Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:22]([O:29][C:30](=[O:37])[C@@H:31]1[CH:35]([Br:36])[CH2:34][CH2:33][NH:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.ClCCl>[CH2:22]([O:29][C:30](=[O:37])[C@@H:31]1[CH:35]([Br:36])[CH2:34][CH2:33][N:32]1[C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H]1NCCC1Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)O)C(=O)N1CCC(Br)[C@H]1C(=O)OCc1ccccc1

Procedure:
A solution of 20 mmoles of pyro-L-glutamic acid and 20 mmoles of 3-bromo-proline benzyl ester toluene sulfonic acid, neutralized with N-ethyl morpholine, in dichloromethane: DMF(4:1) is cooled in an ice bath with stirring. A solution of 20 mmoles of dicyclohexylcarbodiimide in dichloromethane is ddded to the above reaction mixture. The reaction mixture is stirred in an ice water bath for one hour and then at room temperature overnight. Dicyclohexylurea is removed by filtration and the product is washed in ethyl acetate. Solvents of the combined filtrates are removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate is added to the residue and the organic solution is washed until neutral. The organic phase is dried over anhydrous MgSO4, filtered and then the solvent is removed with a rotary evaporator. The material is crystallized from isopropanol and ether yielding the named product.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:15]#[N:16])[CH:6]=1)=[O:4].[NH4+].[OH-].[H][H]>[Ni].CCO>[CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:15][NH2:16])[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc2c(C#N)cccc2c1
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=O)c1ccc2c(CN)cccc2c1
Yield: 97 %

Procedure:
A suspension of 5-cyano-naphthalene-2-carboxylic acid dimethylamide, 4, (18.93 g, 84.51 mmol), 28% NH4OH (24 mL) and EtOH (500 mL) is reacted with hydrogen (1 atmosphere) in the presence of Ra—Ni (8 g) catalyst for 4 days. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to afford 18.66 g (97% yield) of the desired product. 1H NMR (300 MHz, CD3OD): δ 8.23 (d, J=8.7 Hz, 1H), 8.70-8.11 (m, 2H), 7.63-7.78 (m, 3H), 4.69 (s, 2H), 3.20, (s, 3H), 3.09 (s, 3H). LRMS: 228.99 (M+1), 211.96 (M+1-NH3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[N:16]=[C:17]([Cl:19])[CH:18]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.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]>[Cl:19][C:17]1[CH:18]=[C:13]([NH:11][C:9]2[CH:10]=[C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[N:8]=2)[C:14](=[O:21])[N:15]([CH3:20])[N:16]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CN1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Temperature: 90 °C
Yield: 55.9 %

