Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.ClC(OCC)=O.[NH2:27][CH:28]1[C:41](=[O:42])[N:30]2[CH:31]([C:36]3[NH:40][N:39]=[N:38][N:37]=3)[C:32]([CH3:35])([CH3:34])[S:33][C@H:29]12.[OH-].[Na+:44]>CN1CCOCC1.O.O1CCCC1>[CH3:20][O:19][C:13]([CH:14]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1)[CH:15]=[CH2:17])=[O:18].[Na+:44].[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:27][CH:28]2[C:41](=[O:42])[N:30]3[CH:31]([C:36]4[NH:37][N:38]=[N:39][N:40]=4)[C:32]([CH3:34])([CH3:35])[S:33][C@H:29]23)=[O:12])=[CH:7][CH:8]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: NCc1ccc(CC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: C=CC(NCc1ccc(CC(=O)[O-])cc1)C(=O)OC
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccc(CN)cc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
Sodium 4-[(1-methoxycarbonyl-2-propenyl)aminomethyl]phenylacetate is prepared from 4-aminomethylphenylacetic acid [Zaugg and Horrom, J. Am. Chem. Soc. 80, 4317 (1958)] and methyl acetoacetate by the method described by Dane and Dockner [Chem. Ber., 98, 789 (1965)]. A suspension of this salt (2.15 g, 7.5 mmole), 7 drops of N-methylmorpholine and 100 ml. of tetrahydrofuran is stirred at -20° C.; ethyl chloroformate (0.81 g. 7.5 mmole) is added and the mixture is stirred for 60 minutes. 6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam (1.80 g., 7.5 mmoles) is suspended in a 50:50 mixture of tetrahydrofuran and water (40 ml), and the pH is adjusted to 7.5 with 1 N sodium hydroxide solution whereby a homogeneous solution is obtained. This is added to the above suspension, in one portion, the new mixture is stirred at -20° C. for 1 hour and then it is allowed to warm to room temperature over 1 hour. Most of the tetrahydrofuran is removed in vacuo, the resultant aqueous solution is cooled in an ice bath, and the pH is adjusted to 1.5 with 3 N hydrochloric acid. After 30 minutes the pH is adjusted to 2.5, and the solution is extracted with ethyl acetate. The aqueous phase is adjusted to pH 6.0 and freeze-dried. The resultant lyophylate is combined with that from another preparation (5 mmoles) and chromatographed on Sephadex LH-20 (150 g) eluting with water. Like fractions (tlc analysis) are combined and freeze-dried, yielding the title compound as a colorless amorphous solid (570 mg., 11% yield), m.p. 190°-200° C. IR(KBr): 1770, 1650 and 1515 cm-1. NMR (DMSO-d6 -D2O): 7.4 ppm (s, 4H), 5.65 ppm (d, J=4 Hz, 1H), 5.45 ppm (d, J=4 Hz, 1H), 5.2 ppm (s, 1H), 4.1 ppm (s, 2H), 3.6 ppm (s, 2H), 1.6 ppm (s, 3H) and 1.0 ppm (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[CH:32][C:31]([C:34]4[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=4)[C:37](O)=[O:38])=[CH:30][C:24]=3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[CH:32][C:31]([C:34]4[CH:42]=[CH:41][CH:40]=[C:36]([C:37]([N:11]5[CH2:12][CH2:13][CH:9]([C:6]6[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=6)[CH2:10]5)=[O:38])[CH:35]=4)=[CH:30][C:24]=3[C:25]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:17][CH:16]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: Fc1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N4CCC(c5ccc(F)cc5)C4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
3-(4-Fluorophenyl)pyrrolidine hydrochloride (25 mg, 0.12 mmol) was added to a stirred suspension of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (20 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIPEA (50 μL, 0.29 mmol) in DMF (0.5 mL). The reaction was stirred at r.t. overnight, then diluted with MeOH, filtered, and purified by prep HPLC. Concentration afforded the title compound (22 mg, 79% yield) as a pink solid. 1H NMR (˜1:1 ratio of amide rotamers, 500 MHz, DMSO-d6) δ ppm 8.44-8.54 (m, 1 H) 7.98-8.06 (m, 2 H) 7.66-7.91 (m, 5 H) 7.52-7.61 (m, 2 H) 7.36-7.44 (m, 3 H) 7.33 (dd, J=8.55, 5.49 Hz, 1 H) 7.18 (t, J=8.85 Hz, 1 H) 7.12 (t, J=8.85 Hz, 1 H) 4.01 (dd, J=11.14, 7.17 Hz, 0.5 H) 3.72-3.82 (m, 1.5 H) 3.56-3.69 (m, 1.5 H) 3.36-3.55 (m, 1.5 H) 2.87 (d, J=4.58 Hz, 1.5 H) 2.84 (d, J=4.58 Hz, 1.5 H) 2.27-2.34 (m, 0.5 H) 2.24 (dd, J=6.56, 3.51 Hz, 0.5 H) 2.04-2.12 (m, 0.5 H) 2.00 (dd, J=19.84, 10.38 Hz, 0.5 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=3 min, stop time=4 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.89 min, (ES+) m/z (MH+)=537. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=14.43 min, purity=99%; column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=13.18 min, purity=99%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[N+:9]([O-])=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH:12]=3)[CH:7]=1.[CH:26]([N:29](CC)C(C)C)(C)C.C[Si](C#N)(C)C>C(#N)C.C(OCC)(=O)C>[C:26]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:25])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[N:14]=[CH:15]2)#[N:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c[n+]1[O-]
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C#N)n1
Temperature: 100 °C
Yield: 28.9 %

