Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH3:15])[CH2:11][C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[C:8]([CH3:13])[C:9]=2[CH3:12])[CH2:4]1)[CH3:2].[CH3:16][O:17]C(Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C:3]1([CH3:15])[CH2:11][C:10]2[C:5](=[C:6]([CH3:14])[C:7]([CH:16]=[O:17])=[C:8]([CH3:13])[C:9]=2[CH3:12])[CH2:4]1)[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCC1(C)Cc2c(C)cc(C)c(C)c2C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1(C)Cc2c(C)c(C)c(C=O)c(C)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 17.7 g of the 2-ethyl-2,4,5,7-tetramethylindane in 100 ml of dry dichloromethane was continuously added 9.5 ml of α,α-dichloromethyl methyl ether and 11.6 ml of TiCl4 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 18.26 g of the title compound as brown solid.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[N:22]=[C:23](N)[S:24][CH:25]=4)=[N:19][N:20]=3)[N:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Br-:27].[Na+].N([O-])=O.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2].CC(O)C.C(Cl)(Cl)Cl>[Br:27][C:23]1[S:24][CH:25]=[C:21]([C:18]2[N:16]3[N:17]=[C:12]([N:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[CH:13]=[CH:14][C:15]3=[N:20][N:19]=2)[N:22]=1
Reactant: Nc1nc(-c2nnc3ccc(N4CCCCC4)nn23)cs1
Reactant: [Br-]
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: O
Product: Brc1nc(-c2nnc3ccc(N4CCCCC4)nn23)cs1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 6.9 %

Procedure:
A solution mixture of concentrated sulfuric acid (1.5 ml) and water (3 ml) was cooled to −5° C., and 4-(6-piperidin-1-yl-1,2,4-triazolo[4,3-b]pyridazin-3-yl)-1,3-thiazol-2-amine (0.90 g), copper (II) sulfate (1.50 g) and sodium bromide (0.62 g) were added successively, and the mixture was stirred at 0° C. for 5 minutes. Then, a solution of sodium nitrite (0.25 g) in water (1.6 ml), followed by stirring at room temperature overnight. The reaction solution was combined with water, chloroform and 2-propanol, and insoluble materials were filtered off. The resultant organic phase was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1) to obtain crude crystals, which were then recrystallized from ethanol-diethyl ether to obtain 3-(2-bromo-1,3-thiazol-4-yl)-6-piperidin-1-yl-1,2,4-triazolo[4,3-b]pyridazine (75 mg) as pale yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[BH4-].[Na+].[NH4+].[Cl-]>C(O)C.O>[CH2:11]([C:9]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=2)[C:7]2[CH:35]=[CH:36][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCc1nc2cc(C(C)O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
A mixture N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (Example 78, 238 mg, 0.47 mmol) and 2N NaOH (0.1 ml) in ethanol (10 ml) was added a mixture of NaBH4 (178 mg, 0.47 mmol) and 2N NaOH (0.1 ml) in ethanol (4 ml) at room temperature. The mixture was stirred at room temperature for 4 h. The mixture was added water (10 ml) and neutralized with NH4Cl. The mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1:4/1:6)/CH2Cl2:methanol (10:1) to afford 198 mg (83%) of the title compound as white solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:44]=[CH:43][C:27]([CH2:28][N:29]2[CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=[N:30]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][C:27]4[CH:43]=[CH:44][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[CH:33]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Br)cc34)cn2)cc1
Yield: 57.95 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (750 mg, 1.78 mmol) was coupled with 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 5) (671 mg, 2.13 mmol) in sodium carbonate (614 mg, 4.4 mol), bis(triphenyl phosphine)palladium(ii) dichloride (62 mg, 2.13 mmol) and toluene/ethanol/water (10/10/5 ml) to afford 550.0 mg (57.95% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 8.56-8.50 (m, 3H), 8.25 (s, 1H), 8.08 (s, 1H), 7.97-7.94 (d, 2H), 7.41-7.39 (d, 2H), 7.27-7.24 (d, 2H), 6.91-6.89 (d, 2H), 5.27 (s, 2H), 3.72 (s, 3H), 2.32 (s, 3H). MS: m/z=539.0 (M+2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.BrN1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: O=Cc1ccnc(Cl)c1
