Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>CC(O)C.C(OCC)(=O)C>[C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](Nc1ncnc2sc3c(c12)CCN(C(=O)OC(C)(C)C)C3)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1ncnc2sc3c(c12)CCNC3)c1ccccc1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
tert-Butyl 4-{[(1R)-1-phenylethyl]amino}-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 17A (413 mg, 1.00 mmol) was dissolved in 2-propanol (4 mL), and 4 M gaseous hydrogen chloride in dioxane (0.5 mL, 2 mmol) was added. The mixture was heated to 80° C. for 3 h. Further hydrogen chloride solution (0.5 mL) was added, and the mixture was heated to 80° C. for further 30 min. Subsequently, the solution was diluted with ethyl acetate, washed with satd. aqueous sodium carbonate solution, dried over sodium sulfate, and the solvent was removed in vacuo. The product was purified by column chromatography on silica gel (eluent: DCM/MeOH 10:1) to yield 244 mg (78%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].[OH-].[Ca+2].[OH-]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc2ccc[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-methylquinoline (20.0 g, 140 mmol) in dichloromethane (700 mL) was added 3-chloroperoxybenzoic acid (50%, 62.6 g, 182 mmol) and stirred at room temperature for 2 h. Solid calcium hydroxide (13.4 g, 182 mmol) was added and 15 min later the mixture was filtered through celite, rinsed with dichloromethane and the liquors evaporated to dryness to give the title compound. The compound was used as such for the next step. 1H NMR (400 MHz, acetone-d6): δ 8.45 (m, 2H), 7.93 (d, 1H), 7.80 (d, 1H), 7.55 (d, 1H), 7.35 (m, 1H), 2.60 (s, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.Br.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)(=O)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: COc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(O)c2)s1
Yield: 3.7 %

Procedure:
To the (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxamide) (900 mg), 48% aqueous hydrobromic acid (10 mL) and glacial acetic acid (10 mL) were added. After heating under reflux for 4 h, saturated aqueous sodium carbonate and solid sodium carbonate were added to adjust to pH 10. The aqueous layer was extracted with chloroform and the combined extracts were dried over magnesium sulfate. After filtration and evaporation, residue was purified by flash chromatography using 5%-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent. The product obtained was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The hydrochloride salt was prepared by evaporation of the product-containing fractions, dissolution of the residue in methanol, addition of excess hydrogen chloride solution (1M in diethyl ether) and evaporation. Recrystallisation from methanol/diethyl ether gave the hydrochloride salt of the title compound as a colourless solid (32 mg); MS (ES+) 329 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]([CH3:16])[CH2:14][OH:15])=[CH:7]2)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C.O.C([O-])(O)=O.[Na+]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]([CH3:16])[CH2:14][OH:15])=[CH:7]2
Reactant: CC(CO)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(CO)c1cc2cc(N)ccc2[nH]1
Temperature: 120 °C
Yield: 81.5 %

Procedure:
To a solution of 2-(5-nitro-1H-indol-2-yl)propan-1-ol (0.13 g, 0.60 mmol) in ethanol (5 mL) was added tin chloride dihydrate (0.67 g, 3.0 mmol). The mixture was heated in the microwave at 120° C. for 1 h. The mixture was diluted with ethyl acetate before water and saturated aqueous NaHCO3 were added. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na2SO4, filtered and evaporated under reduced pressure to give 2-(5-amino-1H-indol-2-yl)propan-1-ol (0.093 g, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH:11][C:10]1[C:9](=[O:19])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1.O>[O:19]=[C:9]1[C:10]2[NH:11][C:12]3[C:4](=[CH:3][C:2]([C:20]#[N:21])=[CH:14][C:13]=3[C:15]([F:18])([F:17])[F:16])[C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1CCCc2c1[nH]c1c(C(F)(F)F)cc(Br)cc21
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C(F)(F)F)c2[nH]c3c(c2c1)CCCC3=O
Temperature: 210 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
6-Bromo-8-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one (600 mg, 1.8 mmol) and CuCN (480 mg, 5.4 mmol) were mixed together in NMP (6 mL) and stirred at 210° C. under N2 atmosphere for 15 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and filtered through a pad of Celite®. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to obtain the crude material which was purified by washing with 10% EtOAc-hexane to afford the title compound as a pale brown solid (400 mg, 80%). 1H NMR (200 MHz, CDCl3, δ in ppm) 9.26 (bs, 1H), 8.22 (s, 1H), 7.86-7.90 (m, 1H), 3.09 (t, J=12.0 Hz, 2H), 2.77-2.70 (m, 2H), 2.40-2.31 (m, 2H). IR cm−1 2240 (CN)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[N:21]/[O:22][CH2:23][C:24](O)=[O:25])=[C:16]([CH3:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[F:44][C:45]([F:49])([F:48])[CH2:46][NH2:47]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:29])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[N:21]/[O:22][CH2:23][C:24]([NH:47][CH2:46][C:45]([F:49])([F:48])[F:44])=[O:25])=[C:16]([CH3:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of [1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-meth-(E)-ylideneaminooxy]-acetic acid (i.e. the product of Step 2, 200 mg) in CH2Cl2 (12 mL) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (130 mg). After 15 min, 2,2,2-trifluoroethyl amine (64 μL, 80 mg) and N,N-4-dimethylaminopyridine (80 mg) was added and the mixture was stirred at room temperature over night. After concentration in vacuum, the residue was purified by flash chromatography on silica gel to obtain the title compound (100 mg, 43%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[ClH:21]>CO.O1CCOCC1.[Pt]=O>[ClH:21].[F:19][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:10][C@@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@H]1CCN[C@@H](c2ccc(C(F)(F)F)cc2)C1
Reaction time: 2 h

