Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[N:5][C:6]([CH2:10][CH3:11])=[C:7](I)[N:8]=1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO[CH2:28][CH2:29][O:30][CH3:31].C([O:35][CH2:36][CH3:37])(=O)C>>[CH2:10]([C:6]1[C:7]([C:15]2[CH:14]=[C:13]3[C:37](=[CH:28][C:29]=2[O:30][CH3:31])[C:36](=[O:35])[CH2:17][CH2:16]3)=[N:8][C:3]([CH2:1][CH3:2])=[C:4]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:5]=1)[CH3:11]
Reactant: CCOC(C)=O
Reactant: CCc1nc(NC(CC)CC)c(CC)nc1I
Reactant: COCCOC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCc1nc(-c2cc3c(cc2OC)C(=O)CC3)c(CC)nc1NC(CC)CC
Temperature: 25 °C
Yield: 15 %

Procedure:
A round bottom flask was charged with [PdCl2(dppf)][CH2Cl2] (0.0327 g, 0.044 mmol), potassium acetate (0.4397 g, 4.48 mmol) and bis(pinacolato)diboron (0.416 g, 1.64 mmol) under N2. Anhydrous DMSO (10 mL) and 5-bromo-6-methoxyindan-1-one (0.360 g, 1.49 mmol) were added. After stirring the mixture at 80° C. for 5 hrs, the reaction was cooled to 0° C. The brown solution was partitioned between ethyl acetate and H2O and separated. The organic layer was washed with water (2×5 mL), dried with MgSO4, filtered and concentrated to give 0.367 g of a brown oil. The crude oil was used without further purification. A round bottom flask fitted with a condenser and stir bar was charged with crude intermediate (0.310 mg, 1.10 mmol), 3,6-diethyl-N-(1-ethylpropyl)-5-iodopyrazin-2-amine (0.344 g, 0.90 mmol), [PdCl2(dppf)][CH2Cl2] (0.040 g, 0.055 mmol), potassium phosphate (0.934 g, 4.40 mmol), and anhydrous ethylene glycol dimethyl ether (3 mL) under N2. After stirring at 90° C. for 17 hours the reaction was cooled to ambient temperature, partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with water (3×10 mL), dried with MgSO4, filtered and concentrated to provide a yellow powder. The crude product was dissolved in a minimum amount of ethyl acetate, and purified via flash chromatography (20% ethyl acetate in heptane) to give 0.050 g (15%) 5-{3,6-diethyl-5-[(1-ethylpropyl)amino]pyrazin-2-yl}-6-methoxyindan-1-one as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1 H), 7.28 (s, 1 H), 4.10-4.20 (m, 2 H), 3.83 (s, 3 H), 3.10-3.20 (m, 2 H), 2.75-2.80 (m, 2 H), 2.69 (br s, 2 H), 2.35-2.60 (s, 2 H), 1.60-1.80 (m, 2 H), 1.50-1.55 (m, 2 H), 1.20-1.40 (m, 6 H), 0.99 (t, J=8 Hz, 6 H). MS (ESI+) for C23H31N3O2 m/z 382.2 (M+H)+. Anal. Calcd. for C23H31N3O2: C, 72.41; H, 8.19; N, 11.01. Found C, 72.20; H, 8.14; N, 10.80.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:27]([NH:34][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(Cl)n3)c2)c1
Reactant: NCc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(NCc4ccccc4)n3)c2)c1
Temperature: 110 °C
Yield: 19.8 %

Procedure:
A mixture of (S)—N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-3-methylbenzamide (55 mg, 0.15 mmol), benzylamine (0.033 mL, 0.3 mmol), bis(tri-t-butylphosphine)palladium(0) (8 mg, 0.015 mmol) and sodium tert-butoxide (22 mg, 0.225 mmol) in dry toluene (1 mL) was heated in a microwave reactor at 110° C. for 1 hour. After this time the mixture was allowed to cool to room temperature and was diluted with ethyl acetate (5 mL)/methanol (5 mL), filtered through Celite and concentrated under reduced pressure to give a yellow solid which was purified by flash chromatography (silica, ethyl acetate/hexanes) followed by passage through a column of Sephadex with methanol as eluant to give the (S)—N-(3-(1-(6-(benzylamino)pyrazin-2-ylamino)ethyl)phenyl)-3-methylbenzamide (13 mg, 20%) as an unstable blue oil.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=O.[CH2:13]1[CH2:17]O[CH2:15][CH2:14]1>>[C:13]1(/[CH:17]=[CH:11]/[C:7]2[S:6][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:3][CH:2]=[CH:15][CH:14]=1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: O=Cc1cccs1
Product: C(=C/c1cccs1)\c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Benzyldiethylphosphonate (5.7 g, 25 mmol) was dissolved in THF (50 mL) and cooled to -78° C. and nBuLi (2.5 M in hexane, 25 mmol) was added dropwise and the mixture was stirred for 30 min. Then a solution of thiophene-2-carboxaldehyde (2.8 g, 25 mmol) in THF (10 mL) was added dropwise at -78° C. The cold bath was removed and the reaction was warmed to room temperature, heated for 2 h at reflux and the reaction was then cooled and saturated aqueous NH4Cl was added. The mixture was diluted with water and extracted with ether. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated to provide a solid which was purified by recrystallization from hexane to give 2.6 g of intermediate.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[N:9]=2)[C:5]([CH3:23])=[CH:4][N:3]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:31][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)[N:9]=3)[C:5]([CH3:23])=[CH:4][N:3]=2)[CH2:25][CH2:26]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Cc1cnc(F)cc1-c1cccc(NCc2cccc(F)c2)n1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(N[C@H]2CC[C@H](N)CC2)cc1-c1cccc(NCc2cccc(F)c2)n1
Temperature: 130 °C

