Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([O:26][CH3:27])[CH:5]=2.C(O)=[O:29]>>[C:12]([CH:11]1[CH:10]([C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)[C:9]2[C:4](=[CH:5][C:6]([O:26][CH3:27])=[CH:7][CH:8]=2)[O:3][C:2]1=[O:29])#[N:13]
Reactant: COc1ccc2c(c1)OC(N)=C(C#N)C2c1cc(OC)c(OC)c(OC)c1
Reactant: O=CO
Product: COc1ccc2c(c1)OC(=O)C(C#N)C2c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-3-cyano-7-methoxy-4-(3,4,5-trimethoxyphenyl)-4H-chromene (260 mg, 0.7 mmol) was dissolved into approximately 5 mL of formic acid. The obtained white suspension was stirred approximately 1 h at room temperature until it solubilized. The solvent was evaporated. The residue was dissolved into ethyl acetate (20 mL), washed with sodium bicarbonate saturated solution (2×20 mL), brine (20 mL), dried over sodium sulfate and concentrated to give approximately 210 mg of a mixture of diastereoisomers. 1H NMR (CDCl3): 7.12 (d, J=8.2 Hz, 0.5H), 6.82-6.67 (m, 2.5H), 6.41 (s, 1H), 6.37 (s, 1H), 4.48-4.43 (m, 1H), 4.25-4.02 (m, 1H), 3.86-3.78 (4s, 12H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([OH:72])=[O:71])=[C:68]([C:75]([F:78])([F:77])[F:76])[CH:67]=1>C(Cl)Cl>[CH3:32][O:71][C:70](=[O:72])[C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[CH:67][C:68]=1[C:75]([F:76])([F:77])[F:78]
Reactant: Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (166 mg, 0.29 mmol) in methylene chloride (10 mL), HATU (Aldrich, 195 mg, 0.54 mmol) was added followed by the addition of DIPEA (0.25 mL, 1.425 mmol) and 4-amino-2-trifluoromethyl-benzoic acid (made above, 125 mg, 0.57 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 40 mg.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:2]1.[C:23](=[O:26])([O-])[O-:24].[K+].[K+].[CH3:29][N:30]([CH3:33])[CH:31]=O>>[C:2]([CH2:3][CH:4]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:2]1)[CH2:29][N:30]1[CH2:33][CH2:13][N:12]([C:23]([O:24][C:7]([CH3:6])([CH3:14])[CH3:8])=[O:26])[CH2:15][CH2:31]1)#[N:1]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCN(CC(CC#N)n2ccc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a mixture of (E)- and (Z)-tert-butyl 4-(3-cyanoallyl)piperazine-1-carboxylate (4.0 g, 0.016 mol; prepared as in Example 1, Steps 1-2) and 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (4.2 g, 0.013 mol, prepared as in WO2009/114512, Example 82) in N,N-Dimethylformamide (25 mL) was added potassium carbonate (5.540 g, 0.0401 mol). The mixture was stirred at 60° C. for 17 hours. Additional (E)- and (Z)-tert-butyl 4-(3-cyanoallyl)piperazine-1-carboxylate (4.0 g, 0.016 mol) was added and the reaction was stirred at 60° C. for 24 hours. A further portion of (E)- and (Z)-tert-butyl 4-(3-cyanoallyl)piperazine-1-carboxylate (4.0 g, 0.016 mol) was added. After 3 nights of heating, most of the starting material had been converted to desired product as determined by LCMS. The mixture was then filtered, diluted with EtOAc, washed with water (3 times), brine (once), dried over sodium sulfate, decanted and concentrated. Purification via preparative HPLC-MS (eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded a brown foam (4.20 g, 55%). 1H NMR (300 MHz, CDCl3): δ 8.81 (s, 1H), 7.66 (t, 1H), 7.34 (d, 1H), 6.97 (dd, 1H), 6.89 (t, 1H), 6.84 (d, 1H), 5.66 (s, 2H), 4.47-4.36 (m, 1H), 3.57-3.50 (m, 2H), 3.45-3.37 (m, 4H), 3.06 (dd, 1H), 3.00-2.90 (m, 2H), 2.83 (dd, 1H), 2.57-2.35 (m, 4H), 1.45 (s, 9H), 0.96-0.86 (m, 2H), −0.06 (s, 9H); LCMS (M+H)+: 566.3.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Br:7][CH2:8][C:9](=[O:17])[C:10](=[N:14][O:15][CH3:16])[C:11](O)=[O:12]>ClCCl>[Br:7][CH2:8][C:9](=[O:17])[C:10](=[N:14][O:15][CH3:16])[C:11]([Cl:2])=[O:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CON=C(C(=O)O)C(=O)CBr
Solvent: ClCCl
Product: CON=C(C(=O)Cl)C(=O)CBr
Temperature: -20 °C

