Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[N:15]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:14]1=[O:37].CN1CCOCC1.Cl[S:46]([CH2:49][C:50]([O:52][CH2:53][CH:54]1[C:66]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:60]2[C:55]1=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:51])(=[O:48])=[O:47]>ClCCl>[CH:56]1[C:55]2[CH:54]([CH2:53][O:52][C:50](=[O:51])[CH2:49][S:46]([NH:12][N:13]3[CH2:17][CH:16]([C:18]4[CH:23]=[CH:22][C:21]([CH:24]5[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:15]([CH2:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[C:14]3=[O:37])(=[O:47])=[O:48])[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]=2[CH:59]=[CH:58][CH:57]=1
Reactant: O=C(CS(=O)(=O)Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C3CC3)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CCN2C(=O)N(NS(=O)(=O)CC(=O)OCC3c4ccccc4-c4ccccc43)CC2c2ccc(C3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-amino-3-[2-(4-methoxyphenyl)ethyl]-4-(4-cyclopropylphenyl)-2-imidazolidinone p-toluenesulfonic acid salt (2.61 g, 0.0050 mol), dichloromethane (12 mL), and N-methylmorpholine (1.53 mL, 0.014 mol) is added a solution of 9H-fluoren-9-ylmethyl chlorosulfonylacetate, 14, (1.76 g, 0.0052 mol) in dichloromethane (7 mL) slowly over 7 minutes at 15° C. to 20° C. The reaction is stirred at ambient temperature for 45 minutes, and then washed twice with 0.1 N HCl and water. The organic phase is dried (sodium sulfate) and concentrated to a foamy solid. The residue is purified over silica (0%-50% ethyl acetate/hexanes gradient) to afford 2.1 g of the desired compound. 1H NMR (CDCl3) δ 7.81 (d, J=7.5 Hz, 2H), 7.69 (d, J=7.5 Hz, 2H), 7.45 (m, 2H), 7.36 (m, 2H), 7.27 (s, 1H), 7.17 (m, 2H), 7.10 (m, 2H), 7.02 (m, 2H), 6.82 (m, 2H), 4.63 (m, 2H), 4.45 (t, J=8.4 Hz, 1H), 4.35 (m, 3H), 3.94 (t, J=8.4 Hz, 1H), 3.78 (s, 3H), 3.65 (m, 1H), 3.38 (t, J=8.1 Hz, 1H), 2.92 (m, 1H), 2.74 (m, 1H), 2.64 (m, 1H), 1.94 (m, 1H), 1.03 (m, 2H), 0.74 (m, 2H). MS 652 (MH+). Anal. calcd. for C37H37N3O6S¾H2O: C, 66.80; H, 5.83; N, 6.32. Found: C, 66.78; H, 5.72; N, 6.30.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C>[Br:15][CH:10]([CH3:11])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:8][CH:7]=1)=[O:12]
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Add p-trifluoromethylpropiophenone (75 g, 360 mmol, 1.0 equiv) to acetic acid (375 mL). Add bromine (18.1 mL, 352 mmol, 0.98 equiv) in acetic acid (375 mL) in a drop-wise fashion over 45 minutes. After completion of the addition, warm the mixture to an internal temperature of 40° C., and stir for 90 minutes. Remove the volatile components under reduced pressure, and dissolve the residue in Et2O (300 mL). Treat with a saturated sodium bicarbonate aqueous solution (4×200 mL) being cautious of vigorous gas evolution. Separate the organic phase, and dry over MgSO4. Remove the solids by filtration; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a colorless oil which solidifies on standing (93 g, 92.0% yield). 1H NMR (400 MHz, d6-DMSO) δ 8.13 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 5.27 (q, J=6.5 Hz, 1H), 1.93 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=2)[C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1.[ClH:35]>>[ClH:35].[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:13]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[C:14]([F:16])([F:17])[F:15])=[CH:10][CH:11]=1
Reactant: COCOc1ccc(C(=C(c2ccccc2)c2ccc(OCCN(C)C)cc2)C(F)(F)F)cc1
Agent: Cl
Product: CN(C)CCOc1ccc(C(=C(c2ccc(O)cc2)C(F)(F)F)c2ccccc2)cc1
Yield: 74 %

Procedure:
0.76 g (1.62 mmoles) of 1-[4-(2-dimethylamino-ethoxy)-phenyl]-1-phenyl-3,3,3-trifluoro-2-[4-(methoxy-methoxy)-phenyl]-propene are dissolved in 8 ml of a 1% methanolic hydrochloric acid. The solution is heated for 0.5 hour, then evaporated, and the product is crystallized from isopropanol. 0.56 g (74%) of the aimed compound is obtained; m.p.: 196°-220° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH3:11])[C:16]([S:17][CH3:18])=[CH:15][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCNCc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CCN(Cc1ccc(Cl)nc1)C(=C[N+](=O)[O-])SC
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a 100 ml three necked round bottom flask was added N-((6-chloropyridin-3-yl)methyl)ethanamine (17.0 g, 0.1 mol), (2-nitroethene-1,1-diyl)bis(methylsulfane) (15.0 g, 0.09 mol), dry ethanol (50 mL). The mixture was refluxed. After completion, the reaction mixture was cooled to r.t. and concentrated under reduced pressure to obtain crude product as oil, which was purified by column chromatography to afford 5.3 g N-((6-chloropyridin-3-yl)methyl)-N-ethyl-1-(methylthio)-2-nitroethenamine in 18.5% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cncc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cncc(F)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (224 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4N hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 127 mg, 65%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:12].[CH3:21][O:22][C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:12]
