Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]([CH2:34][C:35]3[N:40]=[CH:39][C:38]4[O:41][CH2:42][CH2:43][O:44][C:37]=4[CH:36]=3)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:21]2)[C:9](=[O:45])[CH:8]=1)(=O)=O.[CH3:48][N:49](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:48]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([N:26]([CH2:34][C:35]3[N:40]=[CH:39][C:38]4[O:41][CH2:42][CH2:43][O:44][C:37]=4[CH:36]=3)[C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:24][CH2:25]2)[C:9](=[O:45])[CH:8]=1)#[N:49]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cc(OS(=O)(=O)C(F)(F)F)c3ccc(F)cc32)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cc(C#N)c3ccc(F)cc32)CC1
Temperature: 90 °C
Yield: 58 %

Procedure:
A solution of 1-{2-[4-((2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]ethyl}-7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl trifluoromethanesulfonate (0.131 g, 0.19 mmol), zinc cyanide (0.027 g, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (0.017 g, 0.019 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (0.042 g, 0.076 mmol) in DMF (3 ml) was degassed with argon then heated at 90° C. for 18 h. The mixture was allowed to cool then separated between ethyl acetate and brine. The organics were isolated, dried and concentrated. Chromatography (10 g silica SPE gradient elution with ethyl acetate/methanol 0-3%) provided the title compound (0.062 g, 58%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[O:17]C(=O)[N:15]3[CH2:19][CH2:20][CH2:21][C@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[OH-].[K+]>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)([C@H:14]2[CH2:21][CH2:20][CH2:19][NH:15]2)[OH:17])[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:8]=1
Reactant: O=C1OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN1
Temperature: 65 °C
Reaction time: 22 h
Yield: 79 %

Procedure:
To a stirred solution of crude (7aR)-1,1-bis(3,5-bis(trifluoromethyl)phenyl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one ((R)-32, 11.03 g, 20.0 mmol) in methanol (MeOH, 80 mL, 1975 mmol) was added solid potassium hydroxide (KOH, 3.366 g, 60.0 mmol, 3.0 equiv) at room temperature. The resulting dark reaction mixture was heated to 65° C. and stirred at 65° C. for 22 h. When LCMS showed the reaction was deemed complete, the reaction mixture was cooled to room temperature before the solvent was evaporated under reduced pressure. The residue was then treated with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was then purified by Combiflash (SiO2) with 0-30% EtOAc/hexane gradient elution to afford (2R)-bis(3,5-bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol ((R)-33, 8.30 g, 10.51 g theoretical, 79% yield for 2 steps) as a yellow viscous paste. For (R)-33: 1H NMR (CD3OD, 400 MHz) δ ppm 8.24 (s, 2H), 8.16 (s, 2H), 7.85 (s, 2H), 4.49 (t, 1H, J=7.7 Hz), 2.92 (m, 2H), 1.74 (m, 2H), 1.67 (m, 1H), 1.55 (m, 1H); C21H15F12NO (MW, 525.33), LCMS (EI) m/e 526.0 (M++H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:12]3[C:13](=[O:25])[N:14]([CH2:19][C:20]([O:22]CC)=[O:21])[C:15]([Cl:18])=[CH:16][N:17]=3)[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CCO>[CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:12]3[C:13](=[O:25])[N:14]([CH2:19][C:20]([OH:22])=[O:21])[C:15]([Cl:18])=[CH:16][N:17]=3)[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cn1c(Cl)cnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O

