Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:29][NH:28][C:26](=[O:27])[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:33])[F:32])=[CH:31][CH:30]=2)[CH2:8][CH2:7]1
Reactant: NNC(=O)COc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(COc1ccc(OC(F)(F)F)cc1)NNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared from 3,4-dichlorobenzyl-4-piperidone (J. Med. Chem, 1999, 42, 3629; 100 mg), 2-[4(trifluoromethoxy)phenoxy]acetohydrazide (100 mg), sodium triacetoxyborohydride (100 mg), and 0.02 ml acetic acid, stirred together for 2 hours in dichloromethane by the method of Example 369 step ii. MS [M+H]+ (ES+) 492 1H NMR: (CDCl3) δ 1.4-1.6 (3H, m) 1.7 (2H, m), 2.0 (2H, m) 2.7-2.9 (2H, m), 3.4 (2H, m), 4.4 (3H, m), 5.3 (1H, s) 6.9 (2H, m), 7.2-7.5 (4H, m), 7.8 (1H, d).
Reaction SMILES: CC1CC[O:4]C1.[C:7]([CH2:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])#[N:8]>>[C:7]([CH2:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])(=[O:4])[NH2:8]
Reactant: COC(=O)C(C)CC#N
Reactant: CC1CCOC1
Product: COC(=O)C(C)CC(N)=O

Procedure:
A process for producing 3-methyltetrahydrofuran, wherein in a first step, prussic acid is reacted with methyl methacrylate to produce methyl 3-cyanoisobutyrate. The methyl 3-cyanoisobutyrate is then reacted with water and sulfuric acid to produce a resultant product which is reacted with a C1 -C8 aliphatic alcohol to produce a methylsuccinic acid ester. The methylsuccinic acid ester is catalytically hydrogenated to prepare the 3-methyltetrahydrofuran. Alternatively, the methyl 3-cyanoisobutyrate is hydrated to produce methyl 3-carbamoylisobutyrate, which is then reacted with a formic acid ester to form a methylsuccinic acid ester and formamide and the resultant methylsuccinic acid ester is catalytically hydrogenated. The 3-methyltetrahydrofuran is produced in high selectivity and in a commercially advantageous manner from inexpensive reactants. The 3-methyltetrahydrofuran is useful as a commoner for producing polyether glycol, which is utilized as starting raw material for preparing spandex fiber.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.O[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:14][C:12]([F:15])([F:13])[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][N:17]2[C:18](=[O:27])[C:19]3=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]3[C:21]2=[O:22])=[N:7][CH:8]=1
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCOc1ccc(C(F)(F)F)cn1
Yield: 84.2 %

Procedure:
To a mixture of 20.0 g of 2-(3-hydroxypropyloxy)-5-trifluoromethylpyridine, 14.7 g of N-hydroxyphthalimide, 23.6 g of triphenylphosphine, and 200 ml of tetrahydrofuran was slowly added dropwise 20.0 g of diisopropyl azodicarboxylate with stirring under ice cooling in a stream of nitrogen gas. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 27.8 g (yield, 84%) of N-(3-(5-trifluoromethyl-2-pyridyloxy)propyloxy)phthalimide, m.p., 97.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(Cl)c1

Procedure:
The title compound was synthesized from methyl 4-(3-chlorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (261 mg, 0.90 mmol) and lithium hydroxide (188 mg, 4.50 mmol in 3 mL H2O), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc to afford the title compound. 147 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.06-2.17 (m, 1H) 2.53-2.64 (m, 1H) 2.64-2.73 (m, 2H) 2.73-2.85 (m, 2H) 3.26-3.36 (m, 1H) 6.52 (d, J=1.32 Hz, 1H) 7.08 (dt, 1H) 7.19-7.26 (m, 3H) 8.87 (br. s, 1H). LCMS m/e 276 (M+H). Purity>98% (HPLC).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([C:11](O)([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.[C:52](=[O:55])([O-])O.[Na+]>C1COCC1.CO>[Br:18][CH2:16][C:15]([C:7]1[CH:8]=[C:9]([C:11]([O:55][CH3:52])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:17]
Reactant: [Br-]
Reactant: CC(=O)c1cc(C(C)(C)C)cc(C(C)(C)O)c1
Reactant: O=C([O-])O
Agent: C[N+](C)(C)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
1-[3-tert-Butyl-5-(1-hydroxy-1-methylethyl)phenyl]ethanone (O2.100; 500 mg) was initially charged in a mixture of THF and methanol (3.5/3.5 ml) while stirring at RT, and admixed with phenyltrimethylammonium tribromide (800 mg). After stirring at RT for 7 h, the mixture was admixed with water and saturated sodium hydrogencarbonate solution. Then it was extracted three times with EA, and the combined EA phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (70 g cartridge, n-heptane/EA gradient). 454 mg of the title compound were obtained. LC-MS rt: 1.23 min [M+H−HOMe]+: 295.1 (met. b)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:25](Br)[CH2:26][CH3:27]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH3:27])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCBr
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Product: CCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21