Reactant: COc1ccccc1C(=O)CN
Reactant: COC(=O)CCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCC(=O)NCC(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
Add triethylamine (8.1 g, 79.9 mmol) dropwise to a solution of 2-amino-1-(2-methoxyphenyl)ethanone hydrochloride (13.6 g, 67.4 mmol) and octanedioic acid monomethyl ester (14.0 g, 74.2 mmol) in methylene chloride (600 mL) at 0° C. under nitrogen, and then add EDC HCl (15.5 g, 81.0 mmol). Stir the mixture for 4 hours and warm to room temperature with stirring for an additional 18 hours. Dilute the mixture in ethyl acetate (1.2 L), wash sequentially with water (300 mL), 1 N HCl (300 mL), brine (300 mL), saturated sodium, bicarbonate solution (300 mL) and brine (300 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure to afford 7-[2-(2-methoxyphenyl)-2-oxoethylcarbamoyl]heptanoic acid methyl ester (20.0 g, 88%), which is used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[N:35]([CH:41]1[CH2:46][CH2:45][C:44](=[O:47])[NH:43][C:42]1=[O:48])[C:34]2=[O:49].CCOC(C)=O>CN(C)C=O>[O:48]=[C:42]1[CH:41]([N:35]2[C:34](=[O:49])[C:33]3[C:37](=[CH:38][CH:39]=[C:31]([CH2:30][NH:29][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=4)=[O:11])[CH:32]=3)[C:36]2=[O:40])[CH2:46][CH2:45][C:44](=[O:47])[NH:43]1
Reactant: CSc1ccc(C(=O)O)nc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A stirred mixture of 5-methylsulfanyl-pyridine-2-carboxylic acid (0.34 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (15 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.77 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×75 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient, product eluted at 90% EtOAc). The product fractions were combined and concentrated to give 5-methylsulfanyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.55 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 2.89 min (98.58%); mp: 185-187° C.; 1H NMR (DMSO-d6) δ 1.83-2.18 (m, 1H), 2.52-2.68 (m, 5H), 2.78-3.02 (m, 1H), 4.64 (d, J=6.4 Hz, 2H), 5.14 (dd, J=5.4, 12.9 Hz, 1H), 7.76-7.91 (m, 4H), 7.92-8.00 (m, 1H), 8.53 (d, J=1.9 Hz, 1H), 9.52 (t, J=6.3 Hz, 1H), 11.11 (s, 1H); 13C NMR (DMSO-d6) δ 13.93, 21.99, 30.93, 42.36, 48.99, 122.08, 123.51, 129.78, 131.56, 133.56, 133.83, 139.66, 145.03, 145.90, 147.57, 164.11, 166.99, 167.13, 169.80, 172.72; LCMS: MH=439; Anal Calcd for C21H18N4O5S: C, 57.53; H, 4.14; N, 12.78. Found: C, 57.17; H, 4.04; N, 12.54.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16](O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22](F)=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].[NH2:32][C@@H:33]([CH3:46])[C:34]([NH:36][C:37]1([C:40]2[N:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:39][CH2:38]1)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[N:41]1[CH:42]=[CH:43][CH:44]=[N:45][C:40]=1[C:37]1([NH:36][C:34]([C@@H:33]([NH:32][C:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)([CH3:29])[C:9](=[O:28])[N:10]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:27])[CH:20]=4)[C:11]3=[N:15][CH:14]=2)=[O:17])[CH3:46])=[O:35])[CH2:38][CH2:39]1
Reactant: C[C@H](N)C(=O)NC1(c2ncccn2)CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
To a solution of (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (85 mg, 0.19 mmol) and (S)-2-Amino-N-(1-pyrimidin-2-yl-cyclopropyl)-propionamide (49 mg, 0.18 mmol) in THF (1.0 mL) and DMF (0.7 mL), was added HATU (80 mg, 0.21 mmol) followed by DIPEA (0.15 mL, 0.88 mmol). The reaction was stirred at room temperature for 20 h. The THF was removed under a stream of N2 and the reaction mixture was purified by reverse phase HPLC. The purified material was then passed through a basic amino group functionalized solid phase extraction cartridge to give 80 mg of the title compound as a solid, m/z 647.34 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[I:12]I>CO.[Ag+].FC(F)(F)C([O-])=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[C:11]([I:12])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: II
Reactant: COC(=O)c1ccc(N)nc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: COC(=O)c1cnc(N)c(I)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.5 %

Procedure:
