Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1([CH2:18][CH3:19])[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:7][C:6]1=O.[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N)[CH3:22].O.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1([CH2:18][CH3:19])[C:6]2[NH:29][C:24]3[C:25](=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:21][CH3:22])[C:7]=2[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:9][CH2:10]1
Reactant: C=CCCCCC1CCC(CC)(CC(=O)OC)C(=O)C1
Reactant: CCc1ccccc1NN
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCCCCC1CCC(CC)(CC(=O)OC)c2[nH]c3c(CC)cccc3c21
Yield: 64 %

Procedure:
A solution of 1-ethyl-4-(5-hexenyl)-2-oxocyclohexaneacetic acid methyl ester isomer B (4.24 g, 15.14 mmol) and 2-ethylphenylhydrazine (2.27 g, 16.7 mmol) in 30.3 mL of toluene was refluxed under nitrogen for 22 hours with azeotropic removal of water. The toluene was then removed in vacuo and replaced with 10.8 mL of acetic acid. The solution was treated with borontrifluoride etherate (2.79 g, 19.7 mmol, 2.42 mL) and refluxed for 20 minutes under nitrogen. The reaction mixture was poured into 120 mL of water and extracted with 4×80 mL of ether. The pooled extracts were washed with 2×110 mL of 1M HCl and 2×80 mL of 2.5N NaOH. Drying (MgSO4) and flash chromatography (75 mm diameter column, 8% ethyl acetate in petroleum ether eluent) afforded 3.72 g (9.73 mmol, 64%) of 1,8-diethyl-4-(5-hexenyl)-2,3,4,9-tetrahydro-1H-carbazole-1 -acetic acid methyl ester. Of this, 3.68 g (9.66 mmol) were refluxed in a solution of ethanol (30.9 mL) and 2.5N NaOH (7.7 mL) for 45 minutes under nitrogen. The ethanol was then removed in vacuo and the residue was suspended in 120 mL of 1N HCl. It was extracted with 4×40 mL of ether and the pooled extracts were dried over MgSO4. Flash chromatography (50 mm diameter column, 10% ethyl acetate in petroleum ether eluent, 2% H3PO4 in MeOH treated silica gel) afforded 3.41 g (9.18 mmol, 95%) of a light yellow solid which was recrystallized from 85:15 petroleum ether:benzene. This resulted in 1.98 g of a white powder which were dried at 84° C. for 31 hours followed by recrystallization from 85:15 petroleum ether:benzene once again. Drying at 84° C. for 24 hours resulted in 1.41 g of a white powder, m.p. 96°-97° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[NH:4][N:5]=[C:6]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[OH-].[Na+].CO>O>[Cl:1][C:2]1[C:3](=[O:30])[NH:4][N:5]=[C:6]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COC(=O)CCCCCOc1n[nH]c(=O)c(Cl)c1NCc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2c(OCCCCCC(=O)O)n[nH]c(=O)c2Cl)cc1OC
Reaction time: 1 h

Procedure:
A mixture comprising 240 mg of 4-chloro-5-(3,4-dimethoxybenzylamino)-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 1) prepared in Preparation Example 1, 65 mg of sodium hydroxide, 10 ml of methanol and 1 ml of water, was stirred at 60°-70° C. for 1 hour. After the reaction liquor was evaporated under reduced pressure, water was poured to the residue, and the resultant solution was adjusted to pH 1-2 with dilute hydrochloric acid, whereupon the product was extracted with chlorform. The extract was washed with water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 192 mg of the above identified compound as colorless crystals having a melting point of from 150.5° C. to 151.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](N1C=CN=C1)([N:19]1C=CN=C1)=O.C(N(CC)CC)C.Cl.CN>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:16])[NH:19][CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 4 h
Yield: 77.6 %