Procedure:
To a solution of 2′-fluoro-N-(3-fluorobenzyl)-5′-methyl-2,4′-bipyridin-6-amine (18 mg, 0.058 mmol) and trans-cyclohexane-1,4-diamine (39.6 mg, 0.347 mmol), in NMP (0.3 mL) was added DIPEA (20 μL, 0.115 mmol). The mixture was heated at 130° C. for 48 h. The mixture was allowed to cool then diluted with water and then extracted with EtOAc (×3). The combined organics were washed with saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC and then lyophallized to yield N2′-(trans-4-aminocyclohexyl)-N6-(3-fluorobenzyl)-5′-methyl-2,4′-bipyridine-2′,6-diamine (4.2 mg), LCMS (m/z): 406.3 (MH+), retention time=0.53 min as a TFA salt.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:17])=[CH:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]([CH3:14])=[C:8]([CH3:15])[C:7]=1[OH:16].FC(F)(F)S(O)(=O)=O.O>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1([CH3:17])[CH2:4][CH2:5][C:6]2[C:7](=[C:8]([CH3:15])[C:9]([CH3:14])=[C:10]([OH:13])[C:11]=2[CH3:12])[O:16]1
Reactant: CC(=CCc1c(C)c(O)c(C)c(C)c1O)CCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCl)O2
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
2-(1-Chloro-2-methylbut-2-en-4-yl)-1,4-dihydroxy-3,5,6-trimethylbenzene (4.2 g, 16 mol) was suspended in carbon tetrachloride (200 ml). Trifluoromethanesulfonic acid (1.44 ml, 2.44 g, 16 mmol) was then added and the reaction mixture was stirred. After 30 min., water (100 ml) was added and the mixture was extracted with methylene chloride (100 ml). The organic phase was dried (MgSO4) and concentrated. This gave crude 2-chloromethyl-6-hydroxy-2,5,7,8-tetramethylchroman (5.3 g). Recrystallization from hexane (40 ml) gave 2.7 g (64 percent) of pure 2-chloromethyl-6-hydroxy-2,5,7,8-tetramethylchroman. The melting point of the product was 77 to 82° C. Other data regarding the product was:
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([C:15]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[F:35])[CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[O:16])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:36][C:37]([CH3:44])([CH3:43])[C:38](=[O:42])[C:39](O)=[O:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:34]1[CH:33]=[CH:32][C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[CH:18][C:17]=1[C:15]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:39](=[O:40])[C:38](=[O:42])[C:37]([CH3:44])([CH3:43])[CH3:36])[CH2:10][CH2:9]1)=[O:16]
Reactant: CC(C)(C)C(=O)C(=O)O
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)C(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 87 h
Yield: 9.4 %

Procedure:
4-(3-(1,4-diazepane-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one TFA salt (320 mg, 0.65 mmol), 3,3-dimethyl-2-oxobutanoic acid [1.6 g (60%), 7.39 mmol], DIPEA (3 ml, 17.4 mmol), and HATU (1.5 g, 3.92 mmol) were mixed in DMF (50 ml). After the resulting reaction mixture was stirred at room temperature for 87 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by preparative TLC (EA:PE=1:1) to afford the desired product (30 mg, 9.1%) as an off white solid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+].CO>>[C:30]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:29]=[CH:28][C:23]4[N:24]=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:7])[N:9]=1)#[N:31]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4nc(C)oc4c3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2ccc(Oc3ccc4c(C#N)nc(C(=O)NCC(=O)O)c(O)c4c3)cc2o1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-(2-methyl-benzooxazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester (81 mg, 0.19 mmol), glycine (292 mg, 3.89 mmol), and 0.5 M sodium methoxide/methanol (7.4 mL) was refluxed for twenty-six hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 mL) and extracted with dichloromethane (2×35 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (5.5 mL). The precipitate was filtered, washed with water and dried in vacuo to give the title compound as a brown solid (72 mg): MS: (+) m/z 419.30 (M+1); (−) m/z 417.28 (M−1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12]>C(O)C.O>[CH3:12][C:11]1([CH3:13])[S:14][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:9][CH:10]1[C:15]([OH:17])=[O:16]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(S)[C@H](N)C(=O)O
Solvent: CCO
Solvent: O
Product: CC1(C)SC(c2ccccc2)NC1C(=O)O
Reaction time: 0.25 h

