Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S([CH:28]([N+]#[C-])[N+:29]#[C-:30])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]2[O:13][CH:30]=[N:29][CH:28]=2)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Reactant: [C-]#[N+]C([N+]#[C-])S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(S(C)(=O)=O)c(-c2cnco2)c1Cl

Procedure:
25 g (0.09 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate (Ex. A.1.), 17.6 g (0.09 mol) of tosylmethylene isocyanide and 6.2 g (0.045 mol) of finely pulverulent potassium carbonate are stirred together with 450 ml of methanol at reflux temperature for 5 hours. The solvent was subsequently stripped off, the residue was taken up in ethyl acetate, and the mixture was extracted with water. The ethyl acetate phase was dried using sodium sulfate and concentrated.
Reaction SMILES: [CH:1]1([CH2:7][CH:8](O)[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:14][C:15](=[O:25])[CH:16]([CH:22]([CH3:24])[CH3:23])C(OCC)=O)C>CCO.CCO.CCO.CCO.[Ti]>[CH:1]1([CH2:7][CH:8]=[CH:9][CH2:10][CH:16]([CH:22]([CH3:24])[CH3:23])[C:15]([OH:25])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: C=CC(O)CC1CCCCC1
Agent: [Ti]
Solvent: CCO
Product: CC(C)C(CC=CCC1CCCCC1)C(=O)O
Reaction time: 1 h

Procedure:
23.15 g (0.15 mol) of 1-cyclohexyl-3-buten-2-ol, 6.85 g (0.03 mol) of tetraethyl orthotitanate and 61.5 ml (0.30 mol) of isopropylmalonic acid diethyl ester are placed in a flask and stirred for 1 hour at 170° and then for 24 hours at 200°. Excess malonic acid ester is distilled off at 20 mbar, and the residue is dissolved in 120 ml of ethanol and, after the addition of 120 ml of 6N KOH, stirred under reflux for 7 hours. After cooling, the reaction mixture is filtered and the filtrate is extensively concentrated by evaporation in a rotary evaporator. The aqueous phase is extracted once with ether, acidified to pH 1 with 6N HCl while cooling with ice and then extracted three times with ether. The combined organic phases are washed with brine, dried with MgSO4 and concentrated by evaporation in a rotary evaporator. The residue is distilled at 137°-140°/0.025 mbar.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].[CH2:28]1[O:30][CH2:29]1.B(F)(F)F.CCOCC>CCOCC>[CH:19]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[CH2:28][CH2:29][OH:30])([CH3:21])[CH3:20]
Reactant: CC(C)[Si](Oc1ccc2ccccc2c1Br)(C(C)C)C(C)C
Reactant: C1CO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc2ccccc2c1CCO)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
n-Butyllithium (16.4 mL of 1.6 M soln in hexanes, 26.3 mmol) was stirred with Et2O (60 mL) at −78° C. in an argon-purged, round-bottom flask. A solution of (1-bromo-naphthalen-2-yloxy)-triisopropyl-silane (7.10 g, 18.8 mmol) in Et2O (˜5 ml) was added dropwise to the stirring n-BuLi solution. The reaction was stirred at −78° C. for ten minutes and then a solution of ethylene oxide (1.41 mL, 28.2 mmol) and BF3-Et2O (3.81 mL, 31.0 mmol) in Et2O (˜5 ml) was added via syringe. The reaction was stirred at −78° C. for one hour and then at room temperature for two hours. The reaction was carefully quenched with H2O and was extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated. The crude product was purified by gradient elution flash chromatography (SiO2, 100% hexanes to 10% EtOAc-hexanes) to give 2-(2-triisopropylsilanyloxy-naphthalen-1-yl)-ethanol (3.41 g, 9.91 mmol) as a colorless oil in 53% yield. MS (APCI) m/z 343.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCNCC2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine-1-carboxylate (101 mg, 0.18 mmol) in DCM (2 mL) at 0° C. was added TFA (0.2 mL). After stirring at room temperature for 2 h, the reaction mixture was diluted with DCM, washed with satd NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo to give 4-((5-(2-(3,4-Dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine as a white solid that was used directly for the next step.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:20])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>N1C=CC=CC=1>[C:1]([NH:5][CH2:6][CH:7]([O:20][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1)[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1cccc2c1CC(=O)N2
Reactant: O=C(Cl)c1cccnc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)NCC(COc1cccc2c1CC(=O)N2)OC(=O)c1cccnc1
Reaction time: 96 h

