Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(C(C)=O)C>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[S:7][C:6]=3[CH:11]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=c1oc2ccc(O)cc2s1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)Oc1ccc2oc(=O)sc2c1

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (16.8 grams) was mixed with 3-(trifluoromethyl)phenyl isocyanate (18.7 grams) and 1.01 grams of triethylamine in 200 milliliters of methyl ethyl ketone. This solution was heated at reflux temperature for one hour, after which the solvent was removed by evaporation in vacuo. The resulting residue was recrystallized twice from ethyl acetate, leaving the desired purified product, 5-[3-(trifluoromethyl)phenylcarbamoyloxy]-1,3-benzoxathiol-2-one. The product was a white crystalline solid which exhibited a melting point of 166.5°-168° C. Elemental analysis calculated for C15H8F3NO4S (percent): carbon--50.71; hydrogen--2.27; nitrogen--3.94. Found: carbon--51.0; hydrogen--2.29; nitrogen--4.11.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH2:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH2:13]([NH:5][CH2:4][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:12])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C(CN)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C(CNCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-methyl-2-phenyl-butylamine (1.3 g, 8 mmol), benzaldehyde (271 μL, 2.66 mmol) and CH2Cl2 (50 mL) is stirred for 20 min at RT. NaBH(OAc)3 (840 mg, 3.96 mmol) and acetic acid (154 μL, 2.69 mmol) are added. After 2 h the same amounts as indicated above of benzaldehyde, NaBH(OAc)3 and acetic acid are added once again. This procedure is repeated after 4 h. After stirring for 16 h at RT, saturated NaHCO3 solution is added, the CH2Cl2 layer is removed and the aqueous phase is extracted twice with fresh CH2Cl2. The combined organic layers are dried (Na2SO4), evaporated in vacuo and the residue is purified by flash chromatography (hexane/ethyl acetate). The combined pure fractions are evaporated to afford the title compound as a colourless oil. MS: 254.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.03 min.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)=[CH:3][CH:2]=1.[O:21]=[C:22]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:23](O)=[O:24]>>[OH:21][C@@H:22]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:23]([N:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=1)[CH2:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1)=[O:24]
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1
Reactant: O=C(O)C(=O)c1cccnc1
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2cccnc2)cc1
Yield: 26.2 %

Procedure:
In analogy to example 13, p-tolyl-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (95 mg, 0.34 mmol, prepared as in example 14, step1) was coupled to oxo-pyridin-3-yl-acetic acid (54 mg, 0.36 mmol) and reduced to give the title compound as a colorless oil (37 mg, 25%) MS m/e: 416.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([C:18]([N:20]([CH3:42])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:30]([CH3:41])[CH2:29]3)=[CH:23][CH:22]=2)=[O:19])[CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[N:17]=[C:16]([C:18]([N:20]([CH3:42])[C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[C@@H:30]([CH3:41])[CH2:29]4)=[CH:23][CH:22]=3)=[O:19])[CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(F)cc1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Cl)n3)cc2)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Oc4ccc(F)cc4)n3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 190 °C
Reaction time: 0.33 h
Yield: 46.2 %

Procedure:
To sodium hydride (0.0174 g, 60% dispersion in mineral oil, 0.436 mmol) in DMF (4 mL) was added 4-fluorophenol (0.0488 g, 0.436 mmol) and the mixture stirred under an argon atmosphere for 20 minutes. 1,1-Dimethylethyl (2S)-4-({4-[[(6-chloro-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D107) (0.100 g, 0.218 mmol) was added and the reaction mixture was heated in a microwave at 190° C. for 1.5 h. The reaction mixture was concentrated and the residue partitioned between DCM and water. The aqueous layer was further extracted with DCM and the combined organics were dried over Na2SO4 and concentrated to give a yellow oil which was purified by column chromatography to give the title compound as a colourless oil (0.0539 g). MS (ES): MH+ 535.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([O:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21])[C:16](O)=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1.CCN(C(C)C)C(C)C.C(N=C=NC(C)C)(C)C>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[C@@H:20]([O:19][C@H:15]([C:16](=[O:17])[NH:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:21])[CH3:26]
Reactant: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: Nc1nnn[nH]1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethoxy)-propionic acid (62 mg, 0.165 mmol) in THF (5 ml) at room temperature was added 5-aminotetrazole (38.0 mg, 0.447 mmol), DIPEA (0.086 ml, 0.494 mmol) and followed by 1,3-diisopropylcarbodiimide (0.060 ml, 0.387 mmol). The reaction was stirred at room temperature for 3 hr. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. HPLC retention time=0.99 minutes (condition C); MS (m+1)=444.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:28])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][CH2:3][CH3:4].Cl.[NH2:30][OH:31].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:5][C:6](=[O:28])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([C:18]([NH:30][OH:31])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCOC(=O)CC1c2ccc(C#N)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCOC(=O)CC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A flask was charged with 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-cyano-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 18; 590 mg; 1.53 mmol), hydroxylamine hydrochloride (637 mg; 9.16 mmol) (769 mg; 9.16 mmol) followed by ethanol (15 ml) and the resulting suspension was stirred at 80° C. overnight. More hydroxylamine hydrochloride and sodium bicarbonate (3 equivalents of each) were added and the mixture stirred at 80° C. for ca. 14 h. The mixture was cooled to room temperature, and the precipitate was filtered off and the residue washed with ethanol. The combined filtrate and washings were evaporated in vacuo and the residue partitioned between water and ether. The phases were separated and the aqueous phase extracted twice with ether. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound (547 mg).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][C@H:38]([C:41](O)=[O:42])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([NH:28][C:41]([C@H:38]2[CH2:39][CH2:40][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37]2)=[O:42])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)NC2CC2)C1
Reaction time: 3 h

Procedure:
HATU (0.97 g, 2.5 mmol) and cyclopropylamine (0.14 g, 2.5 mmol) were added to a solution of (3S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (0.50 g, 2.3 mmol) and DIPEA (0.48 mL, 2.7 mmol) in DMF (15 mL). The reaction mixture was stirred for 3 h and the solvent was concentrated. The product was recovered in EtOAc and washed with water, saturated NaHCO3 solution, water and brine. The organic layer was dried over anhydrous MgSO4 and the solvent was concentrated to provide tert-butyl (3S)-3-[(cyclopropylamino)carbonyl]pyrrolidine-1-carboxylate as white solid. The intermediate was recovered in TFA (5 mL) and stirred for 2 h. The solvent was concentrated to provide the title compound as yellow oil that was used for the next step without further purification. Yield: 0.21 g (33%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[C:18]([CH2:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[OH:21])=[CH:17][CH:16]=[CH:15][N:14]=1>ClCCl>[Br:12][C:13]1[C:18]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: OC(Cc1cccnc1Br)c1cccc(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(Cc1cccnc1Br)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a vigorously stirred solution of pyridinium chlorochromate and celite in dichloromethane (20 mL) at room temperature was added a solution of 2-(2-bromopyridin-3-yl)-1-(3-chlorophenyl)ethanol in dichloromethane (10 mL). The mixture was stirred at room temperature for 3 hours then filtered through a plug of silica gel, eluted well with dichloromethane and concentrated in vacuo. Purification by chromatography on silica gel gave 2-(2-bromopyridin-3-yl)-1-(3-chlorophenyl)ethanone (313 mg, 64% yield) as white solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH:17]2[CH2:20][N:19](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18]2)=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH:17]2[CH2:18][N:19]([C:1]([Cl:4])=[O:2])[CH2:20]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(Cl)cc2)C1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution of 32.34 g (0.33 mole) of phosgene in 200 ml of methylene chloride cooled with a tap water bath was treated with 45.5 g (0.33 mole) of potassium carbonate and stirred for 30 min, then 105 g (0.3 mole) of 3-(4-chlorophenoxy)-1-diphenylmethylazetidine in 600 ml of methylene chloride was added dropwise. After stirring for an additional 18 hr, the reaction mixture was filtered to remove the inorganic salts then concentrated in vacuo to a dark oily residue, 127.7 g. A solid formed upon standing which was triturated with boiling 30/60 petroleum ether 3 times to remove diphenylmethyl chloride. The residue, 33 g of dark brown crystalline material, was mainly starting material. Upon standing, a white crystalline material separated from the petroleum ether triturates (4.4 g, m.p. 78°-80° C.). The triturates were concentrated in vacuo, yielding 31 g of pale yellow tacky crystals. Trituration of these crystals with isopropyl ether yielded 21.9 g (35.6%) of pale yellow crystalline product.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].Cl[CH2:12][CH:13]=O.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]2[N:6]([CH:12]=[CH:13][N:9]=2)[C:7]=1[CH3:8]
Reactant: O=CCCl
Reactant: Cc1cc(N)nc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc2nccn2c(C)c1Br
Temperature: 25 °C

Procedure:
5-Bromo-4,6-dimethyl-pyridin-2-ylamine (1.51 g, 7.5 mmol) and chloroacetaldehyde (0.95 ml, 50% in water, 7.5 mmol) were mixed with toluene (12 ml). The mixture was heated to reflux for 3 h, upon which time a dark solid residue appeared at the bottom of the reaction flask. After cooling down to rt, NaHCO3 (20 ml, sat. aq.) and CH2Cl2 (20 ml) were added. Layers were separated and the aqueous layer was further extracted with CH2Cl2 (20 ml×2). The combined CH2Cl2 was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (CH2Cl2/CH3OH, 18:1) to give the 6-bromo-5,7-dimethyl-imidazo[1,2-a]pyridine as a yellow oil (985 mg, 58%, contaminated with some starting material).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:19])[CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.CO.O>CO>[C:9]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][C:5]([OH:19])=[O:4])[CH:8]=1
Reactant: COC(=O)Cc1cccc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.5 mL of a 2 M LiOH solution in methanol was added to a solution of compound 91B in 3:1 MeOH/H2O solution. The reaction was stirred at room temperature for 20 hours. The mixture was concentrated under vacuum and the residue dissolved in water. 10% HCl was then added leading to a white precipitate. The solids were collected, washed thoroughly with water and dried (125 mg, 95%). NMR 1H (ppm, MeOD): 7.58 (d., J3=7.26 Hz, 2H), 7.52-7.47 (m, 2H), 7.43-7.37 (m, 3H), 7.34-7.24 (m, 2H), 3.66 (s, 2H). MS (−ESI): M−H+: 211.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8]O.N1C=CC=CC=1.P(Br)(Br)[Br:19]>C(OCC)C>[CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:19]
Reactant: C[Si](C)(C)C#CCCCCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[Si](C)(C)C#CCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.8 %

Procedure:
To a mixture of 1-trimethylsilyl(hex-1-yn-6-ol) (32.6 g, 190 mmol) and pyridine (0.38 mL) dissolved in diethyl ether (100 mL) was added slowly phosphorus tribromide (7.1 mL, 75 mmol) in diethyl ether (20 mL). Upon addition a precipitate formed and the heterogeneous solution was stirred at room temperature overnight. The mixture was then heated at reflux for 2.5 hours and, upon cooling, was poured onto ice, washed with water, sodium bicarbonate solution, brine and dried (MgSO4). Evaporation of solvent under reduced pressure gave a residue which was distilled (b.p. 80° C., 3.5 mm Hg) to give 22 g (50%) of product. 1H NMR (CDCl3) δ: 0.14 (s, 9H), 1.64-1.72 (quintet, 2H), 1.91-2.02 (quintet, 2H), 2.27 (t, 2H), 3.44 (t, 2H) ppm.
Reaction SMILES: C[S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(=O)(=O)[NH:30][CH2:31][CH3:32])=CC=1C(O)=O.N1CCCC1>>[CH2:31]([NH:30][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH3:32]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CCNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CCNS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 43 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-ethylsulfamoyl-benzoic acid and pyrrolidine and obtained in 43% yield. MS (m/e): 202.2 (MH−, 100%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[Na+].[SH-:11]>C(O)C>[SH:11][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=c1cccccc1Cl
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Product: O=c1cccccc1S
Temperature: -70 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-2,4,6-cycloheptatrien-1-one [2.82 g, described by T. Nozoe et al., Proc. Japan Acad., 28, 483 (1952)] in ethanol (20 ml) is added dropwise to a suspension, cooled to -70° C, of sodium sulfhydrate (2.2 g.) in ethanol (20 ml). The mixture is stirred at -70° C for 2 hours, allowed to warm to room temperature and stirred at room temperature for one hour. The mixture is filtered and the filtrate is evaporated. The residue is suspended in water, the mixture is acidified to pH2 with 10% hydrochloric acid and extracted with ethyl acetate. The organic extract is dried and evaporated. The residue is dissolved in benzene and subjected to chromatography on silica gel. The eluates are evaporated to give the title compound, mp 55° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:35][CH2:34][CH2:33][N:32]3[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:27][CH:26]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:25]3[CH:26]=[CH:27][C:28]([CH:31]4[CH2:35][CH2:34][CH2:33][N:32]4[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:29][CH:30]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCCCNc1ccc2ncc(Br)n2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCCCCNc1ccc2ncc(-c3ccc(C4CCCN4C(=O)OC(C)(C)C)cc3)n2n1
Yield: 66.7 %

Procedure:
To 150 mg (0.530 mmol) of the 3-bromo-N-pentylimidazo[1,2-b]pyridazin-6-amine was added the tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate (237 mg, 0.636 mmol), K3PO4 (225 mg, 1.060 mmol), PdCl2(PPh3)3 (37 mg, 0.053 mmol), 3 mL of DME and 1 mL of water. This mixture was microwaved for 0.5 hr at 140° C. After cooling it was diluted with 25 mL of EtOAC, and washed with about 20 mL of brine. The organic layer was dried over MgSO4, and concentrated. The crude mixture was purified on a 12 g silica gel column (ISCO), eluting with 15-100% EtOAc/Hex to give 159 mg (67%) of the desired product.
Reaction SMILES: [O:1]=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[CH3:20]O>S(=O)(=O)(O)O>[O:1]=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:20])=[O:9]
Reactant: O=C(O)c1cccc(C=CC(=O)c2ccccc2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C=CC(=O)c2ccccc2)c1

Procedure:
A slurry of 3-(3-oxo-3-phenyl-1-propenyl)-benzoic acid (2.84 g, 11.26 mmol) in methanol (150 mL) is treated with a few drops of sulfuric acid and heated under reflux for 8 hours. Upon cooling, a solid forms which is collected by filtration and washed thoroughly with methanol to provide 0.9 g of the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31]([Cl:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>O.CN(C)C=O>[ClH:38].[CH2:31]([N:24]1[C:25]2[C:20](=[CH:19][C:18]([C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:11][CH2:12]3)=[O:17])=[CH:27][CH:26]=2)[CH2:21][CH2:22][C:23]1=[O:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCOc4ccccc4)CC3)ccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)CCC(=O)N2Cc1ccccc1)N1CCN(CCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
480 Milligrams of 6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and 70 ml of 50%-sodium hydride in oil were mixed into 5 ml of dimethylformamide and stirred at a room temperature for 1 hour. Then to this mixture was added a solution of 0.17 ml of benzyl chloride with 3 ml of dimethylformamide was added dropwise slowly and stirred at a room temperature for 4 hours. The reaction mixture was poured in a voluminous amount of water and the organic matters were extracted with chloroform, and the chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue obtained was converted into hydrochloride by adding a concentrated hydrochloric acid and recrystallized from methanol-water to obtain 150 mg of 1-benzyl-6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril monohydrochloride. Colorless powdery crystals. Melting point: 261°-264° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>>[CH3:9][C:10]1[C:11]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:7]4[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3)CC2)c(C)c1
Yield: 47.6 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (137 mg) and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (500 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 1, the title compound (231 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15](=O)[NH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:25]>>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15]([Cl:25])=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: O=c1[nH]ccc2nc(NCc3ccccc3Cl)ncc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccccc1CNc1ncc2c(Cl)nccc2n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
2-(2-Chloro-benzylamino)-6H-pyrido[4,3-d]pyrimidin-5-one 8 (3.00 g, 10.5 mmol) was dissolved in POCl3 (30 mL) and stirred at 90° C. for 15 h. The reaction mixture was carefully poured into ice water and the pH was adjusted to 8 adding 2 N NaOH solution. The precipitate formed was filtered off and dried in vacuo. The product was purified by crystallization from diethyl ether to yield in a colorless solid (3.18 g, 10.4 mmol, 100%).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C:5](=[O:10])[CH:4]=[CH:3]1.O>CO.[Pd]>[OH:8][C@H:7]1[C@H:6]([OH:9])[C@@H:5]([OH:10])[CH2:4][CH2:3][C:2]1=[O:1]
Reactant: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C1CC[C@H](O)[C@@H](O)[C@@H]1O
Yield: 95.3 %

Procedure:
205 mg of (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one obtained in Example 3 was dissolved in 3.5 mL of methanol. 20 mg (50 weight % of water contained) of 5 weight % Pd/C was added thereto and hydrogenated at room temperature (25 degrees centigrade) under ordinary pressure (1 atm). After the completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated to obtain 198 mg (yield: 96%) of (2S,3R,4S)-2,3,4-trihydroxycyclohexane-1-one.