Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: OB(O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccc(-c3ccccc3)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 25.6 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 40 mg, 0.09 mmol), phenylboronic acid (13.2 mg, 0.11 mmol), potassium carbonate (38 mg, 0.272 mmol), tetrakis (triphenylphosphine)palladium (0) (3 mg, 2.7 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered. and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (10 mg, 0.023 mmol, 25% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.91 (s, 1H), 12.97 (br. s., 1H), 10.16 (t, J=5.56 Hz, 1H), 7.69 (d, J=7.33 Hz, 2H), 7.55 (dd, J=11.62, 1.52 Hz, 1H), 7.51-7.43 (m, 3H), 7.38-7.42 (m, 1H), 7.35 (t, J=7.96 Hz, 1H), 5.34 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.18 (sept, J=6.82 Hz, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 440 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH2:4][C:3]([OH:24])=[O:2])=[C:6]([C:15](=[O:23])[C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[NH:7]2)=[CH:12][CH:11]=1
Reactant: COC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A mixture of methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate (Example 8, 1.80 g) and 2N aqueous NaOH (7.5 ml) in MeOH-THF (10 ml-10 ml) was stirred at 80° C. for 1 h. The mixture was cooled and concentrated. The residue was dissolved in water (150 ml) and washed with diethyl ether (50 ml). The aqueous layer was acidified with 2N aqueous HCl (10 ml), and extracted with ethyl acetate (100 ml×2). The combined organic extracts were washed with brine (50 ml), dried (MgSO4), and concentrated. The residual solids were recrystalized from toluene to afford 1.58 g (91%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH2:5][CH:4]([CH3:12])[CH:3]1[C:13](OC)=O.[CH:17](=[C:21]([CH2:24]CCl)[CH2:22]Cl)[CH:18]([CH3:20])[CH3:19]>>[CH:17](=[C:18]1[CH2:20][CH2:13][C:3]2([CH:4]([CH3:12])[CH2:5][C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:7][C:2]2=[O:1])[CH2:19]1)[CH:21]([CH3:24])[CH3:22]
Reactant: COC(=O)C1C(=O)C=C(OC(C)C)CC1C
Reactant: CC(C)C=C(CCl)CCCl
Product: CC(C)C=C1CCC2(C1)C(=O)C=C(OC(C)C)CC2C

