Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])[CH2:9][CH3:10]>CN(C=O)C>[CH3:11][C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[C:34]([C:36]([OH:1])=[O:37])[CH:33]=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:7])[CH2:9][CH3:10]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCOCC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone (534 mg, 0.869 mmol) was added to a solution of 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carbaldehyde (322 mg, 0.724 mmol) in DMF (8 mL). The resulting mixture was stirred overnight at room temperature and used directly for step A. MS (ESI) (M+H)+=460.92.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[N+:12]([C:15]1[CH:20]=[C:19]([C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH:18]=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2s1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 1.7 %

Procedure:
A mixture of 6-bromo-2-benzothiazolinone (5.0 g, 21.7 mmol), 3-nitrophenyl boronic acid (5.0 g, 30.0 mmol), tetrakis(triphenylphosphine)-palladium (0) (1.73 g, 1.5 mmol), and potassium carbonate (8.0 g, 58.0 mmol) in toluene (100 mL), H2O (20 mL), and ethanol (30 mL) was subject to a blanket of nitrogen for 15 minutes at 50° C. and then was heated at 85° C. for 24 hours. The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The organic layer was washed with aqueous ammonium chloride (2×50 mL) and with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 6-(3-nitro-phenyl)-3H-benzothiazol-2-one as a brown solid (0.1 g, 1.8%): mp 276-277° C.; 1H-NMR (DMSO-d6) δ 11 (s, 1H), 8.44 (t, 1H, J=2.7 Hz), 8.21-8.08 (nm, 3H), 7.78-7.69 (m, 2H), 7.24 (d, 1H, J=9.23 Hz); MS (ES) m/z 271 ([M−H]−, 100%); Anal. Calc. For C13H8N2O3S 0.25 H2O: C, 56.41, H, 3.10, N, 10.12. Found: C, 56.48, H, 3.11, N, 9.99.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:19]1[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=1)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7]2)([CH3:3])=[CH2:2]>C1COCC1.CO.[C].[Pd]>[NH:22]1[CH:23]=[C:19]([C:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[CH:10]=2)([OH:18])[CH:15]([CH3:17])[CH3:16])[N:20]=[CH:21]1
Reactant: C=C(C)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 167.4 %

Procedure:
1-(6-Isopropenylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.70 g) was dissolved in THF-methanol (2:1) (12 ml). To the solution were added 10% palladium carbon (170 mg), and the mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The catalyst was filtered and washed with THF. The filtrate was concentrated and the obtained residue was purified by silica gel chromatography (eluent, hexane:THF=1:1). Crystallization from isopropyl ether-hexane gave the titled compound (1.60 g) as a colorless powder.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][C:17](=[O:19])[NH:16][C:15](=[O:20])[CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][C:15](=[O:20])[NH:16][C:17](=[O:19])[CH2:18]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CC(=O)NC(=O)C2)cc1C1=CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CC(=O)NC(=O)C3)cc2C2=CCCCC2)n1
Yield: 10 %

Procedure:
A solution of 70.0 mg (0.131 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with EtOH (2 drops) and TFA (3 mL) at RT for 1.5 h. Solvents were removed in vacuo. Purification of the residue by reverse phase high pressure liquid chromatography (RP-HPLC) (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 5.3 mg (8%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.18 (d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.24 (dd, 1H, J=8.4, 2.4 Hz), 7.15 (d, 1H, J=2.4 Hz), 5.85-5.78 (m, 1H), 3.48-3.38 (m, 1H), 2.90-2.71 (m, 4H), 2.32-2.22 (m, 4H), 1.90-1.73 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C22H21N5O3, 404.2 (M+H). found 404.0.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:29](=[O:30])[C:28]3[C:19](=[C:20]([O:31][CH2:32][CH2:33][CH3:34])[CH:21]=[C:22]4[C:27]=3[O:26][CH2:25][CH2:24][CH2:23]4)[NH:18][CH:17]=2)=[CH:12][CH:11]=1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>C(OCC)(=O)C.O>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][N:18]1[C:19]2[C:28](=[C:27]3[C:22](=[CH:21][C:20]=2[O:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH2:25][O:26]3)[C:29](=[O:30])[C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=2)=[CH:17]1)[CH3:41]
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)c[nH]c13)OCCC2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)OCC)c13)OCCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
Sodium hydride (60% oil base, 80 mg, 2.0 mmol) was added to a DMF solution (10 ml) of 3-(4-methoxyphenyl)-10-propoxy-1,6,7,8-tetrahydro-5-oxa-1-aza-phenanthren-4-one (600 mg, 1.64 mmol), the resulting mixture was then stirred at room temperature for 5 minutes. Ethyl bromoacetate (330 mg, 2.0 mmol) was added thereto and the resulting mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, followed by separation. The thus-obtained organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using medium pressure liquid chromatography (NH silica gel, n-hexane:ethyl acetate=100:0→0:100). The purified product was concentrated under reduced pressure, giving a colorless oily substance ethyl[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetate (700 mg, yield: 95%).
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([C@@H:11]([NH:27][C@H:28]1[CH2:34][S:33][C@H:32]([C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)[CH2:31][N:30]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:29]1=[O:48])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1C(=O)C2=CC=CC=C2C1=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(Cl)Cl.C(O)C>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:27][C@H:28]1[CH2:34][S:33][C@H:32]([C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)[CH2:31][N:30]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:29]1=[O:48])[C:9]([O:8][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:10]
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2cccs2)SC[C@H](N[C@@H](CCCCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)C1=O
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CN1C[C@@H](c2cccs2)SC[C@H](N[C@@H](CCCCN)C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 46.2 %

