Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[S:15][CH2:14][CH2:13][S:12]1.[H-].[Na+].Br[CH2:19][C:20]([NH2:22])=[O:21].O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]([NH2:22])=[O:21])[C:6](=[O:11])[C:5]12[S:12][CH2:13][CH2:14][S:15]1
Reactant: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2CC(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Compound 6 (8 g, 33.7 mmol) was dissolved in dry DMF (80 ml) under a nitrogen atmosphere. The solution was cooled at 0° C. and NaH (1.62 g, 37.13 mmol, 60% dispersion) was carefully added portionwise. When the nitrogen evolution ceased, bromoacetamide (5.6 g, 37.13 mmol) was added. After 30 minutes, the mixture was poured into cold water and the solid filtered off, washed with water and hexane. The crude material was directly crystallized in acetonitrile affording 2-[5′-methyl-2′-oxospiro[1,3-dithiolane-2,3′-indol]-1′(2′H)-yl]acetamide 15 as a white solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[C:13]3[CH:14]=[C:15]([CH3:17])[O:16][C:12]=3[CH:11]=[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:33])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:33][CH2:17][C:15]1[O:16][C:12]2[CH:11]=[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([CH:2]([F:1])[F:25])=[CH:24][CH:23]=3)[C:13]=2[CH:14]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C)oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(CBr)oc2c1
Yield: 50.5 %

Procedure:
To a solution of ethyl 4-[4-(difluoromethyl)phenoxy]-2-methyl-1-benzofuran-6-carboxylate (710 mg, 2.05 mmol) and NBS (438 mg, 2.46 mmol) in CHCl3 (25 mL) was added benzoyl peroxide (49.7 mg, 0.205 mmol). The mixture was refluxed for 14 hours. The solvent was evaporated, and the product was purified via gradient silica gel chromatography using hexanes/EtOAc (100/0 to 70/30) to give the title compound (440 mg, 51%) as a light-yellow solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 4.38 (q, J=7.16 Hz, 2 H) 4.53 (s, 2 H) 6.39-6.89 (m, 2 H) 7.07 (d, J=8.48 Hz, 2 H) 7.49 (d, J=8.48 Hz, 2 H) 7.54 (d, J=0.94 Hz, 1 H) 8.01 (s, 1 H).
Reaction SMILES: O[C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1nn(C)c(=O)c(C)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nn(C)c(=O)c(C)c1Cl
Temperature: 85 °C
Yield: 86 %

Procedure:
A mixture of ethyl 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (1.85 g, 8.72 mmol) and POCl3 (9 mL) was heated for 16 hours at 85° C. POCl3 was removed under reduced pressure. Then the crude material was quenched with ice-water. The mixture was neutralized with saturated aqueous NaHCO3 (pH˜6 to 7) and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 5 to 10 to 20% EtOAc in hexanes) to afford 1.72 g (86%) of the desired product.
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.[CH2:77]([O:79][C:80](=[O:89])[CH2:81][C:82]1[CH:87]=[CH:86][C:85]([NH2:88])=[CH:84][CH:83]=1)[CH3:78].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:77]([O:79][C:80](=[O:89])[CH2:81][C:82]1[CH:83]=[CH:84][C:85]([NH:88][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:86][CH:87]=1)[CH3:78]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Product: CCOC(=O)Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Yield: 82 %

Procedure:
This compound was synthesized in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 20, intermediate c), (4-amino-phenyl)-acetic acid ethyl ester and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate to give the desired compound as a yellow foam (82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:11][N:10]=2)=[CH:5][CH:4]=1.[C:18](OC)(OC)([O:22][CH3:23])[CH2:19][CH2:20][CH3:21]>>[CH3:23][O:22][C:18](=[N:17][S:14]([C:12]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:13]=1)(=[O:16])=[O:15])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(OC)(OC)OC
Reactant: COc1ccc(-c2nsc(S(N)(=O)=O)n2)cc1
Product: CCCC(=NS(=O)(=O)c1nc(-c2ccc(OC)cc2)ns1)OC
Yield: 93.6 %

