Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:7][N:6]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1ncc(C#C[Si](C)(C)C)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (9.38 g, 43.2 mmol) and (trimethylsilyl)acetylene (9.16 mL, 64.8 mmol) in triethylamine (300 mL) were added bis(triphenylphosphine)palladium(II)chloride (3.34 g, 4.75 mmol) and copper(I) iodide (1.64 g, 8.64 mmol). The reaction mixture was allowed to stir for 4 h at 80° C. and then cooled to rt and filtered through Celite®. The filter pad was washed with EtOAc and the filtrate was washed with saturated aqueous NaHCO3 (500 mL) then brine (500 mL). The organic solution was dried over Mg2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-methyl-3-nitro-5-[(trimethylsilyl)ethynyl]pyridine (9.22 g, 91%). LCMS (FAL): Rt=11.04 min, m/z=235.1 (M+H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:47]=[CH:46][C:13]([C:14]2[C:19]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:30]5N(CC)[C:33]6[CH:37]=[CH:38][C:39]([C:41]([OH:43])=[O:42])=[CH:40][C:32]=6[N:31]=5)[CH:26]=4)[N:21]=3)=[CH:18][C:17]([O:44][CH3:45])=[CH:16][CH:15]=2)=[CH:12][CH:11]=1>>[CH2:1]([N:8]1[C:33]2[CH:37]=[CH:38][C:39]([C:41]([OH:43])=[O:42])=[CH:40][C:32]=2[N:31]=[C:30]1[C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:19]1[C:14]([C:13]3[CH:46]=[CH:47][C:10]([Cl:9])=[CH:11][CH:12]=3)=[CH:15][CH:16]=[C:17]([O:44][CH3:45])[CH:18]=1)[CH:29]=[CH:28]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4Cc4ccccc4)ccc3n2)c1

Procedure:
The title compound was prepared from resin 534a and benzylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: Br[C:2]1([Br:10])[CH:9]2[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][OH:13].[Al]>C1(C)C=CC=CC=1.Cl([O-])(=O)(=O)=O.[Ag+]>[Br:10][C:2]1[CH:3]([CH:12]([OH:13])[C:11]([O:15][CH3:16])=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=1
Reactant: COC(=O)CO
Reactant: BrC1(Br)C2CCCCCC21
Agent: [Ag+]
Agent: [Al]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(O)C1CCCCCC=C1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 8,8-dibromobicyclo[5.1.0]octane (2.5 g, i.e. 9.3 mmol) and of methyl glycolate (6.32 mL, i.e. 83.9 mmol) dissolved in 5 mL of anhydrous toluene in a dry round-bottomed flask, under Ar and protected from light by a film of aluminum, are added 3.85 g of silver perchlorate (i.e. 18.6 mmol). The reaction is stirred for 1 hour 30 minutes at room temperature, and the silver salts are then filtered off on a sinter and washed with EtOAc. The solution is concentrated under vacuum to give a viscous brown oil, which is purified by chromatography on silica gel (2-150 EtOAc in cyclohexane) to give the product in the form of a yellow oil of mass m=1.6 g, i.e. 65% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8](=[O:14])[CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8](=[O:14])[CH2:9][C@H:10]([OH:13])[CH2:11][O:12][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CO
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 16.8 g (77 mmol) of the (5S)-5,6-dihydroxy-3-oxohexanoic tert-butyl ester produced in Example 1 in 120 mL of methylene chloride were added 11.2 mL of pyridine and 10.2 mL of benzoyl chloride at 0° C., and the mixture was stirred at 0° C. for 2 hours. After completion of the reaction, the reaction mixture was diluted with 38 mL of water and adjusted to pH 7 with 20% aqueous NaOH solution. The aqueous layer was separated and further extracted with 2 portions of methylene chloride, 120 mL each. The organic layers were combined and dehydrated over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give an oil. This residue was purified by silica gel column chromatography (Kieselgel 60, product of Merck; hexane:acetone=5:1) to give 19.3 g of (5S)-6-benzoyloxy-5-hydroxy-3-oxohexanoic tert-butyl ester (white solid).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23]O)[CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:23][CH2:22][C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][CH:19]=2)[CH:5]=1
Reactant: Cc1cccc(CCO)c1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCCc2cccc(C)c2)c1
Yield: 86.9 %

