Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].Cl[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([S:14][CH2:16][C:17]3[S:21][C:20]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=4)=[N:19][C:18]=3[CH3:32])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(S)ccc2o1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc2o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A mixture of 5-mercapto-benzofuran-2-carboxylic acid methyl ester (300 mg, 1.4 mmol) and 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (550 mg, 1.9 mmol) was dissolved in 5 ml anhydrous acetonitrile followed by addition of cesium carbonate (700 mg, 2.1 mmol). The reaction was then stirred at 60° C. for 2 hours, filtered and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexanes to 45% EtOAc/hexanes), gave the title compound (410 mg, 61%) as a pale yellow solid. M.p. 132–133° C.; IR (thin film) cm−1: 1173; 400 MHz 1H NMR (DMSO-d6) δ 7.95 (d, 2H, J=8.1 Hz), 7.79 (s, 1H), 7.74 (d, 2H, J=8.1 Hz), 7.65 (m, 2H), 7.51 (d, 1H, J=9.0 Hz), 4.44 (s, 2H), 3.82 (s, 3H); MS m/z 464 (M+1); Annl. Calc'd for C22H16F3N1O3S2 C, 57.01; H, 3.48; N, 3.02; found: C, 56.94; H, 3.44; N, 2.84.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-])=O)=[C:11]([CH2:21][C:22](=O)[CH3:23])[CH:10]=2)=[CH:5][CH:4]=1>[Pd].C(OCC)(=O)C>[CH3:23][C:22]1[NH:18][C:12]2[C:11]([CH:21]=1)=[CH:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)=[C:14]([N+:15]([O-:17])=[O:16])[CH:13]=2.[OH:16][NH:15][C:14]1[CH:13]=[C:12]2[C:11]([CH:21]=[C:22]([CH3:23])[NH:18]2)=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: CC(=O)Cc1cc(-c2ccc(CO)cc2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc2cc(-c3ccc(CO)cc3)c(NO)cc2[nH]1
Product: Cc1cc2cc(-c3ccc(CO)cc3)c([N+](=O)[O-])cc2[nH]1
Reaction time: 8 h

Procedure:
A mixture of 1-(4′-hydroxymethyl-4,6-dinitro-biphenyl-3-yl)-propan-2-one (200 mg) and palladium on carbon (10%, 80 mg) in ethyl acetate was shaken in a Parr apparatus under hydrogen atmosphere (50 PSI) overnight. The reaction mixture was then filtered on a CELITE™ pad, the filtrate was evaporated under reduced pressure and the crude residue was purified by flash chromatography to afford [4-(2-methyl-6-nitro-1H-indol-5-yl)-phenyl]-methanol and [4-(6-hydroxyamino-2-methyl-1H-indol-5-yl)-phenyl]-methanol. The two products were combined and dissolved in dichloromethane (5 mL). Zinc dust (a large excess) and glacial acetic acid (1 mL) were added and the resulting mixture was heated at 70° C. for 30 minutes. The reaction mixture was then filtered on a CELITE™ pad, the filter cake was washed with ethyl acetate. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (MeOH/DCM, 5/95) to give 55 mg of [4-(6-amino-2-methyl-1H-indol-5-yl)-phenyl]-methanol. MS=253 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:17][C:16]=1[CH2:31][OH:32].O>C1COCC1>[CH3:1][S:2]([O:32][CH2:31][C:16]1[CH:17]=[C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:15]=1[C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[F:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CO)c2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(COS(C)(=O)=O)c2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Methanesulfonyl chloride (0.164 mL) was added to a solution of (2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)methanol (390 mg) in THF (10 mL) at 0° C., and the mixture was stirred at 0° C. for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)methyl methanesulfonate. To solution (10 mL) of the obtained compound and TBAI (117 mg) in DMF was added sodium hydride (60%, 85 mg) at 0° C., and the mixture was stirred at 0° C. for 5 min, then at 80° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (326 mg) as a colorless oil.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:19])[C:11](=[CH2:18])[CH:12]([O:14][C:15](=[O:17])[CH3:16])[CH3:13].CO[CH2:22][N:23]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[Si](C)(C)C>C(Cl)Cl>[CH3:8][O:9][C:10]([C:11]1([CH:12]([O:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH2:2][CH2:22][N:23]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:18]1)=[O:19]
Reactant: O=C(O)C(F)(F)F
Reactant: C=C(C(=O)OC)C(C)OC(C)=O
Reactant: COCN(Cc1ccccc1)[Si](C)(C)C
Solvent: ClCCl
Product: COC(=O)C1(C(C)OC(C)=O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (0.5 g, 4.38 mmol) was added to a solution of methyl-3-acetoxy-2-methylenebutyrate (5 g, 29.03 mmol) and N-methoxymethyl-N-trimethylsilyl benzylamine (6.89 g, 29.03 mmol) in MeCl2 (50 ml) at 0° C. then stirred overnight at room temperature. The solvent was evaporated and the residue extracted with EtOAc (200 ml) and H2O (50 ml) and saturated NaHCO3 solution (50 ml). The organic layer was separated, dried over MgSO4 filtered and evaporated solvent. The residue chromatographed on silica gel eluting with (v:v) EtOAc:hexanes 3:1 yielding compound 2N as a colorless oil (7 g, 81.7%) LCMS (MH, 306) Retention time=2.08 minutes.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[N:27]=1>O1CCCC1>[CH2:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[N:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccccc1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To freshly prepared dodecylmagnesium bromide (from 30.13 mmol of dodecyl bromide and 26.20 mmol of magnesium) in distilled tetrahydrofuran (50 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline [A. I. Meyers et al., J. Org. Chem., 43, 1372 (1978)] (17.88 mmol) in tetrahydrofuran (30 ml). The resultant yellow solution was stirred under argon at ambient temperature for 20 hours. The solution was cooled in an ice water bath and quenched with aqueous ammonium chloride (100 ml). The reaction product was extracted into diethyl ether (100 ml) and the organic phase was washed with saturated sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulfate. Evaporation of the organic phase afforded a colorless oil which was purified by flash chromatography over silica gel with 5 percent ethyl acetate in hexane as eluant to afford the desired product as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:34].[OH-:36].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:34][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])[CH3:15])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:35])=[O:2].[C:9]([O:12][CH2:13][CH3:14])(=[O:36])[CH3:8]
Reactant: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(-c4ncccn4)cc3)sc2C)cc1C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)c2nc(-c3ccc(-c4ncccn4)cc3)sc2C)ccc1CCC(=O)O
Temperature: 25 °C

