Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccccc1B(O)O
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Product: COc1ccccc1-c1nc(C(F)(F)F)ccc1C#N
Yield: 91 %

Procedure:
Prepared in 91% yield from 2-chloro-6-trifluoromethylnicotinonitrile and 2-methoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 279.0 (M+H)+; 1H NMR (CDCl3) δ 3.83 (s, 3H), 7.15 (dd, J=7.5, 7.5 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.43 (dd, J=7.4, 1.7 Hz, 1H), 7.55-7.63 (m, 2H), 8.12 (d, J=8.1 Hz, 1H), 8.71 (d, J=7.5 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[C:17]([O:23][CH2:24][CH2:25][OH:26])[C:16]=2[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[NH:38][N:37]=[N:36][N:22]=3)[CH:18]=[C:17]([O:23][CH2:24][CH2:25][OH:26])[C:16]=2[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C#N)cc2OCCO)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(-c3nnn[nH]3)cc2OCCO)c1

Procedure:
In analogy to Example 140, by reacting 4-tert-butyl-N-[5-cyano-3-(2-hydroxy-ethoxy)-2-(3-methoxy-phenoxy)-phenyl]-benzenesulphonamide and sodium azide in N,N-dimethylformamide there was obtained 4-tert-butyl-N-[3-(2-hydroxy-ethoxy)-2-(3-methoxy-phenoxy)-5-(1H-tetrazol-5-yl)-phenyl]-benzenesulphonamide as a white foam.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.Cl[C:18]1[N:19]([CH3:31])[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:23]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:31][N:19]1[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:23]=[C:18]1[O:3][CH:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(OC2CCCNC2)nc(-c2ccncn2)cc1=O
Reaction time: 1 h