Procedure:
A solution of 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (55.7 mg, 0.37 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (81.8 mg, 0.37 mmol) cesium carbonate (417 mg, 1.28 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31.8 mg, 0.05 mmol) in dioxane (6 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (25.1 mg, 0.03 mmol) was added and the resulting solution was heated at 90° C. for 18 h. The mixture was cooled to room temperature and diluted with dichloromethane (50 mL) and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined, dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 2% to 7% methanol in dichloromethane) to give 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (61 mg, 57%) as a light yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:32]([N:35]([CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37]O)([CH3:34])[CH3:33].C1(C(N)=O)CC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:37][CH2:36][N:35]([CH:39]([CH3:41])[CH3:40])[CH:32]([CH3:34])[CH3:33])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: CC(C)N(CCO)C(C)C
Agent: NC(=O)C1CC1
Product: COc1ccccc1C(OCCN(C(C)C)C(C)C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-(diisopropylamino)ethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(diisopropylamino)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: O[Li].O.O.C[O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:11]=2[CH:10]=1)=[O:8].C(OCC)(=O)C>C1COCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:11]2[CH:10]=[C:9]([C:7]([OH:8])=[O:6])[S:13][C:12]=2[CH:14]=1
Reactant: COC(=O)c1cc2ccc(Br)cc2s1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
LiOH.H2O (1.85 g, 44 mmol) and water (20 mL) were added to a stirred solution of 6-bromo-benzo[b]thiophene-2-carboxylic acid methyl ester (I-25a: 2.4 g, 8.85 mmol) in THF (25 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was concentrated, acidified with 2N HCl, filtered and the residue was washed with n-hexane to afford 1.9 g of the product (84% yield).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]2=[C:11]([C:14]([OH:16])=O)[N:12]=[CH:13][N:3]12.C(N(CC)CC)C.[CH2:24]([O:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.CN(C=O)C>[CH2:24]([O:31][NH:32][C:14]([C:11]1[N:12]=[CH:13][N:3]2[C:2](=[O:1])[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]=12)=[O:16])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#CCn1nnc2c(C(=O)O)ncn2c1=O
Reactant: NOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CCn1nnc2c(C(=O)NOCc3ccccc3)ncn2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.46 mmol, 100 mg, 1 eq.), O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) (0.55 mmol, 208 mg, 1.2 eq.) and triethylamine (0.55 mmol, 77 μL, 1.2 eq.) were dissolved in THF (30 mL) and DMF (1 mL). The mixture was stirred at room temperature for 1 hour before adding O-benzylhydroxylamine (0.55 mmol, 68 mg, 1.2 eq.) in one portion. After 24 hours of room temperature stirring, the volume of the solution was reduced to 5 mL and poured into ice/water. The formed solid was filtered and washed with water, ethyl acetate and ether, and dried under vacuum. Yield: 72%. δH (DMSO-d6) 11.93 (1H, bs), 8.89 (1H, s), 7.48 (2H, m), 7.40 (3H, m), 5.15 (2H, d, J: 1.84), 4.97 (2H, s), 3.53 (1H, bs).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([C:9]([OH:11])=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([N:19]2[N:20]=[CH:2][C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:9]2=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: O=C(O)c1ccccc1C(Br)Br
Product: O=c1c2ccccc2cnn1-c1ccccc1
Yield: 30.1 %

Procedure:
α,α-dibromo-o-toluic acid (29.4 g) and phenylhydrazine (34.6 g) were allowed to react as in Example 4. There was obtaoined 6.7 g (yield: 30%) of 2-phenyl-1-phthalazinone having a melting poin of 104°-105° C.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(CCC(C2C=CC=CC=2)=O)=CC=1.[C:23]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]/[C:31](/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:25][CH:24]=1>>[C:23]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]/[C:31](/[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:32]\[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:25][CH:24]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(-c2ccccc2)cc1)c1ccccc1
Agent: O=C(CCc1ccc(-c2ccccc2)cc1)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(biphenyl-4-yl)-1-phenylpropan-1-one, (Z)-ethyl 5-(biphenyl-4-yl)-3-phenylpent-2-enoate and (E)-ethyl 5-(biphenyl-4-yl)-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.C(OCC)(=O)C>[C:40]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC(=O)c2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 25.5 mg, 0.588 mmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL), then triethylamine (19.7 μL, 0.141 mmol) and benzoyl chloride (8.2 μL, 0.071 mmol) were added thereto. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (100 mL). The mixture was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (26.7 mg) as a colorless solid. (Yield 63%)
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=O)[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH:32]([NH2:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:26])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:4])[CH3:3]
Reactant: CC(C)N
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](C(=O)O)C3)n3nccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 39.2 %

