Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10](F)=[O:11])[C:6]=1[C:13]([F:16])([F:15])[F:14])[CH:2]([CH3:4])[CH3:3].O[N:18]=[C:19]([C:21]1[CH:38]=[CH:37][C:24]([CH2:25][N:26]2[CH2:29][CH:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]2)=[CH:23][CH:22]=1)[NH2:20].CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[O:11][N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:26]4[CH2:27][CH:28]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:29]4)=[CH:37][CH:38]=3)[N:18]=2)[C:6]=1[C:13]([F:16])([F:15])[F:14])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Reactant: CC(C)Cc1onc(C(=O)F)c1C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Cc1onc(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
A mixture of 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (0.130 g, 0.544 mmol), tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 0.166 g, 0.544 mmol), and Hunig's Base (0.123 mL, 0.707 mmol) in acetonitrile (2 mL) was stirred at room temperature for 2 days. By HPLC, there was ˜7% of the uncyclized intermediate remaining The reaction mixture was gently heated with a heat gun for ˜15 min., resulting in further cyclization. The homogenous mixture was diluted with dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 1% mixture of methanol in dichloromethane afforded tert-butyl 1-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (0.219 g, 0.432 mmol, 80% yield) as a clear, viscous yellow oil. The product had an HPLC ret. time=3.03 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=507.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CCN(CC)S(=O)(=O)c1ccccc1Br
Product: CCN(CC)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N,N-diethylbenzenesulfonamide. MS (ESI): mass calcd. for C20H21FN4O2S, 400.14; m/z found, 401.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.29 (d, J=1.4, 1H), 8.08-8.04 (m, 1H), 8.0-7.94 (m, 1H), 7.70-7.64 (m, 1H), 7.61-7.55 (m, 1H), 7.41-7.36 (m, 1H), 7.32-7.25 (m, 2H), 2.96 (q, J=7.1, 4H), 1.00 (t, J=7.1, 6H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][O:11][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO[Si](C)(C)C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.9 %

Procedure:
To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (3.14 g, 8.78 mmol) (Example 1, Step H) in methylene chloride (45 mL) were added imidazole (0.9 g, 13.17 mmol, 1.5 eq) and t-butyl-dimethylsilyl chloride (2.0 g, 13.17 mmol, 1.5 eq). A white precipitate began to form immediately. The mixture was stirred for 14 h at 25° C. and was then diluted with methylene chloride (100 mL) and washed sequentially with 10% hydrochloric add (20 mL), saturated aqueous sodium bicarbonate (20 mL), and brine (20 mL). The organic layer was concentrated under reduced pressure and the resultant residue was recrystallized from methanol to provide the product (3.27 g, 79%) as a white fluffy crystalline solid. 1H NMR (300 MHz, CDCl3): δ −0.10 (s, 6 H), 0.79 (t, J=6.9 Hz, 3 H), 0.83 (s, 9 H), 1.07-1.20 (m, 4 H), 1.29-1.32 (m, 14 H), 2.23-2.30 (m, 2 H), 3.21 (sept, J=6.6 Hz, 1 H), 3.35 (sept, J=6.6 Hz, 1 H), 4.24 (s, 2 H), 7.05-7.18 (m, 4 H). Anal. calc. for C29H46NOFSi: C, 73.83; H, 9.83; N, 2.97. Found: C, 73.82; H, 9.95; N, 2.86.
