Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:38][CH:37]=3)=[CH:32][N:31]=2)=[CH:26][CH:25]=1)[C:13]([N:15]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1)=[O:14])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@@H:12]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:40][CH:41]=3)=[CH:32][N:31]=2)=[CH:26][CH:25]=1)[C:13]([N:15]1[CH2:16][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:18]1)=[O:14]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N4CC(C(=O)OC)C4)cc3)nc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N4CC(C(=O)OC)C4)cc3)nc2)cc1
Yield: 62.9 %

Procedure:
Prepared using General Procedure 18: A solution of (S)-methyl 1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-propanoyl)azetidine-3-carboxylate (1.2 g, 1.81 mmol) in MeOH (150 mL) was passed over a 10% Pd/C CatCart (55×4 mm) at 65° C. in a Thales Nanotechnology H-Cube reactor at 2.1 mL/min. The solvent was evaporated and the residue purified by column chromatography (Ammonia/MeOH/DCM) to afford 604 mg (63%) of (S)-methyl 1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate. LCMS-ESI (m/z) calculated for C31H38N4O4: 530.3. found 531.0 [M+H]+, tR=1.60 min (Method 6).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:41](=[O:42])[CH:40]=[C:38]([NH2:39])[NH:37][C:35]1=[O:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:43]([O-])=O.[Na+].C(O)(=O)C>C(O)(C)=O.O.[Zn]>[NH2:43][C:40]1[C:41](=[O:42])[N:34]([C@@H:11]2[O:12][C@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:14]([O:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:10]2[O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:35](=[O:36])[NH:37][C:38]=1[NH2:39]
Reactant: Nc1cc(=O)n([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1[nH]c(=O)n([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)c1N
Temperature: -5 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 49 (238 mg, 0.42 mmol) in AcOH—H2O (5: 0.5 mL) was added NaNO2 over 10 min at −5° C. The resulting mixture was stirred at −5° C. for 1 hr, concentrated, and co-evaporated with toluene to give a purple solid, which was treated with acetic acid (5 mL) and Zn dust (460 mg, 7.04 mmol), and heated at 70° C. for 30 mm. The mixture was filtered through a Celite pad, and the filtrate concentrated to a slightly green solid, which was purified by silica gel column chromatography (CHCl3:MeOH=10:1 v/v) to give compound 50 (217 mg, 88%).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1)[OH:5].O[C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[CH3:37][C:26]1[CH:25]=[C:24]([O:5][CH:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=3)[N:7]=2)[CH2:3][CH:2]([CH3:22])[CH3:1])[CH:36]=[CH:35][C:27]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CC(C)CC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC(CC(C)C)c2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Temperature: 0 °C
Yield: 47.1 %

