Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[NH:18][NH2:19]>CO.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11](/[C:14](=[N:19]/[NH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])/[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: CCOC(=O)NN
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOC(=O)N/N=C(\C)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (150 mg, 0.65 mmol) was suspended in methanol (3 ml) and water (1 ml). Ethyl carbazate (78 mg, 0.75 mmol, 1.2 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 18 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with acetone. The resulting white precipitate was collected and washed with acetone to yield the product, one apparent isomer, as a white solid: 96 mg (47%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([C:18]([O:20][CH3:21])=[O:19])=[C:9]([OH:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH:22]([O:35][C:36](=[O:72])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]([C:60](=[O:71])[C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH:51]([C:57](O)=[O:58])[NH:52][C:53]([O:55][CH3:56])=[O:54])=[CH:46][CH:45]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.CN(C)CCCN=C=NCC.ON1C(=O)C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C>[CH:22]([O:35][C:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]([C:60](=[O:71])[C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[C:44]1[CH:45]=[CH:46][C:47]([CH2:50][C@@H:51]([C:57]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[C:9]([OH:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:58])[NH:52][C:53]([O:55][CH3:56])=[O:54])=[CH:48][CH:49]=1)=[O:72])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)NC(Cc1ccc(N(C(=O)C(=O)OCc2ccccc2)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)O
Reactant: COC(=O)c1c(OCCCCN)cc2ccccc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OCc2ccccc2)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)NCCCCOc1cc2ccccc2c(O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.7 %

Procedure:
To a mixture of methyl 3-(4-aminobutoxy)-1-hydroxy-2-naphthoate (18 mg, 0.055 mmol), 2-{benzyloxyoxalyl-[4-(2-carboxy-2-methoxycarbonylamino-ethyl)-phenyl]-amino}-benzoic acid benzhydryl ester (40 mg, 0.058 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (13 mg, 0.068 mmol) and 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (13 mg, 0.080 mmol) in DMF (0.2 mL) was added triethylamine (1 drop). The reaction was stirred at ambient temperature for 5 hours, concentrated under reduced pressure and purified on silica gel eluting with 75% ethyl acetate/hexanes to provide the titled compound (32 mg, 61%).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]CC)(=[O:10])[C:5]([O:7][CH2:8][CH3:9])=O.[OH:14][C:15]1[C:23](C(=O)C)=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][CH2:18][CH2:19]2>CC1C=CC=CC=1>[O:14]=[C:15]1[C:16]2[CH:17]=[CH:18][C:19]3[CH2:20][CH2:21][CH2:22][C:9]=3[C:8]=2[O:7][C:5]([C:4]([OH:11])=[O:10])=[CH:23]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc2c(c1O)CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(=O)c2ccc3c(c2o1)CCC3
Yield: 57 %

Procedure:
Sodium methylate (24 g) was stirred in methylbenzene (300 ml). A mixture of diethyl oxalate (0.16 mol) and intermediate (2-a) (0.16 mol) in methylbenzene (10 ml) was added dropwise. This mixture was stirred and refluxed for 2 hours. The resulting precipitate was filtered off and dried. The solid was stirred in a mixture of hydrochloric acid (10 ml) and acetic acid (500 ml). The reaction mixture was stirred and refluxed for 1 hour. The mixture was poured out into water. The resulting precipitate was filtered off and dried (vacuum), yielding 21 g of 4,7,8,9-tetrahydro-4-oxocyclopenta[h]-benzopyran-2-carboxylic acid (interm. 3-a).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:6][CH:5]([NH2:7])[CH2:4]1.C(Cl)Cl.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[F:2][C:3]1([F:8])[CH2:6][CH:5]([NH:7][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CC(F)(F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CC(F)(F)C1
Reaction time: 16 h

Procedure:
0.60 g 3,3-Difluoro-cyclobutylamine hydrochloride were suspended using 40 ml CH2Cl2 and 2.9 ml of triethylamine added at ambient temperature while receiving a clear solution. Thereafter, 1.0 ml of methanesulfonylchloride were added dropwise at ambient temperature and the mixture left at that temperature for 16 h. The volatiles were removed in vacuo, the residue was redissolved using 200 ml of EE and 100 ml of a saturated aqueous Na2CO3-solution and the layers separated. The organic layer was washed twice using 20 ml of a saturated aqueous NaHSO4-solution each time and washed twice using 30 ml of a saturated aqueous Na2CO3-solution each time. The organic layer was dried over MgSO4 and the solvent removed in vacuo. Yield: 700 mg of a colorless resin.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[F:15]C1C=CC=CC=1CBr.COP(OC)OC>>[F:15][C:13]1[CH:14]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Reactant: Fc1ccccc1CBr
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccccc1F)OC

