Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH3:35])=[S:47])=[C:29]([F:34])[CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: COc1ccccc1C(=O)Cl
Agent: COc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4OC)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
2-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (56 mg, yield 70%).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[C:15]([OH:17])=O)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=O.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:5]=2[C:15]2[O:17][C:22]([C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[O:19][CH3:18])=[N:24][N:25]=2)[CH2:2][CH2:3]1
Reactant: COc1ccccc1C(=O)NN
Reactant: O=C(O)c1c(-c2ccccc2)noc1C1CC1
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Reaction time: 18 h
Yield: 32.7 %

Procedure:
To a suspension of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid (236 mg, 1.03 mmol) in dichloromethane (2 mL) were added 2-methoxybenzhydrazide (205 mg, 1.24 mmol), 2-chloro-1,3-dimethylimidazolium chloride (383 mg, 2.26 mmol) and triethylamine (0.52 ml, 5.15 mmol) at ambient temperature. The resulting suspension was stirred for 18 h at this temperature before diluting with dichloromethane (20 ml) and washing with water (20 mL) and brine (20 mL). The aqueous layers were extracted with dichloromethane and the combined organic layers dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (121 mg, 33%) as a white solid. MS: m/e=360.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[CH2:24]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])[CH3:25].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH2:24]([O:26][C:27]([CH2:28][CH2:29][NH:30][C:12](=[O:14])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:31])[CH3:25]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-amino benzoic acid (5.0 g, 36.5 mmol) in THF (250 ml)/DCM (250 ml) was cooled to 0° C. and treated with triphosgene (3.79 g, 12.76 mmol) followed by TEA (12.70 ml, 91 mmol). After 5 min, a suspension of beta-alanine ethyl ester hydrochloride (11.20 g, 72.9 mmol) and TEA (12.70 ml, 91.00 mmol) in THF (10 ml)/DCM (10 ml) were added and the resulting mixture was allowed to warm to RT and stirred overnight. The reaction mixture was diluted with DCM (100 ml) and the pH was adjusted to 8 by addition of sat. aq. NaHCO3. The mixture was extracted with water (2×250 ml). The combined aqueous extracts were acidified to pH 1 by addition of 2N HCl, extracted with DCM and the combined organic portions were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title product as an off-white solid; LC-MS Rt 0.84 mins; 281.2 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[CH:13]1[C:18]([O:19][CH2:20][CH2:21][OH:22])=[CH:17][CH:16]=[C:15]([O:23][CH2:24]CO)[CH:14]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:22][CH2:21][CH2:20][O:19][C:18]1[CH:13]=[CH:14][C:15]([O:23][CH2:24][CH2:1][O:2][C:3](=[O:12])[C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: OCCOc1ccc(OCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(OCCOc1ccc(OCCO)cc1)c1ccc(O)c(Cl)c1
Temperature: 0 °C
Yield: 94.1 %