Procedure:
To a suspension of phosphorous pentachloride (64.91 gm; 0.3113 moles) in dichloromethane (250 ml), cooled to −20° C. was added a solution of 4-bromo-2-methoxyimino-3-oxo butyric acid (66.41 gm; 0.2965 moles; purity ca. 97%; containing <0.5% of di- and poly-brominated compounds and prepared as per the method disclosed in WO 03/045899) in dichloromethane (250 ml) over a period of 30 minutes at −20° C. to −5° C. The temperature was raised to 5 to 10° C. and the reaction mixture purged with nitrogen gas for one to two hours to expel out hydrogen chloride gas. The solution containing 4-bromo-2-methoxyimino-3-oxo butyric acid chloride (IV) was cooled to −10° C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:3])[CH3:2].[CH2:24]1[O:26][CH2:25]1>C(O)C>[CH:1]([N:4]([CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:24][CH2:25][OH:26])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2=C(CC(C)NC(C)C)C(=O)NCCC2)cc1
Reactant: C1CO1
Solvent: CCO
Product: COc1ccc(C2=C(CC(C)N(CCO)C(C)C)C(=O)NCCC2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
The mixture of 6.3 g of 3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 20 ml of ethylene oxide and 25 ml of absolute ethanol is stirred in a sealed vessel at room temperature for 5 days. The resulting solution is evaporated, the residue crystallized from petrolem ether and recrystallized from ethyl acetate-hexane, to yield the 3-[2-(N-isopropyl-N-hydroxyethylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 109°-111°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][N:18]=4)=[CH:29][N:28]=3)=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnc(F)c2)nc1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(2′-fluoro-2,4′-bipyridin-5-yl)acetic acid 208-3 (42 mg, 0.18 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (31 mg, 0.18 mmol), 1,3-dicyclohexylcarbodiimide (45 mg, 0.22 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.036 mmol) in DMF (0.9 mL) was stirred at room temperature for 10 hours. The crude product was filtered and the filtrate was purified by reverse phase HPLC to give 2-(2′-fluoro-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 208 as white solid. MS m/z 387.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.31 (d, 1H), 9.11 (d, 1H), 8.73-8.71 (m, 2H), 8.62 (d, 1H), 8.52 (dd, 1H), 8.36 (d, 1H), 8.23-8.17 (m, 2H), 8.06-8.02 (m, 1H), 7.95 (dd, 1H), 7.82 (s, 1H), 7.64 (s, 1H), 3.94 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:26]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH:25]=1)=[O:23])[CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO.[Cl-].[Na+]>CC(O)C>[C:38]([O:37][C:26]1[CH:25]=[C:24]([CH:22]([OH:23])[CH2:21][N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:29]=[CH:28][C:27]=1[O:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])(=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)C(=O)Oc1ccc(C(O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Temperature: -10 °C
Yield: 82.2 %

Procedure:
A suspension of 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(pivaloyloxy)acetophenone (2.0 g.) in 2-propanol (20 ml.) was cooled to a -10° C. and sodium borohydride (0.34 g.) added in two portions interspersed by a portion of methanol (4 ml.). After 30 minutes at -10° C. a saturated aqueous solution (150 ml.) of sodium chloride (brine) was added and the mixture was extracted with ether (3×80 ml.). Evaporation of the dried (MgSO4) ethereal extracts gave 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)-N-benzyl-ethylamino]ethanol (1.65 g.) which was dissolved without purification in ethanol (40 ml.). To this solution was added benzyl bromide (0.37 ml., 0.0031 mole) and the mixture was then hydrogenated in the presence of 10% palladium-carbon (0.4 g.) at atmospheric pressure and room temperature during 2 hours. The catalyst was separated, washed with ethanol (10 ml.) and the ethanol washings and reaction solution were evaporated together. The residue was triturated with ether (20 ml.) containing several drops of ethanol to give 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)ethylamino]ethanol hydrobromide, (1.2 g.), m.p. 110°-115° C., identical with that obtained in Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([CH:8]2[C:13](=[O:14])[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9]2)[CH:7]=1.[Cu][C:22]#[N:23].C(Cl)Cl.[OH-].[NH4+]>CN(C=O)C>[CH3:20][O:19][C:5]1[CH:4]=[CH:3][C:2]([C:22]#[N:23])=[CH:7][C:6]=1[CH:8]1[C:13](=[O:14])[NH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9]1
Reactant: N#C[Cu]
Reactant: COc1ccc(Br)cc1C1Oc2ccccc2NC1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C#N)cc1C1Oc2ccccc2NC1=O
Temperature: 160 °C
Yield: 88.5 %