Procedure:
To a stirred solution of 3-(trans-3-cyclopropylmethoxytetrahydrofuran-4-ylamino)-6-chloro-1-ethoxycarbonylmethylpyrazinone from step 6 above (0.5 g, 1.3 mmol) and aqueous NaOH (0.65 mL of a 4.0 N solution, 2.6 mmol) in EtOH (7 mL) was stirred at ambient temperature for 18 h. Aqueous HCl (0.43 mL of a 6.0 N solution, 2.6 mmol) was added and the solvents were removed in vacuo. The residue was partitioned between CH2Cl2 and water. The organic phase was separated, dried over MgSO4, filtered and the solvent was removed in vacuo to give the title compound as an amorphous solid (0.4 g; HPLC RT=5.88 min, method A).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]2=[N:20][C:19]=1[CH2:29][OH:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.O>[CH2:11]([C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]2=[N:20][C:19]=1[CH:29]=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(Cc2ccccc2)c(CO)nc2ccccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1nc2ccccn2c(=O)c1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
26.5 mL (53.0 mmol) of oxalyl chloride in 40 mL dichloromethane was cooled to −78° C. To the resulting solution was added a solution of 7.52 mL (105.9 mmol) of DMSO in 24 mL dichloromethane and stirred at −78° C. for one hour. Then was added a solution of 4.7 g (17.65 mmol) of product from Step 5 (15) in 60 mL dichloromethane and the resulting mixture was stirred at −78° C. for one hour. Then was added 24.6 mL (176.5 mmol) of triethylamine and stirred at −78° C. for one hour. The mixture was then allowed to warm to 0° C. and stirred for another hour. Finally, the mixture was allowed to warm to ambient temperature over the course of one hour. Excess water was added to the reaction mixture and the mixture was extracted (3×) using dichloromethane. The combined organic layers were dried over MgSO4 and activated carbon and the solvent was removed in vacuo. The resulting material was subjected to flash chromatography on a 10 cm column. Elution with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in hexanes, 43% ethyl acetate in hexanes, and 50% ethyl acetate in hexanes yielded 3.1 g (11.7 mmol, 67%) of 3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (16) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[F:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36]O)[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:24]3[O:25][N:36]=[C:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NC(=NO)c1cccc(F)c1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C
Product: Cc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1C

Procedure:
80 mg (0.22 mmol) of the compound from Example 128A and 51 mg (0.33 mmol) of the compound from Example 73A were reacted according to the General Method 2. Yield: 69 mg (65% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[C:25]([N:30]=[C:31]=[O:32])[N:24]=1>C(#N)C.O>[Cl:29][C:27]1[CH:28]=[C:23]([Cl:22])[N:24]=[C:25]([NH:30][C:31]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3]([O:2][CH3:1])=[O:15])(=[O:12])=[O:13])=[O:32])[N:26]=1
Reactant: COC(=O)Cc1ccccc1S(N)(=O)=O
Reactant: O=C=Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
To 2.3 g of 2-(aminosulfonyl)benzeneacetic acid methyl ester in 30 ml of acetonitrile was added 1.5 g of anhydrous potassium carbonate and 1.6 g of 4,6-dichloropyrimidin-2-yl isocyanate. The mixture was stirred at room temperature for 6 hours, diluted with 250 g of water and acidified to a pH of about 4. The resulting solid was filtered and dried to yield 1.6 g of methyl 2-[[(4,6-dichloropyrimidin-2-yl)aminocarbonyl]aminosulfonyl]benzeneacetate, a pale yellow solid, m.p. 115°-118° C. It showed infrared absorption peaks at 1730, 1600 and 1560 cm-1 and nuclear magnetic resonance peaks at 3.7 ppm, methyl ester group; 4.2 ppm, benzeneacetic group; 6.9 ppm, pyrimidin H; 7.4-7.6 ppm, aromatic hydrogens; consistent for the product.
Reaction SMILES: C(OC(N1C[CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C[O:32][C:33](=[O:41])[CH2:34][CH:35]1CCNC[CH2:36]1.O1C2C(=NC=CC=2)O[C@@H](C2C=CC(CN3CCC(C(O)=O)CC3)=CC=2)C1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][CH:35]([CH2:34][C:33]([OH:41])=[O:32])[CH2:36][CH2:12]3)=[CH:20][CH:19]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: COC(=O)CC1CCNCC1
Agent: O=C(O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: O=C(O)CC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
The title product GG is prepared from compound GG-1 (prepared from Intermediate C and piperidin-4-yl-acetic acid methyl ester according to General Method F) according to the procedure used to synthesize Intermediate K.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].Cl.[CH2:21]([O:23][C:24](=[O:30])[C@H:25]([C@@H:27]([CH3:29])[OH:28])[NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1)[CH:27]([OH:28])[CH3:29])[CH3:22]
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(NC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([C@H:8]([NH:45]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C@@H:9]([OH:44])[CH2:10][C@@H:11]([NH:19][C:20](=[O:43])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=[CH:34][CH:33]=2)[C:27]1=[O:42])[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NCC)C>CN(C=O)C>[NH2:45][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:44])[CH2:10][C@@H:11]([NH:19][C:20](=[O:43])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=[CH:34][CH:33]=2)[C:27]1=[O:42])[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)N1CCN(Cc2ccnc3ccccc23)C1=O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)N1CCN(Cc2ccnc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 134A (0.122 g, 0.147 mmol) in DMF (6 mL) was treated with diethylamine (1.5 mL), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compounds.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].Cl[CH2:15][CH2:16][CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][P:19](=[O:23])([O:24][CH2:25][CH3:26])[O:20][CH2:21][CH3:22])[CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4]
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)n(C)c(=O)n2C)OCC
Temperature: 70 °C

Procedure:
10.9 g (0.05 mol) of 1,3-dimethylxanthine were suspended in 150 ml of DMF, treated with 13.7 g (0.06 mol) of diethyl 4-chlorobutanephosphonate and 7.0 g (0.05 mol) of activated potassium carbonate and heated at 70° C. for approximately 4 hours. The solid was then filtered off, the filtrate was concentrated under reduced pressure and the oily residue which remained was taken up in ethyl acetate, filtered again and crystallized from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(OCC)(=O)C>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:9])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Yield: 64.8 %

Procedure:
72.15 g (0.3 mole) of 2-(4-chlorophenoxy-methyl)-2-tert.-butyl-oxirane and 24.15 g (0.35 mole) of 1,2,4-triazole were heated under reflux in 120 ml of ethanol for 48 hours. The mixture was then concentrated, the residue was taken up in 200 ml of ethyl acetate and the ethyl acetate mixture was heated. It was then cooled in an ice bath and the solid was filtered off and rinsed with ethyl acetate. The filtrate was concentrated, the residue was dissolved in ether/hexane and the solution was gassed with hydrogen chloride. The precipitate was filtered off and rinsed with ether and the free base was obtained by adding ethyl acetate/1N sodium hydroxide solution. 60.2 g (65% of theory) of 2-(4-chlorophenoxy-methyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 84°-87° C. were obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.[OH-].[Na+]>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Sc1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccccc1Sc1ccc(Cl)cc1

Procedure:
To a well stirred mixture of 15.7 g. (0.1 mole) of 2-chlorobenzoic acid and 15.0 g. (0.1 mole) of sodium iodide in 250 ml. of 4-chlorothiophenol was rapidly added a solution of 16 g. (0.4 mole) of sodium hydroxide dissolved in 16 ml. of water. The reaction mixture was heated and concentrated under reduced pressure to an internal temperature of about 145° C. to remove the water and some excess 4-chlorothiophenol. The residue was then stirred at 170° C. for about 7 hours, cooled and diluted with 250 ml. of water. The solution was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extractions were washed with water, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from a benzene-hexane mixture to give 2-(4'-chlorothiophenoxy)benzoic acid having a melting point of 239°-240° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1.[Sn](Cl)Cl>>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[NH:13][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:10]([C:23]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)Nc2nccs2)cc1
Agent: Cl[Sn]Cl
Product: COc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Yield: 35.2 %

Procedure:
5-(4-Methoxyphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.52 g) obtained in Example 47 and tin(II) chloride 6 hydrate (1.2 g) were reacted and treated in the same manner as in Example 59 to give 2-(4-aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (0.17 g), melting point 257-258° C. (decomposition).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:25][CH2:26][CH:27](Br)[CH2:28][CH3:29]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Reactant: CCC(Br)CC
Product: CCCCN1CCN(CCNC(=O)c2nn(C(CC)CC)c3ccccc23)CC1

Procedure:
The title compound was synthesized by using N-[2-(4-n-butyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 10 and 3-pentyl bromide according to the same process as in Example 12.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][OH:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.[OH-].[K+]>ClCCl.CN(C)C1C=CN=CC=1.CO>[Cl:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]=[C:17]([OH:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1c2ccccc2C=Cc2c(Cl)cccc21
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: OC1=Cc2ccccc2C=Cc2c(Cl)cccc21
Yield: 18.2 %

