Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=O)C.[NH:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:16]([C:10]4[CH:11]=[CH:12][C:13]([N:35]5[CH2:39][CH2:38][CH2:37][C:36]5=[O:40])=[CH:14][C:9]=4[N:6]4[CH2:7][CH2:8][NH:4][C:5]4=[O:34])=[O:17])[CH2:19][CH2:20]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: O=C1CCCN1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2N2CCNC2=O)CC1
Yield: 44.8 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (165 mg) described in Preparation Example 236 and pyrrolidin-2-one (44 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (75 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (180 mg, 0.60 mmol) [prepared according to the procedure of Example 159], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (203 mg, 0.58 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (340 mg, 0.72 mmol) in Chloroform (6 mL). DIEA (530 μL, 3.03 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (259 mg, 0.41 mmol, 69%): LC-MS (ES) m/z=633 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[CH:16]=3)[CH2:11][C@@H:10]2[OH:31])=[O:7])=[CH:4][CH:3]=1.Cl.[O:35]1[CH2:38][C:37](=O)[CH2:36]1.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH:37]5[CH2:38][O:35][CH2:36]5)[CH2:20][CH2:19]4)[CH:16]=3)[CH2:11][C@@H:10]2[OH:31])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[C@H](NC(=O)c2ccc(F)cc2)[C@@H](O)C3)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(N[C@H]1c2cc(N3CCN(C4COC4)CC3)ccc2C[C@@H]1O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of tert-butyl 4-[(2S,3S)-3-[(4-fluorobenzoyl)amino]-2-hydroxy-indan-5-yl]piperazine-1-carboxylate (300 mg, 0.659 mmol) in 1,4-dioxane (5.0 mL), add 4 M hydrogen chloride in dioxane (5.0 mL) at room temperature and stir for 1 hr. Concentrate the suspension in vacuo. Add to the residue saturated aqueous sodium bicarbonate (50 mL) and extract with ethyl acetate (3×50 mL). Wash the combined organic layers with brine, dry over sodium sulfate, and concentrate in vacuo. Dissolve the residue in methanol (20 mL) and add 3-oxetanone (142 mg, 1.98 mmol), glacial acetic acid (170 μL, 2.96 mmol), and crushed activated 4 Å molecular sieves. Stir the resulting suspension at 50° C. for 1 hr. Add sodium cyanoborohydride (131 mg, 1.98 mmol) at room temperature and stir overnight. Add a saturated sodium bicarbonate solution (20 mL) and stir for 20 min. Extract with dichloromethane (3×50 mL) and wash the combined organic layers with water and brine. Dry the organic portion over sodium sulfate, filter, and concentrate to obtain the title compound (220 mg, 81%). LC-ES/MS m/z 412 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH:8]=[CH:7][CH2:6][CH:5]=[CH:4]1)#[N:2].[NH4+].[OH-]>[Pd].CO>[C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(CC(=O)O)C=CCC=C1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: N#CC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Added 5% Pd/C catalyst (0.65 g, 0.31 mmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid (0.50 g, 3.1 mmol) and 28% NH4OH (42.5 μL, 38.3 μg, 0.31 mmol) in MeOH (15 mL). After shaking the reaction mixture under 50 psi H2 at room temperature for 1 hour, the pressure was slowly released. The reaction was filtered and concentrated under reduced pressure to afford 0.48 g (94%) of crude product
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:15][C:16]=1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([O:40][CH3:41])[CH:33]=1.CCCCCCC.C(OC(C)C)(C)C>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[S:15][C:16]=1[CH2:17][O:18][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([O:40][CH3:41])[CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCCOCc1ccccc1
Reactant: COc1cc(F)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To a solution of 1.34 g of [4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol in 20 mL of dimethylformamide at 0° C. was added 158 mg of a 60% suspension of sodium hydride in mineral oil. The resulting mixture was stirred for 10 minutes at 0° C. then 497 mg of 4-fluoro-2-methoxybenzonitrile were added. After stirring for 30 minutes at 0° C., the temperature was allowed to warm up to room temperature and the reaction mixture was stirred until completion. The solvent was removed under reduced pressure and dichloromethane/water were added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.82 g of crude product as a yellow oil. A 1/1 solution of heptane/diisopropyl ether was added to the residue and the solidified product was filtered off to provide a first crop of 1.26 g of desired product. The mother liquor was concentrated and purified by column chromatography on silica gel (heptane 60/ethyl acetate 40) to give an additional 110 mg. The two fractions were combined to obtain 1.37 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]2)=[O:8].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:15]1[C:16]2[C:11](=[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:27]=[C:2]([Cl:1])[C:3]([O:30][CH3:31])=[CH:4][C:5]=3[O:28][CH3:29])[CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][NH:14]1
Reactant: COc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C(=O)OC(C)(C)C)C3)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(C(=O)Nc2cccc3c2CCNC3)cc1Cl

