Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([O-:16])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=C.Cl>CC(C)=O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([O:16][CH2:13][CH:19]=[CH2:20])[CH:10]=[CH:11][C:2]=1[OH:1]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(O)c(C(=O)OC)c1
Temperature: 60 °C

Procedure:
Methyl 2,4-dihydroxybenzoate (8.60 g, 51.2 mmol) was dissolved in acetone (125 mL, 0.4 M) then treated with K2CO3 (27.2 g, 196.8 mmol) and allyl bromide (6.0 mL, 8.39 g, 69.3 mmol). The reaction was heated at 60° C. for 20 h then acidified to pH 1-2 with 2 N HCl and extracted with Et2O (4×). The combined extracts were washed with saturated aq NaCl (2×), dried over Na2SO4, filtered and concentrated to give 5-allyloxy-2-hydroxy-benzoic acid methyl ester as a crude yellow oil (6.11 g, 57%): 1H NMR (DMSO-d6, 300 MHz) 8 10.74 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 6.55-6.51 (m, 2H), 6.08-5.94 (m, 1H), 5.38 (dd, J1=1.8 Hz, J2=16.8 Hz, 2H), 4.61 (d, J=5.4 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9])(=O)C.[CH3:14]O>>[CH3:14][O:10][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][N:13]=[C:5]([NH2:4])[CH:6]=1
Reactant: CO
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Product: COC(=O)c1ccnc(N)c1

Procedure:
2-Acetylamino-isonicotinic acid (3.10 g, 17.2 mmol) was stirred in 35 mL MeOH at 0° C. HCl (g) was bubbled through the solution for 10 min and then the reaction was heated to reflux. After 16 h the reaction was concentrated in vacuo. The residue was diluted with water and the pH was adjusted to 7 with Na2CO3 (s). A white precipitate formed which was filtered to afford a portion of pure desired product. The aqueous phase was extracted three time with 95:5 DCM/nBuOH. The organic phases were dried over Na2SO4, filtered and concentrated to afford more of the pure desired product as a white solid. 1H NMR (CDCl3) δ 8.19 (d, 1H, J=5.3 Hz), 7.17 (dd, 1H, J=1.4, 5.3 Hz), 7.07 (d, 1H, J=1.3 Hz), 4.64 (bs, 2H), 3.92 (s, 3H). MS [M+H]+=153.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[N:11]1([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:6]([N:14]1[CH2:15][CH2:16][N:11]([C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[CH2:12][CH2:13]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#CCCCN1CCN(c2ncccn2)CC1
Yield: 66.4 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (1.05 g), 2-(piperazin-1-yl)pyrimidine (1.02 g) and diisoproylethylamine (1.2 mL) in THF (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with aq. NaOH 2M (10 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 2:1→2:0) afforded 2-(4-(pent-4-ynyl)piperazin-1-yl)pyrimidine (0.95 g).
Reaction SMILES: Cl.Cl.C(NC1C=CC(C2[O:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](NC(=N)C4C=CC=CC=4)=[CH:25][CH:24]=3)=CC=2)=CC=1)(=N)C1C=CC=CC=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[O:46][C:47]([C:50]3[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=3)=[CH:48][CH:49]=2)=[CH:41][CH:40]=1.C(N(CC)CC)C.[C:64](Cl)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C(#N)C.O>[C:64]([NH:56][C:53]1[CH:54]=[CH:55][C:50]([C:47]2[O:46][C:45]([C:42]3[CH:43]=[CH:44][C:39]([NH:38][C:20](=[O:19])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:40][CH:41]=3)=[CH:49][CH:48]=2)=[CH:51][CH:52]=1)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: N=C(Nc1ccc(-c2ccc(-c3ccc(NC(=N)c4ccccc4)cc3)o2)cc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2ccc(-c3ccc(N)cc3)o2)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)o2)cc1)c1ccccc1
Reaction time: 3 h
Yield: 96 %

Procedure:
