Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:19]=[C:18]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:33])[C:9](=[O:34])[NH:8]2)(O)=[O:2].C(N1C=CN=C1)([N:37]1C=CN=C1)=O.N>O1CCCC1.C(OCC)(=O)C>[C:1]([C:4]1[S:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:19]=[C:18]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:33])[C:9](=[O:34])[NH:8]2)(=[O:2])[NH2:37]
Reactant: O=C(O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 5-carboxy-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (14 mg) in tetrahydrofuran (1 mL) was added 1,1′-carbonylbis-1H-imidazole (9 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: methylene chloride/ methanol=10/1) to give the title compound (13 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][NH2:16])=[N:13][CH:14]=2)[O:3]1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH2:18]([NH:20][C:21]([NH:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:17])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:14][N:13]=1)=[O:22])[CH3:19]
Reactant: CC1(C)OB(c2ccc(CN)nc2)OC1(C)C
Reactant: CCN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCNC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
Into a 50 mL round bottom flask was added C-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methylamine (I-161, 1 g, crude), pyridine (10 mL), and ethyl isocyanate (0.5 mL, 6.5 mmol). The reaction was stirred at room temperature for 30 minutes and then NaHCO3 (sat) was added. The product was extracted with 3×10 mL EtOAc and the combined organics were dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography eluting with 50% acetone/dichloromethane—100% MeOH to afford 289 mg of I-162 as a brown oil in 22% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21](C)[NH:22]C(=O)CC1C=CC=CC=1.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43]([OH:45])=O)[CH:38]=[C:39]([F:41])[CH:40]=1>>[F:41][C:39]1[CH:38]=[C:37]([CH2:42][C:43]([NH:22][CH2:21][C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])=[O:45])[CH:36]=[C:35]([F:34])[CH:40]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: O=C(Cc1cc(F)cc(F)c1)NCC(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that N-[(2,3-cis)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]glycinamide (106a) was used as the amine component and 3,5-difluorophenylacetic acid was used as the acid component to afford the title compound as a 1:1 mixture with the 2S,3S diastereomer (80 mg),white solid, m.p.125-130° C. 1H NMR (300 MHz, d6-DMSO) δ 4.76 (t, 1H, J=7 Hz), 5.12 (d, 1H, J=7 Hz), 6.91-7.49 (m, 12H), 7.67 (d, 1H, J 7 Hz), 8.25 (s, 1H), 10.49 (s, 1H). MS APCI, m/z=482(M+1). LC/MS: 2.27 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Fc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
20 mg of the target compound (0.06 mmol, 7.32%) was obtained using 1-(2-fluorophenyl)piperazine (296 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [I:1]I.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.Cl.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.[OH-].[Na+]>[I:1][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:3][N:4]=1
Reactant: II
Reactant: c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Ic1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
58.1 g of iodine (229 mmol) were introduced in portions into a suspension of 25.6 g of indazole (217 mmol) in 625 ml of methanol and 625 ml of 2N sodium hydroxide solution in the course of 1 hour. The mixture was stirred at room temperature for 3 days and 75 ml of concentrated hydrochloric acid were then added, while cooling with ice, the mixture was rendered acid with 2N hydrochloric acid and 20% strength sodium thiosulphate pentahydrate solution was added until the iodine colour disappeared. The precipitate which had separated out was filtered off with suction, washed neutral with water and dried in a vacuum drying cabinet at 50° C. For purification, the solid was taken up in methanol. After undissolved constituents had been filtered off, the filtrate was concentrated to dryness on a rotary evaporator, the product being obtained as an almost white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11](=O)[CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:4][C:3]=1[CH:19]([CH3:21])[CH3:20].[H][H].[OH-].[K+]>C(O)C.[Pd]>[OH:1][C:2]1[C:3]([CH:19]([CH3:21])[CH3:20])=[CH:4][C:5]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: [H][H]
