Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1[C:8]2[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=2[S:10][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[K+].[K+].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][C:38]=1[C:45]([F:48])([F:47])[F:46]>CCOC(C)=O.O>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][N:12]([C:11]2[S:10][C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[C:7]=2[CH3:6])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=2)(=[O:15])=[O:14])=[CH:39][C:38]=1[C:45]([F:46])([F:47])[F:48]
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2sc3ccccc3c2C)cc1
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)c(C(F)(F)F)c2)c2sc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 12-L 4-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, and thermocouple was charged with DMF (4.9 L), N-(3-methylbenzo[b]thiophen-2-yl)-4-carbomethoxy-benzenesulfonamide (245 g, 0.68 mol) and K2CO3 (112 g, 0.81 mol). 4-Fluoro-3-(trifluoromethyl)benzyl bromide (210 mL, 0.81 mol) was then added drop-wise over 15 min and the resulting mixture was stirred for 18 h at room temperature. The resulting mixture was poured into cold H2O (10 L), stirred for 30 min, to which was then added EtOAc (4 L). The layers were separated and the aqueous phase was extracted with EtOAc (2×1 L). The combined EtOAc layers were washed with brine (1 L), dried over Na2SO4, filtered and evaporated under reduced pressure to yield a residue. The residue was purified using flash column chromatography (SiO2) eluting with heptane-EtOAc to yield N-[4-fluoro-3-(trifluoromethyl)-benzyl]-N-(3-methylbenzo[b]thiophen-2-yl)-4-carbomethoxy-benzenesulfonamide as a white solid. 1H-NMR (DMSO-d6) δ 8.21 (d, 2H), 8.03 (d, 2H), 7.86-7.83 (m, 1H), 7.71-7.63 (m, 3H), 7.45-7.37 (m, 3H), 4.89 (br s, 2H), 3.93 (s, 3H), 1.94 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.O[NH:29][C:30](=[NH:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[O:12][N:37]=[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:29]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(NO)c1ccncc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1nc(-c2ccncc2)no1

Procedure:
A solution of tert-butoxycarbonylaminoacetic acid (11.0 g, 5.71 mmol) and triethylamine (802 μl, 5.71 mmol) in toluene (30 ml) was cooled to 0° C. and isobutylchloroformate (740 μl, 5.71 mmol) introduced dropwise. The reaction mixture was stirred at 0° C. for 10 min and at rt for 30 min, whereupon N-hydroxyisonicotinamidine (652 mg, 4.76 mmol) and powdered 3 Å molecular sieves (4 g) were added. After heating under reflux for 12 h the reaction was cooled, filtered through celite and the solvent removed in vacuo. The residue was dissolved in EtOAc (200 ml) and washed with water (30 ml) and saturated aqueous NaHCO3 (30 ml), then dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (IH-EtOAc, 2:3) to afford the title compound: RT=2.97 min; m/z (ES+)=277.1 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[N+:11]([O-:12])=[C:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:9]2=[CH:8][C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>>[CH3:5][C:6]1[N+:11]([O-:12])=[C:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:9]2=[C:8]([N+:1]([O-:4])=[O:2])[C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc2c([n+]([O-])c1C)CCCCC2
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1c([N+](=O)[O-])c2c([n+]([O-])c1C)CCCCC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Fuming nitric acid (27.0 ml) was added dropwise to ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate N-oxide (3.10 g, 12.4 mmol) at 0° C., and the mixture was stirred at 90° C. for 2 hours. After cooling, the reaction solution was poured into ice water, mixed with 2 N sodium hydroxide aqueous solution and extracted with chloroform, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=40:1) to obtain the title compound (3.38 g, 92.4%) as pale yellow powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:43][C:44](=[O:48])[CH2:45][NH:46][CH3:47])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([N:46]([CH3:47])[CH2:45][C:44]([OH:43])=[O:48])=[O:36])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: CCOC(=O)CNC
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)N(C)CC(=O)O)cc2)cc1

