Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[K].[CH2:21]([OH:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:27][CH2:21][C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1C
Reactant: OCc1ccco1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COCc2ccco2)cc1-c1ccccc1C
Temperature: 90 °C
Yield: 32.8 %

Procedure:
To a stirred solution of the 4-chloromethyl-2-(2-methylphenyl)benzoic acid methyl ester (1.12 g , 4.08 mmol) in toluene (20 mL) under N2 was added the furfuryl alcohol potassium salt prepared in Example 299A (0.84 g, 6.1 mmol) followed by 18-crown-6 (1.6 g, 6.1 mmol). The solution was heated at 90° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with H2O (2×), saturated NaHCO3 solution (2×), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (10% ethyl acetate-hexane) to give the title compound (0.45 g, 33%) as an orange oilwhich was contaminated with ˜10% of the 2-furanmethyl ester.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=O)[CH2:12]3)([O:3][CH3:4])=[O:2].Cl.[NH2:28][OH:29].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=[N:28][OH:29])[CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: NO
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=NO)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
A suspension of 17β-Carbomethoxy-6-oxo-3β,5α-dihydroxy-androstane, 8 g, as prepared in example 17, hydroxylamine hydrochloride (12 g) and sodium acetate trihydrate (16 g) in ethanol (100 mL) is heated at reflux for 1 h. The reaction mixture is cooled to ambient temperature and filtered to afford 17β-carbomethoxy-6-oximino-3β,5α-dihydroxyandrostane as a white solid, mp 234°-237° C. dec. Anal. Calcd. for C21H33NO5.H2O: C, 63.34; H, 8.88; N, 3.53. Found: C, 62.91; H, 8.98; N, 3.27.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)SC)#[N:2].[CH:14]1[C:24]2[CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[CH:19]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>N1C=CC=CC=1.C(OCC)C>[CH:25]1[C:21]2[CH2:22][CH2:23][C:24]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:19]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:4]([NH:3][C:1]#[N:2])=[N:7][C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[C:20]=2[CH:28]=[CH:27][CH:26]=1
Reactant: NCCCCCOC1c2ccccc2CCc2ccccc21
Reactant: CSC(=Nc1ccncc1)NC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: N#CNC(=Nc1ccncc1)NCCCCCOC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
1-Cyano-2-methyl-3-pyridin-4-yl-isothiourea (573 mg, 3.00 mmol) and 5-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-pentylamine (886 mg, 3.00 mmol) were dissolved in pyridine (20 mL). Triethylamine (2 mL, 14 mmol) was added followed by (4-dimethylamino)pyridine (5.0 mg, 0.04 mmol). The reaction mixture was stirred at 86□ C. for 12 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (50 mL). The resulting precipitate was collected by filtration and washed with diethyl ether. The crude product was recrystalized from methanol and diethyl ether to give the desired product as a white crystalline solid (yield 85%). 1H NMR (CDCl3, ppm): 8.54 (dd, 2H), 7.41-7.12 (m, 10H), 5.29 (s, 1H), 3.56-3.41 (m, 4H), 3.32 (dd, 2H), 3.05-2.95 (m, 2H), 1.71-1.41 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH3:27][CH:28]1[NH:33][CH2:32][CH2:31][NH:30][CH2:29]1.CN1C(=[O:40])CCC1>>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:33]4[CH2:32][CH2:31][NH:30][C:29](=[O:40])[CH:28]4[CH3:27])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC1CNCCN1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: CN1CCCC1=O
Agent: [F-]
Agent: [K+]
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNC(=O)C3C)nn12
Temperature: 180 °C
Reaction time: 16 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 55 mg, 0.160 mmol), KF (46.3 mg, 0.798 mmol), 3-methylpiperazine (54.6 mg, 0.479 mmol) were suspended in NMP (532 μL). The RM was stirred at 180° C. for 16 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with EtOAc/MeOH (9/1) and washed with 5% Na2CO3 solution and brine. The organic layer was dried over sodium sulfate and the solvent was removed. A brown solid was obtained (tR 0.9 min (conditions 4), MH+=423)