Procedure:
Methyl 2-oxo-4-isopropoxy-6-methyl-3-cyclohexene carboxylate was reacted with 2-isobutylidene-1,4-dichlorobutane and the resultant alkylated carboxylate cyclized by the same method described in Example 2 to yield 2-isobutylidene-8-isopropoxy-10-methylspiro[4.5]dec-7-en-6-one having the structure: ##STR29## which was crystallized from petroleum ether, mp 88°-91° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:16][CH2:15][CH2:14][C@:11]3([O:13][CH2:12]3)[CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1.[OH-].[NH4+:19]>O>[NH2:19][CH2:12][C@:11]1([OH:13])[CH2:14][CH2:15][CH2:16][C@H:9]([NH:8][C:6]2[C:5]([F:17])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1
Reactant: Fc1cnc(Cl)nc1N[C@H]1CCC[C@@]2(CO2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-fluoro-N-[(3S,5S)-1-oxaspiro[2.5]octan-5-yl]pyrimidin-4-amine, 46a, (0.19 g, 0.73 mmol) was dissolved in water (75 mL) and treated with 30% ammonium hydroxide (10 mL, 86.0 mmol). The suspension was heated to 50° C. for 5 hrs then allowed to stir at room temperature overnight. The volatiles were evaporated under reduced pressure, and the residue, (1S,3S)-1-(aminomethyl)-3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)cyclohexanol, was taken into the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[NH2:2].C[Si](Cl)(C)C>ClCCCl>[Cl:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1]([OH:3])=[N:2][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)ccc1C(N)=O
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1nc(O)c2ccc(Cl)cc2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of ethyl 2-(2-carbamoyl-5-chlorophenylamino)-2-oxoacetate (545 mg, 2.02 mmol) and TEA (11 mL, 80 mmol) in DCE (20 mL) was added trimethylsilyl chloride (3.8 mL, 30 mmol) and the solution was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated aq NaHCO3 and DCM (100 mL). The separated aqueous phase was extracted with DCM (2×100 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10-60% EtOAc/hexanes to afford ethyl 7-chloro-4-hydroxyquinazoline-2-carboxylate as a solid (321 mg, 63%). 1H NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=7.06 Hz, 3H), 4.39 (q, J=7.10 Hz, 2H), 7.60-7.74 (m, 1H), 7.85-7.98 (m, 1H), 8.11-8.23 (m, 1H), 12.82 (br s, 1H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.CN([CH:24]=[O:25])C>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(F)c(-n2cccc2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
Anhydrous DMF (0.82 mL, 10.67 mmol) and POCl3 (0.96 mL, 10.67 mmol) were combined at 0° C. in a 50 mL round bottomed flask. The suspension was warmed to ambient temperature and treated with 1-(2-fluoro-5-nitrophenyl)-1H-pyrrole (2.0 g, 9.7 mmol) as a light yellow solution in anhydrous DMF (8 mL). The resulting mixture was vigorously stirred at room temperature for 5 hours. TLC analysis of the mixture after 5 hours showed the complete conversion of the starting material to the product. The reaction mixture was transferred to a separatory funnel and partitioned (EtOAc//H2O). The organic phase was washed with H2O (3×50 mL), brine (3×50 mL), dried over Na2SO4 and evaporated in vacuo to give a brown residue. The residue was purified by flash chromatography (hexanes 1:1 EtOAc/hexanes) to furnish the title compound as a white solid (1.2 g, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][C:21]=3[C:25](=[O:38])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH3:37])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[I:51]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([I:51])=[N:22][C:21]=3[C:25](=[O:38])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH3:37])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: COc1ccc(CNC(=O)c2ncoc2-c2ccc(N3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)cc2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2nc(I)oc2-c2ccc(N3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)cc2)c(OC)c1
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a solution of 4-{4-[4-(2,4-dimethoxy-benzylcarbamoyl)-oxazol-5-yl]-phenyl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (2.6 g, 4.7 mmol) in 20 mL THF at −78° C. was added a 1M solution of LiHMDS (44 mL, 44 mmol) in THF. The mixture stirred for 0.5 h, then I2 (9 g, 35 mmol) was added in portions. The mixture was stirred at room temperature for 1 h. The mixture was quenched with 15% aqueous Na2S2O3 and extracted with EtOAc and washed with water. The organic phase was dried over Na2SO4. The solvent was removed in vacuo to give the crude product which was purified by silica gel column chromatography (PE/EtOAc=2/1 to PE/EtOAc/DCM=1/1/2) to afford the title compound (2.4 g, yield: 75%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18](O)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:39]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[NH:37][C:18](=[O:19])[C:17]1[CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[CH:16]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCCO)c1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)Nc3ccccc3-c3ccccc3)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoic acid with 2-aminobiphenyl there was obtained N-biphenyl-2-yl-3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[Cl:16][C:17]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:18]=1[C:19]([NH:21][C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=1)=[O:20]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:39]2[CH:40]=[CH:41][C:17]([Cl:16])=[C:18]([CH:38]=2)[C:19]([NH:21][C:22]2[N:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:25]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=2)=[O:20])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)n(-c2ccccc2)n1
Reactant: Nc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3cccc(N)n3)ccc2Cl)n(-c2ccccc2)n1
Temperature: 100 °C
Yield: 51 %

Procedure:
6-amino-2-bromopyridine (835.5 mg, 4.83 mmol), sodium carbonate (1.39 g, 13.2 mmol) and water (0.5 mL) were added to the solution of ethyl 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate in dioxane obtained in Preparation 5. The reaction was degassed with nitrogen for 30 minutes before the addition of Pd(dppf)Cl2 with further degassing for 10 minutes. The reaction was heated to 100° C. for 16 hours. The reaction was cooled and eluted through a pad of silica, eluting with EtOAc (50 mL). The organic solution was washed with water (50 mL) dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30-50% EtOAc in heptanes to afford the title compound as a pale yellow solid (1.02 g, 51%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[C:13](Cl)(=[O:15])[CH3:14].CCN(CC)CC>>[C:13]([O:12][C:9]1[CH:10]=[CH:11][C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:7][C:6]=2[CH:8]=1)(=[O:15])[CH3:14]
Reactant: CCc1cc2ccc(O)cc2s1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CCc1cc2ccc(OC(C)=O)cc2s1
Yield: 147.8 %