Procedure:
0.6 ml of hydrazine monohydrate was added to a solution of 815 mg of t-butyl α-{6(R)-[1(S)-t-butoxycarbonyl-5-phthalimidopentylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetate (prepared as described in Example 1) dissolved in a mixture of 3 ml of methylene chloride and 3 ml of ethanol, whilst ice-cooling, and the mixture was stirred at room temperature for 4 days. At the end of this time, the precipitate which appeared in the reaction mixture was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was mixed with ethyl acetate and the precipitated material was filtered off. The ethyl acetate filtrate was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure to remove the solvent. The residue was subjected to column chromatography through silica gel using mixtures of ethyl acetate and methanol in the proportions 10:1 and 4:1 by volume as the eluent to yield 302 mg of the title compound as syrup.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(OC(C)C)(OC(C)C)OC(C)C.C([O:25][C:26]([C:28]1[CH:53]=[CH:52][C:31]([O:32][C:33]2[C:38]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:30][CH:29]=1)=O)C.C([N-]C(C)C)(C)C.[Li+]>C1(C)C=CC=CC=1.C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:32][C:33]2[C:38]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:43][CH2:44]3)=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:52][CH:53]=1)=[O:25]
Reactant: CCOC(=O)c1ccc(Oc2ncccc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: CC(C)OC(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of benzimidazole (0.351 g, 2.97 mmol) and triisopropyl orthoformate (3.9 mL, 17.61 mmol) in toluene (25 mL) was heated in a 100 mL round bottom flask equipped with a Dean-Stark trap and reflux condenser under an atmosphere of nitrogen. After 1 h the solvent was removed in vacuo. The residue was dissolved in THF (8 mL) and to the solution was added a solution of tert-butyl 4-(2-(4-(ethoxycarbonyl)phenoxy)pyridin-3-yl)piperidine-1-carboxylate (1.07 g, 2.509 mmol) in THF (8 mL). The mixture was cooled (−78° C.) and lithium diisopropylamide (2.0M solution in heptane/THF/ethylbenzene, 1.80 mL, 3.60 mmol) was added dropwise resulting in a reddish solution. After 2 h the reaction was quenched with saturated NH4Cl and allowed to warm to rt. The mixture was partitioned between EtOAc/saturated NaHCO3. The organic layer was washed with brine and dried over Na2SO4. The solution was filtered and the filtrate was evaporated onto silica gel and purified by flash chromatography (Isco, (120 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 499.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: Cl.CCOC(C)=O.C(OC([NH:15][C@@H:16]([CH2:41][OH:42])[C:17]([NH:19][C@@H:20]([C@H:31]([OH:40])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:41][OH:42])[C:17]([NH:19][C@@H:20]([C@H:31]([OH:40])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@@H](N)CO)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To HCl-EtOAc (5 N, 10 mL) was added a solution of (2S,3R)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanamido)-3-hydroxy-3-(4-methoxyphenyl)propanoate (646 mg, 1.32 mmol) in DCM (10 mL). The mixture was stirred at ambient temperature for 30 min and then concentrated. The residue was washed with diethyl ether (5 mL) to afford (2S,3R)-benzyl 2-((S)-2-amino-3-hydroxypropanamido)-3-hydroxy-3-(4-methoxyphenyl)propanoate (HCl salt, 474 mg, 85% yield) as a colorless solid.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[CH:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][C:31]([CH2:29][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reaction time: 18 h
Yield: 73.6 %