Reaction SMILES: [Br:1][C:2]1[N:3]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:4]([S:7][CH2:8][C:9]([OH:11])=O)=[N:5][N:6]=1.[NH2:25][OH:26]>>[Br:1][C:2]1[N:3]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:4]([S:7][CH2:8][C:9]([NH:25][OH:26])=[O:11])=[N:5][N:6]=1
Reactant: NO
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)NO

Procedure:
2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid can be reacted with hydroxylamine to form 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-N-hydroxyacetamide. Use of an N-substituted hydroxylamine, would provide the N-substituted product.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[CH3:2][C:1]1[O:3][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=1
Reactant: CC(N)=O
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(C)n1
Temperature: 85 °C
Yield: 44.4 %

Procedure:
To a solution of acetamide (4.0 g) in tetrahydrofuran (300 ml) was added sodium hydrogen carbonate (28.4 g), followed by addition of 80% ethyl bromopyruvate (21.5 g) at 0° C. The mixture was heated at 85° C. overnight, the temperature was returned to room temperature, the insolubles were filtered using Celite and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (150 ml), and to the solution was added dropwise trifluoroacetic anhydride at 0° C. After concentrated under reduced pressure, to the mixture was added ethyl acetate, and the mixture was washed with saturated sodium hydrogen carbonate solution twice and further with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, followed by distillation under reduced pressure to give ethyl 2-methyloxazole-4-carboxylate (4.67 g).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[C:3]=1[Cl:15].[C:16]([Cu])#[N:17]>>[Cl:15][C:3]1[C:4]2[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:6][C:5]=2[CH:13]=[CH:14][C:2]=1[C:16]#[N:17]
Reactant: FC(F)(F)c1nc2c(Cl)c(Br)ccc2[nH]1
Reactant: N#C[Cu]
Product: N#Cc1ccc2[nH]c(C(F)(F)F)nc2c1Cl

Procedure:
Synthesized as described in Example 197A from 5-bromo-4-chloro-2-(trifluoromethyl)-1H-benzimidazole and CuCN: MS (APCl) m/z 246 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:23])[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:28](Cl)=[O:29]>>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:28]([NH:23][C:10]1[S:11][C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:29]
Reactant: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: O=C(Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1)c1cc(F)cc(F)c1
Yield: 58 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-fluoro-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 9 and 3,5-difluorobenzoyl chloride prepared in the step 1 of Example 16 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1-10:1) to obtain a product as a white solid in a yield of 58.0%, mp: 216-218 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.44 (2H, s, CH2), 7.30 (2H, t, 3JFH=3JHH=8.96 Hz, ArH), 7.51 (2H, d, J=8.68 Hz, ArH), 7.30 (1H, t, 3JFH=9.00 Hz, ArH), 7.68 (2H, dd, 3JHH=8.68 Hz, 4JFH=5.60 Hz, ArH), 7.30 (2H, d, 3JFH=6.16 Hz, ArH), 8.20 (2H, d, J=8.68 Hz, ArH), 12.95 (1H, br, CONH); EI-MS m/e (%): 469.1 (M+, 77), 141.1 (100); HREI-MS Calcd. for C23H14F3N3O3S: 469.0708. found: 469.0710. Anal. Calcd. for C23H14F3N3O3S: C, 58.85; H, 3.01; N, 8.95. found: C, 58.42; H, 2.64; N, 8.80.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH2:19])=[S:18]>>[BrH:1].[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:19]=[C:17]([C:16]4[CH:20]=[CH:21][CH:22]=[C:14]([Cl:13])[CH:15]=4)[S:18][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: NC(=S)c1cccc(Cl)c1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Product: Br
Product: OC12N=C(c3cccc(Cl)c3)SC1Cc1cc(Cl)ccc12

Procedure:
This compound is prepared analogously to the process described in Example 1c using 2-bromo-5-chloroindan-1-one and 3-chlorothiobenzamide; melting point: 205-210° C. (dec.).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH3:10][N:11]([CH:20]1[CH2:21][CH2:22][N:23]([C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:24][CH2:25]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(CCc1ccccc1)C1CCNCC1
