Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:25](=[O:34])[N:26]([CH3:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)C=1>>[CH3:16][C:11]1([CH3:15])[CH2:10][C:9](=[O:17])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:25](=[O:34])[N:26]([CH3:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:7][CH:6]=2)[C:13](=[O:14])[CH2:12]1
Reactant: CC1(C)CC(=O)N(c2ccc(O)cc2)C(=O)C1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(N2C(=O)CC(C)(C)CC2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 1-(4-hydroxyphenyl)-4,4-dimethylpiperidine-2,6-dione (233 mg, 1.00 mmol) ) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol) by applying general procedure 3 (192 mg, 52%, white solid). HPLC-MS m/z=367 (M+1); Rt=3.78 min.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:10]([C:12]([CH3:14])=[CH2:13])[N:11]=1)=[O:5].[H][H]>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)=[C:10]([CH:12]([CH3:13])[CH3:14])[N:11]=1)=[O:5]
Reactant: C=C(C)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Yield: 71.9 %

Procedure:
Into a solution of Compound 68a (63.6 mg, 0.15 mmol) in EtOAc (2.0 mL) was added 5% Pd/C (50 mg). The mixture was stirred at room temperature under 1 atmosphere of hydrogen for 2 hours. The mixture was filtered through a short plug of silica, the filtrate was concentrated, the residue was purified by column chromatography on silica gel (eluted with 10-70% ethyl acetate in hexanes) to give Compound 69 (46 mg, 72%) as a white solid.
Reaction SMILES: [N:1]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:5]([C:6]([O:8]CC2C=CC=CC=2)=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12>[Pd].C(O)C>[C:22]([O:21][C:19]([N:1]1[C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.5 %

Procedure:
To a 250 mL round bottom flask charged with a stir bar and (2S,3aS,6aS)-2-benzyl 1-tert-butyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (5.76 g, 16.68 mmol) was added 10% Palladium on carbon (1.77 g). Ethanol was poured over the mixture and the reaction mixture was evacuated and flushed with hydrogen gas three times. The suspension was stirred at room temperature under an atmosphere of hydrogen for 24 hours. Upon completion, the reaction mixture was filtered through celite and concentrated to give (2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (4.45 g, >99%). MS (ESI) m/z 256.21 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][C@H:17]([NH:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH2:16]2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[F:1][C:2]1[C:7]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@H:17]([NH:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH2:16]3)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Br)cc2C1
Reactant: OB(O)c1ccc(F)nc1F
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3ccc(F)nc3F)cc2C1

Procedure:
To a solution of (2,6-difluoro-3-pyridinyl)boronic acid (2 g, 12.56 mmol) in dry 1,4 dioxane (30 ml), polymer supported Pd(PPh3)4 (126 mg, 0.5 mmol/g, 0.063 mmol) was added along with N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (2 g, 6.28 mmol) and 7.3 ml of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with AcOEt and water. The aqueous phase was separated and acidified with 3N HCl and extracted with AcOEt. Then pH was reverted to basic by addition of NaHCO3 and another extraction with AcOEt was performed. All the organic extracts were collected, dried on Na2SO4, filtered and evaporated. The crude was finally purified on a 40M+ silica cartridge eluting with a cyclohexane/AcOEt 80/20 mixture. 798 mg of title compound were recovered as whitish solid (36%) Due to the use of the chiral Intermediate 6, the title compound is believed to be N-[(2S)-5-(2,6-difluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Reactant: Nc1ccccc1
Product: Cc1cccc(Cl)c1C(=O)Nc1ccccc1

Procedure:
In one embodiment, the step comprises combining 2-chloro-6-methylbenzoyl chloride with aniline to afford 2-chloro-6-methyl-N-phenylbenzamide. In one embodiment, the step is optionally carried out in the presence of a base (e.g., an amine base such as Et3N).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH:13]=[N:14][NH:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([N+]([O-])=O)[CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][C:13]1[C:28]([CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:15]([CH:16]([CH3:17])[CH3:18])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NN=CCCNC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])C(=Cc1ccc(F)cc1)CC1OCCO1
Solvent: C1CCOC1
Product: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of [3-(isopropyl-hydrazono)-propyl]-carbamic acid benzyl ester (60.0 mg, 0.228 mmol) and 2-[3-(4-fluoro-phenyl)-2-nitro-allyl]-[1,3]dioxolane (54.0 mg, 0.213 mmol) in THF (2 mL) was stirred at rt for 3 days. The mixture was treated with additional [3-(isopropyl-hydrazono)-propyl]-carbamic acid benzyl ester (1.4 equiv.) and was stirred at 60° C. for 18 h. Additional [3-(isopropyl-hydrazono)-propyl]-carbamic acid benzyl ester (2.1 equiv.) was added, and the mixture was stirred at 60° C. for 18 h. The mixture was concentrated to oil and the residue was purified by FCC to give the title compound.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>[Pd].C1COCC1.C(O)C>[N:1]1([C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])[CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 16 h
Yield: 89.9 %

