Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(OC)[C:3]([C:5]1[C:13]2[N:12]=[C:11]([CH3:14])[N:10]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:6]=1)=[O:4].[CH3:34][Mg]Cl>O1CCCC1>[CH3:14][C:11]1[N:10]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:8]=[C:7]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:6]=[C:5]([C:3](=[O:4])[CH3:34])[C:13]=2[N:12]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2ccccc12
Solvent: C1CCOC1
Product: CC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of N,2-dimethyl-N-(methyloxy)-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxamide (82 mg, 0.184 mmol) in Tetrahydrofuran (THF) (10 mL) was added a 3.0 M solution of methylmagnesium chloride (0.123 mL, 0.369 mmol) in THF at 0° C. The resulting reaction mixture was stirred at 0° C. for 2 h and then quenched very carefully with saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with brine (50 mL), dried over (MgSO4), and filtered. The solution was concentrated under reduced pressure. The crude product was purified on a silica column (40˜60% EtOAc/Hexane) to give the product (46 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (s, 3H), 3.00 (s, 3H), 3.02-3.10 (m, 4H), 3.59-3.73 (m, 4H), 6.06 (s, 2H), 6.33 (d, J=6.82 Hz, 1H), 7.21-7.42 (m, 3H), 7.52-7.76 (m, 2H), 7.86 (d, J=8.34 Hz, 1H), 8.02 (d, J=7.33 Hz, 1H), 8.25 (d, 1H). MS (ES+) m/e 399.9[M+H]+.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH:19]([CH3:21])[CH3:20])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[CH:19]([CH3:21])[CH3:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](C(C)C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 14 (447 mg, 1.59 mmol) and 1-bromopentadecane (1.16 g, 4.0 mmol), alcohol 68 was obtained as a colorless oil (340 mg, 43% yield).
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29](S(C)=O)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29]([O:7][CH2:6][CH:2]4[CH2:1][O:5][CH2:4][O:3]4)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCC1COCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCC2COCO2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To a solution of glycerol formal (0.729 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a white precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a white solid (0.195 g, 51%). Mass (m/z): 384.1 (M++1), 382.1 (M+−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH2:10])[CH:3]=1.[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][NH2:11])[CH:3]=1
Reactant: COc1ccc(Br)cc1N
Reactant: O=N[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(Br)cc1NN
Yield: 89.1 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-bromo-2-aminoanisole (9.09 g), NaNO2 (3.45 g), and SnCl2.2H2O (22.6 g). Workup gave 8.7 g (89%) of (5-bromo-2-methoxyphenyl)hydrazine which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15](O)=O>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:14]([CH3:15])=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: NNc1cnc2ccc(Br)cc2n1
Solvent: O
Product: Cc1nnc2cnc3ccc(Br)cc3n12
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.84 mmol) and AcOH (5 mL) was refluxed overnight. After cooling to r.t., the mixture was treated with water (10 mL); the solid was collected on a filter and dried by vacuum to give 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline as gray solid (200 mg, yield: 91.0%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C@@H:3]([C:5]1[CH:14]=[CH:13][C:8]2OCCO[C:7]=2[CH:6]=1)[OH:4].[CH3:21][O:22]C1C=CC=CC=1C=O>>[NH2:1][C@H:2]([CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)[C@@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:13][C:14]=1[O:22][CH3:21])[OH:4]
Reactant: COc1ccccc1C=O
Reactant: N[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Product: COc1ccccc1[C@@H](O)[C@H](N)CN1CCCC1

Procedure:
Prepared in a manner similar to (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol as described in U.S. Pat. No. 6,855,830 and starting with 2-methoxy-benzaldehyde. Clear oil. HPLC system A 98% (tR=4.52 min) NMR (500 MHz, CDCl3) δ 7.47-7.48 (d, 1H), 7.25-7.29 (1H, M), 6.80-7.02 (m, 1H), 6.87-6.88 (d, 1H), 5.065 (s, 1H), 3.83 (s, 3H), 3.71-3.73 (1H, M), 3.22-3.24 (m, 1H), 2.80-2.84 (m, 1H), 2.55-2.58 (m, 5H), 1.80 (m, 4H).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]([OH:11])[CH2:12][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 28.6 %

Procedure:
A mixture of (R)-tert-butyl-dimethyl-(3-oxiranyl-propoxy)-silane (13 g, 60 mmol; prepared as in Org. Lett. (2005), 7, 3997) and 6-amino-4H-benzo[1,4]thiazin-3-one (10.8 g) in EtOH/H2O (9:1, 325 mL) was heated at reflux overnight. The volatiles were removed under reduced pressure and the residue purified by CC (Hept/EA 1:1) to give the desired intermediate as a brown oil (6.8 g, 28% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](S(C)(=O)=O)[N:14]=3)[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[N:9]2)=[CH:5][CH:4]=1.[CH2:34]([NH2:36])[CH3:35]>O1CCOCC1.O>[CH2:34]([NH:36][C:15]1[N:14]=[C:13]([C:11]2[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[N:9][N:8]([CH2:7][C:6]3[CH:32]=[CH:33][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:12]=2)[CH:18]=[CH:17][N:16]=1)[CH3:35]
Reactant: CCN
Reactant: COc1ccc(Cn2cc(-c3ccnc(S(C)(=O)=O)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc([N+](=O)[O-])c2)n1
Yield: 94 %