Procedure:
To a mixture of sodium hydride (60 wt % in mineral oil, 0.24 g, 6.0 mmol) in N,N-dimethylformamide (15 ml) at room temperature under nitrogen atmosphere was added a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (1.0 g, 5.0 mmol) in N,N-dimethylformamide (5 ml) dropwise. After the mixture was stirred for one hour, 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (1.1 g, 5.0 mmol) was added to the mixture. The resulting mixture was stirred overnight and poured into water. Extractive workup was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. To the residue was added 4N hydrogen chloride in ethyl acetate (10 ml) and the resulting slurry was stirred at room temperature for 2 hours. After concentration under reduced pressure, the residue was dissolved in water. The aqueous solution was washed with ethyl acetate and basified with potassium carbonate. Extraction with chloroform was performed three times and the organic layer was dried over anhydrous sodium sulfate. After concentration, analytically pure 1-methyl-2-(piperidine-3-yloxy)-1H-[4,4′]bipyrimidinyl-6-one was isolated as a white solid (0.66 g, 2.3 mmol, 46%). This compound was used for the next reaction without further purification.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)[N:9]=[CH:8][N:7]=C2OC1C=C(C=CC=1)N.C1(N=C=[O:31])C=CC=CC=1>C1COCC1>[C:10]1([NH:9][C:8](=[O:31])[NH2:7])[CH:5]=[CH:4][CH:3]=[CH:12][CH:11]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) in THF (3 mL) was added phenyl isocyanate (33 uL, 0.3 mmol) and the solution stirred at room temperature overnight. The reaction was concentrated in vacuo, diluted with EtOAc, and filtered to give 14346,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-phenylurea (63 mg, 0.15 mmol, 50%). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 7.61-7.56 (m, 2H), 7.48-7.35 (m, 4H), 7.32-7.21 (m, 3H), 7.02-7.89 (m, 2H), 3.99 (s, 6H); LC-MS (ESI) m/z 417 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[N:26]1[N:27]=[CH:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]=12.C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[N:26]1[N:27]=[CH:28][N:29]2[CH2:34][CH2:33][N:32]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH2:31][C:30]=12
Reactant: c1nnc2n1CCNC2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCn4cnnc4C3)n2n1
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (80 mg, 0.50 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (20-45% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (71.4 mg, 66%). ESI-MS: m/z 433.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33]Cl)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][N:39]5[CH2:40][CH2:41][C:37]([F:42])([F:36])[CH2:38]5)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC1(F)CCNC1
Reactant: Nc1ncnn2c(C3CCN(C(=O)CCl)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: Nc1ncnn2c(C3CCN(C(=O)CN4CCC(F)(F)C4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 87.2 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-[1-(chloroacetyl)pyrrolidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.206 mmol) was reacted with 3,3-difluoropyrrolidine (44 mg, 0.412 mmol) using the procedure of Example 132 to yield 100 mg (87%) of title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.91 (s, 1 H), 7.80 (d 1 H), 7.67 (m, 3 H), 7.38 (m, 4 H), 7.11 (d, 1 H), 6.63 (d, 1H), 5.63 (s, 2 H), 3.95-3.10 (m, 11 H), 3.05-2.60 (m, 4 H), 2.50-2.05 (m, 2 H); ES-MS m/z 557.3 [M+H]+, HPLC RT (min) 2.56.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH2:9][CH3:10])[CH:8]=1)#[N:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Al]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:21]([O:20][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][CH3:10])=[C:6]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(C#N)c(=O)[nH]c1COCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: c1ccccc1
Product: CCc1cc(C#N)c(OCc2ccccc2)nc1COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a partial suspension of 3-cyano-5-ethyl-6-benzyloxymethyl-2(1H)-pyridinone (1.36 g, 5.08 mmol) in dry benzene (20 mL) was added benzyl bromide (0.80 mL, 6.7 mmol) and then silver carbonate (1.43 g, 5.2 mmol). This mixture was covered with aluminum foil and allowed to stir at room temperature. After 24 hours, the reaction was estimated to be ~80% complete. Additional silver carbonate (0.40 g, 1.45 mmol) was added and the mixture was stirred for another 24 hours until complete. The silver salts were removed by filtration, rinsed with benzene and the combined benzene washings were evaporated to give the pure product as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].P(C)(C)C>C1COCC1.O.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@@:10]2([NH2:22])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OCc3ccccc3)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OCc3ccccc3)[C@@](N)(C(=O)OCc3ccccc3)[C@@H]21
Reaction time: 4 h
Yield: 51.3 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-benzyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-3) (120 mg, 0.276 mmol) in THF (4 mL) and H2O (0.4 mL) was added Me3P (0.30 mL, 0.30 mmol, 1 M sol. in THF) and stirring was continued at 23° C. for 4 h. The reaction mixture was diluted with ether, washed with sat. NaHCO3 -sol., brine and dried over Na2SO4. The crude product was purified by silica gel column chromatography with hexane/EtOAc 1:1 (+small amount of Et3N) to give (1S,2R,3R,5R,6S)-2-amino-3-benzyloxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIV-3) (58 mg, 51%) as a yellow oil. 1H-NMR (250 MHz, CDCI3) □1.23 (3H, t, J=7.1 Hz), 1.72 (1H, t, J=3.5 Hz), 1.93 (2H, bs), 2.00 (1H, m), 2.10 (1H, dd, J=7, 3.5 Hz), 2.19 (1H, m), 2.27 (1H, dd,J=12,7 Hz), 3.46 (1H, dd,J=8, 7 Hz), 4.10 (2H, q,J=7.1 Hz), 4.47 (2H, s),5.20 (1H,d,J=12 Hz), 5.30 (1H, d,J=12 Hz), 7.18-7.42 (10H,m);MS[ISP] 410 [(M+H)+ ]; □D20 +3.54° (c=0.90, CHCl3).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].CC(C)([O-])C.[Na+]>C(O)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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2]>[CH3:15][O:14][C:6]1[CH:5]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[O:12][CH3:13]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Ru+2]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: CCO
Product: COc1cc(C(C)O)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (3.8 mg, 4 μmol, 1 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in ethanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 80° C. After the mixture was cooled to room temperature, 3,4,5-trimethoxyacetophenone (0.4 mmol), ethanol (2 mL) and a solution of sodium t-butoxide in ethanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 48 h under H2 (10 atm) at 0° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(3,4,5-trimethoxyphenyl)ethanol was obtained and the ee value (ee=97%) was measured by GC analysis.
Reaction SMILES: Cl.C[O:3][C:4]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1.[BrH:22]>C(O)(=O)C>[BrH:22].[OH:3][C:4]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:7]2[N:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: COc1cc2ncn(-c3ccccc3)c2cc1C(=O)O
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cc2c(cc1O)ncn2-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 5-methoxy-1-phenylbenzimidazole-6-carboxylic acid hydrochloride (0.60 g, 2.24 mmol) in a 33% solution of HBr in glacial acetic acid (50 mL) was refluxed for 30 hours. After cooling to room temperature, the resulting precipitate of the hydrobromide salt of Example 52 was filtered off (0.51 g, 68%): mp 288-290° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5](/[CH:6]=[CH:7]/[C@H:8]2[CH2:12][O:11]C(C)(C)[N:9]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(#N)C.O.C(OCC)(=O)C.C1COCC1>[NH2:9][C@@H:8](/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:23][CH:22]=1)[CH2:12][OH:11]
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2ccc(Br)cc2)COC1(C)C
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@@H](/C=C/c1ccc(Br)cc1)CO
Temperature: 80 °C
Yield: 67.9 %

