Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7])=O.Cl.[NH2:19][OH:20].N1C=CC=CC=1.Cl>CO>[OH:20][N:19]=[CH:1][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: COC(C1=CN(C)CS1)c1ccccc1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(C1=CN(C)CS1)c1ccccc1C=NO
Yield: 75.7 %

Procedure:
To 1.39 g (6 mmol) of 5-(2-formyl-α-methoxybenzyl)-3-methylthiazole in 12 ml of methanol was added 0.83 g (12 mmol) of hydroxylamine hydrochloride and 1.07 ml (13.2 mmol) of pyridine and stirred under reflux for 2 hours. After completion of the reaction, 200 ml of 0.1N hydrochloric acid was added and extracted twice with 100 ml of dichloromethane. The dichloromethane layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylthiazole (1.20 g, 81.2%) as oil.
Reaction SMILES: C[Si](I)(C)C.[CH3:6][N:7]1[C:13](=[O:14])[CH:12]([NH:15]C(=O)OC)[CH2:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=2[CH2:8]1.C(OCC)(=O)C>ClCCl>[NH2:15][CH:12]1[CH2:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=2[CH2:8][N:7]([CH3:6])[C:13]1=[O:14]
Reactant: COC(=O)NC1Cc2ccccc2CN(C)C1=O
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1Cc2ccccc2CC(N)C1=O
Temperature: 25 °C
Yield: 56.5 %

Procedure:
0.6 ml of trimethylsilyl iodide is added to a solution of 203 mg (0.93 mmol) of product 2 in 10 ml of dichloromethane, and the mixture is then refluxed for 3 hours. After cooling to room temperature and adding 50 ml of ethyl acetate, the organic phase is extracted with 2×25 ml of 1N hydrochloric acid solution. The aqueous phases are combined, cooled and then basified by addition of 5N sodium hydroxide. The basic aqueous phases are then saturated with NaCl, and then extracted with 3×25 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate and evaporated under reduced pressure to give an oily residue. This residue is chromatographed on silica gel, eluting with a 90/10 dichloromethane/methanol mixture. 100 mg (57%) of the expected product 3 are obtained in the form of an oil.
Reaction SMILES: Cl.Cl.[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:11]=[CH:10][N:9]=1)[CH:4]([CH3:6])[CH3:5].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH2:3]([O:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:29](=[O:30])[CH2:28][NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:16][CH2:15]2)[CH:13]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COc1cc(N2CCNCC2)ncn1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Product: CC(C)COc1cc(N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)ncn1

Procedure:
The title compound was prepared according to the procedure described in Example 3 using 4-isobutoxy-6-(piperazin-1-yl)pyrimidine dihydrochloride and 2-((tert-butoxycarbonyl)amino)acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8].C(N(CC)CC)C.[P:17](Cl)(Cl)([O:19][CH3:20])=[O:18]>CCOCC>[CH3:20][O:19][P:17]1(=[O:18])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[O:1]1
Reactant: Cc1ccc(O)c(O)c1
Reactant: COP(=O)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COP1(=O)Oc2ccc(C)cc2O1
Yield: 88319 %

