Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C(O[C:5](=[O:11])[C:6]([O:8][CH2:9]C)=[O:7])C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>CO.CC(OC)(C)C>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH2:20][C:5](=[O:11])[C:6]([O:8][CH3:9])=[O:7])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)C(=O)CC(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 48.5 %

Procedure:
Sodium (1.0 g, 43 mmol) was dissolved in MeOH (50 mL) and then evaporated to a dry white powder. To the powder was added MTBE (100 mL) and diethyloxalate (5.14 g, 35.2 mmol). To the resulting solution was added a solution of 1-(4-methylphenyl)ethanone (5.0 g, 37.3 mmol) in MTBE (50 mL) dropwise over 45 min. The resulting suspension was allowed to stir for 1 h, and the precipitate was filtered and washed with MTBE/hexanes (1:1, 50 mL). The solid was suspended in 1 N HCl (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were dried (MgSO4), filtered, and concentrated to an oily residue which crystallized on standing at rt. The yellow solid was triturated with MTBE/hexanes (1:1) and filtered to give the title compound (3.76 g, 46%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)(=[O:27])=[O:26]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(S(=O)(=O)N2CCOCC2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (10.9 mmol) in 150 mL of dichloromethane at 0° C. was added triethylamine (1.53 mL, 10.9 mmol), followed by morpholine (1.34 mL, 15.3 mmol). After 30 minutes, the mixture was poured into ethyl acetate and saturated NaHCO3 solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the titled product. ESI+MS: 557.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23](O)=[O:24])=[CH:15][CH:14]=1.C(OC([N:33]1[CH:37]=[C:36]([CH:38](OCC)[O:39]CC)[N:35]=[C:34]1[NH2:45])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CN(C=O)C.CCOC(C)=O.O.CC(C)=O.O>[CH:38]([C:36]1[N:35]=[C:34]([NH:45][C:23]([C:16]2[C:17]3[N:18]=[CH:19][CH:20]=[N:21][C:22]=3[C:13]([C:3]3[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[Cl:1])=[CH:14][CH:15]=2)=[O:24])[NH:33][CH:37]=1)=[O:39]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3nccnc23)c1Cl
Reactant: CCOC(OCC)c1cn(C(=O)OC(C)(C)C)c(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.3 %

Procedure:
A mixture of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (300 mg, 0.791 mmol) (Step 179.1), 2-amino-4-diethoxymethyl-imidazole-1-carboxylic acid tert-butyl ester (226 mg, 0.791 mmol) (Step 179.8), TBTU (305 mg, 0.949 mmol, 1.2 equiv) and DIEA (409 mg, 3.17 mmol, 4 equiv) in DMF (6 mL) was stirred for 48 h at rt. After further addition of 2-amino-4-diethoxymethyl-imidazole-1-carboxylic acid tert-butyl ester (80 mg, 0.280 mmol) (Step 179.8), the reaction mixture was stirred for additional 72 h at rt, diluted with EtOAc/H2O and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc/Hex, 1:1) to afford 470 ring of a mixture of products. Part of this mixture (280 mg) was dissolved in acetone (3 mL) and H2O (2 mL) and treated with PPTS (10.9 mg). The reaction mixture was stirred for 7 h at rt, heated to 50° C., stirred for 20 h, allowed to cool to rt and diluted with EtOAc/H2O. The resulting yellow precipitate was collected by vacuum filtration and dried to provide 128 mg of the title compound: ES-MS: 472 [M+H]+; tR=4.16 min (System 1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:29][C:30]2[CH:35]=[CH:34][C:33]([O:36]C3CCCCO3)=[CH:32][CH:31]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)[CH2:14]2)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)C.O.[OH-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:29][C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH:15]3[CH2:21][CH:19]([CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]3)[CH2:20]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CCCC(Oc3ccc(OC4CCCCO4)cc3)c3ccc(C#N)cc3)C2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCCC(Oc3ccc(O)cc3)c3ccc(C#N)cc3)C2)C1
Temperature: 35 °C
Reaction time: 48 h
Yield: 72.7 %

Procedure:
tert-Butyl 7-{4-(4-cyanophenyl)-4-[4-(tetrahydro-2H-pyran-2-yloxy)-phenoxy]butyl}-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (iv) above; 2.33 g; 4.0 mmol), was dissolved in THF (40 mL), acetic acid (20 mL) and H2O (10 mL). The mixture was stirred at 35° C. for 2 days. The mixture was made basic with 10 M NaOH (whilst cooling). Extraction with DCM, separation of the organic layer, evaporation of the solvent and chromatography on silica (CH3CN) gave 1.43 g (72%) of the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[N:20](C(=O)C)[C:21](=[O:23])[CH3:22])=[CH:7][CH:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][C:21](=[O:23])[CH3:22])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(-n2c(N(C(C)=O)C(C)=O)nc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1nc2ccccc2n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67 %