Procedure:
1 g of 4-(3-tert-butylamino-2-hydroxypropoxy)oxindole, 20 cc of chloroform, 10 cc of pyridine and 0.713 g of nicotinoyl chloride are allowed to stand at room temperature for 4 days, the mixture is then concentrated by evaporation as carefully as possible at reduced pressure and the residue is taken up in water. The reaction mixture is rendered alkaline with a 10% ammonia solution, is extracted with methylene chloride, and subsequently an excess of 2 N hydrochloric acid in ethanol is added. The solvent and excess hydrochloric acid are carefully removed by evaporation at reduced pressure and the dihydrochloride of the title compound is crystallized from ethanol, needle druses. M.P. 215°-218° .
Reaction SMILES: C([O-])=O.[NH4+].[NH2:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][C:7]=1[N+:16]([O-])=O>CO.O.[Pd]>[NH2:16][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:6]=1[NH2:5])[O:10][CH2:11][CH2:12][OH:13]
Reactant: Nc1ccc(OCCO)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(OCCO)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 113.3 %

Procedure:
A degassed solution of ammonium formate (1.4 g) in MeOH/water (10/1) was added to 2-(4-amino-3-nitrophenoxy)ethan-1-ol (234 mg), followed by Pd/C (10%). The flask was closed and the reaction mixture was stirred at RT for 20 h. The reaction mixture was filtered off and Pd/C was further washed with MeOH/water. The filtrate was lyophilized to afford 225 mg of black solid. 1H-NMR (DMSO): 8.19 (s, 1H); 6.41 (d, 1H, 8.3 Hz); 6.17 (d, 1H, 2.7 Hz); 5.98 (dd, 1H, 2.8 Hz and 8.3 Hz); 4.98 (br s, NH2); 3.77 (t, 2H, 5.2 Hz); 3.63 (t, 2H, 5 Hz).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:38]([O:45][N:46]=[CH:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16]([N:49]1[CH2:50][CH2:51][C:47](=[N:46][O:45][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:48]1[CH3:52])=[O:18])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: C(=NOCc1ccccc1)C1CCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(=NOCc2ccccc2)CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of boc-L-α-cyclohexylglycine (1.27 g, 4.92 mmole), 1-hydroxylbenzotriazole (0.99 g, 7.38 mmole), diisopropylethylamine (2.54 g, 19.68 mmole), and O-benzotriazole-N,N,N,N-tetramethyl-urounium hexafluorophosphate (2.80 g, 7.38 mmole) in dichloromethane (30 ml) is stirred for 15 minutes at room temperature. A solution of pyrrolidine-2-carbaldehyde-O-benzyl-oxime (˜1.00 g, 0.49 mmole) in dichloromethane is added. The reaction solution is stirred for three hours at room temperature and then quenched with saturated NaHCO3 aqueous, extracted with dichloromethane. The organic layer is combined, dried, and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; from 20% to 70% of ethyl acetate in hexane) to provide 1.81 g (83% over 2 steps) of the title compound. M+H+=444.2
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1/[C:22](=[N:24]/O)/Cl>C1COCC1.O>[CH:7]1([C:10]2[O:16][N:24]=[C:22]([C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[O:19][C:18]([F:17])([F:30])[F:31])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: O/N=C(\Cl)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2OC(F)(F)F)noc1C1CC1

