Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[C:28]([O:32][C:33]([N:35]([CH:49]([CH3:51])[CH3:50])[CH2:36][C:37]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)([OH:41])[C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([C:37]([OH:41])([C:38]([N:25]2[CH2:26][CH2:27][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:23][CH2:24]2)=[O:39])[CH2:36][N:35]([CH:49]([CH3:50])[CH3:51])[C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:47][CH:46]=1
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)N(CC(O)(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)N(CC(O)(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 59 %

Procedure:
DIPEA (35.5 mg, 0.275 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.69 mmol), 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid (29.5 mg, 0.082 mmol), and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5.0 mL) at room temperature. The resulting mixture was stirred overnight, diluted with EtOAc, washed with saturated aqueous. NaHCO3 and saturated aqueous NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g) and eluted by a mixture of EtOAc and hexane (60:40) to give tert-butyl 2-(4-chlorophenyl)-2-hydroxy-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a clear oil (27 mg, 70%). LCMS (APCI+) [M-Boc+H]+ 558.1; Rf: 4.41 min.
Reaction SMILES: C(OC(=O)C(CC)CCN1C(=S)[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:27])C.[CH2:31]([N:33]([CH2:47][CH3:48])[C:34](=[O:46])[CH2:35][C:36]1([CH2:42][N:43]=[C:44]=[S:45])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>C(Cl)(Cl)Cl.O>[CH2:34]([O:46][C:9]([C:10]1[NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:15][C:16]=2[CH:17]=1)=[O:27])[CH3:35].[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[O:15][C:16]3[CH:17]=[C:10]4[C:9](=[O:27])[N:43]([CH2:42][C:36]5([CH2:35][C:34]([N:33]([CH2:31][CH3:32])[CH2:47][CH3:48])=[O:46])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]5)[C:44](=[S:45])[N:11]4[C:12]=3[CH:13]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Reactant: CCN(CC)C(=O)CC1(CN=C=S)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CCN(CC)C(=O)CC1(CN2C(=O)c3cc4oc(-c5ccc(Cl)cc5)cc4n3C2=S)CCCCC1
Product: CCOC(=O)c1cc2oc(-c3ccc(Cl)cc3)cc2[nH]1
Temperature: 120 °C
Reaction time: 6 h
Yield: 20 %

Procedure:
2-(4-Chloro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (15 mg, 0.05 mmol) was prepared as described hereinabove (see, preparation of Compound 4), and placed in a heavy-walled glass tube with a threaded Teflon plug. N,N-diethyl-2-(1-isothiocyanatomethyl-cyclohexyl)-acetamide (84 mg, 0.2 mmol, 4 molequivalents) and K2CO3 (10 mg, 0.07 mmol, 1.4 molequivalents) were added thereto, the glass tube was sealed and the mixture was heated while stirring at 120° C. for 6 hours. The mixture was then dissolved in chloroform, washed with water, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The purified product was isolated by HPLC, using an acetonitrile:water gradient as eluent, to give Compound 24 (5.16 mg, 20% yield) as an orange solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].C([Mg]Br)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:22]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH:10]=2)[NH:14][CH:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc2[nH]cc(Cc3ccccc3)c2c1
Temperature: 0 °C
Yield: 32.3 %

Procedure:
5-(2-Cyanophenyl)indole (2.3 mmole, 0.50 g) was dissolved in 3 ml THF, cooled to 0° C. Ethyl magnesium bromide (2.41 mmoles, 1.21 ml of 2.0M solution in ether) was added dropwise. Benzyl bromide (94.6 mmole, 0.80 g) was added dropwise to the solution. The reaction was refluxed for 24 hours and poured into aqueous ammonium chloride and ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated. The intermediate was chromatographed over silica gel eluted with 10% ethyl acetate in hexane to yield 229 mg of 3-benzyl-5-(2-cyanophenyl)indole. (MS)
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].P(Br)(Br)[Br:31].CN(C=O)C>C(Cl)Cl>[Br:31][CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Yield: 49.6 %

Procedure:
The title compound was made in a similar way as that of the intermediate C6, using 3-(1-hydroxyethyl)-4-(3-(morpholinosulfonyl)phenyl)-1H-isochromen-1-one (intermediate B9, 163 mg, 0.392 mmol), 1M PBr3 (0.68 ml, 0.667 mmol) in DCM (3.2 ml) at RT. The crude was tritured with DMF to give the title compound (93 mg, 49%). The solution was purified via reverse phase chromatography with a Biotage C18 SNAP 30 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%); Phase B ACN 99.9%, formic acid 0.1%) to give further compound (68 mg, 36.2%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)c1cc2ccccc2[nH]1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)c1cc2ccccc2n1CCCCl
Temperature: 60 °C
Reaction time: 16 h
Yield: 104.7 %

