Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=3)[CH2:13][CH2:12]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1nccc(N2CCC(C=O)CC2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nccc(N2CCC(CN3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Yield: 36.7 %

Procedure:
To a solution of 1-(2-methylpyrimidin-4-yl)-4-(formyl)piperidine (4.25 g) and N-t-butoxycarbonyl piperazine (5.34 g) in methanol/acetic acid (99:1) (100 ml) was added sodium cyanoborohydride (5.41 g) portionwise over 30 minutes and the resultant suspension stirred at ambient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 10% methanol in ethylacetate to give 1-(tert-butoxycarbonyl)-4-[1-(2-methylpyrimidin-4-yl)-4-piperidylmethyl]piperazine (2.85 g) as a solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=2)[C:9]#[N:10])[CH2:3][CH2:2]1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=2)[C:9](=[NH:10])[O:12][CH2:13][CH3:14])[CH2:2][CH2:3]1
Reactant: CC[O-]
Reactant: N#Cc1cncc(C2CC2)c1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1cncc(C2CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.3 %

Procedure:
To a solution of 5-cyclopropylnicotinonitrile (0.45 g, 3.1 mmol) in ethanol was added sodium ethoxide (0.212 g, 3.1 mmol). The reaction mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure to afford the title compound (0.45 g) which was used without further purification. MS (ES+APCI) (M+H) 191.2; LCMS retention time 1.149 min (Method L1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:18]=[C:17]([Cl:19])[S:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[Br:13][C:14]1[CH:18]=[C:17]([Cl:19])[S:16][C:15]=1[S:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:21]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2sc(Cl)cc2Br)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-bromo-5-chlorothiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (29.0 mg) with purity >90%. MS (pos) m/z 445.0, 447.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][C:10]([NH:14]C(OCC3C=CC=CC=3)=O)([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][C:10]([NH2:14])([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCCC(NC(=O)OCc3ccccc3)(CC1)C2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C12CCCC(N)(CC1)C2
Reaction time: 6 h
Yield: 83.8 %

Procedure:
5-Benzyloxycarbonylamino-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (2.0 g, 6.05 mmol) was dissolved in ethanol (50.0 mL). Pd/C (10%) (0.32 g, 0.30 mmol) was added. The mixture was hydrogenated under 50 psi H2 at rt for 6 hrs. The catalyst was removed by filtration through a layer of Celite®. The filtrate was concentrated under reduced pressure to afford 1.0 g (84%) of the desired product. ESI-MS m/z: 198 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1)(=O)C.[BrH:21]>O>[BrH:21].[BrH:21].[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(CNc2nc3ccccc3s2)CC1
Agent: Br
Solvent: O
Product: c1ccc2sc(NCC3CCNCC3)nc2c1
Yield: 79 %

