Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:53]([O:55][C:56]([C:58]1[O:59][C:60]2[CH:66]=[CH:65][C:64](Br)=[C:63]([CH3:68])[C:61]=2[CH:62]=1)=[O:57])[CH3:54].[C:69]([O:73][C:74]([N:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1)=[O:75])([CH3:72])([CH3:71])[CH3:70]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CCCCCC.C1(C)C=CC=CC=1>[C:69]([O:73][C:74]([N:76]1[CH2:81][CH2:80][N:79]([C:64]2[CH:65]=[CH:66][C:60]3[O:59][C:58]([C:56]([O:55][CH2:53][CH3:54])=[O:57])=[CH:62][C:61]=3[C:63]=2[CH3:68])[CH2:78][CH2:77]1)=[O:75])([CH3:72])([CH3:70])[CH3:71]
Reactant: CCOC(=O)c1cc2c(C)c(Br)ccc2o1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(C)c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 360.4 %

Procedure:
Toluene (30 ml) was stirred under argon atmosphere for 30 minutes at room temperature. Cesium carbonate (4.83 g, 0.015 mol), palladium acetate (0.19 g, 0.0008 mol), BINAP (0.66 g, 0.001 mol), 5-Bromo-4-methyl-benzofuran-2-carboxylic acid ethyl ester (3 g, 0.010 mol) and piperazine-1-carboxylic acid tert-butyl ester (2.16 g, 0.001 mol) was added with a regular interval of 30 minutes under argon atmosphere. The reaction mixture was stirred for 30 minutes at room temperature and then heated to reflux. The mixture was maintained at reflux for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and the inorganic material was filtered. The filtrate was then washed with water (2×15 ml), brine solution (50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product as dark brown solid. Column chromatography using 5/95 ethyl acetate/hexane yielded 4-(2-ethoxycarbonyl-4-methyl-benzofuran-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 34.1%)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCOCC>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:2]([CH3:3])[CH3:1])=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CNC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C=C(c2ccc(OCc3ccccc3)cc2)N(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
Dimethylamine (55 mL, 0.15 mol) in 100 mL of toluene was added over ten min at 0°-5° C. to a 600 mL toluene suspension of 1-(4-benzyloxyphenyl)-2-(4-methoxyphenyl)ethan-l-one (50 g, 0.15 mol), then stirred 15 min at 0° C. A 50 mL toluene solution of TiCl4 (9.8 mL, 0.09 mol) was added dropwise over 1 h to the reaction mixture, keeping the temperature below 5° C. The brown suspension was stirred 16 h at rt then filtered through Hyflo Super Cel to give a yellow filtrate. Two Et2O washes of the filter bed were combined with the filtrate and the solution was concentrated to a thick amber oil. The oil was triturated with Et2O/ pet. ether and filtered to give 41 g (77%) of yellow solid: mp 60° C.; 1H NMR (CDCl3) d 2.64 (s, 6H, NMe2), 3.71 (s, 3H, OCH3), 5.07 (s, 2H, OCH2), 5.42 (s, 1H, =CH), 6.57-6.60 (d, 2H, J=9 Hz, ArH), 6.67-6.70 (d, 2H, J=9 Hz, ArH), 6.86-6.89 (d, 2H, J=9 Hz, ArH), 6.90-6.93 (d, 2H, J=9 Hz, ArH), 7.18-7.21 (d, 2H, J=9 Hz, ArH), 7.40-7.45 (m, 5H, ArH); MS(FD) 360[M+1]+Anal. Calcd for C24H25NO2 : C, 80.19; H, 7.01; N, 3.90. Found: C, 80.41; H, 7.12; N, 4.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].C(O[CH:15](OCC)[CH2:16][Cl:17])C.Cl>O>[Cl:17][CH2:16][CH:15]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7][O:8]1
Reactant: COc1cccc(CCO)c1
Reactant: CCOC(CCl)OCC
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1)CCOC2CCl
Yield: 9.6 %

Procedure:
A mixture of 30 g of 3-methoxyphenethyl alcohol, 30 g of chloroacetaldehyde diethyl acetal and 50 ml of concentrated hydrochloric acid was heated at 60°-80° C for 30 minutes, and, after cooling, water was added to the reaction mixture. The resultant oil was extracted into ethyl acetate, rinsed with water and dried. By this procedure was obtained 4.0 g of 1-chloromethyl-6-methoxyisochroman as an oil.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(O)C.C1C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)n1
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(OCCCCCCCC)nc3F)cc2)cc1
Yield: 13.2 %