Procedure:
To a cold solution of tert-butyl 1H-indole-2-carboxylate (1.15 g, 4.94 mmol, 1 equiv) in dimthylformamide sodium hydride (60% dispersion) (237 mg, 5.92 mmol, 1.2 equiv) was added and the reaction stirred until all the sodium hydride has been consumed. 1-bromo-3-chloropropane (1.46 ml, 14.88 mmol, 3 equiv) was added and the reaction stirred at 60° C. for 16 h. The reaction was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purifed using the Biotage flash chromatography system (SNAP, 50 g cartridge, Rf=0.5, gradient—5%-25% ethyl acetate in hexanes) to afford the title compound as an oil (1.52 g, quant); MS for C16H20ClNO2 m/z 293.12 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH:3]1[O:5][CH2:4]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:4][CH:3]([OH:5])[CH:2]([CH3:1])[CH2:6][CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:4][CH:3]([OH:5])[CH:2]([CH3:1])[CH2:6][CH3:7]
Reactant: NCCCCCCN
Reactant: CCC(C)C1CO1
Product: CCC(C)C(O)CNCCCCCCNCC(O)C(C)CC

Procedure:
Condensation of 3-methyl-1-pentene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-3-methylpentylamine] (I: R = CH3CH2 (CH3)C, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[C:14]2[O:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH3:24][O:25][C:26](=[O:45])[C@H:27]([CH2:35][C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([OH:43])=[C:38]([Cl:44])[CH:37]=1)[NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31].CN(C)C=O>CC(C)=O>[CH3:24][O:25][C:26](=[O:45])[C@H:27]([CH2:35][C:36]1[CH:37]=[C:38]([Cl:44])[C:39]([O:43][CH2:8][C:9]2[C:14]3[O:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[C:40]([Cl:42])[CH:41]=1)[NH:28][C:29](=[O:34])[C:30]([F:33])([F:31])[F:32]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(O)c(Cl)c1)NC(=O)C(F)(F)F
Reactant: ClCc1cccc2cc(-c3ccccc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)[C@H](Cc1cc(Cl)c(OCc2cccc3cc(-c4ccccc4)oc23)c(Cl)c1)NC(=O)C(F)(F)F
Temperature: 0 °C
Yield: 52 %

Procedure:
Potassium carbonate (180 mg, 1.30 mmol) and 7-chloromethyl-2-phenylbenzo[b]furan. (171 mg, 0.705 mmol) were added in turn to a solution of 3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (221 mg, 0.614 mmol) in acetone (3 ml) with stirring under ice cooling and the mixture was stirred under argon atmosphere at the same temperature for 5 hrs. Dimethylformamide (2 ml) and n-tetrabutylammonium iodide (23 mg, 0.062 mmol) were added to the mixture and stirred at room temperature for 21 hrs. The reaction mixture was poured into ice-water (50 ml) and extracted with ethyl acetate. The extract was washed with water and saturated brine solution in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=5) to give 3,5-dichloro-N-trifluoroacetyl-O-[(2-phenylbenzo[b]fur-7-yl)methyl]-L-tyrosine methyl ester (182 mg, 52%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[S:3]1C=C[CH:5]=[C:4]1CC(O)=O.[CH3:12][C:13]1([CH3:23])[O:18][CH2:17][C:16]([CH2:21][CH3:22])([CH2:19]I)[CH2:15][O:14]1.[OH2:24]>CN(C)C=O>[C:4]([S:3][CH2:19][C:16]1([CH2:21][CH3:22])[CH2:17][O:18][C:13]([CH3:23])([CH3:12])[O:14][CH2:15]1)(=[O:24])[CH3:5]
Reactant: O
Reactant: O=C(O)Cc1cccs1
Reactant: CCC1(CI)COC(C)(C)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(CSC(C)=O)COC(C)(C)OC1
Reaction time: 2 h