Procedure:
Compound 77A (176 mg, 0.5 mmol) in MeOH (4 ml) was treated with K2CO3 (69.1 mg, 0.5 mmol) and stirred at ambient temperature for about 40 minutes. The reaction mixture was concentrated to remove MeOH, diluted with EtOAc and acidified to pH 5 with 1N HCl solution. The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to provide the title compound 77B as an off-white solid in 67% yield: 1H NMR (300 MHz, DMSO-d6) δ ppm 10.26 (1H, s), 9.84 (1H, s), 7.63 (1H, m), 7.20 (5H, m), 6.93 (2H, m), 1.94 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[I:21]N1C(=O)CCC1=O>CC(O)=O>[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[C:18]([I:21])[CH:19]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nnc(-c2ccc(O)cc2)c(-c2ccccc2)n1
Solvent: CC(=O)O
Product: Nc1nnc(-c2ccc(O)c(I)c2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-phenol (vide supra; 140 mg, 0.530 mmol) was reacted with AcOH (2 mL) and 1-iodopyrrolidine-2,5-dione (119 mg, 0.530 mmol). The mixture was stirred at room temperature for 1 hour then concentrated in vacuo and purified by column chromatography (35 mg, 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>C1COCC1.CCN(CC)CC>[C:4]([C:3]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:2]=1[NH:1][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)(=[O:5])[NH2:6]
Reactant: CCCOc1ccc(N)c(C(N)=O)c1
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1ccc(NC(=O)c2cccnc2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 2-amino-5-propoxy-benzamide (760 mg, 3.91 mmol) in THF (15 mL) and Et3N (1 mL) was added nicotinoyl chloride (607 mg, 4.30 mmol) in anhydrous THF (15 min) dropwise. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the volatiles were removed. The residue was washed with H2O (10 mL). The pH was adjusted to approximately 5 by adding dilute HCl (2N in water). The resulting solid was collected and dried in vacuo to give 1.00 g of iii-a as a pale yellow solid (89.0%). LCMS m/z=300.1 (M+1) (Method B) (retention time=1.60 min).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7]C(=O)C)=[C:5]([C:11]#[C:12][Si](C)(C)C)[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.C([OH:25])C.[OH-].[Na+]>C(OCC)(=O)C.O>[NH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:11](=[O:25])[CH3:12]
Reactant: CCO
Reactant: CC(=O)Nc1c(C#C[Si](C)(C)C)c(-c2ccccc2)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1c(-c2ccccc2)nn(C)c1N
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of N-(1-methyl-3-phenyl-4-((trimethylsilyl)ethynyl)-1H-pyrazol-5-yl)acetamide (2.3 g, 7.4 mmol), ethanol (20 mL) and 25% aq. NaOH solution (20 mL) was heated with stirring at 90° C. for 6 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo. The residue was purified using chromatography (silica gel, gradient 0 to 40% ethyl acetate/CH2Cl2), followed by trituration in diethyl ether to provide the title compound as a white solid (724 mg).
Reaction SMILES: CC[O:3][C:4]([C:6]1[N:24](C(OC(C)(C)C)=O)[C:9]2=[N:10][CH:11]=[C:12]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5].[ClH:32]>O1CCOCC1>[ClH:32].[CH:21]([N:18]1[CH2:19][CH2:20][CH:15]([O:14][C:12]2[CH:13]=[C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:24][C:9]3=[N:10][CH:11]=2)[CH2:16][CH2:17]1)([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)cnc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)O)cc3c2)CC1
Reaction time: 16 h
Yield: 98 %

Procedure:
The solution of 0.24 g (0.56 mmol) 5-(1-isopropyl-piperidin-4-yloxy)-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 1.2 ml dioxan is treated with 0.56 ml concentrated hydrochloric acid and stirred for 16 hours under reflux. The volatile components were removed at a rotary evaporator and the residue was dried under high vacuum to give 0.19 g (98%) of the product as a brown foam which was pure enough for the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([CH2:10]O)=[CH:9][C:2]=12.P(Br)(Br)[Br:13].O.[OH-].[Na+]>C(Cl)Cl.C1COCC1>[Br:13][CH2:10][C:8]1[S:7][C:3]2[C:2](=[N:1][CH:6]=[CH:5][N:4]=2)[CH:9]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc2nccnc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: BrCc1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a suspension of thieno[3,2-b]pyrazin-6-ylmethanol 87 (408 mg, 2.455 mmol) in CH2Cl2 (8 mL) and THF (8 mL) was added phosphorus tribromide (1/166 mL, 12.27 mmol) and stirred overnight at rt. Water was added, alkalized with 2N NaOH and extracted with EtOAc. Organic layer was washed with NaHCO3 (aq) solution, brine, dried and evaporated. Purification by chromatography (CH2CL2) gave pure 6-(bromomethyl)thieno[3,2-b]pyrazine 47 (356 mg, 63%). NMR (400 MHz, CDCl3) 4.80 (s, 2H), 7.71 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.64 (d, J=2.3 Hz, 1H). (m/z)=229 and 231 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[NH:22]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=[CH:23]1>>[N:22]1([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]([N:9]3[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]3)=[O:13])=[CH:15][CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1=CC=CNC=C1
Product: CCC(CC)N1CCN(C(=O)c2ccc(CN3CCCCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 12 and azepine.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH2:21][CH2:20][CH:19]([O:22][CH2:23][C:24]4[C:25]([C:32]5[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:39])=[N:26][O:27][C:28]=4[CH:29]([CH3:31])[CH3:30])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[N:9]([CH3:40])[CH:8]=1)=[O:6]>O1CCOCC1>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:32]=1[C:25]1[C:24]([CH2:23][O:22][CH:19]2[CH2:18][CH2:17][N:16]([C:12]3[CH:11]=[C:10]4[C:15]([C:7]([C:5]([OH:6])=[O:4])=[CH:8][N:9]4[CH3:40])=[CH:14][CH:13]=3)[CH2:21][CH2:20]2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: COC(=O)c1cn(C)c2cc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)CC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COC1CCN(c2ccc3c(C(=O)O)cn(C)c3c2)CC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
A solution of 2N lithium hydroxide (0.9 mL, 5 equiv, 1.8 mmole) is added to a solution of 6-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid methyl ester (200 mg, 1.00 equiv, 0.36 mmole) in 1,4-dioxane (4 mL). The mixture is stirred at 90° C. for 24 h. The organic solvent is removed, HCl (1M) is added to adjust the pH to 3-4, and the resulting aqueous solution is extracted with dichloromethane. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography (12 g silica) eluting with a gradient of ethyl acetate in hexane (10% to 100%) to provide the title compound as a pale brown solid (168 mg, 86%). ES/MS m/z 542.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:15]2[CH:16]=[C:17]([CH2:20][C:21]3[CH:22]=[C:23]([C:28]4(OC)[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:24]=[CH:25][C:26]=3[Cl:27])[CH:18]=[CH:19][C:14]=2[O:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClCCl>[CH2:1]([N:8]1[C:15]2[CH:16]=[C:17]([CH2:20][C:21]3[CH:22]=[C:23]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:24]=[CH:25][C:26]=3[Cl:27])[CH:18]=[CH:19][C:14]=2[O:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CC3(CC3)O4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CC3(CC3)O4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
To a stirred solution of (3R,4S,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (340 mg, 0.6 mmol) in acetonitrile-dichloromethane (6 mL, 1:1 mixture) was added triethylsilane (0.4 mL, 2.4 mmol) and boron trifluoride diethyletharate complex (0.15 mL, 1.2 mmol) at −5° C. After stirring for 4 h at 0° C., the reaction was quenched with saturated aq. sodium bicarbonate solution (5 mL). The volatiles were evaporated under reduced pressure, and the resulting mixture was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with brine (10 mL), dried over sodium sulphate, and concentrated. The resulting residue was purified by silica gel column chromatography to furnish (2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (300 mg).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N.CC1C2COC(=O)C=2C(O[C@@H]2O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]2O)=C(C/C=C(/CCC(O)=O)\C)C=1OC.[CH2:50]([NH2:62])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>>[CH2:1]([NH:62][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCCCCCCO
Agent: COc1c(C)c2c(c(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: N
Product: CCCCCCCCCCCCNCCCCCCCCCCCC

Procedure:
The same procedure as in Example 3 was repeated except for using 150 g (0.81 mol) of lauryl alcohol in place of stearyl alcohol and using ammonia in an amount of 69 g (4.06 mol), thereby conducting the reaction for 11 h. The initial maximum pressure as measured at a reaction temperature of 220° C. was 21 MPaG. The resultant reaction product was analyzed in the same manner as in Example 1. As a result, it was confirmed that the conversion of the raw alcohol was 96.3%, the selectivity to lauryl amine was 74.9%, the amount of dilauryl amine produced is 12.3%, and the amount of the other by-products produced was 10.9%.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].[Br-].[Cl-].Cl.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17]Cl.C[O-].[Na+]>CO.C(O)(C)C.C(O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:7][C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1]
Reactant: Cc1occc1S
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Br-]
Solvent: CC(C)O
Solvent: CO
Solvent: CCO
Product: Cc1occc1SCc1ccccn1

