Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([C@@H:57]([NH2:66])[CH2:58][O:59][C:60]([O:62][CH:63]([CH3:65])[CH3:64])=[O:61])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:66][C@H:57]([C:55]1[NH:54][C:53]2[CH:67]=[CH:68][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][O:59][C:60]([O:62][CH:63]([CH3:65])[CH3:64])=[O:61])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Reactant: CC(C)OC(=O)OC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)OC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 40 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and (R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-isopropoxycarbonyloxyethylamine in tetrahydrofuran. Yield: 40%; C25H24Cl2N4O5 (531.394); mass spectrum: (M+H)+=531/533/535 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])C.[Mg]>CO>[CH3:1][O:3][C:4]([CH:6]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1COc2ccccc2N1
Agent: [Mg]
Solvent: CO
Product: COC(=O)C1COc2ccccc2N1

Procedure:
4.0 g of 3(R,S)-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine (Example 20)) are stirred together with 0.8 g of magnesium powder in 100 ml of methanol at room temperature for 2 h. When the exothermic reaction has ended, the mixture is concentrated, the residue is taken up in methylene chloride and the organic phase is washed with 0.1N hydrochloric acid. After customary working up, the crude product is purified over 250 g of silica gel (mobile phase B): Rf (B)=0.26.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=1[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21](OC)=[O:22].O>O1CCCC1>[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=1[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[CH2:21][OH:22]
Reactant: COC(=O)c1cccc(-c2c(F)c(F)c(F)c(F)c2F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(-c2c(F)c(F)c(F)c(F)c2F)c1
Temperature: 25 °C
Yield: 121.6 %

Procedure:
To a stirred suspension of 0.5 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran, cooled to -78°, was added dropwise methyl 3-(2,3,4,5,6-pentafluorophenyl)benzoate (2.6 g, 0.009 mole) in 50 ml of dry tetrahydrofuran. Upon complete addition, the reaction mixture was stirred while warming to room temperature. A solution of 10% water in tetrahydrofuran was then added dropwise to the reaction mixture to destroy excess lithium aluminum hydride. An additional 50 ml of water was then added, and the liquid phases separated. The aqueous layer was washed with two 50 ml portions of diethyl ether. The ether washes were combined with the organic layer from the reaction mixture and dried. The mixture was filtered and the filtrate evaporated under reduced pressure to give 3-(2,3,4,5,6-pentafluorophenyl)benzyl alcohol (3.0 g) as an oil, which solidified on standing. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH:2]([C:4]1[C:13]([C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[C:12]([OH:22])[C:11]2[C:6](=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3]>C(O)(=O)C>[CH3:3][CH:2]1[C:4]2=[N:5][C:6]3[C:7]([C:23]([F:26])([F:25])[F:24])=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]([OH:22])=[C:13]2[C:14](=[N:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[O:15]1
Reactant: CC(Cl)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Solvent: CC(=O)O
Product: CC1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O
Temperature: 140 °C
Reaction time: 0.15 h
Yield: 99 %

Procedure:
A mixture of 6 g of 2-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide [described in Examples 5 and 14 of U.S. patent application Ser. No. 262,952] and 50 ml of acetic acid was placed in an oil bath heated to 140° C. and held there for 9 minutes and then cooled to room temperature. The mixture was held at 16° C. for one hour and was vacuum filtered. The product was washed with acetic acid, then with ether and dried under reduced pressure at 80° C. to obtain 5.4 g of 1,3-dihydro-3-methyl-1-[(2-thiazolyl)-imino]-5-trifluoromethyl-furo[3,4-b]quinoline-9-ol in the form of an acetate. The latter was added to 100 water to which was added an aqueous saturated sodium bicarbonate solution to adjust the pH to 6. The mixture was vacuum filtered and the product was washed with water and dried under reduced pressure at 70° C. to obtain 4.2 g of 1,3-dihydro-3-methyl-1-[(2-thiazolyl)-imino]-5-trifluoromethyl-furo[3,4-b]quinoline-9-ol melting at 260° C. (decomposition).
Reaction SMILES: [Na].[K].[CH2:3]([S:5][CH2:6][C@H:7]([CH3:16])[C@@H:8]([OH:15])[C@H:9]([NH:13]C)[C:10]([OH:12])=[O:11])C.O[C@H]([C@H](C)CSC)C(NC)C#N.[Cl-].[NH4+]>>[NH2:13][C@@H:9]([C@H:8]([OH:15])[C@H:7]([CH3:16])[CH2:6][S:5][CH3:3])[C:10]([OH:12])=[O:11]
Reactant: CCSC[C@H](C)[C@@H](O)[C@H](NC)C(=O)O
Agent: CNC(C#N)[C@H](O)[C@H](C)CSC
Agent: [Cl-]
Agent: [K]
Product: CSC[C@@H](C)[C@@H](O)[C@H](N)C(=O)O