Procedure:
Sodium hydride (340 mg., 50% dispersion in paraffin oil) was added carefully to a stirred solution of thiolacetic acid (500 mg.) in dry dimethylformamide (100 ml.) at 20°. After 30 minutes 2,2-dimethyl-5-ethyl-5-iodomethyl-1,3-dioxane (2.0 g.) was added. The mixture was refluxed with stirring for 2 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solution was evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with 1:4 ether:hexane. 5-Acetylthiomethyl-5-ethyl-2,2-dimethyl-1,3-dioxane was obtained as a pale yellow oil (1.5 g.)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>CC(O)=O>[CH2:16]([O:15][C:14]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH3:17]
Reactant: CCOC(=O)c1ccc(OCC)c(OCC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCC)c(OCC)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 93.8 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of ethyl 3,4-diethoxybenzoate (6.43 g, 27 mmol) in AcOH (50 mL) was dropped fuming nitric acid (90%, 6.3 g) and the reaction was heated at 50° C. overnight, to afford ethyl 4,5-diethoxy-2-nitrobenzoate as a solid (7.175 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.05 (s, 1H), 4.37 (q, 2H), 4.18 (m, 4H), 1.50 (m, 6H), 1.35 (t, 3H); LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCCCO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCCCCO)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and 4-amino-1-butanol, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=446.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10](Cl)([Cl:12])=[S:11]>C(Cl)Cl>[ClH:12].[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:10]=[S:11])=[CH:7][N:6]=1
Reactant: COc1ccc(N)cn1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N=C=S)cn1
Product: Cl
Temperature: 25 °C
Yield: 47.4 %

Procedure:
5-Amino-2-methoxypyridine (11 ml, 0.10 mol) is added dropwise at reflux, with stirring to a solution of thiophosgene (8.4 ml, 0.11 mol) in methylene chloride. Refluxing is continued for a further hour and cooled to room temperature. The resulting solid is filtered off, washed with ether to give 9.6 g of the title intermediate product.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=O)(C)(C)C.[Cl:15]C1C=C(OC[C@@H]2CCCN2C(OC(C)(C)C)=O)C=NC=1.C(O[C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[CH2:48]O)=O)(C)(C)C>>[ClH:15].[ClH:15].[CH3:48][C:44]1[C:45]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:46][CH:47]=[CH:41][N:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: Cc1ncccc1OC[C@H]1CCCN1
Product: Cl

Procedure:
Replacing (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol of Example 15 with (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (Aldrich Chemical Co.), and following the procedure of steps 15a and 15b, the title compound was prepared. The MS and 1H NMR spectra were similar to compound 15a.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([OH:16])[CH:9]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:1][CH3:2])=[C:10]([OH:16])[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Br)cc1O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC=Cc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of ethyltriphenylphosphonium bromide (8.44 g, 22 mmol, 2.2 eq.) in toluene (60 mL), a solution of potassium tert-butoxide (2.60 g, 22 mmol, 2.2 eq.) in THF (15 mL) was added dropwise. The resulting red mixture was stirred at r.t. for 4 hours. The mixture was then cooled to −78° C. and a solution of 4-bromo-2-hydroxybenzaldehyde (2.12 mg, 10 mmol, 1.0 eq.) in toluene (10 mL) was added dropwise. The resulting solution was allowed to slowly warm to r.t. and further stirred at r.t. for 20 hours. The reaction was quenched with sat. aq. NH4Cl soln. (30 mL). The mixture was diluted with water (30 mL). The layers were separated and the aq. phase was extracted with Et2O (3×30 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane/AcOEt 8:2) to yield 5-bromo-2-(propenyl)-phenol as a yellow oil as an unseparable mixture of E- and Z-isomer (ca. 85:15).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[O:15][CH3:16])=[O:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.[CH2:28](N(CC)CC)C>CN(C=O)C.O>[CH2:1]([O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:27][CH:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH3:26])[C:7]=2[C:6]=1[O:15][CH3:16])=[O:4])[CH3:28]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1OC
Reactant: COc1ccc(C(C)N)cc1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc2ncnc(NC(C)c3ccc(OC)cc3)c2c1OC