Procedure:
A mixture of 140 parts of 1-acetyl-N-(2-benzothiazolyl)-4-piperidinemethanamine and 1500 parts of a hydrobromic acid solution 24% in water was stirred and refluxed for 5 hours. The reaction mixture was evaporated and the residue was suspended in boiling ethanol. After cooling, the product was filtered off and dried, yielding 122 parts (79%) of N-(4-piperidinylmethyl)-2-benzothiazolamine dihydrobromide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:17][CH2:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)CCn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
A mixture of 4-(4-nitrophenyl)-1H-imidazole (for a preparation see Intermediate 120) (3.5 g, 18.5 mmol), 1,1-dimethylethyl 2-propenoate (2.37 g, 2.71 mL, 18.5 mmol) and DBU (2.82 g, 2.79 mL, 18.5 mmol) in DMF (50 mL) was stirred at 50° C. for 16 h then was cooled to room temperature and partitioned between AcOEt (100 mL) and water (100 mL). The layers were separated and the organic phase was washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 25 to 50% AcOEt in hexanes) gave 1,1-dimethylethyl 3-[4-(4-nitrophenyl)-1H-imidazol-1-yl]propanoate (2.6 g, 8.19 mmol, 44%) as an orange solid. LCMS (method G): Retention time 0.90 min, [M+H]+=318.0
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.O(CC)CC.C([Li])CCC.[N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:26]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:16]=[CH:17][CH:18]=[CH:19]2)[OH:27]
Reactant: c1ccsc1
Reactant: O=Cc1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc2ncccc2c1)c1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a stirred and cooled (-5°/0° C.) solution of 5.4 parts of thiophene in 21.3 parts of 1,1'-oxybisethane were added portionwise 43.5 parts of a solution of n. butyllithium in hexanes 1.6M. After stirring for 20 min. at 0° C., there was added a solution of 5 parts of intermediate 16, namely 6-quinolinecarboxaldehyde, in 71.2 parts of tetrahydrofuran. Stirring at 0° C. was continued for 1 hour and then the reaction mixture was poured into 200 parts of ice-water. The product was extracted with 1, 1'-oxybisethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2C12 /CH3OH 95:5). The eluent of the desired fraction was evaporated, yielding 2.4 parts (31.1%) of α-(2-thienyl)-6-quinolinemethanol (interm. 17).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][OH:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C=C[C@@H]1[C@H](CO)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=C[C@@H]1[C@H](COC(C)=O)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (54.2 g, 0.17 mol) and 4-(dimethylamino)pyridine (0.5 g, 4.1 mmol), in anhydrous pyridine (400 mL) was reacted with acetic anhydride (30 mL, 0.32 mol) at 0° C. for 1 hour then allowed to warm to room temperature. The reaction was stirred an additional 16 hours. The pyridine was removed in vacuo at 30° C. The residue was partitioned between ethyl acetate (100 mL) and of water (400 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL) and the combined ethyl acetate layers were washed with brine, dried with MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 49.6 g, 81%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:17]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCCl>[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:20]2[CH:21]=[CH:22][C:17]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:12](=[O:13])[C:11]4[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=4)=[CH:28][CH:29]=3)=[CH:18][CH:19]=2)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccc(Cc2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 47 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
In a 10-liters three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 1300 g (9.75 mole) of aluminum chloride and 4.2 liters of 1,2-dichloroethane were mixed, and 1323 g (7.13 mole) of paranitrobenzoyl chloride was introduced with ice cooling to be dissolved. After warming the reaction solution to 47° C., a solution of 500 g (2.97 mole) of diphenylmethane in 500 milliliters of 1,2-dichloroethane was added dropwise for 3 hours and 30 minutes. After the dropwise addition was ended, the solution was stirred at 50° C. for 4 hours. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was poured in 7 liters of ice water, and then extracted with 7 liters of chloroform. The solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, and then dried with magnesium sulfate. After removing off chloroform by a rotary evaporator, filtration was carried out when crystals being deposited sufficiently. Filtered substances were treated with a silica gel column and recrystallized from chloroform/ethyl acetate, to obtain 867 g of 1,1-bis(4-(4-nitrobenzoyl)phenyl)methane as crystals.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[CH2:18]([C@H:20]1[O:22][CH2:21]1)[Cl:19]>C1(C)C=CC=CC=1>[Cl:19][CH2:18][C@@H:20]([OH:22])[CH2:21][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and lithium chloride (12.6 g, 0.30 mol) were added to 100 mL of toluene. The mixture was stirred at 25° C. for 30 minutes. (S)-epichlorohydrin (18.6 g, 0.2 mol) was then added and stirred at 60° C. for 8 hours. The mixture was filtered and the solvent was evaporated to provide 52 g of colorless oil in 90% yield. HPLC: 99.3%.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[O:8]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:7]([OH:8])[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCC(OC(C)=O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCCC(O)c1ccccn1