Procedure:
Methyl 2-[4-(trifluoromethyl)phenyl]isonicotinate (5 g) was dissolved in MeOH (180 ml) and HCl in dioxane (4.5 ml, 4N). To this solution was added platinum oxide (500 mg) and the mixture was hydrogenated at 30 psi for 2 h. The mixture was filtered through Hyflo® to remove the catalyst and the solution was evaporated and azeotroped with toluene to yield the product as a white crystalline solid (5 g). 1H NMR (400 MHz, CDCl3) δ: 1.95-2.03 (1H, m), 2.09-2.17 (1H, m), 2.33 (1H, d, J 14.5), 2.44 (1H, d, J 14.2), 2.95-3.02 (1H, m), 3.35-3.39 (1H, m), 3.60-3.64 (1H, m), 3.75 (3H, s), 4.51 (1H, dd, J 2.7, 12.6), 7.74 (2H, d, J 8.2), 7.83 (2H, d, J 8.2); M/Z (ES+) 288 (MH+).
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.[NH2:18][CH:19]([C:24]1[S:25][C:26]2[CH2:32][CH2:31][CH2:30][CH2:29][C:27]=2[CH:28]=1)[C:20]([O:22][CH3:23])=[O:21].C(NC(C1SC2CCCCC=2C=1)C(O)=O)(OC(C)(C)C)=O>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[S:25][C:26]3[CH2:32][CH2:31][CH2:30][CH2:29][C:27]=3[CH:28]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1cc2c(s1)CCCC2
Agent: CC(C)(C)OC(=O)NC(C(=O)O)c1cc2c(s1)CCCC2
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2c(s1)CCCC2

