Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[S:6][C:5]=1C(O)=O)[CH:2]=[CH2:3]>N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[Cu]>[CH2:1]([C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[S:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1c(C(=O)O)sc2c1c(=O)n(C)c(=O)n2C
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: C=CCc1csc2c1c(=O)n(C)c(=O)n2C
Temperature: 235 °C

Procedure:
Copper powder (231 mg, 3.642 g atom) was added to a suspension of Step 7 intermediate (3.4 g, 12.142 mmol) in quinoline (60 ml) and the resulting mixture was stirred and heated at 235° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 1 N HCl and water. The combined organic layers were dried and concentrated. The purification of crude product by silica gel column chromatography by using 5% ethyl acetate in petroleum ether gave 2.17 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 3.41 (s, 3H), 3.55 (s, 3H), 3.71 (s, 2H), 5.09-5.15 (m, 2H), 5.97-6.10 (m, 1H), 6.50 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:8][C:9](=O)[N:10]=2)[CH:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([Cl:14])[N:10]=2)[CH:7]=1
Reactant: O=C1CN2C=C(Br)C=CC2=N1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cn2cc(Br)ccc2n1
Temperature: 105 °C

Procedure:
A mixture of 1.4 g of 6-bromo-3H-imidazo[1,2-a]pyridin-2-one in 5 ml of POCl3 is heated at 105° C. for 2 hours and then cooled to ambient temperature and concentrated under reduced pressure. The residue is taken up between water and dichloromethane and a 30% aqueous solution of NH4OH is added until a basic pH is obtained. The organic phase is then separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue is then purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 760 mg of compound are obtained.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])C>ClC1C=CC=CC=1>[CH3:14][O:13][C:8]1[C:7]2[S:6][CH:5]=[CH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(CSc1ccccc1OC)OCC
Solvent: Clc1ccccc1
Product: COc1cccc2ccsc12
Temperature: 155 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
A solution of 1-[(2,2-diethoxyethyl)thio]-2-methoxybenzene (18 g, 70.3 mmol) in dry chlorobenzene (100 mL) was added slowly to a stirred solution of polyphosphoric acid (50 g) in dry chlorobenzene (300 mL) at 145° C. After addition was complete the resulting black solution was stirred at 155° C. for a further 18 hrs. After this time the reaction was allowed to cool to room temperature before being filtered through a pad of CELITE™, the solid cake was washed with dichloromethane (200 mL) and the combined organic extracts were concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [95:5] to give a pale yellow oil (8.7 g, 75%); δH (300 MHz, CDCl3) 7.45-7.29 (4H, m, Ar), 6.75 (1H, d, Ar), 4.00 (3H, s, OCH3).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]#[N:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:15]#[N:16])([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[C:18]([F:17])([F:28])[F:29])[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: COC(=O)C(C#N)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C#N)(C(=O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 58.9 %

Procedure:
0.10 g (2.6 mmols) of sodium hydride was suspended in 20 ml of tetrahydrofuran. To the suspension was added dropwise, while stirring and cooling, 5 ml of a tetrahydrofuran solution in which 0.42 g (2.0 mmols) of methyl 2-(4-chlorophenyl)cyanoacetate and 0.41 g (2.6 mmols) of 2-trifluoromethylbenzoyl chloride had been dissolved. The mixture was stirred at room temperature over night. The reaction mixture was poured into ice water. The water phase thereof was acidified by diluted hydrochloric acid and twice extracted with 30 ml of ethyl acetate. The ethyl acetate extraction solutions were mixed, washed with a saturated brine solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue thus-obtained was purified by silica gel column chromatography (n-hexane:benzene=1:1), giving 0.45 g of the desired product (yield 59%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Temperature: 140 °C
Yield: 80.8 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-(3-morpholin-4-ylazetidin-1-ylmethyl)thieno[3,2-d]pyrimidine (100 mg, 0.24 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (94 mg, 0.36 mmol), tetrakis(triphenylphosphine)palladium (28 mg, 0.02 mmol) and Cs2CO3 (160 mg, 0.48 mmol) in dioxane (6 mL) and H2O (3 mL) was purged with argon then heated at 140° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with DCM/MeOH then eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%) to afford 213 as a white foam (98 mg, 81%). LCMS (Method G): RT 9.09 min, [M+H]− 506.3. 1H NMR (CDCl3, 400 MHz): δ 8.42-8.39 (m, 1 H); 7.46-7.42 (m, 1 H); 7.32-7.24 (m, 3 H); 4.02 (t, J=4.7 Hz, 4H); 3.97 (s, 2 H); 3.89 (t, J=4.7 Hz, 4 H); 3.73 (m, 4 H); 3.63 (s, 2 H); 3.06 (m, 3 H); 2.93 (s, 3 H) and 2.33 (m, 4 H)
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Reactant: OB(O)c1cc(F)ccc1F
Product: COC(=O)c1ccc2occ(-c3cc(F)ccc3F)c2c1
Yield: 70 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and (2,5-difluorophenyl)boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 70%) was obtained as colorless crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[C:14]1([CH3:23])[C:15]([C:20]([OH:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCCC1>[CH2:23]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([OH:22])=[O:21])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCCCCCCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccccc1C(=O)O
Reaction time: 0.08 h