Procedure:
To a slurry of 3-(5-fluoro-2-methylphenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (50 mg, 0.1 mmol) in acetonitrile (0.4 mL) was added N,N-diisopropylethylamine (0.05 mL, 0.3 mmol), followed by trimethylsilyl cyanide (0.06 mL, 0.44 mmol). The mixture was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as a white solid (10 mg, 20%). 1H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 9.52 (s, 1H), 8.84 (s, 1H), 8.56 (s, 1H), 7.48-7.35 (m, 2H), 7.26 (td, J=8.5, 2.8 Hz, 1H), 2.37 (s, 3H), 2.13 (m, 1H), 0.99-0.83 (m, 4H). LCMS (Method E): RT=5.495 min, M+H+=347.1.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].[NH:40]([C:44]1[S:45][CH:46]=[C:47]([CH2:49][S:50][CH2:51][CH2:52][NH2:53])[N:48]=1)[C:41]([NH2:43])=[NH:42]>>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:28]([NH:53][CH2:52][CH2:51][S:50][CH2:49][C:47]2[N:48]=[C:44]([NH:40][C:41]([NH2:43])=[NH:42])[S:45][CH:46]=2)=[O:29])[CH3:25])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(CCCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Product: CN(CCCCCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.59 g (1.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,7-heptanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=630 ([M+H]+, 3), 109 (100); IR (KBr): 1666 cm-1 (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 125° C. (isopropanol/ether).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10](#[N:12])[CH3:11].[H-].[Na+]>C1COCC1>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:11][C:10]#[N:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 109.4 %

Procedure:
A solution of ethyl trifluoroacetate (14.2 g, 0.1 mol) and anhydrous acetonitrile (5.0 g, 0.12 mol) in THF (100 mL) was added dropwise to a suspension of NaH (60%, 6.0 g, 0.15 mol) in THF (100 mL) at 80° C. The resulting mixture was heated to reflux overnight, and then cooled to RT. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc and 10% aq HCL. The organic layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo to yield crude 4,4,4-trifluoro-3-oxo-butyronitrile (15 g), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH:12](OCC)OCC.O.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[O:10][CH:11]=[CH:12][C:4]=2[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCOC(COc1ccc(OC)cc1Br)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Br)c2occc2c1
Temperature: 70 °C
Yield: 14 %

Procedure:
To a mixture of the product from step B (2.7 g, 8.5 mmol) in toluene (10 mL) was added PPA (1.0 mL). The reaction was heated at 70° C. for 1 hr. The reaction was cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and the water phase was adjusted to pH 7-8 by NaOH (2 mol/L). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluted with PE) to afford the title compound (0.27 g, 16%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.68 (d, J=2.1 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 3.86 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:38]=C(C3CC3)N[N:35]=2)[C:30](=[O:42])[N:29]([CH3:43])[CH:28]=1)(=[O:3])[CH3:2].BrC1C=C(NC2C=[CH:58][C:57]([CH:60]3[CH2:63][N:62]([CH2:64][CH3:65])[CH2:61]3)=[CH:56]N=2)C(=O)N(C)C=1.C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N1C(=O)C2SC3CCCCC=3C=2CC1)(=O)C>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:38]=[CH:58][C:57]([CH:60]3[CH2:63][N:62]([CH2:64][CH3:65])[CH2:61]3)=[CH:56][N:35]=2)[C:30](=[O:42])[N:29]([CH3:43])[CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Product: CCN1CC(c2ccc(Nc3cc(-c4cc(F)cc(N5CCc6c(sc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)C1
Yield: 67 %

