Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: ClCCCBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCCl
Reaction time: 10 h
Yield: 243.5 %

Procedure:
A stirred solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (600 g, 3.61 mol, Purchased from Shanghai Bangcheng Chemical Co., Ltd.) and anhydrous potassium carbonate (698 g, 5.055 mol) in 2500 mL of N,N-dimethylformamide was added drop-wise with an N,N-dimethylformamide solution of 1-bromo-3-chloropropane (795.9 g, 1.4 mol) while maintaining the temperature below 25° C. Then the resulted mixture was kept at 25° C. for 10 h. After completion of the reaction, the precipitate was filtered and the filter cake was washed by a small amount of N,N-dimethylformamide. The filtrate was poured into ice water slowly with vigorous stirring. The precipitate was filtered, washed with water, and dried to give 827.2 g solid. Yield: 93.8%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[C:15]([C:16]([O:18]C)=O)=[CH:14][S:13][CH:12]=1)=[O:9].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[Na+].[I-].C([O-])(O)=O.[Na+].[OH-].[Na+]>CC(O)C.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[C:16](=[O:18])[C:15]3=[CH:14][S:13][CH:12]=[C:11]3[NH:10][C:8]2=[O:9])[CH2:31][CH2:30]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: O
Solvent: CC(C)O
Product: COc1ccccc1N1CCN(CCCCCn2c(=O)[nH]c3cscc3c2=O)CC1
Yield: 109.7 %

Procedure:
The above urea (8.0 g, 23 mmol) was reacted with 1-(2-methoxyphenyl)piperazine hydrochloride (10.48 g, 45 mmol), NaI (1.72 g, 11 mmol) and NaHCO3 (7.69 g, 92 mmol) in 50 mL of 2-propanol at reflux for 6 hours under a nitrogen blanket. After cooling, water was added and the 2-propanol was removed by distillation. The brown residue was dissolved in CH2Cl2 and washed with water and brine and dried (MgSO4). After the solvent has been removed in vacuo, the tan residue was dissolved in MeOH and treated with 1.1 equivalents of 50% NaOH and the solution was refluxed for 3.5 hours. The pH of the solution was adjusted to 6 with 2N HCL and the methanol was removed by distillation. The resulting oil was dissolved in CH2Cl2 and washed with water and brine and dried (MgSO4). Solvent removal produced 10.81 g (91%) of 3-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentyl]thieno[3,4-d]pyrimidine-2,4-dione which was crystallized from CH2Cl2 /ether to afford a tan solid, mp 148°-153° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][CH2:20][C:21]2[C:26]([CH2:27]O)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][CH2:20][C:21]2[C:26]([CH2:27][C:31]#[N:33])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2ncccc2CO)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2ncccc2CC#N)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.4 %

