Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:28])[CH:13]=[CH:14][C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)[CH3:10]>CS(C)=O>[CH2:9]([O:11][C:12]([C@@H:13]1[CH2:2][C@H:14]1[C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)=[O:28])[CH3:10]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=Cc1ccc(-c2ccc(F)cc2)nc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 ml of dry dimethyl sulfoxide were added slowly to a mixture of 9.30 g (42.3 mmol) of trimethylsulfoxonium iodide and 976 mg (40.1 mmol) of sodium hydride. The mixture was stirred at room temperature for 15 min, and then 8.5 g (31.3 mmol) of 3-[6-(4-fluoro-phenyl)-pyridin-3-yl]-acrylic acid ethyl ester were added. The reaction mixture was stirred at room temperature for 18 h and then poured onto ice/water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The obtained raw product was purified by column chromatography (silica gel, dichloromethane). Yield: 6.75 g.
Reaction SMILES: ClC1C=CC2N=C([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)OC=2C=1.Cl.Cl[C:19]1[N:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[CH:24][CH:25]=2)[N:20]=1.C(OC(N1CCC(N)C1)=O)(C)(C)C>>[Cl:29][C:23]1[CH:22]=[C:21]2[C:26]([CH:27]=[N:28][C:19]([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)=[N:20]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc2cnc(Cl)nc2c1
Reactant: Clc1ccc2nc(NC3CCNC3)oc2c1
Agent: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: Cl
Product: Clc1ccc2cnc(NC3CCNC3)nc2c1

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride (example 1, step 1) the title compound was prepared from 2,7-dichloro-quinazoline (Synthesis 1978, 5, 379-82) and 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available) and subsequent cleavage of the tert-butyl oxy carbonyl protecting group under acidic conditions. (MH+) 249.1.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:13]1(C)C=CC=C[C:14]=1[ClH](C1C=CC=CC=1C)(C1C=CC=CC=1C)C(Cl)=O.C(N(CC)CC)C>C(#N)C.[Pd]>[CH:13]([C:2]1[N:3]=[N+:4]([O-:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)=[CH2:14]
Reactant: [O-][n+]1nc(Cl)nc2ccccc21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1nc2ccccc2[n+]([O-])n1

Procedure:
3-chloro-1,2,4-benzotriazine 1-oxide was treated with a slight excess of tri-N-butylvinyltin in a mixture of acetonitrile, tritoluyl phosgene and triethylamine, using palladium II catalysis (Pd II acetate) in a sealed tube at 100° C. for 48 hours. Removal of solvent and purification by column chromatography gave 3-vinyl-1,2,4-benzotriazine 1-oxide (33). Reduction with 9-borabicyclo [3.3.1]nonane (9-BBN) followed by oxidation with sodium hydroxide and hydrogen peroxide gave the title compound 3-(1-hydroxyethyl)-1,2,4-benzotriazine 1-oxide (34).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1.[H][H]>[Ni].C1COCC1.CO>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1

Procedure:
2-(4-(6-Bromo-3-nitroquinolin-4-ylamino)phenyl)-2-methylpropane nitrile (Compound of Preparation C, 16 g, 42 mmol) was hydrogenated using Raney-Ni (7 g), THF-MeOH [(1:1), 250 mL] under 25 psi of hydrogen for 1 hour at RT. After completion of the reaction, the catalyst was filtered-off and the filtrate was evaporated to dryness to obtain the title compound. Yield: 13 g (88%); 1H NMR (DMSO-d6, 300 MHz): δ 8.609 (s, 1H), 7.908 (s, 1H), 7.829-7.836 (d, 1H, J=2.1 Hz), 7.744-7.773 (d, 1H, J=8.7 Hz), 7.425-7.462 (dd, 1H, J=9 Hz, 2.1 Hz), 7.236-7.265 (d, 2H, J=8.7 Hz), 6.511-6.540 (d, 2H, J=8.7 Hz), 5.448 (s, 2H), 1.600 (s, 6H); MS: m/z 381 (M+).
Reaction SMILES: C([O:8][C:9](=[O:40])[C@@H:10]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:36]([O:35][C:33]([NH:32][C@@H:10]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([OH:40])=[O:8])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reaction time: 16 h

