Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[CH:13](=[N:11][NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=Cc1ccccc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 93.0 g (0.5 mol) of p-toluenesulfonohydrazide and 700 ml of methanol, and 63.6 g (0.6 mol) of benzaldehyde was dropwise added thereto in one hour while stirring at room temperature and heated under reflux for about 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[OH:7].S(=O)(=O)(O)O>>[N:11]1[CH:12]=[CH:13][C:8]([CH:6]2[O:7][CH2:2][CH2:3][NH:4][CH2:5]2)=[CH:9][CH:10]=1
Reactant: OCCNCC(O)c1ccncc1
Agent: O=S(=O)(O)O
Product: c1cc(C2CNCCO2)ccn1

Procedure:
2-(Pyridin-4-yl)morpholine is prepared by treating 2-(2-hydroxyethylamino)-1-(pyridin-4-yl)ethanol with fuming sulfuric acid at 170° C. according to F. Zymalkowski and F. Koppe (Arch. Pharmaz. 1961, 294, 453-468).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:48]/[O:49]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:12]([NH:14][C@@H:15]2[C:46](=[O:47])[N:17]3[C:18]([C:30]([O:32]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:31])=[C:19]([S:22][CH2:23][C:24]4[S:28][N:27]=[N:26][C:25]=4[CH3:29])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:48]/[OH:49])/[C:12]([NH:14][C@@H:15]2[C:46](=[O:47])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([S:22][CH2:23][C:24]4[S:28][N:27]=[N:26][C:25]=4[CH3:29])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: Cc1nnsc1CSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: Cc1nnsc1CSC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 10.4 %

Procedure:
Under N2 atmosphere, a solution of aluminum chloride (1.88 g, 14.05 m mol) in anisole (4.5 ml) was added slowly to a solution of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(4-methyl-1,2,3-thiadiazol-5-yl)methylthio]-3-cephem-4-carboxylate (2.60 g, 2.81 m mol) in anisole (4.5 ml) and nitromethane (18 ml) at −30˜20° C. After the mixture was stirred for 1 hour at the same temperature, the reaction was quenched with 1N hydrochloric acid (18 ml), and poured into water/ethyl acetate. The aqueous layer was separated, and the organic layer was reextracted with water. The combined aqueous layer was concentrated in vacuo, chromatographed on a HP-20 column (eluent: water-methanol). After concentration, the resulting precipitate was collected by filtration, and dried in vacuo to afford 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(4-methyl-1,2,3-thiadiazol-5-yl)methylthio]-3-cephem-4-carboxylic acid (150.8 mg).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:9](=[O:26])[N:10]([C:22]([CH3:25])([CH3:24])[CH3:23])[N:11]=[CH:12][C:13]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(Cl)Cl.O>[C:27]1([S:33]([NH:7][C:8]2[C:9](=[O:26])[N:10]([C:22]([CH3:23])([CH3:25])[CH3:24])[N:11]=[CH:12][C:13]=2[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)n1ncc(NCc2ccncc2)c(N)c1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(NS(=O)(=O)c2ccccc2)c1=O
Reaction time: 0.33 h

Procedure:
Into 6 ml of a pyridine solution of 0.55 g of 4-amino-2-tert-butyl-5-(4-pyridylmethylamino)pyridazin-3-(2H)-one, 0.36 g of benzenesulfonyl chloride was dropwise added at room temperature. The mixture was reacted overnight, and 80 ml of water and 100 ml of methylene chloride were added to the system. The mixture was adjusted to pH4 with dilute hydrochloric acid under cooling with ice, and then stirred for 20 minutes. The organic layer was dried over anhydrous sodium sulfate and then concentrated. To the residue, 4 ml of ethyl acetate was added, and the mixture was mashed, whereupon crystals were collected by filtration. The obtained crystals were subjected to column chromatography, and using an eluent (n-hexane:ethyl acetate=1:5), 0.30 g of the desired product (Compound No. 32) having a melting point of from 189° to 190° C., was obtained.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]([NH:13]C(=O)C(F)(F)F)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([O:4][CH2:5][C@@H:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:13])[CH:2]=[CH2:3]
Reactant: C=CCOC[C@H](NC(=O)C(F)(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=CCOC[C@H](N)c1ccccc1
Yield: 54.4 %

Procedure:
Step Q (3): (R)-N-(2-(Allyloxy)-1-phenylethyl)-2,2,2-trifluoroacetamide (3.0 g, 11.0 mmol) from step Q (2), potassium carbonate (7.59 g, 55 mmol), methanol (300 mL) and H2O (20 mL) were heated to reflux for 16 h. The mixture was concentrated in vacuo. Water was added, and the aqueous layer was repeatedly extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford 1.06 g (54% yield) of (R)-2-(allyloxy)-1-phenylethanamine as a yellow oil. The crude mixture was used without further purification. LC-MS (M+H)+=178.18. 1H NMR (300 MHz, CDCl3) δ ppm 2.02 (s, 2H) 3.38 (t, J=9.15 Hz, 1H) 3.48-3.63 (m, 1H) 3.99 (d, J=5.49 Hz, 2H) 4.19 (dd, J=9.15, 3.66 Hz, 1H) 5.05-5.31 (m, 2H) 5.74-5.99 (m, 1H) 7.15-7.42 (m, 5H).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([CH2:31][O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:12][O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.[Pd]>[Si:14]([O:13][CH2:12][CH:11]([NH2:10])[CH2:31][O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](OCC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](OCC(N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Yield: 84.3 %

Procedure:
A solution of [2-(t-butyldiphenylsilyloxy)-1-(t-butyldiphenylsilyloxymethyl)ethyl]carbamic acid benzyl ester (13.6 g, 19.5 mmol) (obtained as described in Reference Example 39(2)) in methanol (410 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (13.6 g) at room temperature for 3.5 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (98:2→9:1) as the eluant to afford 2-(t-butyldiphenylsilyloxy)-1-(t-butyldiphenylsilyloxymethyl)ethylamine (9.34 g, yield 84%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16](=O)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH2:25]([SH:28])[CH2:26][SH:27].B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([S:28][CH2:25][CH2:26][S:27]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:12])=[O:11]
Reactant: SCCS
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)SCCS2
Yield: 266.3 %

Procedure:
100 mg (0.27 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 1 ml of dichloromethane and 0.034 ml (0.405 mmol) of ethane-1,2-dithiol and 0.025 ml (0.203 mmol) of boron trifluoride diethyl etherate were added thereto with stirring under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction solution was added a 1N aqueous sodium hydroxide solution and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resulting solid was washed with diethyl ether and then with hexane to give 325 mg of the title compound as a white powder (76% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].CN1CCOCC1.[Cl:40][CH2:41][C:42](Cl)=[O:43]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N:21]([CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)[C:42](=[O:43])[CH2:41][Cl:40])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NCc3cccc4ccccc34)ccc21
Reactant: O=C(Cl)CCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N(Cc3cccc4ccccc34)C(=O)CCl)ccc21
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4.0 g (9.6 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-1-methyl-5-naphth-1-ylmethylamino-benzimidazole and 1.1 mL (10.0 mmol) of N-methylmorpholine in 80 ml of dichloromethane was cooled to 10° C. A solution of 0.8 mL (10.0 mmol) of chloroacetylchloride in 15 ml of dichloromethane was added dropwise to the solution within 15 min. The mixture was then stirred for 30 min at ambient temperature. It was washed with water and dilute potassium carbonate solution, dried and concentrated by evaporation. The product is chromatographed on silica gel.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[C:32]([C:36]1[S:37][CH:38]=[C:39](/[CH:41]=[CH:42]/[C:43]2[C:44]([OH:54])=[N:45][N:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:47]=2)[N:40]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([C:36]1[S:37][CH:38]=[C:39](/[CH:41]=[CH:42]/[C:43]2[C:44]([O:54][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:45][N:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:47]=2)[N:40]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CC(C)(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(C(C)(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.49 g), 4-[(E)-2-(2-tert-butyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (1.32 g), potassium carbonate (1.00 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (1.11 g, yield 45%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C.O=P(Cl)(Cl)Cl>CC#N>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1

Procedure:
trans-Methyl 4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)-cyclohexane carboxylate (29.00 g, 93.02 mmol) was dissolved in anhydrous MeCN (930 mL), anhydrous DMF (9 mL) and POCl3 (10.4 mL, 110 mmol) and heated at 55° C. under nitrogen for 3 h. The reaction mixture was concentrated in vacuo, then, the solid residue was taken up in DCM, then, basified to pH 10 with 2M ammonia in isopropanol. The mixture was concentrated in vacuo, re-dissolved in DCM, and then loaded onto TEA-basified silica gel. The crude product was purified by a silica gel column chromatography (eluted with 2:3 EtOAc/DCM) to obtain the title compound as a yellow powder; 1H NMR (CDCl3, 400 MHz) δ 1.63 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.85 (ddd, J=13.2, 13.2, 13.2, 2.8 Hz, 2H), 2.10 (dd, J=14.4, 3.2 Hz, 2H), 2.19 (dd, J=14.0, 3.2 Hz, 2H), 2.46 (tt, J=12.4, 3.6 Hz, 1H), 2.96 (tt, J=11.6, 3.2 Hz, 1H), 3.70 (s, 3H), 7.33 (dd, J=5.2, 1.2 Hz, 1H), 7.61 (d, J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 294.17/296.14 (100/86) [MH+]. HPLC: tR=2.85 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl.[C:2]1([NH:8][C:9](=[O:12])[NH:10][NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13](=[C:15]1[C:23](=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[OH:14]>O.C(O)C>[N:13](=[C:15]1[C:16](=[O:25])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]1=[N:11][NH:10][C:9]([NH:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:12])[OH:14]
Reactant: O=c1c(=NO)c(=O)c2ccccc12
Reactant: NNC(=O)Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(NN=c1c(=NO)c(=O)c2ccccc12)Nc1ccccc1

Procedure:
0.01 mol of 4-phenyl semicarbazide hydrochloride in solution in 10 ml water was added to a solution of 0.01 mol of 2-oximino indan-1,3-dione in 60 ml ethanol. The reaction mixture was refluxed for 1 hour. The precipitate formed was centrifuged when hot, dried and recrystallised from acetonitrile.
Reaction SMILES: [NH2:1][C:2](N)=[O:3].[C:5](=[O:8])([O-:7])[O-:6].[Na+:9].[Na+]>>[O-:3][C:2]#[N:1].[Na+:9].[C:5](=[O:6])([O-:8])[O-:7].[Na+:9].[Na+:9]
Reactant: NC(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#C[O-]

Procedure:
The following series of tests was carried out in a static bed, i.e. without continuous mixing of the reactants. Urea and sodium carbonate were reacted in a molar ratio of 1.7:1 to form an intermediate sodium cyanate-sodium carbonate mixture having the composition 75.0% NaCNO and 21.2% Na2CO3. Various amounts of water were added to samples of this mixture on a weight percent basis, the water was thoroughly mixed with the sample, and all were dried in a forced air oven at 110°-140° C. After cooling, additional urea was mixed into each sample and the components were ground together in a mortar. The samples were then heated to 150°-160° C and held at that temperature overnight (16-18 hours). The sodium cyanate content was determined, and the results are summarized in the following table.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.[C:10]12[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:15][C:14](=[O:21])[O:13][C:11]2=[O:12].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>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=3[C:11](=[O:12])[O:13][C:14]2=[O:21])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(CO)ccn1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-aminopyridine-4-methanol (commercially available from CB Research, 25.05 g, 201.79 mmol), isatoic anhydride (32.91 g/201.74 mmol), and triphenylphosphine (52.92 g/201.76 mmol) in THF (400 ml) at 20° C. was added diisopropyl azodicarboxylate (40.8 g/201.77 mmol) drop-wise. The reaction mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C. and the precipitated material was isolated by filtration and washed with a small amount of THF, to afford the title compound as a yellow solid material (18.93 g). The filtrate was evaporated under reduced pressure. To the residual oil was added dichloromethane. The resulting precipitate was isolated by filtration affording more product (1.21 g). The filtrate was extracted with 0.1M HClaq., and the pH of the aqueous layer was adjusted to ca. 7-8 with aqueous sodium bicarbonate, then extracted with EtOAc. The organic layer was evaporated under reduced pressure, and the resulting solid material was suspended in THF (100 ml). The solid material was isolated by filtration to yield more product (9.10 g). The filtrate was concentrated to ca. 45 ml, affording more precipitate and an additional amount of the title compound (1.77 g) after filtration and drying under vacuum. 13C-NMR (DMSO-d6) δ 160.0, 158.7, 148.1, 148.0, 145.0, 141.2, 137.1, 129.5, 123.8, 115.0, 111.7, 109.9, 104.5, 46.8.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH2:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]([N:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]([C:23]1[CH:22]=[C:21]([NH:20][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C:4]2([C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[NH:11][C:3]2=[O:2])[CH2:19]3)[N:26]=[CH:25][N:24]=1)=[O:28])[CH3:31]
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: CCNc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)c1ccccc1

Procedure:
100 mg (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 34 μL (0.24 mmol) N-ethylaniline, 0.10 mL (0.72 mmol) TEA and 85 mg (0.27 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Yield: 83.6 %

Procedure:
At 100° C., 167.0 g of 4-hydroxy-3-nitrobenzaldehyde, 311.0 g of potassium carbonate, and 211.0 g of benzyl chloride are agitated in 2 l of dimethylformamide for 16 hours. The resultant reaction mixture is poured into 10 l of water, the thus-separated solid product is filtered off and recrystallized from ethanol, yielding 215.0 g of 4-benzyloxy-3-nitrobenzaldehyde, mp 100°-102° C.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:31]([F:34])([F:33])[F:32])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([O:29]C)=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.CO>O.O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:31]([F:33])([F:32])[F:34])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([OH:29])=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of lithium hydroxide monohydrate (350 mg, 8.34 mmol) in water (10 mL) was added to a stirred solution of methyl 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxylate (i.e. the product of Step B, 650 mg, 1.39 mmol) in tetrahydrofuran (10 mL), followed by the addition of methanol (10 mL). The resulting mixture was stirred overnight at room temperature and then partitioned between water and diethyl ether. The aqueous layer was acidified with 6 N aqueous hydrochloric acid to pH 2 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound as a white solid (450 mg). 1H NMR (CDCl3): δ 9.08 (d, 1H), 8.80 (d, 1H), 8.31 (d, 1H), 7.71 (m, 2H), 7.57 (m, 3H), 7.46 (dd, 1H), 4.28 (d, 1H), 3.91 (d, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].FC(F)(F)S(O)(=O)=O>ClC(Cl)(Cl)C(=N)OCC#CC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:2][C:1]#[C:3][CH3:4])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CC#CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CC#CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4",3"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylene chloride in cyclohexane) is added 2-butynyl trichloroacetimidate (20 μl neat) and the reagents are allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) is added slowly via syringe and the mixture stirred at room temperature. After 16 hours the reaction is quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics are washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel gives the title compound.