Procedure:
To a solution of 2-(5-bromo-2-methoxyphenyl)-2H-1,4-benzoxazin-3(4H)-one (I11) (0.90 g, 2.70 mmoles) in DMF (10 mL) was added copper (I) cyanide (1.3 g, 5 equiv.) and the mixture heated at 160° C. for 12 hours. The mixture was cooled and methylene chloride (100 mL) and aqueous ammonium hydroxide (10 mL) were added. The methylene chloride layer was separated and dried over MgSO4 which afforded the required product (I12) (0.67 g, 89%) upon evaporation in vacuo.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.Cl.[C:27]1([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C=[O:42])C>>[C:27]1([C:33]2([OH:42])[CH2:37][CH2:36][N:35]([C:14]([C:10]3[CH:11]=[N:12][O:13][C:9]=3[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])=[O:16])[CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: CC(c1ccccc1)c1oncc1C(=O)O
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccc1)c1oncc1C(=O)N1CCC(O)(c2ccccc2)C1
Reaction time: 2 h

Procedure:
A solution of 5-(1-phenylethyl)isoxazole-4-carboxylic acid (11 mg, 0.05 mmol) TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (26 μL, 0.15 mmol, 3 equ) in DMF (0.3 mL) was added to 3-phenylpyrrolidine hydrochloride (10 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (5 mg). MS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1627.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([OH:27])[CH3:26]>>[CH2:25]([O:27][CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6])[CH3:26]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC=CC(=O)c1cccnc1

Procedure:
A mixture of 0.10 mole of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one and 0.20 mole of p-toluenesulfonic acid in 150 ml of anhydrous ethanol was refluxed for 10 hours. The solvent was removed and the residue partitioned between water and dichloromethane. The organic layer was dried over magnesium sulfate and the solvent removed, giving 3-ethoxy-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [C:1]([N:11]1[CH2:13][C:12]1([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:16]([CH:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[OH:21])([CH3:19])([CH3:18])[CH3:17].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][C:12]([CH3:14])([CH3:15])[CH2:13][O:21][CH:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:16]([CH3:19])([CH3:18])[CH3:17])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1(C)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(O)C(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(COC(C(C)(C)C)C(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2,2-Dimethyl aziridine and di-t-butylmethanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-2-amino-2-methyl-1-[di-(t-butyl)-methoxy]propane.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[C:22]2[S:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1ccc(Oc2ccccc2)cc1
Yield: 54.9 %

