Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[H-].[Na+].[C:17]([O:22][CH3:23])(=[O:21])[C:18]#[C:19][CH3:20]>C1C=CC=CC=1>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([O:10]/[C:19](/[CH3:20])=[CH:18]\[C:17]([O:22][CH3:23])=[O:21])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CC#CC(=O)OC
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC1(C)CC(O/C(C)=C\C(=O)OC)C(C)C(C)(CC)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of 3.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidinol (Compound 1) in 30 ml of benzene was added, in small portions at room temperature, 0.72 g of 50 % sodium hydride. The mixture was then stirred for 30 minutes at room temperature. A solution of 2.2 g of methyl tetrolate in 10 ml of benzene was then added dropwise, with ice-cooling to the mixture and the whole mixture was stirred at room temperature for 64 hours. The mixture was then poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulphate. After removing the solvent, the residue was distilled under reduced pressure, giving 3.4 g of Compound 97 as a pale yellow oil (bp 109° - 111° C/0.15 mmHg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([OH:11])[CH2:5]2.C1N=CN([C:17](N2C=NC=C2)=[S:18])C=1>C(Cl)Cl>[N:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([OH:11])[CH2:5]2)=[C:17]=[S:18]
Reactant: Nc1ccc2c(c1)CC(O)C2
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: OC1Cc2ccc(N=C=S)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
5-Amino-indan-2-ol (149 mg, 1 mmol) was dissolved in CH2Cl2 (10 mL) and TCDI (thiocarbodiimidazole, 178 mg, 1 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 30 min. Silica gel was added to the reaction mixture and dried. Purification of silica gel coated crude product by column chromatography (EtOAc:Hexane=3:7) afforded the title product as a white solid (132 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[O:21]([CH2:28][CH2:29]O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:29][CH2:28][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.81 g) in dimethylformamide (25 mL) under argon was treated with 55% sodium hydride (0.437 g), stirred for 15 minutes and treated with the mesylate of 2-phenoxyethanol (2.38 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude residue in dichloromethane was passed through a plug of silica gel (5 g) and evaporated and the resulting solids were crystallized from diethyl ether-hexane to give 1.85 g of alpha-oxo-4-[[2-(phenoxy)ethyl]oxy]benzeneacetic acid methyl ester mp 79°-81° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C1C=C(Cl)C=C(C(OO)=O)C=1>CC(O)=O.C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[C@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:22][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
According to literature methods for the preparation of oxycodeinone from thebaine,[16] oripavine (1.00 g of 78% w/w, 2.62 mmol) was treated with two portions of m-CPBA (0.82 g in total of max 77% reagent, approx. 3.66 mmol) in HOAc (4.5 mL) and TFA (0.35 mL). When the reaction was complete, the mixture was poured into ice-water (20 mL). After stirring for 30 min, the solid was removed by filtration. The filtrate was extracted with CHCl3 (5 mL×2), made basic to pH 9 with conc. NH4OH, and extracted with CHCl3/i-PrOH (5:1; 20 mL×4). The latter extracts were combined, dried (Na2SO4), filtered and concentrated to give oxymorphinone (B1) as an off-white solid, 670 mg (85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH:5]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13](=[O:15])[NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH3:12])[CH:5]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)c1cccc(O[C@@H](C)C(=O)O)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc(O[C@@H](C)C(=O)Nc2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Cool a solution of 3-((S)-1-carboxy-ethoxy)-benzoic acid methyl ester (0.32 g, 1.43 mmol) in pyridine (5 mL) to 0° C. and add 4-aminobenzonitrile (0.20 g 1.69 mmol) followed by phosphorous oxychloride (0.15 mL, 1.60 mmol). Stir the mixture at 0° C. for 1 hour then dilute with water and extract with EtOAc. Wash the combined organic portion with a 2N solution of hydrochloric acid then dry over anhydrous sodium sulfate and concentrate under reduced pressure to provide 0.42 g of 3-[(S)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid methyl ester as a foam.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:21]3[S:20][C:19]([NH2:35])=[C:18]2[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:52])C=1>C(Cl)Cl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@H:21]3[S:20](=[O:52])[CH:19]([NH2:35])[C:18]=2[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=C(Cc2ccc(O)cc2)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: NC1C(Cc2ccc(O)cc2)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1=O

