Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][C@H:27]([CH3:33])[CH2:28][NH:29][C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[CH3:34]>>[CH3:34][C:10]1[CH:11]=[C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][C@H:27]([CH3:33])[CH2:28][NH:29][C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1
Reactant: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: ClCc1cscn1
Product: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(C)c3)c12
Yield: 20 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting materials) to give the title compound as a white solid in 20% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.78 (s, 3H), 2.23 (s, 3H), 3.41 (dt, 1H), 3.58 (dt, 1H), 4.87 (m, 1H), 5.25 (s, 2H), 7.11 (d, 1H), 7.21 (d, 1H), 7.29 (d, 1H), 7.53 (d, 1H), 7.63 (dd, 1H), 7.69 (t, 1H), 7.76 (d, 1H), 8.23 (t, 1H), 8.44 (s, 1H), 9.14 (d, 1H), 9.96 (s, 1H); Mass spectrum MH+ 464.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of 5-nitroindazole (10.0 g, 61.3 mmol) in acetonitrile (100 mL) was added potassium carbonate (16.9 g, 122.6 mmol) and benzyl bromide (13.6 g, 79.7 mmol). The resulting yellow reaction mixture was heated with stirring at 70° C. overnight. Upon cooling down, the solid was filtered off and washed with methylene chloride. The filtrate was concentrated to dryness and the resulting residue was purified by flash chromatography eluting with 17–25% ethyl acetate in hexanes (v/v) yielding 7.0 g (44%) of the corresponding 1-Benzyl-5-nitro-1H-indazole as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CON(C)[C:18]([CH:20]([NH:29][C:30]([CH:32]([NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19]>CCOCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:18]([CH:20]([NH:29][C:30]([CH:32]([NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19]
Reactant: CON(C)C(=O)C(CCc1ccccc1)NC(=O)C(CC(C)C)NC(=O)OCc1ccccc1
Reactant: c1ccc2occc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(CCc1ccccc1)C(=O)c1cc2ccccc2o1
Temperature: -15 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
A solution comprised of benzofuran (0.302 g, 2.56 mmol) in anhydrous ether (5 mL) was cooled to −15° C. under a nitrogen atmosphere and then a solution of n-butyllithium (1.6 mL in hexanes) was added dropwise over 2 minutes. The mixture was stirred for 1 hour and then a solution comprised of benzyl 1-[1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (0.3 g, 0.64 mmol) in diethyl ether was added. The mixture was stirred at −15° C. until the reaction was complete. The mixture was quenched with a solution of acetic acid (0.153 mL) in diethyl ether (50 mL). The organic phase was washed with brine (40 mL), dried (MgSO4) and concentrated in vacuo. The product was purified from the residue by flash chromatography eluting with 2:3 ethyl acetate/hexanes to provide benzyl 1-[1-(benzofur-2-ylcarbonyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (70 mg, 0.13 mmol) as a white solid. 1H NMR (CDCl3): δ 0.8-0.99 (d, J=4 Hz, 6H), 1.5 (m, 1H), δ 1.6-1.72 (m, 2H), δ 1.99-2.18 (m, 1H), δ 2.22-2.41 (m, 1H), δ 2.6-2.75 (m, 2H), δ 4.21 (m, 1H), δ 5.01 (m, 1H), δ 5.17 (s, 2H), δ 5.50 (m, 1H), δ 6.75-6.81 (d, J=7 Hz, 1H), δ 7.10-7.37 (m, 11H) 7.4-7.59(m, 3H), δ 7.64 (d, J=7 Hz, 1H). (C32H34N2O5).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][NH:15][C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:20]=1)=[O:4].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([C:36]([OH:39])([CH3:38])[CH3:37])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:26]4[N:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[C:29]([C:36]([OH:39])([CH3:37])[CH3:38])=[CH:28][N:27]=4)[C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:20]=1)=[O:4]
Reactant: CC(C)(O)c1cnc(Cl)nc1C(F)(F)F
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)(C)O)c(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 165 °C
Reaction time: 21 h
Yield: 61.7 %