Procedure:
3-(3,5-Di-tertiary butyl-4-hydroxyphenyl)-1-propyl-1H-pyrazolo[3,4-b]pyridine, melting at 97°-98° C. is prepared by reacting the compound of Example 1 with propyl bromide in a similar manner as Example 9, and recrystallizing from hexane.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:30][CH:31]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([NH:13][C:11](=[O:12])[NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([F:17])[C:2]([C:26]3[CH:31]=[N:30][C:29]([N:32]4[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]4)=[N:28][CH:27]=3)=[CH:16][C:6]=2[N:7]=1)[CH3:15]
Reactant: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)c(F)cc2s1
Temperature: 97.5 °C
Yield: 19.9 %

Procedure:
A solution of 1-(5-bromo-6-fluoro-benzothiazol-2-yl)-3-ethyl-urea (0.05 g, 0.15 mmol), tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate (0.12 g, 0.31 mmol) and K3PO4 (0.13 g, 0.61 mmol) in DMF-H2O (5.0 mL, 3:2) was degassed by flushing with nitrogen for 15 min. Dichlorobis(triphenylphosphine)-palladium(II) (0.021 g, 0.03 mmol) was then added to the reaction mixture followed by degassing with nitrogen for another 15 min. The resulting reaction mixture was then heated to 95-100° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature and poured onto ice-cold water followed by extraction with EtOAc (2×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was then purified over silica gel (100-200 M, 1.60% MeOH-DCM) to obtain the desired product (0.015 g, 20%). 1H-NMR (400 MHz, DMSO-d6): δ 1.08 (t, J=7.20 Hz, 3H), 1.43 (s, 9H), 3.20 (m, 2H), 3.42 (br s, 4H), 3.79 (br s, 4H), 6.71 (br s, 1H), 7.76 (d, J=6.80 Hz, 1H), 7.92 (d, J=10.40 Hz, 1H), 8.62 (s, 2H) and 10.74 (br s, 1H). MS: 502.27 (M+H)+. Qualitative HPLC Purity (Acquity BEH C-18, 100×2.1 mm, 272 nm): 99.21% (Rt=6.51 min).
Reaction SMILES: B(O)(O)C1C=CC=C(C(O)=O)C=1.FC(F)(F)S(OC1CCN(C(OC(C)(C)C)=O)CC=1)(=O)=O.C([O:36][C:37]([C:39]1[CH:40]=[C:41]([C:45]2[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH:50]=2)[CH:42]=[CH:43][CH:44]=1)=[O:38])C>>[C:54]([O:53][C:51]([N:48]1[CH2:47][CH:46]=[C:45]([C:41]2[CH:40]=[C:39]([CH:44]=[CH:43][CH:42]=2)[C:37]([OH:38])=[O:36])[CH2:50][CH2:49]1)=[O:52])([CH3:57])([CH3:55])[CH3:56]
Reactant: CCOC(=O)c1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C(O)c1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(C(=O)O)c2)CC1

Procedure:
3-(dihydroxyborane)benzoic acid (4.65 g, 28.0 mmol) was coupled to tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (6.65 g, 20.0 mmol) in an analogous fashion to that described previously for the synthesis of tert-butyl 4-[3-(ethoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE 6, Step A) to give 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]benzoic acid.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:10]([NH:15][CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:22](=[O:24])[CH3:23])(=O)C>>[CH:1]1([C:7]([C:9]2[C:10]([N:15]([CH2:16][CH3:17])[C:22](=[O:24])[CH3:23])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCNc1ncccc1C(=O)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Product: CCN(C(C)=O)c1ncccc1C(=O)C1CCCCC1

Procedure:
An acetic anhydride solution (20 ml) of 1.5 g of 3-cyclohexylcarbonyl-2-ethylaminopyridine was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (toluene-ethyl acetate) to give 1.1 g of N-(3-cyclohexylcarbonyl-2-pyridyl) -N-ethylacetamide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:14])OCC.[NH2:15][C:16]1[C:21]([O:22][CH2:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])=[CH:20][CH:19]=[CH:18][N:17]=1>C(O)C>[ClH:2].[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[CH2:23][O:22][C:21]1[C:16]([NH:15][C:10](=[NH:14])[CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=N)Cc1ccccc1Cl
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1Cl)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of ethyl 2-chlorophenylacetimidate hydrochloride (5.07 g, 0.0216 mol), 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (4.95 g, 0.0196 mol)and ethanol (150 ml) was heated under reflux for 2 hours. The solvent was evaporated off and the resultant oil was purified by chromatography (silica gel, 1% methanol/dichloromethane) and trituration with ether. Yield 0.7 g (8%), m.p. 156°-158 ° C.
Reaction SMILES: [NH2:1][C:2]1[C:23](C(F)(F)F)=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])=[CH:7][C:6]=1[S:16]([OH:19])(=[O:18])=[O:17].[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([N:40]=[C:41]=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1>N1C=CC=CC=1>[NH4+:1].[F:28][C:29]([F:43])([F:44])[C:30]1[CH:31]=[C:32]([NH:40][C:41](=[O:42])[NH:1][C:2]2[CH:23]=[C:22]([C:29]([F:44])([F:43])[F:28])[CH:21]=[CH:20][C:3]=2[O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13])=[CH:7][C:6]=2[S:16]([O-:19])(=[O:18])=[O:17])[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1
Reactant: CCC(C)(C)c1ccc(Oc2cccc(C(F)(F)F)c2N)c(S(=O)(=O)O)c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(S(=O)(=O)[O-])c1
Product: [NH4+]

Procedure:
2-(2-Amino-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzenesulfonic acid (260 mg, 0.0006 mol) and 3,5- bis(trifluoromethyl)phenyl isocyanate (130.9 ml, 0.0005 mol) were mixed in pyridine (5 ml), under argon, for sixteen hours at room temperature. The solvent was evaporated and the residue flash chromatographed (silica gel, methylene chloride/isopropanol/ammonium hydroxide), dried and evaporated to give the title compound. 1H NMR (250 MHz, DMSO) ∂ 9.20 (s, 1H), 8.90 (s, 1H), 7.90 (s, 1H), 7.50 (s, 2H), 7.25 (d, 1H), 7.05 (s, 1H), 6.80-6.30 (m, 4H), 1.0 (q, 3H),.0.065 (s, 6H), .0.045 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21].C([O-])(=O)C.[Na+].C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[O:10][C:9]([CH2:11][N:26]3[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCCl
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
2-Chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde (65 mg, 1.0 eq) was dissolved in 1,2-dichloroethane (9.7 ml) and treated with hydrochloride salt of 1-methanesulfonylpiperazine (69 mg, 1.4 eq), sodium acetate (28 mg, 1.4 eq) and trimethyl orthoformate (0.27 ml, 10 eq). Reaction mixture was stirred at room temperature for 12 h. Sodium triacetoxyborohydride (62 mg, 1.2 eq) was added and reaction mixture was stirred at room temperature for 8 h. Reaction mixture was quenched with saturated aq. NaHCO3 and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (70 mg, 68%): MS (Q1) 416 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[N:30]1([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:44][CH:43]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.044 g, 0.11 mmol) and EtOH (4.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.029 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 6%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.020 g, 33%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.78 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H) and 3.53 (s, 2H) (C6H4CH2N and NCH2CO), 3.75 (br s, 4H, piperazine N(CH2)2), 7.24 (d, J=3.5 Hz, 1H, thiazole-H), 7.48 (m, 3H, 3,5-C6H4— and thiazole-H), 8.12 (d, J=9.7 Hz, 2H, 2,6-C6H4—), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][OH:4].C(N([CH2:20][CH3:21])CC)C.[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>ClCCl>[C:22]([O:4][CH2:3][CH:2]([NH:1][C:3](=[O:4])[CH2:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCC(N)CO
Solvent: ClCCl
Product: CCCCCCCCCCC(COC(=O)CCCCCCC)NC(=O)CCCCCCC
Reaction time: 8 h
Yield: 168.6 %

Procedure:
To a solution of 2 g of 2-aminododecanol, 3 g of triethylamine in 50 ml of dichloromethane is added 3.5 g of octanoyl chloride. The reaction mixture is stirred overnight and then quenched by pouring into ice. This is extracted with dichloromethane and the organic solution is washed with aqueous bicarbonate solution, water and brine. The organic phase is dried over magnesium sulfate, filtered and concentrated to give 3.8 g of the product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=O)[CH2:11][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:11][CH3:12])=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc2[nH]ncc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a stirred mixture of Zn power (1.65 g, 10.0 eq) in dry THF at rt under N2 was slowly added TiCl4 (4.0 eq, 1.1 mL). The resulting mixture was heated at reflux for 1 h and cooled to rt. A mixture of 1-(1H-indazol-5-yl)propan-1-one (1.3 g, 3.0 eq) and (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (0.7 g, 1.0 eq) in dry THF was added, warmed to 80° C., refluxed for additional 1 h, quenched with Na2CO3 (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the title product (0.3 g, 70%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.53 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.71-6.88 (m, 1H), 6.72 (d, J=8.8 Hz, 2H), 6.43 (d, J=8.8 Hz, 1H), 4.35 (t, J=7.2 Hz, 1H), 4.24 (t, J=7.2 Hz, 1H), 3.83 (t, J=6.0 Hz, 1H), 3.70 (t, J=6.0 Hz, 1H), 2.47-2.54 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([N:28]=CN(C)C)(=[O:27])=[O:26])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:6]=1[CH:7]=[O:8].O>CCO.Cl>[Cl:1][C:2]1[N:3]=[C:4]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([NH2:28])(=[O:26])=[O:27])(=[O:17])=[O:18])=[CH:12][CH:11]=2)[C:6]=1[CH:7]=[O:8]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Yield: 72.7 %

Procedure:
230 mg of 2-[4-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)benzenesulfonyl]-N-dimethylaminomethylenebenzenesulfonamide are refluxed for 2 h in 3 ml of EtOH and 3 ml of a saturated aqueous HCl solution. The reaction mixture is allowed to cool and poured onto 10 ml of water, and the product is filtered off. Chromatography on silica gel using MTB yields 151 mg of an amorphous solid.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=2[F:48])[CH2:17][O:16][C@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:14]1[CH2:39][OH:40]>C(Cl)Cl>[F:48][C:42]1[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:41]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:39][OH:40])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:16][CH2:17]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Yield: 96.7 %

Procedure:
Benzoyl isothiocyanate (1.24 mL, 9.2 mmol) was added to a stirred solution of ((2S,3R,4S)-4-amino-4-(2,4-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl)methanol (4.2 g, 8.4 mmol) in dry DCM (20 mL) at RT under nitrogen. After 1 hour the volatiles were removed in vacuo and then the residue was purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 30% EtOAc in n-hexane) to give the title compound (5.4 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.71-2.83 (m, 1 H) 3.12 (dd, J=10.15, 4.52 Hz, 1 H) 3.27 (dd, J=10.15, 3.67 Hz, 1 H) 3.83 (d, J=5.26 Hz, 2 H) 4.19-4.27 (m, 1 H) 4.55 (d, J=9.78 Hz, 1 H) 5.18 (d, J=9.78 Hz, 1 H) 6.82-6.96 (m, 2 H) 7.17-7.32 (m, 9 H) 7.36-7.41 (m, 6 H) 7.49-7.57 (m, 3 H) 7.60-7.67 (m, 1 H) 7.89-7.94 (m, 2 H),
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=O)[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:14]1[CH:13]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[CH:10]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccccc2)c2cc(C(c3ccc(F)cc3)n3ccnc3)ccc2[nH]1
Product: Fc1ccc(C(c2ccc3nc(Cl)cc(-c4ccccc4)c3c2)n2ccnc2)cc1
Yield: 99 %

Procedure:
A mixture of (±)-6-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]4-phenyl-2(1H)-quinolinone (0.0253 mol) in phosphoryl chloride (30 ml) was refluxed for 1 hour. The mixture was evaporated till dryness and the product was used without further purification, yielding 10.4 g (99%) of (±)-2-chloro-6-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-4-phenyl-quinoline (interm. 1).