Procedure:
The product from Example 104A and sarcosine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.15-7.38 (m, 8 H), 7.02 (m, 4 H), 6.87 (m, 4 H), 4.12 (s, 1 H), 4.06 (s, 2 H), 4.01 (s, 2 H), 3.99 (s, 1 H), 2.99 (s, 2 H), 2.91 (s, 3 H), 2.82 (s, 1 H), 2.76 (m, 2 H), 2.62 (m, 2 H), 2.39 (s, 3 H); MS (ESI) m/z 616 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:14]1[CH:15]=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.[I-].[K+]>[N+:20]([C:19]1[CH:14]=[CH:15][C:16]([C:23]([F:24])([F:25])[F:26])=[CH:17][C:18]=1[NH:12][CH:9]1[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)([O-:22])=[O:21]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1CCC(Nc2cc(C(F)(F)F)ccc2[N+](=O)[O-])CC1
Temperature: 90 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
Ethyl-4-amino-1-piperidine-carboxylate (16.0 g, 92 mmol) was added to a stirred suspension of 3-chloro-4-nitrobenzotrifluoride (19.0 g, 84 mmol), sodium carbonate (8.9 g, 84 mmol) and potassium iodide (0.14 g, 0.84 mmol) in dimethylformamide (200 mL). The mixture was heated to 90° C., stirred for 15 hours and then allowed to cool. The reaction mixture was diluted with water (200 mL) and ethyl acetate (200 mL). The aqueous phase was separated and the organic phase was extracted with water (2×200 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica, eluting with ethyl acetate/hexane (1:5) to give the title compound (12.0 g, 40% yield) as an orange solid. (Rf: 0.4 (ethyl acetate/hexane 1:5))
Reaction SMILES: CP(C1C=CC(N)=C(S(C(C)C)(=O)=O)C=1)(C)=O.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([P:41]([CH3:44])([CH3:43])=[O:42])=[CH:37][C:36]=2[S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])[C:31]([Cl:51])=[CH:30][N:29]=1.[N:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N:58]1[CH2:63][CH2:62][N:61]([C:64]2[O:68][C:67]([NH2:69])=[N:66][N:65]=2)[CH2:60][CH2:59]1>>[Cl:51][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([P:41]([CH3:44])([CH3:43])=[O:42])=[CH:37][C:36]=2[S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])=[N:33][C:28]([NH:69][C:67]2[O:68][C:64]([N:61]3[CH2:60][CH2:59][N:58]([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][N:52]=4)[CH2:63][CH2:62]3)=[N:65][N:66]=2)=[N:29][CH:30]=1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1nnc(N2CCN(c3ccccn3)CC2)o1
Agent: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)o2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine. 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine is then reacted with 5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-amine according to the procedure described in Example 32.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:19][CH2:20][CH2:21][C:22]#[N:23]>>[C:22]([CH2:21][CH2:20][O:19][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:23]
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: N#CCCO
Product: N#CCCOC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 113° C. and MS: m/e=308.3 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 3-hydroxy-propionitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19]C)=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:14]([Cl:22])=[C:15]([F:21])[CH:16]=[CH:17][C:18]=3[OH:19])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](c1c(O)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (1.015 g, 2.646 mmol) in CH2Cl2 (25 mL), cooled to −78° C., 1.0 M of boron tribromide in CH2Cl2 (8 mL, 8 mmol) was added in parts, over the course of 10 min. The solution was allowed to warm to ambient temperature for 18 h (acetone/dry ice bath removed at 1.5 h). The reaction mixture was cooled to 0° C., after which methanol was added to quench the reaction. After stirring at rt for 30 min, the reaction solution was concentrated in vacuo. The sample was resuspended in CH2Cl2 and a standard aqueous workup with saturated aqueous NaHCO3 solution was performed. The organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was dissolved in minimal CH2Cl2/MeOH, adsorbed onto a pre-packed silica solid load cartridge (RediSepRf 25 g size), and purified by the ISCO/Teledyne purification system [RediSepRf silica column, 12 g size], using a 0-50% EtOAc:CH2Cl2 solvent gradient. Fractions containing product were combined and concentrated in vacuo, giving the title material as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=9.50 (br s, 1H), 8.34 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 6.99 (dd, J=8.6, 8.6 Hz, 1H), 6.62 (dd, J=9.1, 4.5 Hz, 1H), 5.03 (dtd, J=7.3, 7.2, 1.3 Hz, 1H), 1.77 (d, J=7.1 Hz, 3H). MS (ES+): m/z 370.97/372.98 (100/43) [MH+]. HPLC: tR=1.56 min (TOF, polar—3 min).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](C2C=CC(O)=CC=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.F.C1(O)C=CC=CC=1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)([CH3:10])=[CH2:9]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: F
Solvent: Oc1ccccc1
Product: C=C(C)c1ccc(O)cc1
Reaction time: 3 h
Yield: 63.4 %

