Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][C@@H:16]2[CH2:18][C@H:13]1[CH2:14][N:15]2[C:19]([C@@H:21]([NH:26]C(=O)OC(C)(C)C)[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][C@@H:16]2[CH2:18][C@H:13]1[CH2:14][N:15]2[C:19](=[O:20])[C@@H:21]([NH2:26])[C:22]([CH3:23])([CH3:24])[CH3:25])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1nc2ccccc2[nH]1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1nc2ccccc2[nH]1
Yield: 79.8 %

Procedure:
A solution of 1,1-Dimethylethyl ((1S)-1-{[(1S,4S)-5-(1H-benzimidazol-2-ylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)carbamate (5.8 g, 12.7 mmol) in 60 ml TFA/DCM (20%) was stirred at room temperature for 1 h. The reaction mixture was basified by addition of sat. aqueous Na2CO3 and then extracted with DCM (3×50 mL). The DCM solution was dried over anhydrous Na2SO4 and concentrated to give the title compound (3.6 g) as a pale yellow solid. LCMS (m/z): 356.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:11][C:10](=[O:12])[CH2:9][C:6]1[C:5]2[CH:13]=[CH:14][C:2]([OH:1])=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: O=C(O)Cc1coc2cc(O)ccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1coc2cc(O)ccc12
Temperature: 25 °C

Procedure:
A mixture of (6-hydroxy-benzofuran-3-yl)-acetic acid (for preparation see WO 2008001931; 14.0 g), concentrated sulfuric acid (5 mL), and methanol (250 mL) is stirred at reflux temperature for 4 h. After cooling to room temperature, the mixture is concentrated. Ethyl acetate is added to the residue, and the resulting mixture is washed with water, saturated aqueous NaHCO3 solution and brine and dried (MgSO4). The solvent is evaporated, and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 2:1→1:2) to give the title compound. Mass spectrum (ESI+): m/z=207 [m+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([CH3:16])[NH:10][C:9](=[O:17])[C:8]=3[C:7]=2[CH:18]=1.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([F:31])[CH:21]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:16][C:11]1[NH:10][C:9](=[O:17])[C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][NH:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([F:31])[CH:21]=4)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Reactant: CCOC(=O)c1ccc(N)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1F
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a 500 mL 3-neck flask equipped with a magnetic stirrer, a nitrogen inlet, and a reflux condenser were added 5.00 g of 9-bromomethyl-3-methylbenzo(f)quinazolin-1(2H)-one, 3.02 g of ethyl 4-amino-2-fluorobenzoate, 4.17 g of NaHCO3, and 42 mL of anhydrous DMF. The reaction mixture was heated to 100° C. with stirring under nitrogen for 1.5 h.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C@@H:7]1[CH2:11][C@H:10](OC(=O)C)[CH:9]=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].O[C@@H]1C[C@H](OC(=O)C)C=C1.[N-:28]=[N+:29]=[N-:30].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Na+]>O1CCCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:28]([C@H:10]1[CH2:11][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:8]=[CH:9]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@@H]1C=C[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [Pd]
Agent: CC(=O)O[C@@H]1C=C[C@H](O)C1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](N=[N+]=[N-])C1
Temperature: 50 °C
Yield: 80.7 %