Procedure:
A solution of 3-(2-pyridyl)-1,3-propanediol diacetate (1 mmole) in methanol-water (3:1) was treated with potassium carbonate (5 mmole) at 25° C. for 3 h. Evaporation and chromatography gave 3-(2-pyridyl)-1,3-propanediol as a solid.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:21])[C@@H:11]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[BH4-].[Na+]>CO.C(Cl)Cl>[O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:10]2)[CH2:7][CH2:6]3
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](N3CCCC3)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reaction time: 12 h

Procedure:
After dissolving 39.2 g of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17-one in a mixture of 392 ml of methanol and 56 ml of methylene chloride. 14.7 g Sodium borohydride are portionwise added while stirring and introducing nitrogen at such a rate that the temperature reaches room temperature as a maximum. The solution containing a precipitate is left to stand for 12 hours, then methylene chloride is evaporated, and the residue is diluted with water. The precipitate is filtered, thoroughly washed with water, dried and recrystallized from methanol to obtain the title product in a yield of 33.3 g (89.5%), m.p.: 167°-169° C.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([S:8]([CH3:11])(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>C1COCC1.O.O>[CH3:11][S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:12])=[O:3])(=[O:10])=[O:9]
Reactant: CCOC(=O)C(C)(C)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
To a solution of 500 mg (2.6 mmol) of 2-methanesulfonyl-2-methyl-propionic acid ethyl ester in THF/water (4/1, 5 mL) were added 270 mg (6.6 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was further diluted with water (20 mL) and then washed with DCM (2×15 mL). The basic aqueous layer was cooled in an ice bath and acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with isopropanol/chloroform (1/1, 3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 413 mg of 2-methanesulfonyl-2-methyl-propionic acid. The compound did not ionise under LCMS conditions, thus the structure was confirmed by 1H-NMR spectroscopy:
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([O:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:25]([O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26].Cl>O1CCOCC1.O>[CH:40]1[C:41]2[CH:29]([CH2:28][O:27][C:25]([N:13]3[CH2:12][C:11]4([CH2:10][CH2:9][N:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:18][CH2:17]4)[O:16][CH2:15][CH2:14]3)=[O:26])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]=2[CH:37]=[CH:38][CH:39]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: c1ccc(CN2CCC3(CC2)CNCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCOC2(CCN(Cc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
To a solution of compound 402 (2.81 g, 11.4 mmol) in 1,4-dioxane (53 mL) was added 10% sodium bicarbonate in water (21.5 mL) followed by 9-fluorenylmethyl chloroformate (2.96 g, 11.4 mmol). The resulting mixture was stirred at room temperature for four hours, and then neutralized with 3N HCl. The solution was concentrated to a solid and then purified by flash chromatography (0-10% methanol in DCM with 1% NH4OH) to give compound 403 as a white solid (1.2 g, 22.5%). LCMS-ESI (POS), M/Z, M+1: Found 469.1, Calculated 469.2.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])(=[O:20])=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3[C:10]([CH:15]([CH3:16])[N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH3:30])(=[O:20])=[O:19])[C:2]=2[CH:7]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccccc3C2C)c(OC)c1

Procedure:
The title compound was prepared from N-[1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethyl]-2,4-dimethoxybenzenesulfonamide (550 mg, 1.27 mmol), anhydrous N,N-dimethylformamide (1 mL), and potassium carbonate (351 mg, 2.5 mmol) according to the procedure and in the same manner as described in Example 105, step d, and the product (525 mg, 99%) isolated as a white solid;
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1ccc(F)cn1
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(F)cn2)nc2nc(N)sc12
Yield: 57.3 %

Procedure:
The title compound was prepared by General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (940 mg, 3.1 mmol) and 2-[(1R)-1-chloroethyl]-5-fluoropyridine (0.81 g, 5.1 mmol). The product was purified by flash column chromatography to yield 0.75 g (56% yield) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:37][C:38](=[O:40])[CH3:39])[CH2:7][NH:8][C:9](=[O:36])[C:10]1[C:15]([I:16])=[C:14]([N:17]=[C:18]=[O:19])[C:13]([I:20])=[C:12]([C:21](=[O:34])[NH:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:11]=1[I:35])(=[O:3])[CH3:2].[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][NH2:45]>ClCCl>[C:31]([O:30][CH:24]([CH2:23][NH:22][C:21](=[O:34])[C:12]1[C:11]([I:35])=[C:10]([C:9](=[O:36])[NH:8][CH2:7][CH:6]([O:37][C:38](=[O:40])[CH3:39])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:15]([I:16])=[C:14]([NH:17][C:18]([NH:41][CH2:42][CH:43]([OH:46])[CH2:44][NH:45][C:18]([NH:17][C:14]2[C:13]([I:20])=[C:12]([C:21](=[O:34])[NH:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:11]([I:35])=[C:10]([C:9](=[O:36])[NH:8][CH2:7][CH:6]([O:37][C:38](=[O:40])[CH3:39])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:15]=2[I:16])=[O:19])=[O:19])[C:13]=1[I:20])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:33])[CH3:32]
Reactant: NCC(O)CN
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)NCC(O)CNC(=O)Nc2c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 18 h

Procedure:
To a solution of acetic acid 1-acetoxymethyl-2-[3-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-5-isocyanato-benzoylamino]-ethyl ester in dichloromethane was added 1,3-diamino-2-hydroxypropane (0.5 equivalent). The reaction mixture was stirred for 18 hours and then purified by column chromatography to give Acetic acid 2-acetoxy-3-[3-[3-(3-{3-[3,5-bis-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo phenyl]-ureido}-2-hydroxy-propyl)-ureido]-5-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-benzoylamino]-propyl ester. This was dissolved in methanol and treated with aqueous ammonia. The material was purified by preparatie HPLC to give 1,3-bis-[N,N′-Bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-5-ureido-isophthalamide]-2-hydroxypropane as a white powder after freeze drying.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: COC(=O)Cc1nc2nc(C)cc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1nc2nc(C)cc(Cl)n2n1

Procedure:
A solution of the product obtained in Step 3 (1.5 g) in 15 ml of phosphorus oxychloride was refluxed for two hours, excess phosphorus oxychloride was distilled off, the residue was dissolved in chloroform, and the solution was washed with ice water. After removing the solvent from the organic layer under reduced pressure, the residue was purified by silica gel chromatography, affording 1 g of the objective compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J36) (239 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow oil (180 mg, 44%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:14]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][C:11]([NH2:12])=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1.[CH3:25]I>CN(C)C=O.[Ag]=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:14]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][C:11]([NH:12][CH3:25])=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1
Reactant: COCCOCOc1cc(N)c([N+](=O)[O-])cc1OCOCCOC
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CNc1cc(OCOCCOC)c(OCOCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
1.57 g (4.54 mmol) of 4,5-di(2-methoxyethoxymethoxy)-2-nitroaniline obtained in step (C) of Reference Example 34 was dissolved in 16 ml of N,N-dimethylformamide, and 2 g (8.63 mmol) of silver oxide and 10 ml (160 mmol) of methyl iodide were added thereto. The mixture was stirred at room temperature for one hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate/hexane=1/1). The eluted fraction containing the desired compound was concentrated to obtain 0.85 g of crude 4,5-di(2-methoxyethoxymethoxy)-N-methyl-2-nitroaniline. (B) 0.85 g of the crude product obtained in the above reaction (A) was dissolved in 16 ml of ethanol, and 0.4 g of a 10% palladium carbon catalyst was added thereto. The catalytic hydrogenation was conducted at 80° C. for two hours. The catalyst was removed by filtration, and then to the filtrate, 1 g (6.25 mmol) of potassium O-ethyl dithiocarbonate was added. The mixture was refluxed at a boiling point for two hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water. The solution was adjusted to pH5.0 with acetic acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate/hexane=3/1) to obtain 67 mg of the above-identified compound.