Procedure:
Following the procedure of Compound 11, 2-fluorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10]([C@H:12]1[CH2:37][CH2:36][C@:14]2([O:18][CH:17]=[C:16]([C:19]3[CH:24]=[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([F:33])([F:32])[F:31])[CH:22]=[CH:21][C:20]=3[O:34][CH3:35])[CH2:15]2)[C@@H:13]1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:11]>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10]([C@H:12]1[CH2:37][CH2:36][C@:14]2([O:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([F:31])([F:32])[F:33])[CH:22]=[CH:21][C:20]=3[O:34][CH3:35])[CH2:15]2)[C@@H:13]1[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1)=[O:11].[CH3:8][O:9][C:10]([C@H:12]1[CH2:37][CH2:36][C@:14]2([O:18][CH2:17][C@@H:16]([C:19]3[CH:24]=[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([F:31])([F:32])[F:33])[CH:22]=[CH:21][C:20]=3[O:34][CH3:35])[CH2:15]2)[C@@H:13]1[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1)=[O:11]
Reactant: COC(=O)[C@H]1CC[C@@]2(CC(c3cc(-n4ccnc4C(F)(F)F)ccc3OC)=CO2)[C@@H]1c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CC[C@@]2(C[C@@H](c3cc(-n4ccnc4C(F)(F)F)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Product: COC(=O)[C@H]1CC[C@@]2(C[C@H](c3cc(-n4ccnc4C(F)(F)F)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylsilane (0.0062 mL, 4.5 mg, 0.039 mmol) was added to a solution of (5R,6S,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]non-2-ene-7-carboxylic acid methyl ester (6.8 mg, 0.013 mmol) in 0.204 mL of trifluoroacetic acid at RT. The mixture was stirred 1 h at RT, then overnight at 60° C. After removing the solvent under reduced pressure, the residue was dissolved in 3.0 mL of ethyl acetate, washed with 2.0 mL of saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated. The crude product was purified by preparative TLC, eluting twice with 3% ethyl ether in dichloromethane, to give 1.0 mg of (3S,5R,6S,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]nonane-7-carboxylic acid methyl ester and 2.6 mg of the title compound. 1NMR (400 MHz, CDCl3): δ 7.37 (dd, 2H, J=9, 6 Hz ), 7.19 (d, 1H, J=1 Hz), 7.15 (dd, 1H, J=9, 3 Hz ), 7.09 (d, 1H, J=2 Hz ), 7.08 (d, 1H, J=1 Hz ), 7.03 (t, 2H, J=9 Hz ), 6.82 (1H, J=9 Hz ), 3.78 (s, 3H), 3.70 (t, 1H, J=8 Hz ), 3.62 (t, 1H, J=8 Hz ), 3.56 (s, 3H), 3.14 (ddd, 1H, J=11, 10, 7 Hz ), 3.12 (d, 1H, J=11 Hz ), 2.87 (quintet, 1H, J=8 Hz ), 2.33-2.23 (m, 2H), 2.08-1.88 (m, 4H). Mass spectrum (ESI): m/z=519 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([F:18])[CH:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>C(O)C.O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:21][OH:22])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([F:18])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(CC(=O)c2ccc(Br)cc2)cc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CSc1ccc(CC(=NO)c2ccc(Br)cc2)cc1F
Temperature: 75 °C
Yield: 99.6 %

Procedure:
To a solution of 1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone (1.50 g, 4.42 mmol) in a mixture of ethanol (12 ml) and water (6 ml) were added hydroxylamine hydrochloride (615 mg, 8.84 mmol) and anhydrous sodium acetate (715 mg, 8.84 mmol) at room temperature. The mixture was heated for 2 h at 75° C. and then diluted with diethyl ether (200 ml), washed with water (50 ml×2) and saturated sodium bicarbonate (50 ml×2), and dried over magnesium sulfate. Removal of solvent gave 1.56 g (˜100%) of 1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone oxime as an orange solid.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][OH:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.O>[CH3:31][S:32]([O:11][CH2:10][C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:12]\[C:13]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])=[O:23])(=[O:34])=[O:33]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 28A (300 mg, 0.85 mmol) in CH2Cl2 (10 mL) containing triethylamine (257 mg, 2.54 mmol) was treated with methanesulfonyl chloride (145 mg, 1.27 mmol) at 0° C. The mixture was stirred for 30 min at 0° C., diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:24])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:24][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][CH2:21]1
Reactant: COC1CCN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CCN(CCOc2ccc(NC(=O)c3cccc(F)c3)cc2-c2c(Br)cnn2C)CC1
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy)benzenamine (0.024 g, 0.060 mmol) in CH2Cl2 (0.9 mL) was added 3-fluorobenzoyl chloride (0.0086 mL, 0.0714 mmol) and triethylamine (0.011 mL, 0.077 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.027 g, 56%). LCMS m/z (%)=531 (M+H79Br, 94), 533 (M+H81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.42 (s, 1H), 7.95 (dd, J=2.1, 8.5 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.79-7.75 (m, 1H), 7.74-7.72 (m, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.63-7.57 (m, 1H), 7.45 (dt, J=2.6, 8.3 Hz, 1H), 7.29 (dd, J=3.7, 9.1 Hz, 1H), 4.47-4.38 (m, 1H), 4.35-4.28 (m, 1H), 3.69 (s, 3H), 3.27 (s, 3H), 3.53-1.37 (m, 11H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][NH2:11].[C:12]([N:16]1[C:20](=[O:21])[C:19](Cl)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:17]1(=[O:30])=[O:29])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:11][CH2:10][CH2:9][CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:17]1(=[O:29])=[O:30])([CH3:15])([CH3:13])[CH3:14]
Reactant: NCCCOc1ccccn1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccccn2)=C(c2ccccc2)S1(=O)=O
Yield: 65 %