Procedure:
Following the same procedure, at 30° C. for 3 hours using 22.8 grams (0.10 mole) of bisphenol A and 100 grams (5 moles) of hydrogen fluoride, a mixture containing 5.1 gms of phenol, 7.7 gms of bisphenol A and 8.5 gms of p-isopropenylphenol (monomer, dimers and oligomers) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]3)[C:14](=[O:30])[C:13]=1[CH:12]=2.[NH2:31][CH2:32][C@@H:33]([OH:44])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[CH3:43].CCN(CC)CC>CCO>[CH3:43][C:37]1[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:36]=1[O:35][CH2:34][C@H:33]([OH:44])[CH2:32][NH:31][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]3)[C:14](=[O:30])[C:13]=1[CH:12]=2
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Reactant: CCN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1CCC(N2C(=O)c3cc4nc(-c5c(NC[C@@H](O)COc6ccc(C)cc6C)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 95 °C

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-ethyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (143 mg, 0.336 mmol) and (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (78 mg, 0.403 mmol) in EtOH (200 mL) was added Et3N (5.35 mL, 38.4 mmol) and the mixture was heated at 95° C. for 16.5 h and then concentrated. Chromatography of the crude with CH2Cl2/MeOH/28% aqueous NH4OH (160:10:1) (65 mg, 33%). 1H NMR (DMSO-d6) δ 1.02 (t, J=6 Hz, 3H), 1.63 (m, 2H), 1.83 (m, 2H), 2.19 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.29-2.40 (4H), 2.98 (m, 2H), 3.53 (m, 1H), 3.70 (m, 1H), 3.91-4.08 (3H), 4.18 (m, 1H), 5.52 (d, J=4 Hz, 1H, NH), 6.23 (d, J=7 Hz, 1H), 6.83 (d, J=7 Hz, 1H), 6.91 (d, J=7 Hz, 1H), 6.97 (s, 1H), 7.38 (d, J=7 Hz, 1H), 7.65 (s, 1H), 8.09 (br s, 1H), 10.95 (br s, 1H, NH), 11.08 (br s, 1H, NH); ESI-MS m/z 585.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH:20][C:21](=[O:79])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:34][C:35]4[CH2:40][C:39]([F:42])([F:41])[CH2:38][CH2:37][C:36]=4[C:43]4[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=4)[CH2:30][CH2:29]3)=[CH:24][C:23]=2[O:50][C:51]2[CH:59]=[CH:58][CH:57]=[C:56]3[C:52]=2[CH:53]=[N:54][N:55]3C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.FC(F)(F)C(O)=O>ClCCl>[NH:55]1[C:56]2[C:52](=[C:51]([O:50][C:23]3[CH:24]=[C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]5[CH2:40][C:39]([F:41])([F:42])[CH2:38][CH2:37][C:36]=5[C:43]5[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=5)[CH2:30][CH2:29]4)[CH:26]=[CH:27][C:22]=3[C:21]([NH:20][S:17]([C:4]3[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]4([F:16])[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[C:2]([Cl:1])[CH:3]=3)(=[O:19])=[O:18])=[O:79])[CH:59]=[CH:58][CH:57]=2)[CH:53]=[N:54]1
Reactant: O=C(NS(=O)(=O)c1cnc(OCC2(F)CCOCC2)c(Cl)c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NS(=O)(=O)c1cnc(OCC2(F)CCOCC2)c(Cl)c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2[nH]ncc12
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 521I (0.24 g) dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL). After stirring for 1 hour, the reaction was concentrated, dissolved in dichloromethane (5 mL) and quenched with saturated NaHCO3 (5 mL). The reaction was diluted with water (10 mL) and saturated NaHCO3 (15 mL) and the product extracted into dichloromethane (2×25 mL). The combined organics were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was loaded onto silica gel (Reveleris 40 g) and eluted using a gradient of 0.5% to 3% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes). The product was collected, concentrated, dissolved in acetonitrile and concentrated, and dried in vacuum oven at 75° C. overnight to give the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 13.12 (s, 1H), 12.24-11.44 (m, 1H), 8.31 (d, 1H), 7.91 (d, 1H), 7.83 (s, 1H), 7.57 (d, 1H), 7.40 (d, 2H), 7.13 (d, 4H), 6.81 (dd, 1H), 6.56 (d, 1H), 6.16 (dd, 1H), 4.52 (d, 2H), 3.79 (dt, 2H), 3.70-3.51 (m, 2H), 3.20 (s, 4H), 2.76 (dd, 4H), 2.49 (m, 8H), 2.02-1.71 (m, 4H).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13].C([BH3-])#N.[Na+]>>[CH:12]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][NH:3][O:2][CH3:1])([CH3:14])[CH3:13]
Reactant: CON=Cc1ccccc1OC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccccc1OC(C)C