Procedure:
3,4-Dihydroxytoluene (1.686 g, 13.58 mM) was dissolved in 40 ml of ether and, using 2.748 g of triethylamine and 2.022 g of methyl dichlorophosphate, the reaction mixture was treated in the same manner as in Reference Example 5. There was obtained 2,400 g (88.4% yield) of 2-methoxy-5-methyl-2-oxo-1,3,2-benzodioxaphosphole as a viscous oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][CH:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (67 mg, 79%), MS (ISP) m/z=455.5 [(M+H)+], mp 191° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (75 mg, 0.19 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:33]=[CH:34][N:35]=[C:36]([F:37])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCOCC1.CO.O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:33]=[CH:34][N:35]=[C:36]([F:37])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)CC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
Compound 258 (0.100 g, 0.20 mmol) was suspended in dioxane (4.8 mL) and methanol (4.8 mL). A solution of lithium hydroxide, monohydrate (0.0092 g, 0.22 mmol) in 2.0 mL of water was added to the suspension. The reaction was warmed to 70° C. After 1 hour, solvent was removed in vacuo. The residue was dissolved in water (3 mL). Dichloromethane was added (1 mL) and the pH was brought to ca. pH 10 with dilute NaOH. The organics were removed and the aqueous was brought to ca. pH 4 with dilute HCl. The resulting precipitate was filtered. Purification by RP-HPLC on C18 column (10-90% CH3CN in water with 0.1% TFA) provided compound 259 (5 mg) as a TFA salt. 1H NMR (500 MHz, DMSO-d6) δ 1.28-1.41 (m, J=12.17, 12.01, 12.01, 3.18 Hz, 2 H) 1.68-1.94 (m, 5 H) 1.99-2.09 (m, 2 H) 2.09-2.19 (m, 2 H) 2.21-2.34 (m, 4 H) 2.81 (t, 11.49 Hz, 2 H) 3.71 (d, J=12.23 Hz, 2 H) 5.53 (quin, J=9.11 Hz, 1 H) 7.72 (d, J=9.05 Hz, 1 H) 7.98 (br. s., 1 H) 8.06 (d, J=8.56 Hz, 1 H) 8.11-8.18 (m, 1 H) 8.25 (dd, J=4.65, 2.93 Hz, 1 H) 9.51 (s, 1 H) 11.43 (br. s., 1 H) ppm. LCMS-ESI (POS), M/Z, M+1: Found 490.1, Calculated 490.2.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([C:22]2[N:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#[N:25])[CH:21]=1>>[F:30][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)=[CH:21][C:20]=1[C:22]1[N:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: N#Cc1cccnc1-c1cc(Br)ccc1F
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Product: N#Cc1cccnc1-c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 45.5 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (102 mg, 0.5 mmol) and 2-(5-bromo-2-fluorophenyl)nicotinonitrile (208 mg, 0.75 mmol) were coupled following the procedure given in Example 6 to afford 2-[2-fluoro-5-(8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridin-3-yl)phenyl]-nicotinonitrile (91 mg, 45%) as a white solid: δH (360 MHz, CDCl3) 6.98 (1H, dd, J 7 and 6), 7.44-7.54 (2H, m), 7.67-7.72 (1H, m), 7.79 (1H, dd, J 7 and 2), 7.88 (1H, s), 8.15 (1H, dd, J 7 and 2), 8.24 (1H, d, J 7), 8.95 (1H, d, J 2); m/z (ES+) 401 (100%, [MH]+).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]([OH:12])=O)[CH2:4]1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH3:2])[CH2:4]1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC1CCCN(CC(=O)O)C1
Agent: Cl
Product: CC1CCCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Yield: 42.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-methylpiperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 46, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(3-methylpiperidin-1-yl)acetamido)propanamide (17.8 mg, 42.8%). 1H-NMR (400 MHz, DMSO-D6): σ 10.20 (s, 1H), 7.94 (d, 1H), 7.56 (d, 2H), 7.29 (m, 5H), 7.21 (m, 2H), 7.01 (m, 4H), 4.69 (m, 1H), 4.52 (s, 2H), 3.73 (m, 2H), 2.93 (m, 2H), 2.73 (m, 2H), 1.98 (s, 1H), 1.58 (m 5H), 0.81 (m, 4H). MS (EI) for C30H34FN3O4: 520.7 (MH+).
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2F)=O)[CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.Cl.[CH2:22]([NH:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1>[CH2:22]([N:29]1[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([OH:13])[CH:9]=2)[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NNCc1ccccc1
Reactant: O=C(c1ccc(O)cc1F)C1CCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Oc1ccc2c(C3CCC3)nn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclobutyl(2-fluoro-4-hydroxyphenyl)methanone (6.967 g) which can be prepared according to the method described in Reference example 9, etc., sodium acetate (14.16 g; manufactured by Kanto Chemical Co., Inc.), and benzylhydrazine-dihydrochloride (10.55 g; manufactured by Sigma-Aldrich Co.) were suspended in xylene (85 mL; manufactured by Wako Pure Chemical Industries, Ltd.). By using a dean-stark apparatus, the mixture was stirred overnight at reflux. After cooling to room temperature, solid obtained after filtering the precipitate was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The organic layer was combined, washed twice with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the title compound was obtained (8.003 g).
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=C)[C@]5(O)[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[CH2:30]=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1>>[OH:2][C@:48]12[CH2:47][C:46](=[O:49])[CH2:45][CH2:44][C@:43]1([CH3:50])[C@@H:42]1[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]1)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32][C:31]2=[CH2:30]
Reactant: C=C1C[C@H]2[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCCC[C@]12O
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Yield: 85 %

Procedure:
The title compound II-ap was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-methyleneandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/AcOEt 60/40). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.91 (1H, s), 4.81 (1H, bs), 4.58 (1H, bs), 2.82 (1H, d), 2.42-1.10 (17H, m), 0.94 (3H, s), 0.77 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CS(O[CH2:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)=O.[Na+].[I-]>>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:22][CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [I-]
Agent: [Na+]
Product: Clc1ccc(CN2CCC(CNCCC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 54 %