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN(CCc1ccccc1)C1CCN(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 ml of phenyl isocyanate was added to a solution of 1.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]piperidine in 15 ml of chloroform. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added diethyl ether for crystallization. The resulting crystals were collected by filtration and recrystallized from ethyl acetate to obtain 0.7 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-anilinocarbonylpiperidine as colorless prism-like crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2=[O:17].[N-:18]=[N+:19]=[N-:20].[Na+].CN(C=O)C>O>[N:18]([C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2=[O:17])=[N+:19]=[N-:20]
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(N=[N+]=[N-])ccn2c1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
An oven-dried 25 ml round-bottom flask was purged with argon and charged with ethyl 8-chloro-4-oxo-4H-quinolizine-3-carboxylate (2) (250 mg, 1 mmol), NaN3 (300 mg, 4.6 mmol), and 5 ml DMF. The reaction mixture was stirred at 40° C. for 1 h, cooled to room temperature, and poured into 100 ml water. The aqueous layer was extracted three times with 100 ml chloroform, and the combined organic layers were washed three times with 100 ml water. The organic solvent was evaporated and the crude product was purified by flash chromatography (ethyl acetate) to give a deep red crystalline solid (218 mg, 85%). M.p. 145-150° C. 1H NMR (δ, CDCl3): 1.42 (t, J=7 Hz, 3H), 4.41 (q, J=7 Hz, 2H), 6.53 (d, J=8 Hz, 1H), 6.84 (dd, J=2 Hz, J=7 Hz, 1H), 7.08 (d, J=2 Hz, 1H), 8.37 (d, J=8 Hz, 1H), 9.36 (d, J=7 Hz, 1H). MS: m/z 258.0751; required for C12H10N4O3: 258.0753.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:15])=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CN(C)C=O.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cc1cc(C(C)=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)Cc1cc(C(C)=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(5-acetyl-2-hydroxyphenyl)acetate (8.0 g) was dissolved in N,N-dimethylformamide (120 ml), and benzyl bromide (5 ml) and potassium carbonate (5.8 g) were added to the solution, then the resulting mixture was stirred for 16 hours at room temperature. Ice (ca. 100 g) and hexane (200 ml) were added to the reaction mixture, and water (200 ml) was added to the resulting mixture with vigorously stirring. The precipitated crystal was collected by filtration and recrystallized from dichloromethane-hexane to give methyl 2-(5-acetyl-2-benzyloxyphenyl)acetate (10.1 g) having a melting point of 85-87° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:29])[CH2:16][CH:17]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:18][C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:30]([O-])([OH:32])=[O:31].O>C(O)(=O)C>[N+:30]([C:12]1[CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[CH:10][C:11]=1[NH:14][C:15](=[O:29])[CH2:16][CH:17]([C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH2:18][C:19]([OH:21])=[O:20])([O-:32])=[O:31]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Oc2ccccc2)cc1)c1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CC(CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
N-(4-Phenoxyphenyl)-3-(4-chlorophenyl)glutaramic acid (1.41 g) was dissolved in acetic acid (3 ml) with heating. The solution was allowed to cool to 30° C. With vigorous stirring fuming nitric acid (0.7 ml) was rapidly added in portions. The resulting hot, orange coloured solution was stirred at rt for 0.5 h. With ice cooling water (15 ml) was added slowly. From the gummy, yellow precipitate the aqueous layer is removed by decantation. Crystallisation is induced by heating with methanol (4 ml). After cooling to rt the precipitate is isolated by filtration, washed with methanol, and dried in vacuo to yield bright yellow crystals (1.21 g) of N-(2-nitro-4-phenoxyphenyl)-3-(4-chlorophenyl)glutaramic acid.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[CH3:7]S(C)=O.[CH2:11]([O:18][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(Cl)Cl>[CH2:11]([O:18][CH:19]([CH:20]([OH:21])[CH:1]([CH3:2])[CH3:7])[CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Reactant: CS(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(OCc1ccccc1)C(O)C(C)C