Procedure:
The title compound was prepared by combining a solution of 630 mg (2.46 mmol) of acetic acid (1S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-cyclopent-2-enyl ester [synthesized by silylation of commercially available acetic acid (1S,4R)-4-hydroxy-cyclopent-2-enyl ester (Curran, et al. Tetrahedron 1997, 53, 1983-2004)] in 6 mL tetrahydrofuran with a solution of 320 mg (4.91 mmol) of sodium azide in 1.3 mL of water. To this biphasic mixture was added a solution of 112 mg (0.12 mmol) of tris(dibenzylideneacetone)dipalladium(0) and 258 mg (0.98 mmol) of triphenylphosphine in 2 mL tetrahydrofuran, and the reaction mixture was heated to 50° C. for 6 h, when the reaction was complete. Sat. sodium chloride solution was added, and the aqueous phase was repeatedly extracted with ether. The combined organic phase was dried over sodium sulfate, filtered and evaporated. The crude material was purified by silica gel chromatography to yield 475 mg of the title compound (35). 1H NMR (400 MHz, DMSO) δ=0.09 (s, 3H), 0.10 (s, 3H), 0.88 (s, 9H), 1.49 (dt, J=3.9, 14.0 Hz, 1H), 2.69 (dt, J=7.4, 14.1 Hz, 1H), 4.22-4.26 (m, 1H), 4.75-4.79 (m, 1H), 5.92-5.95 (m, 1H), 6.05 (dt, J=1.8, 5.4 Hz, 1H)
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24](Cl)(Cl)=[S:25].O.C(=O)([O-])[O-].[Ca+2]>ClCCl>[CH:1]1([C:7]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:8]=2[N:9]=[C:24]=[S:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)c1cc(Oc2ccccc2)cc(C2CCCCC2)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cc(Oc2ccccc2)cc(C2CCCCC2)c1N=C=S
Reaction time: 5 h

Procedure:
A solution of 7.0 g of 2-cyclohexyl-4-phenoxy-6-isopropylaniline in 20 ml of dichloromethane is added dropwise, with efficient stirring, to 3.1 g of thiophosgene, 40 ml of dichloromethane, 20 ml of water and 5.0 g of ground calcium carbonate. The reaction mixture is stirred for 5 hours under reflux, then cooled and filtered over kieselguhr. The organic phase is separated, washed with water, dried over sodium sulfate and the solvent is removed under vacuum. The title compound of formula ##STR10## is obtained in the form of yellow crystals which melt at 58°-60° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36][CH2:37][CH3:38])=[CH2:35])CCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH2:37]([O:36][C:34]([C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1)=[CH2:35])[CH3:38]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 110 °C
Yield: 47.1 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (693 mg, 1.51 mmol) from Example 29, tributyl (1-ethoxyvinyl)tin (1.10 g, 3.03 mmol) and DMF (10 mL) was purged with argon. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (262 mg, 0.23 mmol). The reaction vessel was sealed and the mixture was heated at 110° C. for 2 h. The mixture was allowed to cool to rt. The mixture was partitioned between water and DCM and the organic layer was separated. The aqueous layer was extracted with additional DCM. The combined organic layers were washed with water then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM to 15% MeOH in DCM to afford (1R,2R)-2-((6-((6-(1-ethoxyvinyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (320 mg, 47%) as a solid. LCMS (ESI) m/z 450 (M+H)+.
Reaction SMILES: FC1C=C(O)C=CC=1CN1CCN(C)CC1.F[C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][C:35]=1[CH2:36][N:37]1[CH2:42][CH2:41]N(C)[CH2:39][CH2:38]1)[O:21][CH:22]1[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1.N1CC(OC2C=CC(CN3CCN(C)CC3)=C(F)C=2)C1.N1CCCC1.COC1C=CC(C=O)=C([C:79]([F:82])([F:81])[F:80])C=1>>[NH:24]1[CH2:23][CH:22]([O:21][C:20]2[CH:33]=[CH:34][C:35]([CH2:36][N:37]3[CH2:38][CH2:39][CH2:41][CH2:42]3)=[C:18]([C:79]([F:82])([F:81])[F:80])[CH:19]=2)[CH2:25]1
Reactant: CN1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2F)CC1
Reactant: COc1ccc(C=O)c(C(F)(F)F)c1
Agent: CN1CCN(Cc2ccc(O)cc2F)CC1
Agent: CN1CCN(Cc2ccc(OC3CNC3)cc2F)CC1
Solvent: C1CCNC1
Product: FC(F)(F)c1cc(OC2CNC2)ccc1CN1CCCC1
Yield: 20 %

Procedure:
Using similar protocols as described in Examples 29A, 29B, 29C and 29D employing pyrrolidine and 4-methoxy-2-(trifluoromethyl)benzaldehyde as starting materials afforded 0.58 g (20%) of 45A as an oil. 1H NMR (500 MHz, CDCl3): δ 1.78 (s, 4H), 2.53 (d, 4H), 3.71 (s, 2H), 3.80 (m, 2H), 3.93 (m, 2H), 5.01 (m, 1H), 6.87 (dd, 1H), 7.00 (d, 1H), 7.64 (d, 1H), MS (APCI+) m/z 301 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[F:32])[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(=O)OCC)=S)=[N:18][CH:19]=2)=[O:8])=[CH:5][C:4]([CH3:33])=[N:3]1.[Cl-].O[NH3+].C([N:40](CC)C(C)C)(C)C.C(O)C>O.CO>[NH2:23][C:21]1[N:20]=[C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:29]=[CH:30][C:31]([F:32])=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=4)=[O:8])[CH:11]=3)=[CH:19][N:18]2[N:40]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(F)c(NC(=O)c3cc(C)nn3C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)nn4c3)ccc2F)n(C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl) carbonyl]amino}-4-fluorophenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (1.15 g, 2.43 mmol), hydroxylammonium chloride (1.18 g, 17.0 mmol), N,N-diisopropylethylamine (2.12 mL, 12.2 mmol), ethanol (10 mL) and methanol (10 mL) was stirred at 80° C. for 8 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (650 mg, 70%) as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[OH-].[Na+]>O>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(NS(=O)(=O)c2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1ccc(NS(=O)(=O)c2ccccc2C(=O)O)cc1
Temperature: 85 °C

Procedure:
Reaction scheme II is carried out by slowly adding the cooled reaction mixture into a 4 liter beaker containing 250 ml water and 300 ml of hydrochloric acid (37%), and equipped with an efficient stirrer, taking care that the mixture does not foam over. The dispersion is chilled in a refrigerator over night. The crude N-(p-n-butylphenyl)-o-carbomethoxy benzene sulfonamide settles on the bottom of the beaker as a brownish, viscous mass. The water layer is poured off and replaced by a solution of 80 g sodium hydroxide in 1.5 liter of water. The resulting solution is heated for 2 hours at 85° C. to hydrolize the methyl ester (reaction scheme III). ##STR16##
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]([O:15]C)=[O:14])=[O:6])([CH3:3])[CH3:2].[OH-].[K+].Cl>O.C(O)C>[CH:1]([NH:4][C:5]([C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]([OH:15])=[O:14])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c(C)noc1C(=O)NC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1noc(C(=O)NC(C)C)c1C(=O)O
Yield: 73.8 %

Procedure:
2.6 g of the ester from Example 1 and 0.8 g of potassium hydroxide in 20 ml of water and 20 ml of ethanol are stirred for 16 hours at room temperature. Thereafter, the mixture is diluted with water, acidified with concentrated hydrochloric acid and extracted by shaking with dichloromethane. Evaporating down gives 1.8 g of 5-isopropylaminocarbonyl-3-methylisoxazole-4-carboxylic acid as colorless crystals of melting point 86°-92° C. (compound No. 1004).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28]CC)=[O:27])=[CH:22][CH:21]=2)=[O:18])[CH2:11][CH2:12][N:13]=1.[OH-].[Na+]>Cl>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][CH:25]=2)=[O:18])[CH2:11][CH2:12][N:13]=1
Reactant: CCOC(=O)c1ccc(NC(=O)NCCN2CCN=C2c2ccccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCN1CCN=C1c1ccccc1Cl)Nc1ccc(C(=O)O)cc1
Reaction time: 8 h

Procedure:
22.6 g of the 1-[2-[2-(2-chlorophenyl)-2-imidazolin-1-yl]-ethyl]-3-(4-ethoxycarbonyl-phenyl)-urea hydrochloride obtained according to Example 19 are dissolved in 900 ml of 95% alcohol and the base is liberated with 50 ml of 1 N sodium hydroxide solution. After adding 200 ml of 2 N sodium hydroxide solution, the mixture is stirred overnight. It is then neutralised with 200 ml of 2 N hydrochloric acid and slightly acidified with 51 ml of 1 N hydrochloric acid. The resulting mixture is evaporated to dryness in a rotary evaporator and the residue is twice boiled thoroughly with 100 ml of alcohol. The residue consists of sodium chloride; after substantial concentration, the solution yields crystalline 1-[2-[2-(2-chlorophenyl)-2-imidazolin-1-yl]-ethyl]-3-(4-carboxyphenyl)-urea hydrochloride, which is recrystallised from methanol/isopropanol and then melts at 240°-242° with decomposition.
Reaction SMILES: Br[C:2]1[C:7]([O:8]COCC[Si](C)(C)C)=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCC.C([Li])(C)(C)C.COC[O:30][C:31]1[C:32]([C:41](OC)=[O:42])=[CH:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2.O>C1COCC1>[OH:30][C:31]1[C:32]([C:41]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:42])=[CH:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2
Reactant: C[Si](C)(C)CCOCOc1cccnc1Br
Reactant: COCOc1cc2ccccc2cc1C(=O)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: O=C(c1cc2ccccc2cc1O)c1ncccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.6 %

Procedure:
To a solution of 2-bromo-3-(β-trimethylsilylethoxymethoxy)pyridine (8.51 g) in THF (150 ml) was added dropwise at -78° C. a 1.7M t-butyl lithium pentane solution (35 ml) under argon atmosphere, then the mixture was stirred for 20 minutes. To the mixture was then added dropwise at -78° C. a solution of methyl 3-methoxymethoxy-2-naphthoate (6.68 g) in THF (50 ml). The mixture was warmed up to room temperature and stirred for 2 hours, to which was added water to quench the reaction, followed by extraction with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. To the residue were added acetone (200 ml) and 1N sulfuric acid (36 ml), then the mixture was stirred for 5 hours at 50°-60° C. The reaction mixture was cooled by aeration, which was then neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(3-hydroxy-2-naphthoyl)-3-hydroxypyridine (3.93 g) (Compound A-21). The physical properties and spectrum data are shown in Table 1 and Table 5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([C:21]([N:18]3[CH2:17][CH2:16][CH:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH2:20][CH2:19]3)=[O:22])[CH:24]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc(N)c2)CC1
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3nc(Cl)ncc3F)c2)CC1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-[[4-(ethoxycarbonyl)piperidino]carbonyl]aniline were reacted to provide 2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamine. LCMS: purity: 96%; MS (m/e): 407 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[S-:9][C:10]#[N:11].[NH4+].S([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]([NH2:11])=[S:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#C[S-]
Agent: Cl
Agent: O=S([O-])O
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: NC(=S)Nc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
A solution of 3-bromoaniline (10.89 ml, TCI) in 20% aqueous hydrochloric acid (18.2 ml) was added with ammonium thiocyanate (8.02 g, WAKO) and sodium hydrogensulfite (701 mg, WAKO), and stirred at 100° C. for 22 hours. The reaction mixture was added with chloroform (20 ml) for extraction, and the organic layer was dried. Then, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=2:1) to obtain the title compound (Intermediate 74, 4.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C(OO)(=[O:11])C.Cl>CC(O)=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:11]
Reactant: CC(=O)OO
Reactant: Cc1ccnc(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(Cl)c1
Temperature: 70 °C
Yield: 101.6 %

Procedure:
A mixture of 2-chloro-4-methylpyridine (10.0 g, 78.3 mmole) and 34% peracetic acid (76.05 g, 91.0 mmole) in glacial AcOH (10 mL) was heated at 70° C. for 3 hr. The reaction mixture was cooled, conc. HCl (35 mL) was added, and the mixture was concentrated on the rotavap. Recrystallization from n-butanol followed by trituration with ether gave the title compound (7.16 g, 51%) as a white solid: MS (ES) m/e 143.9 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10]([CH2:12][C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[O:14])=[O:11])=[CH:2]1.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10]([CH2:12][C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[O:14])=[O:11])=[CH:2]1
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1cc(NC(=O)CS(=O)c2c[nH]c3ccccc23)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)CS(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc23)no1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
In a 10 mL vial, 2-((1H-indol-3-yl)sulfinyl)-N-(5-methylisoxazol-3-yl)acetamide (50.0 mg, 0.165 mmol) from Step D was dissolved in DMF (5 mL) and cooled to 0° C. Sodium hydride (60% by weight, 13.0 mg, 0.330 mmol) was then added in one portion and the reaction mixture vigorously stirred at 0° C. for 15 minutes. 3-chloro-benzylbromide (21.6 μL, 0.165 mmol) was added in one portion and the reaction mixture was stirred while being allowed to warm to ambient temperature over 3 hours. The reaction mixture was quenched with water (2 mL) and the solution was extracted with ethyl acetate (3×2 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give an oily residue which was purified on a silica gel column (0-50% ethyl acetate:hexanes over 19 min) to yield the title compound (24 mg, 0.056 mmol, 34% yield). LCMS>98% 220 nm, RT=1.26 min, m/z=428 (m+1). 1H NMR (400 MHz, DMSOD6) 11.32 (s, 1H), 8.19 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.38 (s, 1H), 7.21-7.36 (m, 4H), 7.15 (d, J=7.2 Hz, 1H), 6.61 (s, 1H), 5.52 (s, 2H), 4.58 (d, J=13.1 Hz, 1H), 4.14 (d, J=13.1 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]=[CH:22][N:23]([CH3:25])[CH3:24])=[CH:3][CH:4]=3)=[N:9][CH:10]=[N:11]2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(-c2ncnn2-c2ccc(F)cc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CN(C)C=Nc1ccc(-c2ncnn2-c2ccc(F)cc2)cc1

Procedure:
A solution of 5.0 g. of 5-(p-aminophenyl)-1-(p-fluorophenyl)-1H-1,2,4-triazole in 20 ml. of dimethylformamide dimethylacetal is heated to reflux for 1.5 hours while the methanol formed is collected by distillation. The reaction mixture is cooled, 15 ml. of ether is added and the mixture is cooled further, giving 5.5 g. of the desired product, mp. 159°-161° C.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[N:9][C:4]2=[CH:3][CH:2]=1.S1C2=NC=CC=C2C(CN)=C1>>[N:1]1[N:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[N:9][C:4]2=[CH:3][CH:2]=1
Reactant: N#Cc1ccn2nccc2n1
Agent: NCc1csc2ncccc12
Product: NCc1ccn2nccc2n1

Procedure:
Intermediate M was prepared from pyrazolo[1,5-a]pyrimidine-5-carbonitrile (M−1) following similar procedures for synthesizing intermediate J from J-4, as described above. MS (m/z): 149 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]([CH2:17][CH2:18][OH:19])[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH2:31])=[C:25]([CH3:32])[CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:21][O:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH:31][C:14]([C:13]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:9][C:10](=[O:20])[N:11]([CH2:17][CH2:18][OH:19])[CH:12]=2)=[O:16])=[C:25]([CH3:32])[CH:24]=1
Reactant: COc1cc(C)c(N)cc1OC
Reactant: O=C(O)C1=CN(CCO)C(=O)NC1c1ccc(F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(NC(=O)C2=CN(CCO)C(=O)NC2c2ccc(F)cc2)cc1OC
Yield: 23.5 %

Procedure:
4-(4-Fluoro-phenyl)-1-(2-hydroxy-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid(180 mg), 4,5-dimethoxy-2-methyl-phenylamine (86 mg) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 265 mg) were dissolved in 10 mL DMF, followed by 0.2 mL di-iso-propylethyl amine. The mixture was heated at 50° for 72 hours, then cooled, diluted with aqueous pH 2 buffer and ethyl acetate, and the layers separated. The organic layer was washed with saturated sodium bicarbonate and brine, then dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed in 3% MeOH/DCM. The fraction containing the product was washed with 10% aqueous HCl, and concentrated in vacuo to yield 52 mg of 4-(4-fluoro-phenyl)-1-(2-hydroxy-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid(4,5-dimethoxy-2-methyl-phenyl)-amide, MS (M+H)=430.