Procedure:
Potassium carbonate (11 g, 79.7 mmol, 1.09 equiv) was suspended in THF (100 mL) and the mixture was stirred. A solution of methyl 3-cyclopropyl-3-oxopropanoate (11 g, 77.5 mmol, 1.06 equiv) in 50 ml THF was added to the above stirred mixture and stirred fo(30 min at −10°C. To this reaction mixture was added a solution of (Z)-2-(trifluoromethoxy)benzoyl chloride oxime (17.6 g, 73.3 mmol, 1.00 equiv) in THF (50 mL) at −5°C. and then allowed to stir fo(6 h at 35°C. The reaction mixture was diluted with 200 mL of H2O, extracted with ethyl acetate (2×300 mL). The organic layer was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, concentrated under vacuum, and then purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100-1:20) eluent to afford methyl 5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylate as a white solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[N:20]1[NH:21][C:22](=[O:29])[N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:21]2[C:22](=[O:29])[N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=[N:20]2)=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: O=c1[nH]nc2ccccn12
Agent: Cl
Product: O=c1n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)nc2ccccn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. M/e+ 376 for C20H15 ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.68 (d, J=6.9 Hz, 1H), 8.18 (d, J=8.4 Hz, 2H), 7.80 (d, J=7.3 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.25 (m, 1H), 7.09 (dd, J=4.0, 2.9 Hz, 2H), 6.89 (m, 1H), 6.52 (m, 1H), 5.54 (s, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](I)[CH3:12]>>[CH2:11]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1])[CH3:12]
Reactant: CCI
Reactant: O=Cc1ccc(O)c(F)c1
Product: CCOc1ccc(C=O)cc1F

Procedure:
Following a similar procedure to that described in reference example 3, but starting from 3-fluoro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde and using ethyl iodide instead of 2-iodopropane, the title compound of the example was obtained as an oil (48% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:21][NH2:22])[CH2:18][CH2:17][O:16][C:15]([CH3:20])([CH3:19])[CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:40])([F:39])[C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])[N:26]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:21][NH:22][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][CH:38]=[C:30]([C:27]5[N:26]=[C:25]([C:24]([F:40])([F:39])[F:23])[O:29][N:28]=5)[CH:31]=4)[CH2:18][CH2:17][O:16][C:15]([CH3:19])([CH3:20])[CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(CN)(c2nc(-c3ccc(F)cc3)cs2)CCO1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC1(C)CC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2nc(-c3ccc(F)cc3)cs2)CCO1
Yield: 17 %

Procedure:
This compound was synthesized from (4-(4-(4-fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (7 mg, yield 17%): 1H NMR (500 MHz, CD3OD) δ 8.41 (t, J=1 Hz, 1H), 8.23 (d, J=4 Hz, 1H), 7.96-7.90 (m, 3H), 7.76 (s, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.69-7.04 (t, J=8.8 Hz, 2H), 3.88 (m, 2H), 3.60 (s, 2H), 2.52 (m, 2H), 1.95 (m, 2H), 1.29 (s, 3H), 0.81 (s, 3H). MS (ESI) m/z: Calculated for C27H24F4N4O3S: 560.15. found: 561.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cccc2cccnc12
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a stirred solution of 100 mg (0.348 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (pal Piaz, V et al., J. Med. Chem. 1997, 40, 1417) in 5 ml of ethanol, 75 mg (0.522 mmol) of 8-aminoquinoline was added. The resulting mixture was stirred at room temperature for two hours and the final product was collected by filtration and washed with diethylether to yield the title compound (100 mg, 74.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[NH:13][C:12](=O)[C:11]3=[CH:15][CH:16]=[CH:17][N:10]3[N:9]=2)[CH:7]=1.P(Cl)(Cl)([Cl:21])=O.CN(C)C1C=CC=CC=1>>[Cl:21][C:12]1[C:11]2=[CH:15][CH:16]=[CH:17][N:10]2[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:18])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2cc(Cl)ccc2F)nn2cccc12
Solvent: CN(C)c1ccccc1
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2cccn2n1
Temperature: 110 °C
Yield: 56 %