Procedure:
Amine preparation: To a solution of 1-(tert-butoxycarbonyl)-3-piperidine-carboxylic acid (0.50 g) in DMF (3 mL) was added 1,1′-carbonyldiimidazole (0.70 g). The reaction mixture was stirred for 4 h and then triethylamine (0.60 mL) followed by methylamine hydrochloride (0.29 g) was added. After stirring for 24 h the reaction mixture was then diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-methylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (0.41 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1.O.[SH2:20].[Na].Cl>O>[SH:20][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cnn2c(C(F)(F)F)cc(Cl)nc12
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: O
Product: COC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Reaction time: 1 h

Procedure:
A mixture of 2.30 g of methyl 5-chloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 2.0 g of sodium hydrogen sulphide monohydrate in 60 ml of water was stirred at 60° for 1 hour. The reaction mixture was cooled, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in a vacuum until crystallization occurred. Petroleum ether was added and the solid product was filtered off under suction. There was obtained methyl 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]-pyrimidine-3-carboxylate.
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.[Na].[C:6]1([CH2:16][OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[I-].[Na+]>COCCOC>[C:6]1([CH2:16][O:17][CH2:3][S:2][CH3:1])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccc2ccccc12
Reactant: CSCCl
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: COCCOC
Product: CSCOCc1cccc2ccccc12
Yield: 50 %

Procedure:
Methylthiomethyl 1-naphthylmethyl ether was prepared by the reaction of chloromethyl methyl sulfide with the sodium salt of naphthalene-1-methanol in DME in the presence of sodium iodide as described for analogous reactions by E. J. Corey and M. C. Bock in Tetrahedron letters 38 3269(1975); yield 50%, b.p. 105°-115° C./0.01 mmHg. 1H NMR (CDCl3): δ2.17 (Me), 4.70 (CH2S), 5.01 (CH2Naph), 7.1-8.2 (Naph).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[N+:14]([O-])([OH:16])=[O:15]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][C:2]1([CH3:13])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2ccccc2B(O)O1
Reactant: O=[N+]([O-])O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC1(C)Cc2ccc([N+](=O)[O-])cc2B(O)O1
Temperature: -45 °C
Reaction time: 0.75 h
Yield: 45 %

Procedure:
A solution of 3,3-dimethyl-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (0.82 g, 4.7 mmol) in nitrobenzene (2.5 mL) was added dropwise to fuming nitric acid (10 mL) maintained at −45° C. The reaction was stirred for 45 minutes at this temperature, and then poured onto wet ice (400 mL). This mixture was allowed to stand for 90 minutes, gradually warming to room temperature. The resultant aqueous suspension was extracted with dichloromethane (3×50 mL). The combined organic portions were washed with water (2×50 mL) until the aqueous portion showed a pH of 7. The dichloromethane solution was then dried over sodium sulfate and concentrated to dryness. The resulting oil was triturated with heptane to produce 3,3-Dimethyl-7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (s, 6H) 3.02 (s, 2H) 7.47 (d, J=8.4 Hz, 1H) 8.25 (dd, J=8.3, 2.6 Hz, 1H) 8.47 (d, J=2.5 Hz, 1H) 8.85 (s, 1H). Amount obtained: 468 mg, 45% yield.
Reaction SMILES: C([C@H:3]1[CH:8]([CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][N:4]1[C:11](=[O:18])[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)C.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][C:11]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:8]([CH:9]=[O:10])[CH2:3]1)=[O:18]
Reactant: CC[C@H]1C(CO)CCCN1C(=O)Cc1cccs1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C[C@H]1CCCN(C(=O)Cc2cccs2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.6 %