Procedure:
2.10 g (7.50 mmol) of 2-fluoro-6-octyloxypyridine-3-boronic acid (prepared as described in Example 5) in 35 ml of ethanol are refluxed together with 2.70 g (7.50 mmol) of 4-bromo-4'-octyloxybiphenyl and 0.29 g (0.24 mmol) of tetrakis(triphenylphosphine)palladium in 46 ml of benzene and 2.5 g (23.40 mmol) of sodium carbonate in 11 ml of water for 20 hours. After distributing the reaction mixture between water and dichloromethane, the organic phase is washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, dichloromethane) and recrystallization from acetonitrile give 0.50 g of 2-fluoro-6-octyloxy-3-[4-(4-octyloxyphenyl)phenyl]pyridine. ##STR32##
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C@H:20]1[O:25][C@@H:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:21][C@@H:20]([CH3:19])[O:25][C@@H:24]([CH3:26])[CH2:23]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CO
Product: C[C@@H]1CN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was added cis-2,6-Dimethylmorpholine (105 μL, 0.848 mmol). The resulting mixture was stirred at RT overnight. An additional 2 equ. of cis-2,6-Dimethylmorpholine was then added and the mixture was again stirred overnight at RT. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give (2S,6R)-4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,6-dimethylmorpholine (223 mg, 0.616 mmol, 87% yield). LC-MS (M+H)+=332.1. 1H NMR (500 MHz, MeOD) δ ppm 7.11-7.24 (2H, m), 6.99-7.09 (2H, m), 4.39-4.51 (2H, m), 4.20 (1H, s), 3.70 (2H, td, J=4.12, 2.44 Hz), 3.14-3.25 (1H, m), 3.03-3.13 (1H, m), 2.69-2.80 (2H, m), 2.54-2.68 (1H, m), 1.95-2.13 (1H, m), 1.23 (6H, d, J=6.10 Hz).
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:20]O>>[CH3:20][O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: CO
Product: COC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (26 mg) in anhydrous methanol (1 ml) at 0° C. is treated with ethereal CH2N2 until a yellow color persists. The mixture is stirred 15 more minutes in the cold and then evaporated in vacuo. Chromatography of the residue on silica gel provides benzyl 3-methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[C:24](=[C:26]([O:42][CH3:43])[CH:27]=[CH:28][C:29]=3[C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[O:25][C:19]=2[CH2:18]1)=[O:16])[CH3:13].O>CN(C=O)C>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:30]([C:29]1[CH:28]=[CH:27][C:26]([O:42][CH3:43])=[C:24]2[O:25][C:19]3[CH2:18][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:22][CH2:21][C:20]=3[C:23]=12)=[O:31]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c23)C1

Procedure:
To a solution of 4-amino-3,5-dichloro pyridine (0.125 g, 0.765 mmol) in dry DMF, sodium hydride (0.0162 g, 0.675 mmol) was added at 0° C. followed by 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylate (0.197 g, 0.45 mmol). Water was added to RM. Solid filtered out and purified on Silica Gel column with CHCl3: EtOAc to yield N-(3,5-dichloropyridin-4-yl)-2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])=[CH:4][C:3]=1[CH2:14][OH:15].C(N(CC)CC)C.[C:23](Cl)(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCCC1>[C:23]([O:15][CH2:14][C:3]1[CH:4]=[C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[O:6][C:2]=1[CH3:1])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CC[Si](CC)(CC)c1cc(CO)c(C)o1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCc1cc([Si](CC)(CC)CC)oc1C
Temperature: 25 °C