Procedure:
Methyl 3-[4-(azetidine-1-carbonyl)-2-chloro-phenoxy]-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 17) (372 mg, 0.81 mmol) was added to a suspension of 10% palladium on carbon (37 mg, catalytic) in THF (10 mL) and ethanol (10 mL) and the resulting mixture was stirred under an atmosphere of hydrogen for 16 hours. The suspension was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (10 mL) and brine (10 mL), dried (MgSO4) and evaporated under reduced pressure to afford the product (309 mg, 90%). 1HNMR δ (300 MHz, CDCl3) 2.10-2.23 (m, 1H), 2.36 (quintet, 2H), 2.52-2.65 (m, 1H), 2.94 (s, 3H), 3.32-3.54 (m, 2H), 3.89 (s, 3H), 4.18-4.39 (m, 4H), 4.90 (t, 1H), 6.94 (s, 1H), 7.01 (d, 2H), 7.32 (s, 1H), 7.48 (s, 1H), 7.64 (d, 2H); m/z 425 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(NCC(=O)c1cccs1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1cccs1
Yield: 65.9 %

Procedure:
5 g of N-(4-chlorobenzoyl)-N-[(2-thienylcarbonyl)methyl]amine, 1.03 g of 50% sodium hydride and 2.98 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 4.3 g of ethyl 3-(4-chlorobenzoylamino)-3-(2-thienylcarbonyl)propionate are thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][C@@H:5]([OH:13])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26].[Cl-].[Na+]>CS(C)=O>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[N:7]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:6][C@@H:5]([OH:13])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)NC[C@@H](O)c2cc(Cl)sc21
Reactant: COCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCCCN1C[C@@H](O)c2cc(Cl)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 204.1 %

Procedure:
A mixture of (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (5, 65.4 g) and potassium carbonate (113.3 g) in dimethylsulfoxide (350 mL) was treated with 1-bromo-4-methoxybutane (20.6 g) and the mixture was stirred at ambient temperature for 4 hours. Another 20.6 grams of 1-bromo-4-methoxybutane was then added and the mixture was stirred at ambient temperature for 18 hours. TLC analysis after this period indicated incomplete reaction, so another 4.6 grams of 1-bromo-4methoxybutane was added and the mixture was stirred at ambient temperature for another 3 hours. At this point, TLC indicated complete reaction. The mixture was poured into saturated aqueous sodium chloride (1 L) and extracted with diethyl ether (3×150 mL). The organic phase was washed sequentially with 100 mL each of 10% aqueous sodium hydroxide, 1:1 5.25% sodium hypochlorite/water, and saturated aqueous sodium chloride, dried over sodium sulfate, and stripped of solvent by rotary evaporation. Residual solvent was removed under vacuum to provide 82 grams (92%) of (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(4-methoxybutyl)-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide as a light yellow oil: IR (film) 3500, 3350, 3070, 2950, 2850, 1525, 1480, 1440, 1380, 1330, 1160, 1120, 1080, 1020, 1100 cm-1 ; [α]25D +11.4° (c=1.1, methanol); Anal. Calcd for C11H16ClNO4S2 : C, 40.55; H, 4.95; N, 4.30. Found: C, 40.47; H, 4.99; N, 4.27.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].Cl.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]2[S:35][C:34]3[N:36]4[C:27](=[CH:28][N:29]=[C:30]4[CH:31]=[CH:32][CH:33]=3)[CH:26]=2)=[O:24])[CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1.[I-].[Na+]>C(N(CC)CC)C.C(#N)C>[C:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]2[S:35][C:34]3[N:36]4[C:27](=[CH:28][N:29]=[C:30]4[CH:31]=[CH:32][CH:33]=3)[CH:26]=2)=[O:24])[CH2:20][CH2:21]1)#[N:9]
Reactant: N#Cc1ccccc1OCCCCl
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: N#Cc1ccccc1OCCCN1CCC(NC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Yield: 82.9 %