Procedure:
2-(5-Chloro-2-fluoro-phenyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (60 mg, 0.228 mmole) was added to phosphorous oxychloride (1 ml). Added 57 microliters N,N-dimethylaniline (catalyst) and heated to 110° C. overnight. Removed excess phosphorous oxychloride under vacuum, residue treated with ice, and product extracted with chloroform. Dried chloroform extract over sodium sulfate (anh.) and removed solvent to give crude product. Product was purified by silica gel chromatography eluted with chloroform to give 36 mg product (yield: 56%).
Reaction SMILES: [CH:1]([C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](O)=[O:6])=O.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=[C:4]2[C:3]=1[CH:1]=[N:17][NH:18][C:5]2=[O:6]
Reactant: NN
Reactant: COc1cc(OC)c(C=O)c(C(=O)O)c1
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c2cn[nH]c(=O)c2c1
Yield: 86 %

Procedure:
The 2-formyl-3,5-dimethoxybenzoic acid (2.7 g, 13 mmol) is partially dissolved in 300 mL of ethanol, and 6.2 mL of hydrazine hydrate are then added. The mixture is refluxed for 6 hours. After cooling, the precipitate formed is filtered off and then dried. 2.3 g of a white solid are obtained (86% yield).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[N:13]1([C@H:11]2[CH2:12][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:26]5[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:10]2)[CH2:15][CH2:16][CH2:17]1
Reactant: COc1ncc(B(O)O)cn1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 61A for the product of Example 1E, and substituting 2-methoxypyrimidine-5-boronic acid (Frontier Scientific, Inc., Logan, Utah, USA) for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.07 (d, J=8.48 Hz, 1H) 7.97 (d, J=2.03 Hz, 1H) 7.59 (dd, J=8.48, 2.03 Hz, 1H) 4.08 (s, 3H) 3.93-4.06 (m, 1H) 3.18-3.34 (m, 5 H) 2.49-2.61 (m, 1H) 2.34-2.47 (m, 3H) 2.03-2.19 (m, 2H). MS: (M+H)+=353.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.II.[I:22](O)(=O)(=O)=O>C(O)(=O)C.O>[I:22][C:14]1[CH:13]=[CH:12][C:11]2[C:10]3[C:18](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:17](=[O:19])[C:16]=2[CH:15]=1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2-c2ccc(I)cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 266.6 %

Procedure:
Add acetic acid (45 mL), concentrated sulfuric acid (5.4 grams, 0.055 moles), water (10 mL), 9-fluoreneone (9.01 grams, 0.05 moles), iodine (6.0 grams, 0.0237 moles), and periodic acid (2.85 grams, 0.0125 moles) to a 250 mL, 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Heat the reaction mixture to 45° C. and stir 1 hour, then warm to 50° C. and stir an additional 2.5 hrs. Warm the mixture to 60° C. and add additional acetic acid (45 mL). Stir the reaction mixture for an additional 10 hours, cool to room temperature and stir the reaction mixture at room temperature for about 8 hours. Collect the precipitate by filtration. Transfer the filter cake and acetic acid (40 mL) to a 250 mL, 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Heat the mixture to 70° C. and add additional acetic acid with continued warming until a clear solution is observed. Reduce the reaction mixture to 50° C. and stir at 50° C. for 2 hours. Slowly cool the reaction mixture to 25° C. and stir 1 hour. Recover the precipitate by vacuum filtration. Air-dried the resulting filter cake to provide the title compound (10.2 g, 66.6% yield). 1H NMR (CDCl3, 500.0 MHz): δ 7.95 (d, 1H, J=1.5); 7.81 (dd, 1H, J=2, 8); 7.64 (d, 1H, J=7.5); 7.50 (m, 2H); 7.33-7.24 (m, 2H).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][CH:17]([CH3:23])[C:18]#[C:19][C:20](O)=[O:21].[CH2:24]([NH2:36])[CH2:25][C:26]1[CH:35]=[CH:34][C:31]([O:32][CH3:33])=[C:28]([O:29][CH3:30])[CH:27]=1>O1CCCC1>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][NH:36][C:20](=[O:21])[C:19]#[C:18][CH:17]([CH3:23])[CH3:16])[CH:35]=[CH:34][C:31]=1[O:32][CH3:33]
Reactant: CC(C)C#CC(=O)O
Reactant: COc1ccc(CCN)cc1OC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(CCNC(=O)C#CC(C)C)cc1OC
Temperature: 22.5 °C
Reaction time: 48 h
Yield: 62.9 %