Procedure:
To a solution of 5-chloro-2,4-dimethoxy-N-[2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]benzamide (1 g) in dichloromethane (30 ml) at 0° C. was added trifluoracetic acid (3 ml). The mixture was then stirred at room temperature for 3h before pouring into saturated aqueous sodium bicarbonate (100 ml) and extracting with dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as an off white solid (700 mg).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[C:4]2=[CH:3][CH:2]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[CH:15]([NH:18][CH2:13][CH:12]([OH:14])[CH2:11][O:10][C:9]1[C:4]2[N:5]([N:1]=[CH:2][CH:3]=2)[CH:6]=[CH:7][CH:8]=1)([CH3:17])[CH3:16]
Reactant: c1cc(OCC2CO2)c2ccnn2c1
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1cccn2nccc12

Procedure:
Then, the Compound (6) is reacted with isopropylamine to produce 1-(isopropylamino)-3-(pyrazolo[1,5-a]pyrid-4-yloxy)-2-propanol (A), with approximately quantitative yields being achieved.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(CCl)n1
Temperature: 25 °C

Procedure:
N-(6-Hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (2.03 g) in CH2Cl2 (75 mL) was treated at RT with thionyl chloride (1.785 mL) and then heated to reflux for 1.5 h. The reaction mixture was cooled to RT and partitioned between water and AcOEt, the layers were separated, the organic layer dried over MgSO4, filtered and evaporated to give N-(6-chloromethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.66 g) as a brown liquid. MS (ESI): 227.2 (MH+).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:25]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[CH2:31]CO)([O-:27])=[O:26]>C(Cl)Cl>[Br:5][CH2:1][CH2:31][C:30]1[CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:36]=[CH:35][CH:34]=1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CCBr)c1
Reaction time: 0.5 h
Yield: 114.8 %

Procedure:
Carbon tetrabromide (2.48 g) and triphenylphosphine (2.35 g) were added to a mixture of 3-nitrophenethyl alcohol (1.0 g) and methylene chloride (20 ml) under cooling with ice and stirred for 30 min under cooling with ice. The reaction mixture was distilled under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1) to give 1.58 g of the titled compound quantitatively.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@H](NC(=O)c1ccc(O)cc1)C(=O)OC
Temperature: 22 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 5.0 g of N-(4-benzyloxybenzoyl)-L-glutamic acid dimethyl ester in 175 ml ethanol and 25 ml ethyl acetate were added 0.6 g of 5% Pd/C. The mixture was shaken under a hydrogen atmosphere (3 atm) at 22° C. for 3 hours. The reaction mixture was then filtered through Celite and evaporated to an oil which was dissolved in ethyl acetate and, again, filtered through Celite. The filtrate was evaporated to give 3.8 g of the title compound as an oil: 300-MHz 1H NMR (CDCl3) δ2.10-2.21 (m, 1H), 2.24-2.38 (m, 1H), 2.41-2.58 (m, 2H), 3.65 (s, 3H), 3.79 (s, 3H), 4.76-4.85 (m, 1H), 6.86 (d, J=9 Hz, 2H), 7.11 (d, J=10 Hz, 1H), 7.67 (d, J=9 Hz, 2H), 7.78 (b s, 1H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.C(O)C.O1CCCC1.[OH-].[Na+]>[Cl-].[Na+].O>[OH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
The 17β-ethyl carboxylate prepared in Example 1B (0.9259 g, 2.793 mmol) is dissolved in 60 mL warm ethanol/tetrahydrofuran (1:1), 6M sodium hydroxide is added (NaOH, 10.0 mL, 60 mmol) and the reaction is stirred at room temperature for 2 ½ hours. The reaction mixture is diluted with brine (100 mL) and extracted with EtOAc (3×50 mL). The combined organic phases are washed with brine (50 mL) and ammonium chloride (NH4Cl), dried over magnesium sulfate, filtered and evaporated to give a crude reaction product. The crude product is recrystallized from ethanol to give colorless crystals (0.3132 g, 1.0822 mmol) of 17β-hydroxy-4-aza-androst-5(6)-en-3-one. The mother liquor is concentrated and the recrystallization procedure above repeated in order to give a second crop of crystals. (0.3945 g, 1.363 mmole).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH2:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].C(OC1(OCC)CCCO1)C>O.C(O)C.C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:13]2[CH:16]=[CH:15][CH:14]=[CH:19]2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)c(C)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)[O-]
Agent: CCOC1(OCC)CCCO1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(C)c(-n2cccc2)c1

Procedure:
A mixture of 18 g. of methyl 3,5-diamino-4-methylbenzoate, 0.7 g. of p-toluenesulfonic acid, 8.2 g. of sodium acetate, 32 g. of diethoxytetrahydrofuran, 10 ml of glacial acetic acid, 100 ml. of ethanol and 100 ml. of water was boiled at reflux for 3 hours. The alcohol was removed in vacuo and the residue extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with ethyl acetate and recrystallization from high-boiling petroleum ether, there was obtained methyl 3-amino-4-methyl-5-(pyrrol-1-yl)benzoate, having a melting point of 112° C.
Reaction SMILES: [CH:1](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=Cc2ccccc2)Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C1c2ccccc2CC1Cc1ccccc1

Procedure:
2-Benzylideneindan-1-one (6.0 g) was hydrogenated in 100 ml of ethanol using 0.1 g of 10% palladium on carbon as catalyst at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated to dryness.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Cl)[CH:22]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH:22]=1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1cccnc1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccnc2)c1
Yield: 33.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (122 mg, yield: 33.4%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17]CCCCCCC)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].OC1C=C(O)C=CC=1C(C1C=CC=CC=1)=O.OC1C(C(C)(C)C)=CC(C)=CC=1N1N=C2C=CC(Cl)=CC2=N1.OC1C(C(C)(C)C)=CC(C(C)(C)C)=CC=1N1N=C2C=CC(Cl)=CC2=N1.OC1C=CC(C)=CC=1N1N=C2C=CC=CC2=N1.OC1C(C(CC)(C)C)=CC(C(CC)(C)C)=CC=1N1N=C2C=CC=CC2=N1.C(OC1C=CC=CC=1)(=O)C1C(=CC=CC=1)O.C(C1C=C(C(C)(C)C)C=CC=1C1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1C([O-])=O)(C)(C)C>>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1ccc(-c2c(C(=O)[O-])cc(C(C)(C)C)c(O)c2C(C)(C)C)c(C(C)(C)C)c1
Agent: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1

Procedure:
2-hydroxy-4-octoxybenzophenone: 2,4-dihydroxybenzophenone; 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole; 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole; 2-(2'-hydroxy-5'-methylphenyl)benzotriazole; 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole; phenyl salicylate: 2,4-di-t-butylphenyl-3,5-di-t-butyl-4-hydroxybenzoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(OCc3ccccc3)c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 5,6-dihydro-4-(3-hydroxyphenyl)pyridine-1(2H)-carboxylate (crude, 100 mg) and potassium carbonate (300 mg) in DMF was added benzyl bromide (60 μL) at room temperature. The resulting mixture was stirred at 80° C. for 16 h. The mixture was cooled down, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The product (60 mg) was purified by combiflash using hexane/ethyl acetate (max. EtOAc 10%) to afford tert-butyl 4-(3-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate which was then converted to the final compound using procedures analogous to those for example 1. MS(ESI): (M+H)+=462.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH3:49][CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([N:52]3[CH2:53][CH2:54][CH2:55][CH:50]([CH3:49])[CH2:51]3)=[O:24])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC1CCCNC1
Reactant: C[C@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCN(C(=O)[C@@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.018 g) in DCM (0.5 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.018 g), HOBT (0.013 g) and triethylamine (0.039 ml) and the mixture was stirred at room temperature for 75 min. 3-Methylpiperidine(0.010 ml) was added and the resultant mixture stirred at room temperature for 48 h. The mixture was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The organic extract concentrated under reduced pressure and the residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 2:1, 1:1; ethyl acetate; ethyl acetate:methanol 2:1, 1:1) to give the title compound (0.007 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[C:24]=1[N+:30]([O-:32])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[NH2:29][C:25]1[C:24]([N+:30]([O-:32])=[O:31])=[C:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
Tert-butyl 4-hydroxyphenylcarbamate (3.63 g, 17.4 mmol) was dissolved in dry DMF (150 mL). Potassium tert-butoxide (2.62 g, 23.4 mmol) was added and the stirring was continued for 30 minutes at room temperature. 4-Chloro-3-nitropyridin-2-amine (3.0 g, 17.3 mmol) was added as a solid in one portion and the reaction mixture was subsequently heated at 85° C. for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate (800 ml) and washed with water (lx 800 ml) and brine (2×800 ml). The organic layer was dried with magnesium sulphate and evaporated. The crude was chromatographed over silica (eluant ethyl acetate:cyclohexane 1:2) to yield 4.0 g (63% yield) of tert-butyl 4-(2-amino-3-nitropyridin-4-yloxy)phenylcarbamate.
Reaction SMILES: C(OC([C:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]=1[NH:12][CH2:13]C1C=CC=CC=1)=O)C.C(OC(C1CCN(C(OC(C)(C)C)=O)CC1=O)=O)C.C(N)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]([O:22][C:20]([N:9]1[CH2:8][CH2:7][CH:6]2[CH:11]([NH:12][CH2:13]2)[CH2:10]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CCOC(=O)C1=C(NCc2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2CNC2C1
Yield: 92.5 %

Procedure:
5-Benzylamino-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester. 3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8.15 g, 30 mmol) from Step A and benzyl amine (3.43 g, 31.8 mmol) were dissolved into toluene (150 mL). The mixture was refluxed vigorously for 72 h and the generated water was collected into Dean-Stark apparatus. The residual solution was concentrated to yield the title compound (10.2 g, 92.5%). MS (ESI) mass calcd. for C20H28N2O4, 360.45, m/z found, 361.2 [M+H]+. The crude product was carried to the next step without any purification.