Procedure:
A mixture of 1.5 g of 3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-sulfonamide and 4.1 g of trimethyl orthobutyrate was warmed at reflux for 0.5 hour. The mixture was cooled and triturated with hexane (3×) to give 1.84 g of solid. Recrystallization from cyclohexane/benzene (6:1) gave 1.63 g of fluffy solid. This was combined with 0.7 g sample from another identical small scale reaction. This combined material (2.33 g) had m.p. 159°-161°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:13][NH:14][CH:15]=2)C=CC=CC=1.BrCCC=C.N1C=CC=C(C2C(O)=CN(COCC[Si](C)(C)C)N=2)C=1>C(OCC)C>[CH2:9]([O:10][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][NH:14][CH:15]=1)[CH2:8][CH:7]=[CH2:1]
Reactant: c1ccc(CCCOc2c[nH]nc2-c2cccnc2)cc1
Agent: C=CCCBr
Agent: C[Si](C)(C)CCOCn1cc(O)c(-c2cccnc2)n1
Solvent: CCOCC
Product: C=CCCOc1c[nH]nc1-c1cccnc1
Yield: 43 %

Procedure:
Compound 32D was prepared following the procedure as described for the synthesis of compound 32A (see Scheme 5) using 4-bromo-but-1-ene as the alkyl halogenide and 3-pyridin-3-yl-1-(2-trimethylsilanyl-1-ethoxymethyl)-1H-pyrazol-4-ol (30). Work-up and flash chromatography (diethyl ether) afforded compound 31 D. Yield 43% (oil, TLC diethyl ether Rf 0.37), which was subsequently deprotected (TBAF/THF) to afford 3-(4-but-3-enyloxy-1H-pyrazol-3-yl)-pyridine (32D).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:18][C:16]([F:17])([F:19])[C:13]1[N:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(C(F)(F)F)nc2)cc1