Procedure:
3-Hydroxy-4-nitro-benzoic acid methyl ester (1.00 g, 5.07 mmol) and 2-(3-methylphenyl)-ethanol (0.829 g, 6.09 mmol) were reacted in analogy to step 1 of example 1 to give 1.39 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N+:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br)([O-:31])=[O:30]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[N+:29]([O-:31])=[O:30])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8.23 g, 0.032 mol) in tetrahydrofuran (85 mL) was slowly added a solution of sodium bis(trimethylsilyl)amide (44 mL, 0.044 mol). After the resulting mixture had been stirred at −78° C. for 1 h, a solution of 2-nitrobenzyl bromide.(8.21 g, 0.038 mol) was added. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. It was then concentrated and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The final product was purified from the complex reaction mixture by way of column chromatography on silica gel (eluent-hexanes-ethyl acetate 4:1) to give the desired product (1.61 g, 13%) as brown oil. Mass spec.: 415.38 (M+Na)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:17])[C@@H:7]([OH:16])[C@@H:8]([N:13]=[N+]=[N-])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4]>[C].[Pd].CO>[CH2:1]([NH:5][C:6](=[O:17])[C@@H:7]([OH:16])[C@@H:8]([NH2:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H](O)[C@H](CCCC)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@@H](O)[C@@H](N)CCCC
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To 30 ml of a methanol solution containing 304 mg (1.25 mmol) of (2S,3S)-N-butyl-3-azido-2-hydroxyheptanamide was added 30 mg of 5% palladium carbon, and the resulting mixture was stirred under hydrogen atmosphere for 18 hours. Insoluble materials were filtered off, and the filtrate was distilled under reduced pressure to obtain 254 mg (Yield: 94%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:23][N:24]([CH3:33])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][CH3:32]>>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:29]([CH2:28][CH2:27][CH2:26][CH2:25][N:24]([CH3:33])[CH3:23])[CH2:30][CH2:31][CH3:32])=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCCNCCCCN(C)C
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Product: CCCN(CCCCN(C)C)C(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1

Procedure:
4-(7-Chloro-4-quinolylamino)benzoyl chloride hydrochloride is reacted with 1 -dimethylamino-4-propylaminobutane in a similar manner to Example 1 to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([NH2:13])=[C:4]([C:9]([NH2:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Si:14]([O:21][CH2:22][C:23]1[O:24][CH:25]=[CH:26][C:27]=1B(O)O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:13][C:3]1[C:2]([C:27]2[CH:26]=[CH:25][O:24][C:23]=2[CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[CH:11][CH:10]=[C:9]([NH2:12])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)(C)[Si](C)(C)OCc1occc1B(O)O
Reactant: COC(=O)c1c(N)ccc(Br)c1N
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(N)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1N
Temperature: 70 °C
Yield: 59.8 %

Procedure:
A mixture of methyl 3-bromo-2,6-diaminobenzoate (Intermediate 25, 2.6 g), 2-(tert-butyldimethylsilanyloxymethyl)furan-3-boronic acid (Intermediate 37, 3.5 g), cesium carbonate (11.35 g), tri-tert-butylphosphonium tetrafluoroborate (0.334 g) and tris-(dibenzylideneacetone)dipalladium (0.529 g) in dioxane (72 mL) and water (18 mL) was degassed and purged with nitrogen then heated at 70° C. for 75 minutes. After cooling, ethyl acetate and water were added and the mixture was filtered through Celite. The filtrate was separated and the organic layer was washed with brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-20% to give methyl 2,6-diamino-3-[2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl]benzoate (2.39 g) as a viscous oil which was used without further characterization.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[C:7]([N+:16]([O-])=O)[CH:6]=1>CO.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:3][O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[C:7]([NH2:16])[CH:6]=1
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: COc1cc(N)c(C(N)=O)cc1OC
Temperature: 0 °C