To a stirred suspension of methyl 6-aminonicotinate (10 g, 65.7 mmol) and trifluoroacetic acid silver salt (36.3 g, 164.3 mmol) in methanol (250 mL) was added iodine (41.7 g, 164.3 mmol) at 25° C. and the reaction mixture was stirred at 25° C. for 72 h. The mixture was filtered, washed with methanol and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed consecutively with a saturated sodium thiosulfate solution, brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford 6-amino-5-iodo-nicotinic acid methyl ester (13.8 g, 77%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 3.89 (s, 3H), 5.46 (br. s., 2H), 8.47 (br. s., 1H), 8.67 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccncc2)c(-c2ccc(F)cc2)n[nH]1
Product: Fc1ccc(-c2nnc(Cl)cc2-c2ccncc2)cc1

Procedure:
A stirred mixture of 6-(4-fluorophenyl)-5-(4-pyridyl)-2H-pyridazin-3-one (105 mg, 0.40 mmol) and phosphorus oxychloride (2 ml) was heated at reflux for 2 h. It was evaporated, followed by co-evaporation with toluene and drying of the resultant product in an oil pump vacuum for several hours. Then dichloromethane was added and dil. ammonium hydroxide to neutrality with cooling. The organic solution was washed with water, dried and evaporated to leave the title compound. MS (m/z): 286.0 (M)+; C15H9ClFN3 requir. 285.7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[OH:18])=[CH:3][N:2]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+].COC1C=C(OC)C=CC=1C[N:34]([C:47]1[S:48][CH:49]=[N:50][N:51]=1)[S:35]([C:38]1[CH:43]=[C:42]([CH3:44])[C:41](F)=[CH:40][C:39]=1[F:46])(=[O:37])=[O:36].C(Cl)Cl.FC(F)(F)C(O)=O>Cl>[F:46][C:39]1[CH:40]=[C:41]([O:18][C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14]([F:16])([F:17])[F:15])=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)[C:42]([CH3:44])=[CH:43][C:38]=1[S:35]([NH:34][C:47]1[S:48][CH:49]=[N:50][N:51]=1)(=[O:36])=[O:37]
Reactant: Oc1ccc(OC(F)(F)F)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(C)c(F)cc2F)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2nncs2)c(F)cc1Oc1ccc(OC(F)(F)F)cc1-c1ccnnc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
2-pyridazin-4-yl-4-(trifluoromethoxy)phenol (Preparation 888, 30 mg, 0.12 mmol) was taken up in dimethyl sulfoxide (1 mL, 20 mmol) and potassium carbonate (30 mg, 0.22 mmol) added, followed by N-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 889, 51.7 mg, 0.117 mmol). The reaction was heated at 60° C. for 72 hours. The reaction was cooled and diluted with 1N HCl. The resulting precipitate was collected by filtration. The solid was dissolved in methylene chloride (1.0 mL, 16 mmol) and dried over magnesium sulfate. The solution was then treated with trifluoroacetic acid (45 uL, 0.58 mmol) and stirred for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC. Product fractions were combined and the solvent removed in vacuo to give a residue. The product was purified a second time by column chromatography (4 g silica gel column, 0 to 10% methanol in methylene chloride gradient elution). Product fractions were combined and concentrated in vacuo to give 11.2 mg of colorless glass.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[N+:26]([O-])([OH:28])=[O:27].O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:10]([N+:26]([O-:28])=[O:27])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)[nH]c(=O)c1C(=O)OCC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccc(OC)cc2)[nH]c(=O)c1C(=O)OCC
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
In 8 ml of acetic anhydride was suspended 1.2 g of 3,4-diethoxycarbonyl-6-(4-methoxyphenyl)-2(1H)pyridone. After the mixture was cooled to -30° C. 0 36 ml of fuming nitric acid was added dropwise, followed by stirring for 45 minutes. After water was added, stirring was continued for further 1 hour. The viscous product was collected by filtration, crystallized with diethyl ether and washed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][O:26][CH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH2:32][C@@H:28]1[CH2:27][O:26][CH3:25])=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC[C@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC[C@H]1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, (R)-2-methoxymethylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.56 minutes; C22H22Cl2N4O3 (461.35); mass spectrum: (M+H)+=461.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[C:24]3[O:23][CH2:22][C:21](=[O:25])[N:20]([CH3:26])[C:19]=3[CH:18]=[CH:17][CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[C:24]4[O:23][CH2:22][C:21](=[O:25])[N:20]([CH3:26])[C:19]=4[CH:18]=[CH:17][CH:16]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:28])[CH:3]=2)=[CH:31][C:30]=1[F:29])=[O:37]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1cccc2c1OCC(=O)N2C)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3cccc4c3OCC(=O)N4C)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 8-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a light yellow oil. MS (m/e)=552.3 [M+H+].
