Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](O)=O)[CH3:2].C=O.N1C=CC=CC=1.N1CCCCC1>O>[CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: C=C(CCCc1ccccc1)C(=O)OCC

Procedure:
50 g of 3-phenylpropylmalonic acid monoethyl ester, 7.5 g of paraformaldehyde, 37.5 ml of pyridine and 2.5 ml of piperidine are stirred together at 50° C. for 5 hours. After cooling, 350 ml of water are added to the reaction mixture, and the mixture is then extracted 3 times with 150 ml of hexane each time. After washing with 1 N hydrochloric acid, water and sodium bicarbonate solution, the organic phase is concentrated and distilled. 5-Phenyl-2-methylenevaleric acid ethyl ester is obtained as a colorless liquid of b.p. 78° to 79° C. under 0.02 mm Hg.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH:7]=[C:8]([CH3:26])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=[CH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=1[CH3:24])CCC.[Cl-].COC1C=C(C)C(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=C(C)C=1.C(OC(=O)C=C(C)C=CC=C(C=O)C)CCC>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH3:24])[C:15]([CH:14]=[CH:13][C:12]([CH3:25])=[CH:11][CH:10]=[CH:9][C:8]([CH3:26])=[CH:7][C:6]([OH:27])=[O:5])=[C:20]([CH3:21])[CH:19]=1
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)cc1C
Agent: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1
Agent: [Cl-]
Product: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)O)c(C)c1

Procedure:
By the procedure described in Example 14, 9-(4-methoxy-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester is manufactured from 4-methoxy-2,6-dimethylbenzyl-triphenylphosphonium chloride by reaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester. From this product, there is produced by the procedure of Example 15, 9-(4-methoxy-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid of melting point 207°-208° C.
Reaction SMILES: C[NH:2][NH:3][C:4]([NH:6][C:7](=O)[CH2:8][NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19])=[S:5].[OH-].[K+].[CH2:23](O)C>O>[CH2:16]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:18][CH3:19])[C:10]=1[NH:9][CH2:8][C:7]1[N:6]([CH3:23])[C:4](=[S:5])[NH:3][N:2]=1)[CH3:17]
Reactant: CCc1cccc(CC)c1NCC(=O)NC(=S)NNC
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1cccc(CC)c1NCc1n[nH]c(=S)n1C
Yield: 97 %

Procedure:
29.6 g (0.1 mole) of 1-methyl-4-[(2,6-diethylanilino)-acetyl]-thiosemicarbazide were suspended in 150 ml of ethanol and, after added 7 g of potassium hydroxide in 20 ml of water, the mixture was heated under reflux for 1 hour. Thereafter, most of the solvent was distilled off and 250 ml of water were added to the residue. After acidifying the mixture to pH 5 with glacial acetic acid, the precipitate which formed was filtered off and washed thoroughly with water. After drying, 27 g (97% of theory) of 2,6-diethyl-N-[(1-methyl-2-thiono-1,3,4-triazol-5-yl)-methyl]-aniline of melting point 117° to 121° C. were obtained. ##STR83##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH2:20])[N:14](C(C)(C)C)[N:15]=2)[CH:6]=[CH:7][CH:8]=1.[N:21]1([C:26]2[CH:35]=[CH:34][C:29]([C:30](OC)=[O:31])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1.C[Al](C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:20][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:35][CH:34]=3)[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-n2cccn2)cc1
Reactant: COc1cccc(CCc2cc(N)n(C(C)(C)C)n2)c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=CO
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(-n4cccn4)cc3)[nH]n2)c1
Temperature: 82 °C
Reaction time: 8 h

Procedure:
5-[2-(3-Methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine (0.2 g, 0.73 mmol) was dissolved in toluene (10 ml) and to this was added methyl 4-pyrazol-1-ylbenzoate (177 mg, 0.88 mmol) and AlMe3 (0.93 ml, 1.8 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (15 ml), quenched with damp sodium sulfite and further stirred for 20 mins before being filtered. The solvent was removed in vacuo to yield a yellow gum. This gum was dissolved in formic acid (12 ml) and heated at 82° C. overnight. The reaction mixture was evaporated to dryness and the resulting product was passed through a SCX column, eluting initially with methanol followed by 2N ammonia/methanol. After solvent removal, a yellow solid was obtained which was triturated with hot acetonitrile to afford a white solid. The solid was filtered and dried (155 mg, 55%); 1H NMR (400.132 MHz, DMSO) δ 2.92 (s, 4H), 3.74 (s, 3H), 6.48 (s, 1H), 6.60 (s, 1H), 6.77 (d, 1H), 6.84-6.82 (m, 2H), 7.20 (t, 1H), 7.81 (s, 1H), 7.96 (d, 2H), 8.14 (d, 2H), 8.63 (s, 1H), 10.69 (s, 1H), 12.18 (s, 1H); MS: m/z 388 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=O.N1C=CC=CC=1.S(Cl)(Cl)=O.[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)=[O:3])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Yield: 9 %

