Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O-:23].[Na+]>CO.C(OC(=O)C)C>[CH3:22][O:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(N(C)c2nc(OC)nc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.167 mmol) in 2 ml methanol was added sodium methoxide (500 μl, 25% by wt. in methanol). The solution was stirred at 80° C. for 1 h, and it was diluted with 50 ml ethylacetate. The solution was washed with water, dried and concentrated. The product was purified using small silica column and isolated as off white solid (22 mg, 54%). 1H NMR (CDCl3): 7.89 (d, J=8.4 Hz, 1H), 7.53 (ddd, J=8.7, 5.4 and 2.4 Hz, 1H), 7.19-7.14 (m, 2H), 6.99-6.93 (m, 2H), 6.90-6.85 (m, 2H), 4.14 (s, 3H), 3.86 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: [CH:1]([NH2:3])=[S:2].Cl[CH:5]([CH:11]=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7]>CC(C)=O>[S:2]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:3]=[CH:1]1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: NC=S
Solvent: CC(C)=O
Product: CCOC(=O)c1cncs1
Yield: 60 %

Procedure:
To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of ethyl 2-chloro-2-formylacetate. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf =0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. NMR (CDCl3 δ1.39 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 8.50 (s, 1H), 8.95 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:24]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: BrCCCCC1CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)C=Cc1ccc(NCCCCC2CCCCCC2)cc1

Procedure:
A mixture of ethyl p-aminocinnamate, 5.9 g. 4-bromobutylcycloheptane and one equivalent of anhydrous powdered potassium carbonate in 50 ml. hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated. Crystallization from acetonitrile provides the title compound as white crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21](O)=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:29](=[O:32])([O-])[O-].[Na+].[Na+]>C(N(CC)C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:21](=[O:22])[N:8]([CH2:1][CH3:2])[CH:9]=[C:20]([CH:29]=[O:32])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)O
Agent: CCN(C=O)CC
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1cc(C=O)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Yield: 60 %

Procedure:
Dissolved in 4.0 ml of diethylformamide was 0.4 g of the 2-(4-benzylpiperazino)-4-methylpyrimidine-5-carboxylic acid obtained in Referential Example 3. At room temperature, 0.5 ml of phosphorus oxychloride was added dropwise. Thereafter, the contents were heated and reacted at 100° C. for 1.5 hours. After cooling, the reaction mixture was poured in an aqueous solution of sodium carbonate to neutralize same, followed by extraction with chloroform. After washing the chloroform layer with water, it was dried with anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure to obtain 0.29 g of the intended product (yield: 60%).
Reaction SMILES: [NH2:1][C:2](=[O:40])[CH2:3][C:4]1[CH:39]=[CH:38][CH:37]=[CH:36][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]1[C:26]2[C:21](=[CH:20][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=4[CH2:3][C:2]([NH2:1])=[O:40])[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][N:11]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:23][NH:24]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc3c(c2)CCNC3)ncc1C(F)(F)F
Yield: 73.1 %

Procedure:
tert-Butyl 6-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I82) (136 mg, 0.245 mmol), DCM (10 mL) and TFA (1 mL) were stirred together at room temperature. After three hours the solution was concentrated and the residue treated with 1M sodium hydroxide (25 mL). The resulting suspension was extracted with ethyl acetate (3×50 mL) and the combined organic extracts washed with brine (100 mL), dried and evaporated to give the title compound (21) (81.6 mg, 74% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 8.65 (s, 1H), 7.51 (s, 1H), 7.48 (dd, J=8.3, 2.1 Hz, 1H), 7.42 (s, 1H), 7.26-7.21 (m, 1H), 7.19-7.13 (m, 3H), 6.96 (d, J=8.3 Hz, 1H), 6.90 (s, 1H), 3.81 (s, 2H), 3.49 (s, 2H), 3.17 (d, J=3.1 Hz, 1H), 3.14-3.06 (m, 2H), 3.05-2.97 (m, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.67 (t, J=5.6 Hz, 2H).
Reaction SMILES: [CH2:1]([C:4]12[CH2:11][O:10][C:7]([CH2:12][C:13]([O-:15])=[O:14])([O:8][CH2:9]1)[O:6][CH2:5]2)[CH2:2][CH3:3].[Na+].[CH2:17](Br)[C:18]#[CH:19].O>CN(C)C=O>[CH2:1]([C:4]12[CH2:9][O:8][C:7]([CH2:12][C:13]([O:15][CH2:19][C:18]#[CH:17])=[O:14])([O:6][CH2:5]1)[O:10][CH2:11]2)[CH2:2][CH3:3]
Reactant: CCCC12COC(CC(=O)[O-])(OC1)OC2
Reactant: C#CCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC(=O)CC12OCC(CCC)(CO1)CO2
Reaction time: 24 h

Procedure:
A mixture of sodium 2-{4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl}acetate (1.0 g) and propargyl bromide (1.8 ml of 80% solution in toluene, supplied by Aldrich) in dry dimethylformamide (30 ml) was stirred at 20° for 24 hours. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica (pre-eluted with 1:3 dichloromethane:hexane containing 3% triethylamine) and eluting with 1:3 dichloromethane:hexane containing 3% triethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ClC1C=C(C=CC=1S(NC1CC1)(=O)=O)C(O)=O.Cl.Cl.[CH3:37][C:38]1[N:42]([CH:43]2[CH2:49][CH:48]3[N:50]([CH2:51][CH2:52][C:53]4([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)[CH:45]([CH2:46][CH2:47]3)[CH2:44]2)[C:41]2[CH:65]=[CH:66][CH:67]=[CH:68][C:40]=2[N:39]=1.CC1N(C2CC3N(CCC4(C5C=CC=CC=5)CCN(C(C5C=CC=CC=5S(NC(=O)OC(C)(C)C)(=O)=O)=O)CC4)C(CC3)C2)C2C=CC=CC=2N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])=[C:6]([C:7]([N:56]2[CH2:55][CH2:54][C:53]([CH2:52][CH2:51][N:50]3[CH:45]4[CH2:46][CH2:47][CH:48]3[CH2:49][CH:43]([N:42]3[C:41]5[CH:65]=[CH:66][CH:67]=[CH:68][C:40]=5[N:39]=[C:38]3[CH3:37])[CH2:44]4)([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:58][CH2:57]2)=[O:9])[CH:10]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(O)c1cc(Cl)ccc1S(=O)(=O)NC1CC1
Agent: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C(O)c1ccc(S(=O)(=O)NC2CC2)c(Cl)c1
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2cc(Cl)ccc2S(=O)(=O)NC2CC2)CC1
Yield: 11 %

Procedure:
The title compound was prepared from a mixture of 5-chloro-2-[(cyclopropyl amino)sulfonyl]benzoic acid and 3-chloro-4-[(cyclo propylamino)sulfonyl]benzoic acid 2c and endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford 4-chloro-N-cyclopropyl-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide 3 as a white solid (15 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H, J=8.1 Hz), 7.65 (m, 1H), 7.54 (m, 1H), 7.41-7.12 (m, 9H), 5.48 (s, 1H), 4.60 (m, 1H), 4.20 (m, 1H), 3.45-3.23 (m, 6H), 2.56 (s, 3H), 2.40-2.33 (m, 3H), 2.20-2.17 (m, 1H), 1.97-1.58 (m, 10H), 0.70-0.56 (m, 4H). ES-LCMS m/z 688.35 (M+2H). Analytical HPLC (Method Y) Rt 3.34 (89.34%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[OH:38])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:40][N:41]([CH2:43][CH2:44]O)[CH3:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:38][CH2:44][CH2:43][N:41]([CH3:42])[CH3:40])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCO
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1c(O)ccc2ccccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1c(OCCN(C)C)ccc2ccccc12
Temperature: 25 °C
Yield: 37.5 %