Procedure:
To a mixture of [2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]methanol (2.10 g), triethylamine (1.05 g) and ethyl acetate (100 mL) was dropwise added methanesulfonyl chloride (1.19 g) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (50 mL) was added an aqueous solution (5 mL) of sodium cyanide (0.51 g) at room temperature and the mixture was stirred at room temperature for 2 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.49 g, 70%) of 2-[2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:22][C:23](=O)[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:45](OCC)C>C1(C)C=CC=CC=1.C[Ti](C)(C1C=CC=C1)C1C=CC=C1>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@H:10]([O:22][C:23]([C:24]1[CH:25]=[C:26]([C:34]([F:36])([F:37])[F:35])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)=[CH2:45])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nnnc1[C@@H]1C[C@@]2(c3ccccc3)[C@H](OC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: CCOCC
Agent: C[Ti](C)(C1C=CC=C1)C1C=CC=C1
Solvent: Cc1ccccc1
Product: C=C(O[C@@H]1CC[C@H]2[C@H](c3nnnn3C)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
Dimethylbis(cyclopentadienyl)titanium (12 ml, 0.45M solution in toluene) was added to a solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-6-(1-methyl-1H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 33b; 0.83 g, 1.35 mmol) in toluene (20 ml). The mixture was stirred at 100° C. for 3 hours. On cooling to room temperature the mixture was poured into 100 ml of 1:1 diethyl ether:iso-hexanes. The mixture was filtered through Celite™and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20 and 50% ethyl acetate/iso-hexanes to yield the title compound (0.57 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]([OH:7])[C:5]([Cl:9])([Cl:8])[C:4]([OH:13])([C:10]([OH:12])=[O:11])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]2[C@@:22]34[C@H:30]5[N:31]([C:32]([CH2:34][C@@H:35]6[O:36][CH2:37][CH:38]=[C:39]7[CH2:40][N:25]([C@H:26]3[CH2:27][C@@H:28]7[C@H:29]56)[CH2:24][CH2:23]4)=[O:33])[C:19]2=[CH:18][C:17]=1[O:41][CH3:42]>CO>[CH3:14][O:15][C:16]1[CH:21]=[C:20]2[C@@:22]34[C@H:30]5[N:31]([C:32]([CH2:34][C@@H:35]6[O:36][CH2:37][CH:38]=[C:39]7[CH2:40][N:25]([C@H:26]3[CH2:27][C@@H:28]7[C@H:29]56)[CH2:24][CH2:23]4)=[O:33])[C:19]2=[CH:18][C:17]=1[O:41][CH3:42].[Cl:1][C:2]1[C@@H:6]([OH:7])[C:5]([Cl:9])([Cl:8])[C@:4]([OH:13])([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: O=C(O)C1(O)C=C(Cl)C(O)C1(Cl)Cl
Agent: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Solvent: CO
Product: O=C(O)[C@]1(O)C=C(Cl)[C@@H](O)C1(Cl)Cl

Procedure:
To (±)-3,5,5-trichloro-1,4-dihydroxycyclopent-2-ene-1-carboxylic acid (3) (A. W. Burgstahler, T. B. Lewis, and M. O. Abdel-Rahman, J. Org. Chem., 1966, 31, 3516; C. J. Moye and S. Sternhell, Aust. J. Chem., 1966 19, 2017) (10 g, 40.4 mmol) in methanol (1l) was added (-)-brucine (15.94 g, 40.4 mmol) in methanol (1l). Crystallisation at room temperature gave two crops (8.50 and 2.33 g respectively) of relatively pure (-)-brucine salt of the acid (4), [α]D25 - 110° (c 0.24, CHCl3). Recrystallisation from methanol gave the pure (-)-brucine salt of the acid (4) (9.64 g, 74%) as colourless plates, m.p. 143°-146°, [α]D25 -120° (c 0.247, CHCl3 ) (Found : C, 54.1; H, 4.85; Cl, 16.4; N, 4.05. C29H31Cl3N2O8 requires C, 54.25; H, 4.85; Cl 16.55; N, 4.35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:14])[CH2:10][CH:11]([CH3:13])[CH3:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)CC(O)c1ccc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CC(=O)c1ccc(Cl)cc1Cl