Procedure:
Following General Procedure B: To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (680 mg, 1.8 mmol) and methyl 4-formylbenzoate (295 mg, 1.8 mmol) in CH2Cl2 (10 mL) was added NaBH(OAc)3 (763 mg, 3.6 mmol) and the mixture stirred for 18 h. The resulting crude material was taken up in neat TFA (2 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (10 mL) was cautiously added, and the resulting mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were dried (MgSO4), and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 50:2:1 CH2Cl2/MeOH/NH4OH) afforded the title compound (565 mg, 74%) as a white solid. 1H NMR (CDCl3) δ1.64-1.75 (m, 1H), 2.01-2.08 (m, 2H), 2.26-2.28 (m, 1H), 2.74-2.76 (m, 1H), 2.81-2.86 (m, 1H), 3.81 (s, 2H), 3.86 (s, 3H), 3.94 (d, 1H, J=17 Hz), 4.09 (dd, 11H, J=9, 7 Hz), 4.21 (d, 1H, J=17 Hz), 7.18-7.22 (m, 3H), 7.44 (br d, 1H, J=8 Hz), 7.49 (d, 2H, J=8 Hz), 7.50-7.53 (m, 11H), 7.64-7.66 (m, 1H), 7.91 (d, 2H, J=8 Hz), 8.70 (dd, 1H, J=5, 1 Hz); 13C NMR (CDCl3) δ21.2, 23.6, 29.0, 48.7, 51.9, 53.7, 111.0, 118.6, 121.5, 122.3, 129.3, 128.9, 129.5, 134.7, 137.2, 144.8, 146.8, 155.7, 157.1, 166.8. ES-MS m/z 427 (M+H). Anal. Calcd. for C26H26N4O2.0.6H2O.0.3CH2Cl2: C, 68.26; H, 6.05; N, 12.11. Found: C, 68.57; H, 6.12; N, 11.75.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])C2)C1)[CH3:2].[ClH:21]>CO>[ClH:21].[ClH:21].[ClH:21].[ClH:21].[CH2:19]([NH:15][CH2:16][CH2:17][CH2:18][NH:13][CH2:12]/[CH:11]=[CH:10]/[CH2:9][NH:5][CH2:6][CH2:7][CH2:8][NH:3][CH2:1][CH3:2])[CH3:20]
Reactant: CCN1CCCN(C/C=C/CN2CCCN(CC)C2)C1
Agent: Cl
Solvent: CO
Product: CCNCCCNC/C=C/CNCCCNCC
Temperature: 25 °C

Procedure:
A mixture of 0.18 g (0.642 mmol) of (E)-1,4-bis(3-ethyl-hexahydropyrimidin-1-yl)but-2-ene, 2.5 ml of methanol and 2.56 ml (5.12 mmol) of 2N hydrochloric acid is heated for 72 h under reflux. The reaction mixture is then cooled to room temperature, and 10 ml of methanol are added, whereupon the title compound precipitates in crystalline form. The crystallisate, which is washed with methanol and diethyl ether and dried under a high vacuum at 120° C., melts at >260° C. 1H-NMR (D2O): δ1.27(t,6H); 2.04-2.15(m,4H); 3.07-3.18(m,12H); 3.77(d,4H); 6.04-6.06(m,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][N:19]3[CH3:18])[C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCCC1=O
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Solvent: CCCCCC
Product: CN1CCCCC1=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21

Procedure:
By the procedure of Example B1, but using 1:1 hexane:ethyl acetate as chromatography eluant and pentane for crystallization, 1-(3-chlorophenyl-2-(1H,3H)-indolone (2.0 g, 8.2 mmoles) and N-methyl-2-piperidone (1.3 ml, 11.5 mmoles) were converted to title product, 180 mg (6.5%) m.p. 162°-165°.
Reaction SMILES: NC(C1C=C(Cl)C=CC=1OC)C#N.OC(C)(C)CC(O)=O.[Si]([O:29][C:30]([CH3:48])([CH3:47])[CH2:31][C:32]([NH:34][CH:35]([C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[O:45][CH3:46])[C:36]#[N:37])=[O:33])(C(C)(C)C)(C)C>>[Cl:44][C:42]1[CH:41]=[CH:40][C:39]([O:45][CH3:46])=[C:38]([CH:35]([C:36]#[N:37])[NH:34][C:32](=[O:33])[CH2:31][C:30]([OH:29])([CH3:48])[CH3:47])[CH:43]=1
Reactant: COc1ccc(Cl)cc1C(C#N)NC(=O)CC(C)(C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(O)CC(=O)O
Agent: COc1ccc(Cl)cc1C(N)C#N
Product: COc1ccc(Cl)cc1C(C#N)NC(=O)CC(C)(C)O