Procedure:
Procedure G′: 4-(6-Trifluoromethyl-pyridin-3-yl)-benzoic acid methyl ester (0.57 g, 2 mmol) is dissolved in tetrahydrofuran/water (9:1)(25 ml), lithium hydroxide monohydrate (0.9 g, 2.2 mmol) is added and the mixture is heated under reflux overnight. The mixture is concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is acidified and the resulting precipitate is collected by filtration to give the 4-(6-trifluoromethyl-pyridin-3-yl)-benzoic acid. MS (FIA)267 (MH−)
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C)C=O>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([O:8][CH2:25][CH2:24][O:23][CH3:22])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 11) (305 mg) was dissolved in dimethylformamide (2 ml), potassium carbonate (622 mg) and 2-bromoethyl methyl ether (208 mg) were added. The reaction was stirred at room temperature for 1.5 hours and then at 50° C. for 12 hours. The solvent was removed under reduced pressure. The crude product was purified on silica (10 g) eluted with a solvent gradient of pentane:ethyl acetate (1:0 to 0:1) to yield the title compound as a white solid (201 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH:13]=[CH:12]1.[H-].[Na+].CN(C=O)C>O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=3[CH:13]=[CH:12]2)=[CH:4][CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: N#Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ccc3c(C#N)cccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (30.3 g, 193 mmol) was added to a slurry of 1H-indole-4-carbonitrile (25.0 g, 176 mmol) and NaH (7.74 g, 193 mmol) in DMF (586 mL, 176 mmol) at 0° C., and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated to afford a crude residue, which was purified by column chromatography eluting with an ethyl acetate/hexanes gradient to give 1-(4-methoxybenzyl)-1H-indole-4-carbonitrile (46.0 g, 175 mmol, 99%). 1H NMR (400 MHz, CDCl3) 7.89 (d, J=8.2 Hz, 1H), 7.81 (d, J=3.1 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 6.64 (d, J=2.7 Hz, 1H), 5.44 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[N:34]=[C:35]([CH2:38][CH3:39])[O:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[O:36][CH:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[N:34]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCc1nc(CCl)co1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)co1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (590 mg; compound B50) is reacted with 4-(chloromethyl)-2-ethyl-1,3-oxazole (200 mg; compound D15) in the presence of potassium carbonate (190 mg) in DMF (15 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/2 (v/v)] as a solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1.O>[CH2:31]([O:30][C:28]([N:16]1[CH2:17][CH2:18][N:13]([C:11]([N:9]2[CH2:8][CH:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:10]2)=[O:12])[CH2:14][CH2:15]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: O=C(N1CCNCC1)N1CC(Oc2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)N2CC(Oc3ccc(F)cc3)C2)CC1
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 1-[3-(4-fluorophenoxy)-1-azetidinylcarbonyl]piperazine and 1.4 g (0.01 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.01 mole) of ethyl chloroformate. After stirring for 15 minutes, a small piece of ice was added and stirring continued for 72 hr. The reaction mixture was diluted with water and the oil which separated solidified on standing. The solid residue was purified by column chromatography (silica gel; washed with chloroform and eluted with ethyl acetate) to give the product 2.5 g (71%) which was recrystallized from benzene/ligroin to yield 2.35 g (66.7%) of white crystalline product, m.p. 89°-90° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[N:21][CH:22]=1>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.C1(C)C=CC=CC=1>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:21][CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: COC(=O)c1cc(Br)cc(S(C)(=O)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A mixture of methyl 3-bromo-5-(methylsulfonyl)benzoate (1.0 g, 3.4 mmol), 5-methyl-2-(tributylstannyl)pyridine (1.2 mL, 3.5 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol), and toluene (10 mL) under argon was subjected to microwave irradiation at 120° C. for 2 hours. The mixture was cooled to room temperature. The precipitate was collected by filtration and rinsed with hexane to afford the title compound as a light brown solid (432 mg). The filtrate was concentrated and the residue was purified via flash chromatography to afford another crop of the product as a light yellow solid (200 mg). 1H NMR (400 MHz, CDCl3): 8.91 (t, J=1.4 Hz, 1H), 8.80 (d, J=1.7 Hz, 1H), 8.61 (s, 1H), 8.58 (d, J=0.8 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 4.00 (s, 3H), 3.15 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Yield: 85 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5.83 g, 15 mmol), 4-fluorophenylboronic acid (3 g, 22 mmol), PdCl2(PPh3)2 (1 g, 1.4 mmol), and aqueous Cs2CO3 solution (2 M, 8.0 mL) in 1,4-dioxane (50 mL) was heated to reflux for 2 h. The mixture was filtered, and the filtrate was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5.3 g, 88%).
Reaction SMILES: C(O)C.[OH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.Cl[C:26]1[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[CH:27]=1>C(N(CC)CC)C>[CH3:32][N:31]1[C:26]([N:7]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][OH:4])=[CH:27][C:28](=[O:35])[N:29]([CH3:34])[C:30]1=[O:33]
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCNCCO)CC2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(N(CCO)CCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O

Procedure:
To 10 ml of ethanol were added 1.0 g of the thus obtained compound 75, 0.52 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione and 2 ml of triethylamine as starting materials, and the resulting mixture was treated in the same procedure as in Example 39-(2) to obtain 0.73 g of 1,3-dimethyl-6-{N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)piperazin-1-yl]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:23]=[CH:22][C:15]3[N:16]=[C:17](S(C)=O)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].Cl.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[OH:32].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[OH:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]1[NH:25][C:17]1[S:18][C:14]2[CH:13]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=3)[CH:23]=[CH:22][C:15]=2[N:16]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCC[C@@H]4O)sc3c2)ccn1
Temperature: 110 °C

