Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[CH:9]([OH:25])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1([CH2:42][C:43](Cl)=[O:44])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[C:26]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:43](=[O:44])[CH2:42][C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)[CH2:14]3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[CH:9]([OH:25])[CH2:8]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Cc1cccc2ccccc12
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccc4ccccc34)CC21
Yield: 45.9 %

Procedure:
By working according to the procedure of Example A, starting from 0.62 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol and 0.35 g of 1-naphthylacetyl chloride, 0.4 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2methoxyphenyl)-2-[(1-naphthyl)acetyl]perhydro-4,5-isoindolediol is obtained, melting at 188°-190° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[N+](C1C=CC(S(O[CH2:23][C@H:24]2[CH2:26][C:25]2([F:28])[F:27])(=O)=O)=CC=1)([O-])=O.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:23][C@H:24]2[CH2:26][C:25]2([F:28])[F:27])=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: Cc1cc(Br)ncc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ncc1OC[C@H]1CC1(F)F
Reaction time: 15 h
Yield: 47.3 %

Procedure:
To a solution of 6-bromo-4-methylpyridin-3-ol (0.50 g) and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate (1.077 g) in DMF (50 mL) was added sodium hydride (60% in oil, 0.106 g) under ice-cooling, and the mixture was stirred for 15 hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.35 g).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[C:9]([N+:17]([O-])=O)=[C:8]([CH:20]([CH3:22])[CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.O.[Sn](Cl)Cl>C(O)C>[N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[C:9]([NH2:17])=[C:8]([CH:20]([CH3:22])[CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)c1nc(-n2ccnc2)nc(-n2ccnc2)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)c1nc(-n2ccnc2)nc(-n2ccnc2)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 2,4-bis(1H-imidazol-1-yl)-5-nitro-6-(2-propyl)pyrimidine (16 g, 53.5 mmol) in 300 mL of ethanol and add 35 g of tin (II) chloride dihydrate. Stir for 2 hours at ambient temperature. Remove the solvent under vacuum and slurry the residue in 2 L of CH2Cl2. Wash with 2×3 L 10% KOH. Dry the CH2Cl2 portion over MgSO4, treat with charcoal, filter, and concentrate the filtrate under vacuum. Crystallize the residue from ethyl acetate to provide 2,4-bis(1H-imidazol-1-yl)-6-(2-propyl)pyrimidin-5-amine.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:22])=[CH:5][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncc(Sc2ccncc2)s1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1ncc(S(=O)c2ccncc2)s1
Yield: 58.1 %