Procedure:
3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic acid methyl ester (698 mg, 1.43 mmol) is dissolved in tetrahydrofuran (2 mL) and 5N sodium hydroxide (2 mL) solution is added with stirring at room temperature. The reaction is heated to reflux and monitored by HPLC. Upon complete conversion, the reaction is allowed to cool to room temperature and neutralized with 5N hydrochloric acid (2 mL), diluted with ethyl acetate, and extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic acid (462 mg, 0.9755 mmol) may also be obtained by recrystalization from ethyl acetate (68% yield), MS (ES): ?? (M++1).
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[C:1]1([O:11][C:12]2[CH:17]=[CH:16][N+:15]([O-:26])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Oc3ccncc3)cccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(Oc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of Example 136 A (6.62 g; 29 9 mmol) in dichloromethane (40 ml) is treated with m-chloroperbenzoic acid, 80% strength (7 10 g; 32 9 mmol), stirred at room temperature for 24 h and then heated to reflux for a further 2 h The reaction mixture is washed twice with satd aqueous NaHCO3 solution. The combined aqueous phases are extracted with dichloromethane and the combined dichloromethane phases are dried (Na2SO4) and concentrated in vacuo. The residue is crystallized from dichloromethane/petroleum ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH:16][C:17]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[C:26]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([C:18]1[C:17]([OH:16])=[C:29]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:27][C:26]=1[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(C(=O)OC)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)ccc(C(F)(F)F)c1O
Product: CCOC(C(=O)O)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1

Procedure:
According to a method similar to Example (31) and Example (17-4), from methyl (4-bromophenyl)(ethoxy)acetate (110 mg, 0.4 mmol) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (170 mg, 0.34 mmol) obtained in Example (22-4), the title compound was obtained as a grayish white powder (35 mg, yield: 19%).
Reaction SMILES: [C:1]([C:4]1[O:5][CH2:6][CH2:7][N:8]=1)([CH3:3])=[CH2:2].[C:9](Cl)(Cl)=[O:10].[OH-:13].[Na+]>O.C(Cl)Cl>[C:4]([O:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10])(=[O:13])[C:1]([CH3:3])=[CH2:2]
Reactant: [OH-]
Reactant: C=C(C)C1=NCCO1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=C(C)C(=O)OCCN=C=O
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 95 %