Procedure:
2-(3-Chloropropan-1-yl)oxybenzonitrile (503 mg) was added, at room temperature, to an acetonitrile solution (20 ml) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (800 mg), 1,8-diazabicyclo[5.4.0]-7-undecene (662 mg), triethylamine (1.09 g) and sodium iodide (285 mg). The mixture was heated under reflux for 7.5 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, which was subjected to extraction with chloroform. The extract solution was washed with a saturated aqueous saline solution, which was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (ethyl acetate/methanol=2/1) to afford the object compound (816 mg, 83%) as a reddish purple oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](/[C:12](=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/C(OC(C)(C)C)=O)=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>NC(N)=S.C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10](=[O:11])[CH2:12][C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:1]2)=[CH:4][CH:5]=1
Reactant: COc1ccc(C(=O)/C(=C\c2ccccc2)C(=O)OC(C)(C)C)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(N)=S
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)O[C@@H](c1ccccc1)CC2=O
Yield: 70.8 %

Procedure:
Prepared according to general procedure using (E)-tert-butyl 2-(2-hydroxy-4-methoxyphenylcarbonyl)-3-phenylprop-2-enoate (71 mg, 0.20 mmol), thiourea catalyst III (14 mg, 0.020 mmol) in 2.0 mL toluene for 42 h at −25° C. and p-toluenesulfonic acid (19 mg, 0.10 mmol) for 18 h. Purification via column chromatography with 10% EtOAc/hexanes afforded 36 mg (71%) of 13 as a white solid in 89% ee. [α]D: +58.5 (EtOH, c=0.5). Analytical data for 13: IR (film) 1683.3, 1608.6, 1442.7, 1258.9 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=8.5 Hz, 1H), 7.50-7.39 (m, 5H), 6.63 (dd, J=8.8, 2.1 Hz, 1H), 6.52 (d, J=1.5 Hz, 1H), 5.48 (dd, J=13.4, 2.4 Hz, 1H), 3.85 (s, 3H), 3.06 (dd, J=16.8, 13.4 Hz, 1H), 2.85 (dd, J=16.8, 2.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 190.8, 166.4, 163.7, 139.0, 129.1, 129.0 (x2), 126.4, 115.4, 110.5, 101.1, 80.2, 55.9, 44.5; LRMS (electrospray): Exact mass calcd for C16H14O3 [M]+, 254.09. Found [M+1], 255.6.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=[CH:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.ClCCl.[Br-].[Br-].[Br-]>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:11]=[CH:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
To chloroform (80 ml) solution of phenyl N-(4-methoxyphenyl)-3-(phenoxy)acrylimidate (2.4 g) was added dropwise with borone tribromide dichloromethane solution (1.0M:14.0 ml) under ice-cooling and stirred for one hour at the same temperature and 2.5 hours at room temperature. Chloroform (200 ml) was added to the reaction solution and it was successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain phenyl N-(4-hydroxyphenyl)-3-(phenoxy)acrylimidate (0.46 g) as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:8][C:7]=2[CH:29]=1.C(S)C.[Na]>CN(C=O)C.O.CCOC(C)=O.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:8][C:7]=2[CH:29]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Na]
Solvent: CCS
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 0.4 g (1 mmol) of [6-Methoxy-2-(4-methoxyphenyl)benzo[b]thien-3-yl][4-methoxyphenyl]methanone in 2 mL of DMF was added to a solution of 3 mL of 0.5M sodium ethanethiol in DMF. The reaction mixture was heated to 80° C. for 4 hours. The reaction mixture was allowed to cool and diluted with 10 mL of water and 10 mL of EtOAc and neutralized with 1N HCl. The reaction mixture was extracted three times with 30 mL portions of EtOAc. The combined organic extracts were washed four times with 20 mL portions of brine and dried with MgSO4 and evaporated to dryness. The crude product was chromatographed on silica eluting with 30% EtOAc in hexane, and evaporated to dryness. This yielded 0.31 g of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])=[N:7][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:8]1[N:9]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:12])[C:11]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[N:7]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2c(Cl)nccc2nc(-c2ccccc2O)n1CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2c(Cl)nccc2nc(-c2ccccc2OCc2ccccc2)n1CCc1ccccc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
5-Chloro-2-(2-methoxy-phenyl)-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one was subjected to the same deprotection conditions found in the final step of Example 1 to provide the desired 5-chloro-2-(2-hydroxy-phenyl)-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one. A mixture of 5-chloro-2-(2-hydroxy-phenyl)-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one (88 mg, 0.233 mmol), potassium carbonate (64 mg, 0.466 mmol, 2 equiv.) and benzyl bromide (0.029 mL, 0.245 mmol, 1.05 equiv.) in 2 mL of acetone was heated to reflux overnight. The reaction mixture was cooled to RT, filtered through celite, concentrated and the residue purified on preparative TLC plate using 1:1 ethyl acetate:heptane to give 95 mg (87%) of the desired product.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[CH:25][C:24]([C:30]([OH:32])=[O:31])=[N:23]2)=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])(C)C.C(O)(C(F)(F)F)=[O:34].C(Cl)Cl.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[CH:25][C:24]([C:30]([OH:32])=[O:31])=[N:23]2)=[CH:17][CH:16]=1)(=[O:8])=[O:7])(=[O:34])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)nc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
1-[6-(2-t-Butylsulfamoylphenyl)pyridin-3-ylmethyl]-5-propyl-1H-pyrazole-3-carboxylic acid (480 mg, 1.0 mmol) was dissolved in TFA (2.8 mL, 36.8 mmol) and heated at 40° C. for 3 hours. The mixture was diluted with toluene and concentrated (azeotrope×3). The residue was dissolved in DCM (5.53 mL, 86.2 mmol), then triethylamine (1.8 mL, 12.6 mmol) and acetic anhydride (992 μL, 10.5 mmol) were added. The resulting solution was stirred at room temperature for 1 hour. Additional triethylamine and acetic anhydride were added to drive the reaction. The reaction was then quenched with water (150 μL) and dried through azeotrope with toluene to yield the title compound (108 mg), which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11]OC(C)(C)C>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][Cl:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OCl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NCl)cc1