2,5-Bis[4-(benzimidoylamino)phenyl]furan Dihydrochloride (Compound 6b) To a chilled solution of 2,5-bis(4-aminophenyl)furan (0.25 g, 1.0 mmol) in dry acetonitrile (10 ml) was added triethylamine (0.22 g, 2.1 mmol) followed dropwise by benzoyl chloride (0.30 g, 2.1 mmol) and the resulting suspension was stirred at room-temperature for 3 hours. Water (10 ml) was then added and the precipitate was collected, rinsed with water, followed by MeOH, and finally dried in vacuo to give 2,5-bis(4-benzamidophenyl)furan as a tan solid (0.44 g, 96%), mp 312-314.5° C. 1H NMR (DMSO-d6): 6.98 (s, 2H), 7.52-7.62 (m, 6H), 7.80 (d, 4H), 7.89 (d, 4H), 7.97 (d, 4H), 10.33 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])[C:7]2=[O:12].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([CH3:32])[C:29](O)=[O:30])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C@H:28]([CH3:32])[C:29]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])[C:7]3=[O:12])=[O:30])=[CH:26][CH:27]=1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](C(C)C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](C(C)C)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O

Procedure:
(R)-Methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-methylbutanoate (0.3 g, 0.001 mol), (S)-2-(4-chlorophenyl)propanoic acid (0.4 g, 0.002 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.8 g, 0.002 mol), N,N-diisopropylethylamine (0.6 g, 0.004 mol) were stirred in N,N-dimethylformamide (3 mL, 0.04 mol) at room temperature over a weekend. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (20 mL×3), dried over Na2SO4, purified via flash chromatography (12 g of silica gel, 0-90% EtOAc/Hexane) and then prep. HPLC gave a light yellow oil. MS m/z 441.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O>[CH2:26]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:14]=2)[C:10]([CH:18]=[O:19])=[C:11]1[CH:15]([CH3:16])[CH3:17])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure C. To a solution of ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 2.08 g, 8.04 mmol) in DMF (15 ml) was added K2CO3 (3.32 g, 24.1 mmol) and benzyl bromide (1.91 ml, 16.1 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:11])[C:8](Cl)=O.CN(C)C=O.[C:18]1([Mg]Br)[CH:23]=[CH:22]C=[CH:20][CH:19]=1>ClCCl.C1(C)C=CC=CC=1>[C:7]([C:8]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1)(=[O:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Br[Mg]c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
90.0 g (381.8 mmol) of a benzene compound represented by the above formula (8) was dissolved in 450 ml of dichloromethane and cooled to 0° C. 148.8 g (1145.4 mmol) of oxalyl chloride and 4 ml of N,N-dimethylformamide were added dropwise to this solution. After the addition, the resulting mixture was heated to 25° C. and stirred for 2 hours. After the reaction, the solvent and an excess of oxalyl chloride were distilled off under reduced pressure. The obtained residue was dissolved in 450 ml of tetrahydrofuran and cooled to −50° C. 172 ml (343.6 mmol) of phenyl magnesium bromide (2.0 M diethyl ether solution) was added dropwise to this solution. After the addition, the resulting mixture was heated to 25° C. and stirred for 4 hours. After the reaction, 200 ml of toluene was added, the reaction product was washed in water, the solvent was removed, and the obtained product was purified by reslurrying with methanol to obtain a benzophenone derivative represented by the following formula (22) as 73.3 g (248.1 mmol, yield rate of 65%) of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:37])[CH3:36])[C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2CCc3ccccc32)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-((S)-Indan-1-ylaminomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:35](I)[CH3:36]>O>[CH2:35]([O:22][C:21]([C:19]1[O:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23])[CH3:36]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC)o1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 10.0 g (0.031 mole) of 5-tetradecyloxy-2-furoic acid, 4.3 g (0.034 mole) of potassium carbonate, and dimethyl formamide is stirred at room temperature after which 15.6 g (0.10 mole) of ethyl iodide is added. The mixture is heated to 50° C with stirring overnight then poured into water and extracted with ether. The ether layer is washed with water and salt water then dried over sodium sulfate, filtered, and the ether is distilled off and replaced by ethanol. Upon cooling the ethanol solution a solid is obtained which is 5-tetradecyloxy-2-furoic acid ethyl eseter, M.P. 39°-40° C.