Procedure:
Following the procedures as described for 136e and starting with 5-bromo-3-(5-(1-ethylazetidin-3-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one (250a) and (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 212b, compound 233a was obtained in 67% yield. LCMS: (M+H)+ 597
Reaction SMILES: CS([O-])(=O)=O.[C:6]([CH:9]([CH:11]([C:13](O)=O)O)O)(O)=O.[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+].[CH2:33]([C:35]([CH3:37])=O)[CH3:34]>>[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:6][CH2:9][CH2:11][C:13]2[C:37]3[CH:6]=[CH:9][CH:11]=[CH:13][C:35]=3[CH2:33][CH2:34][C:35]3[CH:37]=[CH:19][CH:21]=[CH:22][C:33]=3[CH:34]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CCC(C)=O
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@@H]1CCCN(CCCC2=Cc3ccccc3CCc3ccccc32)C1
Yield: 36 %

Procedure:
A mixture of the above methanesulfonate (2.5 g), (R)-3-piperidinecarboxylic acid ethyl ester tartrate (4.6 g, 15.1 mmol), dry potassium carbonate (6,3 g, 45.4 mmol), and methyl ethyl ketone (100 ml) was heated at reflux temperature for 48 hours under an atmosphere of nitrogen. The cooled reaction mixture was quenched with water (100 ml) and extracted with diethyl ether (100 ml). The organic extract was washed with saturated brine (80 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product (3.1 g) was purified by column chromatography on silica gel (600 ml) using a mixture of ethyl acetate/heptane (1:2) as eluent. This afforded 1.9 g of crude (R)-1-(3-(11,12-dihydro-dibenz[a,e]cycloocten-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester. The ethyl ester was suspended in water (150 ml) and concentrated hydrochloric acid was added to pH=1. The aqueous phase was washed with diethyl ether (100 ml) basified to pH=8 with 20% sodium hydroxide and extracted with diethyl ether (2×100 ml). The combined organic extracts were washed with brine (80 ml), dried (MgSO4), filtered and the solvent was evaporated in vacuo affording 1.1 g (36%) of (R)-1-(3-(11,12-dihydro-dibenz[a,e]cycloocten-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.CN(C1C=CC=CN=1)C.[CH2:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1)[CH3:38]>C1(C)C=CC=CC=1>[CH2:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45]([O:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:26])([F:27])[F:16])=[CH:24][CH:23]=2)=[O:46])[CH2:41][CH2:40]1)[CH3:38]
Reactant: CC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](C(=O)Oc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
First, 4.6 g of dicyclohexylcarbodiimide in 80 ml of toluene are added to a mixture of 4 g of 4-trifluoromethoxyphenol and 20 ml of toluene, 0.2 g of dimethylaminopyridine is then added, the mixture is stirred at room temperature for I hour, and 3.8 g of trans-4-ethylcyclohexanecarboxylic acid are then added. After work-up and purification by chromatography and/or crystallization, 4-(trifluoromethoxy)phenyl trans-4-ethylcyclohexanecarboxylate is obtained.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:8][C:9]1[CH:10]([CH3:21])[N:11]=[C:12]([O:18][CH2:19][CH3:20])[C@H:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[CH3:7].[Cl:22][C:23]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:40][CH2:41]CI.O>CCCCCC.C1COCC1>[Cl:22][C:23]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:40]([CH3:41])[CH2:21][C@:10]1([CH3:1])[C:9]([O:8][CH2:6][CH3:7])=[N:14][C@@H:13]([CH:15]([CH3:16])[CH3:17])[C:12]([O:18][CH2:19][CH3:20])=[N:11]1
Reactant: FC(F)(F)c1cccc(Oc2ccc(CCCI)c(Cl)c2)c1
Reactant: [Li]CCCC
Reactant: CCOC1=N[C@@H](C(C)C)C(OCC)=NC1C
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC1=N[C@](C)(CC(C)c2ccc(Oc3cccc(C(F)(F)F)c3)cc2Cl)C(OCC)=N[C@H]1C(C)C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a solution of n-butyllithium in hexane (1.54 mol/L, 3.59 mL) was added at −78° C. into a solution of (5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine (905 mg) in THF (16 mL), and the resultant solution was stirred at −78° C. for 30 minutes. Next, A solution of 2-chloro-1-(3-iodopropyl)-4-(3-trifluoromethylphenoxy)benzene (2.47 g) in THF (4 mL) was added to the reaction mixture, and the resultant solution was stirred at −78° C. for 30 minutes and then at 0° C. for 1 hour. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:1) to obtain the target product (1.59 g) as a colorless oil.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[N+:20]([C:23]1[CH:24]=[CH:25][C:26]2[N:32]3[C:33]([CH2:36]Cl)=[N:34][N:35]=[C:31]3[CH2:30][N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[C:27]=2[CH:45]=1)([O-:22])=[O:21]>CC(N(C)C)=O>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]2[N:32]3[C:33]([CH2:36][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:34][N:35]=[C:31]3[CH2:30][N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[C:27]=2[CH:45]=1)([O-:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-nitro-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-nitro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Br:1]Br.[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]3[C:21]([O:35][CH3:36])=[CH:22][C:23]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32]([CH3:34])=[O:33])=[CH:24][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].CCOC(C)=O>C(O)(=O)C>[Br:1][C:24]1[C:14]2[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=3)[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]=2[C:21]([O:35][CH3:36])=[CH:22][C:23]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([CH3:34])=[O:33]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3S(C)=O)cc(OC)c21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3S(C)=O)cc(OC)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 501.7 %

