Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[NH:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14]([N:16]([CH2:19][CH2:20]Cl)[CH2:17][CH3:18])[CH3:15].O>CN(C)C=O>[OH2:9].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[N:10][CH2:15][CH2:14][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=N)(=O)c1ccc(Br)cc1
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCN=S(C)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 121.3 %

Procedure:
A solution of 4-bromophenyl-methylsulfoximine (10.0 g, 42.7 mmol) in dimethylformamide (50 mL) was added dropwise to a stirring slurry of sodium hydride (2.04 g, 51.2 mmol, 60% oil dispersion washed (3×20 mL) with hexane) which was maintained at 0° C. After stirring for 30 minutes, a solution of diethylaminoethyl chloride (6.58 g, 48.3 mmol) in dimethylformamide (20 mL) was added dropwise. The reaction mixture was warmed at 60° C. for 18 h. The reaction mixture was then cooled to ambient temperature, and 5 mL of water was added. The resulting solution was concentrated in vacuo. The residue was partitioned between 0.1N aqueous HCl (100 mL) and methylene chloride (100 mL). The layers were separated, and the aqueous layer was extracted with methylene chloride (2×50 mL). The aqueous layer was then made basic with 50% aqueous sodium hydroxide, and the resulting slurry was extracted with methylene chloride. These combined organic extracts were washed with saturated sodium chloride, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (flash, SiO2, 9:1 methylene chloride:methanol) to give 9.1 g (62%) of clear oil.
Reaction SMILES: C(OO)(=[O:3])C.[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][OH:16])[CH3:13])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:13][CH:12]([CH2:11][CH2:10][CH:9]1[O:3][C:7]1([CH3:8])[CH3:6])[CH2:14][CH2:15][OH:16]
Reactant: CC(=O)OO
Reactant: CC(C)=CCCC(C)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(CCO)CCC1OC1(C)C
Reaction time: 4 h
Yield: 83 %

Procedure:
210 g (1.1 M) of 40% peracetic acid were added dropwise within 1 h to a stirred suspension of 156 g (0.95 M; purity 95%) of citronellol kept at 0° and 53 g (0.5 M) of sodium carbonate in 200 ml of toluene. The reaction mixture was kept under stirring at 20° during 4 h then it was washed with water, a 5% solution of sodium sulfite and a 10% aqueous solution of NaHCO3. After drying over anhydrous sodium sulfate, evaporation of the solvent and distillation (70°-78°/20×102Pa), 139 g (yield 83%; purity 98%) of the desired epoxyde were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:13][N:14]([CH3:26])[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.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>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[N:14]([CH3:13])[CH3:26])=[CH:18][CH:19]=2)=[CH:6][N:7]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1nc(Br)cnc1N
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: [Na+]
Solvent: O
Solvent: CC#N
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (6.01 g, 25.9 mmol, 1.0 Eq.), 4-(dimethylcarbamoyl)phenylboronic acid (5.00 g, 25.9 mmol, 1.0 Eq.), Na2CO3 (5.49 g, 51.8 mmol, 2.0 Eq.) and Pd(PPh3)4 (2.99 g, 2.59 mmol, 0.1 Eq.) in acetonitrile (30 mL) and water (30 mL) were heated at 90° C. for 16 hours. After cooling to ambient temperature the precipitate was removed by filtration. The aqueous filtrate was acidified to pH4 by addition of 1M HCl and then extracted with dichloromethane (3×20 mL), dried over MgSO4 and concentrated in vacuo to give the sub-title product as a yellow solid (2.42 g, 65% Yield). 1H NMR (400.0 MHz, DMSO) δ 2.95 (3H, br s), 3.00 (3H, br s), 7.49-7.51 (2H, m), 7.58 (2H, br s), 8.15 92H, d), 8.95 (1H, s), 13.25 (1H, br s) ppm; MS (ES+) 287.13.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:35]=[CH:34][N:33]=[C:32]([F:36])[CH:31]=2)=[CH:18][C:17]=1[F:38])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([F:40])[CH:46]=3)=[CH:28][C:29]=2[C:30]2[CH:35]=[CH:34][N:33]=[C:32]([F:36])[CH:31]=2)=[CH:18][C:17]([F:38])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2ccnc(F)c2)cc1F
Reactant: OB(O)c1cccc(F)c1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2ccnc(F)c2)cc1F
Reaction time: 0.08 h
Yield: 29 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6-chloro-2′-fluoro-[4,4′-bipyridin]-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 6.8 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.7 mg (10 mol %) of Pd(PPh3)4, 10 mg (0.10 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][Cl:25].C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[CH2:8][N:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:22][CH2:23][CH2:24][Cl:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccccc1CNCc1ccccn1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)Oc1ccccc1CN(CCCCl)Cc1ccccn1