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][N:10]([CH3:37])[C:11]([C:13]1[N:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)[C:23](O)=[O:24])=[N:17][CH:18]=1)=[O:12].[CH3:38][C:39]1[N:43]=[C:42]([NH2:44])[S:41][N:40]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:37][N:10]([CH3:9])[C:11]([C:13]1[CH:18]=[N:17][C:16]([O:19][C:20]2[CH:21]=[C:22]([C:23](=[O:24])[NH:44][C:42]3[S:41][N:40]=[C:39]([CH3:38])[N:43]=3)[CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)=[CH:15][N:14]=1)=[O:12]
Reactant: CN(C)C(=O)c1cnc(Oc2cc(O[C@H]3CCN(C)C3=O)cc(C(=O)O)c2)cn1
Reactant: Cc1nsc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nsc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)cn3)cc(O[C@H]3CCN(C)C3=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.142 mL, 1.07 mmol) was added to a solution of 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 45) (358 mg, 0.9 mmol) in DCM (7 mL) and stirred at ambient temperature for 30 minutes. 3-Methyl-1,2,4-thiadiazol-5-amine (CAS no. 17467-35-5) (206 mg, 1.8 mmol) and pyridine (0.147 mL, 1.8 mmol) were added and the reaction stirred for 20 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and DCM (15 mL), washed with water (10 mL) and filtered to give a solid which was washed with water and dried. The filtrate was washed with citric acid (1N, 10 mL), water (10 mL), saturated sodium bicarbonate solution (10 mL), brine (10 mL), dried (MgSO4) and evaporated. The residue was combined with the solid isolated from the filtration and purified by flash chromatography on silica eluting with a gradient of 0-3% methanol in DCM to afford the product (322 mg, 72%). 1H NMR δ (300 MHz, CDCl3) 1.93-2.06 (m, 1H), 2.45 (s, 3H), 2.55-2.66 (m, 1H), 2.80 (s, 3H), 3.03 (s, 6H), 3.19-3.53 (m, 2H), 5.14 (t, 1H), 7.30 (s, 1H), 7.63 (s, 1H), 7.72 (s, 1H), 8.43 (s, 1H), 8.58 (s, 1H), 11.9-12.8 (br s, 1H); m/z 498 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]CCCC.[CH2:15]([N:17]([CH2:32][CH3:33])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[C:21]1=[O:22])[CH3:16].[NH4+].[Cl-]>C1COCC1>[CH2:32]([N:17]([CH2:15][CH3:16])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23]([OH:24])([C:5]2[S:1][C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[C:21]1=[O:22])[CH3:33]
Reactant: c1ccc2sccc2c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2cc3ccccc3s2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To benzo[b]thiophene (86.8 mg, 2.1 eq) in anhydrous THF (2 mL) at −40° C. (bath temperature) was added n-BuLi (0.423 mL, 1.53 M in hexanes, 2.1 eq). The resulting colourless solution was stirred for 30 minutes, after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added. Stirring was continued at −40° C. for 9 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration, the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1%-2% MeOH in CHCl3) to give the title compound as a yellow oil (43.0 mg, 30%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:35]([O:42][CH2:43][C:44](Cl)=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.CCOC(C)=O.O>[CH2:1]([CH:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:44](=[O:45])[CH2:43][O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(=O)COCc3ccccc3)C(Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (73 mg, 0.2 mmol) in THF (1.5 mL) at room temperature was treated with triethylamine (42 μL, 0.3 mmol) followed by benzyloxyacetyl chloride (19 μL, 0.2 mmol). The reaction mixture was stirred for 2 h then diluted with EtOAc (2 mL) and water (2 mL). The organic phase was isolated and further washed with an additional portion of a water (2 mL) followed by a brine solution (2 mL). The organic component was dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 20% then 40% EtOAc/hexane as eluant to afford intermediate 1-[2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-benzyloxy-ethanone as an oil (69 mg, 67%). LC/MS 7.64 min, [M+1]+ 515.