Procedure:
A solution containing lithium diisopropylamide (0.1 mole) was prepared by treating a solution of dissopropylamine (14.1 ml, 0.1 mole) in tetrahydrofuran (200 ml) at 0° C. with n-butyl lithium (41.2 ml of a 2.43M solution, 0.1 mole), and stirring for 5 minutes. To this was added a solution of o-toluic acid (6.8 g, 0.05 mole) in tetrahydrofuran (50 ml). The ice bath was removed and the intense red solution was stirred for 30 minutes. This solution was slowly pipetted into a solution of undecylbromide (11.8 g, 0.05 mole) in tetrahydrofuran (50 ml) at -20° C. After the addition, the cooling bath was removed and the solution stirred for 30 minutes. A small amount of water was added and most of the tetrahydrofuran was removed under reduced pressure. The residue was poured into water, acidified with 3N hydrochloric acid and extracted with ether. The ether was dried, evaporated and the residue was recrystallized from acetonitrile, then from hexane, to give the product.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:12]([F:13])=[C:11]([NH:14][C:15](=[O:30])[C:16]([F:29])([F:28])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([F:27])=[CH:19][CH:18]=2)[CH:10]=[CH:9][C:8]=1[NH2:31])(=O)C.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:31][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:30])[C:16]([F:29])([F:28])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([F:27])=[CH:19][CH:18]=2)=[C:12]([F:13])[C:7]=1[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCc1c(N)ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c(F)c1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 2-{2-amino-5-[2,2-difluoro-2-(4-fluoronaphthyl)acetylamino]-6-fluorophenyl}ethyl acetate (3.8 g, 8.8 mmol), as prepared in the preceding step, in MeOH (40 mL) and THF (20 mL) was added a solution of K2CO3 (1.68 g, 12 mmol) in water (30 mL). The mixture was stirred at room temperature for 3 hours. Additional water (50 mL) was added, and the resulting mixture was extracted with EtOAc (3×50 mL). The extracts were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound (3.3 g, 96%) as an off white solid. 1H-NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.4 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.13 (s, 1H), 7.81 (m, 2H), 7.64 (m, 2H), 7.19 (t, J=8.7 Hz, 1H), 6.47 (d, J=8.7 Hz, 1H), 4.07 (s, 2H), 3.89 (t, J=5.6 Hz, 2H), 2.85 (t, J=5.5 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:22][C:23]([C:25]2[N:26](COCC[Si](C)(C)C)[CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN1C(=O)CC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1C(=O)CC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1=O
Yield: 8.1 %