Procedure:
To a mixture of 2-amino-5-(4-pyridylthio)thiazole (4.0 g) in a mixture of chloroform (300 ml) and N,N-dimethylformamide (10 ml) was added dropwise the solution of 3-chloroperbenzoic acid (4.5 g) in chloroform (100 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 26 hours under ice cooling. The reaction mixture was washed with aqueous sodium bicarbonate and water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subject to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(4-pyridylsulfinyl)thiazole (2.5 g, yield: 58.1%).
Reaction SMILES: [S:1](=[C:4]1[N:9]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][NH:6][C@@H:5]1[C:18]([O-:20])=O)(=[O:3])=[O:2].[NH2:21]O.Cl>CN(C=O)C>[S:1](=[C:4]1[N:9]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][NH:6][C@@H:5]1[C:18]([NH2:21])=[O:20])(=[O:2])=[O:3]
Reactant: NO
Reactant: O=C([O-])[C@H]1NCCN(C(=O)N2CCOCC2)C1=S(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)[C@H]1NCCN(C(=O)N2CCOCC2)C1=S(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Step 5—Formation of N-hydroxy-1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carbox-amide Methyl 1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxylate (1.11 g, 2.2 mmol) was dissolved in DMF (17 mls) to which was added 50% aqueous NH2OH (20 mls) and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured into cold 1.0N HCl (100-120 mls) and extracted with EtOAc (4×). The combined EtOAc extractions were washed with 10% aqueous LiCl (4×), saturated NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc) and the resulting pure oil was dissolved in 1:1 acetonitrile:water and lyophilized to give N-hydroxy-1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxamide as a white solid (659 mg, 59%). LC/MS Calcd for [M+H]+ 509.1, found 509.1. 1HNMR (400 MHz, CD3OD): δ 7.69 (d, 2H, J=9.2 Hz), 7.04 (m, 4H), 6.95 (d, 2H, J=9.2 Hz), 4.30 (m, 1H), 3.76 (m, 1H), 3.50 (m, 7H), 3.10 (m, 4H), 2.90 (dd, 1H, J=13.2, 4.4 Hz), 2.72 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:35]([CH3:37])[CH3:36])[N:11](/[CH:20]=[CH:21]/[C@@H:22](O)[CH2:23][C@@H:24]([OH:33])[CH2:25][C:26](OC(C)(C)C)=[O:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-:38].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:35]([CH3:37])[CH3:36])[N:11](/[CH:20]=[CH:21]/[C@H:22]3[O:38][C:26](=[O:27])[CH2:25][C@H:24]([OH:33])[CH2:23]3)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H]1C[C@@H](O)CC(=O)O1
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethyleth-1-yl (3R,5S,E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoate (25.6 mg) in redistilled THF (1.4 ml) was treated with aqueous sodium hydroxide solution (0.1M, 0.5 ml) and the clear colourless solution was stirred at room temperature. After 3.5 h the reaction mixture was concentrated to ca 0.5 ml. The residue was diluted with water (3 ml), acidified to pH4 with hydrochloric acid (2M), ammonium sulphate added and then extracted with ethyl acetate (4×3 ml). The combined extracts were dried and evaporated to a white gummy solid (25 mg). This was dissolved in dry dichloromethane (1.4 ml) and then treated with 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulphonate (42.4 mg). The resulting solution was stirred at room temperature. After 18.5 h the reaction mixture was diluted with water (5 ml) and then extracted with dichloromethane (3×5 ml). The combined extracts were washed with brine (5 ml), dried and evaporated to a cream solid (23 mg). The solid was filtered through a short colum of 70-230 mesh silica developing and eluting with System A (3:1) to give the title compound as a cream solid (18 mg), νmax (CHBr3) 1735cm-1 (lactone), δ(CDCl3) values as for those described for the racemate obtained in Example 10.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Yield: 98.7 %

Procedure:
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (450 mg, 2.05 mmol, prepared as described at Wing Kin Chow et al. Chemistry—A European Journal, 2011, 17(25), 6913-6917) was treated with 4-methoxybenzene-1-sulfonyl chloride (850 mg, 4.11 mmol) according to the method described In Preparation 15b to give 788 mg (99% yield) of the title compound as an oil. Purity 99%.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:35]([CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[O:36])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: O=C(O)C1CCOCC1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2c1OCC2
Agent: Cl
Product: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](NC(=O)C4CCOCC4)CC3)CC2)c2c1OCC2

Procedure:
The title compound, white solid (60 mg, 88%), MS (ISP) m/z=457.5 [(M+H)+], mp 223.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:9]([C:10](O)=[O:11])[CH:8]=1)=[O:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>O1CCCC1.CN(C)C=O>[CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:9]([C:10]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:11])[CH:8]=1)=[O:2]
Reactant: O=COCCOc1cc(C(=O)O)nc2ccccc12
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=COCCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12

Procedure:
N,N' -Carbonyldiimidazole (1.55 g) was added to 4(2-formyloxyethoxy)quinaldic acid (2.5 g) in hot tetrahydrofuran (200 ml) and the solution was heated under reflux for 1.5 hours. 5-Aminotetrazole (0.85 g) in dimethylformamide (4 ml) was added and the mixture was heated under reflux for 2.5 hours. 4(2-Formyloxyethoxy)-N(1H-tetrazol-5-yl)quinaldamide was filtered off and dried, m.p. 263°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[N+:30]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([OH:22])[CH:14]=2)=[CH:8][C:7]=1[C:23]([CH3:26])([CH3:25])[CH3:24].[K+].[Br-]>>[NH2:30][C:29]1[CH:28]=[CH:27][C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([OH:22])[CH:14]=3)=[CH:8][C:7]=2[C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:3][C:2]=1[OH:1]
Reactant: CC(C)(C)c1cc(Oc2ccc([N+](=O)[O-])c(O)c2)ccc1Oc1ccc([N+](=O)[O-])c(O)c1
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)c1cc(Oc2ccc(N)c(O)c2)ccc1Oc1ccc(N)c(O)c1
Yield: 80.2 %