Procedure:
One mole of benzaldehyde was dissolved in 100 cc of 90% ethanol with continuous stirring. One mole of penicillamine was dissolved in water with continuous stirring. The two solutions were then mixed together while stirring was continued. The solution was left to stand at room temperature. Within 15 minutes, a white precipitate occurred. The white precipitate was washed with distilled water through sintered glass. The washed precipitate was then dryed at 100° C. to obtain crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:17]([F:29])=[C:18]([CH:24]=[C:25]([F:28])[C:26]=1F)[C:19]([O:21][CH2:22][CH3:23])=[O:20].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:26]2[C:25]([F:28])=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([F:29])[C:16]=2[CH3:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(F)c(F)c(C)c1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N2C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C2)c(C)c1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of (3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidine (1.80 g, 8.97 mmol), ethyl 3-methyl-2,4,5-trifluorobenzoate (2.18 g, 10.0 mmol), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (2.24 mL, 15 mmol) in dimethyl sulfoxide (20 mL) was stirred under a nitrogen atmosphere at an external temperature of 60° C. for 70 hours. The temperature of the mixture was cooled to room temperature. The resultant mixture was poured to a 10% aqueous citric acid solution, followed by extraction with ethyl acetate (200 mL×3), washing by water (200 mL), saturated aqueous sodium hydrogencarbonate (150 mL), and saturated brine (150 mL), and dried over anhydrous sodium magnesium. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=6:1), to thereby yield the title compound as colorless crystals (2.51 g, 70.2%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[O:25][CH2:24][CH:23]=[CH:22][C:17]4=3)[NH:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:28]([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[O:25][CH2:24][CH:23]=[CH:22][C:17]4=3)[N:12]([CH2:38][CH2:37][CH2:36][CH2:35][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=Cc2c(ccc3[nH]c4c(c23)CCN(Cc2ccccc2)CC4)OC1
Reactant: BrCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C1=Cc2c(ccc3c2c2c(n3CCCCOc3ccccc3)CCN(Cc3ccccc3)CC2)OC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
To a solution containing the compound of Example 3 (0.08 g., 0.24 mmol) in N,N-dimethylformamide (5.00 mL) was added sodium hydride (0.011 g., 60% in oil, 0.29 mmol) at 0° C. The mixture was stirred at room temperature for 20 minutes, then cooled to 0° C. 4-Phenoxybutyl bromide (0.072 g., 0.32 mmol) was added to the mixture, the resulting mixture was stirred at room temperature for 16 hours. Water and ethyl acetate then were added to the mixture, and the organic and aqueous phases were separated. The aqueous layer then was extracted with ethyl acetate (2×). The combined ethyl acetate solution was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was subjected to preparative thin layer chromatography (silica gel, 50% EtOAc/hexane) to yield the alkylated compound (0.033 g, 29%) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.42, 7.13, 7.03, 6.95, 6.87, 6.71, 5.81, 4.69-4.67, 4.09, 3.93, 3.75, 3.17-3.14, 2.97-2.94, 1.87-1.76; MS (ESI+) m/z 479 (M++1).
Reaction SMILES: CCO.C([O:11][C:12]1[CH:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:11][C:12]1[CH:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(O)cc(-c2ccccc2)c1

Procedure:
In a nitrogen atmosphere, 10% palladium-carbon (900 mg) was added to a mixed solution of EtOH (40 mL)-THF (8 mL) of methyl 5-benzyloxybiphenyl-3-carboxylate (1.55 g), and stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction liquid was filtered through Celite, and concentrated under reduced pressure to obtain the title compound as a white powder. Not purified, this was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:25])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[H][H]>C(OCC)(=O)C.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:25])[C:15]=1[O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: [H][H]
Reactant: COc1ccc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1
Yield: 55.6 %