Procedure:
A solution of 130 mg (0.237 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-methyl-2,6-dioxo-piperidin-4-yl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with MeOH (200 μL) and TFA (3 mL) at RT for 1.25 h. MeOH (30 mL) was added, the mixture was concentrated to half volume, MeOH (20 mL) was added, and the solvents were removed completely in vacuo at <35° C. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25-50% EtOAc-hexane and by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 8.0 mg (8%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.19 (d, 1H, J=8.4 Hz), 8.03 (s, 1H), 7.24 (dd, 1H, J=8.4, 2.4 Hz), 7.16 (d, 1H, J=2.4 Hz), 5.87-5.82 (m, 1H), 3.47-3.37 (m, 1H), 3.16 (s, 3H), 2.96-2.91 (m, 4H), 2.33-2.25 (m, 4H), 1.92-1.77 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H23N5O3, 418.2 (M+H). found 418.1.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([C:16](O)=[O:17])=[CH:14][N:13]=[C:12]([S:19][CH3:20])[N:11]=2)[CH2:4]1.C[N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([C:16]([NH2:22])=[O:17])=[CH:14][N:13]=[C:12]([S:19][CH3:20])[N:11]=2)[CH2:4]1
Reactant: CO[C@H]1CCC[C@@H](Nc2nc(SC)ncc2C(=O)O)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CCC[C@@H](Nc2nc(SC)ncc2C(N)=O)C1
Yield: 95.4 %

Procedure:
4-((1R,3S)-3-Methoxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (1.1662 g, 3.92 mmol) and HATU (2.237 g, 5.88 mmol) were stirred in DMF (7.84 mL) for 5 min at room temperature, then ammonium chloride (1.049 g, 19.61 mmol) and DIEA (3.42 mL, 19.61 mmol) were added while stirring. The reaction was allowed to stir at room temperature for 1 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL), brine (25 mL), dried over sodium sulfate, filtered, and concentrated. The residual DMF was removed by suspending the oily residue in 100 mL water and 100 mL hexanes. The biphasic suspension was stirred vigorously for 30 min, filtered and washed with hexanes to afford 4-((1R,3S)-3-methoxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxamide (1.1081 g, 3.74 mmol, 95% yield) as an off-white solid. MS (ESI) m/z 397.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:23]([CH3:22])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CNc1ccccc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
4-Chloro-3-nitrobenzene-1-sulfonyl chloride (10.6 g, 0.041 mol) was dissolved in toluene (50 ml); and triethylamine (4.14 g, 0.041 mol) was then added. To the resulting solution, N-methylaniline (4.4 g, 0.041 mol) was added under stirring. The reaction mixture was incubated at 70-80° C. for 1 h. Thereafter, it was allowed to cool. The cooled solution was washed twice with 30 ml of water and concentrated under vacuum. The residue was recrystallized from ethanol. The yield of 4-chloro-N-methyl-3-nitro-N-phenylbenzene sulfonamide was 9.4 g (61%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.O1CCCC1.ClS([N:33]=[C:34]=[O:35])(=O)=O>O>[C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[N:13]3[C:34]([NH2:33])=[O:35])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=O)N1C(=O)Cc2ccc(-c3ccccc3)cc21
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To 4.5 g. (21.5 mmole) of 6-phenyl-2-oxindole in a mixture of 100 ml. of toluene and 25 ml. of tetrahyrofuran was added, with stirring, at 5° C., 2.2 ml. (25.8 mmole) of chlorosulfonyl isocyanate. Stirring was continued for 1 hour at 0°-5° C. and then 100 ml. of water was added. The solid was recovered by filtration and added to a mixture of 40 ml. of glacial acetic acid and 80 ml. of water. The resulting mixture was heated at 100° C. for 1 hour, cooled and filtered. The residue was dried to give 3.1 g. of the title compound, mp. 188°-189° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH:20]1[CH2:22][CH2:21]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CC1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCC1CC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and hydroxymethylcyclopropane, there is obtained cyclopropylmethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 80°-83° C., mass spectrum m/e: M+ 292 (2), 237 (80), 194 (100);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([CH2:17][C:18]([OH:20])=O)[CH:15]=[N:14][CH:13]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:21])#[N:2].[Li].[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([CH2:17][C:18]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=3)=[O:20])[CH:15]=[N:14][CH:13]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:21])#[N:2]
Reactant: CC(O)(c1ccc(C#N)c(F)c1)c1cncn1CC(=O)O
Reactant: NCCc1ccccc1-c1cccc(O)c1
Agent: On1nnc2ccccc21
Agent: [Li]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(O)(c1ccc(C#N)c(F)c1)c1cncn1CC(=O)NCCc1ccccc1-c1cccc(O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {5-[1-(4-cyano-3-fluorophenyl)-1-hydroxyethyl]imidazol-1-yl}acetic acid, lithium salt from Step H (40 mg, 0.145 mmol), 1-amino-2-(3′-hydroxybiphenyl-2-yl)ethane from Example 6, Step C (33 mg, 0.155 mmol), 1-hydroxybenzotriazole hydrate (23 mg, 0.17 mmol), EDC (33 mg, 0.17 mmol), and N,N-diisopropylethylamine (40 mg, 0.31 mmol) in dry, degassed DMF (1 mL) was stirred at ambient temperature for 18 hrs. The solvent was removed under reduced pressure and the residue was partitioned between sat. aq. NaHCO3 (1 mL) and CHCl3 (3 mL). The aqueous layer was extracted further with CHCl3 (2×2 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography, eluting with 6% MeOH/0.6% NH4OH in CH2Cl2 to give the titled product as a white solid.
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]([C:11]1[C:12]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[N:13][N:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23]([OH:25])=[O:24])=[C:16]([F:30])[C:15]=12)=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:16]1[C:15]2[N:14]([N:13]=[C:12]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:11]=2[C:9](=[O:10])[NH:8][CH3:6])[CH:19]=[CH:18][C:17]=1[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: Cc1ccc(C(=O)O)cc1-c1ccn2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12