Procedure:
A solution of (R)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 84, 100 mg, 0.236 mmol), isopropylamine (14 mg, 0.236 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 25-35% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (43 mg, 39%). 1HNMR (DMSO-d6) δ: 10.92 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.97-8.04 (m, 2H), 7.92 (d, J=7.6 Hz, 1H), 7.55-7.66 (m, 2H), 7.39 (s, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.26 (t, J=12.4 Hz, 2H), 3.84 (dq, J=13.8, 6.7 Hz, 1H), 3.36 (dd, J=12.4, 10.4 Hz, 1H), 2.98-3.14 (m, 1H), 2.53-2.58 (m, 1H), 1.67-2.01 (m, 4H), 1.39-1.51 (m, 6H), 1.05 (t, J=6.2 Hz, 6H). ESI-MS: m/z 465.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:41])=[C:11]([CH3:40])[C:12]=1[C:13]([C:15]1[CH:34]=[CH:33][C:18]([O:19][S:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([OH:32])[CH:24]=2)(=[O:22])=[O:21])=[C:17]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43].[I-].[Mg+2].[I-]>CCOCC>[C:42]([O:32][C:25]1[CH:24]=[C:23]([S:20]([O:19][C:18]2[CH:33]=[CH:34][C:15]([C:13]([C:12]3[C:11]([CH3:40])=[C:10]([CH3:41])[O:9][C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])=[CH:16][C:17]=2[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:22])=[O:21])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])(=[O:44])[CH3:43]
Reactant: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccccc4)oc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
A stirred solution containing 4-[4-(2-benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.235 g, 0.409 mmol), acetic anhydride (3.3 mL) and magnesium iodide (0.113 g, 0.409 mmol) in ether (8 mL) was refluxed for 0.5 h. The reaction was allowed to cool to ambient temperature, quenched with H2O (100 mL), extracted with ether and concentrated. The mixed anhydride/product was dissolved in THF (6 mL), treated with H2O (6 mL) and refluxed for 0.5 h. The reaction was allowed to cool to ambient temperature, quenched with H2O (100 mL), extracted with ether and concentrated. Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 18 & 25% EtOAc/pet ether step gradient followed by crystallization from acetone/hexane gave 0.201 g (80%) of the title compound as an off white solid, mp 55-90° C. 1H NMR (DMSO-d6) δ1.23-1.32 (m, 2 H), 1.50-1.53 (m, 2 H), 1.64-1.72 (m, 4 H), 1.76 (s, 3 H), 2.17 (s, 3 H), 2.23 (s, 3 H), 2.92 (quintet, 1 H), 3.79 (s, 2 H), 6.98-7.00 (m, 2 H), 7.15-7.23 (m, 4 H), 7.53 (dd, 1 H), 7.58 (d, 1 H), 7.84 (d, 1 H), 7.88 (dd, 1 H), 8.12 (d, 1 H) 13.7 (br s, 1 H). mass spectrum (−ESI) m/z 615 (M−H). Anal. Calcd. for C34H32O9S .0.5H2O: C, 65.27; H, 5.32; N, 0.00. Found: C, 65.33; H, 5.30; N, 0.03.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C([O-])([O-])=O.[Na+].[Na+]>CN(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>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:14]2[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=2)=[CH:7][N:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1cc(Br)cnc1F
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: CN(C)C=O
Product: Cn1cc(-c2cnc(F)c(F)c2)cn1
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A mixture of 5-bromo-2,3-difluoropyridine (1.9 g, 9.79 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.038 g, 9.79 mmol), Na2CO3 (2.076 g, 19.59 mmol) and Pd(PPh3)4 (1.131 g, 0.979 mmol) in DMF (8 ml) was bubbled with N2 for 10 min and was then heated to 80° C. for 10 h. After being cooled to rt, the mixture was filtered and the filtrate was diluted with EA, washed with water and brine, dried over anhydrous MgSO4. Filtered and concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100% to 20%) to afford the title compound as a white solid (1.5 g, 57.4% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, 3H), 7.99 (d, 1H), 3.87 (s, 3H). LCMS (method B): [M+H]+=196, tR=1.91 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[N:5]([CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC2C=CC=CC=2)=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC(OC)OC)[CH3:2].[C:37](OCC)(=[O:39])C.CCCCCC>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[NH:5][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:39][CH3:37])[CH:15]=1)[CH3:2]
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OC)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)NC(Cc1cccc(OC)c1)c1ccc(O)c(OC)c1
Reaction time: 15 h
Yield: 56 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-methoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (10.5 g, 20 nmol) in ethyl acetate (100 mL) and ethanol (50 mL) was added 10% palladium on activated carbon (2 g). The mixture was hydrogenated at 1 atm for 15 hrs. The solution was filtered through a Celite® plug and evaporated to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded (2,2-dimethoxy-ethyl)-[1-(4-hydroxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl-carbamic acid ethyl ester as a colorless oil. (4.87 g, 56% yield).
Reaction SMILES: [Br:1]CC(C1C=CC(Cl)=C(S(=O)(=O)N(C)C)C=1)=O.C(NC(=S)NC1C=CC=CC=1)(CC)C.Br.[CH:33]([N:37]1[C:41]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([S:50](=[O:55])(=[O:54])[N:51]([CH3:53])[CH3:52])[CH:44]=2)(O)[CH2:40][S:39][C:38]1=[N:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([CH2:35][CH3:36])[CH3:34]>>[BrH:1].[CH:33]([N:37]1[C:41]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([S:50](=[O:54])(=[O:55])[N:51]([CH3:53])[CH3:52])[CH:44]=2)=[CH:40][S:39][C:38]1=[N:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([CH2:35][CH3:36])[CH3:34]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CCC(C)N1C(=Nc2ccccc2)SCC1(O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Agent: Br
Agent: CCC(C)NC(=S)Nc1ccccc1
Product: CCC(C)n1c(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)csc1=Nc1ccccc1

