Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[O:13][CH:12]([CH2:15][OH:16])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][CH:12]2[CH2:11][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[C:14]=3[O:13]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OCC1Cc2cccc(C3CCCC3)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(C4CCCC4)c3O2)cc1

Procedure:
Treatment of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (4.08 g, 18.7 mmol) with p-toluenesulfonyl chloride (3.92 g, 21.9 mmol) in anhydrous pyridine (76 mL) generally according to the procedure described for Intermediate 10 gave (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a tan oil. Treatment of the tosylate with sodium azide (4.39 g, 67.57 mmol) generally according to the procedure described for Intermediate 98 afforded 4.1 g of (±)-2-(azidomethyl)-7-cyclopentyl-2,3-dihydro-1-benzofuran as a yellow oil. Treatment of the azide with palladium on carbon (0.41 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 2.5 g (58%) of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 174° C.; Anal. calcd. for C14H900N2HCl: C, 66.26; H, 7.94; N, 5.52. Found C, 66.13; H, 7.71; N, 5.5.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])=[O:2].OO.[CH:18](O)=[O:19]>>[N+:13]([C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:1]([O:19][CH3:18])=[O:2])([O-:15])=[O:14]
Reactant: O=CO
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C=O)c1
Agent: OO
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a stirred solution of methyl 3-formyl-4-nitrobenzoate (1.5 g, 7.18 mmol) in formic acid (2 mL) was added hydrogen peroxide (2.5 mL, 30% in water). The reaction mixture was stirred at r.t. for 16 h. Additional hydrogen peroxide (2.5 mL, 30% in water) was added, and the reaction mixture stirred at r.t. for 8 h before being concentrated in vacuo. The residue was dissolved in 2% HCl in MeOH (40 mL). The solution was stirred at 70° C. for 4 days, then concentrated in vacuo. The residue was dissolved in DCM (10 mL), and the solution washed with aqueous sat. NaHCO3 (2×10 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (1.52 g, 87%) as a colourless oil. δH (CDCl3) 8.43 (1H, s), 8.29 (1H, dd, J 1.8 and 8.6 Hz), 7.92 (1H, d, J 8.3 Hz), 3.99 (3H, s), 3.95 (3H, s). LCMS (ES+) 240.0 (M+H)+, RT 1.80 minutes (Method 12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(C(Cn2cncn2)OCc2ccccc2)cc1

Procedure:
Following the procedure of Example 9, Step 2, 1-p-chlorophenyl-2-(1,2,4-triazol-1-yl)-ethanol (4.48 g), benzyl chloride (2.54 g) and sodium hydride (1 g; 50%) were reacted to give the title compound as a crystalline solid. Analysis:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:30]2[CH2:31][CH2:32][N:27]([S:24]([C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[O:15][CH3:14])(=[O:26])=[O:25])[CH2:28][CH2:29]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)c(OC)c1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)c(OC)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-[(2,4-dimethoxyphenyl)-sulfonyl]piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-[(2,4-dimethoxyphenyl)sulfonyl]piperazine.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([NH2:21])=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:11]=1)=[O:5])C.Cl.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:4]([C:6]1[C:7]([NH2:21])=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cn2cc(-c3ccccc3)nc2cc1N
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cn2cc(-c3ccccc3)nc2cc1N
Yield: 60 %

Procedure:
According to the procedure described in step 1 of example 18 7-amino-2-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid ethyl ester was reacted with methylamine hydrochloride to give the title compound as off-white solid (60%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH:18](Br)=[CH:19][C:20](=[CH2:22])[CH3:21].C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Reactant: C=C(C)C=CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC=C(C)C)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a stirred solution of (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (5.16 g, 20 mmol), isoprenyl bromide (3.0 g, 20 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and the mixture refluxed foe 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethy acetate: hexane. The product 2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester was isolated as a colourless oil. Yield: 3.0 g, 93%.
Reaction SMILES: CO.[NH2:3][C:4]1[C:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:11]=2)=[CH:8][CH:7]=[C:6]([NH2:23])[N:5]=1.[OH-].[Na+].Br[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32]>CN(C)C=O>[NH2:3][C:4]1[C:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]#[N:32])=[CH:18][CH:17]=3)[CH:11]=2)=[CH:8][CH:7]=[C:6]([NH2:23])[N:5]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a methanol (6.3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (100 mg, 0.36 mmol) described in Manufacturing Example 18-1-1 was added a 2 N sodium hydroxide aqueous solution (180 μL, 0.36 mmol). This mixture was concentrated under a reduced pressure. N,N-dimethylformamide (1.3 mL) and 3-bromomethyl-benzonitrile (58 mg, 0.29 mmol) were added to the residue, which was stirred for 15 minutes at 60° C. This reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (24 mg, 17%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:18](=[O:17])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
To 150 g (735 mmol) (S)-1-(4-bromophenyl)ethylamine in 2 L DCM are added 459 mL (918 mmol) of an aq. Na2CO3 solution (c=2 mol/L). To this mixture a solution of 164 g (749 mmol) BOC2O in 350 mL THF is added dropwise at r.t. and stirring is continued for 1 h. Then the mixture is poured onto water and stirred for additional 20 min. The layers are separated, the org. layer is washed with water (2×), dried over Na2SO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:8]=[CH:9][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O-:4])=[O:3].C(N(CC)CC)C.Br[CH2:30][CH:31]=[CH2:32]>CN(C)C=O>[CH2:32]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:6][C:5]=2[N+:2]([O-:4])=[O:3])[CH2:13][CH2:14]1)[CH:31]=[CH2:30]
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCN1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide hydrochloride (0.27 g), triethylamine (0.2 mL) and 3-bromoprop-1-ene (0.1 g) was dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature overnight. The solvent was dried under vacuum. The mixture was chromatographed on silica gel with 0-20% methanol in dichloromethane.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[NH:24][NH2:25]>>[C:28]([O:27][C:23]([NH:24][NH:25][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[O:14])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1