Procedure:
To a solution of (S,E)-tert-butyl 4-(4-bromostyryl)-2,2-dimethyloxazolidine-3-carboxylate (13 g) in acetonitrile (30 ml) were added sequentially water (35 ml) and a solution of trifluoroacetic acid (18.3 ml) in water (50 ml). The mixture was heated at 80° C. for 3 hours. The mixture was then cooled to room temperature and diluted with ethyl acetate/THF (1:1). The resulting mixture was washed sequentially with 1 N aq. sodium hydroxide solution and saturated brine, the phases were then separated and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was triturated in diethyl ether (40 ml) and the resulting crystals were collected by filtration to afford (E)-(S)-2-amino-4-(4-bromo-phenyl)-but-3-en-1-ol (5.59 g, 68%) as a brown solid. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: 0-30% MeOH in dichloromethane) to afford a further amount of (E)-(S)-2-amino-4-(4-bromo-phenyl)-but-3-en-1-ol (2.21 g, 27%) as a brown solid. MS (ISP): 227.1 ([{81Br}M+H—NH3]+), 225.1 ([{79Br}M+H—NH3]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([NH2:18])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)C1C=CC=CC=1.NOS(O)(=O)=O.Cl.ClC1C=CN=CC=1>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([NH:18][C:35]1[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: Nn1ccc2cc(OCc3ccccc3)ccc21
Agent: Cl
Agent: Clc1ccncc1
Agent: NOS(=O)(=O)O
Solvent: CN1CCCC1=O
Product: c1ccc(COc2ccc3c(ccn3Nc3ccncc3)c2)cc1

Procedure:
The title compound was prepared from 5-benzyloxy-1H-indol-1-amine (which had been prepared from 5-benzyloxy-1H-indole and hydroxylamine-O-sulfonic acid in substantially the same manner as in Example 25) and 4-chloropyridine hydrochloride in N-methyl-2-pyrrolidinone at 70° C. for 1.5 hours in substantially the same manner as in Example 1, m.p. 143°-145° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+:19]>CO>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[O-:16])([CH3:4])([CH3:3])[CH3:2].[Na+:19]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(C)(C)C)c([O-])c(C(C)(C)C)c1
Temperature: 50 °C

Procedure:
Procedure A- 2,6-Di-t-butyl-4-methylphenol (13.2 grams, 0.06 mole) was dissolved in 75 milliliters of absolute methanol. Nitrogen gas was passed through the solution while sodium methoxide (3.24 grams, 0.06 mole) was added at ambient temperature. The reaction mixture was warmed to about 50° C an maintained there for about 15 minutes. Thereafter the methanol was evaporated to dryness to yield the desired sodium 2,6-di-t-butyl-4-methyl-phenoxide.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7](/[CH:9]=[CH:10]/[N+:11]([O-])=O)=[CH:8][C:4]=2[CH:3]=1.[Li+].[BH4-].C[Si](Cl)(C)C>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([CH2:9][CH2:10][NH2:11])=[CH:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])/C=C/c1cc2cc(F)ccc2s1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1cc2cc(F)ccc2s1
Yield: 95.3 %

Procedure:
Using analogous conditions and workup as described for the preparation of I-14b above, (E)-5-fluoro-2-(2-nitrovinyl)benzo[b]thiophene (I-50d: 1.2 g, 5.375 mmol) was reacted with LiBH4 (468.34 mg, 21.503 mmol), trimethylsilyl chloride (4.649 g, 43 mmol) and THF (50 mL) to afford 1 g of the product (100% yield). LCMS: 98.10%, m/z=196.0 (M+1)
Reaction SMILES: C([O:3][CH:4]1[C:9]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[O:7]CO1)C.Cl>C(O)C.C1COCC1.O1CCOCC1.O>[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=1[CH:4]=[O:3]
Reactant: CCOC1OCOc2cccc([N+](=O)[O-])c21
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(O)cccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 4-ethoxy-5-nitro-4H-1,3-benzodioxine (5.80 g, 25.755 mmol) in ethanol (15 mL) and THF (10 mL) was added 4N HCl in 1,4-dioxane (20 mL). The mixture was stirred at 60° C. for 6 hrs and 90° C. for 6 hrs. After cooled to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1) to give 2-hydroxy-6-nitrobenzaldehyde as a pale yellow oil (4.450 g, yield; quant.).
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[N:23]([CH:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N+:24]=[N-:25]
Reactant: COC(=O)CCCc1ccc(C(Cl)Cc2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCc1ccc(C(Cc2ccccc2)N=[N+]=[N-])cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 92 %

Procedure:
A suspension of 3.30 g of methyl 4-[4-(1-chloro-2-phenylethyl]phenyl]butyrate and 1.35 g of sodium azide in 15 ml of N,N-dimethylformamide was stirred at 100° C. for 3.5 hours. The reaction mixture was added with water and then extracted with ether. The ether layer was washed with water and dried, and then the solvent was removed under reduced pressure to yield 3.10 g of pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[NH:17][C:16]3[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:14]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=3)[C:15]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]=3[N:17]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(S(C)(=O)=O)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2c(S(C)(=O)=O)cccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-6-(((1S)-1-(7-(methylsulfonyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile (36 mg, 0.10 mmol), potassium carbonate (21 mg, 0.15 mmol) and 4-fluorobenzyl bromide (15 μL, 0.12 mmol) in DMF (3 mL) was stirred at rt in a sealed flask for 18 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by flash chromatography over silica gel, using 2.5% MeOH in DCM as eluent gave 4-amino-6-(((1S)-1-(1-(4-fluorobenzyl)-4-(methylsulfonyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile: 1H NMR (400 MHz, CDCl3) δ 8.08 (1H, s), 7.88 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=8.0 Hz), 7.31 (1H, t, J=8.0 Hz), 6.93 (4H, t, J=8.0 Hz), 6.19 (1H, t, J=8.0 Hz), 5.80-5.71 (1H, m), 5.52 (1H, d, J=16.0 Hz), 5.50 (1H, d, J=16.0 Hz), 5.31 (2H, br), 3.47 (3H, s), 1.62 (3H, d, J=8.0 Hz); LC-MS (ESI) m/z 466.0 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)C1C=CC=CC=1.C(OP([CH:27]([O:33][CH:34]([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])(OCC)=O)C>>[OH:8][C:9]1[CH:10]=[C:11]([CH2:12][CH:27]([O:33][CH:34]([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: CCOC(=O)C(OC(C)C)P(=O)(OCC)OCC
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OC)c(O)c1)OC(C)C

Procedure:
Using 3-benzyloxy-4-methoxybenzaldehyde and ethyl 2-(diethoxyphosphoryl)-2-isopropoxyacetate, the title compound was obtained in the same manner as described in Example 46b).
Reaction SMILES: CC(NC(C)C)C.C([Li])CCC.CCCCCC.[F:19][C:20]([F:34])([F:33])[C:21]([NH:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([O:31][CH3:32])=[O:30])=[O:22].[Br:35]CCBr>C1COCC1>[Br:35][C:27]1[S:26][C:25]([C:29]([O:31][CH3:32])=[O:30])=[C:24]([NH:23][C:21](=[O:22])[C:20]([F:19])([F:33])[F:34])[CH:28]=1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: BrCCBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a stirred mixture of N-(1-methylethyl)propan-2-amine (40.0 mL, 285 mmol) and THF (400 mL) at −78° C. was added slowly 1.6 M n-butyllithium in hexane (165 mL, 264 mmol). The mixture was allowed to 0° C. over 2 h. Then, the mixture was cooled to −78° C. again. Then, a solution of methyl 3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (20.3 g, 80 mmol) in THF (80 mL) was added to the mixture slowly. After 1 h, 1,2-dibromoethane (41.2 mL, 476 mmol) was added at once. The stirring was continued at −78° C. for 1 h, and the dry ice-acetone bath was removed. After further stirring for 30 min, the mixture was poured into saturated aqueous NaHCO3 (1 L) and EtOAc (1 L). After shaking well, the organic layer was collected, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give an orange oil. This residue was purified by column chromatography (Purif, silica gel, hexane to 90:10 hexane/EtOAc) to afford the title compound (10.4 g, 39%) as a beige solid:
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:10]=3[OH:28])[N:8]=[C:4]2[CH:3]=1.N1C2C=CC=CC=2N=N1.ClC1C=CC2=NN(C3C=C(C)C=CC=3O)N=C2C=1>>[OH:28][C:10]1[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[N:7]1[N:8]=[C:4]2[CH:3]=[CH:2][CH:30]=[CH:29][C:5]2=[N:6]1
Reactant: CCCCCCCCCCCCc1cc(C)cc(-n2nc3ccc(Cl)cc3n2)c1O
Agent: Cc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: c1ccc2[nH]nnc2c1
Product: CCCCCCCCCCCCc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
In like manner, 5-chloro-2-(2-hydroxy-3-dodecyl-5-methylphenyl)-2H-benzotriazole is prepared by substituting for the benzotriazole used above an equivalent amount of 5-chloro-2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole.