Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.CCN(C(C)C)C(C)C.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1>[Br:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:44]([NH:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])=[N:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)=[N:9][CH:10]=1
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Reactant: O=C=Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br)Nc1ccccc1
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a suspension of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (100 mg, 0.2 mmol) and DIEA (0.14 mL, 0.8 mmol) in 1,4-dioxane (5 mL) was added phenyl isocyanate (35 mg, 0.3 mmol). The resulting solution was stirred overnight and concentrated. The crude residue was directly purified by prep HPLC using acetonitrile/water to give the title compound (68 mg).
Reaction SMILES: CC1(C)COB([C:8]2[CH:29]=[CH:28][C:11]3[C:12]4[N:16]([CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)[CH:15]=[C:14]([C:20]2[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=2)[N:13]=4)OC1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]([O:44][C:45]([N:47]1[CH:52]2[CH2:53][CH2:54][CH:48]1[CH:49]=[C:50](OS(C(F)(F)F)(=O)=O)[CH2:51]2)=[O:46])([CH3:43])([CH3:42])[CH3:41]>COCCOC.O>[C:40]([O:44][C:45]([N:47]1[CH:52]2[CH2:53][CH2:54][CH:48]1[CH:49]=[C:50]([C:8]1[CH:29]=[CH:28][C:11]3[C:12]4[N:16]([CH2:17][CH2:18][O:19][C:10]=3[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=1)[N:13]=4)[CH2:51]2)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OCC(C)(C)CO3)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CC4CCC(C3)N4C(=O)OC(C)(C)C)cc1OCC2
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
A vessel was charged with 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (237 mg, 0.56 mmol), PdCl2dppf.DCM (46 mg, 0.06 mmol, 10 mol %) and cesium carbonate (456 mg, 1.40 mmol) before being evacuated and refilled with nitrogen. To the resultant mixture was added a solution of 3-trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (402 mg, 0.56 mmol) in DME (2 mL), followed by water (0.2 mL). The reaction was evacuated and refilled with nitrogen before being stirred at 110° C. for 1.5 h. The reaction mixture was partitioned between ethyl acetate and water, the organic phase was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to give 3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester as a colourless oil (177 mg, 0.35 mmol, 63%). LCMS RT=4.84 min, [M+H]+=503
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](N2CCC(O)CC2C)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:29]1[NH:34][C:33](=[O:35])[C:32]2=[C:36]([CH3:40])[N:37]=[C:38]([CH3:39])[N:31]2[N:30]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]2)(=[O:19])=[O:20])=[CH:14][C:13]=1[C:29]1[NH:34][C:33](=[O:35])[C:32]2=[C:36]([CH3:40])[N:37]=[C:38]([CH3:39])[N:31]2[N:30]=1)[CH3:10]
Reactant: OCC1CCNCC1
Reactant: CCOc1ccc(S(=O)(=O)N2CCC(O)CC2C)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 90 mg (0.784 mmol) of 4-hydroxymethylpiperidine, 22 mg (18% of theory) of 2-[2-ethoxy-5-(4-hydroxy-methylpiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]([OH:16])=O)[N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:50]1[CH:54]=[CH:53][N:52]=[C:51]1[NH:55][C:56]([C:58]1[C:66]2[NH:65][C:64]([NH2:67])=[N:63][C:62]=2[CH:61]=[CH:60][CH:59]=1)=[O:57]>CN(C=O)C>[NH:52]1[CH:53]=[CH:54][N:50]=[C:51]1[NH:55][C:56]([C:58]1[C:66]2[NH:65][C:64]([NH:67][C:14]([C:9]3[N:10]=[CH:11][C:12]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=4)=[O:16])=[N:63][C:62]=2[CH:61]=[CH:60][CH:59]=1)=[O:57]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: O=C(O)c1cc2ccc([N+](=O)[O-])cc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1)c1cc2ccc([N+](=O)[O-])cc2cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a solution of 44 mg (0.2 mmol) of 7-nitro-isoquinoline-3-carboxylic acid in DMF (1 mL) was added 113 mg (0.3 mmol) of HBTU and DIEA (0.3 mL). The mixture was stirred for 10 min and then 40 mg (0.16 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B) was added. The reaction was heated at 80° C. for 1 h. After the usual work up, the residue was purified by column chromatography eluting with DCM/methanol (v/v=10:1) to afford 8 mg (9%) of 7-nitro-isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 443 (M+1)+.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH3:15][O:16][C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][CH:20]1[CH2:25][CH:24]([CH3:26])[CH2:23][C:22](=[O:27])[CH2:21]1>O1CCCC1>[CH3:15][O:16][C:17]([CH3:28])([CH3:29])[CH2:18][CH2:19][CH:20]1[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]([OH:27])[CH2:21]1
Reactant: COC(C)(C)CCC1CC(=O)CC(C)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC1CC(C)CC(O)C1
Reaction time: 16 h

Procedure:
A solution of lithium tri-sec-butylborohydride (267 mL of a 1 M solution in tetrahydrofuran, 0.27 mol) was added to a cooled (-65~C) solution of 3-(3-methoxy-3-methlybut-1-yl)-5-methylcyclohexan-1-one (48.6 g, 0.22 mol) dissolved in tetrahydrofuran (350 mL). The solution was stirred at 25~C for 16 hours and was quenched by addition of sodium hydroxide (10% aqueous, 165 mL) followed by hydrogen peroxide (30% aqueous, 170 mL). Workup yielded 3-(3-methoxy-3-methylbutyl)-5-methyl cyclohexan-1-ol as a mixture of diastereoisomers (ratio 90.1:7.2:2.7), bp0.75 120-122~C (40.7 g. This compound and mixtures of diastereomers possess strong, tenacious, sandalwoody, musky notes. NMR(CDC13)δ0.6 (q,1H), 0.9(d,3H), 1.0-1.1(m,2H), 1.1(s,6H),1.2-1.3 (m,2H), 1.4-1.6(m,2H), 1.6-1.9(m,5H), 2.2(brs,1H), 3.2(s,3H), 4.1(m,1H). IR(neat) 3400, 2975, 2925, 1460, 1385, 1365, 1210, 1090, 1015 cm-1 ; MS(m/e) 43, 73, 93, 111, 149, 167, 182, 199, 200.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C@@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:20][Br:21])=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C@@H:19]([O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[CH2:20][Br:21])=[CH:15][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
Borane methylsulfide complex (42.4 ml of ˜10M solution, 424 mmol) was added drop wise to a solution of methyl 2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl)benzoate (Preparation 21, 91.0 g) in tetrahydrofuran (1600 ml). The resulting mixture was then heated to reflux for 2 hours and then cooled to 0° C. before quenching with methanol (270 ml). The mixture was left to stir, at room temperature for 16 hours and then the solvent removed in vacuo. The residue was partitioned between dichloromethane (500 ml) and water (500 ml). The aqueous phase was separated and extracted with more dichloromethane (500 ml) and the combined organic extracts washed with saturated aqueous sodium chloride (500 ml), dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (100:0 changing to 80:20, by volume) to give the title compound (68.7 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCc1nc2c(Cl)cccc2s1
Reactant: Brc1ccccn1
Product: Clc1cccc2sc(CCC#Cc3ccccn3)nc12
Yield: 14.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (166 mg, 1.05 mmol) and 2-but-3-ynyl-4-chloro-benzo[d]thiazole (233 mg, 1.05 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 46 mg (0.15 mmol, 14%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:25]([N:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:28][CH2:27]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)c1
Yield: 53.4 %

Procedure:
3-[3-(3-nitrophenyl)-4,5-Dihydroisoxazol-5-yl]propanal (21.9 mg, 0.088 mmol), 1-(diphenylmethyl)piperazine (20.3 mg, 0.080 mmol), molecular sieves (5 beads), and NaBH(OAc)3 (51.1 mg, 0.241 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 20.7 mg (48.4%) of the target compound was obtained.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC=C(C)[N+]=1[O-:17].C(OO)(=O)C>C(OCCCC)(=O)C.C(OCC)(=O)C>[CH:1]1([C:7]([OH:17])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: CC(=O)OO
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)C1CCCCC1
Yield: 105 %

Procedure:
To a stirred solution of 5.0 g (44.6 mmol) of cyclohexanecarboxaldehyde in n-butyl acetate (45 mL) cooled in a wet-ice bath (ca. 2° C.) was added 5.5 g (44.6 mmol) of 2,6-dimethylpyridine N-oxide (2,6-lutidine N-oxide). To this solution was then added slowly dropwise 24.6 mL (66.9 mmol) of a 23.0 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 20 min). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 4 hours. The cold reaction solution Was then transferred into a separatory funnel, was diluted with n-butyl acetate (50 mL), and was washed with a 1% aqueous solution of sodium thiosulfate (Na2S2O3, 50 mL). The butyl acetate layer was further washed with two portions of water (50 mL each), and the combined water washes were back-extracted with n-butyl acetate (50 ml). The combined butyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 50 mL each). The combined NaOH solutions were acidified to pH=1 with a 10% aqueous solution of hydrochloric acid. The resulting solution was extracted with two portions of dichloromethane (75 mL each), and the extract was dried over anhydrous Na2SO4. The extract was filtered and concentrated in vacuo to give 6.0 g (99%) of cyclohexanecarboxylic acid, containing small levels of unidentified impurities.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:53][O:54][CH2:55][C:56]([CH3:61])([CH3:60])[C:57](O)=[O:58]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:57](=[O:58])[C:56]([CH3:61])([CH3:60])[CH2:55][O:54][CH3:53])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: COCC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.250 g, 0.678 mmol) in THF:DMF (5 mL:1 mL), TBTU (0.653 g, 2.3 mmol), TEA (4.0 mL) were added and the reaction mass was stirred at RT for 1 h. To the reaction mixture, 3-methoxy-2,2-dimethylpropanoic acid (0.134 g, 1.01 mmol) was added and stirring was continued at RT for 2 days. After completion of the reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to obtain crude product. The obtained crude was purified with column chromatography on basic alumina by eluting with 5.0% MeOH:DCM to afford 0.110 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.15 (s, 6H), 1.18 (s, 3H), 3.09 (t, 2H), 4.32 (d, J=11.4 Hz, 2H), 7.43 (dd, J=4.5 Hz, 3.6 Hz, 1H), 7.45 (d, 1H), 7.86 (d, J=5.4 Hz, 2H), 8.15 (t, 1H), 8.20 (d, 2H), 12.50 (br s, 1H); MS (m/z): 483.20 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([NH2:16])=[O:15])[CH:9]=[C:8]2[CH:17]=[O:18])[CH:2]=[CH2:3].CC(=CC)C.[O-:24]Cl=O.[Na+].Cl>C1COCC1.C(O)(C)(C)C.O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:15])[NH2:16])[CH:9]=[C:8]2[C:17]([OH:24])=[O:18])[CH:2]=[CH2:3]
Reactant: [O-][Cl+][O-]
Reactant: C=CCOc1ccc2c(c1)c(C=O)cn2C(N)=O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(c1)c(C(=O)O)cn2C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Allyloxy-3-formyl-indole-1-carboxylic acid amide (530 mg, 2.17 mmol) was dissolved in a mixture of THF (38 mL) and t-butanol (12 mL). 2-methyl-2-butene 2 M solution in THF (40 mL, 80 mmol) was added, followed by a water (9.5 mL) solution of NaClO2 (80%, 2.45 g, 21.7 mmol) and NaH2PO4 (2.08 g, 17.4 mmol). The resulting solution was stirred at RT for 1 h, until consumption of the starting material. HCl 1N (3 mL) was added, and the organic solvents were concentrated. The remaining aqueous layer was filtered and the resulting precipitate was washed with water and Et2O to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:2)=0.08; LC/MS: 261.1 [M+H]+, 259.0 [M−H]−, 216.1 [M−CONH2]−, 519.1 [2M−H]−; tR (HPLC conditions a): 2.8 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][C@@H:35]([CH2:54][CH3:55])[C@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[C:47]([CH3:52])=[N:48][CH:49]=[CH:50][CH:51]=2)[C:41]1=[O:53])[C:37](O)=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[C:47]([CH3:52])=[N:48][CH:49]=[CH:50][CH:51]=2)[C:41]1=[O:53])[CH:35]([CH3:34])[CH2:54][CH3:55])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccnc2C)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccnc2C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A solution containing the product from Example 8B (2.0 g, 4.40 mmol) in DMF (10 mL) was treated with the product from Example 15C (1.34 g, 4.39 mmol), EDAC (1.01 g, 5.27 mmol), HOBT (0.7 g, 5.19 mmol), and NMM (0.96 mL, 8.72 mmol), stirred at 25° C. for 16 hours, treated with Example 15C (0.13 g), EDAC (0.5 g), HOBT (0.35 g), NMM (1 mL), and DMF (5 mL), stirred for 64 hours at 25° C. and concentrated. The concentrate was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-4% methanol/dichloromethane to give the title compound (1.76 g, 54% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.68 (d, J=6.62 Hz, 3 H), 0.81 (m, 15 H), 1.26 (m, 1 H), 1.49 (m, 2 H), 1.78 (m, 1 H), 2.45 (m, 5 H), 2.70 (m, 3 H), 2.90 (m, 2 H), 3.04 (m, 2 H), 3.59 (m, 4 H), 3.87 (m, 2 H), 4.13 (m, 2 H), 4.31 (s, 2 H), 4.79 (d, J=5.52 Hz, 1 H), 6.80 (d, J=9.19 Hz, 1 H), 7.05 (s, 3 H), 7.19 (m, 5 H), 7.51 (m, 2 H), 7.86 (d, J=8.82 Hz, 1 H), 8.36 (d, J=3.68 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:20]([CH3:19])[CH3:30])=[CH:28][CH:27]=3)=[O:18])=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CN(C)CCc1ccc(N)cc1
Product: CN(C)CCc1ccc(NC(=O)/C=C/c2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared analogously to Example 143 starting from (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylic acid (Z34b) and 4-(2-dimethylamino-ethyl)-phenylamine. The crude product was purified by column chromatography (silica gel, dichloromethane/EtOH/conc. aqueous ammonia 50:10:0.1).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7](O)=O)[C@@H:3]([CH3:6])[O:4][CH3:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:41]1([C:46]2[CH:47]=[C:48]([NH2:53])[C:49]([NH2:52])=[CH:50][CH:51]=2)[CH2:45][CH2:44][CH2:43][CH2:42]1.C(O)(=O)C.FC(F)(F)C(O)=O>CN(C)C=O.C(OCC)(=O)C>[CH:41]1([C:46]2[CH:51]=[CH:50][C:49]3[NH:52][C:7]([C@@H:2]([NH2:1])[C@H:3]([O:4][CH3:5])[CH3:6])=[N:53][C:48]=3[CH:47]=2)[CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(C2CCCC2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@H](C)[C@H](N)c1nc2cc(C3CCCC3)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a solution of Boc-Thr(Me)-OH (113 mg, 0.48 mmol) in N,N-dimethylformamide (3.0 mL) was added HATU (225 mg, 0.592 mmol). The mixture was stirred for 30 minutes and then 4-cyclopentylbenzene-1,2-diamine (Compound 84, 118 mg, 0.669 mmol) was added. After stirring for 2 days, the solution was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. To the resulting residue was added acetic acid (3 mL, 50 mmol) and the mixture allowed to stir for 2 days. The reaction mixture was then concentrated in vacuo and purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes. The resulting brown oil was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (0.5 mL, 6 mmol). After stirring for 3 hours, the reaction mixture was concentrated in vacuo, redissolved in methylene chloride, and washed with saturated aqueous sodium hydrogen carbonate solution.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@H:14](/[CH:17]=[CH:18]/[CH:19]([OH:27])[C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:12]2)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@H:14](/[CH:17]=[CH:18]/[CH:19]([OH:27])[C:20]([F:25])([F:26])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:12]2)([OH:3])=[O:2]
Reactant: CCCCC(F)(F)C(O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)OC)C[C@H]2C[C@H]1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(F)(F)C(O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1

Procedure:
(1S,2S,3R,5S)-(E)-7-(4-Carbomethoxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (18) (0.175 g) was dissolved into methanol, to which 1N aqueous solution of sodium hydroxide was added, and the mixture was stirred until the mixture became completely clear. After a usual work-up a crude product, (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (19), was obtained. Yield: 0.172 g
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>O1CCCC1>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
To a solution of 3-aminopyridine (1.0 g, 11 mmol) and triethylamine (1.3 g, 13 mmol) in tetrahydrofuran (30 mL) was added at 0° C. trichloroacetyl chloride (1.4 mL, 13 mmol), and the mixture was stirred at 0° C. for 20 minutes. The reaction solution was concentrated, and ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was washed with diisopropyl ether and collected by filtration to obtain the title compound (2.3 g, yield 89%) as colorless powder.