Procedure:
A stirred solution of 4-chloro-5-methoxythieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (1.0 g, 3.8 mmol), 1-(4-methoxyphenyl)ethylamine (0.8 g, 5 mmol) and triethylamine (1 mL) in DMF (20 mL) was warmed to 60° C. for 1 hour. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography over silica gel (25 percent EtOAc in hexanes) affording product as a powder (700 mg, 1.5 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][CH2:12][C@@H:13]([OH:32])[C@@H:14]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.F[C:34](F)(F)[C:35]([OH:37])=O.[C:40](C1NC=CN=1)(=O)C.[ClH:48]>C(Cl)Cl.CCOCC>[ClH:48].[C:35]([O:32][C@H:13]([CH2:12][NH:11][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:10])[CH3:9])[C@@H:14]([NH:24][C:25](=[O:31])[CH3:40])[CH2:15][C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1)(=[O:37])[CH3:34]
Reactant: CC(=O)c1ncc[nH]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC(C)(C)c1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H](CNC(C)(C)c1cccc(Br)c1)OC(C)=O
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To 365 mg (0.71 mmol) of tert-butyl (1S,2R)-3-{[1-(3-bromophenyl)-1-methylethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate 30 in 2 mL of CH2Cl2 is added 1 mL of trifluoroacetic acid, and the mixture is stirred for 30 min. It is concentrated in vacuo, diluted with ethyl acetate, and washed with 10% Na2CO3 and then brine. The solution is dried over Na2SO4, filtered and concentrated to a colorless oil. This is dissolved in 3 mL of CH2Cl2 and 172 mg (1.56 mmol) of acetyl imidazole is added. After 2.5 h the mixture is concentrated and taken up in ethyl acetate and 1 N KH2PO4. The organic phase is washed with 1N KH2PO4, with brine, dried over Na2SO4, concentrated, and chromatographed over silica gel. Elution with 4% methanol (containing 1% of NH4OH) in CH2Cl2 affords a sticky solid. This is dissolved in ether and treated with ethereal HCl. Concentration afford 260 mg (0.49 mmol, 68%) of compound 31 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.79 (n m, 1 H), 7.59 (m, 2 H), 7.36 (t, J=8 Hz, 1 H), 6.69-6.62 (m, 3 H), 5.15 (m, 1 H), 4.17 (m, 1 H), 3.07 (d, J=12.5 Hz, 1 H), 2.87-2.75 (m, 2 H), 2.61 (dd, J=7, 13.5 Hz, 1 H), 2.21 (s, 3 H), 1.95 (s, 3 H), 1.92 (s, 3 H), 1.84 (s, 3 H); IR (diffuse reflectance) 2985, 2958, 2940, 2755, 2738, 2730, 1749, 1645, 1628, 1596, 1569, 1463, 1372, 1227, 1118 cm −1. MS (CI)m/z(rel intensity) 497 (MH+, 86), 500 (15), 499 (99), 497 (86), 419 (28), 283 (18), 231 (22), 136 (17), 77 (46), 60 (13), 58 (18). HRMS (ESI) calcd for C23H27N2O3F2Br+H1 497.1252, found 497.1248.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].CS(Cl)(=O)=O.[CH2:22]([N:24](CC)CC)C>C(OCC)(=O)C>[C:22]([CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:24]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(CO)cc1C(=O)OC
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC#N)cc1C(=O)OC

Procedure:
1.30 g of dimethyl 4-hydroxymethylphthalate was dissolved in 15 ml of ethyl acetate, and 0.58 ml of methanesulfonyl chloride and 1.55 ml of triethylamine were added under cooling with ice with stirring, followed by stirring at room temperature overnight. Insoluble matters were filtered off, and then, the solvent was distilled off under reduced pressure. The residue was dissolved in 13 ml of dimethylformamide, and then, 0.54 g of sodium cyanide was added, followed by stirring at room temperature for 3 hours. The reaction solution was extracted by an addition of ethyl ether and water, and the organic layer was post-treated in accordance with a usual method. Then, the product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 0.78 g of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].ClCCl>CO>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: C=CC(=O)OC
Solvent: ClCCl
Solvent: CO
Product: CCCCN(CCCC)CCC(=O)OC
Temperature: 50 °C
Yield: 94.5 %

Procedure:
A! A solution of dibutylamine (1 l, 5.88 moles) in methanol (2.35 l), kept under stirring at 50° C., was slowly added dropwise with methyl acrilate (1.051 l, 11.76 moles). The mixture was then brought to room temperature and kept under stirring for 1 hour, thereafter 1.174 l of dichloromethane were added and the product extracted with 4.7 l of 3N HCl. The organic phase was washed with water (3×2.35 l). The aqueous phase was brought to pH-9 with 5N sodium hydrate and extracted with dichloromethane (2×2.35 l). The organic phase was washed with 2.35 l of distilled water, then anhydrified over sodium sulfate and evaporated under vacuum thus obtaining 1197 g of methyl N,N-dibutyl-3-amino-propionate (yield: 94.5%) as a pale yellow oil which was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH:7]([Br:26])[CH:8]1[O:25][C@H:11]2[CH2:12][C@@H:13]([OH:24])[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH:7]([Br:26])[CH:8]1[O:25][C@H:11]2[CH2:12][C@@H:13]([OH:24])[C@H:14]([CH2:15][CH2:16][C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: [H][H]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1O
Agent: [Pd]
Solvent: CCO
Product: CCCCC[C@H](O)CC[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1O
Yield: 59.7 %

Procedure:
350 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-dihydroxyprost-13-enoic acid methyl ester (prepared as described in Example 2) were hydrogenated at a pressure of one atmosphere in 6 ml of ethanol containing 120 mg of 5% palladium on charcoal at room temperature. The reduction was stopped after the absorption of one equivalent of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:1) as eluent to give 210 mg of the title compound having the following physical characteristics: