Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Br:8][C:6]1[CH:7]=[C:2]([N:1]([S:27]([CH3:26])(=[O:29])=[O:28])[S:27]([CH3:26])(=[O:29])=[O:28])[C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[N:4][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of tert-butyl 3-amino-5-bromopyridin-2-ylcarbamate (96.3 mg, 0.33 mmol) and diisopropylethylamine (128 uL, 074 mmol) in dichloromethane (2 mL) was cooled to 0° C., and to it was added methanesulfonyl chloride (52 uL, 0.67 mmol). The mixture was allowed to warm to rt over 2 h. The mixture was then diluted with dichloromethane and was then washed with aqueous citric acid (10%) followed by water. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (gradient, 100% hexanes to 70% hexanes:30% ethyl acetate) to provide tert-butyl 5-bromo-3-(N-(methylsulfonyl)methylsulfonamido)pyridin-2-ylcarbamate (77 mg, 0.17 mmol, 52% yield) as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, 1H), 7.79 (d, 1H), 7.10 (s, 1H), 3.44 (s, 6H), 1.52 (s, 9H); MS (EI) for C12H18BrN3O6S2: 388, 390 (Br isotopes, MH+-t-butyl).
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[O:15][CH3:16].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cc(O)ccc1N
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
Sodium hydride (60 wt %, 3.2 g) was added to dimethyl sulfoxide (50 ml), and the mixture was stirred at 50° C. for 20 min. 4-Amino-3-methoxyphenol (5.6 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinazoline (7.0 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by suction filtration to give the title compound (7.3 g, yield 72%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>N1C=CC=CC=1>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(C2Sc3ccccc3NC(=O)C2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C2Sc3ccccc3NC(=O)C2COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
3 g of 2,3-dihydro-3-hydroxymethyl-2-(p-tolyl)-1,5-benzothiazepin-4(5H)-one prepared as described in Reference Example 3 was dissolved in 15 ml of pyridine. 1.3 g of methanesulfonyl chloride was added to the solution and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the precipitated crystals were separated by filtration and recrystallized from dichloromethane-n-hexane to obtain 3.3 g of 2,3-dihydro-3-[(methylsulfonyloxy)methyl]-2-(p-tolyl)-1,5-benzothiazepin-4(5H)-one as colorless needles having a melting point of 207° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(F)c1
Yield: 85 %

Procedure:
To a solution of 3-fluorophenyl acetic acid (10.0 g, 64.9 mmol) in ethanol (300 mL), is added a catalytic amount of H2SO4 (98%, 1 mL) and the mixture reacted for 12 hours at 100° C. (LC-MS monitoring: complete conversion). The solvent is evaporated and the residue is partitioned between EtOAc and water; the organic layer is separated and dried over Na2SO4 in order to obtain 10.1 g of (I8) as a white solid (85% yield).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][C@H:10]([CH3:13])[CH2:11][OH:12].F[C:15]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:21][C:20]1[C:19]([F:22])=[CH:18][CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[C:15]=1[O:12][CH2:11][C@H:10]([O:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][O:3]1)[CH3:13]
Reactant: C[C@H](CO)OC1CCCCO1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](COc1c([N+](=O)[O-])ccc(F)c1F)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled suspension of 720 mg of sodium hydride (60%) in 12 ml of anhydrous toluene was added dropwise a solution of 2.88 g of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol (IIIR, Rc=THP) in 12 ml of anhydrous toluene, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 10 minutes. The mixture was added dropwise to a solution of 2.66 g of 2,3,4-trifluoronitrobenzene in 12 ml of anhydrous toluene with stirring under cooling with ice. The mixture was stirred at an external temperature of 5° C. for 24 hours. To the mixture were added ice-water and benzene, and the resulting mixture was shaken. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield 2,3-difluoro-6-nitro-{[(R)-2-(tetrahydropyran-2-yl)oxypropyl]oxy}benzene (IR, Xa=Xb=F, Rc=THP) in quantitative yield. This compound was dissolved in 38 ml of anhydrous ethanol and to this was added 450 mg of pyridinium tosylate. The mixture was heated under refluxing for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed successively with 1 N hydrochloric acid, a 5% sodium bicarbonate aqueous solution and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 3.20 g of the oily titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21](=O)[CH:22]=[CH:23]N(C)C)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:44]=[CH:43][C:33]([CH2:34][O:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH2:42])=[NH:41])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([C:21]3[CH:22]=[CH:23][N:42]=[C:40]([NH:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:44][CH:43]=4)[N:41]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(COCCCNC(=N)N)cc1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COCCCNc2nccc(-c3c(-c4ccc(F)cc4)nn4cc(C(F)(F)F)ccc34)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine (Example 65f. 2.0 g, 5.3 mmol), N-(3-(4-methoxybenzyloxy)propyl)-guanidine (2.7 g, 7.95 mmol), and potassium carbonate (2.2 g, 15.9 mmol) was stirred in N,N-dimethylformamide (20 mL) in a 100° C. oil bath for 18 h. The mixture was cooled to room temperature, water (200 mL) was added the mixture was extracted with chloroform. The chloroform extracts were dried over anhydrous MgSO4, filtered, and the solvent was evaporated. The crude material was purified by chromatography on silica gel using 30% EtOAc/hexanes as eluent to afford the title compound as a white solid, 2.1 g (72%). 1H NMR (acetone-d6) δ 9.18 (s, 1H), 8.67 (d, 1H, J=9.4 Hz), 8.15 (d, 1H, J=5.1 Hz), 7.77 (m, 2H), 7.56 (d, 1H, J=9.2 Hz), 7.34 (m, 4H), 6.90 (d, 2H, J=8.6 Hz), 6.50 (s, 1H), 6.38 (d, 1H, J=5.1 Hz), 4.49 (s, 2H), 3.80 (s, 3H), 3.63 (m, 4H), 1.98 (m, 2H). MS (+ve ion electrospray) 551 (30), (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][C@H:13]([CH2:22][OH:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:24]OC(C1C2OC[C@H](CO)N(C3C=CC(CC)=CN=3)C=2C=CC=1)=O.[H-].[Na+].CI>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][C@H:13]([CH2:22][O:23][CH3:24])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CCc1ccc(N2c3cccc(C(=O)OC)c3OC[C@@H]2CO)nc1
Reactant: COC(=O)c1cccc2c1OC[C@H](CO)N2c1ccc(C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H]1COc2c(C(=O)OC)cccc2N1c1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
3.0 g (9.5 mmol) of (S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-carboxylic acid methyl ester (compound 22) obtained in (34-6) were dissolved in 50 mL of THF. The solution was cooled to 0° C. and 1.1 g (28.6 mmol) of NaH was added slowly. The solution was stirred at 0° C. for 10 min and then at room temperature for 5 min. The solution was re-cooled to 0° C. and 120 uL (19.1 mmol) of MeI was added slowly. The mixture was placed at the same temperature for 1-2 hr and stirred while heating to room temperature. When the reaction terminated, the reaction mixture was neutralized by slow addition of 1N HCl solution, and dissolved in ethyl acetate and washed with distilled water and saturated sodium chloride solution, followed by drying over magnesium sulfate and concentration under reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate/hexane=1/2) to obtain the title compound (2.7 g, yield: 85%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][P:5]([CH3:12])(=[O:11])[O:6]CC(C)C>Cl>[NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][P:5]([CH3:12])(=[O:6])[OH:11]
Reactant: CC(C)COP(C)(=O)C[C@@H](O)CN
Agent: Cl
Product: CP(=O)(O)C[C@@H](O)CN
Temperature: 25 °C

Procedure:
A solution of 1.1 g of isobutyl P-[3-amino-2(S)-hydroxy-propyl]-P-methyl-phosphinate in 20 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 12 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and co-evaporated four times with 25 ml of water. The crude material is dissolved in water, washed with ether and the aqueous layer is treated with activated charcoal. The solution is filtered hot, the filtrate is concentrated under reduced pressure, the residue dissolved in 20 ml of ethanol and treated with 1 ml of propylene oxide. The mixture is stirred until the precipitated solid is free of halogen. The solid is then filtered and recrystallised from methanol/acetone give P-[3-amino-2(S)-hydroxy-propyl]-P-methyl-phosphinic acid, m.p. 221°-222.5°, 31P-NMR spectrum: δ=+38.9 ppm (D2O), [α]D25 =-6.0° (c=0.887% in H2O).
Reaction SMILES: [I:1]I.N[C:4]1[C:8]([CH:9]2[CH2:11][C:10]2([Br:13])[Br:12])=[CH:7][N:6]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:5]=1.N(OC(C)(C)C)=O>ClCCl>[Br:12][C:10]1([Br:13])[CH2:11][CH:9]1[C:8]1[C:4]([I:1])=[N:5][N:6]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[CH:7]=1
Reactant: II
Reactant: Nc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1(Br)Br
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cl)c(-n2cc(C3CC3(Br)Br)c(I)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodine (0.55 g) was added to a stirred solution of the title compound of Example 8 (0.40 g) in dichloromethane (10 ml), followed by the dropwise addition of t-butyl nitrite (0.21 g). The reaction mixture was stirred at room temperature for 2 hours, then partitioned between dichloromethane and aqueous sodium thiosulphate solution and the organic phase separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using hexane and then dichloromethane as eluants, followed by reverse phase HPLC on C18 silica, using a mixture of acetonitrile:water:methanol (30:60:10) as eluant, to produce the title compound as an off-white foam. δ (CDCl3): 1.84 (t,1H), 2.26 (dd,1H), 2.67 (dd,1H), 7.20 (s,1H), 7.72 (s,2H). MS (thermospray): M/Z [M+H] 602.4; C13H6Br2Cl2F3IN2 +H requires 602.74.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][N:13]1[CH2:19][CH:18]2[CH2:20][CH2:21][CH:15]([CH2:16][CH2:17]2)[CH2:14]1.[NH2-].[Na+].O>C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH2:11][CH2:12][N:13]2[CH2:19][CH:18]3[CH2:20][CH2:21][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(CCN1CC2CCC(CC2)C1)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 20 parts of α-phenylacetonitrile in 300 parts by volume of toluene is added 94 parts of 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane dissolved in 500 parts by volume of toluene. The mixture is heated with stirring to about 80° C. and then 17 parts of sodium amide is added slowly over a period of 30 minutes. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether, the ether extract dried over calcium sulfate and distilled to afford 2-phenyl-4-(3-azabicyclo[3.2.2]non-3-yl)butyronitrile.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 70.7 %

Procedure:
0.9 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylate is refluxed for 4 hours in a mixture of 8 ml of glacial acetic acid, 0.6 ml of water and 0.2 ml of concentrated sulphuric acid. At reflux temperature, the reaction mixture is then treated with 10 ml of water. The solid is filtered off with suction at room temperature, washed with water and dried. 0.58 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid (71% of theory) is obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:22]([C@@H:25]1[C@@H:29]([C:30](=[O:33])[NH:31][CH3:32])[O:28][C@@H:27]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH:43][CH2:44][C:45]2[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:46]=2[O:47][CH2:48][C:49](O)=[O:50])[C@@H:26]1[OH:57])=[N+:23]=[N-:24].[NH:58]1[CH2:63][CH2:62][NH:61][CH2:60][C:59]1=[O:64]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:32][NH:31][C:30]([C@@H:29]1[C@@H:25]([N:22]=[N+:23]=[N-:24])[C@@H:26]([OH:57])[C@H:27]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH:43][CH2:44][C:45]2[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:46]=2[O:47][CH2:48][C:49](=[O:50])[N:61]2[CH2:62][CH2:63][NH:58][C:59](=[O:64])[CH2:60]2)[O:28]1)=[O:33]
Reactant: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC(=O)O)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Reactant: O=C1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC(=O)N4CCNC(=O)C4)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Reaction time: 20 h

Procedure:
EDCI (44 mg, 0.23 mmol), HOBT (30 mg, 0.22 mmol) and DMAP (40 mg) were added to a mixture of (2R,3R,4S,5S)(2-{[9-(4-Azido-3-hydroxy-5-methylcarbamoyl-tetrahydro-furan-2-yl)-9H-purin-6-ylamino]-methyl}-4-chloro-phenoxy)-acetic acid (60 mg, 0.116 mmol) and piperizin-2-one (35 mg, 0.35 mmol) in anhydrous DMF (3 mL). After 20 hours at room temperature, the mixture was concentrated, pre-adsorbed onto silica gel and purified by flash chromatography (6-8% methanol/dichloromethane) to afford the title compound as a colorless solid. MS: 600 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:36](=[O:37])[C:35]5[CH:34]=[CH:33][C:32]([N:29]6[CH2:30][CH2:31][O:26][CH2:27][CH2:28]6)=[CH:40][CH:39]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, white solid (31.1 mg, 73.2%), MS (ISP) m/z=520.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 4-morpholinobenzoic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[S:10][CH:9]([CH2:11]O)[CH2:8][S:7]1.OCC1CSC[S:16]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[S:10][CH:9]([CH2:11][SH:16])[CH2:8][S:7]1
Reactant: OCC1CSCS1
Reactant: OCC1CSC(c2cccs2)S1
Product: SCC1CSC(c2cccs2)S1

Procedure:
The same method was followed as in Example 1 except that 2-(thiophen-2-yl)-4-hydroxymethyl-1,3-dithiolane produced in Example 5 was used in stead of 4-hydroxymethyl-1,3-dithiolane synthesized in Manufacturing Example 1 to obtain 2-(thiophen-2-yl)-4-mercaptomethyl-1,3-dithiolane represented by the following formula (2-9).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC(C(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 2-(3,4-dichlorophenyl)pent-4-enoate (2.47 g, 9.53 mmol) in tetrahydrofuran (15.0 mL) was added a solution of lithium hydroxide monohydrate (2.00 g, 47.6 mmol) in water (15.0 mL). The mixture was vigorously stirred at rt for 12 hrs. The resulting mixture was acidified by addition of 12.0 M of hydrochloric acid in water (3.97 mL, 47.6 mmol) at 0° C., and extracted with EtOAc (×3). The combined organic layer was dried and concentrated to provide 2-(3,4-dichlorophenyl)pent-4-enoic acid as a yellow syrup (2.65 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 7.45-7.35 (m, 2H), 7.21-7.11 (dd, J=8.3, 2.1 Hz, 1H), 5.76-5.59 (ddt, J=17.0, 10.2, 6.8 Hz, 1H), 5.14-4.99 (m, 2H), 3.65-3.56 (t, J=7.7 Hz, 1H), 2.88-2.74 (dt, J=14.8, 7.5 Hz, 1H), 2.58-2.43 (dt, J=14.3, 6.9 Hz, 1H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][C:14]1[C:23]2[C:18](=[C:19]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[N:1]1([CH2:13][C:14]2[C:23]3[C:18](=[C:19]([NH:24][C:25](=[O:34])[C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:33])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C(Nc1cccc2c(CBr)ccnc12)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc2c(Cn3cnc4ccccc43)ccnc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a stirred solution of benzimidazole (26.5 mg) in N,N-dimethylformamide (1 ml) was added sodium hydride (60% in oil, 8.6 mg) in an ice bath, and the mixture was stirred at the same temperature for half an hour. To this mixture was added 4-bromomethyl-8-(2,6-dichlorobenzoylamino)quinoline (80 mg) one portion, and the reaction mixture was stirred at the same temperature for half an hour and then at ambient temperature for one hour. Water was added thereto, and the resulting precipitate was collected by filtration. The solid was washed with hot 95% aqueous ethanol (1 ml) and allowed to cool to ambient temperature. The solid was collected by filtration and air-dried to give 4-(1H-benzimidazol-1-ylmethyl)-8-(2,6-dichlorobenzoylamino)quinoline (65 mg) as an off-white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[Li+].[OH-].O1CCOC[CH2:14]1.O>>[CH3:14][O:9][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1
Reactant: C1COCCO1
Reactant: O=C(O)c1cc(I)ccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(I)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ester 11a′ (Z=ethyl, n=1; 25 mg, 0.07 mmol) in dioxane/water (3:1, 3 mL), LiOH (15.0 mg, 0.35 mmol) solid was added. The resulting mixture was stirred vigorously at rt for 3 h. The organic solvent was removed under reduced pressure, and the residue was dissolved in H2O (10 mL), acidified with aq. HCl (1.0 M) to pH value 3-4, and then extracted with DCM (3×15 mL). The combined organic layers were dried over MgSO4, the solvent was removed, and the residue was dried in high vacuum to afford the desired acid 11b′ (R=OEt, n=1; 22 mg, 95%) as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[F:12][C:13]1([F:19])[CH2:16][CH:15]([CH2:17]O)[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:12][C:13]1([F:19])[CH2:16][CH:15]([CH2:17][O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: OCC1CC(F)(F)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCC3CC(F)(F)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.6 g, 24.3 mmol) in THF (60 mL) were (3,3-difluorocyclobutyl)methanol (2.97 g, 24.3 mmol) and triphenylphosphine (9.56 g, 36.45 mmol) added. Diisopropyl azodicarboxylate (7.18 mL, 36.5 mmol) was added dropwise. The reaction mixture was stirred at r.t. overnight. The material was purified by flash column chromatography using a gradient of 0-100% EtOAc in heptane, providing 3.67 g (60% yield) of the title compound. 1H NMR (500 MHz, DMSO-d6) ppm 2.30 (br. s., 1H) 2.42-2.52 (m, 6H) 2.54-2.62 (m, 1H) 2.63-2.66 (m, 2H) 2.67-2.76 (m, 2H) 2.98-3.04 (m, 2H) 4.08 (d, 2H) 7.10 (d, 1H) 7.26 (dd, 1H) 7.48 (d, 1H); MS (ES+) m/z 253 [M+H]+.