Reaction SMILES: [NH:1]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:54]([N:56]1[CH2:67][CH2:66][CH2:65][C@H:57]1[C:58]([O:60]C(C)(C)C)=[O:59])=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN(C=O)C>C(O)(C(F)(F)F)=O>[NH:1]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:54]([N:56]1[CH2:67][CH2:66][CH2:65][C@H:57]1[C:58]([OH:60])=[O:59])=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 8 ml of TFA were dissolved 800 mg of Boc-Tyr-Gly-Gly-Phe-Met-Lys(Boc)-Pro-OBut, and the solution, after shaking at room temperature for 60 minutes, was concentrated. To the concentrate was added diethyl ether, followed by recovering the resulting precipitates by filtration and drying. The precipitates were dissolved in 10 ml of DMF, and 0.34 ml of TEA and 440 mg of Boc-ONB were added to the solution followed by stirring at 0° C. for 2 hours and at room temperature for 10 hours. The solution was evaporated under reduced pressure to dryness. To the residue was added diethyl ether. The resulting precipitates were recovered by filtration and then placed on a column (2.5×115 cm) of Sephadex LH-20. Elution was conducted with MeOH and fractions of 195 to 225 ml were collected, then the solvent was evaporated to dryness under reduced pressure. To the concentrate was added diethyl ether, and the mixture was subjected to filtration to give the product. Yield 680 mg (90.9%); m.p. 151° C. (decomp.); [α]D24 -28.0° (c=0.52, DMF); Rf1 =0.25, Rf2 =0.64.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:18][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[2-(Bromomethyl)phenoxy](tert-butyl)dimethylsilane was prepared according to the literature procedure (J. Chem. Soc. Perkin Trans.1; 1988; 1417). To a solution of (2-([tert-butyl(dimethyl)silyl]oxy}phenyl)methanol (9.9 g/41.5 mmol) in acetonitrile (200 ml) was added carbon tetrabromide (14.5 g/43.6 mmol), triphenylphosphine (11.4 g/43.6 mmol) successively at 0° C., and then the resulting solution was stirred at room temperature for 16 hours. The solvent was evaporated. The residue was purified by column chromatography (SiO2, 200-350 mesh/hexane:ethyl acetate=100:1-20:1-10:1) to afford a colorless oil (12.0 g/96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[C:22]([CH2:26][OH:27])[CH:23]=[CH:24][CH:25]=2)=[N:10]1.C(N(CC)CC)C.[CH3:35][S:36]([Cl:39])(=[O:38])=[O:37].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:35][S:36]([O:27][CH2:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:11]2[C:12]3[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][C:17]=3[N:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:10]=2)[CH:21]=1)(=[O:38])=[O:37].[Cl:39][CH2:26][C:22]1[CH:21]=[C:20]([C:11]2[C:12]3[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][C:17]=3[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:10]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1nccc2c1c(-c1cccc(CO)c1)nn2-c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1nccc2c1c(-c1cccc(CCl)c1)nn2-c1c(F)cccc1F
Product: COc1nccc2c1c(-c1cccc(COS(C)(=O)=O)c1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)methanol (400 mg) and triethylamine (0.228 mL) in THF (3 mL) was added methanesulfonyl chloride (0.126 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 3-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzyl methanesulfonate (386 mg) and 3-(3-(chloromethyl)phenyl)-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridine (48 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.C([O:15][C:16]([C:18]1[C:27]2[C:26]3=[N:28][N:29]([CH3:31])[CH:30]=[C:25]3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=O)C.O>C(Cl)Cl.[NH4+].[Cl-].CCOCC>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16]([C:18]1[C:27]2[C:26]3=[N:28][N:29]([CH3:31])[CH:30]=[C:25]3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=[O:15]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1c[nH]c2c1-c1nn(C)cc1CCC2
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: Cn1cc2c(n1)-c1c(C(=O)Nc3ccccc3F)c[nH]c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a solution of 2-fluoroaniline (103 mg, 0.926 mmol) in CH2Cl2 (2.0 mL) at 0° C. under N2 is slowly added AlMe3 (0.46 mL, 2.0 M in toluene). The resulting solution is stirred at room temperature for 1 h. Next, 2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester (60 mg, 0.231 mmol) is added in one portion. The resulting mixture is then stirred at reflux for 2 h. After cooling, the reaction mixture is carefully diluted with saturated aq NH4Cl (˜5 mL) and some H2O. The mixture is stirred vigorously for 30 min. and then extracted three times with CH2Cl2 (containing some (˜5%) MeOH). The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 40:1 CHCl3—MeOH followed by 30:1 CHCl3—MeOH and finally 20:1 CHCl3—MeOH afforded, after concentration of the fractions containing pure product, a residue, which is then granulated with Et2O. The suspension is filtered, and the solid washed with Et2O and dried, affording 45 mg (60%) of 2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid (2-fluoro-phenyl)-amide as an off-white solid. Electrospray mass spectrum: m/z 325 [M+1].