Reaction SMILES: FC1C=NC(N2CC(C(OC(C)(C)C)=O)N(C)C2=O)=NC=1.[CH3:22][N:23]1[CH:27]([C:28]([O:30]C(C)(C)C)=[O:29])[CH2:26][N:25]([C:35]2[N:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][N:36]=2)[C:24]1=[O:43].FC(F)(F)C(O)=O>ClCCl>[CH3:22][N:23]1[CH:27]([C:28]([OH:30])=[O:29])[CH2:26][N:25]([C:35]2[N:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][N:36]=2)[C:24]1=[O:43]
Reactant: COc1ccnc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)n1
Agent: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccnc(N2CC(C(=O)O)N(C)C2=O)n1
Yield: 92.6 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (500 mg, 2.497 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloro-4-(methyloxy)pyrimidine (361 mg, 2.497 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1220 mg, 3.75 mmol), Xantphos™ (108 mg, 0.187 mmol) and tris(dibenzylideneacetone)dipalladium(0) (57.2 mg, 0.062 mmol) and the mixture was heated at reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (×2, 20 ml). The organic layers were combined, washed with water (20 ml) and brine (20 ml), dried over magnesium sulphate and then evaporated in vacuo. The residue was purified by flash-silica gel chromatography eluting with 0-10% methanol in dichloromethane. The fractions containing product were combined and solvent evaporated in vacuo to give a yellow oil. The residue was purified again by flash-silica gel chromatography, eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylate as a yellow oil (100 mg, 13% yield). LC/MS [M+H]+309. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylate (100 mg, 0.324 mmol) in dichloromethane (0.6 ml)/trifluoroacetic acid (0.300 ml) was stirred at room temperature for 24 hours. The solution was evaporated and the residue was co-evaporated with toluene (×3) and then dichloromethane (×4). The product was then dried in a vacuum oven (50° C.) to give crude 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylic acid as a yellow gum (95 mg, ˜0.3 mmol) which was used in the next reaction. LC/MS [M+H]+253.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:32])[C:9]([N:11]([C:20]2[C:25]([Cl:26])=[C:24]([O:27][CH3:28])[CH:23]=[C:22]([O:29][CH3:30])[C:21]=2[Cl:31])[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH:3]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]2)=[CH:36][C:35]=1[N+:53]([O-:55])=[O:54].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>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:31][C:21]1[C:22]([O:29][CH3:30])=[CH:23][C:24]([O:27][CH3:28])=[C:25]([Cl:26])[C:20]=1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])[C:9](=[O:10])[N:8]([C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:47])[CH2:44][CH2:45]3)=[CH:36][C:35]=2[N+:53]([O-:55])=[O:54])[CH:3]=1)[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c([N+](=O)[O-])c2)CC1
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Cl)ncn2)c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 100 °C
Yield: 45.3 %

Procedure:
1-(6-chloropyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)urea (175 g, 0.34 mmol), tert-butyl 4-(4-amino-3-nitrophenyl)piperazine-1-carboxylate (90 g, 0.28 mmol), Pd2(dba)3 (13 g, 0.014 mmol), Brettphos (13 g, 0.028 mmol) and sodium tert-butoxide (54 g, 0.56 mmol) were placed in a reaction vial (2 to 5 ml) and purged with nitrogen. Toluene (1.0 ml) was added and nitrogen was bubbled for 5 min then the reaction mixture was heated at 100° C. overnight. Heating was stopped and cooled to room temperature. The reaction mixture was filtered through pad of Celite®. The filtrate was evaporated and resulting material was purified by flash chromatography on silica eluting with 20% to 70% EtOAc/Hexane to afford the title compound (102.4 mg, yield: 45%). 1H-NMR (400 MHz, CDCl3) δ 0.01 (s, 9H) 0.85-0.98 (m, 2H) 1.50 (s, 9H) 3.03 (s, 3H) 3.17 (br. s., 4H) 3.56-3.66 (m, 4H) 3.75-3.97 (m, 8H) 5.22 (s, 2H) 6.50 (s, 1H) 6.95 (s, 1H) 7.65 (s, 1H) 8.46 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Fc1ccc(-c2cnc(Cl)nc2)cc1

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (500 mg, 2 mmol), 4-fluorophenylboronic acid (430 mg, 3.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (210 mg, 0.26 mmol) and potassium carbonate (1.8 g, 13 mmol) in 1,4-dioxane (6 mL) was irradiated under microwave at 120° C. for 30 min. After cooling, the solvent was evaporated. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes to give the desired product. (376 mg) LCMS: (M+H)=209.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[CH3:14]>C(O)C.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]([CH3:14])=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH:10]=1
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1cc(N)ccc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2-Methyl-5-nitrophenyl)acetic acid methyl ester 14 (32 g, 153 mmol) is dissolved in ethanol (750 mL). To this solution is added 10% palladium on carbon (3.2 g). After purging the reaction flask of oxygen, a balloon filled with hydrogen is fitted. The reaction is stirred at rt for 16 h. After removing the catalyst by filtering through a celite plug and removing the solvent in vacuo, the crude product is purified using flash chromatography (ethyl acetate:petroleum ether=5:1). The product 7 is isolated as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.9 (d, J=7.8 Hz), 6.59 (m, 1H), 6.56 (m, 1H), 3.69 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][Cl:12].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+].O>C(O)(=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:16][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: ClCCCc1ccccc1CCl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCc1ccccc1CCCCl

