Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H]1(C(O)=O)O[C@@H]1C(O)=O.Br[C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([OH:14])=[O:13].[C:22]([OH:25])(=[S:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>>[C:22]([S:24][C@@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:25])[CH3:23]
Reactant: CC(O)=S
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Agent: O=C(O)[C@H]1O[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Yield: 75 %

Procedure:
In the just cited patent application EP-0 524 553 (R)-2-bromo-3-phenyl-propionic acid is reacted, under nitrogen, with thioacetic acid/potassium carbonate in the presence of 1M sodium hydroxide to give (S)-2-acetylthio-3-phenyl-propionic acid which is extracted in ethyl acetate with a yield of 75%.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(COc2ccccc2C(F)(F)F)SS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCC1=CC=C(COc2ccccc2C(F)(F)F)SS1
Reaction time: 7 h
Yield: 58 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethylsilyloxy)methyl]-6-[(2-trifluoromethylphenyloxy)methyl]-1,2-dithiin obtained above (70 mg, 0.16 mmol) in 2 mL THF was added a mixture of 1.0 mL of 1M tetrabutylammonium fluoride in THF and 0.6 mL of acetic acid. The reation mixture was stirred for 7 h until TLC analysis showed the reaction to be complete, then concentrated in vacuo. The residue was partitioned between 20 mL of water and 20 mL ethyl acetate. The organic phase was washed with 3% solution of aqueous sodium bicarbonate (50 mL), water, dried over sodium sulfate, and then concentrated to a small volume. The residue was purified by silica gel chromatography (ethyl acetate-hexane, 1:3) to yield 30 mg (58%) of the title compound; 1H NMR (CDCl3):δ7.60 (dd, J=8.0, J=l.6, 1 H), 7.50 (t, J=8.4, 1 H), 7.08 (t, J=8.0, 1 H), 6.99 (d, J=8.0 Hz, 1 H), 6.54 (d, J=6.0 Hz, 1 H), 6.44 (d, 1 H, J=6.0), 4.76 (s, 2 H), 4.30 (s, 2 H), 1.93 (bs, 1 H); 13C NMR (CDCl3):161.14, 135.73, 133.26, 128.84, 127.31 (q, J=5.4), 126.59, 125.06, 123.33, 120.90, 113.11, 69.45, 64.59; EI-MS:m/z 320.62.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH2:3][C:4](=[C:14]([C:12]#[N:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][C:7]([CH3:10])([CH3:9])[NH:8]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C1CC(C)(C)NC(C)(C)C1

Procedure:
155 g (1 mol) of triacetonamine, 113 g of ethyl cyanoacetate, 300 ml of benzene and 31 g of ammonium acetate are kept under reflux for 1.5 hours under a water separator. The benzene phase is treated with 50% of potassium carbonate, the organic phase is dried over sodium sulphate and the benzene is then stripped off in vacuo. Ethyl 2,2,6,6-tetramethyl-4-piperidinylidene-cyanoacetate is obtained as an oily residue.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH3:5][C:6]([CH3:10])=[CH:7][CH2:8]Br>O1CCCC1>[CH3:5][C:6]([CH3:10])=[CH:7][CH2:8][O:4][CH2:1][C:2]#[CH:3]
Reactant: CC(C)=CCBr
Reactant: C#CCO
Solvent: C1CCOC1
Product: C#CCOCC=C(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 29.6 ml (0.5 mol) of 2-propyn-1-ol in 500 ml of tetrahydrofuran was treated at -78° under argon with 67.3 g (0.6 mol) of potassium tert.-butylate. The mixture was stirred at -78° for 4 hours. 69.4 ml (0.6 mol) of 3,3-dimethylallyl bromide were then added and the mixture was stirred at -78° for a further 3 hours and at at room temperature for 20 hours. The reaction mixture was poured on to ice/water and extracted twice with ether. The combined organic phases were dried over magnesium sulphate and concentrated. There was obtained 1-[(3-methyl-2-butenyl)oxy]-2-propyne as a yellow oil which was processed without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:33]([CH3:47])[CH2:34][CH2:35][N:36]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:36][CH2:35][CH2:34][CH:33]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[O:15][C:16]2[N:17]=[C:18]([C:22]#[N:23])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13]1)[CH3:47]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(Oc2cccc(C#N)n2)c2ccc(C#N)cc2)CC1
Product: CC(CCN)N1CCC(C(Oc2cccc(C#N)n2)c2ccc(C#N)cc2)CC1

Procedure:
Using general procedure C with 4-[(4-cyano-phenyl)-(6-cyano-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 43) (200 mg, 0.48 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (168 mg, 0.77 mmol) and then using general procedure D afforded 6-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-cyano-phenyl)-methoxy]-pyridine-2-carbonitrile as a colourless syrup (40 mg, 22% over 3 steps).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:8])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.CCOCC>[OH:4][CH2:3][C:2]([CH3:8])([CH3:1])[O:9][C:10]1[C:11]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]([OH:20])[CH2:15][CH2:14][CH2:13]2
Reactant: CCOC(=O)C(C)(C)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CO)Oc1ccc2c(c1CCc1ccccc1)CCCC2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of ethyl 2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propanoate (1.00 g, 2.62 mmol) in tetrahydrofuran (4 mL) was added to an ice-cooled suspension of lithium aluminum hydride (150 mg, 3.94 mmol) in tetrahydrofuran (1 mL) the mixture was stirred at room temperature for 1 h, and was then cooled in ice and treated sequentially with water (0.15 mL), 15% aqueous sodium hydroxide (0.15 mL) and water (0.45 mL). The mixture was stirred at room temperature for 10 min, and was then diluted with ether (5 mL) and filtered. The filtrate was concentrated to give 6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-1,2,3,4-tetrahydro-1-naphthalenol as a white solid, 0.856 g, 95% yield. NMR spectrum was consistent with structure. Calcd. for C22H28O3: Theory: C, 77.61; H, 8.29. Found: C, 77.42; H, 8.34. 3. 6-(2-Hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]2[N:28]([CH:29]=1)[C:9]1[N:10]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[C:11](=[O:18])[C:12]3[C:17]([C:8]=1[N:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3.Br>>[OH:2][C:3]1[CH:4]=[N:5][C:6]2[N:28]([CH:29]=1)[C:9]1[N:10]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)[C:11](=[O:18])[C:12]3[C:17]([C:8]=1[N:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COc1cnc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Agent: Br
Product: O=c1c2ccccc2c2nc3ncc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Yield: 25.8 %

Procedure:
A suspension of 9-methoxy-6-(4-nitrophenyl)-pyrimido[2′,1′:2,3]imidazo[4,5-c]-isoquinolin-5(6H)-one (17) (0.26 mmol, 0.100 g) in a concentrated aqueous HBr solution (5 ml) was refluxed overnight. The reaction mixture was evaporated under reduced pressure. The crude product was brought on a filter and washed with methanol, isopropanol and isopropylether successively to give the hydrobromide salt of 9-hydroxy-6-(4-nitrophenyl)-pyrimido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (97) (0.025 g, yield=8%, purity (LC)=90%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:3])[CH3:2]>C1COCC1.CO.[OH-].[Na+]>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(OCCCc2cccnc2)cc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1cc(OCCCc2cccnc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Methyl 3-isopropoxy-5-(3-pyridin-3-ylpropoxy)benzoate (2.70 g) was dissolved in a mixed solvent of THF (30 ml) and methanol (30 ml), and 1N aqueous sodium hydroxide solution (25 ml) was added to the mixed solution. The mixture was stirred overnight at room temperature and concentrated under reduced pressure to dryness. 1N Aqueous hydrochloric acid solution (25 ml) was added thereto, and the precipitated crystals were collected by filtration and washed with water to give 3-isopropoxy-5-(3-pyridin-3-ylpropoxy)benzoic acid (1.55 g, 60%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:27]1[C:32]2[N:33]3[C:46]4[C:45]([C:31]=2[CH:30]=[CH:29][CH:28]=1)=[CH:44][CH:43]=[CH:42][C:41]=4[NH:40][C:39]1[C:34]3=[CH:35][CH:36]=[CH:37][CH:38]=1.N#N.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:27]1[C:32]2[N:33]3[C:46]4[C:45]([C:31]=2[CH:30]=[CH:29][CH:28]=1)=[CH:44][CH:43]=[CH:42][C:41]=4[N:40]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:39]1[C:34]3=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc2c(c1)Nc1cccc3c4ccccc4n-2c13
Reactant: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(N4c5ccccc5-n5c6ccccc6c6cccc4c65)cc3)cc2)cc1
Temperature: 25 °C