Procedure:
(R)-methyl-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (224 mg, 0.639 mmol) and 2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (192 mg, 0.799 mmol) were combined in a small vial and azeotroped with benzene to remove any residual water. A mixture of dioxane (1 mL) and iPr2NEt (0.22 mL, 1.28 mmol) was degassed with N2 for 10 minutes. This mixture was then added to the reaction vial and sealed with a Teflon® coated cap which was then wrapped with Teflon® tape. The resulting suspension was then placed in a 165° C. silicone oil bath at which point the mixture became homogeneous. The resulting solution stirred at 165° C. for 21 h. After the solvents were removed by rotovap, the mixture was purified using ISCO FCC, eluting with 50% EtOAc in Hexanes to obtain 219 mg of (R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate as a white solid (62% yield, 40% ee).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([CH2:17][CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: ClCCN1CCOCC1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Agent: Cl
Product: N#Cc1ccnc(-c2cn(CCN3CCOCC3)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(2-chloroethyl)morpholine hydrogen chloride according to the procedure for the preparation of Example 43, part A. [M+H] Calc'd for C15H17N5O, 284. Found, 284.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>>[C:17]([NH:1][C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1nn(C)c(C)c1N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(C)nn(C)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.8 %

Procedure:
Under anhydrous conditions, a mixture of 4-amino-1,3,5-trimethyl-1H-pyrazole (10 g, 80 mmol) and triethylamine (16.7 mL, 120 mmol) was treated dropwise with acetyl chloride (6.3 mL, 88 mmol). The reaction mixture was stirred at ambient temperature for 72 hours. The triethylamine hydrochloride was removed by vacuum filtration. The filtrate was concentrated in vacuo and the residue triturated with Et2O to give 9.6 g of title compound as a tan solid (72% yield, m.p. 118-119° C.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:39]3[CH2:40][CH2:41][N:36]([CH2:42][CH2:43][OH:44])[CH2:37][CH2:38]3)=[O:34])[C@H:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OCCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 2-piperazine-1-yl-ethanol (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C32H39N6O3Cl2 [(M+H)+] 625.2455, observed 625.2457.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>CN(C)C=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([Cl:26])=[O:20])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: -15 °C
Yield: 66 %

Procedure:
A slurry of 2.30 g (7.52 mmoles) of 4-(4-phenoxyphenyoxy)benzoic acid, 30 ml of thionyl chloride and 2 drops of N,N-dimethylformamide is refluxed under nitrogen atmosphere for 16 hours. Excess thionyl chloride is distilled off to yield an oil, and 200 ml of anhydrous n-hexane is added. The solution is cooled to -15° C., and the resulting precipitate is filtered and dried under nitrogen atmosphere. The precipitate is dissolved in a minimum volume of hot n-hexane, the solution is filtered, and the filtrate is cooled to -15° C. to yield 1.82 g (66 percent yield of 4-(4-phenoxyphenoxy)benzoyl chloride having a melting point of 85° C. to 89° C. by DSC measurement.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11]O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.O=S(Cl)[Cl:21]>>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][Cl:21])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](CO)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCC[C@H]1CC[C@H](CCl)CC1
Temperature: 25 °C