Temperature: -50 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 3.05 g of oxalyl chloride in 40 ml of dry methylene chloride chilled with a dry ice- acetone bath was portionwise added under nitrogen atmosphere a solution of 3.75 g of dimethylsulfoxide in 10 ml of methylene chloride. The above addition was carried out keeping the oxalyl chloride solution at a temperature (inner temperature) below -60° C. To this solution was added a solution of 3.25 g of 2-benzyloxy-3-hexadecyloxy-1-propanol in 20 ml of methylene chloride, and then the dry ice-acetone bath was removed to allow the reaction solution to reach -10° C. The reaction solution was again chilled to -50° C. and, after addition of 5.28 g of triethylamine, allowed to reach 25° C. The reaction liquid was poured into 100 ml of water, and the separated organic layer was taken out. The organic layer was washed successively with 1N hydrochloric acid and aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in 40 ml of dry tetrahydrofuran. Under nitrogen atmosphere, 8.0 ml of 2.0M isopropyl magnesium chloride-containing tetrahydrofuran was portionwise added to the above solution, keeping the inner temperature of the solution below 8° C. by chilling the solution with ice. The mixture was stirred overnight at room temperature. To the mixture (under chilling with ice) was portionwise added 16 ml of 1N hydrochloric acid, and further added ether. The organic layer was separated. The aqueous layer was then extracted with ether. The organic layer and the ether extract were combined, washed successively with an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by chromatography using silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 2.16 g of the desired compound (mixture of isomers).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH2:18]([O:20][C:21]([CH2:23][O:24][C:25](=[C:31](OC)N(C)C)[C:26](OCC)=[O:27])=[O:22])[CH3:19]>C1(C)C(C)=CC=CC=1>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]3[C:26](=[O:27])[C:25]([O:24][CH2:23][C:21]([O:20][CH2:18][CH3:19])=[O:22])=[CH:31][N:17]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)COC(C(=O)OCC)=C(OC)N(C)C
Reactant: CC(C)c1csc(CCc2ccnc(N)c2)n1
Solvent: Cc1ccccc1C
Product: CCOC(=O)COc1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Yield: 25.3 %

Procedure:
4-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-aminopyridine (100 mg) and ethyl 2-ethoxycarbonylmethoxy-3-methoxy-3-dimethylaminopropenoate (150 mg) were heated at 140° C. in xylene (1 ml) for 7 hours with stirring. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (41 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH3:60])=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH3:60])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (20 mg) and triethylamine (12 μL) are dissolved in dichloromethane (2 mL), treated with methyl chloroformate (4.5 μL) and stirred for 12 hours at room temperature. Triethylamine (12 μL) and methyl chloroformate (4.5 μL) are added and the mixture is stirred for 5 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is directly used in the next step. LC (method 5): tR=1.20 min; Mass spectrum (ESI+): m/z=773 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:59](Br)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (200 mg, 0.294 mmol) is dissolved and potassium carbonate (487 mg, 3.53 mmol, 12 eqv.) is suspended under argon in absolute DMF (50 mL) and the mixture is heated to 55° C. A solution of octyl bromide (35.8 μl, 0.206 mmol, 0.7 eqv.) in absolute DMF (10 mL) is added dropwise during 30 min. and the mixture is stirred at 55° C. for 2 h. The solvent is removed in vacuo at 50° C., water (80 mL) is added and the mixture is extracted with ethyl acetate (3×40 mL). The combined organic fraction is dried (Na2SO4) and the solvent evaporated. The residue is purified by chromatography on a column (300 g) of silica gel. Tetra-alkylated and tri-alkylated compounds are eluted with toluene:ethyl acetate (30:1 by vol.). The third fraction (di-substituted compound, trans-isomer) is eluted with toluene:ethyl acetate (15:1 by vol.). The fourth fraction (di-substituted compound, cis-isomer) is eluted with toluene:ethyl acetate (10:1 by vol.) and the desired product (mono-alkylated compound) is eluted with toluene:ethylacetate (5:1 by vol.). The solvent is removed under reduced pressure and the residue dried under high vacuum to give the product as a violet solid.