Procedure:
NaBH4 (400 mg) was added with stirring over 4 hours to a solution of 4,5-dimethoxy-2-nitrobenzamide 2 (1.58 g; 7 mmol) in MeOH containing catalytic amount of CuSO4. The reaction mixture was poured into ice-water (200 mL) with stirring to give 4,5-dimethoxy-2-aminobenzamide 3 which was directly refluxed with HCOOH (20 mL) for 5 hours. After removal of solvent, the residue was recrystallized from DMF to give pure crystals 4 (1.18 g; 81.5%). m.p. 295.0-297.0° C.; 1H NMR (DMSO-d6): δ 12.03 (br, s, 1H, —NH) ,7.99 (s, 1H, 2-H), 7.42 (s, 1H, 5-H), 7.11 (s, 1H, 8-H), 3.88, 3.85 (s, s, 6H, —OCH3); IR(KBr)υmax: 3015, 2840, 1648, 1504, 1261, 1070 cm−1; GC/MS m/z206(M+, 100), 191(M+ —CH3,31.5), 163(16.7), 120(15.2).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]([N:22]3[CH2:23][CH:24]([CH2:26][OH:27])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:32]=[N:31][CH:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC (Condition 4) tR=5.02 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=463.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.56-2.68 (m, 1H) 3.37-3.52 (m, 4H) 3.71 (t, J=8.60 Hz, 2H) 4.68 (t, J=1.00 Hz, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.77-7.90 (m, 3H) 8.04 (d, J=2.35 Hz, 1H) 8.49-8.55 (m, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.76 (d, J=2.35 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=1.[H-].[Na+].I[CH3:33].O>CN(C)C=O>[CH3:33][NH:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=1
Reactant: CCCc1c2nc(C(=O)OCC)cc(N)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c2nc(C(=O)OCC)cc(NC)c2cc2c(=O)cc(C(=O)OCC)oc12
Reaction time: 0.5 h

Procedure:
Diethyl 6-amino-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (0.4 g) was dissolved in dry dimethylformamide (15 ml), and added dropwise with stirring to a suspension of sodium hydride (50%, 0.053 g, washed with dry ether) in dry dimethylformamide (10 ml) under a dry nitrogen atomosphere. After about 30 minutes at ambient temperature a deep red colour had developed, and iodomethane (0.23 ml) was added dropwise and stirring continued at room temperature for a further five hours. The whole ws then poured into water and extracted with chloroform. The organic extracts were combined, dried over magnesium sulphate, evaporated in vacuo, and the resulting oil chromatographed on alumina to give the title compound (0.11 g), mp 235°-237° (from ethanol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:51])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)=[C:41](Br)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:51])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[C:42]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OCC2CC2)c(Br)c1
Product: CCOC(=O)Cc1ccc(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-bromo-4-cyclopropylmethoxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br.Br[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CN(C)C=O>[N:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:1][C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccnc1S
Reactant: BrCc1ccncc1
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccnc1SCc1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
2-Mercaptonicotinic acid (7.8 g, 50 mmol) and 4-(bromomethyl)pyridine hydrobromide (12.6 g, 50 mmol) were suspended in N,N-dimethylformamide (100 mL) under ice-cooling. Triethylamine (21 ml, 150 mmol) was added dropwise to the suspension, and the whole was stirred at room temperature for 6 hours. Water (300 mL) was added to the reaction mixture, then the aqueous layer was washed with ethyl acetate (100 mL). 2 N hydrochloric acid was added to the aqueous layer to adjust to pH 7, and the precipitated solid was filtered off. The solid was washed with water and diethyl ether, and dried at 50° C. under reduced pressure to give 7.5 g of the title reference compound as a gray solid. (Yield 61%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:10]C1C(=O)C(Br)=CC(Br)(Br)C=1>>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1ccccc1N
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Product: COc1cc(Br)ccc1N

Procedure:
2-Methoxyaniline was brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one to give 4-bromo-2-methoxyaniline which was reacted with di-tert-butyldicarbonate in tetrahydrofuran to protect the amine group. The product was treated with butyllithium at -78° C. and then with trimethyltin chloride to give 4-tert-butoxycarbonylamino-3-methoxyphenyl trimethyl stannane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:2][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:14]([C:15]5[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=5)[N:13]=[CH:12][CH:11]=4)=[CH:6][C:5]=23)=[CH:26][CH:25]=1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1ccc(CC#N)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(C)cc4)cc23)cc1

Procedure:
The title compound, light brown solid (17 mg, 12%), MS (ISP) m/z=382.4 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=4)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:32][O-:33].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([O:33][CH3:32])[N:26]=4)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)n5)CC4)nc23)c(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N2CCC(Nc3nc4c(-c5ccc(F)cc5Cl)cccn4n3)CC2)n1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 190b) (71 mg, 0.155 mmol) in MeOH (1.5 mL) was added sodium methoxide solution (30% in MeOH, 35 L, 0.186 mmol) and the reaction mixture was stirred in a sealed tube under Argon at 60° C. for 18 hours and then heated in the microwave to 150° C. for 30 minutes. The mixture was then evaporated.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[O:17]=[C:18]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][C:25]2[C:20](=[N:21][CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:24]=2)[NH:19]1.C(OCC)(=O)C>ClCCCl.O>[CH3:1][N:30]1[CH2:29][CH2:28][C:27]2([CH2:26][C:25]3[C:20](=[N:21][CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:24]=3)[NH:19][C:18]2=[O:17])[CH2:32][CH2:31]1
Reactant: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C)CC1)C(=O)N2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.2 g, 5.73 mmol) and paraformaldehyde (172 mg, 5.73 mmol) were successively added to a suspension of (E)-ethyl 3-(2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate (904 mg, 2.87 mmol) in 1,2-dichloroethane (40 mL) at room temperature. The reaction mixture was then heated up to 70° C. and stirred for 2 hours. After cooling down to room temperature, the reaction mixture was diluted by addition of ethyl acetate (50 mL) and water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium hydrogenocarbonate (3×60 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title product was obtained as a white solid (862 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:16]=[CH:15][C:11]3[N:12]=[CH:13][NH:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[N:19]1[S:20][N:21]=[C:22]2[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][C:23]=12.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH2:28][C:25]2[CH:26]=[CH:27][C:22]3[C:23]([CH:24]=2)=[N:19][S:20][N:21]=3)[C:8]2[CH:16]=[CH:15][C:11]3[NH:12][CH:13]=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc2nsnc2c1
Reactant: Clc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(CN(Cc2ccc3nsnc3c2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-chlorobenzyl)benzimidazol-5-amine (258 mg; 1 mmol; 1 eq.), (benzo-[c][1,2,5]-thiadiazol-6-yl)methylbromide (252 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.151 g (37.2%); MS m/z: 406.4/408.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.77 (s, 2H); 4.88 (s, 2H); 6.73-6.79 (m, 2H); 7.32-7.38 (m, 5H); 7.69 (dd, 1H, 4J=1.5 Hz, 3J=9.2 Hz); 7.86 (s, 1H); 7.92 (s, 1H); 8.05 (d, 1H, 3J=9.2 Hz); 11.87 (br s, 1H); HPLC (METHOD [A]): rt 15.88 min (95.9%)
Reaction SMILES: N[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]([CH2:16][CH2:17][CH:18](N(CCC)CCC)[CH3:19])[CH2:6]2.C(=O)([O-])[O-].[K+].[K+].C([C:38]1[CH:48]=[CH:47][CH:46]=[C:40]2[C:41]([NH:43][C:44](=[O:45])[C:39]=12)=[O:42])(OCC)=O.O>CN(C=O)C>[CH2:41]([N:43]([CH2:44][CH2:39][CH3:38])[CH2:19][CH2:18][CH2:17][CH2:16][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][N:43]3[C:44](=[O:45])[C:39]4[C:40](=[CH:46][CH:47]=[CH:48][CH:38]=4)[C:41]3=[O:42])[CH:4]=2)[CH:8]1[O:12][CH2:13][O:14][CH3:15])[CH2:40][CH3:46]
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: CCCN(CCC)C(C)CCC1Cc2cc(CN)ccc2C1OCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)CCCCC1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1OCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 130.9 %

Procedure:
The compound (189 mg) obtained in Example 11-10 was dissolved in DMF (5.6 ml) and added with potassium carbonate (108.5 mg) and carbethoxyphthalimide (172.0 mg) and the whole was stirred at room temperature for 3 hours. The reaction solution was added with water and subjected to extraction with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (253 mg) as a yellow oily substance.