Reaction SMILES: C(#N)C.[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1.[C:10]([O:18]OC(C)(C)C)(=[O:17])[C:11]1C=CC=CC=1>[Cu+2].[Cu].C(O)(=O)C>[C:10]([O:18][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:17])[CH3:11]
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Reactant: C1=CCCCC1
Agent: [Cu+2]
Agent: [Cu]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)OC1C=CCCC1
Reaction time: 3 h

Procedure:
A mixture of 0.6 g of di-L-prolinato Copper (II), 0.7 g of copper powder, 15 ml of acetonitrile, 5 ml of acetic acid, 15 ml of cyclohexene and 5 ml of t-butyl peroxybenzoate was stirred at 20° to 25° C for 3 hours in a nitrogen atmosphere. After it was confirmed on TLC (thin layer chromatography) that the residual t-butyl peroxybenzoate was no longer present, the remaining copper powder was filtered off and the filtrate was admixed with 50 ml of benzene. The organic layer was successively washed with a 2N hydrochloric acid, an aqueous solution saturated with sodium chloride, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. After removing the solvent, the residue was distilled under reduced pressure to obtain 1.40 g of 2-cyclohexenyl acetate. B.P. 75°-76° C/21 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:15][O:16][CH2:17][C:18]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=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]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1.C([Li])CCC.C[O:43]B(OC)OC.[OH-].[Na+].OO.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([OH:43])[CH:3]=[C:4]([CH2:15][O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:22][CH2:23]3)[CH:5]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Reactant: COB(OC)OC
Agent: OO
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(O)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-(((5-bromo-4′-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (0.47 g, 0.85 mmol) was dissolved in dry tetrahydrofuran (5 mL) and stirred at room temperature for 15 min. The stirred mixture was cooled to −78° C. and treated with a solution of n-butyllithium (1.6 M in hexanes, 0.61 mL, 0.98 mmol) over several minutes. After 30 min, the mixture was treated with trimethylborate (0.28 mL, 2.55 mmol). The reaction mixture was stirred at 78° C. for 1 h, then allowed to warm to room temperature over several hours. The mixture was cooled to 0° C. and treated with a 10 N sodium hydroxide solution (60 μL) and hydrogen peroxide (30% in water, 0.44 mL, 3.9 mmol). The reaction was warmed to room temperature over several hours and then treated with saturated ammonium chloride. The reaction was diluted with ethyl acetate. The layers were separated and the organic layer washed with brine (2×), dried over sodium sulfate, filtered, and concentrated. Flash chromatography on silica gel (30% ethyl acetate/hexanes) afforded 280 mg (67%). 1H-NMR (CDCl3, 500 MHz) δ 7.38-7.43 (m, 2H), 7.19-7.35 (m, 5H), 7.02-7.09 (m, 2H), 6.86-6.88 (m, 1H), 6.79 (s, 1H), 6.46 (s, 1H), 4.33 (s, 2H), 3.70-3.74 (m, 2H), 3.38 (s, 2H), 2.98-3.07 (m, 2H), 2.13-2.17 (m, 2H), 1.83-1.92 (m, 2H), 1.41 (s, 9H). Mass spec.: 492.41 (MH)+.