Procedure:
37 g (0.22 mol) of trans-4-butylcyclohexylmethanol and 18 g (0.23 mol) of anhydrous pyridine were given dropwise addition of 32 g (0.27 mol) of SOCl2 in an ice water bath while stirring, and then stirred for 3 hours at 105°-110° C. with a mantle heater. The reactant was cooled to room temperature, poured into a beaker containing concentrated HC1 and ice, the oily layer was taken off, the water layer was extracted with chloroform, combined with the oily layer and washed with 10% HCl and water. The chloroform was extracted, and the remaining oily substance was distilled under reduced pressure (b. p. 80° C./3 mmHg) to obtain 38 g (0.20 mol) of trans-4-butylcyclohexylchloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([CH3:36])=[CH:31][C:30]=1[S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[N:10][N:11]=1)[S:37]([C:30]1[CH:31]=[C:32]([CH3:36])[C:33]([F:35])=[CH:34][C:29]=1[F:28])(=[O:39])=[O:38]
Reactant: COc1ccc(CNc2nncs2)c(OC)c1
Reactant: Cc1cc(S(=O)(=O)Cl)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(C)c(F)cc2F)c(OC)c1
Yield: 66 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 86a by using N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (WO 2010/079443; 1.00 g, 3.98 mmol), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 4.78 mL, 4.78 mmol), 2,4-difluoro-5-methylbenzenesulfonyl chloride (WO 2010/079443; 0.989 g, 4.36 mmol) and THF (20 mL), to yield the title compound (1.16 g, 66%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:11]3[O:15]C(C)(C)C(C)(C)[O:12]3)[CH:8]=2)[C:3]1=[O:20].Cl>CC(C)=O>[CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:11]([OH:15])[OH:12])[CH:8]=2)[C:3]1=[O:20]
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Agent: Cl
Solvent: CC(C)=O
Product: CN1Cc2cc(B(O)O)ccc2C1=O
Temperature: 10 °C
Yield: 72.3 %

Procedure:
To a solution of crude 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (Example 31, step (ii), 53 g) in acetone (600 mL) was added aqueous HCl solution (2M, 600 mL) and the solution was heated at reflux for 18 h. The solution was concentrated under vacuum to remove acetone and then cooled to 10° C. The resulting precipitate was filtered and dried under vacuum to afford the sub-titled compound (26.8 g).
Reaction SMILES: [C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:34]=[CH:33][S:32][C:18]=4[N:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=4)[C:25]([O:27]C)=[O:26])[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2.[OH-].[Na+]>O1CCOCC1.O>[C@@H:5]12[O:8][C@@H:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:34]=[CH:33][S:32][C:18]=4[N:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=4)[C:25]([OH:27])=[O:26])[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:4]2
Reactant: COC(=O)c1cccc(-c2nc(Nc3cccc(N4C[C@H]5CC[C@@H](C4)O5)c3)c3ncsc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(-c2nc(Nc3cccc(N4C[C@H]5CC[C@@H](C4)O5)c3)c3ncsc3n2)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
The mixture of methyl 3-(7-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (0.094 g, 0.2 mmol) and NaOH (0.079 g, 2.0 mmol) in dioxane (10 mL) and H2O (5 mL) was stirred at 30° C. for 2 h. It was concentrated, residue diluted with water, washed with ether (2×5 mL) and the aqueous layer was adjusted to pH=4 by the addition of conc. HCl, then the solid formed was filtered and purified by recrystallization (15 mL, MeOH:EtOAc:ether=5:20:100, v/v/v) to afford 3-(7-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (0.042 g, 46%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 13.23 (s, 1H), 10.15 (s, 1H), 9.42 (s, 1H), 8.98 (s, 1H), 8.61 (d, 1H, J=7.8 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.68-7.62 (m, 2H), 7.41 (d, 1H, J=8.1 Hz), 7.23 (t, 1H, J=8.4 Hz), 6.65 (d, 1H, J=8.4 Hz), 4.44 (s, 2H), 3.43-3.36 (m, 2H), 2.89 (d, 1H, J=9.3 Hz), 1.86 (s, 4H). LC-MS: 460 [M+H]+, tR=1.64 min. HPLC: 95.36% at 214 nm, 96.48% at 254 nm, tR=5.20 min.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:16])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[Br:17][C:8]1[CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](=[O:16])[N:4]([CH:1]([CH3:2])[CH3:3])[C:9]=1[CH3:10]
Reactant: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)c(C)n(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in Example 1(5) (1.12 g, 5.00 mmol) and N-bromosuccinimide (890 mg, 5.00 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h, and then the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=2/1˜1/1) to give 1.34 g (91%) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a solution of 6-chloro-2-methyl-3-nitropyridine (0.5 g, 2.9 mmol) in pyrrolidine (0.7 mL, 8.7 mmol) was added K2CO3 (0.8 g, 5.8 mmol). The reaction mixture was heated at 110° C. for 2 h. Water (2 mL) was then added and the title compound (0.6 g, 99%) was collected by filtration. LCMS (ES+) 208 (M+H)+, RT 3.019 minutes (method 1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](C2C=CC(C(O)=O)=CC=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][CH:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:8]4[CH:7]=[CH:6][C:5]([C:3](=[O:2])[NH:41][CH:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH3:33])=[CH:10][CH:9]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CC(N)c1ccccc1
Product: CC(NC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1)c1ccccc1
Yield: 114.6 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with DL-alpha-methylbenzylamine (available from Aldrich Chemical Company, Inc.; 75 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(1-phenyl-ethylcarbamoyl)-biphenyl-2-carboxylic acid (69 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.22 (br s, 1H), 8.90 (d, J=8.0 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.39-7.45 (m, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.18-7.28 (m, 1H), 5.20 (quin, J=7.3 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[C:5]([CH3:10])[C:4]=1[CH3:11].[CH2:12]([OH:15])[CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][O:15][C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[C:5]([CH3:10])[C:4]=1[CH3:11]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: OCCO
Agent: [Na]
Product: Cc1c(OCCO)cc[n+]([O-])c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4.60 g (0.2 mol) of metallic sodium was dissolved in 80 ml of ethylene glycol under cooling with ice to obtain a solution. This solution was stirred in a nitrogen atmosphere at 100° C. for one hour, followed by the addition of 15.76 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide at a room temperature. The obtained mixture was stirred at 120° C. for 2 hours. After the completion of the reaction, the reaction mixture was distilled to dryness to remove the ethylene glycol. The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol=19:1) to obtain 13.28 g of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide as a white crystal.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[N:19][CH:20]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:23]1[N:22]=[C:21]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:16]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Yield: 95.5 %