Procedure:
Obtained by a procedure analogous to that indicated in Example 1(a), from 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone and 3-sec.-butyl-1-phenylthiourea, or by a procedure analogous to that of Example 1(b), from 3-sec.-butyl-4-(4-chloro-3-dimethylsulfamoylphenyl)-2-phenyliminothiazolidin-4-ol hydrobromide. Colorless crystals; melting point 250° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])[CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.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]>[F:22][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccc(C(F)(F)F)cc1-c1cc(Cl)c2cccnc2n1
Reactant: Nc1ccncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Fc1ccc(C(F)(F)F)cc1-c1cc(Nc2ccncn2)c2cccnc2n1
Temperature: 140 °C

Procedure:
To a solution of 307 mg (0.94 mmol) 4-chloro-2-(2-fluoro-5-trifluoromethyl-phenyl)-[1,8]naphthyridine in 10 ml dioxane under nitrogen, 89 mg (0.94 mmol) 4-aminopyrimidine, 612 mg (1.88 mmol) cesium carbonate, 54 mg (0.093 mmol) 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 34 mg (0.038 mmol) tris(dibenzylideneaceton)-dipalladium(0) were added and heated in a microwave apparatus to 140° C. for 30 minutes. The reaction mixture was partitioned between dichloromethane and water. The organic phase was dried and the product chromatographed on a silica gel column with dichloro-methane/methanol. This yielded [2-(2-fluoro-5-trifluoromethyl-phenyl)-[1,8]naphthyridin-4-yl]-pyrimidin-4-yl-amine as beige crystals; HPLC-MS: 1.72 min, [M+H] 386.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:41](=[O:42])[N:23]3[CH:24]([C:29](Cl)=[N:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[NH3:46]>C(Cl)(Cl)Cl>[C:1]1([C:7]([NH:20][CH:21]2[C:41](=[O:42])[N:23]3[CH:24]([C:29](=[N:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[NH2:46])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(CN=C(Cl)C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(CN=C(N)C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 13.1 g. (22 mmoles) of 6-(triphenylmethylamino)-2,2-dimethyl-3-{chloro-[N-(4-methoxybenzyl)imino]methyl}penam in 45 ml. of ethanol-free chloroform, a 1.33 N ammonia solution in chloroform is added all at once. The resulting mixture is stirred 5 minutes at 0° C. and then for 45 minutes at 25° C. The mixture is then filtered, and the filtrate rotoevaporated to an amber oil. Addition of ether (100 ml.) affords a precipitate which is filtered and then taken up in 150 ml. chloroform. The chloroform solution is washed first with 100 ml. 0.5N NaOH; and then with three 150 ml. portions of water. It is then dried over anhydrous sodium sulfate and rotoevaporated to afford the title compound as an orange foam. Rotoevaporation of the filtrate obtained after the ether precipitation procedure affords more of the title compound, as an orange foam. Total yield= 12.05 g. (95%). 1H--NHR (CDCl3 ) ppm (δ) 1.33 (3H, s, 2--CH3); 1.60 (3H, s, 2--CH3); 3.81 (3H, s, --OCH3); 4.17-4.68 (3H, m; 3-, 5- and 6-H); 4.24 (2H, s, --CH2 --), 4H, AB with Ha within 7.2-7.68 multiplet; Hb centered at 6.89, J= 9 HZ. (CH3O--C6H4 --), 7.2-7.68 (15H, m, C6H5). Infrared (CH2Cl2) λmax (μ) 5.62 (s, strong); 5.75-5.83 (broad s, strong); 5.97 (broad s, strong).