Procedure:
1,4-Bis(4-amino-3-hydroxyphenoxy)-2-tert-butyl benzene was synthesized in a manner analogous to Example 2 from 1,4-bis(3-hydroxy-4-nitrophenoxy)-2-tert-butyl benzene. Yield: 80.2%; mp 110˜113° C.; IR (KBr): 3400, 3360, 3210, 1576, 1499 cm−1; MS (EI) m/z 380 (M+, 100); Elemental Anal. Calcd. for C22H24N2O4: C, 69.47; H, 6.32; N, 7.37. Found: C, 69.24; H, 6.43; N, 7.31.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:29])[N:17]([CH3:28])[C:18]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:19][CH:20]=2)=[CH:11][C:10]=1[F:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH:22]1([CH2:21][C:18]2[N:17]([CH3:28])[C:16](=[O:29])[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:30])[CH:11]=3)=[CH:20][N:19]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cn1c(CC2CCCCC2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(CC2CCCCC2)ncc(-c2ccc(O)c(F)c2)c1=O
Temperature: 25 °C

Procedure:
A solution of 5-(4-(benzyloxy)-3-fluorophenyl)-2-(cyclohexylmethyl)-3-methylpyrimidin-4(3H)-one (0.046 g, 0.11 mmol) in TFA (2 mL) was stirred at 40° C. for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product was obtained (0.026 g; 73%) as a white foamy solid. LRMS (APCI pos) m/e 317 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:5]=[C:4]([C:29]2[C:34]([O:35]CC3C=CC(OC)=CC=3)=[CH:33][CH:32]=[CH:31][C:30]=2[O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[N:3]=1.[ClH:50]>O1CCOCC1.C(OCC)(=O)C>[ClH:50].[NH2:1][C:2]1[N:3]=[C:4]([C:29]2[C:30]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)=[CH:31][CH:32]=[CH:33][C:34]=2[OH:35])[CH:5]=[C:6]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[C:7]=1[CH2:8][S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(CSc3ccccc3)c(N)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1nc(-c2c(O)cccc2OCC2CC2)cc(C2CCCNC2)c1CSc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 3-{2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-[(phenylsulfanyl)methyl]-4-pyridinyl}-1-piperidinecarboxylate in 1,4-dioxane (2 mL) was added 4 N HCl in dioxane (2 mL). The mixture was stirred at room temperature overnight, and diluted with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give 2-[6-amino-5-[(phenylsulfanyl)methyl]-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol hydrochloride.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(O)C.[S:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])(=[O:24])[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:27][CH:28]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 76.27 %

Procedure:
(compound 33a, 1.45 g, 4.19 mmol) in a mixture of toluene:ethanol (10:40 ml) was added (4-sulfamoylphenyl)boronic acid (0.84 g, 4.19 mmol) and potassium carbonate (1.16 g, 8.39 mmol) at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100° C. for 16 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite, the celite cake was washed with Ethanol (2×25 ml). The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (1.35 g, 76.27%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[CH3:21][N:20]([CH3:22])[C:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CN(C)C(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: OB(O)c1cncnc1
Product: CN(C)C(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
1-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidine-4-carboxamide was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 267. NMR (CDCl3): 1.71-1.4 (m, 2H, CH2), 1.9-1.99 (m, 2H, CH2), 2.14-2.20 (m, 2H, CH2), 2.52-2.57 (m, H, CH), 2.97 (s, H, CH3), 3.04-3.07 (m, 5H, CH3+CH2), 3.80 (s, 2H, CH2), 3.91-3.93 (m, 4H, 2×CH2), 3.98-4.02 (m, 4H, 2×CH2), 7.19 (s, H, ArH), 9.29 (s, H, ArH), 9.70 (s, 2H, 2×ArH). MS: (ESI+): MH+=468.26
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([CH:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of ethyl(2RS,3RS)-2-((4-fluorophenyl)methyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionate (27.5 g, 74.3 mmol) in methanol (300 ml) was added 1N aqueous sodium hydroxide solution (150 ml, 150 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was poured into 1N aqueous hydrochloric acid solution (180 ml), and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave (2RS,3RS)-2-((4-fluorophenyl)methyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionic acid (22.45 g, 88%).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([CH3:13])[CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:15].[Na+].[Cl-].[Na+]>CO.O>[C:1]1([S:7]([CH2:8][CH:9]([CH3:13])[CH2:10][CH2:11][OH:12])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCO)CSc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(CCO)CS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.96 g of 4-phenylthio-3-methyl-1-butanol were dissolved in 100 ml of methanol, a solution of 2.57 g of sodium metaperiodate in 50 ml of water added, and the mixture stirred at room temperature overnight. Then, an aqueous solution of sodium chloride was added, the resulting mixture extracted with diethyl ether, the ether layer washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the ether distilled off. There was obtained a slightly yellow liquid. This was purified by silica gel column chromatography (developing solvent: methylene chloride-ethyl acetate) to give 1.60 g of a colorless to slightly yellow liquid. The characteristic signals of this substance on its 1H-NMR spectrum were as follows:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[N:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[C:26]4[C:34]([NH2:36])=O)=[CH:20][C:18]=3[CH:19]=2)[S:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:6]([C:10]1[N:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[C:26]4[C:34]#[N:36])=[CH:20][C:18]=3[CH:19]=2)[S:13][CH:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4c(C(N)=O)cc5ccccc54)ccc3o2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4c(C#N)cc5ccccc54)ccc3o2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.4 %

Procedure:
Phosphorus oxychloride (0.14 ml) was added into N,N-dimethylformamide (0.86 ml) under ice-cooling. After 10 minutes, solution of 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-2-carboxamide (0.43 g) in N,N-dimethylformamide (5 ml) was added to the solution. And then the solution was stirred for several minutes at room temperature and poured into saturated sodium hydrogen carbonate aqueous solution. The resulting precipitates were collected by filtration and washed with water and air-dried to give 4-tert-butyl-2-{5-[(2-cyanoindol-1-yl)methyl]benzofuran-2-yl}thiazol (0.43 g).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[C:12](=[O:30])[N:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:14]=[CH:15][C:16]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:8][CH:7]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.ClCCl>[Br:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[C:12](=[O:30])[N:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:14]=[CH:15][C:16]=2[N:17]2[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][OH:4])[CH2:19][CH2:18]2)=[CH:8][CH:7]=1
Reactant: O=c1c(Oc2ccc(Br)cc2)c(N2CCNCC2)cnn1-c1ccc(Cl)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1c(Oc2ccc(Br)cc2)c(N2CCN(CCO)CC2)cnn1-c1ccc(Cl)cc1

Procedure:
1.35 ml (18.11 mmol) of 2-bromoethanol are added dropwise to a mixture of 4.18 (9.05 mmol) of 4-(4-bromophenoxy)-2-(4-chlorophenyl)-5-(1-piperazinyl)-3(2H)-pyridazinone (Example 57A), 0.15 g of potassium iodide 3.75 g (27.2 mmol) of potassium carbonate in 25 ml of 1,4-dioxane. Stirring under reflux overnight is followed by dilution with dichloromethane and washing twice with water, drying and concentration. Purification is by flash chromatography on silica gel (gradient: dichloromethane/methanol from 99:1 to 97:3).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH:11]=[CH:12]OC)=[CH:4][CH:3]=1.[NH2:17][NH:18][C:19]([NH2:21])=[S:20]>CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:21][C:19](=[S:20])[N:18]3[N:17]=[CH:12][CH:11]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC=CC(=O)CC(=O)c1ccc(I)cc1
Reactant: NNC(N)=S
Solvent: CO
Product: S=c1[nH]c(-c2ccc(I)cc2)cc2ccnn12

Procedure:
A mixture of 1-(4-iodo-phenyl)-5-methoxy-pent-4-ene-1,3-dione (compound F1)(1.9 g) and thiosemicarbazide (5 g) in methanol (220 ml) is heated to reflux temperature. After the reaction is completed the solid is filtered and washed with methanol. The filtrate with the product is purified by flash silica gel chromatography.