Procedure:
53 μl (0.122 mmol) bromine are added to a solution of 496 mg (1.03 mmol) 2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-benzyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 22 ml glacial acetic acid. The reaction mixture is stirred at room temperature for 10 min. Then 25 ml EtOAc are added and this solution is washed with 4N NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:4) to afford 340 mg of the title compound as colorless crystals.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]([C:27](=[O:29])[CH3:28])=[C:25]([Cl:30])[N:24]=[C:23]3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:27]([C:26]1[N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][CH:17]=2)[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:24][C:25]=1[Cl:30])(=[O:29])[CH3:28]
Reactant: CC(=O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reaction time: 24 h
Yield: 97.5 %

Procedure:
1.0 g of 4′-(5-acetyl-4-chloro-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acid tert-butylamide and 230 μl of anisole are dissolved in 5 ml of trifluoroacetic acid and allowed to stand at RT for 24 h. The volatile constituents are then removed in vacuo and the residue is digested with 50 ml of heptane. 870 mg of an amorphous solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[C:15]#[CH:16].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:18]([S:17][CH2:14][C:15]#[CH:16])([CH3:22])[CH3:21]
Reactant: C#CCSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C#CCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 21 °C
Reaction time: 17 h
Yield: 74.8 %

Procedure:
2-Amino-1-(2 -mercapto-2-methylpropylamino)benzene (5.59 g, 2.85×10-2 mol) and 2-(2-propynylthio)-2-methylpropanal (6.07 g, 4.28×10-2 mol, 150 M%) were mixed, then 125 ml methanol and 5.27 ml (5.7×10-2 mol, 200 M%) acetic acid were added and solids were allowed to dissolve. Sodium cyanoborohydride (5.39 g, 8.56×10-2 mol, 300 M%) was added to the reaction solution in three equal portions. The reaction was stirred at 21° C. for 17 hr, then quenched with 100 ml 0.5 M HCl, stirred for 15 min, and then extracted with 2×150 ml ether. The ether layers were combined, washed with 60 ml saturated NaCl solution and dried over Na2SO4. The solvent was removed on the rotary evaporator and the residue was purified by filtration through flash silica in a 600 ml sintered glass funnel 3/4 full of silica, eluting with 500 ml portions of 2×hexane and 2×90% hexane/ether to produce 6.88 g (75% yield) 2-(2-mercapto-2-methyl-propylamino)-1-[2-(2-propynylthio)-2-methylpropylamino]-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=CC1CCCC1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/C1CCCC1

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (1.16 g, 6.59 mmol) was reacted with cyclopentanecarbaldehyde (0.77 g, 7.85 mmol) (Wiley) and piperidine (0.67 g, 7.85 mmol) in methanol to give a mixture of E- and Z-6-Chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one as a brown oil (Yield 0.8 g, 49%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:5]=1>[Pd].CO>[NH2:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:7]=1)[C:3]([NH:2][CH3:1])=[O:19]
Reactant: CNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(N)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure V using N-methyl-3-morpholino-5-nitrobenzamide (0.183 g, 0.690 mmol), 10% palladium on carbon (0.011 g, 0.103 mmol), and methanol (3 mL) to afford 3-amino-N-methyl-5-morpholinobenzamide as a beige amorphous solid. Mass Spectrum (ESI) m/e=236.2 (M+1).