Procedure:
To a suspension of 1.76 g of 5-carboxyoxindol in 200 ml of methylene chloride was added 2 ml of pyridine. After completion of addition, to the suspension was added dropwise 1.4 g of thionyl chloride with stirring held at 0° to 20° C. After completion of addition, the mixture was stirred at the same temperature for 1 hour, and a solution of 1.74 g of benzylpiperazine in 10 ml of methylene chloride was added dropwise thereto. The mixture was then stirred for 4 hours at room temperature. The reaction mixture was thoroughly washed with an aqueous potassium carbonate solution, then washed with water, and dilute hydrochloric acid, dried over sodium sulfate, and the solvent was distilled off. The residue was isolated and purified by silica-gel column chromatography [silica-gel: WAKO C-200, eluent: chloroform:methanol (V/V)=20:1] followed by recrystallization from isopropyl alcohol to give 298 mg of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([C:15]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[F:35])[CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[O:16])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[O:36]=[C:37]([CH3:41])[C:38](O)=[O:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:34]1[CH:33]=[CH:32][C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[CH:18][C:17]=1[C:15]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:38](=[O:39])[C:37](=[O:36])[CH3:41])[CH2:10][CH2:9]1)=[O:16]
Reactant: CC(=O)C(=O)O
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)C(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 46.4 %

Procedure:
4-(3-(1,4-diazepane-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one TFA salt (320 mg, 0.65 mmol), 2-oxopropanoic acid [0.3 ml (d=1.26), 4.29 mmol], DIPEA (1 ml, 6 mmol), and HATU (510 mg, 1.34 mmol) were mixed in DMF (30 ml). After the resulting reaction mixture was stirred at room temperature for 60 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:2) to afford the desired product (136 mg, 45.1%) as an off white solid.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[SH:12].Cl[CH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>CN(C)C=O>[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: ClCc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(SCc3nc4ccccc4s3)nc2c1
Reaction time: 2 h
Yield: 58.1 %

Procedure:
1.5 g (50 mmol-80%) of sodium hydride were added under nitrogen to a stirred solution of 7.6 g (50 mmol) of 2-benzimidazolethiol in 76 ml of dimethylformamide and after one hour, 7.2 g (40 mmol) of 2-chloromethyl-benzothiazole were added with ice cooling. The mixture stood at room temperature for 2 hours and the solution was concentrated under reduced pressure in a nitrogen stream. The residue was dissolved in ethyl acetate and the solution was washed with ice cold 2N sodium hydroxide solution and aqueous saturated sodium chloride solution, was dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 6.91 g (58% yield) of 2-(1H-benzimidazol-2-yl-thiomethyl)-benzothiazole in the form of pale yellow crystals after crystallization from dichloromethane melting at 159°-162° C.
Reaction SMILES: [OH:1][CH:2]([CH2:15][CH2:16][P:17]([O:22]CC)([O:19]CC)=[O:18])[CH2:3][O:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:14].Br[Si](C)(C)C>CN(C)C=O>[OH:1][CH:2]([CH2:15][CH2:16][P:17]([OH:19])([OH:22])=[O:18])[CH2:3][O:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:14]
Reactant: CCOP(=O)(CCC(O)COn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2OCC(O)CCP(=O)(O)O
Yield: 82.5 %

Procedure:
A solution of 9-[2-hydroxy-4-(diethoxyphosphoryl)butoxy]adenine (0.50 g, 0.14 mmol) and bromotrimethylsilane (0.184 ml, 1.4 mmol) in dry dimethylformamide (3 ml) was stirred at room temperature for 3 hours. The solvent was then evaporated and the residue was coevaporated with dimethylformamide (2×5 ml) and methanol:water (9:1) solution. The product crystallised from water:methanol (9:1) solution to give the title compound (35 mg, 83%); m.p. 265°-267° C. 1H NMR: δH [(CD3)2SO] 1.6 (4H, m, CH3CH2CH2P), 3.8 (1H, m, CHCH2CH2P) 4.25 (2H, m, OCH2) 7.41 (2H, br. s, D2O exchangeable, NH2), 8.16 (1H, s, H-2), 8.36 (1H, s, H-8). Found: C, 35.78; H, 4.52; N, 22.25%. C9H17N5PO5 requires: C, 35.65; H, 4.65; N, 23.1%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]=[C:28]=[O:29]>O1CCCC1>[CH3:26][NH:27][C:28](=[O:29])[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=1
Reactant: Oc1cccc(C2CCCN2Cc2ccncc2)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2Cc2ccncc2)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirred solution of 3-[1-(4-pyridinylmethyl)-2-pyrrolidinyl]phenol (0.60 g) in dry tetrahydrofuran (16 ml) was added milled potassium carbonate (0.36 g), followed by methyl isocyanate (0.15 ml), dropwise, at ambient temperature, under nitrogen, with stirring. The mixture was stirred for 17 hrs and filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, ether). The appropriate fractions were collected and concentrated to afford 0.63 g (86%) of product. Trituration of the residue with petroleum ether gave the analytical sample, mp 92°-105° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=O)=[O:7].[CH2:10]([NH2:12])[CH3:11].C(O)C>C(OCC)C.C(N(CC)CC)C>[CH2:10]([N:12]1[CH2:3][CH2:4][CH2:5][S:6]1(=[O:9])=[O:7])[CH3:11]
Reactant: O=S(=O)(O)CCCCl
Reactant: CCN
Agent: [Cl-]
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCN1CCCS1(=O)=O
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 24 g of chloride of 3-chloropropanesulfonic acid in 150 ml ethyl ether is added drop-by-drop a solution of 12 g ethylamine and 10 ml ethyl ether. The addition of the ethylamine solution is carried out under stirring and with cooling with the aid of an ice bath. After addition of the solution, the stirring is continued for 1 hour. A white precipitate of ethylamine chlorhydrate forms, which is removed by filtration upon fritted glass. Ethyl ether is removed by evaporation under reduced pressure and, to the residue obtained, is added a mixture of 4.8 g soda pellets, 400 ml ethanol and 12.5 g triethylamine. The mixture is subjected to reflux for 2 hours. After cooling, the solvent is evaporated and the residue is distilled under vacuum. There is obtained 14.2 g (yield: 70%) of N-ethylpropanesultam (boiling point under 0.1 torr: 88° C.).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:41])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21](OCCCC)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].[NH2:44][C:45]1[NH:49][N:48]=[N:47][N:46]=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:41])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([NH:44][C:45]4[NH:49][N:48]=[N:47][N:46]=4)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)Cc1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Cc2ccc(OC(F)(F)F)cc2)C2CCc3cc(C(=O)Nc4nnn[nH]4)ccc32)CC1

Procedure:
Butyl 1-((trans-4-tert-butylcyclohexyl){[4-(trifluoromethoxy)phenyl]acetyl}amino)indane-5-carboxylate, enantiomer A (55 mg) or enantiomer B (45 mg), was saponified with aqueous LiOH and then coupled to 5-amino tetrazole following the procedure described (Step D., Example 1/2) to give 1-((trans-4-tert-butylcyclohexyl){[4-(trifluoromethoxy)phenyl]acetyl}amino)-N-1H-tetrazol-5-ylindane-5-carboxamide. Enantiomer A: HPLC/MS: m/z=585.2 (M+1), Rt=2.75 min. 1H NMR (DMSO-d6): δ 12.30 (1H, br s), 7.90 (1H, s), 7.85 (1H, d, J=8.0 Hz), 7.31 (4H, s), 7.04 (1H, d, J=8.0 Hz), 4.83 (1H, m), 3.77 (2H, m), 3.37 (1H, m), 2.96 (1H, m), 3.08-3.00 (1H, m), 2.91-2.84 (1H, m), 2.41-2.31 (1H, m), 2.24-2.19 (1H, m), 1.78 (2H, m), 1.61 (2H, m), 1.18-0.95 (4H, m), 0.85 (9H, s). Enantiomer B: HPLC/MS and 1H NMR (DMSO-d6) are identical to those of enantiomer A.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[S:15][C:14]2[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:12][C:11]([Cl:22])=[N:10][C:9]=2[CH:8]=1)[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[S:15][C:14]2[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:12][C:11]([Cl:22])=[N:10][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To as solution of 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-acrylic acid ethyl ester (2 g) in ethyl acetate (100 mL) was added a suspension of Pd/C (200 mg) in ethanol (10 mL). The flask was flushed with nitrogen and then a hydrogen balloon was fitted. The reaction mixture was stirred at room temperature for 16 h. The mixture was then filtered through Celite and the filtrate concentrated to give 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)propionic acid ethyl ester as a yellow solid (1.83 g).
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: OCC1CO1
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: CO
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:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(Br)cn1
Reactant: OB(O)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(Br)cc2)cn1