Procedure:
This material was prepared by treatment of 2-ethyl-6-hydroxybenzo[b]thiophene 134b (1.60 g, 9 mmole) with acetyl chloride (1 ml, 1.10 g, 14 mmole) and Et3N (2 ml, 1.45 g, 14 mmole) in a manner as previously described for example 8b to give a white solid (2.93 g, 93%). 1H NMR (DMSO-d6) δ 7.72 (1H, d, J=8.5 Hz), 7.68 (1H, d, J=2.2 Hz), 7.15 (1H, s), 7.08 (1H, dd, J=2.2, 8.5 Hz), 2.89 (2H, q, J=7.5 Hz), 2.28 (3H, s), 1.29 (3H, t, J=7.5 Hz).
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=[NH:17])[NH2:16])=[N:7]1.C[O:23][CH:24]=[C:25]([C:30](OC)=O)[C:26]([O:28][CH3:29])=[O:27].C[O-].[Na+]>CO>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]2[N:16]=[C:24]([OH:23])[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][N:17]=2)=[N:7]1
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O

Procedure:
10.0 g (32.7 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride (example 5A) and 8.54 g (49.1 mmol) of dimethyl (methoxymethylene)malonate were initially charged in 400 ml of methanol, and 1.77 g (32.7 mmol) of sodium methoxide were added cautiously. The mixture was reacted at 50° C. overnight. The precipitate formed was filtered off, washed with a little methanol and dried under high vacuum. Thus, 6.54 g (52% of theory) of the target compound were obtained.
Reaction SMILES: O[Li].O.C([O:7][CH:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[C@H:10]([CH3:30])[CH2:9]1)(=O)C.C1COCC1.[NH4+].[Cl-]>O>[OH:7][CH:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[C@H:10]([CH3:30])[CH2:9]1
Reactant: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
LiOH—H2O (6.577 g, 156.7 mmol) was added to a 0° C. solution of (5R)-tert-butyl 4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (23.6 g, 62.69 mmol) in 2:1 THF:H2O (320 mL). The reaction mixture was stirred 10 minutes and then warmed to room temperature. LC/MS looked same at 3 and 4.5 hours. The reaction mixture was cooled to 0° C., and saturated NH4Cl was added. The reaction mixture was stirred for 5 minutes, and most of the THF was removed by rotary evaporation. The mixture was extracted with EtOAc (3×250 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on Biotage 65M: 4:1 DCM:ethyl acetate, then gradient to 1:1 to 1:4 DCM:ethyl acetate. Once product eluting, then ethyl acetate flushed through column, then 30:1 DCM:MeOH eluted rest of product (8.83 g), mixed fractions re-flashed with Biotage 40M using same conditions to give another 2.99 g which give a combined yield of (5R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (11.82 g, 56.38% yield) as a brown foam. LC/MS (APCI+) m/z 335.1 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34]N>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2,5-difluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=435.0 (M+H)+
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)=[S:7])[CH2:2][CH2:3][CH3:4].Cl[CH2:18][C:19](OCC)=[O:20].N1C=CC=CC=1>CCO>[CH2:1]([N:5]1[C:19](=[O:20])[CH2:18][S:7][C:6]1=[N:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]#[N:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=S)Nc1cccc(C#N)c1
Reactant: CCOC(=O)CCl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCN1C(=O)CSC1=Nc1cccc(C#N)c1
Yield: 67.9 %

Procedure:
To a 100 mL flask was added anhydrous EtOH (25 mL), 1-butyl-3-(3-cyanophenyl)thiourea (0.99 g, 4.2 mmol), ethyl chloroacetate (0.51 mL, 5.0 mmol), and anhydrous pyridine (0.5 mL, 5 mmol). After heating under reflux 16 h, the product mixture was concentrated under reduced pressure and chromatographed (silica gel, 2:98 MeOH/DCM) to afford the title product (0.78 g, 67%) as a colorless oil. 1H-NMR (CDCl3): δ 7.40–7.47 (2H, m), 7.25 (1H, m), 7.19 (1H, m), 3.84 (2H, t), 3.84 (2H, s), 1.69 (2H, m), 1.39 (2H, m), 0.97 (3H, t); MS(ESI): 274 (MH+).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].O[CH2:9][NH:10][C:11](=[O:13])[CH3:12]>FC(F)(F)C(O)=O>[C:11]([NH:10][CH2:9][S:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5])(=[O:13])[CH3:12]
Reactant: CC(=O)NCO
Reactant: CC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCSCC(C)C(=O)O
Reaction time: 1 h