Procedure:
38.2 g (280 mmol) of isobutyl chloroformate were added dropwise at 0 to 5° C., as well as 28.3 g (280 mmol) of N-methylmorpholine at 5 to 15° C., to a solution of 28.4 g (254 mmol) of 4-methyl-2-pentynoic acid (ex. 3) in 100 ml of tetrahydrofuran (THF). 46 g (254 mmol) of homoveratrylamine were subsequently added dropwise while cooling with ice and the mixture was allowed to stir at 20 to 25° C. for 48 hours. The reaction solution was then concentrated and the residue was poured into water/10% hydrochloric acid solution and extracted with MTBE. After drying, distilling off the volatile components and chromatographing on silica gel (cyclohexane:MTBE [3:1]), 44 g of the title compound were obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1)=S.ICC.[H-].[Na+].[N:28]#[C:29][NH2:30]>O1CCCC1>[C:29]([NH:30][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:6]=1)=[N:2][CH3:1])#[N:28]
Reactant: N#CN
Reactant: CNC(=S)C1=CC2(CCCCC2)Oc2ccc([N+](=O)[O-])cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Product: CN=C(NC#N)C1=CC2(CCCCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a mixture of 120 mg of N-methyl-6-nitro-spiro[2H-1benzopyran-2,1'-cyclohexane]-4-carbothioamide, 150 μl of iodoethane, and 3 ml of dried tetrahydrofuran was added 23 mg of sodium hydride (60%) with stirring and cooling with ice followed by refluxlng for 2 hours. After cooling to room temperature, 80 mg of cyanamide and 17 mg of sodium hydride (60%) were added thereto, followed by refluxing for 4 hours. Ice-water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (developing solution: ethyl acetate:hexane=2:3) recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 90 mg of N-cyano-N'-methyl-6-nitrospiro[2H-1-benzopyran-2,1'-cyclohexane]-4-carboxamidine having formula shown below.
Reaction SMILES: C([O:4][CH:5]([CH2:21][CH2:22][S:23]([CH3:25])=[O:24])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])(=O)C.[OH-].[Na+]>CO.ClCCl>[CH2:9]([NH:8][C:6](=[O:7])[CH:5]([OH:4])[CH2:21][CH2:22][S:23]([CH3:25])=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCNC(=O)C(CCS(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of 1-(dodecylamino)-4-(methylsulfinyl)-1-oxobutan-2-yl acetate (25 g, 62.6 mmol) in methanol (350 mL) was added 2.5 N NaOH (40 mL, 100 mmol) and the resulting solution was stirred at room temperature for 5 hrs. The reaction was quenched with concentrated HCL (12.5 mL) and then evaporated to a small volume. The resulting mixture was treated with EtOAc (200 mL) and then washed with 1N HCl (150 mL), saturated sodium bicarbonate (50 mL), dried over magnesium sulfate, filtered and evaporated to give a solid. The solid was dissolved in dichloromethane and purified by silica gel chromatography with 0-10% methanol/dichloromethane. The desired fractions were collected and evaporated to give a white solid (16.7 g, 80%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.85 (t, J=6.83 Hz, 3 H) 1.15-1.33 (m, 18 H) 1.33-1.46 (m, 2 H) 1.72-1.87 (m, 1 H) 1.92-2.09 (m, 1 H) 2.51 (d, J=1.27 Hz, 3 H) 2.56-2.87 (m, 2 H) 3.00-3.12 (m, 2 H) 3.90-4.00 (m, 1 H) 5.69 (d, J=5.40 Hz, 1 H) 7.71-7.82 (m, 1 H). m/z 334 (MH+).