Procedure:
To a solution containing 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.070 g, 0.13 mmol) and dichloromethane (8.0 mL) was added TFA (0.84 mL, 10.9 mmol) at room temperature. The solution was maintained for 15 min and concentrated to dryness to afford 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as an off white solid which was used without further purification. LCMS retention time: 1.825 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 444 (MNa+).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[CH:21]12[O:26][CH:22]1[CH2:23][CH2:24][CH2:25]2>C1COCC1>[CH2:1]([N:3]1[C:7]([C@H:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[OH:26])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: C1CC2OC2C1
Reactant: CCn1cccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nccc1[C@H]1CCC[C@@H]1O
Yield: 16.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-ethylpyrazole (97%, 2.53 g, 25.5 mmol), N,N,N′,N′-tetramethylethylenediamine (3.83 mL, 25.5 mmol), butyl lithium (1.63 M solution in hexane; 18.3 mL, 29.8 mmol), cyclopentene oxide (2.66 g, 31.6 mmol) and THF (60 mL), to yield the title compound (750 mg, 16%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][S:37]([NH2:40])(=[O:39])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([NH:34][CH2:35][CH2:36][S:37](=[O:39])(=[O:38])[NH2:40])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: NCCS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)CCNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Yield: 24.6 %

Procedure:
4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (500 mg, 1.042 mmol), 2-aminoethanesulfonamide (142 mg, 1.146 mmol), HATU (594 mg, 1.563 mmol), and Hunig's Base (0.910 mL, 5.21 mmol) were stirred in DCM (Volume: 5 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc to give 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2-sulfamoylethyl)benzamide (150 mg). 1H NMR (400 MHz, MeOD) δ ppm 1.31-1.42 (m, 4H), 3.34-3.40 (m, 2H), 3.79-3.89 (m, 2H), 4.86-4.92 (m, 2H), 7.20-7.33 (m, 4H), 7.58-7.71 (m, 3H), 7.76-7.89 (m, 1H); LC-MS (Condition A), MS m/z (M++H) 585.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O:20][C:21](=O)[C:22](OCC)=[O:23])C.CC(C)([O-])C.[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:17])[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:22]([OH:23])[C:21]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C(Cc1ccccc1)Nc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C1C(O)=C(c2ccccc2)C(=O)N1c1cccc(Cl)c1
Reaction time: 3 h

Procedure:
After the addition of anhydride THF (20 ml) to compound 5c (1.55 g, 7.34 mmol), the temperature was adjusted to 0° C. Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35 g, 11.9 mmol) were added thereto and the agitation for 3 hours was carried out. After the identification of the reaction progress with TLC, the solution was poured into the distilled water and acidified with 1N HCL aqueous solution. Three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the suspension was carried out by EA/HX (⅓).