Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH2:19][OH:20])[CH:16]([N:21]=[N+:22]=[N-:23])[C:15]1=[O:24])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]=[O:20])[CH:16]([N:21]=[N+:22]=[N-:23])[C:15]1=[O:24])([C:10]([CH3:12])([CH3:13])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chromium trioxide (0.06 mol) is added to a solution of pyridine (0.12 mol) in methylene chloride (150 ml) and the mixture is stirred at room temperature for 15 min. A solution of N-(t-butyldimethylsilyl)-3-azido-4-(2-hydroxyethyl)-azetidin-2-one (0.01 mol) in methylene chloride (10 ml) is then added all at once. After stirring at room temperature for 5 min, the mixture is decanted and the dark, gummy residue is washed with more methylene chloride. The combined methylene chloride supernatant is concentrated under vacuum to a residue which is taken up in ether and filtered through celite. The filtrate is washed with 5% hydrochloric acid, 5% sodium bicarbonate solution, and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to yield N-(t-butyldimethylsilyl)-3-azido-4-(2-oxoethyl)azetidin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([OH:16])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:16][CH2:36][CH2:37][CH2:38][OH:39])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OCC)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1C=Cc2cc(OCCCO)c(OC)cc2C1Cc1cccc(OCC)c1
Temperature: 85 °C
Yield: 31 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (737 mg, 1.92 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.6 g, 19.2 mmol) and 3-bromo-1-propanol (0.868 m]L, 9.62 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 6-(3-hydroxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester as a colorless oil (260 mg, 31% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29].CCN(CC)CC>C1(C)C=CC=CC=1>[N+:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][C:28]([N:4]2[C:5]3[C:10](=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]4[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=4)=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=3)[C:2]([CH3:26])([CH3:1])[C:3]2=[O:25])=[O:29])=[CH:36][CH:35]=1)([O-:39])=[O:38]
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)C3(C)C)cc1

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)4-methoxy-benzamide (200 mg), 4-nitrophenyl chloroformate (166 mg; 0.83 mmol) and NEt3 (0.2 ml) in dry toluene (3 ml) is stirred in a microwave apparatus at 150° C. for 800 s. The resulting precipitate is collected by filtration and washed with cold toluene. After drying under reduced pressure the compound (240 mg) is obtained.
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].[F:11][C:12]([F:23])([C:16]([F:22])([Br:21])[C:17]([F:20])([F:19])[Br:18])[C:13](Cl)=[O:14]>N1C=CC=CC=1>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][C:13](=[O:14])[C:12]([F:11])([F:23])[C:16]([F:22])([Br:21])[C:17]([F:20])([F:19])[Br:18]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: O=C(Cl)C(F)(F)C(F)(Br)C(F)(F)Br
Solvent: c1ccncc1
Product: O=C(Oc1c(I)cc(I)cc1I)C(F)(F)C(F)(Br)C(F)(F)Br
Temperature: 50 °C
Yield: 45.2 %