Procedure:
A solution of 3-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-butanol (180 mg, 0.58 mmol) in dry THF (12 mL) under nitrogen was treated with ethyl (4-hydroxy-2-methylphenoxy)acetate (122 mg, 0.58 mmol) and cooled to 0° C. This was treated portion-wise with ADDP (0.3 g, 1.2 mmol), then drop-wise with nBu3P (0.29 mL, 1.2 mmol). The resulting pale yellow suspension allowed to warm to rt slowly over 16 hours. The solvent was removed under vacuum and the residue partitioned between EtOAc (60 mL) and water (60 mL) and the layers separated. The aqueous was re-extracted with EtOAc (60 mL) and the combined organic layer dried (Na2SO4) and reduced. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 49:1) gave the title compound as a colourless oil (137 mg).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C(Cl)Cl.[Cl:29][C:30]1[CH:31]=[C:32]([C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[CH:37]C(O)=O)[CH:33]=[CH:34][CH:35]=1>C(N(CC)CC)C>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[CH:37][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH:33]=[CH:34][CH:35]=1
Reactant: O=CN1CCNCC1
Reactant: O=C(O)C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5.51 ml of diphenylphosphoryl azide and 1.93 ml of N-formylpiperazine were added, in that order, to 100 ml of a methylene chloride solution containing 5.00 g of 3,3-bis(3-chlorophenyl)acrylic acid (prepared as described in preparation 110) and 4.75 ml of triethylamine. The reaction mixture was then stirred at room temperature for 18 hours, after which it was washed with a saturated aqueous solution of sodium bicarbonate and then with water. It was then dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was dissolved in a mixture of 100 ml of ethanol and 50 ml of tetrahydrofuran, and 50 ml of a 10% w/v aqueous solution of sodium hydroxide were added. The resulting mixture was stirred for 8 hours at room temperature, after which it was poured into water. The solution was extracted twice, each time with methylene chloride, and the combined extracts were washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 150 g of silica gel, using mixtures of methylene chloride and methanol ranging from 49:1 to 9:1 by volume as eluent, to give 5.23 g of the title compound as a viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH3:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.O>CN(C)C=O>[CH3:1][N:2]1[C:6]([O:7][CH2:25][C:26]([F:29])([F:28])[F:27])=[C:5]([CH3:8])[C:4]([C:9]([F:11])([F:10])[F:12])=[N:3]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1c(C(F)(F)F)nn(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(F)(F)F)nn(C)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of 4.4 g (24.4 mmol) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 50 ml of N,N-dimethylformamide were added 5.1 g (36.6 mmol) of anhydrous potassium carbonate and 6.3 (26.8 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate, followed by 3 hours of stirring at room temperature. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 6.1 g (yield: 95.3%) of 1,4-dimethyl-5-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-1H-pyrazole as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27]([NH:29][C:30](=[O:39])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[S:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][N:19]=3)[S:17][C:10]=12.[CH3:40][O:41][CH2:42][CH2:43]N.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27]([NH:29][C:30](=[O:39])[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[S:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH2:43][CH2:42][O:41][CH3:40])=[CH:20][N:19]=3)[S:17][C:10]=12
Reactant: COCCN
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCCOCc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a suspension of aldehyde 33 (17.06 g, 30.04 mmol) and 2-methoxyethylamine (13.25 ml, 152 mmol) in THF (300 ml) in a 1 L round-bottom flask was added AcOH (8.71 ml, 152 mmol)). After 1 h, NaBH(OAc)3 (32.2 g, 152 mmol) was added and the reaction mixture was stirred for 20 h at r.t. and was then quenched with HCl 2M (300 mL) After 1 h, NaOH 2N (350 mL) was added until pH 11 and the mixture was concentrated. The solid was subjected to chromatographic purification through a pad of silica gel, eluent 2%-10% MeOH/DCM, to give 15 (8.59 g, 13.86 mmol, 81% yield) as a white solid. MS (m/z): 620.2 (M+1)
Reaction SMILES: [SH2:1].[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21]>N1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[S:1])[NH2:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21]
Reactant: S
Reactant: CN1Cc2c(C#N)ncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)c(Cl)c2C1=O
Reaction time: 64 h
Yield: 73 %

Procedure:
A stream of hydrogen sulphide was conducted for 1/2 hr. through a solution of 3.0 g (0.0103 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 10 ml of pyridine and 1.0 ml of triethylamine. The green solution was left to stand for 64 hrs., then degassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and the suspension obtained was suction filtered. There were obtained 2.45 g (73%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-thiocarboxamide.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]2=[O:19])=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[CH2:15][C:14]2=[O:19])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1CN(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 1-[2-(4-nitrophenyl)ethyl]piperazin-2-one hydrochloride (40 mg, 0.14 mmol) and 1-(2-bromoethyl)-4-nitrobenzene (39 mg, 0.17 mmol) was heated to 60° C. with triethylamine (0.078 mL, 0.56 mmol) for 16 hours. LC showed complete reaction at that point. The desired product was purified by reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 399 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(O)(=O)C.C1C=CC=CC=1>[OH:1][C:2]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][C:5]([CH:6]=[N:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(CNn2ccnc2)cc(C(C)(C)C)c1O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=Nn2ccnc2)cc(C(C)(C)C)c1O

