to a solution of 624 mg of [2-(4-cyanophenylimino)-2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 12 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 6.6 ml of a methanol:acetic acid=10:1 mixed solvent. After adding 1 g of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture. The organic layer was washed with dilute hydrochloric acid and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 4-{[(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzonitrile (414 mg) as a light yellow solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[OH-].[Na+].[C:11]([O:15][C:16](OC([O-])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1>[C:11]([O:15][C:16]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.8 %

Procedure:
To a solution of 108 g of o-phenylenediamine (1.0 mol) in 1000 mL of dioxane was added 500 mL of 1N sodium hydroxide aq., and then 218 g of tert-butyldicarbonate (1.1 mol) in 500 mL of dioxane under ice-cooling. After stirring for 6 hours at room temperature, the mixture was left overnight. The mixture was concentrated to ½ volume by evaporation, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography (eluent: chloroform) to give a solid, which was then washed with diethyl ether to give 68.4 g of N-tert-butoxycarbonyl-o-phenylenediamine (Yield: 32.8%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl>C(OCC)(=O)C>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 0.17 h
Yield: 47 %

Procedure:
To 12.5 g (0.07 mole) of mechanically stirred 1-benzylpiperazine was added 10.0 g (0.07 mole) of 4-nitrofluorobenzene. After 10 minutes the mixture solidified. The yellow solid was suspended in 50 ml of ethyl acetate and ethereal hydrogen chloride was slowly added to the stirring mixture under a nitrogen atmosphere. The solid was collected (filtration) and partitioned between 10% sodium hydroxide solution and benzene. The benzene layer was washed with ten 100 ml portions of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow oil. Upon cooling, the oil crystallized. The solid was recrystallized from 2-propanol/petroleum ether (60°-110° C.) to give 9.8 g (47%) of yellow solid, m.p. 115°-118° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([C:22]2[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[C:20]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:19]=2[N:18]=1)[CH3:16])(C)(C)C.[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39](Cl)[N:38]=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CC(O)C>[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39]([NH:14][C@H:15]([C:17]2[N:21]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)[C:20]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:19]=3[N:18]=2)[CH3:16])[N:38]=[CH:37][N:36]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccn(C)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccn(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
TFA (1 mL) was added to a stirring solution of {(S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (126 mg, 0.35 mmol) in DCM (3 mL). After stirring at RT for 3 h, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to give a brown oil. A mixture of this residue, 4-amino-6-chloropyrimidine-5-carbonitrile (60 mg, 0.39 mmol) and DIPEA (205 μL, 1.17 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) followed by trituration with EtOAc to afford 402 as a white solid (71 mg, 54% over 2 steps). LCMS (Method K): RT 3.27 min [M+H]+ 378.04. 1H NMR (DMSO-d6, 400 MHz): δ 7.97 (1H, s), 7.91 (1H, d, J=2.31 Hz), 7.73 (1H, dd, J=8.66, 4.85 Hz), 7.61 (1H, d, J=7.64 Hz), 7.25 (2H, s), 7.17-7.08 (2H, m), 6.54 (1H, d, J=2.31 Hz), 5.77-5.67 (1H, m), 3.89 (3H, s), 1.52 (3H, d, J=6.87 Hz)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2.C(N(CC)CC)C>C(Cl)Cl.O>[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:1](=[O:3])[CH3:2])[CH2:9]2
Reactant: CC(=O)Cl
Reactant: Fc1ccc2c(c1)CCN2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)C1Cc2cc(F)ccc2N1
Reaction time: 2 h