Procedure:
A solution of 1.51 g of 3-(4-hydroxy-benzyl)-7βphenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid diphenylmethylester in 40 ml of methylene chloride is cooled in an ice bath and treated with 0.52 g of purified 3-chloro-perbenzoic acid. The mixture is allowed to react for 1 hour at room temperature and the reaction solution is extracted successively with a 5% aqueous sodium hydrogen sulphite solution, a 0.5 molar aqueous dipotassium phosphate solution and water. The aqueous phases are re-extracted twice with small amounts of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulphate and evaporated to dryness under reduced pressure. The residue is crystallised from a mixture of methyl acetate and cyclohexane and yields the 3-(4-hydroxybenzyl)-7β-phenylacetyl-amino-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1-oxide, which after further crystallisation from a mixture of methyl acetate and cyclohexane and drying under a high vacuum for 20 hours at 35° melts at 192°-193°; [α]D20 = +36° ± 1° (c = 1.025 in dioxane); thin-layer chromatogram (silica gel: development with iodine): Rf = 0.18 (system: toluene/ethyl acetate 2:1), Rf = 0.36 (system: toluene/ethyl acetate 1:1), Rf = 0.24 (system: toluene/acetone 4:1), Rf = 0.07 (system: toluene/acetone 9:1) and Rf = 0.52 (system: methylene chloride/acetone 6:1); ultraviolet absorption spectrum (95% ethanol): λmax = 268 mμ (ε = 11300) and λmin = 241 mμ: infrared absorption spectrum (in mineral oil): characteristic bands at 2,94μ, 3,00μ, 5,60μ, 5,78μ, 5,85μ, 6,58μ, 6,65μ, 7,30μ, 7,99μ, 8,48μ, 8,70μ, 9,02μ, 9,78μ, 12,03μ, 13,45μ and 14,26μ.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NC1CCc2ccccc2NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)NC1CCc2ccccc2NC1=O
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 50 mg (0.28 mmol) 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1; Step A) in 2 mL methylene chloride at room temperature was added 56 mg (0.30 mmol, 1.05 eq) 3-(t-butoxycarbonylamino)propanoic acid followed by 0.1 mL diisopropylethylamine (74 mg, 0.57 mmol, 2 eq) and 190 mg (0.43 mmol, 1.5 eq) benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate. After 1 hour at room temperature, the mixture was added to 20 mL ethyl acetate and washed with 1M aqueous citric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed in vacuo. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (2:1) to afford 76 mg (0.22 mmol, 77%) of product as a white solid. 1H NMR (200 MHz, CDCl3): 1.40 (s,9H), 1.95 (m,1H), 2.40 (t,6 Hz,2H), 2.6-3.0 (m,3H), 3.36 (q,6 Hz, 2H), 4.52 (m,1H), 5.15 (br t,1H), 6.58 (br d,1H), 7.0-7.3 (m,4H), 7.6 (br s,1H). FAB-MS: calc. for C18H25N3O4 347; found 348 (M+H,35%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6](=[O:32])[CH2:7][C:8](=[O:31])/[CH:9]=[CH:10]/[C:11]1[C:12]([CH:28]2[CH2:30][CH2:29]2)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:2].C(N(CC)CC)C.C(O)=O.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@H:6]([OH:32])[CH2:7][C@H:8]([OH:31])/[CH:9]=[CH:10]/[C:11]1[C:12]([CH:28]2[CH2:29][CH2:30]2)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:2]
Reactant: CCOC(=O)CC(=O)CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dioxo-hept-6-enoic acid ethyl ester (600 mg, 1.347 mmol) in N,N-dimethylformamide (5 ml) under argon is added (1R,2R)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine-RuII-pcymene complex [cf. above] (40 mg, 0.067 mmol) and formic acid-triethylamine 5:2 (v/v)-mixture (2 ml). After stirring at 50° C. for 30 min, triethylamine (4.7 ml, 33.79 mmol) is added to the orange, clear solution, and stirring is continued at 50° C. for 19 hours. Evaporation of the reaction mixture under reduced pressure, followed by silica gel chromatography (toluene/ethyl acetate 3:1) of the dried residue affords (E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid ethyl ester. MS (EI): [M+]447, diastereomeric purity (syn/anti): 90.0/10.0%, enantiomeric purity (3R5S/3S5R): 80.0/20.0% (HPLC on ChiralPak AD-column).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].S(=O)(=O)(O)O.C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]([CH3:21])=O>>[CH3:18][C:19]1([CH3:21])[O:6][CH:3]([CH2:2][Br:1])[CH2:4][O:5]1
Reactant: CC(C)=O
Reactant: OCC(O)CBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)OCC(CBr)O1