Procedure:
100 grams of triiodophenol were dissolved in 100 ml of pyridine with warming to 50° C. 75 grams of 2,2,3,4,4-pentafluoro-3,4-dibromo-butyryl chloride were added dropwise through a dropping funnel with stirring at such a rate that the temperature did not rise above 65° C. The mixture was stirred at 50° C. for an additional 30 minutes, then overnight at room temperature. The mixture was washed in a separatory funnel three times with 500 ml of DI water, then filtered through a column of silica and the solvent evaporated. The material was then chromatographed on a column of silica using FREON 113 (trichlorotrifluroethane) as eluent. Chromatography on silica gave 75.5 grams of material 99% pure. The material solidified at room temperature and has a melting point of 50° C. I.R.(ν, in cm-1)=3050, 3090 (Ar--H); 1800 (C=O); 1570, 1415 (Ar C=C). m/e 62 (47%, C5H2); 69 (18%, CF3); 129 (22%, CF2Br); 131 (70%, CF2Br and C3F5); 189 (60%, C5H2I); 344 (56%, C6H2I2O); 471 (100%, C6H2I3O).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][C@@H:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][CH2:26]4)[C:18]=3[CH:17]=[CH:16]2)[CH:12]=[CH:11]1)(C(C)(C)C)(C)C.F.N1C=CC=CC=1>N1C=CC=CC=1.C1COCC1>[C@@H:25]1([NH:24][C:23]2[C:18]3[CH:17]=[CH:16][N:15]([C@@H:13]4[CH2:14][C@@H:10]([CH2:9][OH:8])[CH:11]=[CH:12]4)[C:19]=3[N:20]=[CH:21][N:22]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a solution of 7-[(1R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopent-2-en-1-yl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (81.9 mg, 0.178 mmol) in pyridine (0.800 mL) and THF (0.800 mL) at 0° C. under an atmosphere of nitrogen was added dropwise pyridine hydrofluoride (0.0500 mL, 0.555 mol). The solution was warmed to rt and stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM to afford the title compound as a white solid (˜70% purity, 35.7 mg, 41%). LC/MS: Rt=1.03 min, ES+ 347 (FA standard).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CB1N2CCCC2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)C2CCCN12
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(CCC[C@H](O)c1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -5 °C
Reaction time: 5.5 h

Procedure:
(4S)-4-Benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (13.87 g, 37.54 mmol) was dissolved in dichloromethane (40 mL). Into a separate flask were added borane-methyl sulfide complex (3.6 mL, ˜38 mmol), 1.0 M®-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole in toluene (1.9 mL, 1.9 mmol) and dichloromethane (20 mL). This mixture was cooled to −5° C. (ice/methanol bath) and the ketone solution was added drop-wise via cannula over 5 min. The reaction was stirred at −5° C. for 5.5 h and then quenched by slow addition of methanol (9 mL), 5% hydrogen peroxide solution (30 mL) and 1 M aqueous sulfuric acid (20 mL) respectively. The reaction was poured into water (500 mL) and extracted with ethyl acetate (500 mL). The organic layer was washed with water (500 mL), 0.1 N hydrochloric acid (300 mL) and brine (300 mL), dried over sodium sulfate, filtered, and concentrated to afford (4S)-4-benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one, which was used in subsequent reactions without further purification; Rf 0.14 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.37-7.24 (m, 5H), 7.19 (d, J=7.3 Hz, 2H), 7.02 (t, J=8.9 Hz, 2H), 4.72-4.61 (m, 2H), 4.21-4.13 (m, 2H), 3.27 (dd, J=13.2, 3.0 Hz, 1H), 2.99-2.94 (m, 2H), 2.74 (dd, J=13.2, 9.6 Hz, 1H), 2.27 (br s, 1H), 1.88-1.66 (m, 4H) ppm; MS [M−OH]+354.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([OH:13])=O)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][C@@H:39]1[NH:44][CH2:43][CH2:42][N:41]([S:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:40]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([N:44]2[CH2:43][CH2:42][N:41]([S:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:52][CH:53]=3)(=[O:46])=[O:47])[CH2:40][C@@H:39]2[CH3:38])=[O:13])[CH:7]=1
Reactant: O=C(O)c1cnn2cc(Br)cnc12
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cc(Br)cnc12
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
To a solution of 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (may be prepared as described in Description 17) (471 mg, 1.946 mmol) in N,N-Dimethylformamide (10 mL) under a flush of argon was added HATU (740 mg, 1.946 mmol) and the reaction stirred for 10 minutes. (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (600 mg, 1.946 mmol) was then added followed by N,N-diisopropylethylamine (0.680 mL, 3.89 mmol) and the reaction stirred for 18 h. The reaction mixture was partitioned between ethyl acetate (60 mL) and water (40 mL). The organic layer was washed with further water (20 mL) and brine (20 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by silica chromatography, 40 M cartridge, eluting 0-75% EtOAC in isohexane and the solvent evaporated to give the title compound (587 mg) as a white solid.
Reaction SMILES: [B-](F)(F)(F)F.[N+:6](=[O:8])=[O:7].N1C(C)=CC(C)=CC=1C.[CH3:18][C@H:19]([NH:22][C:23]([C@@H:25]1[CH2:29][S:28][C:27](=[O:30])[NH:26]1)=[O:24])[CH2:20][OH:21]>C(#N)C>[CH3:18][C@H:19]([NH:22][C:23]([C@@H:25]1[CH2:29][S:28][C:27](=[O:30])[NH:26]1)=[O:24])[CH2:20][O:21][N+:6]([O-:8])=[O:7]
Reactant: O=[N+]=O
Reactant: C[C@@H](CO)NC(=O)[C@@H]1CSC(=O)N1
Agent: F[B-](F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: C[C@@H](CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1
Yield: 29.2 %