Procedure:
Acetyl chloride (3 ml) was added dropwise to a solution of 7 grams of crude 5-fluoro-2,3-dihydro-1H-indole and 3 ml of triethylamine in 100 ml of CH2Cl2 at 0° C. After two hours, the reaction was diluted with water. The methylene chloride layer was seperated, dried and evaporated to afford 7.3 grams of crude product which was purified on silica gel eluting with hexane/ethyl acetate to give 3.3 grams of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=[O:15].[O:17]1[C:21]2=[CH:22][CH:23]=[CH:24][C:25]([NH2:26])=[C:20]2[CH2:19][CH2:18]1.Cl.IC1C=C2C(=CC=1)N=CC(C(N)=O)=C2NC1C=CC=C(OC)C=1>C(#N)C>[ClH:1].[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]2[C:11]([C:2]([NH:26][C:25]3[C:20]4[CH2:19][CH2:18][O:17][C:21]=4[CH:22]=[CH:23][CH:24]=3)=[C:3]([C:14]([NH2:16])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(Cl)ccc2c(Cl)c(C(N)=O)cnc12
Reactant: Nc1cccc2c1CCO2
Agent: COc1cccc(Nc2c(C(N)=O)cnc3ccc(I)cc23)c1
Agent: Cl
Solvent: CC#N
Product: Cc1c(Cl)ccc2c(Nc3cccc4c3CCO4)c(C(N)=O)cnc12

Procedure:
Intermediate 104 was prepared from Intermediate 68 using 2,3-dihydro-1-benzofuran-4-amine in a similar manner to Intermediate 14, using acetonitrile as solvent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1.[OH-].[Na+].P(Br)(Br)([Br:18])=O>>[Br:18][C:8]1[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]cccc1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Product: Brc1ncccc1-c1cccnc1

Procedure:
A mixture of 0.30 g of 3-(3-pyridinyl)-2(1H)pyridinone and 10 ml of phosphorus oxybromide was heated on a steam bath for 18 hours, then poured onto crushed ice and made alkaline with 10N sodium hydroxide. The resulting solid was collected, dissolved in methylene chloride and the solution passed through a short pad of hydrous magnesium silicate. The filtrate was concentrated and while boiling diluted with hexane. Concentration and chilling gave 2'-bromo-3,3'-bipyridine as white crystals, mp 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[C:16]([C:18]3[NH:22][N:21]=[N:20][N:19]=3)[CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[CH:4][CH:3]=1>[Zn].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([S:8][C:9]3[CH:17]=[C:16]([C:18]4[NH:22][N:21]=[N:20][N:19]=4)[CH:15]=[CH:14][C:10]=3[C:11]2=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2nnn[nH]2)cc1Sc1ccc(Cl)cc1
Agent: [Zn]
Solvent: O
Product: O=c1c2ccc(-c3nnn[nH]3)cc2sc2ccc(Cl)cc12