Reaction time: 24 h
Yield: 53.5 %

Procedure:
Into a 500 milliliter round bottom flask equipped with a magnetic stir bar and drying tube, a solution of 28.0 grams (0.181 mole) of 3-bromo-1,2-propanediol in 200 milliliters of acetone was added. Then, 0.5 milliliter of concentrated sulfuric acid was added and the reaction allowed to proceed at room temperature for 24 hours with continuous stirring. The reaction mixture was neutralized with 13.0 grams of K2CO3 for 30 minutes, the solution was filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in 150 milliliter of ether, extracted three times with 150 milliliter portions of water and the organic layer dried over anhydrous sodium sulfate. The filtered ether was evaporated in vacuo and 100 milliliters of hexanes was added, resulting in two layers. The upper layer was decanted and evaporated in vacuo to provide 19.1 grams (53.5%) of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl bromide. The desired analog was then prepared in an analogous manner to that of (±)-3-hexadecylthio-2-methoxy-N,N-dimethyl-N-β-hydroxyethyl-1-propyl ammonium bromide from 2.5 grams (0.013 mole) of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl bromide, 1.3 grams (0.014 mole) of N,N-dimethylaminoethanol, and 15 milliliters of CH3CN. Chromatography with Florisil® (CHCl3 :MeOH 3:1 as eluent) provided 0.860 milligrams (23%) of product as a thick oil. 1H-NMR (CDCl3): delta, 1.25 (s, 3H, CH3), 1.35(s, 3H, CH3), 3.4-3.48[s, 6H, CH2 --N(CH3)2 ], 3.75-4.25(m, 9H, CH, CH2 --O, CH2 --N--CH2 --CH2 --OH). Anal. (C10H22NO3Br) C,H,N.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[C:16]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:35](=[O:36])[C@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH:26][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH3:3]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
Glycine ethyl ester.hydrochloride in an amount of 20.6 g was dissolved in 500 ml of chloroform and 20 ml of triethylamine was added thereto. Then, 57.2 g of carbobenzoxyphenylalanine p-nitorphenyl ester was added to the resulting mixture and the reaction was carried out overnight at room temperaure. The resulting mixture was washed with IN-NaHCO3, water, IN-HCl and water in this order and the chloroform layer was dried over magnesium sulfate MgSO4). After removing the solvent by distillation, the residue was recrystallized from ethyl acetate and petroleum ether to give carbobenzoxy-phenylalanyl-glycine ethyl ester having a melting point of 110°-112° C. in yield of 40.5 g (81%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:23]=[C:22]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:4]=1[C:5]([C:7]1[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]([Cl:19])[C:8]=1[C:9](O)=[O:10])=[O:6].CN(C)C1C=CC=C(N(C)C)C=1.C(OC(=O)C)(=O)C>CCCCCC>[CH3:27][N:2]([CH3:1])[C:3]1[CH:23]=[C:22]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:4]=1[CH:5]1[C:7]2[C:8](=[C:12]([Cl:19])[C:13]([Cl:18])=[C:14]([Cl:17])[C:15]=2[Cl:16])[C:9](=[O:10])[O:6]1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(N(C)C)c1
Agent: CN(C)c1cccc(N(C)C)c1
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(C)C)c1

Procedure:
A mixture of most of the 2-(2,4-bis(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid from part A of this example, N,N,N',N'-tetramethyl-m-phenylenediamine (0.82 g. plus 0.4 g.) and acetic anhydride was heated under reflux. Concentration of a toluene extract of the resulting product gave a tar, which was slurried in hexane, affording 3,3-bis(2,4-bis(dimethylamino)phenyl-4,5,6,7-tetrachlorophthalide (I: X = Y2 = Y4 = (CH3)2N, Z4 = Z5 = Z6 = Z7 = Cl) (m.p. 195°-197° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH3:13])[CH:8]=[C:9](I)[CH:10]=1)=[O:5])[CH3:2].CCN(CC)CC.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)#[CH:22]>C(#N)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH3:13])[CH:8]=[C:9]([C:22]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: C#Cc1cccc(OC)c1
Reactant: CCOC(=O)c1cc(I)cn1CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(C#Cc2cccc(OC)c2)cn1CC