Procedure:
Reduction of 2-isopropoxy-benzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 1-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (83% yield). 1HMR 400 MHz (CDCl3) δ (ppm): 1.35 (6H, d, J=6.1 Hz, CH3), 3.56 (3H, s, OCH3), 4.07 (2H, broad s, NCH2), 4.59 (1H, m, CH), 6.08 (1H, broad s, NH), 6.86-6.91 (2H, m, aromatics), 7.20-7.24 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 90° C. Anal. calcd for C11H17NO2—HCl: C, 57.02; H, 7.83; N, 6.04. Found: C, 56.93; H, 7.64; N, 5.96
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[C:19](\[CH3:25])/[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=3)[S:8][C:7]=2[CH:34]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15](/[CH:18]=[C:19](\[CH3:25])/[C:20]([OH:22])=[O:21])=[CH:16][CH:17]=3)=[C:9]([C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)[S:8][C:7]=2[CH:34]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: C/C(=C\c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 34.7 %

Procedure:
To a solution of (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate (107 mg, 0.225 mmol) in DCM (5.0 mL) at 0° C. was added BBr3 (1.0 M in DCM, 0.902 mL, 0.902 mmol) dropwise. The resulting mixture was stirred at 0° C. for 100 min after which the reaction was quenched by addition of sat. aq. NaHCO3 (4 mL) and acidified to pH 3 by addition of concentrated HCl. The aqueous layer was then extracted with 5% MeOH/EtOAc (4×12 mL) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo to afford the crude product which was dissolved in MeOH and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylic acid (32.4 mg, 0.078 mmol, 34% yield). HRMS (m/z, MH+): 419.0872.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[CH3:30]I>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([N:11]([CH3:30])[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1ccccc1N1CCN(C(=O)Nc2nc(C)c(C)nc2OC)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)N(C)c2nc(C)c(C)nc2OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine (200 mg, 0.54 mmol) was dissolved in dimethylformamide (15 ml) and thereto 60% sodium hydride (21.5 mg, 0.54 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes, and thereto methyl iodide (76.6 mg, 0.54 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][C:18](C)([O-])[CH3:19].[K+].BrC(C)C>CS(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:19]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1O
Agent: [K+]
Solvent: CC(C)Br
Solvent: CS(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1OC(C)C
Temperature: 80 °C
Yield: 94.1 %

Procedure:
Methyl 3-hydroxy-5-phenyl-2-thiophenecarboxylate (20.0 g, 85 mmoles) is dissolved in dimethylsulfoxide (80 mL) under argon and cooled in an ice bath. Potassium t-butoxide (10.1 g, 90 mmoles) is added, followed after 25 minutes by 2-bromopropane (22.1 g, 180 mmoles), and the ice bath is removed. After 24 hours the mixture is heated to 80° C. for 1 hour, then poured into ice water (500 mL), stirred, and acidified with concentrated HCl. The mixture is extracted with dichloromethane (3×200 mL) and the combined extracts are washed with brine, dried over MgSO4 and stripped of solvent under reduced pressure to leave the product as a syrupy residue (22.1 g) sufficiently pure for further use.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34](/[C:39](/[C:58]2[CH:63]=[CH:62][C:61]([C:64]([CH3:67])([CH3:66])[CH3:65])=[CH:60][CH:59]=2)=[CH:40]/[C@@H:41]2[N:45]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH3:56])[C:44](=[O:57])[CH2:43][CH2:42]2)=[N:35][C:36]=1[O:37][CH3:38])(C(C)(C)C)(C)C>O1CCCC1>[C:64]([C:61]1[CH:62]=[CH:63][C:58](/[C:39](/[C:34]2[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][OH:26])=[C:36]([O:37][CH3:38])[N:35]=2)=[CH:40]\[C@@H:41]2[N:45]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH3:56])[C:44](=[O:57])[CH2:43][CH2:42]2)=[CH:59][CH:60]=1)([CH3:67])([CH3:65])[CH3:66]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCO)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 mL) was added to a solution of (5R)-5-[(E)-2-[5-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-6-methoxypyridin-2-yl]-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (140 mg) in tetrahydrofuran (4 mL), and the mixture was stirred at room temperature for three hours. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:10) to give (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(4-hydroxybutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (101 mg, 86%).
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1.CCCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:12]([O:18][C:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[C:10]([O:9][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH3:4])=[O:11])=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: CCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C1CCCCC1C(=O)OCCCCCC
Yield: 120.7 %

Procedure:
A mixture of 1,2-cyclohexanedicarboxylic anhydride (60 g), hexanol (85 g), and p-toluenesulfonic acid (100 mg) in toluene (500 mL) was refluxed for 3 days and water removed from the reaction mixture. After reaction was complete, solvent was removed in vacuo to yield a viscous oil. The crude material was redissolved in heptane and passed through a pad of silica gel to obtain cyclohexane-1,2-dicarboxylic acid dihexyl ester (80 g) as a pale yellow oil.