Procedure:
To a solution of 1-chloro-5-hydroxymethyl-dibenzo [a,d]cycloheptene (8.3 g) in dichloromethane (80 ml) was added p-toluenesulphonyl chloride (6.3 g), pyridine (5.11 g), and 4-dimethylamino pyridine (150 mg). The reaction mixture was refluxed for 15h, cooled washed with water (2×80 ml), dried (Na2SO4), filtered and concentrated in vacuo to leave an oil which was purified by chromatography on flash silica with 15% ethyl acetate in hexane as eluent. The purified tosylate was dissolved in glacial acetic acid (100 ml) with anhydrous sodium acetate (4.4 g) and the solution refluxed for 15h. The mixture was concentrated in vacuo to leave a residue which was partitioned between dichloromethane (3×100 ml) and water (100 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was dissolved in 75% aqueous methanol (160 ml) and treated at 0° C. with potassium hydroxide (10 g). After 14h the reaction mixture was concentrated in vacuo. Chromatography of the residue on flash silica with 15% ethyl acetate in hexane as eluent gave the less polar isomer, 1-chloro-5-hydroxydibenzo[a,e]cyclooctene (1.5 g), m.p. 158°-160° C. δ(360 MHz, CDCl3) 3.12 (1H, dd, J =1.51 and 10.2 Hz, CHAHB --CHOH), 3.63 (1H, dd, J=15.1 and 6.9 Hz, CHAHB --CHOH), 5.57 (1H, dd, J=10.2 and 6.9 Hz, CHAHB --CHOH), 6.74 (1H, d, J=11.9 Hz, ArCHD =CHE --Ar), 7.03 (1H, d, J=11.9 Hz, ArCHD =CHEAr) and 7.07-7.46 (7H, m, aromatics). m/e 256 (M+). i.r.(νmax, nujol) 3350-3100 cm-1 (br, OH). Found: C, 74.5; H, 5.1. C16H13C10 requires: C, 74.9; H, 5.1%. Further elution gave the more polar isomer, 1-chloro-6-hydroxy-dibenzo[a,e]cyclooctene (0.47 g), m.p. 144°-146° C. δ(360 MHz, CDCl3) 3.39 (2H, m, CH--CHOH), 5.13 (1H, m, CH2 --CHOH), 6.77 (1H, d, J=11.9 Hz, Ar--CHA =CHB), 7.02 (1H, d, J=11.9 Hz, ArCHA =CHB) and 7.07-7.38 (7H, m, aromatics). m/e 256 (M+). i.r (νmax, nujol) 3300-3100 cm-1 (br, OH). Found: C, 74.8; H, 5.2. C16H13C10 requires: C, 74.9; H, 5.1%.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-3-(4-chloro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.98 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.92 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes. Yield 362 mg, 86%; HPLC (60/40) 5.06 minutes (97%); mp 227-229° C.; TSPMS 460/462 (MH+, 100%);
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Cl-].S1C=CC=C1[Zn+].[CH2:18]1[CH2:54][O:53][C:20]2([CH2:37][CH2:36][C@H:35]3[C:22](=[CH:23][CH2:24][C@@H:25]4[C@@H:34]3[C@@H:33]([C:38]3[CH:43]=[CH:42][C:41](OS(C(F)(F)F)(=O)=O)=[CH:40][CH:39]=3)[CH2:32][C@@:30]3([CH3:31])[C@H:26]4[CH2:27][CH2:28][C:29]3=[O:52])[CH2:21]2)[O:19]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:54]1[CH2:18][O:19][C:20]2([CH2:37][CH2:36][C@H:35]3[C:22](=[CH:23][CH2:24][C@@H:25]4[C@@H:34]3[C@@H:33]([C:38]3[CH:43]=[CH:42][C:41]([C:7]5[S:6][CH:10]=[CH:9][CH:8]=5)=[CH:40][CH:39]=3)[CH2:32][C@@:30]3([CH3:31])[C@H:26]4[CH2:27][CH2:28][C:29]3=[O:52])[CH2:21]2)[O:53]1
Reactant: C[C@]12C[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)[C@H]3[C@@H](CC=C4CC5(CC[C@@H]43)OCCO5)[C@@H]1CCC2=O
Reactant: c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@]12C[C@H](c3ccc(-c4cccs4)cc3)[C@H]3[C@@H](CC=C4CC5(CC[C@@H]43)OCCO5)[C@@H]1CCC2=O
Temperature: 25 °C

Procedure:
3.3 ml of a 1.6 molar solution of butyllithium in hexane is slowly instilled in a solution of 423 μl of thiophene in 8 ml of tetrahydrofuran at room temperature under protective gas. After 30 more minutes of stirring, 872 mg of dry zinc(II) chloride, dissolved in 5 ml of diethyl ether, is added to the reaction mixture and stirred for one hour at room temperature. The thus produced 2-thienylzinc chloride solution is instilled in a solution of 480 mg of 3,3-(ethylenedioxy)-11β-(4-trifluoromethylsulfonyloxyphenyl)-5-estren-17-one and 51 mg of tetrakistriphenylphosphinepalladium in 10 ml of tetrahydrofuran. The reaction mixture is stirred for eight hours under reflux, cooled to room temperature and mixed with saturated ammonium chloride solution. The aqueous phase is extracted three times with ethyl acetate. The organic phases are washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. Chromatography of the residue on silica gel with a mixture of ethyl acetate/hexane yields 380 mg of the title compound as white foam.