Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])[CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccnc1
Solvent: O
Product: CC(=O)NCc1cccnc1
Yield: 102.9 %

Procedure:
Prepared according to Plater et al. Org. Biomol. Chem. 2009, 7, 1633. To a solution of pyridin-3-ylmethanamine (9.42 ml, 92 mmol) in water (103 ml) at 10° C. was added acetic anhydride (10.47 ml, 111 mmol), stirred at a rate where the internal temperature did not rise above 25° C. After an additional 18 h of stirring, the solution was concentrated in vacuo then co-evaporated with toluene (3×) to afford the title compound (14.22 g, quantitative) as a clear oil. LCMS: Rt=0.12 min, m/z=151.1 (M+1) Method 2m_acidic. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=2.4 Hz, 2H) 7.65 (dd, J=7.8, 1.6 Hz, 1H) 7.30-7.24-(m, 1H) 6.59-6.49 (m, 1H) 4.43 (d, J=6.0 Hz, 2H) 2.02 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:11][C@H:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)[CH3:10])=[CH:40][CH:41]=2
Reactant: C[C@H](N)c1ccc(C(F)(F)F)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(F)(F)F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(4-(trifluoromethyl)phenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:16][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Br)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of the product from Example 238A (0.302 g, 0.926 mmol), iron powder (0.208 g, 3.7 mmol, 4.0 eq) and ammonium chloride (0.059 g, 1.11 mmol, 1.2 eq) in a mixture of methanol (6 mL), tetrahydrofuran (6 mL), and water (2 mL) was heated under reflux for 5 hours and then cooled to room temperature. The reaction mixture was filtered through Celite and the filter pad was rinsed with methanol (25 mL). The filtrate was evaporated under reduced pressure to leave a brown glassy solid (0.27 g, 99%) that was utilized without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH:16][C:17]([CH:19]3[N:24]4[C:25]([CH3:32])=[N:26][C:27]([C:28]([F:31])([F:30])[F:29])=[C:23]4[CH:22]=[CH:21][CH2:20]3)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>Cl.O=[Pt]=O.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH:16][C:17]([CH:19]3[N:24]4[C:25]([CH3:32])=[N:26][C:27]([C:28]([F:31])([F:29])[F:30])=[C:23]4[CH2:22][CH2:21][CH2:20]3)=[O:18])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C(F)(F)F)c2n1C(C(=O)Nc1cnn(-c3ccc(Cl)cc3)c1C(C)C)CC=C2
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(F)(F)F)c2n1C(C(=O)Nc1cnn(-c3ccc(Cl)cc3)c1C(C)C)CCC2
Reaction time: 0.42 h
Yield: 26.9 %

Procedure:
To N-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]-3-methyl-1-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyridine-5-carboxamide (30 mg, 0.064 mmol) was added EtOH (10 mL), 12 N HCl (4 drops), and PtO2 (30 mg). The resulting suspension was evacuated with hydrogen gas twice and stirred under hydrogen gas (55 psi) on Parr shaker for 25 min. the reaction mixture was then filtered through a syringe filter, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give N-[1-(4-chlorophenyl)-5-isopropyl-pyrazol-4-yl]-3-methyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-5-carboxamide (10 mg, 0.0172 mmol, 27% yield) as a TFA salt. 1H NMR (400 MHz, Methanol-d4) δ 7.62 (s, 1H), 7.57 (d, J=11.76 Hz, 2H), 7.42 (d, J=11.76 Hz, 2H), 5.20-5.22 (m, 1H), 3.0-3.18 (m, 2H), 2.8-2.95 (m, 1H), 2.40 (s, 3H), 2.32-2.55 (m, 2H), 1.80-2.05 (m, 2H), 1.27 (d, J=23.4 Hz, 3H), 1.24 (d, J=23.4 Hz, 3H); MS: (ES) m/z calculated for C22H23ClF3N5O [M+H]+ 466.9, found 466.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:36][CH2:32][CH2:33][CH2:34][CH3:35])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCCCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
In 50 ml of THF was dissolved 4.99 g of N-benzyloxycarbonyl-L-proline and then 2.23 g of triethylamine was added to the solution. Then, after slowly adding thereto 2.39 g of ethyl chloroformate under ice-cooling, the reaction was maintained for one hour at 0° C. to 5° C. Then, 2.19 g of n-butylamine was slowly added to the reaction mixture under ice-cooling, the reaction was further performed for one hour at 0° C. to 5° C. The solvent was removed from the reaction mixture, the residue thus formed was dissolved in ethyl acetate, and the solution was washed successively with an aqueous solution of 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution, and a saturated aqueous sodium chloride solution. The organic layer this formed was collected, dried by Glauber's salt, and then concentrated to dryness. The product was recrystallized from water to provide 4.31 g of (S)-1-benzyloxycarbonyl-N-butyl-2-pyrrolidinecarboxamide (30). M.p. 88°-90° C.
Reaction SMILES: [CH2:1]([N:8]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[C:26]([CH:34]=[CH2:35])=[CH:27][N:28]=[CH:29]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.O.CO>[CH2:1]([N:8]([CH:16]1[CH2:21][CH2:20][CH:19]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[C:26]([CH:34]=[CH2:35])=[CH:27][N:28]=[CH:29]3)[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cncc2cccc(N)c12
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: C=Cc1cncc2cccc(NC3CCC(N(Cc4ccccc4)C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A solution of Intermediate 9 (5.73 g), Intermediate 1 (2.92 g), and para-toluenesulfonic acid monohydrate (163 mg, Wako Pure Chemical Industries) in toluene (50 ml) was refluxed by heating for 1 hour. The reaction mixture was cooled to room temperature, then added with methanol (75 ml) and sodium borohydride (6.48 g), and stirred at room temperature for 1 hour. The reaction mixture was added with water (5 ml), and then the solvent was evaporated under reduced pressure. The residue was added with ethyl acetate (100 ml), and the organic layer was washed twice with water (50 ml), and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (2.2 g of trans-isomer, 1.8 g of cis-isomer).
Reaction SMILES: C1CO[CH:20]2[CH:3]([CH2:4][C:5]3[C@H:18]([CH2:19]2)[C@@H:17]2[C@H:8]([C@H:9]4[C@@:13]([CH2:15][C@@H:16]2[F:23])([CH3:14])[C@@H:12]([OH:24])[CH2:11][CH2:10]4)[C@H:7]([CH3:25])[CH:6]=3)[O:2]1.C(O)(=O)C(O)=O.O.C(=O)(O)[O-].[Na+]>CO>[F:23][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:24])[C@H:8]2[C@H:17]1[C:18]1[CH2:19][CH2:20][C:3](=[O:2])[CH2:4][C:5]=1[CH2:6][C@H:7]2[CH3:25]
Reactant: C[C@@H]1C=C2CC3OCCOC3C[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CC2=C(CCC(=O)C2)[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Yield: 42.2 %

Procedure:
A solution of 170 mg of product (C), obtained under 3a), in 22.5 ml of methanol was stirred with 300 mg of oxalic acid and 3 ml of water for 24 hours at room temperature. Then, it was mixed with sodium bicarbonate solution, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 62.7 mg of pure 11β-fluoro-17β-hydroxy-7α-methyl-estr-5(10)-en-3-one (I″) was obtained. Crystallization from hexane yielded 47.6 mg of compound I″ with a melting point of 169.9° C. ([α]D20=+134.4° (c=0.56% chloroform)).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH2:15][CH:16]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(CN2CC=C(c3cc4ccccc4s3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was dissolved in DMF (5 ml), potassium carbonate (412 mg, 2.9 mmol) added, and the reaction mixture stirred at room temperature for 10 minutes. 4-Chlorobenzyl bromide (306 mg, 1.5 mmol) was added and the resulting reaction mixture stirred at room temperature overnight. After dilution with water (50 ml), the product was extracted into ethyl acetate (3×40 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and concentrated. The crude product was triturated with methanol to yield a pale brown solid. Recrystallisation from hot dichloromethane and methanol gave the title compound as a pale yellow solid (60 mg, 18%); (Found: C, 70.33; H, 5.20; N, 4.16. C20H18 ClNS requires C, 70.68; H, 5.34; N, 4.12%); δH (CDCl3), 2.64 (2H, m, NCH2CH2), 2.72 (2H, m, NCH2CH2), 3.18 (2H, m, NCH2CH2), 3.61 (2H, s, NCH2Ar), 6.18 (1H, m, NCH2CH2), 7.12 (1H, s, ArH), 7.28 (6H, m, ArH), 7.66 (1H, d of d, J 6Hz, J 2Hz, ArH), 7.74 (1H, d of d, J 6.7Hz, J 2Hz, ArH). m/z (ES+) 340 (M+1)+.
Reaction SMILES: N=C=N.[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([S:22]([NH:25][CH:26]2[CH2:30][CH2:29][O:28][NH:27]2)(=[O:24])=[O:23])[C:16]=1[O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=S.CS(Cl)(=O)=O.C(N(CC)CC)C>>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[N:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([S:22]([NH:25][CH:26]2[CH2:30][CH2:29][O:28][NH:27]2)(=[O:24])=[O:23])[C:16]=1[O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Oc1c(NC(=S)Nc2ccccc2Br)ccc(Cl)c1S(=O)(=O)NC1CCON1
Agent: CS(=O)(=O)Cl
Agent: N=C=N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1c(N=C=Nc2ccccc2Br)ccc(Cl)c1S(=O)(=O)NC1CCON1
Yield: 88.5 %

Procedure:
Following the general procedure for carbodiimide formation outlined in example 1, N-(2-bromophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″-tetrahydroisoxazylaminosulfonyl)phenyl]thiourea (385 mg, 0.74 mmol), methanesulfonyl chloride (0.12 mL, 1.48 mmol) and triethylamine (0.21 mL, 1.48 mmol) were reacted to form the desired product (385 mg, crude). 1H NMR (CDCl3) δ 0.35 (s, 6H), 1.02 (s, 9H), 1.68 (m, 2H), 1.9 (m, 2H), 3.04 (t, 2H), 4.0 (t, 2H), 7.09 (d, 1H), 7.12 (d, 1H), 7.2 (d, 1H), 7.3 (t, 1H), 7.42 (d, 1H), 7.6 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:35])[N:12]([CH2:21][CH2:22][N:23](C)[C:24](=O)OCC3C=CC=CC=3)[C:13]3[C:18]([C:19]=2[OH:20])=[N:17][CH:16]=[CH:15][CH:14]=3)=[O:9])=[C:4]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:3]=1.Cl>CO>[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:35])[N:12]([CH2:21][CH2:22][NH:23][CH3:24])[C:13]3[C:18]([C:19]=2[OH:20])=[N:17][CH:16]=[CH:15][CH:14]=3)=[O:9])=[C:4]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:3]=1
Reactant: CN(CCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: CNCCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21
Temperature: 25 °C

Procedure:
A solution of benzyl 2-[3-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}carbonyl)-4-hydroxy-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl(methyl)carbamate (0.55 g, 0.94 mmol) in MeOH (10 mL) in a pressure tube was cooled to −78 degrees C. and saturated with HCl gas. The volume in the flask visibly increased. The reaction was allowed to warm to room temperature overnight, then cooled to −78 degrees C. and vented. The reaction was transferred to a round bottom flask and the solvents removed under vacuum. The reaction was suspended in toluene and evaporated to give the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([OH:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][OH:27]>CN(C=O)C>[Cl:1][C:2]1[C:15]([O:16][CH2:25][CH2:26][OH:27])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: O=c1c2ccccc2oc2cc(O)c(Cl)cc12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2oc2cc(OCCO)c(Cl)cc12
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of 2-chloro-3-hydroxy-9-oxo-9H-xanthene (8.0 g), potassium carbonate (13 g), 2-bromoethanol (12 g) and DMF (200 ml) was stirred at 45°-55° C. for 3 hours. After distilling off the solvent under vacuum, water was added to the residue and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from a mixed solvent of DMF and water gave 6.0 g of 2-chloro-3-(2-hydroxyethoxy)-9-oxo-9H-xanthene. m.p. 153°-156° C. This compound produced a mass spectrum having a molecular ion peak at m/e 290.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:16].[K+].C(O)CO>O>[OH:16][C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC(C)(O)c1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
4-Isopropylbenzoic acid (5.0 g, 30.5 mmol) was dissolved in a solution of potassium hydroxide (4.1 g, 2 mL, 73.1 mmol) in water (125 mL). To the reaction mixture was added a solution of potassium permanganate (9.6 g, 60.9 mmol) in water (125 mL). The combined mixture was allowed to stir at 60° C. for 2 hours. The reaction mixture was cooled to 0° C. and treated with ethylene glycol (100 μL) and cooled to 0° C. The solid were removed by filtration and the filtrate was acidified to pH 1 by addition of 6 N HCl solution. The solid was removed by filtration, and the filtrate was extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide 4-(1-hydroxy-1-methyl-ethyl)benzoic acid (5.1 g, 93%) as a white solid. ESI-MS m/z calc. 180.1. Found 181.2 (M+1)+; Retention time: 0.6 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 8.00-7.95 (m, 2H), 7.61-7.56 (m, 2H), 2.64 (s, 1H), 1.54 (s, 6H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=1)=C.O.I([O-])(=O)(=O)=[O:15].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:15])[N:8]=1
Reactant: C=Cc1cc2c(nn1)OCCC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2c(nn1)OCCC2
Temperature: 25 °C
Reaction time: 4.75 h
Yield: 54.3 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro-5H-pyrano[2,3-c]pyridazine (100 mg, 0.617 mmol) in 1,4-dioxane (5.5 ml)/water (1.1 ml) was cooled in ice/water and treated with sodium periodate (306 mg, 1.43 mmol) and a 4% aqueous solution of osmium tetroxide (0.55 ml). The mixture was allowed to warm to room temperature after an hour, and after a total of 4.75 hours stirring, the solvent was evaporated. 1,4-Dioxane was added and evaporated, followed by dichloromethane and the mixture briefly held in an ultrasonic bath. The whole mixture was applied to a silica gel column and eluted with ethyl acetate to give product (55 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[C:5]([O:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.[Sn]>Cl.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[O:8][CH2:9][C:10](=[O:11])[NH:15][C:4]=2[CH:3]=1
Reactant: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: O
Product: O=C1COc2ncc(Br)cc2N1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
In a 500 mL round-bottomed flask was added ethyl 2-(5-bromo-3-nitropyridin-2-yloxy)acetate (5.2 g, 17.04 mmol) in hydrochloric acid, 37% (50 mL) to give a yellow suspension. The mixture was cooled to 0-5° C. followed by the portion wise addition of tin powder (10.1168 g, 85 mmol). Caution must be taken during the addition as it is very exothermic. The mixture was stirred at room temperature for a further 30 minutes after the addition. The reaction mixture was heated to 80° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (250 mL). The precipitate was filtered, washed with water (200 mL) and diethyl ether (200 mL) and dried until constant weight to give the title compound (3.2 g, 82%). 1H NMR (500 MHz, d6-DMSO): 10.41 (2H, s), 7.88 (2H, s), 7.34 (2H, s), 4.85 (2H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>CN(C)C=O>[O:24]([C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: C#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccccc2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 55.9 %

Procedure:
To 6 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.13 g of phenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of 4-phenoxy-6-(2-propynyloxy)pyrimidine (the present compound (51)), m.p.: 71.1° C.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@H:8]([O:20][CH2:21][C@H:22]2[O:29][C@H:26]([O:27][CH3:28])[C@H:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:24]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:23]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:7]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@H:6]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=O)C.CO.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:31]([O:30][C@@H:25]1[C@@H:24]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:23]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:22]([CH2:21][O:20][C@H:8]2[O:9][C@H:10]([CH2:11][O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:5]([OH:4])[C@H:6]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:7]2[O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:29][C@@H:26]1[O:27][CH3:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 6-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.314 g, 2.46 mmol) is dissolved in hot toluene (20 mL) and methanol (80 mL) is added, followed by a few drops of 1 M. methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 2,3,4-tri-O-benzyl-6-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-α-D-glucopyranoside as an amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.O>CN(C=O)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][C:11]3[C:3]([CH2:2][N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)=[CH:4][C:5]([OH:19])=[CH:6][C:7]=3[CH:8]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(-c2cc3cc(O)cc(Cn4ccnc4)c3o2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of benzyl bromide 4 (0.070 g, 0.215 mmole) in 10 mL DMF was added imidazole (0.030 g, 0.437 mmole). After stirring at 60° C. for 3 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 0.059 g (88%) of imidazole 16 as a light tan solid: Mp=269–271° C.; 1H NMR (DMSO-d6) δ 9.88 (s, 1 H), 9.24 (s, 1 H), 7.88 (s, 1 H), 7.72 (d, 2 H, J=8.6 Hz), 7.26 (s, 1 H), 7.04 (s, 1 H), 6.93 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz), 6.83 (d, 1 H, J=2.3 Hz), 6.50 (d, 1 H, J=2.3 Hz), 5.46 (s, 2 H); MS 305 (M−H)−