Procedure:
3-{2-[2-(2-Hydroxy-naphthalen-1-yl)-ethoxy]-benzenesulfonylamino}-N-methoxy-N-methyl-succinamic acid tert-butyl ester (176 mg, 0.32 mmol) was combined with dimethylamino ethanol (0.063 mL, 0.63 mmol), triphenyl phosphine (165 mg, 0.63 mmol), and diethylazodicarboxylate (0.10 mL, 0.63 mmol) in freshly distilled THF (1.6 mL). The reaction was stirred at room temperature for eighteen hours. TLC analysis (silica, 50% EtOAc/hexanes) indicated consumption of the starting naphthol. The reaction mixture was concentrated and purified by gradient elution flash chromatography (SiO2, 30% EtOAc/hexanes to 50% EtOAc/hexanes to 80% EtOAc/hexanes to 100% EtOAc to 10% MeOH/CH2Cl2) to give 3-(2-{2-[2-(2-dimethylamino-ethoxy)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (75 mg, 0.12 mmol) in 38% yield. MS (APCI) m/z 630.2 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[O:2])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1cccc(-n2cccn2)c1
Reaction time: 24 h

Procedure:
A mixture of 3-formylphenylboronic acid (2.00 g, 13.34 mmol), pyrazole (0.46 g, 6.67 mmol), copper(II) acetate (1.82 g, 10.01 mmol), pyridine (1.10 mL, 13.34 mmol), and powdered 4A molecular sieves (2.5 g) in dichloromethane (20 mL) was stirred under an air atmosphere for 24 h. The mixture was then filtered through Celite, the filtered solids were washed with MeOH, and the combined filtrate was concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) yielded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:50])=[O:49])=[CH:45][CH:46]=2)[C:41](=[O:63])[NH:40][N:39]=1>C1COCC1>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:50])=[O:49])=[CH:45][CH:46]=2)[C:41](=[O:63])[NH:40][N:39]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)n[nH]c(=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (46.7 mg, 0.212 mmol) and THF (1.2 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a suspension. Lithium bis(trimethylsilyl)amide (212 μl, 0.212 mmol, 1M in THF) was added drop wise to give a light yellow solution. The mixture was stirred for 15 min. Then, a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.177 mmol) in THF (1.2 mL) was added drop wise. After 1.5 h, more LHMDS (450 μL, 1M in THF) was added at −78° C. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride at −78° C. The reaction was warmed to RT. The product was extracted with EtOAc and the organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g column, 20 to 50% EtOAc/Heptane) to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (40 mg, 38% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.68 (s, 3H), 3.80 (s, 3H), 5.06 (s, 2H), 6.81 (m, J=8.66 Hz, 2H), 7.21 (m, J=8.66 Hz, 2H), 7.45-7.54 (m, 4H), 7.62 (d, J=7.69 Hz, 1H), 8.13 (dd, J=8.60, 2.08 Hz, 1H), 8.53 (d, J=1.82 Hz, 1H), 13.24 (s, 1H). m/z (ESI) 603.0 (M+H)+.
Reaction SMILES: [N+](C1C=C([O:10][C:11](=O)[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)C=CC=1)([O-])=O.[N+](C1C=C(C=CC=1)C=CC(O)=O)([O-])=O.S(Cl)([Cl:40])=O.Cl>CN(C=O)C.C(OCC)(=O)C>[N+:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH:13]=[CH:12][C:11]([Cl:40])=[O:10])([O-:22])=[O:21]
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)Oc1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Yield: 96.9 %

Procedure:
Synthesis of (3′-nitrophenyl)-3-nitrocinnamate 193.2 g (1 mole) of 3-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and poured into hexane. The precipitate was separated by filtration and dried. 205 g of 3-nitrocinnamoyl chloride was yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13](Cl)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:37]=[CH:36][C:27]([O:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13]([O:35][C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:36]=[CH:37][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=4)=[CH:34][CH:33]=3)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 82 %

Procedure:
2-(4-(4-Chlorophenoxy)phenoxy)propionic acid chloride (0.6 g) and 4-(4-nitrophenoxy)phenol (0.5 g) were dissolved in dry tetrahydrofuran (10 ml), and the solution was stirred with an addition of triethylamine (0.3 ml) at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure, the residue was dissolved in methylene chloride (20 ml), and washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water, saturated aqueous sodium hydrogen carbonate, water, and aqueous saturated sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue obtained was purified by medium pressure column chromatography to obtain 4-(4-nitrophenoxy)phenyl 2-(4-(4-chlorophenoxy)phenoxy)propionate (0.8 g)
Reaction SMILES: C([O:4][C@@H:5]([CH3:9])[C:6](Cl)=[O:7])(=O)C.C([O:13][CH2:14][CH:15]([NH:21][C:22]([C:24]1[C:29]([I:30])=[C:28]([NH2:31])[C:27]([I:32])=[C:26]([C:33]([NH:35][CH:36]([CH2:42][O:43]C(=O)C)[CH2:37][O:38]C(=O)C)=[O:34])[C:25]=1[I:47])=[O:23])[CH2:16][O:17]C(=O)C)(=O)C.[OH-].[Na+]>CN(C)C(=O)C>[CH3:9][C@H:5]([OH:4])[C:6]([NH:31][C:28]1[C:29]([I:30])=[C:24]([C:22]([NH:21][CH:15]([CH2:16][OH:17])[CH2:14][OH:13])=[O:23])[C:25]([I:47])=[C:26]([C:33]([NH:35][CH:36]([CH2:42][OH:43])[CH2:37][OH:38])=[O:34])[C:27]=1[I:32])=[O:7]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: C[C@H](O)C(=O)Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 15 h
Yield: 86.7 %

Procedure:
(S)-2-(Acetyloxy)propanoyl chloride (16.5 g, 110 mmol) is added, over 20 min, to a stirred solution of N,N′-bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (53.3 g, 61.1 mmol) in N,N-dimethylacetamide (75 mL) while keeping the temperature of the reaction mixture below 30° C. A further amount of (S)-2-(acetyloxy)propanoyl chloride (0.9 g, 6.0 mmol) is added after 24 and 30 hours and the reaction mixture is stirred at the same temperature for additional 15 hours. 5M NaOH (90 mL, 450 mmol) is dripped over a period of 2 hours into the reaction mixture vigorously stirred at 45° C. After two hours the mixture is concentrated under vacuum and reintegrated with additional N,N-dimethylacetamide (200 mL). After two hours at room temperature the resulting suspension is filtered and the solid washed with N,N-dimethylacetamide (2×20 mL). The mother liquors, combined with the washings, are concentrated to an oily residue, which is diluted with water (200 mL) and nanofiltered. The retentate is loaded onto an Amberlite® XAD-16.00 resin column (160 mL) that is eluted with water. The eluate is concentrated and loaded onto two ion exchange resin columns (Dowex® C350 15 mL, Relite® MG1 10 mL). The eluate is concentrated and the solid residue is crystallized from ethanol to afford Iopamidol (41.2 g, 53 mmol).
Reaction SMILES: C([BH3-])#N.[Na+].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[CH2:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:20]1.C(O)(=O)C>CO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([N:24]2[CH2:19][CH2:20][N:21]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:22][CH2:23]2)[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.89 g (30.1 mmol) of sodium cyanoborohydride were added to a stirred solution of 3.00 g (15.1 mmol) of tert-butyl 4-oxo-1-piperidinecarboxylate and 3.48 g (15.8 mmol) of 1-Z-piperazine in methanol (60 ml) at room temperature. The pH of the solution was adjusted to about pH 7 by dropwise addition of acetic acid and was monitored during the course of the reaction. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was mixed with water (60 ml) and extracted with dichloromethane (4×60 ml). The combined organic phases were washed with saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 3-10% methanol in dichloromethane). Yield: 3.41 g (56%) of colorless oil
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[C:10]([C:11](=[O:13])[CH3:12])=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[N:7]3[N:8]=2)=[CH:15][CH:16]=1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: C1CCNC1
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2c(N3CCCC3)cccc12
Yield: 92.8 %

Procedure:
In a similar manner as described in Example 1, from 1-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridin-3-yl]ethanone (0.30 g, 1.0 mmol) and pyrrolidine (0.43 mL, 5.2 mmol), 1-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (0.30 g, 91%) was obtained as a yellow solid. 1H NMR (CDCl3): δ 7.78 (d, 1H), 7.56 (m, 2H), 7.36 (t, 1H), 7.13 (t, 2H), 6.16 (d, 1H), 3.72 (m, 4H), 2.11 (s, 3H), 1.99 (m, 4H); MS m/z 324 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1cccnc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl (S)-2-amino-3-(3-pyridyl)propionate hydrochloride (Synthetech), the title compound was prepared as a solid (mp 101-103° C.). The reaction was monitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.