Procedure:
To a solution of 1.9 g (S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoic acid benzyl ester in 40 ml ethyl acetate were added 200 mg Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 16 h.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([N:12]1[CH:16]=[C:15]([CH:17]=O)[N:14]=[C:13]1[CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N+]=[N-].[Cl-].[NH4+]>C(O)C>[CH2:5]([N:12]1[C:16]2[NH:20][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][C:15]=2[N:14]=[C:13]1[CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1nc(C=O)cn1Cc1ccccc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2nc(C)n(Cc3ccccc3)c2[nH]1
Reaction time: 1 h
Yield: 6.5 %

Procedure:
To a solution (50 mL) of sodium ethoxide (5.4 g) in ethanol was added dropwise a mixture of 1-benzyl-2-methyl-1H-imidazole-4-carbaldehyde (3.8 g) and ethyl azidoacetate (10.3 g) under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated. The obtained residue was extracted with ethyl acetate. The ethyl acetate layer was is washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in toluene (50 mL), and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography to give ethyl 3-benzyl-2-methyl-3,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (0.35 g, yield 6.5%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 193° C.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25](Br)[CH:26]=O)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]2=[O:37])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([NH2:46])(=[S:45])[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>O1CCCC1.CN(C)C(=O)C.C(OCC)(=O)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:45][C:38]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[N:46][CH:26]=1)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[C:19]2=[O:37])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Reactant: NC(=S)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CSC12
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (mixture of the diastereoisomers) (94 g) in tetrahydrofuran (250 cc) is added in the course of 1 hour 40 minutes to a solution, at 40° C., of thioisonicotinamide (44 g) in N,N-dimethylacetamide (330 cc). The reaction mixture is stirred for 90 minutes at 40°-45° C. and then cooled to -15° C. and treated with methanesulphonyl chloride (18.5 cc) and then triethylamine (53 cc). The mixture is stirred for 1 hour at about -10° C. and then for 16 hours at 25° C. and then diluted with ethyl acetate (1.5 liters) and distilled water (1 liter). The organic phase is washed successively with 0.2 N hydrochloric acid (1.2 liters) and water (2×1 liter), then with a mixture of water (500 cc) and a saturated solution of sodium bicarbonate (150 cc) and finally with water (2×1 liter) and a saturated solution of sodium chloride (200 cc). The residue obtained after evaporation of the solvent to dryness under reduced pressure (30 mm Hg, 4 kPa) at 40° C. is chromatographed on a column (height =56 cm, diameter =80 cm) containing silica gel (0.2-0.06 mm), elution being carried out with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and 800 cc fractions being collected. Fractions 8 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (24 g) in the form of a hard brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:10])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1cc(Cl)ccc1NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=NNc1ccc(Cl)cc1C
Temperature: 35 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of 0.55 g (2.85 mmol) of (4-chloro-2-methyl-phenyl)-hydrazine, in acetic acid (5 ml), was added 0.34 g (2.91 mmol) of ethyl pyruvate. The mixture was stirred 2 hours at 35° C., poured onto an aqueous solution of sat. NaHCO3 and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo, to afford 0.702 g (97%) of 2-[(4-chloro-2-methyl-phenyl)-hydrazono]-propionic acid ethyl ester as a light orange solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][NH2:41])[CH2:35][CH2:34]1)[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl.CC#N>[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][NH:41][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:19][CH:18]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:35][CH2:34]1)[CH3:32]
Reactant: Clc1ncnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Reactant: CCN1CCN(CCN)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1CCN(CCNc2ncnc3oc(-c4ccc(OCCN5CCCC5)cc4)c(-c4ccccc4)c23)CC1

Procedure:
A solution of 27 (60 mg, 0.143 mmol), 2-(4-ethylpiperazin-1-yl)ethanamine (57 mg, 0.362 mmol), and DIEA (0.062 mL, 0.357 mmol) in CH2Cl2 (1 mL) and CH3CN (1 mL) was heated at 70° C. over night, then concentrated. Preparative TLC (SiO2, 20% MeOH in CH2Cl2) afforded the title compound 28. MS for C32H40N6O2: found 541 (M+H+), 539 (M−H+).
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.O.[OH-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(OCC)(=O)C>[CH3:14][S:15]([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:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)On1nnc2ccccc21