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate (prepared from N-Boc-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetic acid [CAS 95361-97-0] using General Procedures G above and the Boc removal procedure described in Example D3 above), the title compound was prepared as a solid. The product was purified by tituration using Et2O/hexanes.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][OH:20].C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH:19]=[O:20]
Reactant: OCc1ccc(F)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(F)cc1Br
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
To a −78° C. cooled solution of oxalyl chloride (8.43 ml; 96.58 mmol) in anhydrous dichloromethane (300 ml) was added dropwise dimethyl sulfoxide (13.71 ml; 193.16 mmol). The mixture was stirred at −78° C. for 5 minutes then a solution of (2-bromo-4-fluorophenyl)methanol (Description 77, 18 g; 87.8 mmol) in anhydrous dichloromethane (150 ml) was added slowly. The resulting mixture was stirred at −78° C. for 15 minutes then triethylamine (36.71 ml; 263.4 mmol) was added and the mixture allowed to warm to room temperature over 1 hour. The mixture was washed with water (2×500 ml), saturated NaCl (200 ml), dried over Na2SO4, filtered through a 2 inch plug of silica gel and evaporated to give the title compound (16 g, 89%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([C:63]([F:66])([F:65])[F:64])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([C:63]([F:65])([F:66])[F:64])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 113 mg light yellow viscous oil (72%). MS (ISP) 497.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[Cs+].[Cs+].IC.C(OCC)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH3:22])[C:10]1=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)c2ccccc2NC1=O
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(NC(=O)OC(C)(C)C)CC(=O)c2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 3-t-butyloxycarbonylamino-3,4-dihydro-1H-1-benzazepine-2,5-dione (500 mg, 1.72 mmol) in 25 ml anhydrous DMF was-added cesium carbonate (562 mg) followed by iodomethane (215 μl). The reaction was stirred for one hour, diluted with ethyl acetate and then washed with water. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to give a yellow solid. Tritiation with diethyl ether gave 3-t-butyloxycarbonylamino-1-methyl-3,4-dihydro-1H-1-benzazepine-2,5-dione as a colourless solid. 1H NMR (250 MHz, CDH3) δ 7.64-7.50 (M, 2H) 7.38-7.24 (t, 1H) 7.20-7.60 (d, 1H,) 5.78-5.66 (br d, 1H,) 4.98-4.82 (M, 1H) 3.40 (s, 3H) 3.36-3.20 (dd, 2H) 2.98-2.80 (dd, 2H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[Cl:16][C:17]1[CH:28]=[CH:27][C:20]2[NH:21][C:22]([C:24](O)=[O:25])=[N:23][C:19]=2[CH:18]=1>>[CH3:7][N:6]([CH3:8])[C:4]([CH:3]([NH:2][C:24]([C:22]1[NH:21][C:20]2[CH:27]=[CH:28][C:17]([Cl:16])=[CH:18][C:19]=2[N:23]=1)=[O:25])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5]
Reactant: O=C(O)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: CN(C)C(=O)C(Cc1ccccc1)NC(=O)c1nc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-N,N-dimethyl-3-phenyl-propionamide hydrochloride (2.0 mmol) and 5-chloro-1H-benzoimidazole-2-carboxylic acid (Crowther et al., J. Chem. Soc. 1949, p.1268, 2.0 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 1:1 ethyl acetate-hexanes (235 mg, 63%): HPLC (60/40) 4.92 min (91%); PBMS 371/373 (MH+, 100%); 1H NMR (CDCl3) δ11.25 (br, 0.6H), 10.9 (br, 0.4H), 8.36 (m, 1H), 7.78 (d, 0.4H, J=7.72 (d, 0.6H, J=8.8 Hz), 7.52 (d, 0.6H, J=2 Hz), 7.41 (d, 0.4H, J=8.4 Hz), 7.35-7.1 (m, 6H), 7.35 (m, 1H), 3.16 (m, 2H), 2.90 (s, 3H), 2.68 (s, ca. 2H), 2.67 (s, ca. 1H).
Reaction SMILES: [O:1]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:30][C:21]1=[N:22][CH:23]=[C:24]([C:26]([O:28]C)=[O:27])[CH:25]=[C:20]1[CH2:19]2.Cl.[OH-].[Na+]>CO>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:30][C:21]1=[N:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[CH:25]=[C:20]1[CH2:19]2
Reactant: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 55 °C
Reaction time: 20 h

Procedure:
A solution of methyl 2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (30.9 g, 73 mmol) in MeOH (400 mL) was saturated with HCl gas, allowing the internal temperature to increase to 55° C. The reaction mixture was cooled to ambient temperature, stirred for 20 h, then concentrated in vacuo. Aqueous 10 N sodium hydroxide (50 mL, 500 mmol) was added to a solution of the residue in MeOH (400 mL), and the resulting mixture was heated at reflux for 2 h. The solution was cooled to ambient temperature and the pH was adjusted to 3 with concentrated HCl. The resulting solid was filtered, washed with water then heptane, and dried to give the title compound. MS: m/z=282.2 (M+1).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:2]2[S:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)=[CH:12][CH:13]=1
Reactant: OCc1ccc(Oc2nc3ncccc3s2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of [4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]methanol (1.0 equiv.) in CH2Cl2 (0.3 M), SOCl2 (1.2 equiv.) was slowly added over 1 h at rt. In some embodiments, an excess of thionyl chloride was used, which was distilled off prior to the subsequent reaction step. After stirring at rt for another 30 min, the precipitated solid was collected by filtration and washed with CH2Cl2 to afford the title compound (100%), which was used without further purification. MS (ESI): mass calcd. for C13H9ClN2OS, 276.0; m/z found, 277.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.55 (dd, J=4.9, 1.7, 1H), 8.47 (dd, J=8.0, 1.7, 1H), 7.62 (dt, J=8.7, 2.1, 2H), 7.52 (dt, J=8.7, 2.1, 2H), 7.39 (dd, J=8.0, 4.9, 1H), 6.42 (br s, 1H), 4.84 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=O)[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=O)([O-:3])=[O:2].[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>CO>[N+:1]([C:4]1[CH:13]=[C:8]([C:9]([NH:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[O:11])[CH:7]=[C:6]([CH:5]=1)[C:14]([NH:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[O:16])([O-:3])=[O:2]
Reactant: NCC(O)CO
Reactant: COC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Solvent: CO
Product: O=C(NCC(O)CO)c1cc(C(=O)NCC(O)CO)cc([N+](=O)[O-])c1
Yield: 84 %

