Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1.[NH:39](C(OC(C)(C)C)=O)[C@H:40]([C:43](O)=[O:44])[CH2:41][CH3:42].C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:39][CH:40]([CH2:41][CH3:42])[C:43]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1)=[O:44]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCC(N)C(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 13E (59 mg, 0.1 mmol) and Boc-Abu-OH (22 mg, 0.11 mmol) in tetrohydrofuran (5 ml) was added 3-(diethoxyphosphoryloxy)-1,2,3-benzo-triazin-4(3H)-one (36 mg, 0.11 mmol) and triethylamine (0.07 ml, 0.5 mmol). The mixture was stirred at room temperature for 16 hours then poured into saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and evaporated. To the residue was added dichloromethane (2 ml) and trifluoroacetic acid (2 ml) then stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by HPLC with NH4OH to provide the title compound. (62 mg, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.90 (t, J=7.54 Hz, 3 H) 1.33 (d, J=6.99 Hz, 6 H) 1.48 (m, 1 H) 1.66 (m, 1 H) 1.90 (s, 3 H) 3.22 (m, 2 H) 7.02 (m, 2 H) 7.40 (d, J=8.46 Hz, 2 H) 7.52 (d, J=8.46 Hz, 2 H) 7.61 (d, J=8.46 Hz, 1 H) 7.72 (m, 5 H) 7.94 (s, 1 H) 8.52 (s, 1 H) 8.79 (s, 1 H) 10.33 (s, 1 H); MS (ESI+) m/z 670, 672 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[NH:30][CH3:31])[C:18]([NH:20][CH2:21][C:22](=[O:26])[N:23]([CH3:25])[CH3:24])=[O:19].[CH2:32](Cl)CCl>CN(C=O)C>[CH3:24][N:23]([CH3:25])[C:22]([CH2:21][NH:20][C:18]([C:17]1[CH:27]=[CH:28][C:29]2[N:30]([CH3:32])[C:31]([NH:11][C:9]3[S:10][C:6]4[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:7]=4[N:8]=3)=[N:14][C:15]=2[CH:16]=1)=[O:19])=[O:26]
Reactant: ClCCCl
Reactant: CNc1ccc(C(=O)NCC(=O)N(C)C)cc1N
Reactant: CCOc1ccc2nc(N)sc2c1
Solvent: CN(C)C=O
Product: CCOc1ccc2nc(Nc3nc4cc(C(=O)NCC(=O)N(C)C)ccc4n3C)sc2c1
Yield: 6.4 %

Procedure:
2-(6-Ethoxy-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (15 mg) was prepared by following General Procedure D starting from 6-ethoxy-benzothiazol-2-ylamine (100 mg), 3-amino-N-dimethylcarbamoylmethyl-4-methylamino-benzamide (150 mg), thioCDI (150 mg) and EDC (150 mg) in DMF (3 mL). LC/MS: m/z 452.6.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]=[O:33])=[N:30][CH:31]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][N:30]=3)=[O:33])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: O=Cc1ccc(F)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(F)cn1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (300 mg) in ethanol (5 mL) were added 5-fluoropyridine-2-carbaldehyde (130 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (26 mg) and triethylamine (52 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (65 mg, yield 16%) as a brown oil. MS: 474 (MH+).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[C:49]([NH:52][CH2:53][CH2:54][NH2:55])(=[O:51])[CH3:50].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[C:49]([NH:52][CH2:53][CH2:54][NH:55][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)(=[O:51])[CH3:50]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCNC(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and N-acetylethylenediamine (0.048 ml, 0.501 mmol). The mixture was stirred for 2 h at rt then to the mixture was added sodium triacetoxyborohydride (0.177 g, 0.835 mmol). The mixture was stirred at rt for 3 days then was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude material was used in the next step with no additional purification. LCMS: m/e 685.4 (M+H)+, 3.86 min (method 6).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH2:11])([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.CN([CH:20]1[CH2:25][CH2:24]CCC1)C1CCCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[C:39]([O:43][CH2:44]C)(=[O:42])C=C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:44][O:43][C:39](=[O:42])[C:25]([CH3:24])=[CH:20][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([NH2:11])([CH3:10])[CH3:9])[CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: CN(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(N)c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(C)=Cc1cccc(C(C)(C)N)c1
Temperature: 80 °C

Procedure:
The mixture of 1-(3-bromo-phenyl)-1-methyl-ethylamine (0.74 g, 3.5 mmol), tris(dibenzylideneacetone)dipalladium (0.19 g, 0.21 mmol), and N-methyldicyclohexylamine (10 mmol) was purged with nitrogen followed by the addition of 1,4-dioxane (7 mL) and tri-tert-butylphospine (85 mg, 0.42 mmol). The mixture was again purged with nitrogen and ethyl acrylate (0.75 mL, 7.0 mmol) was added. The mixture was heated to 80° C. for 1 h, brought to room temperature, poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, washed again with water, dried over magnesium sulfate, concentrated and chromatographed on silica gel using 0-4% MeOHI/CH2Cl2 to afford yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2].C(N(CC)CC)C.Cl>C(N(CC)CC)C.C(O)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CCOC(=O)Cn1ncc2c1CCC[C@@H]2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a stirred solution of (4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (16.7 g, 75.0 mmol) in formic acid-triethylamine azeotropes (molar fraction of triethylamine: 0.2857, 45 mL) was added chloro-[(1S,2S)-N-(p-tolunenesulfonyl)-1,2-diphenylethanediamine](mesitylene)ruthenium(II) (1.86 g, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 hours and then at 45° C. for 2.5 hours with occasional venting. After cooling to room temperature, 1N hydrochloric acid (50 mL) was added, followed by extraction with ethyl acetate (200 mL×3). The organic layers were combined, washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (gradient elution, 0-4% methanol in dichloromethane) to afford ((S)-4-hydroxy-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (14.3 g, 85%) as a white solid with enantiomerical purity ≧99% as determined by Chiralpak™ IA column (condition: gradient: 50% hexane in ethanol, flow rate: 15 mL/min and retention time: 5.8 min for A enantiomer and 8.1 min for B enantiomer).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCOCC1>[F:7][C:6]([F:9])([F:8])[CH2:5][CH:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][OH:4]
Reactant: NC(CO)CC(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NC(CO)CC(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
400 mg of rac-2-amino-4,4,4-trifluorobutan-1-ol (Example 42A, 2.5 mmol, purity about 90%, 1 equivalent) in 36 ml of 1,4-dioxane were admixed at RT with 0.38 ml of 50% aqueous potassium carbonate solution (1.7 mmol, 0.68 equivalent) and 0.54 ml of benzyl chloroformate (3.8 mmol, 1.5 equivalents), and the mixture was stirred at RT for 2 h. Then another 0.11 ml of benzyl chloroformate (0.76 mmol, 0.3 equivalent) and 0.08 ml of 50% aqueous potassium carbonate solution (0.35 mmol, 0.14 equivalent) were added and the mixture was stirred at RT for a further 30 min. Concentration under reduced pressure was followed by purification by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). The resulting crude product was taken up in ethyl acetate and washed twice with saturated aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over sodium sulphate, filtered and concentrated. 490 mg (70% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]1(=O)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1.C(OCC)C>[CH:37]1([NH:1][CH2:2][C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[C@H:12]3[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]3)=[C:5]([NH:22][CH2:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:4]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C1CCCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol) was dissolved (using gentle heating) in dry tetrahydrofuran (20 ml) and the stirred solution treated with a solution of cyclohexanone (22 mg, 0.22 mmol) in dry tetrahydrofuran (2 ml) followed by addition of sodium triacetoxyborohydride (70 mg, 0.33 mmol) and a solution of acetic acid (0.14 ml, 0.25 mmol) in dry tetrahydrofuran (2 ml). The mixture was then stirred at room temperature for 24 hr. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous sodium hydrogen carbonate, brine, dried with anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (95:5:0.5) changing to dichloromethane:methanol:ammonia (90:10:1) to afford the title compound as a solid (80 mg). MS: 573 (MH+).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[CH3:10][O:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14](=[O:17])[CH2:15][Br:16]>>[Br-:16].[CH3:10][O:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14](=[O:17])[CH2:15][N+:6]1[CH:7]=[CH:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH:5]=1
Reactant: c1cc2sccc2cn1
Reactant: COc1ccccc1C(=O)CBr
Product: COc1ccccc1C(=O)C[n+]1ccc2sccc2c1
Product: [Br-]
Yield: 80.7 %