Procedure:
Compound 19 was synthesized with 9 (0.9 g, 3.32 mmol), using 1-bromo-3-chloropropane (10.5 g, 66 mmol) and K2CO3 (0.46 g, 3.32 mmol) following a procedure analogous to that described above for 10. Purification was carried out on a silica-gel column with the following eluents: First with 100% CH2Cl2 and then 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2. The product was isolated as pale yellow oil (65%). 1H NMR (CDCl3) δ 8.491 (m, 1H, Ar), 7.624 (m, 1H, Ar), 7.512 (t, 1H, Ar), 7.111 (m, 2H, Ar), 7.010 (m, 2H, Ar), 3.750 (s, 2H, —CH2—), 3.690 (s, 2H, —CH2—), 3.513 (ddd, 2H, —CH2—), 2.616 (t, 2H, —CH2—), 1.946 (m, 2H, —CH2—), 1.354 (s, 9H, —C(CH3)3). Mass Spec.=346.89 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[OH:27])[C:21](O)=[O:22]>>[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[OH:27])[C:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:22]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)c1ccc(O)c(O)c1
Product: O=C(Nc1ccccc1-c1cc2ccccc2[nH]1)c1ccc(O)c(O)c1
Yield: 54 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3,4-dihydroxybenzoic acid in 54% yield following procedure 1. The product was chromatographed on silica. 100% Purity by LC/MS (230 DAD), Mass-spec (M+H+)=345.83, 1H NMR (MeOH-d4): 6.645 s (1H), 6.80 d, 8 Hz (1H), 7.02 t, 8 Hz (1H), 7.12 td, 8.1 Hz (1H), 7.23 dd, 8.1 Hz (1H), 7.33–7.36 m (2H), 7.39–7.42 m (2H), 7.52 d, 7 Hz (1H), 7.65 dd, 8.1 Hz (1H), 7.94 d, 8 Hz (1H).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([NH:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>C(O)C>[CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)NCC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)NCC(=O)O)c1