Procedure:
Dimethyl 5-nitro-isophthalate and 2.4 molar equivalents of 1-amino-2,3-propanediol were refluxed in methanol for twenty hours and the resulting 5-nitro-N,N′-bis(2,3-dihydroxypropyl)isophthalamide was isolated in 84% yield. The latter compound was suspended in aqueous hydrochloric acid and hydrogenated in the presence of a palladium oxide/charcoal catalyst. The resulting 5-amino-N,N′-bis(2,3-dihydroxypropyl)-isophthalamide was not isolated but the acid solution containing it was iodinated with sodium iodine dichloride to obtain 5-amino-2,4,6-triiodo- N,N′-bis(2,3-dihydroxypropyl)isophthalamide in 71% yield from the nitro compound (over-all yield of 59.5% from dimethyl 5-nitroisophthalate). Subsequent reactions are described for the preparation of 5-[N-(2,3-dihydroxy-propyl)acetamido]-2,4,6 triiodo-N,N′-bis(2,3-dihydroxypropyl)isophthalamide, useful as an X-ray contrast agent.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:10][Si:11]([CH3:26])([CH3:25])[C:12]#[C:13][CH2:14][CH2:15]N1C2C=CC=CC=2N=N1>>[CH3:10][Si:11]([CH3:26])([CH3:25])[C:12]#[C:13][CH2:14][CH2:15][N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1
Reactant: C[Si](C)(C)C#CCCn1nnc2ccccc21
Reactant: c1ccc2[nH]nnc2c1
Product: C[Si](C)(C)C#CCCn1nc2ccccc2n1
Yield: 67 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(A), from benzotriazole (116 mg, 0.97 mmol) to yield 157 mg (0.64 mmol, 67%) of 2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole and 1-(4-trimethylsilanyl-but-3-ynyl)-1H-benzo[d][1,2,3]triazole.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:21]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:21]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:33])=[CH:35][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: CCOC(=NC(=O)c1ccc(Oc2ccccc2)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-phenoxybenzoyl chloride, there is obtained ethyl N-(p-phenoxybenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a foam, mass spectrum m/e: M+ 462 (8), 433 (5), 197 (30), 194 (100);
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[N:15]=[N:16][C:17]([NH:20][NH2:21])=[CH:18][CH:19]=1.[Si:25]([O:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH:35]=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:25]([O:32][CH2:33][C:34]([C:38]1[N:16]2[N:15]=[C:14]([C:13]3[N:12]4[CH2:22][CH2:23][CH2:24][C:11]4=[N:10][C:9]=3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:19]=[CH:18][C:17]2=[N:20][N:21]=1)([CH3:37])[CH3:35])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:26])[CH3:27]
Reactant: CC(C)(C=O)CO[Si](C)(C)C(C)(C)C
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3n2CCC3)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
2-(2,4-Difluorophenyl)-3-(6-hydrazinylpyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (6.00 g, 18.3 mmol, Example #35, Step E) was suspended in DCM (125 μL) then 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanal (4.15 g, 19.2 mmol, J. Org. Chem., 2002, 67, 2474-2480) was added. The mixture was stirred at ambient temperature for about 2 h. Iodobenzene diacetate (6.00 g, 18.6 mmol) was added then the mixture was stirred for about 30 min. Saturated aqueous NaHCO3 (150 mL) was added then the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The material was purified by flash chromatography on silica gel with EtOAc as an eluent to give the title compound (8.67 g, 90%): LC/MS (Table 1, Method g) Rt=2.77 min; MS m/z: 525.3.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH:4]1[C:3](=[O:8])[C:2]([CH3:1])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: CC1(c2ccccc2)CCCCC1=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC1(c2ccccc2)CCCC(Br)C1=O
Reaction time: 2 h
Yield: 101.1 %

Procedure:
A solution of 2-methyl-2-phenyl-cyclohexanone (0.94 g, 5.0 mmol) in chloroform (12 mL) at −5° C. was treated via rapid dropwise addition with a solution of bromine (0.26 mL, 5.1 mmol) in chloroform (6 mL) so as the reaction temperature maintaining below 5° C. The solution was kept at 0° C. for 2 h when the red color had disappeared. The mixture was concentrated under reduced pressure to give the crude title compound (1.35 g, 100%) as a brown oil which was used directly in the next step. MS ISP (m/e): 267.3 [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.22-7.42 (m, 3H), 7.13 (d, 2H), 4.70 (dd, 1H), 2.75 (m, 1H), 2.52 (m, 1H), 1.7-2.4 (m, 4H), 1.36 (s, 3H).