Procedure:
In 10 ml of dry acetonitrile were dissolved 478 mg of nitronium tetrafluoroboron (85% content), 0.43 ml of 2,4,6-collidine was added thereto with stirring under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the resulting mixture were added 500 mg of (4R)-N-[(1S)-1-methyl-2-hydroxyethyl]-2-oxothiazolidin-4-yl-carboxamide, and the mixture was stirred at room temperature for 1 hour and 45 minutes. Then, the solvent was distilled off under reduced pressure and the thus obtained residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (3:7) as an eluent to obtain 178 mg of the desired compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[S:14][CH2:13][C@H:12]([CH2:15]O)[NH:11][C:10]3[N:17]([CH3:26])[N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[N:48]1C(=O)CC[C:49]1=O.C([Na])#N>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[S:14][CH2:13][C@H:12]([CH2:15][C:49]#[N:48])[NH:11][C:10]3[N:17]([CH3:26])[N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1
Reactant: Cc1cc(Br)ccc1[C@H]1SC[C@H](CO)Nc2c1c(-c1ccccn1)nn2C
Reactant: O=C1CCC(=O)N1Br
Agent: N#C[Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1[C@H]1SC[C@H](CC#N)Nc2c1c(-c1ccccn1)nn2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
To a solution of rac-((4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-yl)methanol (0.070 g, 0.16 mmol, Example #K.10) and triphenylphosphine (0.041 g, 0.16 mmol) in DCM (5 ml)/DMF (0.5 ml) at 0° C. was added 1-bromopyrrolidine-2,5-dione (0.028 g, 0.16 mmol). The reaction was stirred at 0° C. for about 2 h. The reaction was partitioned between DCM (25 mL) and saturated solution of NaHCO3 (40 mL). The organic layer was dried with Na2SO4, filtered and was concentrated in vacuo. The resulting residue was dissolved in DMF (1.5 ml) and cyanosodium (0.077 g, 1.57 mmol) was added. The reaction was heated at about 100° C. for about 1 h. The reaction was partitioned between EtOAc (25 mL) and brine (25 mL). The organic layer was washed with brine (25 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/heptane) to give rac-2-((4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-yl)acetonitrile (0.005 g, 0.005 mmol, 3%) as a white solid: LC-MS (Table 1, Method g): LC-MS (Table 1, Method g) Rt=2.57 min, m/z 454/456 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 8.48-8.45 (m, 1H), 7.83-7.80 (m, 1H), 7.75-7.70 (m, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.26-7.17 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.74 (s, 1H), 6.19 (d, J=5.7 Hz, 1H), 4.03-3.92 (m, 1H), 3.77 (s, 3H), 2.95-2.85 (m, 2H), 2.79-2.74 (m, 1H), 2.71-2.63 (m, 1H), 2.50 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[O:27])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1Cc2cccc(Sc3ccccc3Cl)c2N1
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cccc(S(=O)c3ccccc3Cl)c2N1

Procedure:
A solution of 2-oxo-7-(2-chlorophenylthio)indoline (1.0 g.) in chloroform (20 ml.) and m-chloroperbenzoic acid (purity: 85%, 0.73 g.) was treated in a similar manner to that of the Preparation 28-(2) to give crystals of the captioned compound (0.7 g.). mp 243° to 245° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C([O:25][C:26](=[O:35])[C@H:27]([NH2:34])[CH2:28][O:29]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:14])[CH3:15])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:34][C@H:27]([CH2:28][OH:29])[C:26]([OH:35])=[O:25])=[O:19])[N:3]=1
Reactant: CC(C)(C)OC[C@@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)N[C@H](CO)C(=O)O)nc(Cl)c2c1

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, 10/1998, Weidmann et al.) and (R)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=369.0 amu.
Reaction SMILES: O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].[CH3:28]I>C(#N)C>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COCCCCCCCCCCCC(=O)O
Reactant: CI
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COCCCCCCCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Tetramethylammonium hydroxide pentahydrate (1.7 g, 9.4 mmol) was added to a solution of the title product of Example 1 (2.0 g, 8.7 mmol) in 45 mL of anhydrous acetonitrile. After stirring for 4 hours at room temperature, methyl iodide (0.6 mL, 9.6 mmol) was added and the resulting milky solution stirred at room temperature. The solvent was removed by rotary evaporator and partioned between diethyl ether and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (2.1 g) as a pale yellow liquid. The structure was supported by NMR, infrared spectroscopy, elemental analysis and mass spectroscopy.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=O.B(F)(F)F.CCOCC.B.C1COCC1.Cl>C1COCC1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:3][C@H:2]([NH2:1])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:7]1
Reactant: COc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccccn2)CC1
Agent: B
Agent: Cl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1N1CCN(C[C@H](N)Cc2ccccn2)CC1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of (2R)-2-Amino-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-3-pyridin-2-yl-propan-1-one (1.02 g; 3 mmol, from Example 12) in THF (10 mL) was added, dropwise, BF3.Et2O (0.37 mL; 3 mmol). The reaction mixture was heated to reflux, BH3.THF (1.0M/THF) (4.3 mL; 4.3 mmol) was added dropwise at reflux, and the mixture stirred at reflux for 2.5 hours. The mixture was cooled to 0–5° C., cautiously treated with 3N HCl (10 mL), stirred at ambient temperature for 1 hour. The mixture was heated to reflux for 5 minutes, cooled to ambient temperature, concentrated on a rotary evaporator to remove THF. The aqueous residue was washed with ether (5 mL), and the ether layer discarded. The aqueous layer was rendered basic (pH 9–10) with 2.5N NaOH, and the product extracted into ethyl acetate (25 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and the solvent removed in vacuo to yield the free base of the title compound as an amber oil (804 mg; 82%), MS EI, M+ @ m/z 326; 1H NMR, 400 MHz, DMSO-d6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:10]1[CH:14]=[C:13]([C:15](Cl)=[O:16])[O:12][N:11]=1)[CH3:9].O.Cl>ClCCl>[CH2:8]([C:10]1[CH:14]=[C:13]([C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])[O:12][N:11]=1)[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCc1cc(C(=O)Cl)on1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C(=O)Nc2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
11.7 g of aniline are added dropwise to 10.0 g of 3-ethylisoxazole-5-carbonyl chloride in 150 ml of dichloromethane, while cooling with ice. The mixture is stirred overnight at room temperature, water and concentrated hydrochloric acid are added and the organic phase is separated off, washed with sodium bicarbonate solution and evaporated down to give 11.8 g of 3-ethylisoxazole-5-carboxanilide as colorless crystals of melting point 122°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:56](OC)[CH3:57])[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].[CH3:60][O:61][C@H:62](C)[C@H:63](NC(OC)=O)C(O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]1[CH2:57][CH2:60][O:61][CH2:62][CH2:63]1)[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:44])[CH3:45])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:24][CH:25]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]5)cc4)ccc3c2[nH]1)C(C)C

Procedure:
Title compound was prepared by methods analogous to those described for methyl (S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. (ESI) m/z 831 [M+H]+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33]([CH:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)=[O:34])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CN1CCC(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (26.9 mg, 69.5%), MS (ISP) m/z=456.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (31.2 mg, 0.085 mmol) and 1-methylpiperidine-4-carboxylic acid.