Procedure:
450 mg (0.97 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidine were dissolved in a mixture of 10 ml of dioxane and 5 ml of ethylamine 70% in water. The resulting solution was submitted to microwave irradiation in a sealed vial at 140° C. for 45 minutes. The solvent was then removed and the residue was partitioned between dichloromethane and aqueous sodium hydrogenocarbonate. The organic phase was then dried over sodium sulphate and evaporated to dryness. 391 mg (94%) of the title compound were obtained by trituration with diethylether.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:32])[O:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:26][C:25](=[O:32])[NH:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:4]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: O=C(Cl)OC1CCCC1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(CNC(=O)OC2CCCC2)c2ccccc2c1=O

Procedure:
The product of Example 42 and cyclopentyl carbonochloridate were treated using a method similar to that described in Example 128 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.60-11.62 (bs, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.88-8.03 (m, 2H), 7.58-7.64 (m, 1H), 7.23-7.45 (m, 4H), 4.95-5.01 (bs, 1H), 4.47-4.50 (m, 2H), 3.67-3.68 (bs, 2H), 1.76-1.81 (m, 2H), 1.50-1.69 (m, 6H); MS (ESI+) M/Z 455 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH:19][CH:20]=1.C(OCC)(=O)C>CN1CCCC1=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>[F:14][C:15]1[CH:20]=[C:19]([C:2]2[C:10]3[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc2c(Br)n[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 28.4 %

Procedure:
To a solution of 1.0 g of 3-bromo-6-nitro-1H-indazole in 10 ml N-methylpyrrolidone were added 2.0 g of (3-fluorophenyl)tri-n-butyltin, and 480 mg of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 180° C. for 2 hours. To the reaction mixture was added 60 ml of ethyl acetate. The mixture was sequentially washed with water (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:49), to give 302 mg of the title compound as orange crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[O:41]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42]1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:46]([C:43]2[CH:44]=[CH:45][O:41][CH:42]=2)(=[O:48])=[O:47])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccoc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccoc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 48 mg) in tetrahydrofuran (2 mL) were added dropwise a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (259 mg) in tetrahydrofuran (1 mL), 15-crown-5 (266 mg) and furan-3-sulfonyl chloride (147 mg) under ice-cooling and the mixture was stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 335 mg, 92%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([CH3:21])[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:26]>CO>[CH2:24]([O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:26])[C:11]=2[N:12]=1)[CH3:25]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(C)no1
Reactant: N
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(C)no1

Procedure:
A slurry of 4-chloro-2-(ethoxymethyl)-1-[(3-methylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (4.21 g, 11.8 mmol) in a solution of 7 M ammonia in methanol (50 mL) was heated at 150° C. for 22 hours in a Parr pressure vessel. The volatiles were removed under reduced pressure and the resulting solid was triturated with water. A tan solid was isolated and purified by flash chromatography (silica gel, gradient elution from 9:1 to 1:1 chloroform/CMA) to yield 43.2 mg of pure 2-(ethoxymethyl)-1-[(3-methylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 178.0-180.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]2=[O:22])=[C:4]([O:23][CH3:24])[CH:3]=1.C(Cl)Cl.[NH2:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:28][C:29]4[CH:33]=[CH:32][O:31][N:30]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]2=[O:22])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(Br)ccc1-n1c(=O)cnc2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccon1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Br)ccc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A RBF was charged with 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonyl chloride (0.800 g, 1.862 mmol), DCM (3.12 ml), and 3-aminoisoxazole (0.206 ml, 2.79 mmol) to give a thick suspension. Pyridine (6.21 ml) was added relatively quickly, leading to thinner suspension. After 2 h, the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and 2N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-50% 3:1 EtOAc/EtOH in heptane with 10% DCM) to give 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonamide (0.751 g, 1.573 mmol, 85% yield) as a white foam. m/z (ESI) 478.9 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Cl:20])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCCCl
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 73 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 4-chlorobutyryl chloride as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained at a yield of 73%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17](=[O:18])[NH2:19])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1)(=[O:33])=[O:32]
Reactant: Cc1ccccc1C(C)Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(C)Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O

Procedure:
In a similar manner as described for example 49 (step 1), 410 mg of 5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-methylphenyl)ethoxy]thiophene-2-carboxamide, 0.15 ml of methanesulfonyl chloride, and 0.28 ml triethylamine in 15 ml dichloromethane give (1-{5-carbamoyl-4-[1-(2-methylphenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [CH2:1]([C:12]1[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:19]([N:21](CC)CC)C>C(#N)C>[C:19]([C:16]1[CH:17]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:13]=[CH:14][N:15]=1)#[N:21]
Reactant: CCCCCCCCCCCc1cc[n+]([O-])cc1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCc1ccnc(C#N)c1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a solution of 5.00 g (20 mmol) of 4-n-undecylpyridine N-oxide and 4.04 g (40 mmol) of triethylamine dissolved in 20 ml of acetonitrile was dropwise added 7.92 g of trimethylsilylanilide while stirring at room temperature. After the dropwise addition, the mixture was refluxed for 22 hours, concentrated under a reduced pressure, then dissolved in diethyl ether and washed with saturated sodium hydrogen carbonate solution. The product was dried over anhydrous aqueous sodium sulfate and concentrated under a reduced pressure, followed by separation by silica gel column chromatography (ethyl acetate:hexane=1:9) to give the desired product of 3.95 g (solidified) (yield 76.2%).
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.C[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH2:15]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(-c3ccncc3)cc21
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccc(-c3ccncc3)cc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH:18]([S:26](Cl)(=[O:28])=[O:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH:18]([S:26]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:28])=[O:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C=Cc1ccccc1)On1nnc2ccccc21
Temperature: 25 °C
Yield: 75.7 %

Procedure:
In dichloromethane (100 ml) are dissolved 1-hydroxy-1,2,3-benzotriazole (5.4 g) and triethylamine (5.6 ml). To the solution is added β-styrenesulfonyl chloride (8.0 g) with stirring at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is washed twice with water (30 ml) and dried over anhydrous magnesium sulfate-charcoal. After drying, the solvent is distilled off. The residue is dissolved in ethyl acetate (20 ml) and thereto is added n-hexane (50 ml) to give needles of 1-(β-styrenesulfonyloxy)-1,2,3-benzotriazole (9.0 g). A part of the product is recrystallized from ethyl acetate-n-hexane to give a pure product, melting point: 102°-103° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:9]Br>CN(C=O)C>[Br:9][C:6]1[CH:7]=[C:2]([F:1])[C:3]([OH:8])=[N:4][CH:5]=1
Reactant: Oc1ncccc1F
Reactant: BrBr
Solvent: CN(C)C=O
Product: Oc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 3-fluoro-2-hydroxypyridine (1 g, 8.8 mmol) in dry DMF (11 mL) was cooled in an ice bath. Bromine (1.55 g, 9.7 mmol) was added drop-wise over a period of 10 min and the reaction mixture stirred at 0° C. for 1 h then allowed to warm to room temperature and stirred for an additional 2 h. The reaction was quenched with water. The aqueous was extracted with DCM (×4) and the combined organics dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (gradient: 20-100% EtOAc in pet. ether 40-60) yielded 5-Bromo-3-fluoro-2-hydroxypyridine as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:6]=1[F:27])C.Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[F:27][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:5]=1[C:4]([OH:3])=[O:28]
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1F
Agent: Cl
Product: O=C(O)c1cc(CN2CCC(c3cn(Cc4cccnc4)c4ccccc34)CC2)ccc1F

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.063 g (0.17 mmol) of 2-fluoro-5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid ethyl ester and 0.035 mg (0.21 mmol) of 3-chloromethyl-pyridine hydrochloride. After the described purification, 0.053 g (71% of yield) of the expected acid was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:15][C:14]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])=[CH:11][N:10]([CH3:33])[C:5]2=[C:6]([O:8]C)[N:7]=1.[ClH:34].O1CCOCC1>>[Cl:34][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:10]([CH3:33])[CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:15][C:14]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[C:4]=2[CH:3]=1
Reactant: COc1nc(Br)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(CS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(Cl)[nH]c(=O)c21
Temperature: 70 °C
Yield: 74 %

Procedure:
The product from Example 91E (0.064 g, 0.119 mmol) and 4 M hydrogen chloride in dioxane (2 mL, 8.00 mmol) were combined and heated at 70° C. for 2 hours, cooled and concentrated. Purification by trituration (1:1 dichloromethane/heptane) afforded the title compound (0.042 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H) 7.60 (s, 1H) 7.57 (d, J=2.03 Hz, 1H) 7.43-7.52 (m, 1H) 7.19-7.30 (m, 2H) 7.05-7.15 (m, 1H) 6.82 (d, J=8.14 Hz, 1H) 6.68 (s, 1H) 4.53 (s, 2H) 4.07 (s, 3H) 2.94 (s, 3H). MS (ESI+) m/z 479 (M+H)+.