Procedure:
(S)-ethyl 1-(2-thiopheneacetyl)-3-hydroxymethylpiperidine (180.4 ml; 0.75 mmol) was dissolved in dichloromethane (20 ml). Crushed molecular sieves (0.25 g), and commercially available pyridinium dichromate (331.2 mg; 0.88 mmol) were added and the mixture was allowed to stir at ambient temperature for 5 hours. The mixture was then filtered through celite, washed with decolorizing carbon, filtered again and then evaporated under reduced pressure at ambient temperature. Crude product was purified by distillation at approximately 250° C./0.1 torr, giving (S)-1-(2-thiopheneacetyl)-3-piperidinecarboxaldehyde (58 mg) as a thick colorless oil. MS m/z (positive ion) 317 (25), 238 (MH+; 100).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O:12][C:13]([C:15]1[S:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]2)=[N:18][N:19]=1)=O)C>>[CH2:1]([NH:9][C:13]([C:15]1[S:16][C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[CH2:24][CH2:25]2)=[N:18][N:19]=1)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: CCCCCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-octylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.040 g, yield 66%). 1H NMR (300 MHz, CDCl3) δ 7.73-7.7 (m, 1H), 7.63-7.51 (m, 2H), 7.34-7.31 (m, 1H), 7.05 (br. t, 1H), 4.06-4.01 (m, 1H), 3.90-3.81 (m, 1H), 3.75-3.6 (m, 2H), 3.53-3.5 (m, 2H), 3.42-3.28 (m, 4H), 1.59-1.52 (m, 2H), 1.4-1.18 (m, 10H), 0.84 (t, J=5.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.5, 158.2, 156.0, 133.9, 133.9, 132.4, 129.6, 129.0, 127.5, 126.9, 126.8, 126.7, 125.3, 121.7, 49.5, 48.9, 45.9, 40.7, 39.6, 31.7, 29.4, 29.1, 29.11, 26.8, 22.6, 14.0. MS (ES+) m/z 498 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7].[C:34](Cl)(=[O:36])[CH3:35].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:34]([NH:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7])(=[O:36])[CH3:35]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N)c(OCc1ccccc1)c2=O
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 23 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To a solution of intermediate 169, N-(2-amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.033 g, 0.073 mmol) in dry tetrahydrofuran (10 mL) was added acetyl chloride (5.7 μL, 0.08 mmol) and diisopropylethylamine (38 μL, 0.22 mmol). The reaction mixture was stirred at 23° C. for 3 h. NaHCO3 (0.25 M, 20 mL) was then added and the organic material extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate:Hex (1:2 to 2:1) as eluent to afford the title compound (0.025 g, 69% yield). 1HNMR 400 MHz (MeOD) δ (ppm): 7.66 (1H, dd, J=10.5, 2.8 Hz), 7.43–7.25 (6H, m), 6.87 (1H, ddd, (dt), J=8.8, 2.6 Hz), 5.19 (2H, s), 4.47 (2H, m), 4.08 (2H, t, J=4.9 Hz), 3.99 (2H, t, J=4.9 Hz), 2.19 (3H, s), 1.62 (6H, s). LCMS (M+H)+ m/z 495.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([C:11]([OH:13])=[O:12])=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([C:11]([OH:13])=[O:12])=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(C(=O)O)c(C)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1sc2cc(O)ccc2c1C(=O)O
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a solution of 6-methoxy-2-methyl-1-benzothiophene-3-carboxylic acid 48-A (5 g, 22.5 mmol) in CH2Cl2 (50 ml) was added BBr3 (33 ml, 1M CH2Cl2 solution) at −78° C. After being stirred for 1 hour the cooling bath was removed. The reaction was stirred at room temperature overnight. The reaction was quenched with water at 0° C. The mixture was extracted with EtOAc. Insoluble was collected by filtration to yield 2.1 g of 6-hydroxy-2-methyl-1-benzothiophene-3-carboxylic acid (B). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 2.7 g of 48-B.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:23])[N:10]([CH3:22])[C:11](SC)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[O:24]1CCOCC1.[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:23])[N:10]([CH3:22])[C:11]([OH:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: CSc1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(O)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To a 250 mL RBF, was added 5-(3-bromo-phenyl)-3-methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one (9.2 g, 23.7 mmol), 28 mL dioxane, and 24 mL 5 N NaOH in H2O. The mixture was warmed up to 85° C. and stirred for 15 h. The mixture was cooled down to 0° C. and neutralized with 1 N HCl in H2O until pH 5. White solid was precipitated. After filtration and washed with water, the 5-(3-bromo-phenyl)-2-hydroxy-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one was obtained in 5.76 g as white powder. MS (ES+): 358 (M+H)+; (ES−): 356 (M−H).
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]1[C:14]2[C:13](=[O:15])[NH:12][C:11]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)=[N:10][C:9]=2[C:8]([CH2:27][CH2:28][CH3:29])=[N:7]1.S(=O)(=O)(O)O.[N+:35]([O-])([OH:37])=[O:36]>>[CH3:5][N:6]1[C:14]2[C:13](=[O:15])[NH:12][C:11]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[C:19]([N+:35]([O-:37])=[O:36])[CH:18]=3)=[N:10][C:9]=2[C:8]([CH2:27][CH2:28][CH3:29])=[N:7]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(C)=O)cc3)nc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(C)=O)c([N+](=O)[O-])c3)nc12
Temperature: 25 °C