Procedure:
The 3-furyl sulfides of our invention can also be prepared by reacting 3-furan thiols, e.g. 2-methyl-3-furan thiol with an α-picolyl halide (2-pyridyl-methyl halide) (e.g. a bromide or chloride); (i) in the presence of a base such as an alkali metal alkoxide (e.g., sodium methoxide); (ii) at a temperature in the range of 15°-65° C; and (iii) in a suitable solvent, e.g., an anhydrous lower alkanol such as anhydrous methanol, ethanol or isopropanol. Thus, for example, α-picolyl chloride hydrochloride, when reacted with 2-methyl-3-furan thiol in anhydrous methanol in the presence of sodium methoxide at a temperature of 24° C will yield (2-methyl-3-furyl) (2-pyridylmethyl) sulfide.
Reaction SMILES: Cl[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[Na].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:2]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(C(Cl)CCc2ccc(F)cc2)cc1
Agent: [Na]
Product: N#Cc1ccc(C(CCc2ccc(F)cc2)n2ccnc2)cc1

Procedure:
1-[1-(4-cyanophenyl)-3-(4-fluorophenyl)propyl]-1H-imidazole is prepared according to the same procedure using 1-chloro-1-(4cyanophenyl)-3-(4-fluorophenyl)propane and 1H-imidazole sodium derivative as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:11][CH:10]([NH:12]C(=O)OC(C)(C)C)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:12][CH:10]1[CH2:11][N:8]([C:6]([C:5]2[CH:20]=[CH:21][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)c2ccc(Br)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CN(C(=O)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of compound 16c (810 mg, 2.28 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (7 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated. To the residue was added CH2Cl2 and 1N aqueous NaOH solution until the pH of the aqueous layer was approximately 8. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 16d (570 mg). MS m/z (M+H+) 254, 256.
Reaction SMILES: O=[C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][S:4][C:5]#[N:6].[C:13](#[N:17])[CH2:14][C:15]#[N:16].C(N(CC)CC)C.C(O)(=O)C>C(O)C.O>[C:7]1([C:2]2[N:6]=[C:5]([CH:14]([C:13]#[N:17])[C:15]#[N:16])[S:4][CH:3]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC#N
Reactant: N#CSCC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC(C#N)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
In a 100 mL three-neck flask, 10.0 g (56.4 mmol) of 2-oxo-2-phenylethyl thiocyanate and 3.73 g (56.4 mmol) of malononitrile were dissolved in 60 mL of ethanol and admixed with 5.14. g (50.8 mmol) of triethylamine in a gradual manner, so the temperature did not climb above 30° C. This was followed by stirring at room temperature for 12 h. The reaction mixture was diluted with 50 mL of water and acidified with glacial acetic acid. The precipitated solid was separated off and washed three times with 10 mL of a 10:10:1 mixture of water:ethanol:glacial acetic acid each time. The solid was dried to obtain 11.1 g (49.1 mmol) of (4-phenyl-1,3-thiazol-2-yl)malononitrile.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][O:17][CH:18]=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:25][CH:26]1[C:37](=[O:38])[N:28]2[C:29]([C:34]([OH:36])=[O:35])=[C:30]([CH3:33])[CH2:31][S:32][C@H:27]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][O:17][CH:18]=[O:19])[C:10]([NH:25][CH:26]2[C:37](=[O:38])[N:28]3[C:29]([C:34]([OH:36])=[O:35])=[C:30]([CH3:33])[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)O)cs1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Yield: 46.5 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetic acid (syn isomer 2.9 g.), N,N-dimethylformamide (0.8 g.), phosphoryl chloride (1.7 g.) and dry ethyl acetate (23 ml.) were treated in a similar manner to that of the Example 1-(1) to give an activated acid solution. The solution was added to a solution of 7-amino-3-methyl-3-cephem-4-carboxylic acid (2.0 g.) and trimethylsilylacetamide (8.6 g.) in dry ethyl acetate (40 ml.) at -10° C. and stirred at the same temperature for an hour. After adding water (30 ml.) to the reaction mixture, the organic layer was separated and extracted with an aqueous solution of sodium bicarbonate (30 ml.). The extract was adjusted to pH 2.5 with conc. hydrochloric acid and extracted with ethyl acetate (50 ml.). The extract was washed with a saturated aqueous solution of sodium chloride, dried and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 7-[2-(2-formamidothiazol- 4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer, 2.10 g.).