Procedure:
A 3-liter jacketed reactor vessel was charged with 100 ml of methylene chloride and cooled to approximately 0° C. A solution of 2-isopropenyl-2-oxazoline (100 g) in 177 ml of water, a solution of phosgene (131.5 g) in 400 ml of methylene chloride, and a solution of 35 weight percent sodium hydroxide in water were added simultaneously to the reaction vessel with stirring and cooling. The rates of addition were such that the three reagents were added over approximately a 50 minute time span with the temperature being maintained at 10° to 18° C. Stirring was continued for two minutes and the layers allowed to separate. The organic layer was washed twice with 100 ml portions of a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. The colorless concentrate was inhibited with 0.1 g of phenothiazine and the desired product recovered therefrom as a colorless liquid (133.6 g) boiling at 46°-47° C./0.4 mm Hg. Product yield 95-96 percent of theory.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5](=[O:13])[NH:6][C@H:7]1[CH2:12][CH2:11][O:10][C:8]1=[O:9].[OH-:22].[Li+]>CO>[OH:10][CH2:11][CH2:12][C@H:7]([NH:6][C:5]([N:4]([CH2:3][CH2:2][SH:1])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:8]([OH:22])=[O:9]
Reactant: O=C1OCC[C@@H]1NC(=O)N(CCS)CCc1ccccc1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Product: O=C(O)[C@H](CCO)NC(=O)N(CCS)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 48 %

Procedure:
(2S)-2-[3-(2-Mercaptoethyl)-3-phenethylureido]-4-butanolide (Compound No. 1-69, 2.9 g) is dissolved in methanol (19 ml) under a nitrogen atmosphere. A 2 N aqueous lithium hydroxide solution (5.6 ml) is added thereto under ice cooling, and the mixture is stirred under ice cooling for 50 minutes and further at room temperature for 35 minutes. The reaction mixture is concentrated under reduced pressure, a 10% aqueous citric acid solution is added to the concentrate, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.5 g (48%) of the titled compound (Compound No. 8-1).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[CH2:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([CH2:16][C:17]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([O:27][CH3:28])[C:20]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[CH:19][CH:18]=1)(=[O:15])=[O:14])[CH3:2].[H][H]>[Pd].CO>[CH2:34]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([CH2:16][C:17]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([O:27][CH3:28])[C:20]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[CH:19][CH:18]=1)(=[O:15])=[O:14])[CH3:35]
Reactant: CCN(CC)CC=Cc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCCc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Yield: 93 %

Procedure:
A mixture of methyl 6-[2-(3-diethylaminoprop-1-en-1-yl)benzenesulphonyl-methyl]-3-(furan-3-yl)-2-methoxybenzoate (mixture of E and Z isomers, Intermediate 5, 0.03 g) and palladium on carbon (10%, 0.006 g) in methanol (1.2 ml) was stirred in an atmosphere of hydrogen (balloon) for 1 hour. The mixture was filtered through Celite and the filtrate was evaporated to dryness to give methyl 6-[2-(3-diethylaminopropyl)benzenesulphonylmethyl]-3-(furan-3-yl)-2-methoxybenzoate (0.028 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:27])[CH3:29]
Reactant: C#CC1(O)CCCC1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(C#CC3(O)CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (73) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1-ethynylcyclopentanol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.56 (m, 3H), 7.39 (d, J=8 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.26 (s, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.93 (m, 4H), 1.78 (m, 4H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.56.
Reaction SMILES: CN(C(C1C=CC=CC=1)C1C=C([C:11]2[C:12]([NH:22][C:23](=[O:25])[CH3:24])=[C:13]([CH:18]=[CH:19][C:20]=2[Cl:21])[C:14](OC)=[O:15])C=CC=1)C.C(O)C.Cl>C1COCC1>[ClH:21].[OH:15][C:14]1[C:13]2[C:12](=[CH:11][CH:20]=[CH:19][CH:18]=2)[NH:22][C:23](=[O:25])[CH:24]=1
Reactant: COC(=O)c1ccc(Cl)c(-c2cccc(C(c3ccccc3)N(C)C)c2)c1NC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1cc(O)c2ccccc2[nH]1

Procedure:
2.0 g (4.6 mmol) of methyl 3-(dimethylaminophenyl-methyl)phenyl-2-acetamido-4-chlorobenzoate are dissolved in 15 ml of THF. With cooling, 15 ml of a 1 molar solution of THF and KN[Si(CH3)3 ]2 are added dropwise with stirring. The mixture is additionally stirred at room temperature for 1 1/2 hours. The solvent is distilled off and the residue is treated with water. The solution thus obtained is washed with dichloromethane. The aqueous phase is adjusted to an acidic pH using hydrochloric acid and again extracted with dichloromethane. The organic phase separated off is dried. The solvent is distilled off. For further purification of the oil obtained, the product is taken up with ethanol, acidified with ethereal hydrochloric acid, triturated with ether and the product obtained is filtered off with suction. 7-Chloro-3-[dimethylamino-phenylmethyl)phenyl]-1,2-dihydro-4-hydroxyquinolin-2-one hydrochloride, dihydrate, m.p. ~230°, is obtained.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([CH2:25][CH2:26][O:27][C:28](=[O:33])/[CH:29]=[C:30](\[NH2:32])/[CH3:31])#[N:24].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O>CC(O)C>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][O:10][C:11]([C:12]2[CH:38]([C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([Cl:34])[CH:36]=3)[C:29]([C:28]([O:27][CH2:26][CH2:25][C:23]#[N:24])=[O:33])=[C:30]([CH3:31])[NH:32][C:13]=2[CH3:15])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: C/C(N)=C/C(=O)OCCC#N
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1

Procedure:
747 mg (2.52 mmol) of acetoacetic acid 3,3-diphenylpropyl ester, 389 mg (2.52 mmol) of 3-aminocrotonate 2-cyanoethyl ester and 0.285 ml (2.52 mmol) of 3-chlorobenzaldehyde were heated and stirred at 80° C. for two nights in 20 ml of 2-propanol. After 2-propanol was evaporated under reduced pressure, the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [CH:1]1([C:7]2([CH2:12][NH2:13])[S:11][CH2:10][CH2:9][S:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])[CH3:16]>CCCCCC.C(OC(=O)C)C>[CH3:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][C:27]([NH:13][CH2:12][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[S:11][CH2:10][CH2:9][S:8]1)=[O:28])[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NCC1(C2CCCCC2)SCCS1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(C2CCCCC2)SCCS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a stirred solution of (2-cyclohexyl-1,3-dithiolan-2-yl)methylamine (2.17 g 0.100 mole) in 40 ml of n-hexane/ethylacetate (5:1) is added dropwise at room temperature 2,6-bis(1-methylethyl)phenylisocyanate (1.94 g 0.105 mole). The reaction mixture is stirred at room temperature for two hours. Precipitated solid is filtered, washed with n-pentane/ether (1:1) and dried, yielding 3.90 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(2-cyclohexyl-1,3-dithiolan-2-yl)methylurea.
Reaction SMILES: CC1C=CC(S(NC2C=C(C3C=CC4N(C=C(NC(=O)C)N=4)N=3)C=CC=2)(=O)=O)=CC=1.Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=2)[N:37]=1.[CH3:45][S:46]([C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[N:53][CH:54]=1)(=[O:48])=[O:47]>>[CH3:45][S:46]([C:49]1[CH:50]=[C:51]([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=3)[N:37]=2)[CH:52]=[N:53][CH:54]=1)(=[O:48])=[O:47]
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Agent: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Product: CC(=O)Nc1cn2nc(-c3cncc(S(C)(=O)=O)c3)ccc2n1

Procedure:
Following the procedure described for compound N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1, Step 4) (0.084 g, 0.40 mmol) was reacted with 5-(methylsulfonyl)pyridin-3-ylboronic acid (0.14 g, 0.72 mmol, Combi-Blocks, San Diego, Calif.) to afford the title compound as a yellow solid. MS (ESI positive ion) m/z: 332 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.97 (s, 1H), 9.56 (d, J=2.2 Hz, 1H), 9.19 (d, J=2.2 Hz, 1H), 8.89 (t, J=2.2 Hz, 1H), 8.39 (s, 1H), 8.19 (d, J=9.4 Hz, 1H), 8.00 (d, J=9.4 Hz, 1H), 3.31 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1ccc(F)cc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccc(F)cc1C(=O)O
Temperature: 120 °C
Yield: 74.9 %

Procedure:
A solution of 2-(bromoacetamido)-5-fluorobenzoic acid from Example 19 (22.36 g, 91 mmol) and aniline (21 mL, 230 mmol) in dry DMF (150 mL) was heated at 85° C. for 5 hours. TLC showed indicated the presence of unreacted starting. Additional aniline (5 mL, 52 mmol) was added, and the solution was heated at 120° C. for 30 hours. After cooling, the reaction mixture was poured into ice-water (800 mL) and aqueous 5% KOH (100 mL) was added to adjust the pH to 10-11. The excess aniline was removed by extraction with CH2CO2 (3×400 mL) and the aqueous layer was separated and acidified with aqueous 20% HBr. The resulting precipitate was collected, washed with water and dried, yielding 19.64 g (74.6%) of the title compound as white crystals, mp 194-195° C.; 1H NMR (acetone-d6) δ 11.87 (s, 1H), 8.88 (dd, J=5.2, J=9.6, 1H), 7.71 (dd, J=3.2, J=9.2, 1H), 7.45-7.39 (m, 1H), 7.14-7.10 (m, 2H), 6.68-6.64 (m, 3H), 3.92 (s, 2H); 13C NMR (acetone-d6) δ 171.30, 168.14, 163.22, 157.97 (d, J=241.3), 148.97, 138.66, 129.82, 122.60 (d, J=7.1), 121.90 (d, J=21.9), 118.63, 117.78 (d, J=24.0), 113.67, 50.07; MS (EI, m/z) 288.1 (M+)