Procedure:
The 5-bromo-2-methoxypyridine was reacted with 4-bromobenzeneboronic acid using the procedure described in Example 25 for the preparation of the compound of formula 2. The product was purified by flash column chromatography on silica gel using a gradient of n-pentane to 3% ethyl acetate in n-pentane to give 5-(4-bromophenyl)-2-methoxypyridine as an oil (0.56 g), NMR: 3.9(3H,s), 6.9(1H,d), 7.61(4H,s), 8.0(1H,dd) and 8.5(1H,d).
Reaction SMILES: S(O[CH2:6][CH2:7][O:8][S:9](=[O:12])(=[O:11])[NH2:10])(=O)(=O)N.[CH2:13]([OH:18])[CH2:14]CCO>>[S:9]([O:18][CH2:13][CH2:14][CH2:6][CH2:7][O:8][S:9](=[O:11])(=[O:12])[NH2:10])(=[O:11])(=[O:8])[NH2:10]
Reactant: NS(=O)(=O)OCCOS(N)(=O)=O
Reactant: OCCCCO
Product: NS(=O)(=O)OCCCCOS(N)(=O)=O

Procedure:
1,4-Bis-O-sulfamyl-1,4-butanediol is prepared in the same manner as 1,2-bis-O-sulfamyl-1,2-ethanediol in Example 1 except that 1,4-butanediol (34.6 g., 0.385 mol.) is employed as the alkanediol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[C:10]([OH:14])(=[O:13])[CH2:11][SH:12].[OH-].[Na+:16]>CS(C)=O>[Cl:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[CH:11]([SH:12])[C:10]([O-:14])=[O:13].[Na+:16]
Reactant: Clc1ccc(Cl)c(Br)c1
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C([O-])C(S)c1cc(Cl)ccc1Cl
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a 300 ml four-necked flask equipped with a stirrer, a thermometer and a condenser were charged 24.9 g (0.110 mol) of 1-bromo-2,5-dichlorobenzene, 13.19 g (0.143 mol) of thioglycolic acid, 12.06 g (0.286 mol) of 95% sodium hydroxide and 100 g of dimethylsulfoxide, followed by stirring at 120° C. for 4 hours. Then, after distilling off the dimethylsulfoxide under reduced pressure, 100 g of water was added to the residue. After dissolving the residue therein at 100° C., the solution was cooled for crystallization and filtered to yield sodium 2,5-dichlorophenylthioglycolate, which was then dissolved in 100 g of water with heating and acidized with concentrated hydrochloric acid, filtered and dried to yield 19.6 g of a light yellowish white powder of 2,5-dichlorophenylthioglycolic acid. The yield based on 1-bromo-2,5-dichlorobenzene was 75.1%.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N:19]2[C:23](=[O:24])[C:22]3=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=[C:21]3[C:20]2=[O:30])[CH:13]=1)=O)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N:19]2[C:23](=[O:24])[C:22]3=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=[C:21]3[C:20]2=[O:30])[CH:13]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(Cl)cc2C1=O
Reaction time: 4 h

Procedure:
The mixture of 0.75 g of N-(4-benzyloxycarbonylamino-o-tolyl)-4-chlorophthalimide 100 ml of ethyl acetate and 0.1 g of 10% palladium on charcoal is hydrogenated at 2.5 atm. and room temperature for 4 hours whereby the intermediarily formed carbaminic acid decarboxylates. The mixture is filtered, the filtrate concentrated to 10 ml and the precipitate formed collected, to yield the N-(4-amino-o-tolyl)-4-chlorophthalimide melting at 202°-204°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:29][S:30]([O:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:5]4=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1)(=[O:32])=[O:31]
Reactant: O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reaction time: 15 h
Yield: 44.3 %

Procedure:
To a stirred mixture of (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (517 mg, 1.3 mmol) from Example 162, TEA (194 μL, 1.4 mmol), and CH2Cl2 (15 mL) at rt under argon was added methanesulfonyl chloride (152 μL, 2.0 mmol). After stirring the mixture for 15 h, additional TEA (194 μL, 1.4 mmol) and methanesulfonyl chloride (152 μL, 2.0 mmol) were added. After stirring for an additional 18 h, the mixture was diluted with CH2Cl2 and stirred with saturated aq NaHCO3 (50 mL) for 30 min. The layers were separated and the organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with a gradient of 100% hexanes to 100% EtOAc, to afford (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl methanesulfonate (274 mg, 44%) as a clear oil. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.39 (t, J=1.8 Hz, 1H), 8.16 (d, J=7.4 Hz, 1H), 8.04 (dd, J=2.6, 9.5 Hz, 1H), 7.66 (d, J=1.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.22 (dd, J=1.4, 8.2 Hz, 1H), 5.46 (s, 2H), 4.98 (m, 1H), 4.06 (m, 1H), 2.99 (s, 3H), 2.01 (m, 1H), 1.54-1.72 (m, 4H), 1.34-1.50 (m, 3H); LCMS (ESI) m/z 476 (M+H)+.