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:20]=[C:19]2[N:29]([CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:30]=[C:31](I)[C:18]=12>>[Cl:16][C:17]1[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:20]=[C:19]2[N:29]([CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:30]=[C:31]([C:4]3[CH2:3][CH2:2][O:1][CH2:6][CH:5]=3)[C:18]=12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Clc1c(-c2ccccc2)nnc2c1c(I)nn2CCN1CCCC1
Product: Clc1c(-c2ccccc2)nnc2c1c(C1=CCOCC1)nn2CCN1CCCC1

Procedure:
Compound Is was synthesized according to Example 1, using 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-chloro-3-iodo-5-phenyl-1-(2-pyrrolidin-1-ylethyl)pyrazolo[3,4-c]pyridazine instead of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine in Step 8.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](Cl)=[O:18])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.[NH2:22][C@@H:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[O:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([NH:22][C@@H:23]3[C:32]4[C:27](=[CH:28][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=4)[O:26][CH2:25][CH2:24]3)=[O:18])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1
Reactant: N[C@H]1CCOc2cc(C(F)(F)F)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(N[C@H]1CCOc2cc(C(F)(F)F)ccc21)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-5-(1-chlorocarbonylpyrrolidin-2-yl)-1H-1,2,4-triazole (60 mg), (S)-4-amino-7-trifluoromethylchroman and DIEA in dry MeCN was stirred overnight at RT. The solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with water and evaporated after drying over Na2SO4. The residue was purified by chromatography (silica gel, hexane:EtOAc (1:1)→EtOAc) to give 40 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.N(C1C=COC=1C=O)=[N+]=[N-].[C:19]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:20][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=O>C(O)C.N1CCCCC1>[O:4]1[C:3]2[C:2](=[N:1][C:20]([C:19]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=2)[CH:6]=[CH:5]1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: Nc1ccoc1C=O
Agent: [N-]=[N+]=Nc1ccoc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2occc2nc1C(=O)OCC
Reaction time: 3 h
Yield: 24 %

Procedure:
3-Amino-2-formylfuran, prepared from 3-azido-2-formylfuran (8.9 g 0.065 mol) is dissolved in ethanol and to this solution diethyl oxalacetate (12.23 g, 0.065 mol) and ten drops of piperidine are added. In addition pulverized 3 A° molecular sieve is added and the reaction stirred at 65°-60° C. for three hours, then additional diethyl oxalacetate (2.2 g) is added. The reaction is essentially complete after 12 hours at 55°-60° C. On cooling the reaction is filtered, and the filtrate concentrated and then dissolved in ethyl acetate, water washed, then brine washed, dried over anhydrous magnesium sulfate and stripped to dryness. The residue is dissolved in 3:1 hexane:ethyl acetate and passed through a flash chromatographic column in two stages. First it is filtered by vacuum through a four to five inch pad of silica from which the last three fractions containing the required product are collected and combined. These combined fractions are then passed through a six inch column eluting under pressure with ethyl acetate:hexane 3:1 and 2.1. Diethyl furo[3,2-b]pyridine-5,6-dicarboxylate 4.15 g (24%) is obtained after crystallization from hexane-ether, of mp 60°-64° C., and with a mass spectrum m/e of 264.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH:22](O)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C.C(O)=O>[C:11]([C:7]1[CH:8]=[C:9]([CH:22]([CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(O)c1ccccc1
Solvent: O=CO
Solvent: CC(=O)O
Product: CC(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
2,6-Di-t-butyl-4-(α-methylbenzyl) phenol was prepared by refluxing 2,6-di-t-butylphenol (51 g) and 1-phenylethanol (31 g) in acetic acid (40 ml) and formic acid (75 ml) as described for A. The product was obtained as a colorless oil, b.p. 166°-168° at 1.0 mm Hg (62 g); (meas. mass=310.2309. Calc. for C22H30O=310.2296). The pmr spectrum was: δ1.40, 18H, S; δ1.61, 3H, D (J=8 Hz); δ4.06, 1H, Q (J=8 Hz); δ5.02, 1H, S; δ7.01, 2H, S; δ7.22, 5H, S.