Procedure:
To the solution of 4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (70 mg, 0.202 mmol, 1.0 eq) in DMA (600 μL), was added (1S,2S)-2-aminocyclohexanol hydrochloride (92 mg, 0.606 mmol, 3.0 eq) followed by diisopropylethylamine (0.21 mL, 1.21 mmol). The reaction was heated at 110° C. for 24-hours. The neat reaction mixture was purified on reverse phase preparatory HPLC. Pure fractions were lyophilized as TFA salts. M+H=398
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>ClCCl>[CH3:43][O:44][CH2:45][C:46]([NH:23][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22])=[O:47]
Reactant: COCC(=O)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
A mixture of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (example 266) (300 mg, 0.639 mmol), N-ethyldiisopropylamine (0.22 ml, 1.278 mmol) and methoxyacetyl chloride (0.067 ml, 0.639 mmol) in dichloromethane (3 ml) was stirred at 23° C. for 16 h. Diluted with dichloromethane, washed with water, dried the organic layer over MgSO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc, followed by trituration with diethyl ether to give the title compound (46 mg, 13%) as a white solid. MS (ISP) 542.7 [(M+H)+]; mp 188° C.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[OH2:28].[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:32][CH2:31]2)=[CH:16][CH:17]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:32][CH2:31]2)=[CH:16][CH:17]=1
Reactant: Oc1ccc2c(c1)nc(CC1CCNCC1)n2Cc1ccc(F)cc1
Reactant: BrCCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Oc1ccc2c(c1)nc(CC1CCN(CCSc3ccccc3)CC1)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A mixture of 6.48 parts of [(2-bromoethyl)thio]benzene, 6.8 parts of 1-[(4-fluorophenyl)methyl]-2-(4-piperidinylmethyl)-1H-benzimidazol-5-ol, 4.2 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred for 2 hours at reflux temperature using a water separator. After cooling to room temperature, the reaction mixture was poured into water. The layers were separated. The organic layer was washed with 500 parts of water, dried, filtered and evaporated. The residue was taken up in a mixture of trichloromethane and methanol (95:5 by volume) and 25 parts of silica gel. After stirring for 15 minutes, the whole was filtered, washed with the eluent and the filtrate was evaporated. The residue was boiled in 160 parts of 2-propanone. The mixture was stirred overnight at room temperature. The product was filtered off, washed with 2-propanone and crystallized from 280 parts of 2-propanone. The product was filtered off, washed with 2-propanone and dried in vacuo at 50° C., yielding 2.7 parts (27.8%) of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(phenylthio)ethyl]-4-piperidinyl]methyl]-1H-benzimidazol-5-ol hemihydrate; mp. 193.8° C. (570).
Reaction SMILES: [Na].[CH3:2][C:3]1[C:4]([C:9](=O)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:5][CH:6]=[CH:7][N:8]=1.Cl[CH:17]([C:22](=[N:24][NH:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:23])[C:18]([O:20][CH3:21])=[O:19].Cl>CO.C1COCC1>[CH3:23][C:22]1[N:24]([NH:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=2)(=[O:27])=[O:28])[C:9]([C:4]2[C:3]([CH3:2])=[N:8][CH:7]=[CH:6][N:5]=2)=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(=O)c1nccnc1C
Reactant: COC(=O)C(Cl)C(C)=NNS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c(-c2nccnc2C)n(NS(=O)(=O)c2ccc(C)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.81 g of sodium was heated with 20 ml of methanol, then a solution of 6.8 g of 31A in 20 ml of methanol was added and the mixture was stirred at room temperature for 1 hour. Then a solution of 11.2 g of 7B in 25 ml of THF was added, and the mixture was stirred at room temperature for 2 hours. The mixture was stripped of volatiles, 100 ml of methanol was added to the residue and hydrogen chloride gas was bubbled through the mixture, which then was heated at reflux for 2 hours. The mixture was cooled, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with methylene chloride. The extract was stripped of volatiles, and the residue was triturated with 10 ml of ether. The solid product was collected and dried (Na2SO4) to give dimethyl 2-methyl-1-(tosylamino)-5-(3-methyl-2-pyrazinyl)pyrrole-3,4-dicarboxylate (31C), as a light yellow solid, m.p.: 177°-178° C.