Procedure:
A mixture of 26 g. of ethyl N-(4-hexadecylamino-2-thiophenecarbonyl)glycinate, 110 ml. of 1 N sodium hydroxide solution; and 100 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The aqueous solution is washed with diethyl ether, acidified with 6 N hydrochloric acid, and filtered. The white solid is dried in vacuo and recrystallized from acetone to yield the product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][CH3:10])[CH:7]=1.CC1CCCO1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC.Cl>C1(C)C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([B:17]([OH:22])[OH:18])[CH:3]=[N:4][CH:5]=1)#[C:9][CH3:10]
Reactant: CC#Cc1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: CC#Cc1cncc(B(O)O)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
3-Bromo-5-(prop-1-ynyl)pyridine (Intermediate 2, 25 g, 117 mmol), 2-methyl-tetrahydrofuran (60 mL), toluene (200 mL) and triisopropyl borate (33.2 mL, 140.78 mmol) were mixed. The mixture was cooled to −50° C. To the cold mixture was added n-BuLi (59.8 mL, 149.5 mmol) dropwise during 30 min. The mixture was stirred for 60 min. at −50° C. 2M HCl aq. (100 mL) was added. The mixture was then allowed to reach r.t. and stirred for 20 min. The organic and water phase were separated. The organic phase was extracted with NaOH (2M aq.) (2×100 mL). The water phases were combined and the pH was adjusted to pH 5. The product was extracted with 2-methyl-THF (2×100 mL). The organic phase was dried with Na2SO4, filtered and concentrated to give the title compound (16.47 g, 87% yield): 1H NMR (500 MHz, CD3OD) δ ppm 2.11 (s, 3 H) 8.21 (br. s., 1 H) 8.53 (m, 2 H); MS (APCI+) m/z 162.2 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11](C=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.C(O)(=O)C>[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(Oc2ccc(N3CCN(c4ccncc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution of 4-phenoxybenzaldehyde (198 mg) in dichloromethane (20 ml), N-(4-pyridyl)piperazine (163 mg) and acetic acid (240 mg) were added. The mixture was stirred at ambient temperature for 30 mins, and then sodium triacetoxyborohydride (318 mg) was added in one portion. Stirring was continued at ambient temperature overnight. The reaction mixture was poured into 1M hydrochloric acid (50 ml) and washed With ethyl acetate (50 ml). The aqueous layer was made basic with 2M sodium hydroxide solution and extracted with dichloromethane (2×25 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated to give a white solid which was purified by chromatography on silica gel (Mega Bond Elut column) using an increasing concentration of methanol in dichloromethane (up to 4% methanol) as eluant to give 1-(4-pyridyl)-4-(4-phenoxy-phenyl)piperazine (168 mg) as a solid: microanalysis, found: C,76.5; H,6.6; N,11.9%; C22H23N3O requires: C,76.5; H,6.7; N,12.2%; NMR: 3.2-3.45(m,8H); 3.5(s,2H); 6.8(d,2H); 6.9-7.05(m,4H); 7.1-7.2(m,1H); 7.25-7.45(m,4H); 8.1(d,2H); MS: m/z 345 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:6]([N:7]([CH3:9])[CH3:8])=[C:5](Br)[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.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>[Br:1][C:2]1[C:6]([N:7]([CH3:9])[CH3:8])=[C:5]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1sc(Br)c(N(C)C)c1Br
Reactant: OB(O)c1ccc(Cl)cc1
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: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1Br
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a solution of Ethyl 3,5-dibromo-4-(dimethylamino)thiophene-2-carboxylate (compound 34c, 3.0 g, 8.40 mmol) in a mixture of toluene:ethanol (5 ml:30 ml) was added (4-chlorophenyl)boronic acid [1.44 g, 9.24 mmol] and potassium carbonate (2.32 g, 16.80 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) (0.48 g, 0.42 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to 100° C. for 3 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 then washed with ethyl acetate (50 ml). The filtrate so obtained was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 12% ethyl acetate in hexanes as an eluent to obtain the title compound (2.5 g, 76.56%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](OC)(=[O:12])[C:10]#[CH:11]>>[NH:1]1[C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:11]=[CH:10][C:9]1=[O:12]
Reactant: NC1=CC(=O)CCC1
Reactant: C#CC(=O)OC
Product: O=C1CCCc2[nH]c(=O)ccc21

Procedure:
3-Aminocyclohex-2-enone (ex Aldrich) was reacted with methyl propiolate (ex Lancaster) to give 7,8-dihydro-2,5-quinoline-dione according to Speckamp et al J. Trav. Chem. Pays. bas., 91 157 (1972). The latter was converted to 2-chloro-7,8-dihydro-5-quinolinone by analogy with Example VI. The latter compound (2 g) was dissolved in chloroform (200 ml) and treated with bromine (0.53 ml) dropwise at room temperature. After 30 min solid potassium carbonate was added, the mixture was stirred for 1 hour, filtered and solvent removed to give 2-chloro-6-bromo-7,8-dihydro-5-quinolinone (2.86 g). This compound was heated at 110° C. with anhydrous lithium chloride (1.4 g) and dimethylformamide (45 ml) for 3 hours. The mixture was diluted with water, worked-up in conventional fashion and purified by column chromatography on silica (eluting with ether-hexane) to give 2-chloro-5-hydroxyquinoline (0.77 g).
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=1.C(N(CC)CC)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH:41]([C:45](O)=[O:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:14][CH2:15][N:16]([C:45]([CH:41]4[CH2:42][CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40]4)=[O:46])[CH2:17][CH2:18]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: CSc1nn(-c2ccccc2)c2cc(N3CCNCC3)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nn(-c2ccccc2)c2cc(N3CCN(C(=O)C4CCCN(C(=O)OC(C)(C)C)C4)CC3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(methylthio)-1-phenyl-6-(piperazin-1-yl)-1H-indazole hydrochloride (from Example 1, 80 mg, 0.22 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), triethylamine (50 mg, 0.50 mmol, 2.10 equiv), 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (60 mg, 0.26 mmol, 1.20 equiv), HATU (250 mg, 0.66 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield tert-butyl 3-(1-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)piperazine-4-carbonyl)piperidine-1-carboxylate as yellow oil. MS: 536 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH2:23][OH:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CNc1cccn2c(C=O)c(C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1CNc1cccn2c(CO)c(C)nc12
Yield: 79.6 %

Procedure:
The title compound is prepared according to the procedure described for example 2 starting from 8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine (0.15 g) and sodium borohydride (15 mg) in methanol. 0.12 g of the title compound of m.p. 102°-104° C. are isolated.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:15][C:14]([Cl:27])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Na+]>CO>[Cl:27][C:14]1[CH:15]=[C:16]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)=[N:12][CH:13]=1
Reactant: COC(=O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1cc(Cl)cnc1N1CCC(C(=O)O)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a suspension of 0.480 g (1.18 mmol) of 5′-chloro-3′-(3-chloro-benzoylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid methyl ester in a 1:1 mixture of water:methanol (10 mL) is added 1.0 mL (2.5 mmol) of sodium hydroxide as a 10% aqueous solution. The mixture is stirred at room temperature overnight then concentrated under reduced pressure to remove volatile organics. The pH is adjusted to approximately pH 5 by the addition of a 2N solution of hydrochloric acid causing a solid to precipitate from solution. The material is collected by filtration, washed with water, and dried on the filter pad to provide 0.35 g (75%) of 5′-chloro-3′-(3-chloro-benzoylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid as a light yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:20]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[CH:19][C:9]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1.[CH3:33]CCCCC.C(O)C>>[CH2:31]([S:28]([C:25]1[N:24]=[CH:23][C:22]([O:21][C:20]2[C:6]([CH:2]([OH:1])[CH2:3][CH2:4][CH:5]=[CH2:33])=[CH:7][C:8]3[N:12]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[NH:10][C:9]=3[CH:19]=2)=[CH:27][CH:26]=1)(=[O:29])=[O:30])[CH3:32]
Reactant: CCCCCC
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C2CCCO2)cn1
Solvent: CCO
Product: C=CCCC(O)c1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(=O)(=O)CC)nc1

Procedure:
1-(6-((6-(Ethylsulfonyl)pyridin-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazol-5-yl)pent-4-ene-1-ol (520 mg) obtained in Example 11 was optically resolved through an optical resolution column (CHIRALPAK OD 2 cmφ×25 cmL, by Daicel Chemical Industry, mobile phase: hexane/ethanol=1/1, flow rate: 10 ml/min) to obtain its enantiomer A (retention time, 11.7 min) and enantiomer B (retention time, 15.0 min) both as a yellow solid.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+]([O-])=O)[CH:9]=1)([O-])=O.[N+:17]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:8]1[CH:7]=[C:6]([C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Product: O=[N+]([O-])c1cccc(Oc2cc(Oc3cccc([N+](=O)[O-])c3)cc(C(F)(F)F)c2)c1

Procedure:
In an example of the process (i), 3,5-dinitrobenzotrifluoride is condensed with m-nitrophenol in the presence of a base, in an aprotic solvent, to give 1,3-bis(3-nitrophenoxy)-5-trifluoromethylbenzene, which is then reduced to 1,3-bis(3-aminophenoxy)-5-trifluoromethylbenzene, in a high yield.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:10]=[C:11]([O:16][C:17]2[C:22]([F:23])=[C:21]([CH3:24])[CH:20]=[CH:19][C:18]=2N)[CH:12]=[C:13]([Cl:15])[CH:14]=1.[ClH:26].CCOC(C)=O>C(#N)C>[Br:8][C:9]1[CH:10]=[C:11]([O:16][C:17]2[C:22]([F:23])=[C:21]([CH3:24])[CH:20]=[CH:19][C:18]=2[Cl:26])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: Cl
Reactant: Cc1ccc(N)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To an oven dried flask was added CuCl2 (4.06 g, 30.2 mmol). The flask was placed under high vacuum, flushed with nitrogen and acetonitrile (30 mL) was added. t-Butyl nitrite (4.50 mL, 37.8 mmol) was added dropwise. The stirred solution was placed in an oil bath at 50° C. under gentle stream of nitrogen, heated for 5 min and a solution of {2-[(3-bromo-5-chlorophenyl)oxy]-3-fluoro-4-methylphenyl}amine in acetonitrile (40 mL) was added dropwise. The reaction was stirred for 0.5 h, cooled in an ice bath and poured into ice cold, aqueous HCl (1 N, 125 mL). EtOAc (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. The crude material was purified by column chromatography (0% to 25% EtOAc/hexanes gradient) to afford the title compound (3.2 g, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.48-7.47 m, 1H), 7.41-7.38 (m, 1H), 7.32-7.28 (m, 1H), 7.11-7.10 (m, 1H), 7.04-7.03 (m, 1H), 2.27 (s, 3H).