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Argon was gently bubbled to a mixture of ethyl-4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester (4.1 g, 14 mmol), CuI (0.14 g, 0.76 mmol), Et3N (40 ml, 287 mmol) and tetrakis(triphenylphosphosphine) palladium (0) (0.64 g, 0.554 mmol) in ACN (20 mL) over 5 minutes. A prepared solution of 1-ethynyl-3-methoxy-benzene (2.03 g, 15.4 mmol) in ACN (5 mL) was added into it and the new mixture was reflux under Nitrogen for 3 hours. The resulting brown colored reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was diluted with water and extracted with ether. The combined ether extracts were washed with saturated aqueous solution of NH4Cl, brine, dried (MgSO4) and filtered. Evaporation and purification by flash chromatography on silica gel (Hexane/EtOAc 9.7/0.3) gave the title compound as a yellow brownish oil (3.6 g, 84% yield), 1H NMR (400 MHZ, CDCl3) δ 1.31-1.34 (t, 3H), 1.38-1.40 (t, 3H), 3.78 (s, 3H), 4.25-4.27 (q, 2H), 4.30-4.33 (q, 2H), 6.83 (m, 1H), 6.89 (m, 1H), 7.06 (m, 3H), 7.19 (m, 1H), MS m/e (M+H)+ 298.1.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([C@@H:15]1[CH2:20][C@@H:19]([N:21]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)[C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:18][CH2:17][N:16]1[C:39](=[O:49])[C@H:40]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH2:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([C@@H:15]1[CH2:20][C@@H:19]([N:21]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)[C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])[CH2:18][CH2:17][N:16]1[C:39](=[O:49])[C@H:40]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:41][C:5](=[O:7])[CH3:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 2.5 h

Procedure:
35 μl (0.376 mmol) of acetic anhydride are added to a solution of 180 mg (0.313 mmol) of the mixture of (2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine diastereomers in 2 ml pyridine at 0°, and the mixture is stirred at 0° for 2.5 hours. The oily residue after evaporation in a rotary evaporator is taken up in methylene chloride, washed with 5% aqueous citric acid and with 1N sodium bicarbonate solution. The organic phases are dried over magnesium sulfate and evaporated to dryness. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.39, FD-MS: M+ =616.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[C:23]1[CH3:31]>>[CH3:21][N:22]1[CH:26]=[C:25]([S:27]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:29])=[O:28])[N:24]=[C:23]1[CH3:31]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cn(C)c(C)n2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.8 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (21 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (4 mg, 14%) as a brown solid. MS (ESI+) for C17H22N4O3S m/z 386 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2.[BH3:30].[OH:31][C:32]([C:35]([OH:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CC([O-])=O.[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:33][C:32]1([CH3:34])[C:35]([CH3:37])([CH3:36])[O:38][B:30]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]3)[O:31]1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1CCOc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(O)C(C)(C)O
Reactant: B
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1CCOc1ccc(OC(F)(F)F)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
The ethyl 5-bromo-1-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-indole-2-carboxylate (812 mg, 1.7 mmol), pinacol borane (873 mg, 3.4 mmol), X Phos (98 mg, 0.21 mmol) and KOAc (540 mg, 5.5 mmol) were combined in 8 mL of Dioxane. The mixture was degassed under vacuum and backfilled with N2. Palladium acetate (23 mg, 0.1 mmol) was added, and the mixture was degassed and back filled again. The mixture was left to stir overnight at 85° C. EtOAc was added and the mixture was filtered through a pad of celite, concentrated in vacuo, and purified on silica (0-30% EtOAc in hexanes) to give the title product (675 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.N1C=CC=CC=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl>[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35]([N:19]1[CH2:18][CH2:17][C:16](=[C:15]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]3[CH:22]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:36]
Reactant: O=C(Cl)Cc1cccs1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1cccs1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
To a solution of 1.0 gm (3.22 mmole) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine and 0.29 mL of pyridine in 20 mL of dry CH2Cl2 at 0° C. and under an argon atmosphere was added dropwise 0.438 mL (3.55 mmol) of 2-thiopheneacetyl chloride. After 30 minutes the mixture was washed with 1.0N aqueous NaOH and then brine. The organic portion was dried over Na2SO4, filtered and converted in vacuo to provide a residue which was purified via flash chromatography (3% MeOH in CH2 Cl2) and treated with activated carbon to provide the title compound as a glass.