Procedure:
To a stirred solution of 5-methyl-2-triethylsilyl-4-furylmethanol (208 mg. 0.92 mmol) and triethylamine (121 mg, 1.20 mmol) in tetrahydrofuran (10 ml) at 0 degrees under argon was added lauroyl chloride 302 mg, 1.38 mmol). This solution was allowed to warm gradually to room temperature and quenched with a 10% aqueous HCl solution. The organics were extracted into hexanes and the combined fractions were washed with a saturated aqueous solution of sodium bicarbonate, H2O and brine Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by filtration through silica using 2% ethyl ether/hexanes to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]([CH3:25])[C:17]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.Cl.NC(N)=N.[CH2:35](OC(=O)C1(CCCC1)N(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)C)[CH3:36].O>CS(C)=O>[CH2:35]([O:23][C:22](=[O:24])[C:17]1([CH2:21][CH2:20][CH2:19][CH2:18]1)[N:16]([S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:26][C:27]([NH2:29])=[NH:28])=[CH:11][CH:10]=1)(=[O:14])=[O:15])[CH3:25])[CH3:36]
Reactant: CN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reactant: CCOC(=O)C1(N(C)S(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCC1
Agent: Cl
Agent: N=C(N)N
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(N(C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine hydrochloride ##STR91## NaH (31 mg, 80% dispersion in mineral oil, 1.04 mmol) was added to a solution of guanidine hydrochloride (164 mg, 1.67 mmol) in DMSO (4 ml), and the solution heated at 50° C. for 1 h. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine ethyl ester (180 mg, 0.42 mmol) in DMSO (2 ml) was added, and the reaction heated at 80° C. for 3 h. The cooled reaction mixture was poured into water, and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and evaporated in vacuo. The residual yellow oil was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880 NH3 (90:10:1) as eluant, and recrystallised from EtOAc to afford N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine ethyl ester (105 mg, 0.23 mmol) as a yellow solid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4].[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>O1CCOCC1.O>[OH:1][NH:2][C:3]([C:5]1[C:6]([C:13]([O:14][C:5]([CH3:6])([CH3:10])[CH3:3])=[O:16])=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4]
Reactant: N=C(NO)c1ccc(CN)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1nc(CN)ccc1C(=N)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
To a solution of the product of Example 53 (11-5) (0.5 g, 3.01 mmol) in dioxane and water (6 ml each) was added potassium carbonate (832 mg, 6.02 mmol), followed by Boc-anhydride (0.66 g, 3.01 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the remaining residue was dissolved in ethylacetate and washed with sodium bicarbonate (saturated) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash column chromatography in 8/2 ethylacetate/hexanes followed by ethylacetate and 9/1 dichloromethane/methanol afforded 0.43 g product as a white solid. NMR δ (ppm) CDCl3: 8.8 (d, 1H), 7.9 (dd, 1H), 7.3 (d, 1H), 6.6 (bs, 1H), 5.5 (bs, 1H), 4.8 (bs, 1H), 4.4 (d, 2H), 1.4 (s, 9H)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([OH:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N1C=CC=CC=1.Cl>C1C=CC=CC=1.CCOCC>[C:1]([O:23][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCOC(C)=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
a solution of 2.8 g of acetyl chloride in 10 ml of dry benzene was added dropwise, with stirring, to an ice-cold solution of compound III (5.0 g) and 2.8 g of pyridine in 20 ml of dry benzene. Following addition, stirring was maintained at room temperature for 30 minutes and the mixture was then refluxed for 2 hours. The cooled mixture was diluted with 30 ml of ether and treated with sufficient cold 5% HCl to make the mixture strongly acid. The layers were separated and the aqueous layer was shaken once with 20 ml of ether; the combined organic layers were washed with three 10-ml portions of cold H2O and dried over Na2SO4. Evaporation of the solvent and distillation of the residue gave 5.1 g (85%) of compound IV as a colorless liquid boiling at 139°-143° (0.1 mm), nD25 1.4493.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[N:23]([CH2:24][CH2:25][O:26][CH2:27][CH:28]=[CH2:29])[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:10][CH2:9]2)C=CC=CC=1.CC1C=CC=CC=1.[C:37](Cl)(=[O:41])[O:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:27]([O:26][CH2:25][CH2:24][N:23]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:37]([O:38][CH2:39][CH3:40])=[O:41])[CH2:13][CH2:12]1)[CH:28]=[CH2:29]
Reactant: C=CCOCCn1c(CC2CCN(Cc3ccccc3)CC2)nc2cccnc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOCCn1c(CC2CCN(C(=O)OCC)CC2)nc2cccnc21
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a stirred and refluxed mixture of 13.5 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-3-[2-(2-propenyloxy)ethyl)-3H-imidazo[4,5-b]-pyridine and 90 parts of methylbenzene were added dropwise 5.4 parts of ethyl carbonochloridate. Upon complete addition, stirring was continued for 1 hour at reflux temperature. After cooling, the reaction mixture was diluted with water and the whole was treated with potassium carbonate. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 14 parts (75.1%) of ethyl 4-[[3-[2-(2-propenyloxy)ethyl]-3H-imidazo[4,5-b]pyridine-2-yl]methyl]-1-piperidinecarboxylate as a residue (compound 43).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([NH:14]C(OCC2C=CC=CC=2)=O)=[C:11]([OH:13])[CH:12]=1)=[O:5])[CH3:2].C1CCCCC=1.C>C(O)C>[NH2:14][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][C:11]=1[OH:13]
Reactant: CCOC(=O)Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)Nc1ccc(N)c(O)c1