Procedure:
Reaction of thieno[3,2-c]pyridine (13.5 g) with orthomethoxy-phenacyl bromide (21.3 g) according to the procedure of Example 1 gives white crystals (27.34 g) having a melting point (Koefler block) of 258°-260° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]([O:28][C:30](=[O:32])[CH3:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCC(O)/C=C/C=C/c1ccccc1OCCCC(=O)OCC
Solvent: c1ccncc1
Product: CCCCCCCCC(/C=C/C=C/c1ccccc1OCCCC(=O)OCC)OC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 60 mg of 4-[2-[(1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl]-phenoxy]-butyric acid ethyl ester in 0.5 ml of pyridine is mixed with ice cooling and under argon atmosphere with 0.12 ml of acetic anhydride and stirred for 4 hours at room temperature. The reaction mixture is concentrated by evaporation and the residue is chromatographed on silica gel with n-hexane/ethyl acetate=95/5. 42 mg of 4-[2-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-phenoxy]-butyric acid ethyl ester is obtained as a colorless oil.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])[CH3:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:42]2[CH:43]=[C:38]([C:35](=[O:37])[CH3:36])[CH:39]=[CH:40][CH:41]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C(C)=O)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
N,N-dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-acetylphenylboronic acid (67 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (49 mg, yield 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([CH3:19])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH:14]([CH3:16])[CH3:15])[CH:8]=2)=[C:4]([CH3:20])[CH:3]=1.C(N(CC)CC)C.C[CH:29]([C:33](Cl)=[O:34])[C:30](Cl)=[O:31].C1C[O:39][CH2:38]C1>>[CH3:38][O:39][C:33](=[O:34])[CH2:29][C:30]([NH:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH:14]([CH3:16])[CH3:15])[CH:8]=2)=[C:17]([CH3:19])[CH:18]=1)=[O:31]
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: C1CCOC1
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(C)C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-amino-2,6-dimethyl-phenoxy)-2-isopropyl-phenol (39 mg, 0.14 mmol) in THF (2 mL) was added triethylamine (22 μL, 0.16 mmol) and methyl malonyl chloride (16 μL, 0.15 mmol). The resulting mixture was stirred at RT for 18 h. The solution was concentrated and the residue was purified by preparative TLC (2.5% MeOH in CH2Cl2) to give the title compound of Step D (31 mg). MS (APCl−) CaIc.: 371.3, Found: 370.3 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([F:20])[CH:22]=3)=[C:3]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Reactant: Cc1ccc(N)cc1F
Product: CCOC(=O)c1cnn2c(Nc3ccc(C)c(F)c3)c(C(=O)OC)cnc12
Yield: 93 %

Procedure:
In the same manner as in Example 1, step 4 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (3.00 g, 10.6 mmol) obtained in Example 21, step 2 and 3-fluoro-4-methylaniline (1.43 ml, 12.7 mmol), the title compound (3.67 g, 94%) was obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:1][C@H:2]2[CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]4[C@@H:18]3[CH2:17][CH2:16][C@@:15]3([CH3:23])[C@H:8]4[CH2:9][CH:10]=[C:11]3[C:12](=[O:14])[CH3:13])[CH2:3]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
3β-Hydroxy-5α-pregn-16-en-20-one (10 g.) in pyridine (50 ml.) was treated with toluene-p-sulphonyl chloride (10 g.), and the solution was stirred at room temperature overnight and then poured into dilute hydrochloric acid. The precipitate was extracted into chloroform, and the extract was washed with dilute hydrochloric acid and with water, dried over sodium sulphate and evaporated to an oil which crystallised on standing. Recrystallisation from ethyl acetate/petrol gave 3β-toluene-p-sulphonyloxy-5α-pregn-16-en-20-one (13.3g) as off-white prisms, m.p. 146°-148° , [α]D + 24.0°, λmax. (EtOH) 226.5 nm (ε 18,600), 240 nm (infl.) (ε 9550), 272.5 nm (ε 518).
Reaction SMILES: CCN(CC)CC.II.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]([O:33][C:34](=[O:63])[NH:35][CH2:36][C:37]1([C:40]([NH:42][NH:43][C:44]([CH:46]2[CH2:52][CH2:51][C@@H:50]3[CH2:53][N:47]2[C:48](=[O:62])[N:49]3[O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=O)=[O:41])[CH2:39][CH2:38]1)([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[CH2:55]([O:54][N:49]1[C:48](=[O:62])[N:47]2[CH2:53][C@H:50]1[CH2:51][CH2:52][CH:46]2[C:44]1[O:41][C:40]([C:37]2([CH2:36][NH:35][C:34](=[O:63])[O:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:38][CH2:39]2)=[N:42][N:43]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)NNC(=O)C2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Et3N (8.3 g, 0.082 mol) was added to a 0° C. solution of I2 (10.43 g, 0.041 mol), PPh3 (10.76 g, 0.041 mol) in CH2Cl2 (250 mL). The mixture was allowed to warm to rt. After stirring at rt for 0.5 hr, tert-butyl(1-(2-((5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopropyl)methylcarbamate (10 g, 0.0205 mol) was added. The mixture was stirred at rt for another 1 hr. The mixture was concentrated, EtOAc (250 mL) was added, and the mixture was filtered to remove Ph3PO. The filtrate was concentrated and the residue was purified by silica gel column chromatography (gradient elution 33-50% EtOAc/petroleum ether) to afford tert-butyl (1-(5-((5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)methylcarbamate (8 g, 83%) as a white solid. ESI-MS (EI+, m/z): 470.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:6]5[S:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:43]=[CH:42][CH:41]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1ncsc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ncsc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 61 %

Procedure:
In the same manner as in Example 18-4 and using 4-methyl-1,3-thiazole-5-carboxylic acid (531 mg, 3.70 mmol), tetrahydrofuran (10 mL), oxalyl chloride (477 μL, 5.49 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (295 mg, 0.954 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (253 mg, 61%) was obtained as a white solid.