Yield: 94.5 %

Procedure:
69.0 g of 2-chloro-4-pyridinemethanol, 128.3 g of N-bromosuccinimide and 101.9 g of anhydrous sodium carbonate were suspended in 1.8 liters of benzene, and refluxed for 4 hours. After cooling, a saturated aqueous solution of sodium hydrogen carbonate was added little by little with stirring until bubbling ceased. The insoluble matter was removed by filtration. The organic layer was separated, washed with a 10% aqueous solution of sodium thiosulfate once and then a saturated aqueous solution of sodium chloride twice, and dried. The solvent was evaporated to give 64.3 g (yield 95%) of 2-chloro-4-pyridinecarboxaldehyde.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>C1(C)C=CC=CC=1>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[S:3][C:4]=1[CH3:8]
Reactant: C=C1CC(=O)O1
Reactant: Cc1nc(N)sc1C
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1nc(C)c(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of 2-amino-4,5-dimethylthiazole (0.05 mole) in toluene (30 ml), cooled in ice was added diketene (0.05 mole) at such a rate that the temperature did not rise above 20° C. When addition was complete the mixture was stirred at room temperature for 2 hours and evaporated to dryness to give N-(4,5-dimethylthiazol-2-yl)-3-ketobutanamide (4.1 g), Rf (silica; diethylamine/ethyl acetate 1:19) 0.47; m.p. 191°-3° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[CH2:8]([O:15][C:16](=[O:30])[CH2:17][C@H:18]([C:27](O)=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC)=O.Cl.CNC>ClCCl>[CH2:8]([O:15][C:16](=[O:30])[CH2:17][C@@H:18]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:27]([N:3]([CH3:4])[CH3:1])=[O:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Triethylamine (2.8 mL, 20.0 mmol) was added at 0° C. to a solution of Boc-D-aspartic acid 4-benzyl ester (5.00 g, 15.0 mmol) in dichloromethane, then ethyl chloroformate (1.91 mL, 20.0 mmol) was added dropwise. The reaction mixture was stirred for 1 h at 0° C., then a solution of dimethylamine hydrochloride (2.65 g, 32.0 mmol) and triethylamine (4.53 mL, 32.0 mmol) in dichloromethane (100 mL) were added dropwise. The reaction mixture was allowed to reach room temperature over 16 h, then washed with brine, and concentrated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced (R)-3-tert-butoxycarbonylamino-N,N-dimethyl-succinamic acid benzyl ester (3.77 g, 70%). Colorless oil, m/e=351.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:18]3[C:19]4[C:11](=[N:12][NH:13][C:14]=4[N:15]=[C:16]([S:20][CH3:21])[N:17]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI.C(OCC)(=O)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:18]3[C:19]4[C:11](=[N:12][N:13]([CH3:24])[C:14]=4[N:15]=[C:16]([S:20][CH3:21])[N:17]=3)[CH2:10][CH2:9]2)=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN2CCc3n[nH]c4nc(SC)nc2c34)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2CCc3nn(C)c4nc(SC)nc2c34)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4-methoxybenzyl)-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene (3.10 g, 9.48 mmol) in DMF (120 mL) was added Cs2CO3 (15.4 g, 47.43 mmol) and MeI (1.76 mL, 28.45 mmol). The mixture was stirred at room temperature for 16 h. Ethyl acetate (250 mL) and water (150 mL) was added. The EtOAc layer was separated, washed with aqueous NaCl (3×150 mL), dried over Na2SO4, filtered and concentrated. The obtained residue was purified by flash silica gel chromatography (eluent: 50% then 66% EtOAc in hexane). Compound 5-(4-methoxybenzyl)-1-methyl-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene compound 130 was obtained as a white solid (2.12 g, 95%). M.p. 105-108° C.; 1H NMR (CDCl3, 400 MHz) 6 7.25 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.77 (s, 2H), 3.92 (s, 3H), 3.79 (s, 3H), 3.54 (t, J=6.8 Hz, 2H), 3.04 (t, J=6.8 Hz, 2H), 2.61 (s, 3H). LC-Mass (m/e): 342.48 (M+1).
Reaction SMILES: BrC1C=C2C(C(CC([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=O)=CN2)=CC=1.[F:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][C:38]([CH3:41])=[C:37]2[CH2:42][C:43]([OH:45])=O>>[Cl:24][C:22]1[CH:23]=[C:18]([CH2:17][NH:16][C:15]([NH2:30])=[N:14][C:43](=[O:45])[CH2:42][C:37]2[C:36]3[C:40](=[C:32]([F:31])[CH:33]=[CH:34][CH:35]=3)[NH:39][C:38]=2[CH3:41])[CH:19]=[C:20]([Cl:29])[C:21]=1[NH:25][C:26](=[O:28])[CH3:27]
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Reactant: Cc1[nH]c2c(F)cccc2c1CC(=O)O
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c(C)[nH]c3c(F)cccc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(7-fluoro-2-methyl-1H-indol-3-yl)acetic acid in step 22 (A), the title compound was prepared. MS (ESI) (M+H)+=464.00 1H-NMR(500 MHz, CD3OD) δ 7.44 (s, 2 H), 7.24 (d, J=7.93 Hz, 1 H), 6.90-7.01 (m, 1 H), 6.72-6.89 (m, 1 H), 4.52 (s, 2 H), 3.93 (s, 2 H), 2.45 (s, 3 H), 2.19 (s, 3 H).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5]CC1C=CC=CC=1)=O.[H-].[Na+].[CH3:24][N:25]1[C:30]2[CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[CH:33]=[CH:34][C:29]=2[C:28](=O)[O:27]C1=O.Cl>CN(C=O)C.CCOC(C)=O>[OH:27][C:28]1[C:29]2[C:30](=[CH:31][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:34]=2)[N:25]([CH3:24])[C:3](=[O:5])[C:2]=1[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: COC(=O)c1ccc2c(=O)oc(=O)n(C)c2c1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(O)c(C(=O)OCc3ccccc3)c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
To a solution of dibenzyl malonate (2.99 ml, 11.9 mmol) in DMF (41 ml) was added sodium hydride in portions. The cloudy grey mixture was stirred at room temperature for 20 min after which time a clear solution resulted. The solution was further stirred at 120° C. for 20 min before adding a solution of methyl 1-methyl-2,4-dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate (2.82 g, 11.9 mmol) in DMF (41 ml). The resulting yellow solution was stirred at 120° C. for 3 hrs. The reaction mixture was cooled to room temperature, 2N HCl and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc 3×, the combined organics were washed with H2O (1×) followed by sat. NaCl (2×). The organic phase was then dried over MgSO4, filtered and concentrated to give a yellow solid. Purification was performed by ISCO using 10% to 50% Hex/EtOAc gradient, 40 g column to give 300 mg of a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:30]([C:32]1[N:33]=[C:34]([C:45]([O-])=[O:46])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=1)#[N:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:45]([C:34]3[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=[C:32]([C:30]#[N:31])[N:33]=3)=[O:46])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 87.1 %

Procedure:
A solution of 150 mg (0.389 mmol) 5-amino-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (as prepared in the previous step) in 15 mL of CH2Cl2 was treated with 131 mg (0.428 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 3, step (b)), 272 mg (0.584 mmol) PyBroP, and 203 μL (1.17 mmol) DIEA at room temperature for 3 h. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography of the residue on a 50-g silica Varian MegaBond Elut column with 50% EtOAc-hexanes afforded 215 mg (87%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C34H50N6O4Si, 635.4 (M+H), found 635.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:19][CH3:20])[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:29][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:19][CH3:20])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)(=[O:11])=[O:10]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(F)c1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
A solution of N-(5-chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide (Example 130a) (0.159 g) in dry tetrahydrofuran (3 mL) was added to a stirred solution of lithium di-iso-propylamide (prepared from di-iso-propylamine (0.151 g) and n-butyl lithium (2.5M in hexanes)) in tetrahydrofuran (7.0 mL) at −78° C. The resulting solution was stirred at −78° C. for 15 minutes and then hexachloroethane (0.472 g) in tetrahydrofuran (2 mL) was added and the mixture allowed to attain room temperature over a 5 hour period. The reaction was quenched by the addition of 1N hydrochloric acid (10 mL) and extracted into ethyl acetate (2×20 mL). The combined extracts were dried (MgSO4), filtered and concentrated to afford an oil that was purified by chromatography on silica gel eluting with ethyl acetate/iso-hexane mixtures gave the titled compound (0.086 g) as a white solid.
Reaction SMILES: C([O:8][NH:9][C:10]1([CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([N:31]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][C:24]=3[S:23](=[O:43])(=[O:42])[N:22]=2)[C:11]1=[O:44])C1C=CC=CC=1>OS(O)(=O)=O>[OH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([NH:9][OH:8])([CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[C:11](=[O:44])[C:12]=1[C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:30][C:24]=2[S:23](=[O:42])(=[O:43])[N:22]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(CCC(C)C)(NOCc3ccccc3)C1=O)N2)S(C)(=O)=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CN(c1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(CCC(C)C)(NO)C1=O)N2)S(C)(=O)=O
Yield: 66.2 %

Procedure:
A solution of Example 53A (40 mg, 0.056 mmol) an in conc. H2SO4 (0.25 mL) was stirred at 25° C. for 1.5 h. The solution was quenched with water, neutralized to pH 7 with 1 N NaHCO3, and extracted with ethyl acetate. The organic extract was concentrated in vacuo. Column chromatography on silica (10% methanol/dichloromethane) afforded the title compound as a yellow solid (23 mg, 75%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.40-0.59 (m, 1H), 0.64 (dd, J=1.40, 6.62 Hz, 6H), 0.81-0.92 (m, 1H), 0.92-1.03 (m, 1H), 1.18 (t, J=7.17 Hz, 3H), 1.45-1.67 (m, 1H), 1.64-1.82 (m, 1H), 3.11 (s, 3H), 4.12 (q, J=6.99 Hz, 2H), 4.54 (s, 2H), 7.30-7.47 (m, 2H), 7.47-7.87 (m, 4H), 8.06 (d, 1H), 14.92-15.36 (br.s, 1H); MS m/z 621.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.[B].[C:25](N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.IC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:25])[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3[nH]2)c1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: [B]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of 2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (Compound of Example 1) (50 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol/g) (113 mg) and N,N-dimethyl formamide (2 ml) was shaken at room temperature for 30 minutes. To the mixture was added iodomethane (28 mg), and the mixture was further shaken for 1 hour. After the resin was filtered off, the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-chloroform-hexane (1:1:4 to 1:1:0, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to isolate 2-(3-methoxyphenyl)-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (22 mg, 41%) (As a result of this reaction, a mixture of two isomers was obtained, and the isomer having higher polarity is the desired compound.)
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([NH:14][CH2:15][CH:16]([CH3:19])[CH2:17]O)=[O:13])=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:26])=O>ClCCl>[Cl:1][C:2]1[C:11]([C:12]([NH:14][CH2:15][CH:16]([CH3:19])[CH2:17][Cl:26])=[O:13])=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)NCC(C)CO)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)NCC(C)CCl)c1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 6.9 g (20 mmol) of methyl 2-chloro-3-(1′-hydroxy-2′,2′-dimethylethylaminocarbonyl)-4-methylsulfonylbenzoate and 5 ml of thionyl chloride was stirred for 6 hours at room temperature. The solution was diluted with 50 ml of dichloromethane and subsequently concentrated. The residue was dissolved in 20 ml of dichloromethane. The addition of cyclohexane resulted in a crystalline precipitate which was filtered off with suction and dried. This gave 6.4 g (88% of theory) of methyl 2-chloro-3-(1′-chloro-2′,2′-dimethylethylaminocarbonyl)-4-methylsulfonylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:28]([O-:30])=[O:29].[C:31](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC.O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:9])=[O:10])=[CH:4][C:3]=1[N+:28]([O-:30])=[O:29]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 96.5 %

Procedure:
In 640 ml of acetone was dissolved 170 g of 4-chloro-3-nitro-N-hexadecylbenzenesulfonamide prepared in the above step and after adding thereto 79 g of potassium carbonate, 6 ml of polyethylene glycol (average molecular weight: 400), and 71 g of dimethylsulfuric acid, the mixture was refluxed for 5 hours. To the reaction mixture thus obtained was added 240 ml of acetone and after adding dropwise 870 ml or water to the mixture at 40° C., the resultant mixture was cooled to room temperature, whereby crystals deposited. The crystals were recovered by filtration, washed with water and then methanol, and dried to provide 169 g of the above-described compound with a yield of 97%. The melting point thereof was 74° C. to 75° C.