Procedure:
1-Hydroxy-1,2,3-benzotriazole (25.7 g) is suspended into water (50 ml) and thereto is added 1 N aqueous sodium hydroxide (180 ml). To the resulting solution is added dropwise methanesulfonyl chloride (14.0 ml) with stirring under ice-cooling and thereto is further added ethyl acetate (30 ml), and the mixture is stirred for 4 hours. The reaction mixture is extracted with ethyl acetate, and the extract is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and to the resulting residue is added petroleum ether, and the residue is cracked, filtered and dried to give 1-methanesulfonyloxy-1,2,3-benzotriazole (39.1 g), melting point: 88°-91° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:17][CH2:16][CH:15]=[CH:14]2)[CH2:4][CH:3]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>O1CCCC1.[Pt]=O>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:4][CH:3]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)NC1CN(C2C=CCC2)c2ccccc2NC1=O
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CN(C2CCCC2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
Platinum oxide (100 mg) was added to a solution of 2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclopenten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.8 g) in anhydrous tetrahydrofuran (20 ml), the mixture was stirred at room temperature under ambient pressure under hydrogen atmosphere for 2 hours. The reaction mixture was filtrated through a pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:2). Diisopropyl ether was added to the residue for crystallization, to thereby obtain 1.2 g of the title compound.
Reaction SMILES: C(O[C:4]1([O:9][CH2:10]C)[CH2:8][CH2:7][CH2:6][O:5]1)C.C(O)[CH2:13][CH2:14][CH2:15][OH:16]>>[O:5]1[C:4]2([CH2:13][CH2:14][CH2:15][O:16][CH2:10][O:9]2)[CH2:8][CH2:7][CH2:6]1
Reactant: OCCCCO
Reactant: CCOC1(OCC)CCCO1
Product: C1COCOC2(C1)CCCO2

Procedure:
50 grams of 2,2-diethoxytetrahydrofuran and 28.1 grams of 1,4-butane diol previously mixed with 0.05 grams of polyphosphoric acid, were reacted for 3.25 hours over an increasing temperature span of 70° to 130° C., and under atmospheric pressure according to Example 45. Then the reactants were heated under reduced pressure of 120 mm to 2.4 mm Hg for 4 hours at 110° to 125° C. to yield 1,6,8-trioxa-spiro(4,6)undecane. The spiro compound was polymerized in a sealed tube at 125° C. in the presence of a Lewis acid catalyst, i.e. SbF5, PF5 or BF3, to yield the polymer, where n is 10 to 1000. ##STR50##
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:42](Cl)(=O)[C:43](C)([CH3:45])[CH3:44]>ClCCl>[F:34][C:25]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:28]=[CH:29][C:24]=1[NH:23][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:43]([CH3:45])([CH3:44])[CH3:42])[CH2:9][CH2:10]3)[N:15]=[CH:16][C:17]=12
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1

Procedure:
1-{4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-2,2-dimethyl-propan-1-one was prepared according to General Procedure J by the reaction of 4-[4-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 1) with trifluoroacetic acid in dichloromethane followed by reaction with pivaloyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.23 (s, 9H), 1.98-2.03 (m, 4H), 3.06-3.12 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.40-4.46 (m, 2H), 4.99-5.03 (m, 1H), 7.79-7.81 (m, 1H), 7.88-7.92 (m, 1H), 8.21-8.25 (m, 1H), 8.30-8.43 (m, 2H), 10.38 (s, 1H). Mass spectrum MH+=475.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=O.Cl.[NH2:18][C:19]([NH2:21])=[NH:20].[OH-].[Na+]>C(O)C>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[CH:4]=[CH:3][N:18]=[C:19]([NH2:21])[N:20]=1)([O-:15])=[O:14]
Reactant: CN(C)C=CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nccc(-c2ccccc2[N+](=O)[O-])n1
Yield: 40.8 %

Procedure:
3-(dimethylamino)2′-nitroacrylophenone (1.0 g, 4.54 mmol) in absolute ethanol (25 mL) was treated with guanidine hydrochloride (540 mg, 5.68 mmol), and 10N sodium hydroxide (200 μL). The reaction was heated to reflux for 18 hours. Upon cooling a white precipitate was collected by filtration and rinsed with diethyl ether to give 4-(2-nitrophenyl)-2-pyrimidineamine (400 mg). Additional material was obtained by concentration and chromatography on silica, eluting with 1;1 hexane:ethyl acetate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[H-].[Na+].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>CN(C=O)C>[Cl:12][C:13]1[N:18]=[C:17]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: c1ccc2[nH]nnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncc(Cl)c(-n2nnc3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.4 %

Procedure:
A solution of benzotriazole (2.14 g, 18.03 mmol) in DMF (10 mL) was slowly added at 0° C. to a solution of NaH (60% in mineral oil, 0.850 g, 21.3 mmol) in DMF (20 mL) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 minutes; a solution of 2,4,5-trichloropyrimidine (3 g, 16.39 mmol) in DMF (20 mL) was then slowly added at 0° C. The reaction mixture was allowed to reach RT while stirring overnight. The solvent was evaporated under reduced pressure; the residue was taken up with EtOAc and washed 3× with water. The aqueous layers were combined and extracted 3 times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to give a crude oil. This material was purified via flash chromatography (heptane/EtOAc, 8/2) to give 1.5 g (34% yield) of 1-(2,5-dichloro-pyrimidin-4-yl)-1H-benzotriazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[C:34]3[N:35]=[CH:36][S:37][C:33]=3[CH:32]=[CH:31][CH:30]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.CCOC(C)=O.O>[S:37]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:2]3[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])[C:5]4[N:17]([CH3:20])[CH:18]=[N:19][C:4]=4[CH:3]=3)[C:34]=2[N:35]=[CH:36]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: CC1(C)OB(c2cccc3scnc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: C[C@@H](Oc1nc(-c2cccc3scnc23)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
Intermediate 2.06 (30.3 mg, 0.103 mmol), Pd-PEPPSI-IPr precatalyst (7.1 mg, 0.010 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (34 mg, 0.13 mmol), and Cs2CO3 (102 mg, 0.313 mmol) were taken up in DME (1.15 mL) under Ar. Water (0.57 mL) was added and the resulting mixture was heated to 100° C. After 2.5 h, additional Pd-PEPPSI-IPr precatalyst (7.4 mg, 0.011 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (34 mg, 0.13 mmol), and Cs2CO3 (100 mg, 0.31 mmol) were added, and the mixture was stirred for an additional 16 h. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL) and the phases were separated. The aqueous phase was extracted with EtOAc and the combine organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography to provide (R)-4-((R)-1-(6-(benzo[d]thiazol-4-yl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.22. LCMS-ESI+ (m/z): [M+H]+ calcd for C20H20N5O2S: 394.1; found 394.2. 1H NMR (400 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.68 (s, 1H), 8.20 (dd, J=7.6, 1.2 Hz, 1H), 7.96 (dd, J=8.0, 1.2 Hz, 1H), 7.88 (s, 1H), 7.59-7.49 (m, 1H), 5.84-5.73 (m, 2H), 4.04 (s, 3H), 3.63-3.53 (m, 1H), 3.41 (dd, J=9.7, 6.1 Hz, 1H), 3.02-2.86 (m, 1H), 2.58-2.52 (m, 2H), 1.51 (d, J=6.2 Hz, 3H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
The product of Example 129A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.77-11.79 (bs, 1H), 8.40-8.43 (m, 1H), 7.90-8.03 (m, 2H), 7.69-7.74 (m, 1H), 7.63-7.69 (m, 2H), 7.38-7.43 (m, 2H), 7.06-7.21 (m, 3H), 3.77-3.78 (bs, 2H); MS (APCI+) M/Z 410 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:43])[CH:11]([NH:15][C:16](=[O:42])[CH:17]([CH2:27][S:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH:39]([F:41])[F:40])(=[O:30])=[O:29])[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][O:13][CH3:14].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[O:43])[CH:11]([NH:15][C:16](=[O:42])[CH:17]([CH2:27][S:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH:39]([F:41])[F:40])(=[O:30])=[O:29])[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][O:13][CH3:14]
Reactant: COCC(NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1OC(F)F)C(O)c1nc2ccccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: COCC(NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1OC(F)F)C(=O)c1nc2ccccc2o1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
This amide (150 mg, 0.24 mmol) was treated with Dess-Martin periodinane (178 mg, 0.36 mmol) at room temperature. After stirring for 1 hour, 5 ml of saturated Na2S2O3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 39 mg of N-(2-Benzooxazol-2-yl-1-methoxymethyl-2-oxo-ethyl)-2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; H1 NMR(DMSO-d): 8.97, 8.8(1H, dd, J=5.6 Hz, J=5.6 Hz, NH, diastereomeric), 8.02–7.94(1H, m), 7.9–7.84(1H, m), 7.66–7.58(1H, m), 7.55–7.38(3H, m), 7.3–7.18(2H, m), 7.1(1H, t, J=73.6 Hz), 5.54–5.42(1H, m), 4.6–4.4(4H, m), 3.92–3.84(1H, m), 3.82–3.72(1H, m), 3.68–3.1(11H, m), 2.7–2.56(1H, m), 1.7–1.55(1H, m), 1.3–1(1H, m); MS: 622.4(M−1), 624.3(M+1), 646.3(M+Na).