Procedure:
3-Mercapto-2-methylpropanoic acid (2.4 g.) and N-hydroxymethylacetamide (1.8 g.) are dissolved in trifluoroacetic acid and the solution is stored at room temperature for 1 hour. The trifluoroacetic acid is removed in vacuo and the residue is dried in vacuo over potassium hydroxide to yield 3-acetamidomethylthio-2-methylpropanoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1.[OH:30][C@H:31]1[CH2:35][NH:34][C@H:33]([CH2:36][OH:37])[CH2:32]1.CS(C)=O>C([O-])(O)=O.[Na+]>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:3]=[C:2]([N:34]2[CH2:35][C@H:31]([OH:30])[CH2:32][C@H:33]2[CH2:36][OH:37])[N:7]=[CH:6][C:5]=1[N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]1[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1)([CH3:12])[CH3:11]
Reactant: OC[C@@H]1C[C@@H](O)CN1
Reactant: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1-c1ccccc1Cl
Temperature: 13 °C
Reaction time: 9 h
Yield: 28.5 %

Procedure:
To a solution of 0.15 g (0.32 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide and 0.25 g (2.13 mmol) (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine in 2 ml dimethyl sulfoxide 0.2 g (1.55 mmol) Na2CO3 was added and the solution was stirred at 13° C. for 9 h After cooling to ambient temperature, the solution was poured into 20 ml 0.5 N NaHCO3-solution and extracted three times with 30 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 1:2) to give 0.05 g (31%) of the title compound as a white foam. MS m/e (%): 548.3 (M+H+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[C:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]=2)=[CH:16][CH:15]=[CH:14]3)(=[O:10])=[O:9])=[N:3][CH:2]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=3[C:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH:32]=3)[CH:12]=2)(=[O:10])=[O:9])=[N:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3C3=CCNCC3)cccc2c1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
A round bottom flask was charged with tert-butyl 4-(2-(6-(N-(pyrimidin-4-yl)sulfamoyl)naphthalen-1-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate Y) (0.031 g, 0.051 mmol) and DCM (0.508 mL) and trifluoroacetic acid (3.91 μl, 0.051 mmol) was added. The resulting solution was maintained at rt for 18 h and then concentrated. The residue was taken up in minimal MeOH/DMSO and purified by preparative HPLC (Phenomenex C18 150×30 mm, 5 μm: 25 to 85% CH3CN:H2O (1% TFA modifier) over 15 min). Fractions were combined and concentrated to afford N-(pyrimidin-4-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate (8.8 mg, 0.014 mmol) as a colorless film. 1H NMR (400 MHz, CD3OD) δ ppm 1.98-2.28 (m, 2H) 2.73-2.97 (m, 2H) 3.41-3.62 (m, 2H) 5.70 (dt, J=3.15, 1.60 Hz, 1H) 7.16 (dd, J=6.36, 1.08 Hz, 1H) 7.52 (d, J=8.02 Hz, 1H) 7.60 (dd, J=7.04, 1.17 Hz, 1H) 7.64 (d, J=9.00 Hz, 1H) 7.68-7.82 (m, 3H) 7.94 (dd, J=8.90, 1.96 Hz, 1H) 8.17 (d, J=8.31 Hz, 1H) 8.30 (d, J=6.06 Hz, 1H) 8.59 (s, 1H) 8.71 (d, J=1.86 Hz, 1H); m/z (ESI, +ve ion) 510.9 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O.C(Cl)Cl>[CH2:9]1[C:10]2[C:6](=[C:5]([O:4][CH2:3][CH2:2][N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])[CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCOc1cccc2c1CCC2
Agent: [K]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc2c1CCC2
Yield: 85.4 %

Procedure:
A solution of 54.01 g (0.226 mole) of 4-(2-bromoethoxy) indan and 41.81 g (0.226 mole) of potassium phthalimide in 1200 ml of dimethylformamide was stirred overnight at 85° C. The reaction was filtered and dimethylformamide removed in vacuo in a rotary evaporator to give a white solid. The solid was dissolved in methylene chloride and extracted with water. Methylene chloride was evaporated to give a light brown solid. The solid was triturated with diethyl ether to give 59.3 g light brown solid. A portion of the solid was recrystallized from methylene chloride-ethanol-diethyl ether to give a white crystalline solid, m.p. 128.5°-132.0° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCc1ccccn1
Product: CCc1cc(-c2cncc(C(=O)NCc3ccccn3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and pyridin-2-ylmethyl amine to afford the title compound. MS: m/e=349 (M+H).