Procedure:
300 mg of 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)imidazole are heated to about 60°-70° on a water-bath together with 10 drops of glacial acetic acid in 25 ml of benzene. After the dropwise addition of a solution of 250 mg of dicyanodichlorobenzoquinone in 10 ml of benzene, the mixture is warmed for an additional 15 minutes. The reaction mixture is subsequently cooled in an ice-bath and the separated solid is removed by filtration. The filtrate is shaken with 10% sodium carbonate solution. After separation of the organic phase the aqueous phase is extracted once with benzene. The combined organic phases are dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline residue is recrystallized from ethyl acetate/n-hexane and there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)imidazole of m.p. 173°.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:36][C:37]([NH:39][C:40]1[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:47])=[O:38]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:36][C:37]([NH:39][C:40]3[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:47])=[O:38])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=647.2 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and N-chloroacetyl-2,6-dimethylaniline.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([F:31])=[C:16]2[C:21]=1[NH:20][CH:19]=[C:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:17]2=[O:30])C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[F:31][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:21]2[C:16]=1[C:17](=[O:30])[C:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[CH:19][NH:20]2
Reactant: [H][H]
Reactant: COc1ccc(-c2c[nH]c3c(OCCOCc4ccccc4)ccc(F)c3c2=O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c[nH]c3c(OCCO)ccc(F)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.3 %

Procedure:
20% palladium hydroxide/carbon (5.0 g) was added to an ethanol solution (50 ml) of 8-(2-benzyloxyethoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one (6.3 g, 15.0 mmol), followed by hydrogen substitution. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the catalyst was removed and the mixture was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=100:0→20:1). The purified material was concentrated to dryness under reduced pressure, giving a pale yellow powder of 5-fluoro-8-(2-hydroxyethoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one (5.2 g, yield: 99%).
Reaction SMILES: [NH:1]([C:5]1[C:6]([I:29])=[C:7]([C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:8]([I:20])=[C:9]([C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])[C:10]=1[I:11])[C:2]([CH3:4])=[O:3].C[O-].[Na+].[CH2:33]1[O:35][CH:34]1[CH2:36][OH:37]>CO.COCCO>[CH3:4][C:2]([N:1]([C:5]1[C:10]([I:11])=[C:9]([C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])[C:8]([I:20])=[C:7]([C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:6]=1[I:29])[CH2:33][CH:34]([OH:35])[CH2:36][OH:37])=[O:3]
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: OCC1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCO
Product: CC(=O)N(CC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 90 °C
Yield: 63.7 %

Procedure:
5.0 gram 5-acetamino-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzene-dicarboxamide (Compound 1), 0.36 gram of 25% sodium methoxide in methanol, and 1.5 gram glycidol are combined in 2-methoxyethanol and heated to 90° C. for four hours. Solvent is removed under vacuum followed by dissolution of the residue in water. The solution is treated with 1 gram each of Amberlyst A-15 and Amberlite IRA-67 ion-exchange resins to remove sodium methoxide. Water is removed under vacuum to afford an oil. Crystallization from methanol/isopropanol (10:75) afforded 3.5 gram (64.6%) iohexol.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[Cu][C:25]#[N:26]>CN1CCCC1=O>[O:15]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[N:5]1[CH2:4][C:3]1[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:2]=1[C:25]#[N:26]
Reactant: N#C[Cu]
Reactant: COc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1OC
Solvent: CN1CCCC1=O
Product: COc1cc(C#N)c(CN2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.5 h