Procedure:
For example, when sodium (or potassium) ethylmercaptide was used in place of the sodium methylmercaptide in Step A, one obtained (2S,3R,4R)-5-(ethylthio)-3-hydroxy-4-methyl-2-(methylamino)-pentanoic acid. Likewise, when the methylamine hydrochloride of Step H was replaced by ammonium chloride, (2S,3R,4S)-2-amino-3-hydroxy- 4-methyl-5-(methylthio)-pentanoic acid was obtained, and when ethylamine hydrochloride was used, (2A,3R,4S)-2-(ethylamino)-3-hydroxy-4-methyl-5-(methylthio) pentanoic acid was obatined.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.ClC1N=NC(C2C=CC(N3C=CC=N3)=CC=2OC)=CC=1.Cl[C:44]1[N:49]=[N:48][C:47]([N:50]([CH3:61])[CH:51]2[CH2:56][C:55]([CH3:58])([CH3:57])[NH:54][C:53]([CH3:60])([CH3:59])[CH2:52]2)=[CH:46][CH:45]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[C:44]1[N:49]=[N:48][C:47]([N:50]([CH3:61])[CH:51]2[CH2:56][C:55]([CH3:57])([CH3:58])[NH:54][C:53]([CH3:60])([CH3:59])[CH2:52]2)=[CH:46][CH:45]=1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Product: COc1cc(-n2cccn2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1

Procedure:
1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole from Step 3 of Intermediate 2-1, was coupled with Intermediate 1-1 under standard Suzuki coupling methods as described in GENERAL METHOD 1-2 to provide 6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][C:11]([O:13][CH3:14])=[O:12].[C:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=O)[CH3:16].OS(O)(=O)=O.N#N.[NH4+].[OH-]>CO>[C:11]([CH2:10][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH2:16])=[CH:5][CH:6]=[CH:7][CH:8]=2)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)Cc1cc2ccccc2[nH]1
Reactant: CC(=O)c1cccnc1
Agent: N#N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CO
Product: C=C(c1cccnc1)c1c(CC(=O)OC)[nH]c2ccccc12
Temperature: 0 °C

Procedure:
A solution of 6.13 g (0.032 m) of methyl indole-2 acetate, 7.16 g (7.0 mL, 0.059 m) of 3-acetylpyridine, and 10 mL of concentrated H2SO4 in 200 mL of dry MeOH was refluxed for 2 hours in an atmosphere of N2. The clear red solution was poured onto 600 g of ice. It was made alkaline with NH4OH and extracted with 2×500 mL portions of ether. The ether solution was washed with H2O, dried, and concentrated to dryness. The residue was triturated with hexane-ether (1:1), and the crystals that formed were collected and dried; wt 8.0 g; mp 154°-157° C. (lit. mp 160°-161° C.). The material was suitable for the next step. An additional 110 mg separated from the ether-hexane filtrate. Total yield 8.17 g.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[C:6]([CH3:18])=[CH:5][C:3]=1[NH2:4].[CH3:19][CH:20]1[CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[CH2:23][CH2:22][N:21]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:4][C:3]1[C:2]([F:1])=[CH:8][C:7]([C:24]2[CH2:25][CH:20]([CH3:19])[N:21]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:22][CH:23]=2)=[C:6]([CH3:18])[CH:5]=1
Reactant: Cc1cc(N)c(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1C=C(OS(=O)(=O)C(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N)c(F)cc1C1=CCN(C(=O)OC(C)(C)C)C(C)C1
Temperature: 100 °C

Procedure:
To a mixture of 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (587 mg, 2.33 mmol), tert-butyl 2-methyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (968 mg, 2.80 mmol) and sodium carbonate (1.73 g, 16.35 mmol) in DMF/H2O (20/5 mL) was added tetrakis(triphenylphosphine) palladium (0) (135 mg, 5% mmol). The reaction tube was sealed, the mixture was purged with N2 for 3 min and then heated at 100° C. under N2 for 8 h. The reaction was cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with brine and concentrated. The crude product was purified with silica chromatography (50% ethyl acetate in hexanes) to afford tert-butyl 4-(4-amino-5-fluoro-2-methylphenyl)-6-methyl-5,6-dihydropyridine-1(2H)-carboxylate as a yellow oil. The obtained oil was dissolved in methanol (20 mL). To the solution was added Pd/C (10%). The reaction mixture was degassed and purged with H2 for several times and stirred vigorously under 1 atm. H2 overnight. The mixture was filtered and the filtrate concentrated to afford tert-butyl 4-(4-amino-5-fluoro-2-methylphenyl)-2-methylpiperidine-1-carboxylate as a white solid. ESMS m/z 267 (M−56+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:23])[C:14]2=[O:24])=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[Na].ClC1C=CC(N2C(=O)C3CCCCC=3N(C)C2=O)=CC=1C(O)=O.CI>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:23])[C:14]2=[O:24])=[CH:9][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl
Agent: Cn1c2c(c(=O)n(-c3ccc(Cl)c(C(=O)O)c3)c1=O)CCCC2
Agent: [Na]
Solvent: CI
Product: COC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate via the sodium salt of the corresponding carboxylic acid and methyl iodide there is obtained methyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 164°-166° C.,
Reaction SMILES: CS([O-])(=O)=O.[C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:17]=[NH+:18][CH:19]=[CH:20][CH:21]=1)=[O:15])(=[O:8])[CH3:7].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)SCCCCC(=O)c1ccc[nH+]c1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)SCCCCC(=O)c1cccnc1
Yield: 86.3 %

Procedure:
A slurry of 3-(5-acetylmercaptopentanoyl)pyridinium methanesulphonate (7.0 g) in ethyl acetate (50 ml) is stirred with a solution of sodium bicarbonate (5 g) in water (50 ml). The ethyl acetate phase is then washed 3 times with water until its pH is 5, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give S-(4-nicotinoylbutyl) thioacetate (4.3 g) in the form of a dark oil which solidifies upon standing (m.p. 43° C.).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CCOc2cc(O)ccc2C1
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2cc(OCc3cccc(Oc4ccccc4)c3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A solution of ethyl 8-hydroxy-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxylate (0.189 g, 0.800 mmol), 3-phenoxybenzyl alcohol (0.240 g, 1.20 mmol) and tributylphosphine (0.299 mL, 1.20 mmol) in toluene (8 mL) was stirred under ice-cooling. 1,1′-(Azodicarbonyl)dipiperidine (0.279 g, 1.20 mmol) was added by small portions, and the mixture was stirred under nitrogen atmosphere at room temperature for 8 hr. Hexane (4 mL) was added to the reaction mixture, and the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-20% ethyl acetate/hexane) to give the title compound (0.20 g, yield 60%) as a colorless oil.
Reaction SMILES: C=O.[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:21]=[N:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:35])(=[O:8])=[O:7])([CH3:5])[CH3:4].[C:36](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][N:26]([CH3:36])[CH2:25][CH2:24]4)[CH:21]=[N:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:35])(=[O:7])=[O:8])([CH3:5])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCNCC3)cc21
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCN(C)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Add aqueous formaldehyde (37% w/w, 0.15 mmol) to a solution of 1-isopropylsulfonyl-2-amino-6-(1-(piperidin-4-yl)-4-(phenyl)-imidazol-5-yl)-benzimidazole (75 mg) in methanol (10 mL). Stir the mixture at room temperature for 30 minutes, then cool to 0° C. Add acetic acid (0.3 mL) followed by sodium cyanoborohydride (18 mg) and stir over night at room temperature. Concentrate the mixture under reduced pressure and then dissolve the residue in ethyl acetate. Wash the solution twice with 1 N sodium hydroxide and concentrate the organic phase under reduced pressure to provide 60 mg (79%) of the title compound. MS(ES+): m/z=479.6 (M+H)+
Reaction SMILES: Br.[NH2:2][C@@H:3]([CH2:7][CH2:8][Br:9])[C:4]([OH:6])=[O:5].Cl.[CH3:11]O>>[CH3:11][O:5][C:4](=[O:6])[C@@H:3]([NH2:2])[CH2:7][CH2:8][Br:9]
Reactant: N[C@@H](CCBr)C(=O)O
Reactant: CO
Agent: Br
Agent: Cl
Product: COC(=O)[C@@H](N)CCBr

Procedure:
A solution of (5)-(+)-2-amino-4-bromobutyric acid hydrobromide salt (5 g) in a solution of 3M HCl in MeOH (57 mL) was refluxed for 20 h. The reaction mixture was evaporated off to afford after HV drying the desired compound as a brown oil (3.97 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[N:21][CH:22]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[N:21][CH:22]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1cnc[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(Nc1ccc(O)cc1)c1cnc[nH]1
Yield: 100 %

Procedure:
A solution of 3-H-imidazole-4-carboxylic acid (4-benzyloxyphenyl)amide. (3.3 g, 11.2 mmol) in glacial acetic acid (70 mL) was hydrogenated (60 psi) over g of 10% palladium on carbon (0.3 g) at 25° C. for 18 hours. The catalyst was removed by filtration, and the solvent was evaporated in vacuo. The residue was stirred with NaHCO3 solution and the solid collected. There was obtained 2.4 g (100% yield) of the title compound as a yellow solid. MS m/z 204 (MH+). 1 H NMR(DMSO-d6) δ 6.7 (dd, 2H), 7.5 (dd, 2H), 7.7 (s, 1H), 7.8 (s, 1H), 9.1 (s, 1H), 9.6 (s, 1H) and 12.5 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH:25]12[O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[OH:31])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: C1CCC2OC2C1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(C2CCCCC2O)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 100 °C

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, cyclohexene oxide (12 mg, 0.12 mmol) and K2CO3 (35 mg, 0.25 mmol) in DMF (1 ml), was heated at 100° C. for 3 hours. After this time the solution was cool to RT and diluted with ethyl acetate. The resultant solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(2-hydroxycyclohexyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-(24.1 mg, 48%) as yellow solid. MS M+H=455; 1H NMR (CDCl3) δ 8.17 (1H), 7.33 (6H), 7.08 (2H), 4.26 (1H), 3.98 (1H), 2.17 (1H), 1.99 (1H), 1.82 (3H), 1.50-1.30 (3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[N:7]1[S:8][N:9]=[C:5]2[CH:4]=[C:3]([CH:2]=[O:1])[CH:11]=[CH:10][C:6]=12
Reactant: OCc1ccc2nsnc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2nsnc2c1
Yield: 72.3 %

Procedure:
5-Hydroxymethylbenzo-2, 1,3-thiadiazole (2.6 g, 16 mmol) and manganese dioxide (6.0 g, 64 mmol) in chloroform (150 mL) were stirred at room temperature overnight. The reaction mixture was filtered off and the filtrate was evaporated to provide 1.9 g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18]CC)=[O:17])[O:13]2)=[CH:8][CH:7]=1.[CH2:23]([C:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]=1[OH:40])[CH2:24][CH3:25]>>[CH2:23]([C:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]=1[O:40][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([OH:18])=[O:17])[O:13]2)=[CH:8][CH:7]=1)[CH2:24][CH3:25]
Reactant: CCOC(=O)C1(CC)CCc2ccc(OCCCBr)cc2O1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1OCCCOc1ccc2c(c1)OC(CC)(C(=O)O)CC2

Procedure:
The title compound was prepared from ethyl 7-(3-bromopropoxy)-2-ethylchromane-2-carboxylate and 2-propyl-4-(4-chlorophenoxy)phenol (U.S. Pat. No. 6,008,237) following the procedures described in Example 1, Steps B-C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])(=[O:24])=[O:23])[CH3:21])=[N:8][CH2:7]1)C.[BH4-].[Li+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:3][CH2:4][CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:21])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])(=[O:24])=[O:23])=[N:8][CH2:7]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4OC)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a mixture of ethyl(2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (140 mg), lithium borohydride (40 mg) and tetrahydrofuran (5 mL) was added methanol (1 mL), and the mixture'was stirred at room temperature for 2 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=6:4-10:0), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (87 mg, yield: 69%) as colorless needle crystals. MS:446(MH+). melting point 154-155° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.Br.[N:14]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][C:26]([OH:28])=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.[C:30]1([C:36]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:44][CH2:43][C@@H:42]([F:45])[C@@H:41]3[C@H:37]2[CH2:38][NH:39][CH2:40]3)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.C(N(CC)CC)C>[C:46]1([C:36]2([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:44][CH2:43][C@@H:42]([F:45])[C@@H:41]3[C@H:37]2[CH2:38][N:39]([C:26](=[O:28])[CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:40]3)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1N1CCCC1)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 16.6 %

Procedure:
0.28 cm3 of triethylamine and 0.32 g of carbonyldiimidazole are added to a solution, cooled to 4° C., of 0.57 g of (2-pyrrolidinophenyl)acetic acid hydrobromide in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.67 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in 20 cm3 of dry dichloromethane and 0.28 cm3 of triethylamine is added. The reaction mixture is stirred at room temperature for 24 hours and then diluted with 100 cm3 of dichloromethane, washed twice with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm, height 38 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting fractions of 20 cm3. Fractions 26 to 54 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from an acetonitrile and diisopropyl oxide mixture (25/75 by volume). 0.16 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoro-2-[(2-pyrrolidinophenyl)acetyl]perhydroisoindole is obtained in the form of white crystals; melting point 170° C.