Procedure:
Using amino-(5-chloro-2-methoxy-phenyl)-acetonitrile and 3-hydroxy-3-methyl-butyric acid, the title compound was synthesized following the synthetic procedures described for 3-(tert-butyldimethylsilyloxy)-N-((5-chloro-2-methoxyphenyl)(cyano)methyl)-3-methylbutanamide to give N-((5-chloro-2-methoxyphenyl)(cyano)methyl)-3-hydroxy-3-methylbutanamide. LCMS (ESI) m+H=297.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C[C:13](O)=[O:14].[O-]C#N.[Na+].[OH-].[Na+]>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:13]([OH:14])[N:6]=[C:4]2[OH:5]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: CC(=O)O
Agent: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nc(O)c2cc(Cl)ccc2n1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
2-Amino-5-chlorobenzamide (Avocado) (3.00 g, 17.5 mmol, 1.0 eq.) was suspended in 105 mL of H2O and 1.75 mL of HOAc at rt. A 12 mL solution of H20 and sodium cyanate (2.80 g, 43.0 mmol, 2.46 eq.) was then added slowly. Stirred at 35° C. for 1 hour. Added 31.26 mL of 1.0 N NaOH slowly. Solids precipitated. Cooled to 0C. Carefully added conc. HCl to pH=3. Filtered solids. Solids were then stirred in diethyl ether then refiltered and pumped under high vacuum to give 3.36 grams of tan solids as product. LCMS detects (M+H)+=197.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
5-Chloro-2-methylbenzoic acid (46, 5.0 g, 29.3 mmol) was suspended in dichloromethane (30 mL) and thionyl chloride (3.2 mL, 5.2 g, 44 mmol) was added. The solution was stirred at room temperature for 1 hour. Methanol was added and the reaction was allowed to proceed for a further 16 hours. The volatile components were evaporated under reduced pressure. The resulting residue was taken up again in methanol (30 mL) and pyridine (5 mL) was added. The solution was stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford methyl 5-chloro-2-methylbenzoate (5.3 g, 96% yield) that was used in the following step without further purification.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:5]=1[C:6]([CH:8]1[CH2:10][CH:9]1[C:11]#[N:12])=[O:7].[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:5]=1[CH:6]([OH:7])[CH:8]1[CH2:10][CH:9]1[C:11]#[N:12]
Reactant: Cc1ccc(C(=O)C2CC2C#N)c(F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(O)C2CC2C#N)c(F)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
61.0 mg (1.62 mmol) of sodium borohydride were added to 300 mg (1.48 mmol) of the compound from Example 131A in 30 ml of ethanol and 13 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 1 h. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. 280 mg (92% of theory) of a mixture of the diastereomers of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Yield: 78.1 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.200 g, 0.465 mmol) was dissolved in acetone (30 ml) and after adding thereto anhydrous sodium carbonate (0.077 g, 0.558 mmol) and tert-butyl bromoacetate (0.109 g, 0.558 mol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.198 g, 0.363 mmol, 78%).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:23]=3[OH:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1cccc(O)c1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3c(C)cccc3O)CC2)c(OC)nc1C
Yield: 57 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-hydroxy-6-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C>C1CCCCC1>[C:11]([C:7]1[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Reaction time: 0.25 h

Procedure:
2,6-di-t-butylphenol (8 g, 39 mmoles) is dissolved in 25 ml of cyclohexane at 10° C. A (1/1) mixture of nitric acid/acetic acid (5 ml) is added dropwise to the reaction medium maintained at this temperature. Agitation is then carried out for 15 minutes at ambient temperature. Then the precipitate formed is filtered off, rinsed with water and pentane. The 2,6-di-t-butyl-4-nitrophenol obtained (6.34 g, 65%) is dried in an oven and will be used without further purification in the following stages. Pale yellow powder. Melting point: 167-168° C.