Reactant: COC(=O)CCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(CCCC(=O)O)cc(C(C)C)c1O
Yield: 91.7 %

Procedure:
Keto-ester 6 (1.0 g, 3.4 mmol) was dissolved in ethanol (50 mL) and palladium catalyst on charcoal (10%, 50 mg) was added. Hydrogenation was performed with 45 psi of hydrogen gas for 20 h. The catalyst was then filtered off and potassium hydroxide (909 mg, 16.2 mmol) was added, and the reaction mixture was refluxed for 1 h. The solvents were evaporated, and aqueous HCl (50 mL, 4.0 M) was added. The acidic aqueous phase was extracted with methylene chloride (3×30 mL), the combined organic extracts were dried over anhydrous magnesium sulfate and evaporated, giving 8 as white crystals (824 mg, 91%). 1H NMR (300 MHz, CDCl3): δ 6.89 (s, 2H), 3.18 (septet, J=6.9 Hz, 2H), 2.64 (t, J=7.7 Hz, 2H), 2.43 (t, J=7.4 Hz, 2H), 1.98 (q, J=7.7 Hz, 2H), 1.29 (d, J=6.9 Hz, 12H). 13C NMR (90.55 MHz, CDCl3): δ 180.51, 149.56, 134.07, 133.52, 123.83, 35.28, 33.98, 27.60, 27.09, 23.21. HRMS (m/z): [M+H]+ calcd. for C16H24O3 263.1653. found 263.1664.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.C([Li])CCC.CN([CH:25]=[O:26])C>>[C:13]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH:25]=[O:26])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(Br)ccc1N1CCCC1
Agent: [Li]CCCC
Product: CC(C)(C)c1cc(C=O)ccc1N1CCCC1
Yield: 80.1 %

Procedure:
In a manner analogous to example 1 d, the process is carried out by a reaction of 7.6 g (27 mmol) of 1-(4-bromo-2-tert-butylphenyl)pyrrolidine with 16.2 ml (40 mmol) of a 2.5M solution of n-butyllithium and 3.1 ml (40 mmol) of DMF. 5 g of 3-tert-butyl-4-pyrrolidin-1-ylbenzaldehyde are obtained in the form of a yellow oil (yield=80%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19](=O)(OCC)[O:20]CC.CC(C)([O-])C.[K+].O>C1COCC1>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:2]3[N:1]=[C:19]([OH:20])[N:18]=[C:16]([OH:17])[C:3]=3[N:4]=[N:5]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(Cn2nnc(C(N)=O)c2N)cc1
Reactant: CCOC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2nnc3c(O)nc(O)nc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-amino-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (0.9 g) and diethyl carbonate (1.2 mL) in THF (30 mL) was added potassium tert-butoxide (1.2 g). The mixture was refluxed under nitrogen for 6 h. It was then cooled down to room temperature. Water (20 mL) was added and the reaction mixture was concentrated to about 20 mL. It was neutralized with 1N HCl to pH 6 and filtered. Solid was collected and washed with water, and air dried to give desired product. 1H NMR (400 MHz, MeOD-d4) δ 7.24 (d, 2H), 7.21 (m, 1H), 6.92 (d, 2H), 6.88 (m, 1H), 5.52 (s, 2H), 3.78 (s, 3H) ppm; ESMS calculated for C12H11N5O3 (m/z): 273.0, found (M+H+): 274.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39]N)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:36](=[CH:37][CH:38]=1)[NH:39][C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:20]2[CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:29])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccccc3)c(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-(4-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 496.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[H-].[Na+].Cl[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C.C(OCC)(=O)C>[C:21]1([CH2:20][O:19][CH2:18][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[C:1](=[O:14])[NH:2][CH2:3][CH2:4][C:5]2=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NCCc2c1c1ccccc1n2COCc1ccccc1
Reaction time: 0.08 h

Procedure:
a solution of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (1.12 g) in dry DMF (60 ml) was treated with sodium hydride (60% dispersion in oil; 480 mg) and the resulting mixture was stirred under nitrogen until effervescence ceased. The mixture was then cooled to 0° and benzyl (chloromethyl) ether (10% w/v solution in DMF; 0,835 ml) was added over 10 min. Stirring was continued for a further 5 min and then water (10 ml) was added. The reaction mixture was concentrated in vacuo to give an oil which was dissolved in ethyl acetate (100 ml) and washed with water (3×100 ml). The organic phase was dried and adsorbed onto FCC silica. Purification by FCC eluting with System A (150:8:1) gave the title compound 1.1 g), m.p. 133°-135°.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([S:9][CH3:10])[S:8][C:4]=2[CH:3]=1.[CH2:13]([OH:16])[CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(O)=O.[Na+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:10][S:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([CH2:15][CH2:14][CH:13]=[O:16])[CH:12]=[CH:11][C:5]=2[N:6]=1