Procedure:
4-(Aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) was alkylated with 3,3-diphenylpropyl methanesulfonate (1.0 equiv.) in the presence of NaI (2.6 equiv.) in CH2CN at 70° C. for 16 h. General workup and column chromatography (SiO2) afforded 1-(4-chlorobenzyl)-4-{N-(3,3-diphenylpropyl)aminomethyl}piperidine (118 mg, 54%): The purity was determined by RPLC (98%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)[C:8]2[CH:17]=[C:18](I)[CH:19]=[CH:20][C:7]=2[N:6]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C@:28]([OH:32])([C:30]#[CH:31])[CH3:29])[N:24]=1>C(N(CC)CC)C.CS(C)=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:16][C:12]1[N:11]=[C:10]([N:9]2[C:8]3[CH:17]=[C:18]([C:31]#[C:30][C@:28]([C:25]4[N:24]=[C:23]([CH3:22])[O:27][N:26]=4)([OH:32])[CH3:29])[CH:19]=[CH:20][C:7]=3[N:6]=[C:5]2[O:4][CH2:3][CH2:2][F:1])[CH:15]=[CH:14][N:13]=1
Reactant: Nc1nccc(-n2c(OCCF)nc3ccc(I)cc32)n1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc([C@](C)(O)C#Cc2ccc3nc(OCCF)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 25 °C
Yield: 7.2 %

Procedure:
A solution of 4-[2-(2-fluoroethoxy)-6-iodo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (130 mg, 0.33 mmol), (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (148 mg, 0.97 mmol), bis(triphenylphosphine)palladium(II) dichloride (34 mg, 0.05 mmol) in triethylamine (1 mL) and dimethylsulfoxide (1 mL) was irradiated with microwave radiation under nitrogen in a 8-mL vial at 90° C. for 30 min. The resulting solution was cooled to room temperature and diluted with 30 mL of ethyl acetate. The solid material was removed by filtration. The residue was concentrated under vacuum then purified on a silica gel column (ethyl acetate/petroleum ether, 2:1) to give 10 mg (7%) of (2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol as a light brown solid. 1H NMR (400 MHz, MeOD) delta 8.47 (s, 1H), 8.35 (d, J=5.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.39-7.36 (m, 1H), 7.15 (d, J=5.6 Hz, 1H), 4.95-4.90 (m, 2H), 4.85-4.81 (m, 2H), 2.63 (s, 3H), 1.96 (s, 3H); LC-MS: m/z=+424 (M+H)+.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:39][CH:40]([CH3:54])[CH2:41][C:42]([C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=1)=O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:42]([C:44]2[CH:45]=[CH:46][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:52][CH:53]=2)[CH2:41][CH:40]([CH3:54])[CH3:39])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(C(=O)CC(C)C)cc1
Reactant: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=Cc2ccc(Br)cc2)CC(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
4-Bromobenzyltriphenylphosphonium bromide (2.07 g, 4.40 mmol) was suspended in toluene (4.0 mL) and cooled to 0° C. Lithium bis(trimethylsilyl)amide (4.04 mL, 1.0 M in toluene) was added. The ice bath was removed and the reaction was allowed to warm to room temperature and stir for 1 hour. A solution of Intermediate (10) (180 mg, 0.817 mmol) in toluene (0.8 mL) was then added drop-wise, and the reaction was allowed to stir for 18 hours. The reaction was diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted three times with ethyl acetate. The combined organics were washed twice with 1N HCl and once with brine, then dried over magnesium sulfate, filtered, and concentrated. The crude solid was taken up in heptane and the remaining solids (triphenylphospine oxide) were filtered off. The filtrate was concentrated and purified by column chromatography (0-10% ethyl acetate in heptane) to give methyl 4-(1-(4-bromophenyl)-4-methylpent-1-en-2-yl)benzoate (184.7 mg, 61%) as an approximate 1:1 mixture of E/Z isomers. 1H NMR (400 MHz, CDCl3, δ): 8.04-8.00 (m, 2H), 7.97-7.92 (m, 2H), 7.50-7.46 (m, 4H), 7.22-7.16 (m, 6H), 6.77-6.72 (m, 2H), 6.69 (s, 1H), 6.39 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.58 (d, J=7.4 Hz, 2H), 2.37 (dd, J=7.2, 1.2 Hz, 2H), 1.68-1.57 (m, 1H), 1.51 (dt, J=13.5, 6.8 Hz, 1H), 0.88 (d, J=6.6 Hz, 6H), 0.78 (d, J=6.6 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccccc1N
Yield: 100.5 %

Procedure:
Methyl 2-nitrophenylacetate (10.1 g, 51.2 mmol) in 125 mL of methanol containing 221 mg of 10% Pd/C was placed on the Parr hydrogenator at 40 psi. After 5 h the mixture was filtered through celite and evaporated under reduced pressure to give a clear red oil. The solvent was evaporated under reduced pressure to give 8.5 g (100%) of methyl 2-aminophenylacetate as a clear red oil. TLC (silica, EtOAc/hexanes): Rf=0.24. 1H NMR (400 MHz, CDCl3): 7.21 (m, 2H), 6.86 (m, 2H), 3.81 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:48][CH3:49])([CH2:46][CH3:47])[O:4][C@@H:5]1[CH2:9][C@H:8]([OH:10])[C@H:7]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([O:19]C(C)C)=[O:18])[C@H:6]1/[CH:23]=[CH:24]/[C@@H:25]([O:38][Si:39]([CH2:44][CH3:45])([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[CH3:2]>C(C(C)=O)C(C)C>[F:37][C:34]([F:35])([F:36])[C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[O:27][CH2:26][C@H:25]([O:38][Si:39]([CH2:40][CH3:41])([CH2:42][CH3:43])[CH2:44][CH3:45])/[CH:24]=[CH:23]/[C@H:6]1[C@H:5]([O:4][Si:3]([CH2:1][CH3:2])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH2:9][C@H:8]([OH:10])[C@@H:7]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC[Si](CC)(CC)O[C@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O[Si](CC)(CC)CC)COc1cccc(C(F)(F)F)c1
Solvent: CC(=O)CC(C)C
Product: CC[Si](CC)(CC)O[C@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O[Si](CC)(CC)CC)COc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 106.1 %

Procedure:
(Z)-isopropyl 7-((1R,2R,3R,5S)-3-((triethylsilyl)oxy)-2-((R,E)-3-((triethylsilyl)oxy)-4-(3-(trifluoro methyl)phenoxy)but-1-en-1-yl)-5-hydroxycyclopentyl)hept-5-enoate (1.5 g from Example 14) in 10 mL methyl isobutyl ketone and 0.2 g Candida antarcitica lipase was added into 25 mL round-bottom flask. The reaction mixture was stirred at room temperature for 3 days. Then, the Lipase was filtered off and solvent was evaporated off under vacuum to obtain 1.5 g crude product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[O:9])[CH2:5][CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][Mg+].[Br-]>C1COCC1>[OH:9][C:8]([CH:6]1[CH2:5][CH2:4][CH:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]([CH3:1])[CH2:7]1)([C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[CH3:20]
Reactant: C[Mg+]
Reactant: CCOC(=O)C1CCC(C(=O)c2nccs2)CC1C
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(C(C)(O)c2nccs2)CC1C
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 2-methyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate (2.8 g, 10 mmol) in THF (28 mL) at −40° C. was added MeMgBr (3.0 M in THF, 4.0 mL, 12 mmol) at such a rate the internal temperature did not exceed −30° C. The reaction mixture was stirred for 15 minutes at −40° C., and was then quenched with saturated aqueous ammonium chloride (50 mL) and warmed to room temperature. EtOAc (20 mL) was added, the layers separated, and the aqueous layer was extracted a second time with EtOAc (50 mL). The organic layers were combined, dried over MgSO4, filtered, absorbed on silica, and purified by silica gel chromatography to afford ethyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2-methylcyclohexanecarboxylate.
Reaction SMILES: [CH:1]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]=[O:15]>C1(C)C=CC=CC=1>[CH:1]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH:8]=1)[CH:14]=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=O
Reactant: CCCCC=Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CCCCC=Cc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
NMR (200 MHz, DMSO-d6) (mixture of cis and trans isomers): δ9.33 (s, 1H), 7.14 (m, 2H), 6.70 (m, 2H), 6.26 (m, 1H), 6.1-5.35 (multiplets, together 1H), 2.35-2.08 (m, 2H), 1.36 (m, 4H), 0.89 (m, 3H). 4-(1-Hexenyl)phenol in toluene (8 ml) was added to Mg(OMe)2 (7.3 ml, 8% wt/wt solution in methanol, 5.5 mMol) and the resultant red solution heated at reflux for 1 hour. The mixture was then distilled until the reaction temperature rose to 95° C. A suspension of paraformaldehyde (0.78 g, 26 mmol) in toluene (5 ml) was then added and the reaction heated at reflux for three hours. The reaction was allowed to cool to ambient temperature and to stir overnight. The reaction mixture was then diluted with toluene and washed with 2M aqueous H2SO4 (10 ml). The organic layer was washed with water (3×), dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl ether/hexane) to give 5-(1-hexenyl)-2-hydroxybenzaldehyde as a yellow/green oil (0.65 g, 38%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f23) and commercially available acetyl chloride the title compound is obtained as colorless solid.