Procedure:
70 g (345 mmols) of 3-(2-Chloromethylphenyl)-propyl chloride (JACS 75, 2053 (1953) and 50 g (0.61 mmol) of sodium acetate were heated to the boiling point while stirring in 250 ml of glacial acetic acid. It resulted from the thin layer chromatography that the reaction was finished after 41/2 hours. After cooling about 700 ml of water were added and the product was extracted with benzene. The organic phase was washed with water, dried and distilled off after evaporation of the solvent. Boiling point0.1 : 101° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].CS(C)=O.[OH:17][C:18]1[CH:23]=[C:22]([Cl:24])[N:21]=[N:20][C:19]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1CCCCC1.O>[Cl:24][C:22]1[N:21]=[N:20][C:19]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:18]([OH:17])[CH:23]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1[O-]
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCCCC1
Solvent: O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a mixture of 29.8 g (purity: 93.6%; 163 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 5 g of dimethyl sulfoxide was added 10.0 g (purity: 90%; 54.6 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 28 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 300 g of pure water and 200 g of cyclohexane were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 13.3 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 87.9%) and 60.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][SH:28]>>[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][S:28][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)CCS
Product: COC(=O)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 3-mercaptopropionic acid methyl ester.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)=[CH:8]2)(=[O:4])=[O:3].CN(C)C=O.[H-].[Na+].[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(OCC)(=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=3)[CH:8]=[C:9]2[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3nccs3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1nccs1)n2S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
To a mixture of 5-methanesulfonyl-2-(thiazol-2-yl)indole (50 mg) and N,N-dimethylformamide (1.8 ml), 60% sodium hydride (10 mg) was added at 0° C. and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 4-fluorobenzenesulfonyl chloride (52 mg) at 0° C. and the mixture was stirred at 15 to 30° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution successively, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 77 mg of the desired product in a white amorphous form.
Reaction SMILES: [ClH:1].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C@H:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH2:13])=[CH:3]1.[C:25]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(C)C>[ClH:1].[C:19]1([C:17]2[N:18]=[C:14]([C@H:12]3[CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[NH:2][C:3]=4[C:36]4([CH2:37][CH2:38][N:33]([C:25](=[O:32])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:34][CH2:35]4)[NH:13]3)[NH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Agent: Cl
Solvent: CC(C)O
Product: O=C(c1ccccc1)N1CCC2(CC1)N[C@@H](c1nc(-c3ccccc3)c[nH]1)Cc1c2[nH]c2ccccc12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine hydrochloride (1 g, 2.65 mmol) in isopropanol (15 ml) was added N-benzoyl-4-piperidone (2.64 g, 13 mmol). The solution was refluxed for about one hour and cooled to about 20° C. The solvent was removed under reduced pressure. The residue was treated with dichloromethane (30 ml) and stirred for about 30 min at about 20° C. The resulting precipitate was collected by filtration, washed with dichloromethane and diethyl ether, and dried to afford 1.2 g of the title product as the hydrochloride salt. Melting point: 240-244° C.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:25]=[CH:24][C:14]([CH2:15][C:16]3([CH:22]=[O:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[S:6]1(=[O:27])=[O:26])(C)(C)C.FC(F)(F)C(O)=O>>[O:27]=[S:6]1(=[O:26])[CH:7]([C:11]2[CH:25]=[CH:24][C:14]([CH2:15][C:16]3([CH:22]=[O:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[CH2:8][C:9](=[O:10])[NH:5]1
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CC3(C=O)CCC(=O)N3)cc2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: O=CC1(Cc2ccc(C3CC(=O)NS3(=O)=O)cc2)CCC(=O)N1
Temperature: 130 °C

Procedure:
2-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)benzyl]-5-oxopyrrolidine-2-carbaldehyde (4.5 mg, 0.011 mmol) was stirred in trifluoroacetic acid (1 mL, 10 mmol) in a small microwave tube and heated to 130° C. for 60 seconds. The mixture was evaporated and used directly. LCMS found for C15H17N2O5S (M+H)+: m/z=337.