Procedure:
Glacial acetic acid (1.93 ml, 0.0337 mol) was added to N-{4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]-pyrimidin-5-yl)methyl]phenyl}acetamide (1.93 g, 0.0057 mol), followed by concentrated sulphuric acid (5.8 ml) and the mixture cooled in an ice-bath. Concentrated nitric acid (3.86 ml) was then added dropwise and once addition was complete, the reaction was stirred at room temperature for an hour.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:26])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[C@@H:12]([OH:24])[CH2:11][C@H:10]1[OH:25].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:26])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[C:12](=[O:24])[CH2:11][C@H:10]1[OH:25].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CC(=O)CCCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: O=[Cr](=O)=O
Agent: C1CCC(OC2CCCCO2)OC1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(=O)O
Reaction time: 1.5 h

Procedure:
The reaction product from part A, containing 6-keto-PGF1α, bis(tetrahyropyranyl)ether, methyl ester corresponding to formula IV, is oxidized to compound V. A composite from several lots, weighing 0.93 g., in 20 ml. of acetone is treated at -10° C. with 2.0 ml. of Jones reagent. After stirring for 1.5 hr. the reaction mixture is quenched with isopropanol and extracted with diethyl ether. The extract is washed with brine, dried, and concentrated. The residue is subjected to silica gel chromatography, eluting with ethyl acetate (20-50%)-Skellysolve B to yield the formula-V 6-keto-PGE1, bis(tetrahydropyranyl)ether, methyl ester, 0.52 g., having Rf 0.52 (TLC on silica gel in ethyl acetate-Skellysolve B (1:1)); and infrared peaks at 1745 and 1725 cm-1 (free of OH at 3000-3500).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])/[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: COC(=O)CBr
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)/C=C1\CCc2cc(OC)ccc21
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of 5-methoxy-1-indanone (2.50 g, 15.4 mmol) and methyl bromoacetate (1.84 mL, 20.0 mmol) in THF (15 mL) was added dropwise to a mixture of activated zinc dust (1.51 g, 23.1 mmol) in THF (10 mL). During the addition the reaction mixture reached reflux temperature, which was maintained for an additional hour after the addition was completed. After cooling to ambient temperature, the reaction mixture was poured into ice-cold 2.0 N HCl and extracted into EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 afforded 2.45 g of the title compound: 1H NMR (CDCl3) δ 3.04-3.07 (m, 2H), 3.30-3.33 (m, 2H), 3.77 (s, 3H), 3.85 (s, 3H), 6.19 (t, 1H, J=2.5 Hz), 6.83 (dd, 1H, J=2.3, 8.7 Hz), 6.85 (s, 1H), 7.52 (d 1H J=8.5 Hz).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][N:20]=1)[C:14](OC)=[O:15]>C1COCC1>[C:1]([CH2:2][C:14]([C:13]1[CH:18]=[CH:19][N:20]=[C:11]([O:10][CH3:9])[CH:12]=1)=[O:15])#[N:3]
Reactant: COC(=O)c1ccnc(OC)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)CC#N)ccn1
Temperature: -78 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
To a 100 ml flask was added 30 ml of THF and acetonitrile (1.41 ml, 26.9 mmole). The mixture was cooled to −78° C. and then n-butyllithium (16.8 ml, 26.9 mmole, 1.6M solution in hexane) was added. The reaction was stirred for 30 minutes at which time 5 ml of a THF solution of methyl 2-methoxyisonicotinate 105.1.A (1.50 g, 9.0 mmole) was added. After 3 hours at −78° C., the reaction mixture was quenched by 1.7 ml of acetic acid, and was warmed to room temperature. The solvent was removed by rotary evaporation and the crude was purified on a silica gel column to give 105.1.B (676 mg, 43% yield) as orange crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11](Cl)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:22][CH2:23][O-:24].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11]([O:24][CH2:23][CH3:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: Clc1nc(C2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1nc(C2CCNCC2)nc2c1[nH]c1cc(Br)ccc12