Procedure:
The product was synthesized as described in Example 109 A using 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (500 mg, 1.58 mmol) and tert-butyl carbazate (230 mg, 1.74 mmol). 1H NMR (DMSO-d6) δ 10.35 (s, 1H), 8.95 (s, 1H), 8.4 (s, 1H), 8.1 (m, 2H), 7.9 (d, 1H), 7.65 (d, 1H), 7.4 (t, 2H), 1.3–1.5 (m, 9H), ES-MS m/z 371 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:28]([O:33]CC)([O:30][CH2:31][CH3:32])=[O:29])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[OH-].[Li+]>CO.O>[CH2:31]([O:30][P:28]([CH2:27][CH:26]=[CH:25][CH2:24][CH:4]([CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21])[C:3]([OH:36])=[O:2])([OH:33])=[O:29])[CH3:32]
Reactant: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(O)CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
A mixture of 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 159C (25 mg, 0.048 mmol) and lithium hydroxide (200 mg) in a mixture of methanol (3 mL) and water (1 mL) was stirred at 70° C. for 2 hours. The organic solvent was evaporated and the residue acidified with 2N HCl and extracted with ethyl acetate/acetonitrile. The organic extract was concentrated and the residue was purified by preparative reverse-phase HPLC (acetonitrile and 0.1% aqueous CF3COOH), affording 2-[4-(ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid 159E as an oil (15 mg, 89%); 1H NMR (300 MHz, CD3OD) δ 1.25 (t, J=6.9 Hz, 3H), 1.81 (s, 3H), 2.1-2.6 (m, 8H), 3.40 (d, J=6.6 Hz, 2H), 3.77 (s, 3H), 3.97 (m, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H) ppm.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:18]C(=O)[NH:16][CH:15]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:16][CH:15]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)[OH:18]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(Oc3ccccc3)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Yield: 74.9 %

Procedure:
To a solution of (4RS,5SR)-5-(4-phenoxyphenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (6.0 g, 14.5 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (9.0 ml, 72 mmol), and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (300 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (4.21 g, 75%) as a colorless oil. A portion thereof was recrystallized from ethanol-ether as hydrochloride, which was measured for elemental analysis values.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: c1ccc2c(c1)nnn2CNC1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
To a mixture of 12.1 g (0.185 g-atom) of zinc powder (−325 mesh) and 160 mL of anhydrous tetrahydrofuran was added 17.6 mL (0.14 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 17.8 mL (0.14 mole) of ethyl bromodifluoroacetate in 20 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 20 g (0.093 mole) of benzotriazol-1-ylmethyl-cyclopentylamine in 80 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was then distilled under vacuum to give 12.4 g of 3-cyclopentylamino-2,2-difluoropropionic acid ethyl ester as a colorless oil. bp 75-82 degrees at 1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([OH:13])[C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22]>CN(C)C=O>[Cl:1][C:2]1[N:3]([CH2:21][CH3:22])[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11](=[O:13])[CH:12]=1
Reactant: CCI
Reactant: CCOC(=O)c1cnc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)cc1Cl
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A mixture of ethyl 6-chloro-4-hydroxynicotinate (3.7 g), powdered potassium carbonate (3.7 g), iodoethane (5 ml) and dimethylformamide (50 ml) is well stirred for 7 hours at 90° C. After cooling, the reaction mixture is filtered and the solvent evaporated off. The residue is treated with icy water (30 ml) and extracted with dichloromethane (2×30 ml). The combined extract are dried and evaporated to dryness. The residue is boiled 90 minutes with 1N sodium hydroxide (18 ml). After cooling the solution is extracted with diethyl ether (30 ml), that is discharged. The alkaline solution is concentrated to small volume, cooled and acidified to pH 4 with 1N hydrochloric acid. The white material that precipitates is collected and crystallized from ethanol to give 6-chloro-1,4-dihydro-1-ethyl-4-oxo-3-pyridine-carboxylic acid (3 g) m.p. 155°-57° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.FC(F)(F)S(O[CH2:23][CH:24]([F:34])[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])(=O)=O>CN(C=O)C.C(OCC)C>[Si:27]([O:26][CH2:25][CH:24]([F:34])[CH2:23][N:14]1[CH:15]=[C:11]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:4]([CH3:16])([CH3:3])[O:5]2)[CH:12]=[N:13]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCC(F)COS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)OB(c2cnn(CC(F)CO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (0.247 g, 6.17 mmol) was suspended in 10 mL of DMF. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.958 g, 4.94 mmol) was added in 5 mL of DMF dropwise via syringe and the mixture was stirred at room temperature for 30 minutes. Then 3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluoropropyl trifluoromethanesulfonate (1.40 g, 4.11 mmol) was added in 5 mL of DMF dropwise via syringe. After 20 minutes, the reaction mixture was diluted in diethyl ether, washed with water (3×50 mL) and brine then dried over magnesium sulfate, filtered and concentrated to afford 1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([NH:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([NH2:15])=[O:14])=[O:22]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: NC(=O)c1nc(-c2ccccc2)sc1N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: COc1ccc(C(=O)Nc2sc(-c3ccccc3)nc2C(N)=O)cc1OC
Yield: 18.6 %

Procedure:
To a solution of 5-amino-2-phenyl-1,3-thiazole-4-carboxamide (0.3 g, 1.4 mmol) in NMP (1 mL) is added a solution of 3,4-dimethoxybenzoyl chloride (0.41 g, 2.0 mmol) in NMP (3 mL) followed by DBU (0.21 g, 1.4 mmol) and the mixture is stirred at reflux for 4 h. The resulting precipitate is collected by filtration, washed with NMP, acetonitrile, ethanol, ether to give 0.1 g (30%) of the title compound. This is further purified by reverse-phase HPLC: 1H NMR (400 MHz, DMSO-d6) δ [ppm]3.9 (s, 6H); 7.2 (d, J=8.3 Hz, 1H); 7.5 (m, 5H); 8.0 (m, 3H); 8.1 (s, 1H); 12.7 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)[C:14]1=[O:22]
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(Cc2ccc(F)cc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.72 g. of NaH (80% suspension in mineral oil), 7 g. of 8-(2-oxo-benzimidazolin-1-yl)-caprylic acid methyl ester, 100 cc. of DMF, 3.5 g. of 4-fluorobenzylchloride and 0.72 g. of NaJ. Eluant for chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=S)[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:11]=[CH:12][C:4]=2[O:3]1.[NH3:19].C1(C)C=CC=CC=1>CO>[CH3:1][CH:2]1[CH:7]([NH2:19])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: N
Reactant: CC1Oc2ccc(Cn3ccnc3)cc2NC1=S
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1Oc2ccc(Cn3ccnc3)cc2NC1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
155 mg (0.597 mmol of (±)-2-methyl-3-thioxo-6-[(1-imidazolyl)-methyl]-3,4-dihydro-2H-1,4-benzoxazine is mixed with 10 ml of 7N NH3 in methanol, and it is stirred for 2.5 hours at room temperature. After 20 ml of toluene is added, the solvent is then spun off, and the desired compound is obtained quantitatively, melting point 152-156° C.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:30])[CH2:10][CH2:9]1.ClC1C=CC=C(C(OO)=[O:42])C=1.O.N>C(Cl)Cl>[CH3:2][S:3]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:30])[CH2:12][CH2:13]1)=[O:42]
Reactant: CSc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
To a solution of 480 mg (1 mmol) of 3-[1-(3-methylthiobenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro -2(1H)-quinazolinone HCl salt in 10 mL of methylene chloride was added 190 mg (1.1 mmol) of m-chloroperbenzoic acid at temperature of 0° C. to 10° C. The mixture was stirred for 10 hours at ambient temperature, mixed with water, adjusted to pH 10 with a aqueous ammonia and then extracted with chloroform. The organic layer separated was washed with brine, dried on sodium sulfate and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 440 mg (0.96 mmol) of the title compound as an about 1:1 mixture of the diastereomers.