Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:4]1[CH:5]=[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3cccc(OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)O)ccc4c3c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
To a solution of ethyl 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carboxylate (2.1 g, 5.41 mmol) in a mixture of THF (40 mL) and MeOH (14 mL) was added a solution of aq. 1 M sodium hydroxide (13.52 mL, 13.52 mmol). The mixture was stirred at room temperature for 2 days. Removal of solvents left a solid which was suspended in water (150 mL), This was acidified with 1N HCl to pH 2-3 and the solid was collected by filtration, washed with H2O(3×20 mL), and dried under vacuum to afford 1.78 gm of the desired product (83% yield). MS (ESI) m/z 361.1 (M+H). 1H NMR (DMSO-d6) δ ppm 12.79 (1H, br. s.), 11.70 (1H, s), 8.76 (1H, s), 8.38-8.47 (2H, m), 8.35 (2H, dd, J=4.58, 3.36 Hz), 7.82 (1H, d, J=7.93 Hz), 7.59 (1H, br. s.), 7.40-7.52 (3H, m), 6.96 (1H, dd, J=7.93, 2.14 Hz), 3.89 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([CH:25]3[CH2:27][CH2:26]3)=[CH:11][C:12]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[CH:13][C:8]=2[S:7][CH:6]=1.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([CH:25]3[CH2:27][CH2:26]3)=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C3CC3)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(O)cc(C3CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a mixture of methyl(4-cyclopropyl-6-((triisopropylsilyl)oxy)-1-benzothiophen-3-yl)acetate (372 mg) and THF (2 mL) was added TBAF (1M in THF, 1.333 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (201 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH:43]1[CH2:48][CH2:47][O:46][C@@H:45]([CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:44]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:43]1[CH2:48][CH2:47][O:46][C@@H:45]([CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])[CH2:44]1)=[O:7]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CNCCO1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of 3,4-dichlorobenzoic acid (0.5 g), 1-hydroxybenzotriazole (0.376 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.4329), and N,N-diisopropylethylamine (0.485 ml) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 10 min. The mixture was treated with tert-butyl (2R)-morpholin-2-ylmethylcarbamate (0.500 g, known compound WO 9639407A1) and stirred at 20° C. for 24 h. The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml). The phases were separated and the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give the title compound as a yellow oil, (0.774 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.CON(C)[C:21](=[O:28])[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.OS([O-])(=O)=O.[K+]>C1COCC1>[CH:23]1([CH2:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)=[CH:4][CH:3]=2)=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CON(C)C(=O)CC1CCCC1
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(CC1CCCC1)c1ccc(C2OCCO2)cc1
Temperature: -75 °C

Procedure:
2-(4-Bromophenyl)dioxolane from Example C (7 g, 0.03 mole) was dissolved in 75 mls of THF and cooled to -75° C. under argon. Tert.butyl lithium (29 ml of 1.7M solution in hexane) was added slowly at -76° C. maintaining the temperature such that it never rose above -40° C. After addition was complete, the solution was recooled to -78° C. and 4.2 g, 0.024 moles) of the product of Example B was added in THF. After completion of the addition, the solution was allowed to warm to 0° C., poured into 0.5N KHSO4 and extracted with ethyl acetate. After washing with brine, the extract was dried over Na2SO4. After the solvent was removed, the residue was chromatographed on silica with 10% ethyl acetate/hexane to give 2.8 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:23])[NH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][CH3:22])[C:12]([O:14]C)=O)=[CH:7][CH:8]=1)#[N:2].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[C:12](=[O:14])[C:11]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH3:22])=[C:9]([C:6]2[NH:5][C:4](=[O:23])[C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:10]=1
Reactant: CCCOc1ccc(C(=O)OC)cc1-c1ccc(C#N)c(=O)[nH]1
Reactant: CNC
Product: CCCOc1ccc(C(=O)N(C)C)cc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
In a similar method to that of Example 16, methyl 3-(3-cyano-1,2-dihydro-2-oxo-6-pyridinyl)-4-propoxybenzoate (2.14 g) was saponified, converted into the acid chloride and treated with dimethylamine to give 2.0 g of a solid. This was combined with a further 0.2 g obtained in a similar manner, and purified by flash chromatography to give 1.9 g of solid m.p. 201-202° C. Recrystallization of part of this gave the title compound, m.p. 214-215° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:1]([N:8]([CH3:30])[C:9]1[C:10]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)Cc3ccccc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(Cc1ccccc1)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of methyl 3-[benzyl(methyl)amino]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in methanol (20 mL) was added sodium hydroxide (60 mg, 1.50 mmol) in water (5 mL). The resulting solution was stirred overnight at room temperature and the mixture was concentrated in vacuo to give a residue, which was dissolved in water (5 mL), and adjusted to pH to 5 with HCl (2N). The solids were collected by filtration and dried in an oven under reduced pressure to afford 3-[benzyl(methyl)amino]-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (58.3 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=4[N:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[O:25])=[CH:23][C:17]=4[N:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(C(O)c4ccc(Cl)cc4)cc3)nc2c1
Reactant: C1CNCCN1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc2[nH]c(-c3ccc(C(c4ccc(Cl)cc4)N4CCNCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of 2-{4-[(4-chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide (Example 20, 20.0 mg; 0.05 mmol) in CH2Cl2(10 mL) was added thionyl chloride (0.04 mL, 0.06 mmol), and the mixture was stirred at RT for 1 h. Solvent was removed under reduced pressure, and the residue was dried under high vacuum. The crude product was dissolved in acetonitrile (10 mL). Piperazine (21 mg, 0.24 mmol) was added, and the mixture was heated to reflux for 12 h. Solvent was removed under reduced pressure, and purification of the residue by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded 17 mg (77%) of the title compound. HPLC (Method A): Rt=6.44. MS (ESI−): mass calculated for C25H24ClN5, 445.2; m/z found, 444.6 [M−H]−. 1H NMR (500 MHz, CD3OD), δ 8.17 (br s, 1H), 8.09 (d, J=8.4 Hz, 2H), 7.82-7.80 (dd, J=8.5, 1.5 Hz, 1H), 7.66 (d J=8.4 Hz, 2H), 7.63 (br s, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 4.56 (s, 1H), 3.31-3.27 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[C:14](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(OC(F)(F)F)c(Br)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Yield: 22.1 %

Procedure:
To a stirred suspension of 3-Bromo-4-trifluoromethoxy-phenol (20.0 g, 82.6 mol) and potassium carbonate (46.3 g, 330.4 mmol) in acetone (600 ml) was added drop-wise iodomethane (46.9 g, 330.4 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature then filtered and the filtrate was evaporated in vacuo to afford the title compound as a colourless oil (19.8 g, 93%).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.FC(F)(F)C(O)=O.[NH:45]1[CH2:50][CH2:49][S:48](=[O:51])[CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:45]4[CH2:50][CH2:49][S:48](=[O:51])[CH2:47][CH2:46]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: O=S1CCNCC1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCS(=O)CC3)CC2)n1
Yield: 56 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (200 mg, 0.373 mmol), thiomorpholine 1-oxide trifluoroacetate (U.S. Pat. No. 6,372,773) (242 mg, 1.12 mmol), and DIPEA (0.45 mL, 2.61 mmol) was refluxed in THF (60 mL) for 4 days. The THF was removed under vacuum and the residue was dissolved in dioxane (60 mL). Additional thiomorpholine 1-oxide trifluoroacetate (161 mg, 0.745 mmol) and DIPEA (0.45 mL, 2.61 mmol) were added and the mixture was refluxed for 2 days. The solvent was removed under vacuum and the residue was diluted with water. The resulting precipitate was filtered, washed with water, and dissolved in CH2Cl2. The solution was dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (95:5), followed by recrystallization from CH2Cl2/hexane gave 138 mg (56% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-oxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (CH2Cl2/hexane) 229-231° C.; 1H NMR (CDCl3) δ7.85 (d, J=8.0 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 4.05 (s, 3H), 4.01 (br s, 4H), 3.89 (br s, 4H), 3.79 (m, 4H), 3.38 (t, J=5.0 Hz, 4H), 3.15 (m, 4H), 2.99 (dd, J=8.8, 5.4, 2H), 2.79 (m, 6H); Anal. Calcd. for C26H35F2N9O5S2.0.2H2O: C, 47.4; H, 5.4; N, 19.1. Found: C, 47.3; H, 5.5; N, 18.7.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:17]([O:19][C:20](=[O:25])[CH:21](Cl)[CH2:22][CH3:23])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:17]([O:19][C:20](=[O:25])[CH:21]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:2]=2[Cl:1])=[CH:10][CH:9]=1)[CH2:22][CH3:23])[CH3:18]
Reactant: Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)C(Cl)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1
Yield: 45.9 %

Procedure:
A solution of 25.3 g of 4-(2,4-dichlorobenzyl)-phenol and 15 g of α-chlorobutyric acid ethyl ester in 100 ml of dimethyl formamide were stirred for 2 hours at 100° C with 16 g of potassium carbonate. After cooling, the reaction mixture was poured into 1 liter of water. An oil precipitated which was separated and dried over sodium sulfate. By vacuum distillation, 16.8 g of 2-[p-(2,4-dichlorobenzyl)-phenoxi]-butyric acid ethyl ester were obtained. b.p. 180° - 183° C/0.8 mm Hg/nD21 : 1.5912 ##STR7## The following compounds were prepared according to the methods described in the above Examples.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.Br.[CH2:15]([C:17]1[S:18][C:19]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=2[N:26]=1)[CH3:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:24][CH2:25][C:19]4[S:18][C:17]([CH2:15][CH3:16])=[N:26][C:20]=4[CH2:21][CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCc1nc2c(s1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: Br
Product: CCc1nc2c(s1)CCN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 2-ethyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrobromide. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 24 mg (29% of theory). ESI-MS: m/z=406 (M+H)+; Rt(HPLC): 1.19 min. (Method J).
Reaction SMILES: O[Li].[OH2:3].[NH:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=O)[C:5]1=[O:6].C(O[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)(=O)C.Cl.[OH2:29]>COC(C)(C)C>[OH:3][C:19]1[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][C:14]2[C:9]([C:7]=1[C:5]([OH:6])=[O:29])=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CC(=O)OCC(=O)c1ccccc1
Reactant: O
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: [Li]O
Solvent: COC(C)(C)C
Product: O=C(O)c1c(O)c(-c2ccccc2)nc2ccccc12
Temperature: 55 °C
Reaction time: 0.12 h
Yield: 82 %

Procedure:
A 1 L round-bottomed flask was charged with 360 mL of water and LiOH.H2O (34.3 g, 800 mmol) and stirred at 50-60° C. Isatin (30 g, 200 mmol) was added and the reaction stirred for 30 minutes at 50-60° C. The (α-acetoxy acetophenone (40.95 g, 230 mmol, 1.15 equiv.) was added as a solid in one portion and the solution heated at 80-85° C. until <5% by PAR isatin remains as shown by HPLC (typically 3 hours). The reaction was cooled to room temperature, diluted with water (90 mL) and tert-butyl methyl ether (“TBME”) (210 mL) and transferred to a separatory funnel. The mixture was shaken well and the aqueous layer drained into an Ehrlenmeyer flask. The aqueous layer was acidified to pH=3.0-3.5 using conc. HCl (˜61 mL) and monitored with a pH meter. The suspension of yellow solid was heated to 60-70° C., and held at that temperature for 5-10 minutes and filtered through a Buchner funnel. The flask was rinsed with 90 mL of water at 60-70° C. and the filter cake was washed with this rinse. The solid was suction dried for 10 minutes and charged back to the 1 L flask. The flask was charged with 600 mL of water, the suspension heated to 60-70° C., held there for 10 minutes, and filtered through a Buchner funnel. The flask was rinsed with 150 mL of water at 60-70° C. and the filter cake washed with this rinse. The filter cake was dried in a vacuum oven at 80-90° C. and <1 mm Hg. After drying to constant weight, the product 3-hydroxy-2-phenylquinoline-4-carboxylic acid (82%) was obtained as a bright yellow solid: mp 206° C.; IR (cm−1) 3430, 2600, 1634; 1H NMR (300 MHz, DMSO-d6) δ8.75 (1H, δ, J=8.2 Hz), 8.01 (3H, m), 7.59 (5H, m); 13C NMR (75 MHz,DMSO-d6) δ171.03, 153.98, 151.38, 139.68, 135.62, 129.60, 129.38, 128.27, 127.83, 126.27, 125.22, 124.54, 115.26.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[N:19]([C:20]2[N:32]([CH3:33])[C:23]3=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:22]3[N:21]=2)[CH:18]=[CH:17][N:16]=1)C.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:34]([C:15]1[N:19]([C:20]2[N:32]([CH3:33])[C:23]3=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]3[N:21]=2)[CH:18]=[CH:17][N:16]=1)(=[O:38])=[O:36])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1nccn1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1nccn1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.22 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to 3 ml of a solution of 0.13 g of 2-(2-ethylthio-3H-imidazol-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5,b]pyridine in chloroform under ice cooling, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.12 g of 2-(2-ethylsulfonyl-3H-imidazol-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (2)).
Reaction SMILES: [C:1]([N:5]1[C@H:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C@H:8]2[O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].C([Mg]Cl)(C)(C)C.C(O[C@H:28]1[NH:31][C:30](=[O:32])[C@@H:29]1[C@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH3:34])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[Si:36]([O:35][C@@H:33]([C@@H:29]1[C@@H:28]([C@@H:2]([CH3:3])[C:1]([N:5]2[C@H:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:8]3[O:7][C:6]2=[O:17])=[O:4])[NH:31][C:30]1=[O:32])[CH3:34])([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:37])[CH3:38]
Reactant: CCC(=O)N1C(=O)O[C@@H]2Cc3ccccc3[C@@H]21
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)O[C@@H]2Cc3ccccc3[C@@H]21
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, 231 mg (1.0 mmol) of 3-propionyl-(3aS-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one was charged in a 30-ml three-necked flask to dissolve it in 2 ml of tetrahydrofuran. To the resulting solution, 2.75 ml (2.2 mmol) of a tetrahydrofuran solution (0.8M) of t-butylmagnesium chloride was slowly added dropwise at room temperature. After the resulting mixture was allowed to react for 20 minutes under the same conditions, the reaction mixture was cooled to 5° C. and added with 2 ml of a tetrahydrofuran solution of 287 mg (1.0 mmol) of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one at the same temperature. After stirring for 10 minutes, 10 ml of ethyl acetate was added to the reaction mixture, followed by the dropwise addition of 2 ml of a 10% aqueous solution of citric acid. After separation, the organic layer was washed with 2 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of a saturated aqueous solution of sodium cloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by column chromatography, whereby 308 mg (0.67 mmol) of a condensation product was obtained (yield: 67%, β:α=95:5).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.C(N(CC)CC)C.[C:29]([Cl:32])(=[O:31])[CH3:30]>O1CCCC1>[ClH:32].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([O:21][C:29](=[O:31])[CH3:30])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(O)cc12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2onc(OCCN)c2c1
Product: Cl
Temperature: 5 °C
Yield: 109 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-5-hydroxy-1,2-benzisoxazole (100 mg) in tetrahydrofuran (5 ml) was added triethylamine (44 mg) and acetyl chloride (34 mg) with stirring at 5° C., and the mixture was then stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporate under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (101 mg, 88%) as a colorless powder.
Reaction SMILES: COC1C=CC([N+]([O-])=O)=CC=1C=O.C(NC(C1CCNCC1)=O)(C)(C)C.[C:27]([NH:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[C:45]([N+:47]([O-])=O)[CH:44]=[CH:43][C:42]=2[O:50][CH3:51])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[C:45]([NH2:47])[CH:44]=[CH:43][C:42]=2[O:50][CH3:51])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1ccc([N+](=O)[O-])cc1CN1CCC(C(=O)NC(C)(C)C)CC1
Agent: CC(C)(C)NC(=O)C1CCNCC1
Agent: COc1ccc([N+](=O)[O-])cc1C=O
Product: COc1ccc(N)cc1CN1CCC(C(=O)NC(C)(C)C)CC1

Procedure:
The title compound is prepared according to the reactions described for BB-5 above starting from 2-methoxy-5-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination 1-(2-methoxy-5-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide; LC-MS A: tR=0.61 min; [M+H]+=350.18 followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.42 min; [M+H]+=320.24.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:7]=[C:6]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:5]=2[S:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[N:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:10]3[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:7]=[C:6]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:5]=3[S:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: O=c1c2c(Br)csc2c(-c2ccncc2)nn1CCc1ccccn1
Reactant: OB(O)c1ccncc1
Product: O=c1c2c(-c3ccncc3)csc2c(-c2ccncc2)nn1CCc1ccccn1
Yield: 75.2 %

Procedure:
The title compound was prepared in analogy to the process described in Example 3.5 starting from 3-bromo-7-pyridin-4-yl-5-[2-(pyridin-2-yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one and pyridine-4-ylboronic acid. Yield: 75.2%.