Procedure:
300 mg (0.82 mmol) 7-bromo-4-chloro-2-(4-piperidyl)-5H-pyrimido[5,4-b]indole was mixed with an excess of 2 M NaOEt and kept at reflux for 2 h. Then, water was added and the solvent was removed in vacuo. Following LC (CH2Cl2/MeOH, 0-50%), 160 mg (52%) of the title substance was obtained ESI-MS [m/z]: 375, 377 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH3:15])[CH2:9]2)=[N:6][CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].C(=[NH:81])(C1C=CC=CC=1)C1C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:13]([N:10]1[CH2:11][CH2:12][CH:8]([C:5]2[N:4]=[CH:3][C:2]([NH2:81])=[CH:7][N:6]=2)[CH2:9]1)[CH2:14][CH3:15]
Reactant: CCCN1CCC(c2ncc(Br)cn2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCN1CCC(c2ncc(N)cn2)C1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
A dry flask was charged with 5-bromo-2-(1-propyl-pyrrolidin-3-yl)-pyrimidine (300 mg, 1.11 mmol), Pd2(dba)3 (tris(dibenzylideneacetonate) dipalladium (30 mg, 0.032 mmol)), rac-BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (35 mg, 0.056 mmol), tBuONa (150 mg, 1.56 mmol), benzophenone imine (300 mg, 1.65 mmol) and toluene (4 ml). It was then evacuated, flushed with nitrogen and the mixture heated at 80° C. under microwave irradiations for 3 h. After filtration through a pad of celite, the solvent was removed under reduced pressure. The crude material was then dissolved in THF (10 ml) and 1 N aqueous HCl (3 ml) was added. The solution was stirred at room temperature for 45 min and the organic solvent was next removed under vacuo. The resulting aqueous phase was adjusted to pH˜9 with 2 N NaOH solution, washed with heptane:ethyl acetate, 2:1 (50 ml) and concentrated to give the crude amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([O:34][C:35]([NH:37][S:38]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:40])=[O:39])=[O:36])[CH2:31][CH2:32][CH3:33].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:30]([O:34][C:35]([N:37]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[S:38]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:39])=[O:40])=[O:36])[CH2:31][CH2:32][CH3:33]
Reactant: COc1ccc(CO)cc1
Reactant: CCCCOC(=O)NS(=O)(=O)NCC(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOC(=O)N(Cc1ccc(OC)cc1)S(=O)(=O)NCC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of (4-methoxyphenyl)-methanol (1.4 g, 8.5 mmol) and triphenyl-phosphane (2.6 g, 8.5 mol) in dry THF was added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at 0° C. under N2 atmosphere. The mixture was stirred at 0° C. for 2 h, warmed to RT and stirred overnight. After the solvent was removed in vacuo, the residue was purified by column chromatography to afford ethyl 2-((N-(butyloxycarbonyl)-N-(p-methoxybenzyl)sulfamoyl)amino)acetate (2.3 g, 69%) as a white solid. 1H-NMR (CDCl3): δ 7.32 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.71 (m, 1H), 4.76 (s, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.55 (d, J=5.2 Hz, 2H), 1.54 (s, 9H), 1.25 (t, J=7.2 Hz, 3H).