Procedure:
A mixture of 2-(2-bromo-4,5-dimethoxy-benzyl)isoindole-1,3-dione (26.63 g, 0.07079 mol) and copper (I) cyanide (12.7 g, 0.1416 mol) in N-methyl-2-pyrrolidinone (266 mL) was heated to reflux for 18 h under nitrogen. The resulting mixture was concentrated in vacuo and the resulting residue stirred with a mixture of chloroform (250 mL) and water (250 mL) for 30 min. The resulting suspension was filtered through CELITE and the layers separated. The organic layer was extracted with brine (2×), dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was crystallized from methylene chloride/methanol (500 mL) to yield 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5-dimethoxy-benzonitrile as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=1>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[C:2]([NH:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=2[F:28])(=[O:26])=[O:25])[CH:7]=1
Reactant: CN(C)C(=O)CCSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Solvent: c1ccncc1
Product: CN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Yield: 74.3 %

Procedure:
Following General Procedure B, the title compound (476 mg, 75%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide (364 mg, 1.42 mmol) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride (325 mg, 1.42 mmol) in pyridine (5 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([I:10])[CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1>C(O)(=O)C>[O:15]=[C:14]1[CH:13]=[CH:12][C:11](=[O:16])[N:1]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([I:10])[CH:3]=1
Reactant: O=C1C=CC(=O)O1
Reactant: N#Cc1ccc(N)cc1I
Solvent: CC(=O)O
Product: N#Cc1ccc(N2C(=O)C=CC2=O)cc1I
Temperature: 25 °C
Yield: 90.5 %

Procedure:
Compound 489C (3.97 g, 16.3 mmol) and maleic anhydride (2.41 g, 24.4 mmol) were refluxed in glacial acetic acid (15 mL) for 5 h. The reaction was cooled to 25° C. and then poured onto ice (100 mL). The resulting precipitate was isolated by filtration and washed with water (2×25 mL) and dried under vacuum to yield 4,78 g (90%) of compound 489D as a tan solid. HPLC: 82% at 2.68 min (retention time) C Shimadzu VP-ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.1% trifluoroacetic acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 325.04 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:28]([C:38]([O:40][CH3:41])=[O:39])[CH:27]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.O>[Pd].C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:26]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C@H:28]([C:38]([O:40][CH3:41])=[O:39])[CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)[C@@H]1C=C(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1C(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
(2S)-1-tert-Butyl 2-methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-2H-pyrrole-1,2(5H)-dicarboxylate (0.618 g, 1.1 mmol) and 10% palladium on carbon, 50% water (0.58 g) were combined in a flask and treated with nitrogen and 10 mL THF. The reaction mixture was stirred rapidly under H2 balloon for 48 h. The reaction mixture was flushed with nitrogen, filtered, rinsing with DCM and concentrated in vacuo. Purification by silica gel chromatography, 40 g, 0-30% EA/hexanes gave (2S,4R)-1-tert-butyl 2-methyl 4-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-1,2-dicarboxylate as a yellow foam. MS (ESI) m/z: Calculated: 573.2; Observed: 573.7 (M++1).
Reaction SMILES: [CH2:1]([O:4][C:5]([CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([F:45])[C:33]=1[O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:29]Br.Cl>CN(C=O)C>[CH2:1]([O:4][C:5]([C:7]([CH2:29][C:28]1[CH:27]=[C:26]([F:25])[C:33]([O:34][Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:38])[CH3:37])=[C:32]([F:45])[CH:31]=1)([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Reactant: CC(C)[Si](Oc1c(F)cc(CBr)cc1F)(C(C)C)C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.17 g (10.14 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonylheptanedioate (Example 48A) are dissolved in 30 ml of DMF and, at 0° C., 0.45 g (11.15 mmol) of 60% sodium hydride is added in portions, and the mixture is stirred at RT for 30 minutes. After renewed cooling to 0° C., a solution of 5 g (13.18 mmol) of 3,5-difluoro-4-triisopropylsilanyloxybenzyl bromide in 20 ml of DMF is added dropwise, and the mixture is stirred while warming to room temperature overnight. The mixture is poured into ice, weakly acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane, then cyclohexane/ethyl acetate 10:1). 4.57 g (73% of theory) of the title compound are obtained.