Procedure:
A mixture of 9.9 g (50.0 mmol) of 4-phenoxybenzaldehyde, 6.8 g (51.1 mmol) of rhodanine, 15.5 g of sodium acetate and 60 ml of acetic acid was heated on a steam bath for two hours. The reaction solution was then poured into water causing crude product to precipitate. The precipitate was filtered and then washed successively with water followed by diethyl ether to provide 8.6 g of title product, m.p. 195°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(Cl)(Cl)Cl>O>[Br:13][CH2:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([CH3:12])[C:2]=1[Cl:1]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(CBr)c1Cl
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A mixture of 129 g of 2-chloro-1,3-dimethyl-5-nitrobenzene, 125 g of 1-bromo-2,5-pyrrolidinedione, 12 g of dibenzoyl peroxide and 1200 ml of tetrachloromethane was stirred for 2 hours at reflux temperature using a water separator. Twice there was added an extra portion of 20 g of dibenzoyl peroxide during a refiuxing period of 29 hours. After cooling, the reaction mixture was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /hexane 50:50). The eluent of the desired fraction was evaporated, yielding 130 g (70.2%) of 1-(bromomethyl)-2-chloro-3-methyl-5-nitrobenzene (interre. 5).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C:18](O)=[O:19])[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1>O1CCOCC1>[CH3:16][O:15][C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([O:8][CH3:7])[CH:14]=1)[CH2:17][CH2:18][OH:19]
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cc(CCO)cc(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a mixture of LiAlH4 (1.05 g) in dioxane (100 ml) was added a solution of 3,5-dimethoxyphenyl acetic acid (5.32 g) in dioxane (20 ml) portionwise at 0° C. The mixture was stirred at room temperature for 0.5 hour and at 50° C. for 2 hours. The mixture was quenched with conc. NH4OH and filtered through Celite. The filtrate was evaporated to yield 3,5-dimethoxyphenethyl alcohol (5.1 g). IR (Neat) 3400, 1600 cm−1; MS (GC-EI) 182 (M+), 151 (M−MeO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[C:23]([OH:32])(=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:26].C(=O)(O)[O-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:23]([OH:32])=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(F)cc1)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A solution of the title B compound, 4-[2-(4-fluoro-phenyl)-ethylcarbamoyl]-benzene-sulfonyl chloride (171 mg, 0.5 mmol) in THF (2 mL) is added dropwise over 10 min to a solution of the anthranilic acid (68.6 mg, 0.5 mmol) in water (1 mL) containing sodium bicarbonate (126 mg, 1.5 mmol). After stirring for 30 min, the solvent is evaporated under a stream of nitrogen, and water (8 mL) is added. The mixture is stirred for a few min, then filtered. The filtrate is added dropwise to an excess of 1 N aqueous HCl to precipitate a light tan solid. The solid is collected by filtration, washed with water, and dried under vacuum to give 2-{4-[2-(4-fluoro-phenyl)-ethylcarbamoyl]-benzenesulfonylamino}-benzoic acid: m.p. 85-86° C.; ESI-MS 441 [M−1]−.
Reaction SMILES: ClC[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[C:36](=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([CH2:29][N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:4][CH:5]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:23][CH:24]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: CN1CCNCC1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(C)CC4)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (7ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydro-naphthalene-2-carboxamide (150mg), and to the mixture was added 1-methylpiperazine (129 μl). The mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/triethylamine=20/1) and recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-[4-(4-methyl-1-piperazinylmethyl)-phenyl]-3,4-dihydronaphthalene-2-carboxamide (Compound 40) (105mg) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([F:33])[F:32]>C(#N)C>[CH2:1]([N:3]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([F:33])[F:32])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: FC(F)CCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCCC(F)F)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 1-bromo-6,6-difluorohexane (Step II) to give N-[4-[4-[ethyl(6,6-difluorohexyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide, a compound of Formula I'. A mixture of this compound and 0.5 equivalents of fumaric acid was crystallized from acetone to give the titled product, mp 88°-90° C. Anal. calc'd for C21H34F2N2O5S: C, 54.29; H, 7.38; N, 6.03; S, 6.90. Found: C, 54.42; H, 7.58; N, 5.74; S, 6.58.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[C:8]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:19]=2[CH:20]=O)[CH2:14][CH2:13]1)([CH3:11])([CH3:10])[CH3:9].[SH:28][C@@H:29]([CH2:33][C:34]([OH:36])=[O:35])[C:30](O)=[O:31]>C1(C)C=CC=CC=1>[C:8]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:19]=2[CH:20]2[N:5]([CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])[C:30](=[O:31])[C@H:29]([CH2:33][C:34]([OH:36])=[O:35])[S:28]2)[CH2:16][CH2:17]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N1CCN(c2c(F)cc(F)cc2C=O)CC1
Reactant: CC(C)(C)CCN
Reactant: O=C(O)C[C@H](S)C(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cc(F)cc(F)c1N1CCN(C(C)(C)C)CC1
Temperature: 80 °C
Yield: 27.1 %

Procedure:
3,3-Dimethylbutan-1-amine (0.7 g, 6.8 mmol) and 2-(4-tert-butylpiperazin-1-yl)-3,5-difluorobenzaldehyde (0.96 g, 3.4 mmol) were combined in toluene and heated to reflux overnight with a Dean-Stark trap attached. The reaction mixture was concentrated to a brown oil. This oil was redissolved in toluene and (S)-2-mercaptosuccinic acid (510 mg, 3.4 mmol) was added. The reaction mixture was heated at 80° C. for 16 hrs., concentrated to an oil, and triturated with ether to give a beige solid, which was filtered off and dried to give 2-((5S)-2-(2-(4-tert-butylpiperazin-1-yl)-3,5-difluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (0.45 g, 0.92 mmol, 27% yield) as a solid. LC/MS MH+ 498.45.