Procedure:
2-(p-Chlorophenylthio)-4-(5-tetrazolyl)benzoic acid (3.41g) was heated with polyphosphoric acid (70g) on a steam bath for 1 hr. The reaction mixture was decomposed by warming with water, and the product filtered off, washed with water, recrystallised from dimethylformamide, and dried at 156° C. in vacuo, giving 7-chloro-3-(5-tetrazolyl)thioxanthone, decomposes without melting.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:39])[C@H:16]2[CH2:20][C@H:19](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][N:17]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]([NH:48][C:49]1[CH:54]=[CH:53][NH:52][C:51](=[O:55])[N:50]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.ClCCl>[C:8]1([CH:7]([O:14][C:15](=[O:39])[C@H:16]2[CH2:20][C@@H:19]([N:52]3[CH:53]=[CH:54][C:49]([NH:48][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[N:50][C:51]3=[O:55])[CH2:18][N:17]2[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)OC(C)(C)C)C2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)C[C@@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A reaction mixture containing the trans-D tosylate (7) (1.10 g, 2.00 mmol), N4-benzoylcytosine (0.475 g, 2.20 mmol), anhydrous K2CO3 (0.300 g, 2.20mmol) and 18-crown-6 (200 mg) in DMF (10 ml) was stirred at 70-80° C. under argon overnight. The white suspension was diluted with dichloromethane (75 ml), filtered through celite and the organic phase washed with water. Evaporation gave the crude product as an oil which was purified by column chromatography (SiO2, ethyl acetate). The more polar fractions (Rf 0.33) were combined and evaporated to give the N1-isomer (0.299 g, 25%) as a white foam. Recrystallisation from ethanol-water gave white crystals of N-tert-butoxycarbonyl-cis-4-(N4-benzoylcytosin-1-yl)-D-proline diphenylmethyl ester (11), m.p. 133-135° C., (Found C, 65.8; H, 6.5; N, 8.8%; C34H34N4O6.C2H5OH.H2O requires C, 65.6; H, 6.4; N, 8.5%), δH (200 MHz; CDCl3) 1.30 and 1.49 (9H, 2×s, Boc rotamers), 2.20 and 2.90 [2H, br m, CH2(3′)], 3.50-3.80 and 3.95-4.15 [2H, 2×br m, CH2(5′)], 4.45-4.70 [1H, br m, CH(2′)], 5.28 [1H, br m, CH(4′)], 6.87 (1H, s, CHPh2), 7.15-7.40 (10H, m, phenyl CH), 7.40-7.75 [5H, m, CH(5), CH(6) and benzoyl m- and p-CH], 7.89 (2H, d, J=7.4 Hz, benzoyl o-CH), 8.83 (1H, br s, NH); δC (50.28 MHz; CDCl3) 27.7 and 28.0 (Boc CH3 rotamers), 34.4 and 36.0 [CH2(3′) rotamers], 49.6 and 50.5 [CH2(5′) rotamers], 54.3 and 54.9 [CH(4′) rotamers], 57.6 [CH(2′)], 78.0 and 78.3 (CHPh2 rotamers), 81.3 (Boc C), 96.8 [CH(5)], 127.0-129.2 (aromatic CH), 133.4 (benzoyl C), 139.5 (aromatic C), 145.2 and 145.7 [CH(6) rotamers], 153.8 (Boc CO rotamers), 155.6 [C(2)], 162.0 [C(4)], 166.8 (benzoyl CO), 171.3 (ester CO); m/z (ES MS) 595 (M+H+, 100%); νmax (KBr)/cm−1 1743 (C═O), 1704s (C═O); λmax (CHCl3)/nm 266 (ε/dm3.mol−1.cm−1 8.9×104), 312 (3.4×104); [α]D23−13.6 (c=0.50, CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:16]=[N:17][CH:18]=2)[C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24](OCC)([O:28]CC)[O:25][CH2:26][CH3:27]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:16]=[N:17][CH:18]=2)[C:14]=1[CH2:15][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:25][CH2:26][CH3:27])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CCCCBr)(OCC)OCC
Reactant: Cc1c(OCc2ccccc2)ccc2cncn12
Product: CCOC(=O)CCCCCc1c(OCc2ccccc2)ccc2cncn12

Procedure:
The condensation of 6-benzyloxy-5-methylimidazo[1,5-a]pyridine with 5-bromo-1,1,1-triethoxypentane essentially by the procedure described in Example 1 yields 6-benzyloxy-5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine; NMR (CDCl3) 1.4 (3H), 4.17 (2H), 4.97 (2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([OH:9])[CH2:3]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([C:25]2[CH:37]=[CH:36][C:28]([O:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([C:25]2[CH:37]=[CH:36][C:28]([O:29][C:30]([CH3:35])([CH3:34])[C:31]([O:9][C@H:4]3[CH2:5][C@@H:6]([CH3:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3]3)=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CC1CC(O)CC(C)(C)C1
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H](OC(=O)C(C)(C)Oc2ccc(C(=O)c3ccc(Cl)cc3)cc2)CC(C)(C)C1