Procedure:
To a stirred and cooled suspension of N-tert-butyl-3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,3′]bipyridinyl-5′-yl]-benzenesulfonamide (example 288) (0.150 g, 0.29 mmol) in dichloromethane (0.9 mL) was added TFA (6.3 mL) and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.130 g, 97%). MS (ISP) 470.3 [(M+H)+]; mp 235° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:27]([CH3:26])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: CNc1ccccc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccccc1
Yield: 83 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and N-methyl-aniline, the title compound was isolated as a yellow solid in 83% yield (99% purity by HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[Cl:10].[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:11]=[CH:9]2
Reactant: Cc1c(N)ccc(Br)c1Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1c(Br)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3-chloro-2-methylaniline (11 g, 49.9 mmol) in acetic acid (450 mL) was added NaNO2 (5.4 g, 78.3 mmol) in H2O (15 mL) at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 8.15 (s, 1H), 7.62 (d, 1H), 7.52 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH2:11][NH:10][C:8]([C:7]1[CH:6]=[C:5]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)[N:4]=[N:3][C:2]=1[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:9]
Reactant: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)nnc2Cl)cc1OC
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)nnc2N2CCCC2)cc1OC
Temperature: 100 °C

Procedure:
To a solution of 3-chloro-N-(3,4-dimethoxybenzyl)-6-(3,5-dimethylphenyl)pyridazine-4-carboxamide (1-3, 0.011 g, 0.027 mmol, 1.0 equiv) in dioxane (0.27 mL) was added pyrrolidine (0.038 g, 0.53 mmol, 20.0 equiv) and the reaction mixture was heated to 100° C. under microwave heating for 10 minutes. The reaction was cooled and directly purified by normal phase column chromatography (10 to 100% EtOAc in hexanes) to afford the product (1-4) as a white solid. HRMS [M+H] C26H30N4O3 calc'd 447.2391. found 447.2384.