Procedure:
1-(2,4-Dichloro-phenyl)-3-methyl-butan-1-ol (600 mg, 2.57 mmol) and Dess-Martin periodinane (1092 mg, 2.57 mmol) in DCM (25 ml) is stirred at RT for 2 hours. The reaction mixture is added to EtOAc (200 ml) and washed with sat. sodium metabisulfite (200 ml), sat. NaHCO3 (200 ml), brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified using an ISCO combiflash chromatography, eluting with 0 to 100% (EtOAc/iso-hexane) on a 40 g silica-column to give 1-(2,4-Dichloro-phenyl)-3-methyl-butan-1-one as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.45 (1H, d, J 1.9), 7.42 (1H, d, J 8.3), 7.32 (1H, dd, J 8.3, 1.9), 2.83 (2H, d, J 6.9), 2.25 (1H, sept, J 6.7), 1.00 (6H, d, J 6.7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1I)[CH:14]=[CH:13][O:12]2.[CH3:18][S:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:23]1[CH:22]=[N:21][C:20]([S:19][CH3:18])=[N:25][CH:24]=1)[CH:14]=[CH:13][O:12]2
Reactant: CSc1ncc(B(O)O)cn1
Reactant: Fc1ccc(-c2nc3occn3c2I)c(F)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Temperature: 90 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
A round bottom flask was charged with 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]oxazole (0.25 g, 0.72 mmol; Example #8, step C) and 2-(methylthio)pyrimidin-5-ylboronic acid (0.184 g, 1.08 mmol, Indofine), bis(triphenylphosphine)palladium (II) chloride (0.051 g, 0.072 mmol) and cesium carbonate (0.588 g, 1.81 mmol). The reaction mixture was diluted with 1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was degassed under vacuum and purged with nitrogen 3 times and then stirred at about 90° C. for about 4 h. The reaction mixture was cooled to ambient temperature and then diluted with H2O. The mixture was extracted with EtOAc (2×200 mL). The organic layers were combined and concentrated under reduced pressure. The product was purified by silica gel flash chromatography using a gradient of 0-10% EtOAc in DCM to give the title compound as yellow solid (0.17 g, 64%); 1H NMR (DMSO-d6) δ 8.62 (s, 2H), 8.34 (d, J=1.8, 1H), 8.12 (d, J=1.8, 1H), 7.68 (m, 1H), 7.33-7.25 (m, 1H), 7.20 (m, 1H), 2.54 (s, 3H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:14]=[C:15]([C:31]([NH:33][CH3:34])=[O:32])[C:16](=[O:30])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:18]=2[CH3:19])=[O:12])=[CH:6][CH:5]=1>C(O)(=O)C.C1COCC1>[Br:1][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:11]([C:13]1[CH:14]=[C:15]([C:31]([NH:33][CH3:34])=[O:32])[C:16](=[O:30])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:18]=1[CH3:19])=[O:12]
Reactant: BrBr
Reactant: CNC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=O)c1cc(C(=O)C(Br)c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of bromine (30 mg, 19 mmol) in acetic acid—THF was added dropwise to a solution of 5-[(4-chlorophenyl)acetyl]-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (75 mg, 0.162 mmol). After the addition, stirring was continued at RT overnight. The solvents were removed and the residue was purified on an Xterra C8 column using a gradient of acetonitrile/water. Freeze drying of the mixture afforded the title compound (86 mg, 95%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[I-].[Mg+2].[I-].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]1=[O:24]>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]1[C:19](=[O:24])[CH:20]2[CH:21]([CH:5]3[O:1][CH:2]2[CH:3]=[CH:4]3)[C:22]1=[O:23]
Reactant: c1ccoc1
Reactant: Cc1cc(C)c(C2C(=O)C=CC2=O)c(C)c1
Agent: [I-]
Agent: [Mg+2]
Product: Cc1cc(C)c(C2C(=O)C3C4C=CC(O4)C3C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Furan (214 ml, 3.15 mol) and magnesium iodide (7.0 g, 0.025 mol) are added to 2-(2,4,6-trimethylphenyl)cyclopent-4-ene-1,3-dione (27.0 g, 0.126 mol) and the mixture is stirred at room temperature for 4 days. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C1(C)C=CC=CC=1.[CH2:14]([O:25][C:26]1[CH:34]=[CH:33]C(C(O)=O)=[CH:28][CH:27]=1)[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.C(Cl)Cl>[CH2:14]([O:25][C:26]1[CH:27]=[CH:28][C:1]([C:2]([Cl:4])=[O:3])=[CH:33][CH:34]=1)[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC/C=C\CCCOc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCC/C=C\CCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
1 mL of oxalyl chloride (11.5 mmol) and two drops of anhydrous DMF are added under argon to 101 mg of toluene-dried acid 34 (348 μmol) dissolved in 18 mL of anhydrous DCM. The medium is stirred at room temperature for two hours and then concentrated to give 107 mg of a yellow oil, i.e. a yield of 99%.
Reaction SMILES: C1C2C(COC(N[C@H](C(OC(C)(C)C)=O)CSC[C@@H](CCCCCCCC([O-])=O)CCCCCCCCC([O-])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:52]([O:65][C@H:66]([CH2:92][O:93][C:94](=[O:106])[CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101]CCCC)[CH2:67][S:68][CH2:69][C@@H:70]([C:89]([OH:91])=[O:90])[NH:71][C:72](=[O:88])[O:73][CH2:74][CH:75]1[C:87]2[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=2[C:81]2[C:76]1=[CH:77][CH:78]=[CH:79][CH:80]=2)(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]CCCC>>[CH:77]1[C:76]2[CH:75]([CH2:74][O:73][C:72](=[O:88])[NH:71][C@H:70]([C:89]([OH:91])=[O:90])[CH2:69][S:68][CH2:67][C@H:66]([O:65][C:52](=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:92][O:93][C:94](=[O:106])[CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])[C:87]3[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=3)[C:81]=2[CH:80]=[CH:79][CH:78]=1
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: CC(C)(C)OC(=O)[C@H](CSC[C@H](CCCCCCCCC(=O)[O-])CCCCCCCC(=O)[O-])NC(=O)OCC1c2ccccc2-c2ccccc21
Product: CCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCC

Procedure:
The product was prepared from (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropylthio)propane-1,2-diyldioctanoate by following the procedure described for compound 6.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:50]4[CH:51]=[CH:46][CH:47]=[C:48]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])[CH:49]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCOc1cccc(OB([O-])[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCOc1cccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-(propoxyethoxy)phenyl borate (155 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 16 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[3-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 110) (154 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C#N
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (50 mg, 0.2 mmol) and ammonium acetate (130 mg, 1.7 mmol) in methanol (0.98 mL) and acetonitrile (0.99 mL) was heated at 65° C. in a sealed tube for 30 min. After the mixture was cooled, sodium cyanoborohydride (22 mg, 0.35 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step. LCMS calculated for C16H15ClFN2 (M+H)+: m/z=289.1. found: 289.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1Br.C([O-])([O-])=O.[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(#N)C.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]>[OH:14][CH2:13][CH2:12][NH:11][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17]2[C:16]([Cl:15])=[CH:21][C:20]([Cl:22])=[CH:19][C:18]=2[Cl:23])[CH:3]=1)(=[O:10])=[O:9]
Reactant: Clc1cc(Cl)c(Br)c(Cl)c1
Reactant: Nc1cccc(S(=O)(=O)NCCO)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: O=S(=O)(NCCO)c1cccc(Nc2c(Cl)cc(Cl)cc2Cl)c1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 26.2 %

Procedure:
To a stirred solution of 3-Amino-N-(2-hydroxyethyl)-benzene sulfonamide (200 mg, 0.93 mmol), 1,3,5-trichloro-2-bromobenzene (301 mg, 1.16 mmol), K2CO3 (319 mg, 2.31 mmol) and XantPhos (54 mg, 0.093 mmol) in acetonitrile (2 ml) under nitrogen in a microwave tube was added Pd2dba3 (43 mg, 0.047 mmol) in one portion and the tube sealed. The reaction was heated with stirring in a microwave at 150° C. for 45 minutes. The reaction was cooled before filtering through celite. The crude reaction mixture was part-purified by column chromatography eluting with ethyl acetate:hexane and the concentrated fractions further purified by preparative chromatography under acidic conditions to afford the named product (96.3 mg, 26%); 6H (400 MHz, DMSO) 8.45 (1H, s), 7.82 (2H, s), 7.54 (1H, t), 7.33 (1H, t), 7.13 (1H, d), 6.93 (1H, s), 6.76 (1H, d), 4.70 (1H, brs), 3.35 (2H, m) and 2.75 (2H, q); LCMS Rt=3.79 min, m/z (ES−) 392 (M−H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:5][N:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2ccc(N)cc2)cn1
Yield: 82 %

Procedure:
A mixture of 2-methoxy-5-(4-nitro-phenyl)-pyridine (as prepared in the previous step, 102 mg, 0.443 mmol) and 5% Pd—C (80 mg) was stirred under 1 atm H2 in 4 mL of EtOH for 4 h and then filtered through Celite and concentrated in vacuo to afford 73 mg (82%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C12H12N2O, 201.0 (M+H), found 201.3.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:7][C:4]1[S:3][C:2]([O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ncc(Br)s2)c1
Temperature: 140 °C
Yield: 80.4 %

Procedure:
A mixture of 2,5-dibromothiazole (500 mg, 2.06 mmol), methyl 3-hydroxybenzoate (313 mg, 2.06 mmol) and potassium carbonate (341 mg, 2.47 mmol) in DMF (4 mL) was heated at 140° C. in a microwave reactor for 20 min. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (520 mg, 80% yield). LCMS, [M+H]+=315.9.