Procedure:
A degassed solution of 35.6 g (89 mmol) of (4′-bromobiphenyl-4-yl)-diphenylamine and 22.0 g (81 mmol) of 8H-8,12b-diazabenzo[a]aceanthrylene in 1000 ml of dioxane is saturated with N2 for 1 h. Then firstly 1.0 ml (4 mmol) of P(tBu)3, then 0.4 g (2 mmol) of palladium(II) acetate are added to the solution, and 11.7 g (122 mmol) of NaOtBu in the solid state are subsequently added. The reaction mixture is heated under reflux for 18 h. After cooling to room temperature, 1000 ml of water are carefully added. The organic phase is separated off, washed with 4×50 ml of water and dried over MgSO4, and the solvent is removed in vacuo. The pure product is obtained by recrystallisation and final sublimation in a high vacuum.
Reaction SMILES: [OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4]I.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][N:35]1[CH2:36][CH2:37][N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[CH2:33][CH2:34]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CI
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCN(c2ccccn2)CC1

Procedure:
17α-Hydroxy-21-iodopregna-4,9(11)-diene-3,20-dione (4.53 g) is stirred in acetonitrile (50 ml) with 1-(2-pyridinyl)piperazine (1.63 g) and potassium carbonate (1.34 g) at 60° for 5 hr and at 20°-25° for 17 hr. The reaction is partitioned between ether and aqueous sodium bicarbonate. The organic phase is washed with saline, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with methanol/methylene chloride (4/96) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:28]CC1C=CC=CC=1)=[O:5])[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[OH:28])=[O:5])[CH3:2]
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCN2C(=O)OCC)c(O)c1
Yield: 58 %

Procedure:
A mixture of 369 mg (0.77 mmole) of N-ethoxycarbonyl-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinone and 414 mg of 5% palladium on carbon (50% wet) in 5 ml ethanol was stirred under 1 atmosphere of hydrogen at 25° C. until the hydrogen uptake is complete (approximately 3 hours). The reaction is filtered through a filter aid, washing with ethanol and the filtrate evaporated in vacuo. The residual crude oil is purified via column chromatography on 22 g of silica gel eluting in 4 ml fractions with 15% ethyl ether in dichloromethane to yield (fractions 28-42) 174 mg (57%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:17]3[CH2:18][CH2:19][CH2:20][N:14]([CH3:13])[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1cc(Cl)cc2nc(S)oc12
Reactant: CN1CCCNCC1
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc2nc(N3CCCN(C)CC3)oc12

Procedure:
5-Chloro-7-methyl-2-mercaptobenzoxazole (200 mg) was dissolved in toluene (10 ml), N-methylhomopiperazine (1.24 ml) was added dropwise to the solution and then the mixture was stirred with heating for 1 hour. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 5-chloro-7-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (266 mg).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[N:6]1[C:22](=[O:34])[C@@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH3:25])=[O:4].O.[OH-].[Na+].ClCCl>CO>[C:30]([O:29][C:27]([NH:26][C@@H:23]([CH2:24][CH3:25])[C:22]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:3]([OH:4])=[O:2])=[O:34])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2(R/S)-carboxylic acid methylester (2.75 g, 5.76 mmol) in methanol (20 mL), was added the water solution of sodium hydroxide (0.46 g, 11.52 mmol) under nitrogen at 10-15° C. The solution was stirred at room temperature for fourteen hours, then poured into dichloromethane and washed with potassium hydrogen sulphate solution, water. The organic layer was separated and dried over magnesium sulphate, solvent removal gave a yellow foam which was pure enough for the next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:30]=[C:31]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C@@H:47]([C:61]([OH:63])=O)[CH2:48][C:49]3[CH:54]=[C:53]([C:55]([F:58])([F:57])[F:56])[C:52]([NH2:59])=[C:51]([Cl:60])[CH:50]=3)=[O:45])[CH2:40][CH2:39]2)[CH2:36][CH2:35][C:34]2[CH:64]=[CH:65][CH:66]=[CH:67][C:33]=2[NH:32]1.[NH:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:78][CH2:77][CH2:76][C@@H:75]2[C:79]([O:81][CH2:82][CH3:83])=[O:80])[CH2:70][CH2:69]1>CN(C=O)C>[O:30]=[C:31]1[N:37]([CH:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][C@H:47]([CH2:48][C:49]3[CH:54]=[C:53]([C:55]([F:57])([F:58])[F:56])[C:52]([NH2:59])=[C:51]([Cl:60])[CH:50]=3)[C:61]([N:68]3[CH2:69][CH2:70][CH:71]([N:74]4[CH2:78][CH2:77][CH2:76][C@@H:75]4[C:79]([O:81][CH2:82][CH3:83])=[O:80])[CH2:72][CH2:73]3)=[O:63])=[O:45])[CH2:42][CH2:43]2)[CH2:36][CH2:35][C:34]2[CH:64]=[CH:65][CH:66]=[CH:67][C:33]=2[NH:32]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
64 mg (0.20 mmol) TBTU and 28 μL (0.20 mmol) triethylamine were added to a solution of 100 mg (0.18 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF and stirred for 10 min at RT. 45 mg (0.20 mmol) ethyl (R)-1-piperidin-4-yl-pyrrolidine-2-carboxylate were added to the reaction mixture and this was shaken overnight at RT. After filtration through a syringe filter the reaction solution was purified by HPLC without further working up. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][N:1]3[CH:2]([C:11]4[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=4[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2[nH]ccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 1H-indole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 365.00 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([OH:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].[Cl:24][C:25]1[CH:26]=[C:27]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:37][C@@:36]([C:33]4[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:27]5[CH:39]=[CH:40][C:41]([Cl:42])=[C:25]([Cl:24])[CH:26]=5)=[CH:31][CH:32]=4)([OH:38])[O:16][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: COC(=O)C1Cc2cc(O)c(O)cc2CN1C(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@](O)(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 100 °C
Reaction time: 12 h
Yield: 63.5 %