Procedure:
A 300-ml eggplant type flask was charged with 16.3 g of 3-chloro-4-hydroxybenzoic acid methyl ester, 87 g of 1,4-(2-hydroxyethoxy)benzene and further with 0.8 g of PTD (p-toluenesulfonic acid monohydrate) as a catalyst to form a mixture. The mixture was stirred with heating on an oil bath, externally regulated at a temperature of 150° C., to react the mixture for 5 hours. The reaction mixture was poured into ice water followed by extracting with ethyl acetate, drying over anhydrous magnesium sulfate, concentrating and separating with a column using ethylacetate/n-hexane to obtain 29 g of 3-chloro-4-hydroxybenzoic acid 2-[4-(β-hydroxyethoxy)-phenoxy]ethyl ester (melting point: 87° to 88° C.). To 50 ml of an acetonitrile solution containing 10 g of the 3-chloro-4-hydroxybenzoic acid 2-[4-(β-hydroxyethoxy)-phenoxy]ethyl ester, 13.9 g of N-methylpyrrolidone and further 8.78 g of methacrylic acid chloride were added with stirring to form a solution. The solution was stirred at 40° C. for 8 hours to react the solution. Thereafter, excess methacrylic acid chloride was removed by means of vacuum distillation. The reaction mixture remaining therein was poured into ice water and the precipitated crystals were obtained by filtration. The crystals were recrystallized with ethylacetate/n-hexane to obtain 3-chloro-4-hydroxybenzoic acid 2-[4-(β-methacryloyloxyethoxy)phenoxy]ethyl ester (melting point: 105° to 106° C.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:26])=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(N(CC)CC)C.[C:34]1([C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37](Br)[O:36]1)=[O:35].O>CN(C)C=O>[C:34]1([C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]([O:19][C:18]([C:14]2[N:13]3[C:21](=[O:22])[C@@H:11]([NH:10][C:8](=[O:9])[C:7]([C:5]4[N:6]=[C:2]([NH2:1])[S:3][C:4]=4[Cl:26])=[N:23][O:24][CH3:25])[C@H:12]3[S:17][CH2:16][CH:15]=2)=[O:20])[O:36]1)=[O:35]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Cl
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC3OC(=O)c4ccccc43)=CCS[C@H]12)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a solution of 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (209 mg) in N,N-dimethylformamide (5 ml) are added triethylamine (0.07 ml) and phthalidyl bromide (128 mg), and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is poured into water and the separated precipitate is collected by filtration. The solid material is dissolved in ethyl acetate, washed with water, diluted aqueous sodium hydrogen carbonate solution, water, diluted aqueous phosphoric acid and water, dried, and evaporated. Purification of the residue by silica gel column chromatography gives 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid phthalidyl ester (220 mg).
Reaction SMILES: ClC([O:4][CH2:5]C(C)C)=O.C(Cl)(=O)C(C)(C)C.[C:16]1(C)[CH:21]=[CH:20][C:19]([S:22](Cl)(=O)=O)=[CH:18][CH:17]=1.[N+:27](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O>>[OH:4][C:5]1[S:22][C:19]2[CH:20]=[CH:21][CH:16]=[CH:17][C:18]=2[N:27]=1
Reactant: CC(C)COC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)C(=O)Cl
Product: Oc1nc2ccccc2s1

Procedure:
An example of a mixed anhydride is that of isobutyl chloroformate and pivaloyl chloride and carboxylic-sulfonic mixed anhydrides formed for example with p-toluenesulfonyl chloride. As an example of an activated ester, the ester formed with 2,4-dinitrophenol and the one formed with hydroxybenzothiazole may be mentioned.
Reaction SMILES: C(O)(=O)C.C(O)C.[Cl:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([C:18]2[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[N:20]([CH3:31])[N:19]=2)=[C:11]([F:32])[CH:10]=1>[Fe].C(OCC)(=O)C>[NH2:15][C:14]1[C:9]([Cl:8])=[CH:10][C:11]([F:32])=[C:12]([C:18]2[C:22]([C:23]([F:24])([F:25])[F:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[N:20]([CH3:31])[N:19]=2)[CH:13]=1
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Agent: [Fe]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(N)c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Reaction time: 2 h
Yield: 22 %

Procedure:
4,6 g (83 mmol) of iron powder, 14 ml of glacial acetic acid and 30 ml of ethanol were heated to 70-75° C. and the mixture was treated with 7 g (17 mmol) of 3-(4-chloro-2-fluoro-5-nitrophenyl)-l-methyl-4,5-di(trifluoromethyl)-1H-pyrazole. After the mixture had been stirred for 2 hours at reflux temperature, it was treated with 100 ml of ethyl acetate. The mixture was then filtered through kieselguhr, whereupon the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and finally concentrated. The residue was purified by means of silica gel chromatography (eluent: hexane/ethyl acetate=4:1). Yield: 22%.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8]>CCO>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](C(=O)OC(C)(C)C)CC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrazine hydrate (0.59 mL, 12.2 mmol) was added in one portion to a stirred mixture of tert-butyl trans-4-(4-{[methoxy(oxo)acetyl]amino}phenyl)cyclohexanecarboxylate (4.0 g, 11.1 mmol) in EtOH (50 mL) and the reaction mixture was stirred at room temperature for 3 h. EtOH (25 mL) was added and the mixture was filtered to give the title compound (Intermediate 79) (3.7 g, 92%) as a solid; 1H NMR δ 1.4 (9H, s), 1.4-1.5 (4H, m), 1.8-1.9 (2H, m), 1.9-2.0 (2H, m), 2.15-2.3 (1H, m), 2.4-2.55 (1H, m), 4.5 (1H, s), 4.6 (2H, s), 7.2 (2H, d), 7.7 (2H, d), 10.45 (1H, s); MS m/e (M−H)− 360.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[C:18]1[C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:20][C:21]2[C:26]([N:27]=1)=[CH:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=2.CCN(C(C)C)C(C)C>CN(C=O)C>[C:32]1([C:19]2[C:18]([N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=4)[CH2:14][CH2:13]3)=[N:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=3)[N:20]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A solution of 4-(4-(trifluoromethyl)phenyl)piperidine (200 mg, 0.87 mmol, 2.00 equiv), methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), and DIEA (169 mg, 1.31 mmol, 3.00 equiv) in DMF (10 mL) was placed in a 20-mL sealed tube and stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum and purified via silica gel column (ethyl acetate/petroleum ether (1:20)), yielding 180 mg (84%) of methyl 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].N>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(OCc2ccccc2)ccc1N
Yield: 34.4 %

Procedure:
A solution of 4-benzyloxy-2-methyl nitrobenzene (6.4 mmol, 1.5 g) and sodium hydrosulfite (16 mmol, 2.2 g) in 140 mL of MeOH/water (2:1) was refluxed for two hours. Upon cooling, the solution was poured into 500 mL of aqueous ammonia and the product extracted into CH2Cl2 (4×). The organic layer was washed with water, brine and dried over Na2SO4, filtered and concentrated to provide 4-benzyloxy-2-methylaniline (0.47 g, 51%) as a light brown oil. 1H NMR (300 MHz, CDCl3) δ:7.4 (m, 5 H), 6.76 (d, J=2.1 Hz, 1 H), 6.70 (dd, J=7.2, 2.1 Hz, 1 H), 6.61 (d, J=7.2 Hz, 1 H), 4.98 (s, 2 H), 2.15 (s, 3 H).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:19]1([C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Yield: 103.5 %

Procedure:
To a solution of 10.6 g (65.1 mmol) of 4-piperidone monohydrate hydrochloride and 20.0 g (198 mmol) of triethylamine in 150 ml of dimethylformamide, 18.1 g (65.1 mmol) of chlorotriphenylmethane were added at 60° C. in portions under stirring, followed by stirring for further 5 hours at the same temperature. After cooling, the triethylamine hydrochloride thus precipitated was filtered off and the filtrate was concentrated by evaporation under reduced pressure. To the residue, 150 ml of water were added and the resulting mixture was extracted with 300 ml of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was concentrated by evaporation under reduced pressure, whereby 23.0 g (yield: 98.3%) of 1-triphenylmethyl-4-piperidone were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH2:11][CH:12]([OH:17])[CH2:13][CH:14]=[CH:15][CH3:16].[Br:18]N1C(=O)CCC1=O>C(Cl)Cl>[Br:18][CH2:16][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10][C:4]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:17]1
Reactant: CC=CCC(O)CCc1cc(F)ccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1ccc(F)cc1CCC1CCC(CBr)O1
Temperature: 25 °C

Procedure:
To a solution of 1-(2′-methoxy-5′-fluorophenyl)hept-5-en-3-ol (3.5 g, 14.7 mmol) in dry CH2Cl2 (90 mL) at 0° C. was added N-bromosuccinimide (NBS, 3.15 g, 17.0 mmol) portionwise and the reaction was warmed to room temperature for 12 h. Solvent was then removed in vacuo and the residue was purified by flash column chromatography (5% EtOAc in Hexane, Rf=0.12) to result in the trans isomer (2.05 g, 44%) as an oil; and the cis isomer (743 mg, 16%) as an oil; and mixture of both isomers (1.35 g, 29%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[OH:25][CH:26]([CH2:29][OH:30])[CH2:27][NH2:28].CO>O1CCOCC1.O>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([NH:28][CH2:27][CH:26]([OH:25])[CH2:29][OH:30])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: NCC(O)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride (12.0 g, 0.020 mol) was dissolved in 10 ml of dioxane and sodium carbonate (2.1 g, 0.020 mol) was added. To this solution was added a solution of 2,3-dihydroxypropylamine (1.8 g, 0.020 mol) dissolved in 15 ml of dioxane. The mixture was heated to reflux for 10 h. After cooling to room temperature, methanol (25 ml), strongly acidic ion exchange resin (Amberlyst 15, 50 g) and water (25 ml) were added to bring the pH to 3 to 4. After stirring at room temperature for 20 min, the resin was filtered off and the filtrate was evaporated to dryness. The semisolid dark crude product (12.6 g) was acetylated directly in the next step.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:8]=2)[N:6]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccc(I)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(I)cc2c1O
Temperature: 25 °C

Procedure:
4-Iodoaniline (8.60 g) and diethyl ethoxymethylenemalonate (7.90 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 60 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid is filtered, washed with hexanes, and dried to yield 11.20 g of ethyl 4-hydroxy-6-iodoquinoline-3-carboxylate. A mixture of this ester (0.58 g) and 4-chlorobenzylamine (4.0 mL) are heated at 180° C. for 1.5 hours. The reaction is cooled and poured into 50 mL diethyl ether. The resulting solid is filtered, triturated in ethyl acetate, and filtered again to give the desired product (0.50 g).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12](=[N:18]O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)C(C)C)(C)C.O>ClCCl>[CH2:7]([C:8]1[O:9][N:18]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
2-phenyl acetyl chloride (1.0 mL; 7.57 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (15 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.308 g (35%) of the title compound as a white solid.
Reaction SMILES: C[C@H]1COCCN1.[CH3:8][C@H:9]1[CH2:14][O:13][CH2:12][CH2:11][N:10]1[C:15]1[C:16]2[CH2:33][CH2:32][NH:31][CH2:30][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[N:20]=1.C[C@H]1COCCN1C1C2[CH2:58][NH:57][CH2:56][C:43]=2[N:44]=C(C2C=CC([N+]([O-])=O)=CC=2)N=1.[CH2:59]([N:62]=[C:63]=[O:64])[CH2:60]C.C(N=C=O)C>>[CH2:59]([NH:62][C:63]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:20]=[C:15]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][C@@H:9]3[CH3:8])[C:16]3[CH2:33][N:31]([C:32]4[N:57]([CH3:58])[CH:56]=[CH:43][N:44]=4)[CH2:30][C:17]=3[N:18]=2)=[CH:22][CH:23]=1)=[O:64])[CH3:60]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc([N+](=O)[O-])cc2)nc2c1CCNC2
Reactant: C[C@H]1COCCN1c1nc(-c2ccc([N+](=O)[O-])cc2)nc2c1CNC2
Reactant: CCCN=C=O
Agent: CCN=C=O
Agent: C[C@H]1COCCN1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(c2nccn2C)C3)cc1

Procedure:
The title compound was prepared by the procedures described in Example 1, steps 1-5 of Example 259, and steps 1 and 2 of Example 27, by substituting morpholine with (S)-3-methylmorpholine in Example 1, (S)-3-methyl-4-(2-(4-nitrophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)morpholine with (S)-3-methyl-4-(2-(4-nitrophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine in step 1 of Example 259, and propyl isocyanate with ethyl isocyanate in step 2 of Example 27, and: LC-MS: m/z=+463 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([O:27][CH3:28])[N:18]2C2CCCCO2)=[C:14]([NH2:29])[N:13]=1)[CH3:10]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:10][CH:9]([O:11][C:12]1[NH:13][C:14]([NH2:29])=[C:15]2[C:19]([N:20]=1)=[N:18][C:17]([O:27][CH3:28])=[N:16]2)[CH3:8]
Reactant: COc1nc2c(N)nc(OC(C)C)nc2n1C1CCCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Trifluoroacetic acid (1 ml, 12.98 mmol) was added to a stirred solution of 2-[(1-methylethyl)oxy]-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (568 mg, 1.848 mmol) in methanol (10 ml) and the mixture was stirred at room temperature overnight. More trifluoroacetic acid (0.2 ml) was added and the reaction mixture stirred at room temperature for a further 1.5 hours and then evaporated in vacuo. The solid residue was triturated with ethyl acetate, collected by filtration, washed with ethyl acetate and dried in vacuo overnight to give the title compound as a white solid (405 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18].O.O.[Sn](Cl)Cl>O1CCCC1.C(O)C>[F:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH3:18])=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: CSc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccccc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 25 h
Yield: 97.8 %

Procedure:
A solution of 2-fluoro-2′-methylthio-5-nitrobiphenyl (6.00 g, 22.8 mmol) in tetrahydrofuran (50 ml) and ethanol (50 ml) was treated with tin(II) chloride dihydrate (25.70 g, 113.9 mmol) and the mixture was stirred at ambient temperature for 25 h. The solvent was evaporated and the residue stirred with 2 N sodium hydroxide solution (240 ml) for 18 h. The resulting suspension was extracted with dichloromethane (3×200 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (silica gel, 35% EtOAc/isohexane) to give 5.20 g (98%) of the title compound as a white solid: 1H NMR (360 MHz, CDCl3) δ 2.39 (3H, s), 6.60 (1H, dd, J 2.8, 6.0 Hz), 6.646.68 (1H, m), 6.94 (1H, t, J 8.9 Hz), 7.19-7.20 (2H, m), 7.30 (1H, d, J 7.7 Hz), 7.33-7.37 (1H, m).