Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[C:8](Br)=[CH:9][N:10]=1)=[O:5])[CH3:2].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>CCN(CC)CC.C1COCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[C:8]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:9][N:10]=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ncc(Br)n1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc(C#C[Si](C)(C)C)n1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 24.1 %

Procedure:
To a solution of 800 mg (3.43 mmol) of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester in Et3N (10 mL) and THF (10 mL) was added 33 mg (0.17 mmol) of CuI and 120 mg (0.10 mmol) of Pd(PPh3)4 . Trimethylsilylacetylene (0.48 mL, 3.4 mmol) was then added and the reaction was heated at 70° C. under N2. After 12 h, the mixture was cooled and filtered though a pad of celite, and then concentrated and chromatographed (0–50% EtOAc in hexanes) to give 1-methyl-5-trimethylsilanylethynyl-1H-imidazole-2-carboxylic acid ethyl ester as a brown oil (205 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:15])O[C:12](=[O:14])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[NH:22]([N:23]1[C:12](=[O:14])[CH:13]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]1=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: O=C1C=C(c2ccc(Cl)c(Cl)c2)C(=O)O1
Solvent: CC(=O)O
Product: O=C1C=C(c2ccc(Cl)c(Cl)c2)C(=O)N1Nc1ccccc1

Procedure:
2.43 g (10 mmol) of -(3,4-dichlorophenyl)furan-2,5-dione and 1.08 g (10 mmol) of phenyl hydrazine in 50 ml of glacial acetic acid were boiled under ref lux for 5 h. The mixture was cooled and the product was then filtered off and washed first with glacial acetic acid and subquently with pentane. Yield: 1.8 g of a crystalline solid, m.p. 208-210° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>O.CO.C(O)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[CH:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1cccc(Br)c1)c1ccccc1
Yield: 75.6 %

Procedure:
Sodium hydroxide (12.00 g, 300 mmol) and acetophenone (24 g, 200 mmol) were dissolved in water (90 mL) and methanol (300 mL). 3-Bromobenzaldehyde (37 g, 200 mmol) dissolved in ethanol (50 mL) was added dropwise to the acetophenone solution. A slurry quickly formed, which was allowed to two additional hours. The slurry was filtered, was with water until the filtrate was neutral to pH paper, and dried at 80° C. for 12 hours. Light yellow crystals were obtained (43.4 g, 75.6% yield).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:28]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Temperature: 80 °C
Reaction time: 15 h
Yield: 47.4 %

Procedure:
A mixture of 1.0 g (3.41 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide in 30 ml of dimethylformamide was stirred at room temperature for 2 hours and at 80° C. for 15 hours. Subsequently, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide were again added and the mixture was stirred at 80° C. for a further 6 hours. The reaction mixture, cooled to room temperature, was poured into 300 ml of an ice/water mixture and extracted three times with 250 ml of ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The yellow oil (1.82 g) was separated on silica gel using an eluent gradient of 4:1 to 3:2 of a mixture of hexane and ethyl acetate as the eluent. There were obtained 620 mg (72% of theory) of tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate which, after recrystallization from a mixture of methylene chloride and hexane, gave 361 mg (28% of theory) as a white, crystalline product; MS: 383 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][CH2:6][C:7](Cl)=[O:8].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2)(=[O:22])=[O:21].CCN(CC)CC.C(Cl)Cl>CC#N>[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:7](=[O:8])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([Cl:1])[CH:3]=1)[CH2:26]2)(=[O:22])=[O:21]
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CNC2
Reactant: O=C(Cl)COc1ccc(F)c(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COc1ccc(F)c(Cl)c1)N1Cc2ccc(S(=O)(=O)Nc3nccs3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(3-Chloro-4-fluorophenoxy)acetyl chloride (52 mg, 0.23 mmol) was added to a stirring solution of 2,3-Dihydro-1H-isoindole-5-sulfonic acid thiazol-2-ylamide (65 mg, 0.23 mmol), Et3N (64 μl, 0.46 mmol) and CH2Cl2 (500 μl), under N2. The reaction mixture was stirred at room temperature for 30 minutes. Product formation was observed by LC/MS (10-99% CH3CN). Purification by Gilson preparative HPLC (10-99% CH3CN) gave the desired amide. LC/MS (10-99% CH3CN), M/Z: M+1 obs=468.1; tR=2.95 min.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C)C=O.O>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][CH2:32][C:33]#[N:34])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NCC#N)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 55.9 %

Procedure:
To the solution of the product from Example 205 (10 mg, 0.023 mmol) in N,N-dimethylformamide (0.2 mL) was added bromoacetonitrile (2.5 μL, 0.035 mmol) and potassium carbonate (5 mg, 0.035 mmol). The mixture was stirred while heating at 100° C. in a microwave reactor for 1 h. After cooling to 25° C., the orange solution was diluted with water and the pH of the aqueous layer was adjusted to pH 5 with acetic acid. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with water and brine, dried over magnesium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel eluting with 1% methanol/dichloromethane to give the title compound as a yellow solid (6.0 mg, 55%). MS (ESI−) m/z 465 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.99 (d, J=6.62 Hz, 6 H) 1.58 (m, 2 H) 1.68 (m, 1 H) 4.46 (m, 4 H) 6.92 (m, 1 H) 7.16 (m, 2 H) 7.49 (m, 1 H) 7.61 (d, J=9.19 Hz, 1 H) 8.56 (dd, J=7.90, 1.65 Hz, 1 H) 8.89 (m, 1 H) 14.00 (br s, 1 H) 15.39 (br s, 1 H). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (d, J=6.62 Hz, 6 H) 1.48 (m, 2 H) 1.64 (m, 1 H) 4.31 (m, 4 H) 6.49 (t, J=6.62 Hz, 1 H) 6.99 (m, 2 H) 7.13 (m, 2 H) 8.35 (dd, J=7.72, 1.84 Hz, 1 H) 8.51 (dd, J=4.41, 1.84 Hz, 1 H) 15.73 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([S:11](=[O:14])(=[O:13])[NH2:12])=[C:4](F)[CH:3]=1.[CH2:16]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]>O>[CH2:16]([N:20]1[CH2:25][CH2:24][N:23]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[S:11](=[O:14])(=[O:13])[NH2:12])[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reactant: CCCCN1CCNCC1
Solvent: O
Product: CCCCN1CCN(c2cc(Cl)c(C(=O)O)cc2S(N)(=O)=O)CC1
Reaction time: 8 h

Procedure:
126 Grams of 6-chloro-4-fluoro-3-sulfamoylbenzoic acid (0.5 mole) were stirred with 0.2 l of N-butylpiperazine for 2 hours at 110° C. Subsequently the reaction solution was poured into 2 l of water, a small amount of amorphous precipitate formed was separated, and the filtrate was adjusted to a pH of 7.5 with 2N HCl. After having stood overnight at room temperature, the crystalline precipitate was suction-filtered and was recrystallized from a mixture of ethanol and water.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][C:11]2=[O:17])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[OH-].[K+]>CO>[C@H:1]1([N:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][C:11]2=[O:17])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccn([C@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1

Procedure:
The process of claim 27 wherein 1-(β-D-ribofuranosyl)-4-aminopyrimidin-2-one is contacted with potassium hydroxide in methanol to form 1-(α-D-ribofuranosyl)-4-aminopyrimidin-2-one
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:17])[N:9]3[CH2:13][C:12]([OH:16])([CH2:14][OH:15])[C:11]=1[C:10]=23.C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>ClCCl.O1CCCC1.CN(C)C=O.C([Sn](=O)CCCC)CCC>[CH3:35][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:15][CH2:14][C:12]2([OH:16])[C:11]3=[C:2]([Cl:1])[CH:3]=[N:4][C:5]4[CH:6]=[CH:7][C:8](=[O:17])[N:9]([C:10]=43)[CH2:13]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1ccc2ncc(Cl)c3c2n1CC3(O)CO
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)ccc4ncc(Cl)c2c43)cc1
Yield: 95.2 %

Procedure:
A suspension of (4R/S)-3-chloro-4-hydroxy-4-(hydroxymethyl)-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (300 mg, 1.2 mmol) in dichloromethane/tetrahydrofuran/N,N-dimethylformamide (10 ml/10 ml/2 ml) was treated with triethylamine (0.25 ml, 1.8 mmol), para-toluenesulphonyl chloride (220 mg, 1.2 mol) and dibutyltin oxide (15 mg, 0.06 mmol). After 3 hours water was added and the phases separated. The organic phase was washed with saturated aqueous sodium bicarbonate solution then dried and evaporated affording the product (465 mg).
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[C:18]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:12]1([C:10]2[O:11][C:7]3[C:8]([N:9]=2)=[C:18]2[C:4](=[CH:5][CH:6]=3)[NH:21][C:20](=[O:22])[CH2:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1c([N+](=O)[O-])ccc2oc(-c3ccccc3)nc12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(ccc3oc(-c4ccccc4)nc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (5-nitro-2-phenyl-benzoxazole4-yl)-acetonitrile (1.10 g, 3.98 mmol) (Starting Material 5) was suspended in concentrated H2SO4 /H2O (1/1, 25 mL) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. To a solution of the crude acid in acetic acid (10 mL) heated at reflux was added excess zinc dust (1.57 g, 24.2 mmol) portionwise during thirty minutes or until the reaction solution clarified. The mixture was filtered through a Celite® (Fisher Scientific) pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-oxazolo[4,5-e]indol-7-one. (Yield 180 mg, 18%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>C1COCC1.CN(C=O)C>[CH2:22]([NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCNC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. n-Butylamine (247 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated. It was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (88 mg, 70%). NMR 1H (ppm, CDCl3): 7.96 (s, 1H), 7.69 (d, J3=8.01 Hz, 2H), 7.59 (d, J3=7.16 Hz, 2H), 7.51-7.34 (m, 4H), 6.11 (br. s., 1H), 3.51-3.44 (m, 2H), 1.64 (sext., J3=7.59 Hz, 2H), 1.43 (quint., J3=7.98 Hz, 2H), 0.96 (t, J3=7.32 Hz, 3H).
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:8]1[C:16]2[C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][C:9]=1[NH2:21].N1C=CC=CC=1>O1CCCC1>[C:1]([NH:5][C:6]([NH:21][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[C:16]=2[CH:8]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2oc3c(c2c1)CCCC3
Reactant: CC(C)(C)N=C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.6 %

Procedure:
tert-Butylisocyanate (0.55 g, 5.5 mmol) was added to a cooled (0° C.) solution of 6,7,8,9-tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred for 10 minutes at 0° C. and then allowed to warm to ambient temperature for 5 hours. An additional portion of tert-butylisocyanate (0.65 mL) was added the reaction mixture was stirred overnight. The reaction was incomplete, so pyridine (10 mL) was added and the reaction mixture was heated to reflux for 4.5 hours and then concentrated under reduced pressure. The crude material was dissolved in ethyl acetate and washed with 1 N HCl, water, and brine, dried (Na2SO4) and concentrated. The crude material was recrystallized from acetonitrile to provide 1-tert-butyl-3-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-urea (0.71 g). Mp 310-312° C. (DEC); Anal. Calcd. for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78; Found: C, 71.18; H, 7.84; N, 9.79.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].C[O:7][C:8](=O)[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]([N:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]1[CH2:27][C@@H:26]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:25][N:24]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:23]1)=[O:20]>C(O)C.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]([N:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]1[CH2:27][C@@H:26]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:25][N:24]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:23]1)=[O:20]
Reactant: COC(=O)Cn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
Calcium chloride (650 mg) was suspended in ethanol (80 ml) and sodium borohydride (740 mg) was added at 0° C. After stirring at 0° C. for 15 min, a solution of tert-butyl (3S,5R)-3-[[[1-(2-methoxy-2-oxoethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (1.15 g) in THF (80 ml) was added dropwise. After stirring at room temperature for 2 hr, the reaction mixture was diluted with 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:0)-ethyl acetate-methanol (85:15) was concentrated under reduced pressure to give the object product (849 mg).
Reaction SMILES: C(N1C(=O)[C:12](Cl)=[C:11]([O:16]C)[CH:10]=N1)C1C=CC=CC=1.CSC1C=CC(B(O)O)=CC=1.[CH2:29]([N:36]1[C:41](=[O:42])[C:40](Cl)=[C:39]([C:44]2[CH:49]=[CH:48][C:47]([S:50][CH3:51])=[CH:46]C=2)[CH:38]=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(O)C.CC(C)([O-])C.[K+]>>[CH2:29]([N:36]1[C:41](=[O:42])[C:40]([O:16][CH:11]([CH3:12])[CH3:10])=[C:39]([CH2:44][CH2:49][CH2:48][CH:47]([S:50][CH3:51])[CH3:46])[CH:38]=[N:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Reactant: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1
Agent: CC(C)(C)[O-]
Agent: CSc1ccc(B(O)O)cc1
Agent: [K+]
Solvent: CC(C)O
Product: CSC(C)CCCc1cnn(Cc2ccccc2)c(=O)c1OC(C)C

Procedure:
2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog according to the method of Example 7 and then to the 5-trifluoromethylsulfonyloxy-analog following the method of Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid according to the method of Example 9 provided 2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This 4-chloro-intermediate thus prepared was treated with 2-propanol (20 mL, 261 mmol) and potassium t-butoxide (110 mg, 0.98 mmol) at reflux for 45 minutes furnished 2-benzyl-4-(2-propoxy)-5-[4-(methylthio)pentyl]-3(2H)-pyridazinone. This methyl sulfide was oxidized according to the method of Example 10 to provide the title compound (yield: 180 mg, 80%). mp 109-111° C. 1H NMR (300 MHz, CDCl3) δ 1.18 (d, J=6 Hz, 6H), 3.12 (s, 3H), 5.36 (s, 2H), 5.49 (h, J=6 Hz, 1H), 7.35 (m, 3H), 7.47 (dd, J=9 Hz, 3 Hz, 2H), 7.74 (d, J=9 Hz, 2H), 7.79 (s, 1H), 8.03 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 399 (M+H)+. Anal. calc. for C21H22N2O4S: C, 63.29; H, 5.56; N, 7.03. Found: C, 63.17; H, 5.57; N, 6.95.
Reaction SMILES: [Na].[S:2]([CH2:6][C@H:7]1[O:12][C@H:11]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:10]([OH:37])[C@@H:9]([OH:38])[C@@H:8]1[OH:39])([OH:5])(=[O:4])=[O:3].[Cl-].[Ca+2:41].[Cl-]>O>[Ca:41].[S:2]([CH2:6][C@H:7]1[O:12][C@H:11]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:10]([OH:37])[C@@H:9]([OH:38])[C@@H:8]1[OH:39])([OH:5])(=[O:3])=[O:4]
Reactant: [Ca+2]
Agent: CCCCCCCCCCCCCCCCCC(=O)OCCCO[C@H]1O[C@H](CS(=O)(=O)O)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Cl-]
Agent: [Na]
Solvent: O
Product: [Ca]

Procedure:
2.15 g of 3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol sodium salt was dissolved in 60 ml of water, adsorbed to a WAKOGEL® 100C18 (manufactured by Wako Pure Chemical Industries, Ltd.) column, and 500 ml of 1% calcium chloride solution was poured into the column for substitution, and washed with 500 ml of distilled water. Thereafter, elution was performed with 200 ml each of 50%, 80%, and 100% methanol, and reprecipitated from 98% heated ethanol to obtain 1.47 g of 3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol calcium salt.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[N:17]=[C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]4)[S:19][CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1.[OH-].[Li+]>O1CCCC1.CO.CC1CCCO1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[N:17]=[C:18]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]4)[S:19][CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: CCOC(=O)C1CCN(c2nc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)cs2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(c2nc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)cs2)CC1
Temperature: 50 °C
Yield: 100 %

Procedure:
To a solution of ethyl 1-[4-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (38 mg, 0.08 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added 1M aqueous lithium hydroxide (0.5 mL, 0.5 mmol). The reaction was heated to 50° C. for 2 hours. The mixture was then cooled to room temperature, diluted with 2-methyltetrahydrofuran (30 mL), and washed with 0.1N aqueous hydrochloride acid (30 mL) and brine (30 mL). The aqueous fractions were further extracted with 2-methyltetrahydrofuran (30 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide 1-[4-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylic acid (36 mg, 0.08 mmol, quantitative) as a light blue solid. MS APCI: [M+H]+ m/z 450.1. 1H NMR (400 MHz, DMSO): δ 10.23 (s, 1H); 8.82 (d, J=4.9 Hz, 1H); 8.38 (s, 1H); 7.61 (d, J=7.8 Hz, 1H); 7.50 (d, J=7.8 Hz, 1H); 7.32 (t, J=7.8 Hz, 1H); 7.27 (d, J=5.0 Hz, 1H); 7.15 (s, 1H); 6.65 (s, 2H); 3.93 (d, J=12.3 Hz, 2H); 3.22-3.08 (m, 2H); 1.95 (d, J=13.1 Hz, 2H); 1.65 (d, J=14.4 Hz, 2H). rhSyk=++.