Procedure:
0.06 mole (20 g) of 5-(ethoxycarbonylamino) -2-(benzyloxycarbonylamino)phenol in 60 ml of 96° strength ethanol to which 40 ml of cyclohexene and 4 g of palladinized charcoal (10% palladium) are added is heated to reflux for 30 minutes. After removal of the catalyst by filtration while hot, the expected product is precipitated by adding 17.5 ml of ethanolic hydrochloric acid (7M) to the cooled filtrate. After drying, analysis of the product obtained gives the following results:
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:9](Cl)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[OH:7][CH:4]1[CH2:5][CH2:6][CH:1]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: OC1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)OC1CCC(O)CC1
Yield: 25 %

Procedure:
1,4-cyclohexanediol (20.0 g, 172.4 mmol) was dissolved in dichloromethane (200 mL). Cinnamoyl chloride (7.2 g, 43.1 mmol) dissolved in 50 ml dichloromethane was then slowly added. After 2 h of mixing, triethyl amine (5.3 g, 52 mmol) was added slowly. After 48 h of mixing, the solution was washed three times with dilute HCl (1 M) and two more times with H2O before it was dried over MgSO4 and filtered. The product was then dissolved in methanol which resulted in precipitation of the byproduct. After filteration and evaporating the solvents from the filtrate, the product was a obtained as yellow-orange viscous liquid, which was used without further purification. Yield: 25-40%.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.S(Cl)(Cl)=O.[CH3:26]O>>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:26])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid (1.0 g, 3.44 mmol) in MeOH (20 mL) at 0° C. was slowly added thionyl chloride (818.1 mg, 6.89 mmol) over 1 h. The reaction was warmed to RT and stirred for 1 h. The solvent was removed under reduced pressure. The reaction mixture was washed with saturated aqueous NaHCO3 (20 ml) and extracted with DCM (3×10 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 789 mg (97%) of (S)-methyl 2-amino-3-(4-cyanophenyl)propanoate as the HCl salt. LCMS-ESI (m/z) calculated for C11H12N2O2: 204.1. found 205.0 [M+H]+, tR=3.25 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 3H), 7.83 (d, J=8.3 Hz, 2H), 7.51 (t, J=8.8 Hz, 2H), 4.37 (t, J=6.7 Hz, 1H), 3.68 (s, 3H), 3.23 (qd, J=14.4, 7.7 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:14])[CH2:9][CH:10](C)[CH:11]=[CH2:12])[CH2:3]1.CC1(C)CC=C[C:19]([C:23](=[O:29])CC(C)C=C)=C1>>[CH3:15][C:2]1([CH3:1])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2([O:14][CH2:19][CH2:23][O:29]2)[CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:3]1
Reactant: C=CC(C)CC(=O)C1=CC(C)(C)CC=C1
Reactant: C=CC(C)CC(=O)C1=CC=CC(C)(C)C1
Product: C=CCCC1(C2=CCCC(C)(C)C2)OCCO1

Procedure:
##STR8## 1-(3,3-Dimethyl-cyclohexa-4,6-dien-1-yl)-3-methyl-pent-4-en-1-one and 1-(3,3-dimethyl-cyclohexa-1,5-dien-1-yl)-3-methyl-pent-4-en-1-one were thus prepared.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC=O
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 153 %

Procedure:
To a solution of rac-(3S,4R)-[1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (5.59 g, 0.013 mol) and N,N-diisopropylamine (6.81 mL, 0.017 mol) in toluene (60 mL) was added at ambient temperature 1-chloroethyl formate (1.88 mL, 0.017 mol) and the reaction mixture was stirred for 24 h. It was concentrated and the resulting residue was diluted in methanol (60 mL) and stirred for 3 h at ambient temperature. Concentration afforded the crude title compound (6.59 g, 67% purity) as a light brown solid which was directly used without further purification.
Reaction SMILES: C([S:4][CH:5]([CH:16]([C:21]([NH:23][C@H:24]([C:34]([NH:36][CH3:37])=[O:35])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)=[O:8])(=O)C.N>CO>[SH:4][CH:5]([CH:16]([C:21]([NH:23][C@H:24]([C:34]([NH:36][CH3:37])=[O:35])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C:7]([N:9]1[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]1)=[O:8]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)N1CCN(C)CC1)SC(C)=O
Agent: N
Solvent: CO
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(S)CC(=O)N1CCN(C)CC1
Reaction time: 6 h

Procedure:
A solution of 1-[3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]-carbonyl]heptanoyl]-4-methylpiperazine (E18, Isomer A; 60 mg, 0.112 mmol) in methanol (5 ml) was purged with nitrogen and cooled in ice, then was treated with 35% aqueous ammonia (0.4 ml). After 6 h at room temperature, the solvents were evaporated in vacuo and the residue was triturated with hexane to give the title compound as a single isomer (Isomer A), mp 65°-68° C.