Procedure:
The title compound was prepared as described for Example 24 from 1 equivalent of [3-(pyridin-2-yloxy)propyl]amine, 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1 equivalent TEA with a reaction time of 30 mins. The residue was purified by silica gel column chromatography (Horizons Biotage) using 5:1 petroleum ether 40-60° C. in EtOAc as eluent to give the title compound (0.178 g, 65%) as a solid. 1H NMR (500 MHz CDCl3): δ 8.17 (dd, 1H), 7.62-7.57 (m, 1H), 7.54-7.48 (m, 2H), 7.45-7.40 (m, 3H), 6.91-6.88 (m, 1H), 6.74 (d, 1H), 6.00 (t, 1H), 4.28 (t, 2H), 3.04 (q, 2H), 1.83 (quintet, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 163.8, 159.9, 147.0, 138.9, 135.5, 131.8, 129.7, 128.8, 125.4, 117.3, 111.5, 106.9, 63.6, 61.6, 42.0, 28.9, 27.9; Mass Spectrum: M+H+ 416.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19](O)=[O:20].[NH2:22][CH:23]1[CH2:32][CH2:31][CH2:30][C:29]2[N:28]=[C:27]([CH2:33][CH2:34]O)[N:26]=[CH:25][C:24]1=2.[CH:36]1[CH:37]=[CH:38]C2N(O)N=[N:42][C:40]=2[CH:41]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19]([NH:22][CH:23]1[CH2:32][CH2:31][CH2:30][C:29]2[N:28]=[C:27]([CH2:33][CH2:34][N:42]3[CH2:38][CH2:37][CH2:36][CH2:41][CH2:40]3)[N:26]=[CH:25][C:24]1=2)=[O:20]
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)O)cc1
Reactant: On1nnc2ccccc21
Reactant: NC1CCCc2nc(CCO)ncc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)NC2CCCc3nc(CCN4CCCCC4)ncc32)cc1

Procedure:
A solution of (R)-2-(3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetic acid (1.55 g, 5.0 mmol), crude 2-(5-amino-5,6,7,8-tetrahydroquinazolin-2-yl)ethanol (966 mg, 5.0 mmol), HOBT (676 mg, 5.0 mmol) and EDCI (959 mg, 5.0 mmol) in 2.5 mL of DMF was stirred overnight at room temperature. After quenching with sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vacuo. Flash chomatography (SiO2, EtOAc/MeOH=100:15 to 100:20 to 100:25 to 100:30) gave the desired product as a white solid. MS: 486.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[S:32]1[CH:36]=[CH:35][C:34]2[CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=[CH:40][C:33]1=2>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:32]1[CH:36]=[CH:35][C:34]2[CH:37]=[C:38]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)[CH:39]=[CH:40][C:33]1=2
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC1(C)OB(c2ccc3sccc3c2)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2sccc2c1
Yield: 45.1 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 2-(benzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.131 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.047 g (42%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][C:10]2[C:15]3[S:16][C:17]([C:19]([OH:21])=O)=[CH:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:2]=1.[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(NC(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:29]([C:27]1[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]([O:38][CH3:39])=[C:23]([NH:22][C:19]([C:17]2[S:16][C:15]3[C:10]([NH:9][C:7](=[O:8])[C:3]4[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=4)=[CH:11][CH:12]=[CH:13][C:14]=3[CH:18]=2)=[O:21])[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(Nc1cccc2cc(C(=O)O)sc12)c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4cccnc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
The above carboxylic acid (100 mg, 0.335 mmol) and N-(3-amino-5-tert-butyl-2-methoxyphenyl)-methanesulfonamide (91 mg, 0.335 mmol) were dissolved in 2 mL DMF and stirred at room temperature. After about 10 min, HATU (127 mg, 0.335 mmol) and HOBt (45 mg, 0.335 mmol) were added followed by diisopropylamine (87 mg, 0.670 mmol, 120 uL) and the solution was stirred at room temperature. After stirring for eight days, the entire reaction was partitioned between EtOAc (75 mL) and water (50 mL). The layers were separated and the organic portion was washed with water (2×25 mL), brine (25 mL), dried (MgSO4), filtered and the solvent was removed to afford a tan solid. Column chromatography (EtOAc, silica gel) afforded the title compound as a colorless solid (105 mg, 57%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[CH:23]([N:24]2[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]2)[C:22]2=[CH:31][CH:19]([O:20][C:21]2=[O:32])[CH:18]2[CH:14]([O:15][C:16](=[O:34])[CH:17]2[CH3:33])[CH2:13][C:12]2(C)[CH:10]1[O:11]2.O>N1C=CC=CC=1>[C:5]([O:4][CH:1]1[CH:23]([N:24]2[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]2)[C:22]2=[CH:31][CH:19]([O:20][C:21]2=[O:32])[CH:18]2[CH:14]([O:15][C:16](=[O:34])[CH:17]2[CH3:33])[CH2:13][C:12]2([CH3:10])[CH:2]1[O:11]2)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCN(C2C3=CC(OC3=O)C3C(CC4(C)OC4C2O)OC(=O)C3C)CC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(CC3(C)OC13)OC(=O)C2C
Reaction time: 20 h
Yield: 36.9 %