Procedure:
5 g of 3,3,5-trimethylcyclohexanol, CIS form, and then 3.5 g of triethylamine dissolved in 10 ml of chloroform are added to 50 ml of pure chloroform. 12 g of 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionyl chloride diluted in a few ml of chloroform are then added slowly to the solution at low temperature. The mixture is refluxed for three hours and then, after cooling, the organic layer is washed successively with a normal solution of hydrochloric acid, sodium hydroxide and then distilled water. It is evaporated under reduced pressure and the residue is then chromatographed on a silica column with a mixture of petroleum ether and ethyl acetate and finally recrystallized from ethanol to give the title derivative in the form of attractive white crystals melting at 65° C., which in thin layer chromatography give a single spot of Rf 0.45 in the solvent system described in Example 1.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.COCC=C.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18](Br)[CH:19]=1)[CH:15]=[O:16].C[O-].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH2:2][CH2:1][CH2:5][O:4][CH3:3])[CH:19]=1)[CH:15]=[O:16]
Reactant: C1CCOC1
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=CCOC
Solvent: O
Product: COCCCc1cc(Br)cc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a THF solution (0.3 M) of allyl methyl ether (3.1 eq.) at RT was added borane-methyl sulfide complex (1.0 eq.). The solution was stirred at RT for 30 min. To this solution was then added sequentially 3,5-dibromobenzaldehyde (1.0 eq.), Pd(dppf)Cl2 (0.025 eq.) and solid sodium methoxide (1.5 eq.). The resulting mixture was heated to reflux for 15 h. The cooled reaction mixture was diluted with water and extracted with ether. The combined organic extracts were dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 5:95 (v/v) EtOAc:Hex→7:3 (v/v) EtOAc:Hex) afforded the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[OH:10].CN(C)CC(O)=O.Cl.C([O-])([O-])=O.[Cs+].[Cs+].[F:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>O1CCOCC1.[Cu]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[O:10][C:29]1[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=1
Reactant: Fc1ccc(I)cc1
Reactant: COc1cccc(F)c1O
Agent: [Cu]
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(F)c1Oc1ccc(F)cc1
Temperature: 105 °C
Yield: 6350.2 %

Procedure:
To a suspension of 2-fluoro-6-methoxy phenol (1) (2.8 g, 20 mmol), N,N-dimethyl glycine.HCl (837 mg, 6 mmol), Cs2CO3 (13 g, 40 mmol), 1-fluoro-4-iodobenzene (2.3 mL, 20 mmol), in Dioxane (40 ml) was added copper iodone (381 mg, 2 mmol). The reaction mixture was stirred at 105° C. over 1 week. Upon heating the reaction mixture turned from brown to a bright green. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in-vacuo. The crude was purified by silica gel eluted with hexane/EtOAc (10:1), concentrated in-vacuo, to provide 300 g (21% yield) of product (2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([NH:17]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[CH:9]2>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: CCc1cc(C=C(NC(=O)OCc2ccccc2)C(=O)OC)cc2cn[nH]c12
Agent: [Pd]
Solvent: CO
Product: CCc1cc(CC(N)C(=O)OC)cc2cn[nH]c12
Reaction time: 8 h

Procedure:
To a solution of 2-benzyloxycarbonylamino-3-(7-ethyl-1H-indazol-5-yl)-acrylic acid methyl ester (330 mg, 0.78 mmol) in methanol (5 mL) under nitrogen was added palladium on charcoal (10%, 33 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated to give 210 mg (98%) which was used without purification. 1H-NMR (CDCl3, 500 MHz) δ 1.34 (t, J=7.6, 3H), 2.85 (q, J=7.6, 2H), 2.96 (dd, J=13.7, 7.6, 1H), 3.19 (dd, J=13.7, 8.6, 1H), 3.48 (s, 2H), 3.73 (s, 3H), 3.80 (dd, J=7.6, 5.2, 1H), 6.99 (s, 1H), 7.38 (s, 1H), 7.97 (s, 1H). Mass spec.: 248.15 (MH)+.
Reaction SMILES: [BrH:1].C(O)(=O)C.[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.CS(C)=O>C(OCC)C>[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.[BrH:1]
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 70 ml of a 25% hydrogen bromide-acetic acid solution was suspended 8.02 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane, and 2.96 g of dimethyl sulfoxide was added to the suspension under ice cooling. The mixture was stirred at room temperature for 1.5 hours. Then, 140 ml of diethyl ether was added to the reaction mixture, and crystals precipitated were collected by filtration and recrystallized from methanol to obtain 8.55 g of 2-amino-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide.