Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[O:33][C:34]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])=[CH:35][N:36]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:34]6[O:33][C:32]([CH2:30][CH3:31])=[N:36][CH:35]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:22])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cnc(CC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (167 mg; compound C10), 1-[(2-ethyl-1,3-oxazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B34), HBTU (175 mg), DIPEA (0.29 ml) and DCM (3 ml). Purification by flash column chromatography [amino phase silica gel, eluent: EtOAc/methanol, 97.5/2.5 (v/v)] and afterwards by preparative HPLC gives the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH3:8].CN([CH:14]=[O:15])C.C[O-].[Na+]>O>[Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([O:15][CH3:14])=[CH:6][C:7]=1[CH3:8]
Reactant: CN(C)C=O
Reactant: Cc1cc(Cl)nc(C)c1Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C)c(Br)c(C)n1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
3-bromo-6-chloro-2,4-dimethylpyridine obtained in Preparation Example 21 (200 mg) was added to DMF (1 mL). Sodium methoxide (28% solution in methanol, 0.741 mL) was added to the solution, and the mixture was stirred at 60° C. for 15 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (172 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[O:9])[CH:3]=1.[CH:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([OH:24])[CH:16]=1.CCN(C(C)C)C(C)C.CN1CCCC1=O>O>[CH:12]1([CH2:11][NH:10][C:8]([C:4]2[CH:3]=[C:2]([O:24][C:17]3[CH:16]=[CH:15][C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(NCC1CC1)c1cc(Cl)ccn1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CC1)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1

Procedure:
4-Chloro-2-[(cyclopropylmethyl)aminocarbonyl]pyridine (1.5 g), p-nitrophenol (2.0 g), Hunig's base (3.1 ml) and 1-methyl-2-pyrrolidinone (6.2 ml) were stirred together at 160° C. for 3 hours. Water was added, extraction was performed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=4:1, followed by 2:1) using NH type silica gel to obtain 0.35 g of the target substance as a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:18])[N:11]2[C:16]=1[C:15](=[O:17])[NH:14][CH:13]=[N:12]2.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[CH3:18][C:10]1[N:11]2[C:16]([C:15](=[O:17])[NH:14][CH:13]=[N:12]2)=[C:8]([C:3]2[CH:4]=[N:5][N:6]([CH3:7])[C:2]=2[C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=2)[N:9]=1
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(=O)[nH]cnn12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Na+]
Solvent: CCO
Product: Cc1nc(-c2cnn(C)c2-c2ccc(C(F)(F)F)cc2)c2c(=O)[nH]cnn12
Temperature: 100 °C

Procedure:
5-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.647 mmol), [4-(trifluoromethyl)phenyl]boronic acid (96%, 128 mg, 0.647 mmol), tetrakis(triphenylphosphine)palladium(0) (60.1 mg, 0.052 mmol) and sodium carbonate (206 mg, 1.94 mmol) were combined in ethanol (4 mL) and subjected to microwave irradiation at 130° C. for 45 minutes, then heated at 100° C. for 18 hours. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were concentrated in vacuo and purified via silica gel chromatography (Gradient: 50% to 100% [5% methanol/5% triethylamine/90% ethyl acetate] in heptane) to provide the product. Yield: 90 mg, 0.24 mmol, 37%. LCMS m/z 375.4 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.47 (s, 3H), 3.84 (s, 3H), 7.56 (br d, J=8 Hz, 2H), 7.63 (s, 1H), 7.71 (br d, J=8 Hz, 2H), 7.98 (s, 1H).
Reaction SMILES: ClCCl.B(Br)(Br)Br.[Br:8][C:9]1[C:10](=[O:24])[N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[N:12]=[CH:13][C:14]=1[Br:15]>O>[Br:8][C:9]1[C:10](=[O:24])[N:11]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[N:12]=[CH:13][C:14]=1[Br:15]
Reactant: COc1ccc(-n2ncc(Br)c(Br)c2=O)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1c(Br)c(Br)cnn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A 1N dichloromethane solution (5.5 mL) of boron tribromide was added to a dichloromethane solution (30 mL) of 4,5-dibromo-2-(4-methoxyphenyl)-2H-pyridazin-3-one (1.1 g, 3.06 mmols), and stirred overnight at room temperature. Water (30 mL) was added and stirred for 30 minutes. The resulting precipitate was recovered by filtration, washed with water and chloroform and dried to provide the title compound (1.03 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[C:18](O)=[C:17]([F:20])[C:16]([F:21])=[CH:15][CH:14]=1>O.[OH-].[Na+].ClCCl>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:18]3[C:17]([F:20])=[C:16]([F:21])[CH:15]=[CH:14][C:13]=3[N:12]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1ccc(F)c(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Nc1ncc(Br)cc1-c1nc2ccc(F)c(F)c2o1
Temperature: 200 °C
Yield: 22.5 %

Procedure:
To a mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g) and 6-amino-2,3-difluoro-phenol (0.669 g) placed in a round bottom flask was added polyphosphoric acid (10 g). The mixture was heated at 200° C. for 5 hours. A homogenous black mixture was obtained. The mixture was diluted in water and neutralizing to pH 8 with NaOH 2N. The heterogeneous mixture was diluted with dichloromethane. The insoluble was filtered. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried on sodium sulfate, evaporated and dried to afford 5-bromo-3-(6,7-difluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (0.338 g). NMR Spectrum: (DMSOd6) 7.54 (ddd, 1H), 7.70 (ddd, 1H), 7.79 (bs, 2H), 8.34 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 326-328
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]4[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:27].[OH-]>CO>[C:17]1([N:16]2[C:15]3[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]=[C:12]2[CH2:11][N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:27])[C:3]=3[CH:10]=[CH:9]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [NH4+]
Reactant: Clc1ncnc2c1ccn2Cc1nc2ccccc2n1-c1ccccc1
Agent: [OH-]
Solvent: CO
Product: Nc1ncnc2c1ccn2Cc1nc2ccccc2n1-c1ccccc1
Yield: 22 %

Procedure:
A solution of 4-chloro-7-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-7H-pyrrolo[2,3-d]-pyrimidine (1.0 g, 2.7 mmol) in NH4OH (5 mL) and MeOH (10 mL) was stirred at 90° C. in a sealed tube overnight. Then the mixture was concentrated in vacuo. The residue was purified by P-TLC to give 139 (0.2 g, yield 22%) as a white solid. LCMS (ESI), M+H+=339.14. 1HNMR (400 MHz, CDCl3) δ 5.505 (s, 1H), 6.503 (s, 1H), 6.936 (s, 2H), 7.031 (s, 1H), 7.205-7.209 (q, J=1.6 Hz, 1H), 7.219-7.228 (m, 2H), 7.490-7.540 (m, 5H), 7.555-7.559 (d, J=1.6 Hz, 1H), 7.910 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[O:5][CH2:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[Br:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26]Br)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Br:18][C:19]1[CH:20]=[C:21]([CH2:26][NH:1][C:2]2[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=2[F:16])[O:5][CH2:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: CC(C)OC(=O)COc1ccc(F)c(N)c1F
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Br)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1
Temperature: 100 °C
Yield: 31.4 %

Procedure:
To a solution of isopropyl 2-(3-amino-2,4-difluoro-phenoxy)acetate (intermediate IV(b)) (350 mg, 1.43 mmol, 1.0 eq) and 1-bromo-3-(bromomethyl)-5-methyl-benzene (528 mg, 1.99 mmol, 1.4 eq) in DMSO (15 mL) was added K2CO3 (593 mg, 4.29 mmol, 3.0 eq). The reaction was heated at 100° C. for 1 h in a microwave reactor, then diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether: EtOAc, 100:1 to 80:1) to give the title compound as a light yellow oil (192 mg, 16%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([OH:23])=[O:22]>ClCCCl>[CH3:15][N:16]1[CH:20]=[C:19]([C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([Cl:5])[CH:7]=2)[CH:18]=[C:17]1[C:21]([OH:23])=[O:22]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cn1cccc1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1cc(C(=O)c2cccc(Cl)c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
As a modification, the acid is prepared in the following manner: 26.7 g aluminium chloride are added to a solution of 17.7 g 3-chlorobenzoic acid chloride in 300 ml 1,2-dichloroethane. At about 0° C., a solution of 12.5 g 1-methylpyrrole-2-carboxylic acid in 200 ml 1,2-dichloroethane is added portionwise. After stirring for 3 hours at room temperature, the mixture is poured over ice. The resulting precipitate is recrystallized from 250 ml 2-butanone, to give 20 g of the pure acid, m.p.=214° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1CCCCN1
Product: CCOC(=O)C1=C(CN2CCCCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 27.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with piperidine-2-carboxylic acid (0.26 g, 2 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.3 g, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:16])OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][NH2:20]>>[NH2:17][CH2:18][CH2:19][NH:20][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[NH:16]
Reactant: NCCN
Reactant: CCOC(=N)NC(=O)OCc1ccccc1
Product: N=C(NCCN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-benzyloxycarbonyl-O-methyl-isourea (II-OMe) (0.42 g, 2.0 mmol) and 1,2-diaminoethane (Ic) (0.72 g, 12 mmol) was stirred at 40° C. for 3 h and at 25° C. for 1 h. The crystals were collected by filtration. The white crystalline product was washed with toluene (4×1 mL) and dried (vacuum, 30°-35° C., 2 h). The yield of N-(2-aminoethyl)-N'-benzyloxycarbonyl guanidine IIIc was 0.28 g (60% in theory).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=S)[NH:16][N:17]=2)[O:4]1.N([O-])=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[N:16][N:17]=2)[O:4]1
Reactant: CO[C@@H]1O[C@H](c2n[nH]c(=S)n2Cc2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CO[C@@H]1O[C@H](c2nncn2Cc2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A solution of 5-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-benzyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (Preparation 18) (2.2 g, 6.1 mmol) in acetic acid (30 ml) was treated portionwise with sodium nitrite (1.2 g, 18 mmol) over 30 minutes. After an additional 30 minutes, the solvent was removed by evaporation under reduced pressure and the residue was suspended in acetone (30 ml). The insoluble inorganic salts were removed by filtration and the filtrate was evaporated under reduced pressure. The residue was then dissolved in dichloromethane (30 ml), the mixture was filtered again and the filtrate was evaporated under reduced pressure to give the title compound (2.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]([O:24][CH3:25])([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[CH:4]([NH:6]C(OCC)=O)[CH3:5].[OH-].[K+].O>CO>[CH3:1][O:2][C:3]([O:24][CH3:25])([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[CH:4]([NH2:6])[CH3:5]
Reactant: CCOC(=O)NC(C)C(OC)(OC)c1ccc2cc(OC)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(OC)(OC)C(C)N)ccc2c1
Yield: 60.5 %

Procedure:
653 mg (1.8 mmols) of (-)-1-(6-methoxy-2-naphthyl)-2-(ethoxycarbonyl)amino-1-propanone dimethyl acetal and 5 ml of a 30% aqueous potassium hydroxide solution were heated at reflux in 50 ml of methanol for 5 days. After adding 20 ml of water, the mixture was extracted with ethyl acetate (20 ml×3), and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Florisil, ethyl acetate) to obtain 300 mg of (+)-1-(6-methoxy-2-naphthyl)-2-amino-1-propanone dimethyl acetal as colorless crystals having a melting point of 84°-86° C. Yield, 58%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O:14]=[S:15]1(=[O:32])[CH2:20][CH2:19][N:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:17]2=[N:16]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]3[C:17]4=[N:16][S:15](=[O:32])(=[O:14])[CH2:20][CH2:19][N:18]4[CH:21]=[CH:22][CH:23]=3)=[CH:30][CH:29]=2)=[CH:5][CH:4]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A mixture of 4-(trifluoromethyl)phenylboronic acid (495 mg), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (240 mg), diacetoxycopper (316 mg), triethylamine (0.60 mL), and powdered 4A MS (1.5 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (45 mg) as a white solid.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:15])[CH2:6][N:7]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[N:8]1)([CH3:3])[CH3:2]>C1COCC1.[Pd]>[NH2:12][C:10]1[CH:9]=[N:8][N:7]([CH2:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:15])[CH:11]=1
Reactant: CC(C)NC(=O)Cn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)NC(=O)Cn1cc(N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
A mixture of N-isopropyl-2-(4-nitro-1H-pyrazol-1-yl)acetamide (12 g, 56.5 mmol) and Pd/C (1 g) in THF (100 mL) was stirred at room temperature under an atmosphere of hydrogen for 5 h then filtered over Celite. The filtrate was concentrated in vacuo to afford 2-(4-amino-1H-pyrazol-1-yl)-N-isopropylacetamide V-3 (10.3 g, 100%). LC-MS (Method A), RT=1.42 min. (ES+) 183.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[CH:23](/B(O)O)=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(/C=C/c2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-furan-2-yl-pyrimidin-4-yl ester, (E)-styrylboronic acid, tetrakis(triphenylphosphine)palladium(O) and sodium carbonate in dioxane/water. ES-MS m/e (%): 289 (M+H+, 100).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:4]=1.[F:16][C:17]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:16][C:17]1[C:25]([O:26][CH2:2][C:3]2[S:7][N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[N:4]=2)=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20]
Reactant: COc1ccc(-c2nsc(CBr)n2)cc1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nsc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.4 %

Procedure:
To a solution of 5-bromomethyl-3-(4-methoxyphenyl)-[1,2,4]thiadiazole (0.048 g, 0.15 mmol) in DMF (2 ml) was added 2,6-difluoro-3-hydroxybenzamide (0.027 g, 0.15 mmol) and potassium carbonate (0.76 g, 0.55 mmol). The reaction mixture was stirred at 25° C. for 12 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 30 ml water and extracted with ethyl acetate (3×20 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 50% EtOAc-Hexane) to get the desired product (0.011 g, 30%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH3:10]>CO.C(Cl)Cl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH:15]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Oc1ccc(I)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cccc(-c2ccc(O)cc2)c1
Reaction time: 8 h
Yield: 71 %

Procedure:
4-Iodophenol and 3-ethoxycarbonylphenylboronic acid were processed as described in Example 136A, except that the reaction was done overnight at room temperature and the chromatography was conducted twice with 50% CH2Cl2/hexanes followed by a gradient of 0 to 1% MeOH/CH2Cl2 to provide the title compound as a white powder (71% yield). 1HNMR (300 MHz, d6-DMSO) δ 1.34 (t, 3 H), 4.34 (q, 2 H), 6.89 (d, 2 H), 7.50-7.59 (m, 3H), 7.83-7.89 (m, 2 H), 8.11 (dd, 1 H), 9.62 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][S:22]([C:15]2[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])(=[O:24])=[O:23])[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)c1sc(N)nc1C
Product: CCOC(=O)c1sc(NS(=O)(=O)c2c(Cl)cc(Cl)cc2Cl)nc1C

Procedure:
This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 2,4,6-trichlorobenzenesulfonyl chloride as described for EXAMPLE 30 with the exception that it was purified by recrystaliation only. Yield 249 mg, 58%: 1HNMR (DMSO) δ 7.84 (s, 2H), 4.23 (q, 2H), 2.42 (s, 3H), 1.25 (t, 3H); MS-ES (neg) m/z 429.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:17][CH3:18])=[N:10][C:11]([CH3:16])=[C:12]([CH:15]=2)[C:13]#N)[CH:5]=[CH:6][CH:7]=1.BrC1C(OC)=NC(C)=C(C=1)C#N.[Cl:31]C1C=C(B(O)O)C=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:31][CH2:13][C:12]1[C:11]([CH3:16])=[N:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1nc(C)c(C#N)cc1-c1cccc(Cl)c1
Agent: COc1nc(C)c(C#N)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1nc(C)c(CCl)cc1-c1cccc(Cl)c1
Temperature: 100 °C

Procedure:
5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinonitrile. A 20 mL microwave vial was charged with 5-bromo-6-methoxy-2-methylnicotinonitrile (1.2 g, 5.28 mmol), (3-chlorophenyl)boronic acid (990 mg, 6.3 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex (191 mg, 0.26 mmol), ACN (10 mL) and saturated aq. sodium bicarbonate (3 mL). The vial was sealed, purged with nitrogen and heated at 100° C. under microwave irradiation for 10 min. The layers were separated and the aq. phase extracted with EtOAc. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound as an off white solid (995 mg, 74%). [M+H]=259.06.