Reactant: C=CCO
Reactant: CSc1nc2ccc(I)cc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(CCC=O)cc2s1
Temperature: 100 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
A mixture of 6-iodo-2-(methylthio)benzo[d]thiazole (5.0 g, 16.3 mmol), allyl alcohol (2.2 mL, 32.6 mmol), Pd(OAc)2 (0.36 g, 1.63 mmol), tris(o-tolyl) phosphine (1.0 g, 3.3 mmol) and NaHCO3 (2.8 g, 32.6 mmol) in DMF (75 mL) was stirred at 100° C. under nitrogen atmosphere for 4 h. Then the mixture was cooled to rt and water (300 mL) was added. The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10:1 to 5:1 petroleum ether/EtOAc to afford 3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal as a dark yellow oil (2.0 g, 52%). 1H NMR (300 MHz, CDCl3) δ 9.83 (t, J=1.2 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.23 (dd, J=1.8, 8.4 Hz, 1H), 3.05 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 238 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1CCOCC1.ClC1C=C(Cl)C(Cl)=CC=1[O:40][C:41](=O)[CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>CN(C)C=O>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:41](=[O:40])[CH2:42][NH:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
14.2 g (42 mmoles) of glycine benzyl ester p-toluenesulfonate are dissolved in 100 ml of dimethyl formamide, 4.6 ml (42 mmoles) of N-methylmorpholine and 14.2 g (40 mmoles) of tert.-butoxycarbonyl-glycine 2,4,5-trichlorophenyl ester are added, and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated, and the residue is dissolved in a mixture of 150 ml of ethyl acetate and 50 ml of water. The ethyl acetate phase is washed twice with 30 ml of ice-cooled 1 n aqueous hydrochloric acid, each, and then with water, dried over sodium sulfate and evaporated. The residue is triturated with a 1:1 mixture of diisopropyl ether and petroleum ether, filtered, the solid is washed with the same solvent mixture and dried in a desiccator. 11.0 g (82.8%) of tert.-butoxycarbonyl-glycyl-glycine benzyl ester are obtained; m.p.: 83° C., Rf14 =0.1-0.2.
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br>>[C:1]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(C(C)=O)CCOCC1
Agent: Br
Product: CC(=O)C1CCOCC1
Yield: 66.3 %

Procedure:
In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99% and synthesized in the same manner as in Reference example 1 and 1.70 g (10 mmol) of 47% hydrobromic acid, and the mixture was reacted at 120° C. for 1 hour with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.17 g (Reaction yield: 65%) of 4-acetyltetrahydropyran was found to be formed.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[CH:3]=1.C(OC([N:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=2)[CH2:29]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[C:32]([C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[C:4]([O:12][C@@H:13]([C@H:15]4[CH2:19][NH:18][C:17](=[O:20])[CH2:16]4)[CH3:14])[CH:3]=3)[CH:31]=2)[CH2:36][CH2:37][NH:28]1
Reactant: C[C@@H](Oc1cc(Br)cc2ncccc12)[C@H]1CNC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)CNCC3)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
150 mg Example 27, 241 mg 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 15 mg bis(triphenylphosphine)palladium(II) chloride, 671 μL 2N aqueous sodium carbonate and 2 mL DMF were heated for 2 hours at 90° C. The mixture was partitioned between DCM and NaHCO3 (sat aq) and the organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in 10 ml 25% TFA in DCM and stirred at 25° C. overnight then concentrated in vacuo. Purification by flash chromatography using 0-25% MeOH/DCM gave 75 mg (43%) of Example 101 (R)-4-{(R)-1-[7-(1,2,3,4-Tetrahydroisoquinolin-7-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one as yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)C.CO.O.O[Li].O>C1COCC1>[C:15]1([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:22])=[O:3])=[O:21])=[CH:9][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a stirred solution of 4-phenylamino-benzoic acid (3.0 g, 0.01401 mol) in DMF (10 mL), was added DIPEA (5.4 g, 0.04205 mol), HOBt (2.27 g, 0.01682 mol) and EDCI.HCl (6.69 g, 0.03504 mol) at ambient temperature. After 2 minutes amino-acetic acid ethyl ester hydrochloride (2.33 g, 0.01682 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration, washed with water followed by hexane and dried to afford 4 g (95%) of (4-phenylamino-benzoylamino)-acetic acid ethyl ester. To a stirred solution (4-phenylamino-benzoylamino)-acetic acid ethyl ester (4 g, 0.01337 mol) in a mixture of THF (15 mL), methanol (15 mL) and H2O (8 mL) was added LiOH.H2O (2.24 g, 0.0535 mol). The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated. The residue was diluted with water and acidified with 10% aqueous citric acid solution. The resulting precipitate was isolated by filtration and dried to afford 3.3 g (91%) of (4-phenylamino-benzoylamino)-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21]([O:24][C@@H:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>>[C:21]([O:24][C@@H:25]([CH3:29])[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Product: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Exampe 68) and (S)-(−)-2-acetoxypropionyl chloride. m.p.: 236-238° C. (recrystallized from ethyl acetate) IR(KBr)ν: 3287, 1738, 1693, 1624, 1585, 1570, 1545, 1489, 1236, 1188, 739 cm−1. 1H-NMR (DMSO-d6) δ: 12.09 (1 H, br s), 10.67 (1 H, br s), 8.77 (1 H, dd, J=5.5 and 1.8 Hz), 8.10 (1 H, t, J=1.9 Hz), 7.93 (1 H, dd, J=9.1, 1.8 Hz), 7.88 (1 H, dt, J=5.4, 2.3 Hz), 7.64 (1 H, t, J=1.9 Hz), 7.12 (1 H, dt, J=9.1, 2.1 Hz), 5.13 (1 H, q, J=6.8 Hz), 2.18 (3 H, s), 1.35 (3 H, d, J=6.9 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[ClH:30].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:30].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40]([O:1][C:2]2[C:11]3[C:10]4[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=4[C:8]([CH3:17])([CH3:18])[O:7][C:6]=3[CH:5]=[C:4]([CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:3]=2)=[O:41])[CH2:33][CH2:32]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CC1CCC2=C(C1)c1c(O)cc(C(C)CCCc3ccccc3)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC1CCC2=C(C1)c1c(OC(=O)CCCN3CCOCC3)cc(C(C)CCCc3ccccc3)cc1OC2(C)C

Procedure:
0.91 g. (2.33 mmoles) of 1-hydroxy-3-(4-phenyl-1-methylbutyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-5H-dibenzo [b,d]pyran, prepared according to the method of Example 4, 0.48 g. (2.28 mmoles) of γ-morpholinobutyric acid hydrochloride (Cruickshank and Sheehan, J. Am. Chem. Soc. 83, 2891 (1961), m.p. 180° - 182° ) and 0.48 g. (2.35 mmoles) of dicyclohexylcarbodiimide (Aldrich) are combined with 35 ml. of methylene chloride and stirred at room temperature for a total of 40 hours. The insoluble by-product of dicyclohexylurea is removed using a rotary evaporator. The resulting residue is dissolved in about 20 ml. of benzene and a small amount of insoluble material is removed by filtration. The benzene is evaporated and the residue dried in vacuo to give 0.7 g. of material. Crystallization from benzene/pet ether yields the crystalline product.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(CS(N)(=O)=O)cc1
Reaction time: 5 h
Yield: 97.3 %

Procedure:
To 10% palladium on charcoal catalyst (3 g, 50% wet with water) under a nitrogen atmosphere was added a solution of 4-nitro-benzylsulfonamide (17.53 g, 81.1 mmol). in dimethylformamide (175 ml). The atmosphere of nitrogen was replaced with hydrogen and the mixture stirred vigourously for 5 h. The atmosphere was replaced with nitrogen and the mixture filtered through celite. The solvent was removed in vacuo and the residue triturated with diethylether to give a dark brown solid (14.7 g). The solid was heated in acetonitrile (440 ml) and filtered whilst hot (to remove excess catalyst). The filtrate was allowed to cool and the precipitate filtered off and dried in vacuo to give the title compound as a beige solid (12.32 g, 82%). δH [2H6]—DMSO 4.05 (2H, s); 5.11 (2H, s); 6.53 (2H, d, 8.2 Hz); 6.63 (2H, s); 7.01(2H,d, 8.2 Hz).