Procedure:
Acetic anhydride (150 μmol; 15 μl) is added to a solution of the compound of Example 9 (100 μmol; 40 mg) in pyridine (0.5 ml). The solution obtained is stirred for 20 hours then the reaction mass is poured into water. The aqueous phase is extracted twice with ethyl acetate and the organic phase obtained is washed with water then with a solution of sodium chloride. The organic phase is dried over magnesium sulphate, filtered then evaporated. The residue is eluted on silica with a mixture of isopropyl acetate and dichloromethane (20/80). 16 mg of product is obtained in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28]Cl)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)=[CH:24][CH:23]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 51.1 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamyl chloride were reacted to yield the title compound as a pale yellow crystalline powder (yield: 51.1%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].CC#N>C(Cl)Cl.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:11]1[N:16]=[C:15]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Cc1ccc(B(O)O)s1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(Cl)n2)s1
Temperature: 25 °C

Procedure:
A solution of 0.20 g (1.4 mmol) of 5-methyl-2-thiopheneboronic acid, 0.21 g (1.4 mmol) of 2,4-dichloropyrimidine and 49 mg (0.070 mmol) of bis(triphenylphosphine)palladium(II) chloride in 2 mL of a 2 M Na2CO3 aqueous solution and 5 mL of MeCN was heated in a microwave for 10 min at 160° C., then cooled to rt, diluted with CH2Cl2 and MeOH, and dried over MgSO4. The organic solvent was removed in vacuo, and the resulting solid was purified by flash chromatography eluting with a linear gradient of 50% EtOAc in hexane to neat EtOAc to deliver the title compound. MS (M+H)+ 211.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Li]C(C)(C)C.[Si:14]([O:21][CH2:22][C@@H:23]([N:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][N:41]=[C:40](S(C)(=O)=O)[N:39]=2)=[CH:34][C:33]1=[O:48])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1COCC1>[Si:14]([O:21][CH2:22][C@@H:23]([N:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:39]=2)=[CH:34][C:33]1=[O:48])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: Cc1cc(N)ccn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nccc(-c3ccn([C@H](CO[Si](C)(C)C(C)(C)C)c4ccc(Cl)c(F)c4)c(=O)c3)n2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
2-Methylpyridin-4-amine (0.28 g, 2.6 mmol) was placed in THF (5 mL) and cooled to −78° C. t-BuLi (1.5 mL, 2.6 mmol) was added dropwise, and the solution was warmed to 0° C. for 30 minutes. This solution was then added dropwise to a −78° C. THF solution (5 mL) of (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.070 g, 0.13 mmol). The reaction was stirred for an additional 30 minutes at −78° C., then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:10-500:20 DCM/MeOH) to give the product (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.028 g, 38% yield).
Reaction SMILES: OCC1C=CC(C)=CN=1.C([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][N:16]=1)(=O)C>>[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][N:16]=1
Reactant: CCc1ccc(COC(C)=O)nc1
Agent: Cc1ccc(CO)nc1
Product: CCc1ccc(CO)nc1
Yield: 84.8 %

Procedure:
This synthesis was performed analogously to the synthesis reported for 2-hydroxymethyl-5-methyl pyridine. Starting from 2-acetoxymethyl-5-ethyl pyridine (40 g, 223 mmol), pure 2-hydroxymethyl-5-ethyl pyridine (26.02 g, 189 mmol, 85%) was obtained as a slightly yellow oil.