Procedure:
The title compound of Step C (93 mg) was dissolved in ethyl acetate/methanol (4 ml/2 ml) and then 10% palladium on carbon (70 mg) was added. The reaction mixture was placed on Parr shaker for four hours under 50 psi hydrogen at room temperature. The solution was filtered through diatomaceous earth, and concentrated. The residue was purified by preparative TLC (3% methanol in dichloromethane) to afford the title compound (52 mg) as a solid. MS (APCI−) Calc: 397.0, Found: 396.0 (M−1).
Reaction SMILES: C(Cl)CCl.[N:5]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][C@@H:6]1[C:7]([OH:9])=O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.FC(F)(F)C([O-])=O.[NH2:44][C@@H:45]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[N:5]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][C@@H:6]1[C:7]([NH:44][C@@H:45]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:9]
Reactant: N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: O=C([O-])C(F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
EDC (1.68 g, 8.78 mmol) was added to a solution of N-Boc-D-Pro (372 mg, 1.73 mmol) and hydroxybenzotriazole (281 mg, 2.08 mmol) in dry dichloromethane (17.3 ml) and the resulting mixture was stirred at room temperature for 2.5 hours. Distilled triethylamine (482 μl, 3.46 mmol) was then added, followed by the crude trifluoroacetate salt of D-Phe-OBn, prepared as described above. The solution was stirred for an additional 3 hours, diluted with dichloromethane and washed sequentially with a dilute solution of HCl (<5%, pH 3.0), a solution of saturated sodium bicarbonate, and brine. The combined organic layers were dried over MgSO4 and concentrated to obtain a yellow oil. This substance was subjected to silica gel chromatography, eluted with a solution that was 2:1 hexanes:ethyl acetate, and resulted in a yield of 658 mg of N-Boc-D-Pro-D-Phe-OBn as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1.N1CCCC1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:16]3[S:17][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)s1
Yield: 70.3 %

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (1.2 g, 7.2 mmol) was reacted with 5-chloro-thiophene-2-carbaldehyde (1.05 g, 7.2 mmol) and pyrrolidine (0.7 g, 9.9 mmol) to give E/Z-6-chloro-3-(5-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.5 g, 71%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15]([Cl:17])=[O:16])[CH2:4][CH2:3]1
Reactant: CC1CCNCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
9 g (90.75 mmol) of 4-methylpiperidine and 13.9 ml (100 mmol) of triethylamine were added at −30° C. to 54.9 ml (100 mmol) of phosgene in toluene (20 percent) and 100 ml of THF and, after stirring for 2.5 h, the reaction mixture was allowed to warm to room temperature. The reaction mixture was concentrated and the residue was mixed with methylene chloride and filtered off, and the filtrate was concentrated. The crude product (12.7 g) was reacted without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:45])[CH:7]([NH:29][CH:30]([C:35]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20]CC3C=CC=CC=3)[CH:16]=2)[C:11]1=[O:28])([CH3:4])[CH3:3].[H][H]>[Pd].C(O)C>[CH3:1][C:2]([O:5][C:6](=[O:45])[C@H:7]([NH:29][C@H:30]([C:35]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=2)[C:11]1=[O:28])([CH3:4])[CH3:3]
Reactant: CC(C)CC(NC(CCN1C(=O)c2ccc(OCc3ccccc3)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(O)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reaction time: 15 h
Yield: 77.4 %

Procedure:
100 mg of 2-[1-(benzylamino)carbonyl-3-methyl-butylamino]-4-(5-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 76 where the protecting group Rp, 1,1-dimethylethyl, was not removed following the condensation reaction seen in Scheme 2, was added to 10 mg of 10% Palladium on carbon in 2.5 mL absolute ethanol under 1 atmosphere of hydrogen. The mixture was stirred for 15 h and filtered through celite. The solvent was removed by evaporation and the residue was w ashed with hexane. The solvent was removed by evaporation yielding 66 mg of a white solid
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH2:19][CH3:20])=[O:13])=[CH:2]1
Reactant: CCO
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1c[nH]c2ccccc12

Procedure:
A solution of 7.38 g of 3-indolepropionic acid and 5.9 g of thionyl chloride in 50 ml of ethanol is refluxed for 2 hours, cooled and evaporated. The residue is partitioned between ether and cold sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate and evaporated to yield ethyl 3-(3-indolyl)propionate; Rf (ether/SiO2)=0.51; IR (CH2Cl2) 1725 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18]CC)=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27]CC)=[O:26])[CH:3]=1.[NH2:30][C:31]([NH2:33])=[O:32].S(=O)(=O)(O)O>>[NH:30]([C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1)[C:31]([NH2:33])=[O:32]
Reactant: NC(N)=O
Reactant: CCCc1c2nc(C(=O)OCC)cc(Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: O=S(=O)(O)O
Product: CCCc1c2nc(C(=O)O)cc(NC(N)=O)c2cc2c(=O)cc(C(=O)O)oc12
Temperature: 0 °C
Yield: 16.3 %

Procedure:
Diethyl 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (1 g) and urea (50 g) were fused together at 175° C. for 6 hours. The solid after cooling was added to 70% sulphuric acid (200 ml) and heated on a steambath for 8 hours. The mixture was poured into ice-water (2 liters) and the precipitate was collected and washed well with water to afford the sub-title compound (0.15 g): identified by NMR spectroscopy.