Procedure:
To a suitable reaction vessel there was added 6.07 g (0.044 mol) of 4-nitroaniline dissolved in 300 ml of methylene chloride. The solution was cooled with vigorous stirring to -65°, giving a suspension of the nitro compound. A solution of 5.75 g (0.055 mol) of t-butyl hypochlorite in 10 ml of methylene chloride was added to form the 4-nitro-N-chloroaniline and subsequently after 3 hr, 7.4 g (0.071 mol) of methylthio-2-propanone in 10 ml of methylene chloride was added, while stirring was continued for 10 hr. to form the azasulfonium chloride salt. The triethylamine, 4.4 g (0.044 mol), dissolved in 10 ml of methylene chloride was added and the solution was warmed to room temperature to form the 2-methyl-3-methylthio-5-nitroindole. A 50-ml portion of water was added and after separation, the organic layer was extracted thoroughly with a 2N aqueous hydrochloric acid. Drying over anhydrous magnesium sulfate and filtration of the organic solution was followed by evaporation, leaving a solid residue that was stirred for several hrs. with 30 ml of benzene. The remaining precipitate was collected by filtration giving 2.92 g (0.013 mol, 30%) of 2-methyl-3-methylthio -5-nitroindole, mp 197.5°-198.5° (recr. from 95% ethanol); ir (KBr) 3250 cm-1 (NH); pmr (acetone-d6) 1.40 (1H, br, s, NH), 1.02 (1H, d, J=2.0Hz, 4-aryl H), 2.02 (1H, dd, J=8.0 and 2.0 Hz, 6-aryl H), 2.57 (1H, d J=9.0 Hz, 7-aryl H) and 7.42 and 7.73 (3H, s, SCH3 and CH3).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:23]([C:34](O)=[O:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C[CH2:38][N:39]=[C:40]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CNC>C(Cl)Cl.CCOC(C)=O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C@H:23]([C:34](=[O:35])[N:39]([CH3:40])[CH3:38])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 53; 0.100 g, 0.204 mmol), EDCI (0.0548 g, 0.286 mmol) and HOBT (0.0373 g, 0.276 mmol) were mixed in CH2Cl2 (2.5 mL) and the mixture was cooled to 0° C. Triethylamine (0.0712 mL, 0.511 mmol) was added and the mixture stirred for 15 minutes. Dimethylamine (0.153 mL, 0.306 mmol, 2.0M in THF) was added, and the mixture was warmed to ambient temperature and stirred for 5.0 hours. The mixture was diluted with EtOAc (20 mL) and washed with 1N KHSO4 (2×10 mL), followed by saturated aqueous NaHCO3, and brine. The organics were dried over MgSO4, filtered and concentrated, then purified by column chromatography (1 to 5% MeOH/CH2Cl2) to afford 0.080 g (75%) of the desired product.