Procedure:
6,7-Dihydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (0.76 g) was dissolved in anhydrous DMF (20 mL). To this solution 1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (0.93 g) and potassium carbonate (0.7 g) were added and heated to 100° C. The reaction mixture was stirred at this temperature for 12 hours. After the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate (50 mL) and washed with brine (2×50 mL), dried over (sodium sulfate) and concentrated in vacuo to give the crude product. The residue was then purified by flash column chromatography (hexanes:ethyl acetate 90:10 to 60:40) to give the desired product, (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-3-hydroxy-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (0.92 g). 1H NMR (400 MHz, CDCl3): 7.91 (d, 2H), 7.82 (d, 1H), 7.58 (d, 1H), 7.54 (d, 1H), 7.47 (m, 1H), 7.00 (m, 2H), 6.78 (m, 1H), 5.32 (s, 1H), 5.09 (s, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.62 (s, 3H), 3.06 (m, 1H), 1.51 (s, 9H), 1.26 (m, 2H), and 0.88 (t, 2H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1)[CH3:7].CN(C)[C:21](=[O:23])[CH3:22].Cl>CCCCCC.O1CCCC1>[CH2:6]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:21](=[O:23])[CH3:22])=[N:16][CH:17]=1)[CH3:7]
Reactant: CC(=O)N(C)C
Reactant: CCOCCOc1ccc(C)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCCOc1ccc(CC(C)=O)nc1
Reaction time: 0.17 h

Procedure:
2.5 ml of a 2.5 M solution of n-butyllithium in hexane are added dropwise at 5° C. to a solution of 1 g (5.5 mmol) of 5-(2-ethoxyethoxy)-2-methylpyridine in 20 ml of tetrahydrofuran. The mixture is stirred at 0°-5° C. for 10 minutes and then 530 mg (6 mmol) of N,N-dimethylacetamide dissolved in a little tetrahydrofuran are added. After stirring at room temperature for 90 minutes, the pH is adjusted to 5 with dilute hydrochloric acid and the tetrahydrofuran is stripped off. The residue is extracted with ethyl acetate, and the organic phase is dried with sodium sulphate and evaporated. Yield: 580 mg (47% of theory), content according to GC/MS: 75%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:4]=1[C:12]#[N:13])#[N:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CC(C)(C)c1ccccc1O
Product: CC(C)(C)c1ccccc1Oc1ccc(C#N)c(C#N)c1
Yield: 79.7 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-4-nitrobenzene and 3.0 grams of 2-t-butyl-hydroxybenzene, there was obtained 2.2 grams of 1,2-dicyano-4-(2-t-butylphenyloxy)benzene (yield of 80%). Next, as in Synthesis Example 1 but using 1.38 grams of this benzene compound and 0.42 gram of BBr3, there was obtained 0.77 gram of the end product (yield 50%, mp 163°-165° C.).