Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@@H:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH2:11][C@H:10]1[CH2:25][OH:26])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C@@H:12]2[CH2:13][NH:9][C@H:10]([CH2:25][OH:26])[CH2:11]2)=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@H]1CO
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Br)ccc1N[C@@H]1CN[C@H](CO)C1
Reaction time: 2 h
Yield: 87 %

Procedure:
Add 4.0 M hydrogen chloride in dioxane (950 mL) slowly to a solution of (2S,4S)-4-(4-bromo-2-nitro-phenylamino)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 mol, 95 g) in dry dichloromethane (475 mL) at room temperature and stir for 2 h. Filter the precipitated solid and dry under vacuum to obtain the title compound (70 g, 87%) as an orange solid. 1H NMR (400 MHz, CD3OD) δ 1.98-2.05 (m, 1H), 2.71-2.79 (m, 1H), 3.36 (dd, 1H), 3.58-3.63 (m, 1H), 3.76 (dd, 1H), 3.88-3.95 (m, 2H), 4.55-4.58 (m, 1H), 7.03 (d, 1H), 7.66 (dd, 1H), 8.30 (d, 1H).
Reaction SMILES: CS([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([OH:21])[C:15]3[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1C1C=CC=C(Cl)C=1)(=O)=O.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[CH3:36][S:37]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([OH:21])[C:15]3[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:22]=[CH:27][CH:26]=[C:25]([Cl:28])[CH:24]=2)=[CH:6]1)(=[O:39])=[O:38]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)cc(-c1cccc(Cl)c1)n2S(C)(=O)=O
Reactant: CS(=O)(=O)Cl
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cn2S(C)(=O)=O

Procedure:
Alternatively, the compound of Example 2, (±)-1-methylsulfonyl-(3-chlorophenyl)-5-[(4-chlorophenyl) hydroxyl (1-methyl-1H-imidazol-5-yl) methyl] indole was also made analogously to the method described for making Example Y, using methanesulfonyl chloride in place of 4-morpholinecarbonyl chloride. Yield: 77%. MS (Calc.): 526.46, MS(ES): 526.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:40][C:41]([CH3:43])=[CH2:42]>C1COCC1>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH:6]=1)[CH2:42][C:41]([CH3:43])=[CH2:40]
Reactant: C=C(C)CBr
Reactant: COC(=O)Cc1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of [2-(4-fluoro-phenyl)-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-acetic acid methyl ester (130 mg, 0.3 mmol) in THF (5 mL) at −78° C. under argon was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 600 μL, 0.3 mmol). After stirring for 30 minutes, 3-bromo-2-methylpropene (40 mg, 0.3 mmol) was added and stirred for 30 additional minutes. The reaction mixture was allowed to warm up slowly and stirred for another 30 minutes at 0° C. The mixture was then concentrated and purified by column chromatography on silica gel (0-8% ethyl acetate in heptane) to give the product as a colorless oil (80 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=8.29 Hz, 2H), 8.08-8.18 (m, 2H), 7.75 (d, J=8.29 Hz, 2H), 7.67 (d, J=1.88 Hz, 2H), 7.19 (t, J=8.85 Hz, 2H), 4.78 (d, J=18.08 Hz, 2H), 3.95 (dd, J=6.78, 9.04 Hz, 1H), 3.72 (s, 3H), 2.94 (dd, J=9.04, 14.69 Hz, 1H), 2.55 (dd, J=6.40, 14.69 Hz, 1H), 1.77 (s, 3H). MS m/e 444.3 (M+H).
Reaction SMILES: [C:1](Cl)(=O)C.[NH:5]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][NH2:8]>CO>[NH2:8][CH2:7][CH:6]([NH:5][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:9]([O:11][CH3:1])=[O:10]
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C(CN)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Acetyl chloride (0.627 ml, 8.81 mmol) was added dropwise to a suspension of commercially available Z-Dap-OH ((S)-3-amino-2-(((benzyloxy)carbonyl)amino)propanoic acid) (1 g, 4.20 mmol) in methanol (20 ml) at 0° C. The mixture was stirred at 0° C. for 4 hours and at room temperature for 16 hours. The solvent was evaporated under vacuum to afford the title compound.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41]>>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 87.9 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 50 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 569 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:43]=[CH:42][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:32])[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[C@H:13]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)[CH2:12]2)=[CH:8][CH:7]=1>O>[C:1]([NH:5][C:6]1[CH:43]=[CH:42][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:32])[C:18]3[CH:19]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=3)[C@H:13]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)[CH2:12]2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(Cl)c(Cl)c3)C2)cc1
Solvent: O
Product: CC(=O)Nc1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(Cl)c(Cl)c3)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Piridine (23 μl) and acetyl chloride (16 μl) were successively added to a solution of (2R)-4-(4-aminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-piperazine (113 mg) and the whole was stirred at room temperature for 1.5 hours. The mixture was poured into water and the separated oil was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporate in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as an eluent to give (2R)-4-(4-acetylaminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine (98.3 mg). The obtained piperazine was dissolved in ethyl acetate. 4N Hydrogen chloride in ethyl acetate solution (43 μl) was added to the solution and the mixture was evaporated in vacuo. The residue was triturated with n-hexane to give (2R)-4-(4-acetylaminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (92 mg).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:4]1=2.CC1(C)C(C)(C)OB([C:28]2[CH:37]=[CH:36][C:31]3[NH:32][C:33](=[O:35])[NH:34][C:30]=3[CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3](=[CH:2][C:28]3[CH:37]=[CH:36][C:31]4[NH:32][C:33](=[O:35])[NH:34][C:30]=4[CH:29]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=3[CH2:7][O:6][C:5]=2[CH:15]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Fc1ccc2c(c1)OCc1c(F)cccc1C2=CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=C3c4ccc(F)cc4OCc4c(F)cccc43)cc2[nH]1
Yield: 74.4 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3,7-difluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 68 mg, 0.21 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (52 mg, 0.20 mmol), Na2CO3 (2M in water, 251 μL, 0.503 mmol), dioxane (2 mL), and Pd(PPh3)4 (12 mg, 0.010 mmol). Purify on silica gel (12 g) eluting with THF to afford a brown solid. Triturate with acetone to afford 56 mg (74%) of the title compound as a white solid. HPLC (ISO80-10) t=2.42 min, 96%; MS [ES] 375 (M−H); 1H-NMR (DMSO-d6) δ 10.58 (s, 1H), 10.46 (s, 1H), 7.57 (dd, 1H, J=8.8, 7.0 Hz), 7.24 (m, 2H), 7.00 (s, 1H), 6.81 (m, 2H), 6.72 (m, 2H), 6.64 (dd, 1H, J=10.6, 2.6 Hz), 6.59 (s, 1H), 5.55-5.19 (br d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([C:15]1[CH:24]=[CH:23][C:18]([CH2:19][NH:20][O:21][CH3:22])=[CH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]([O:21][CH3:22])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)=[CH:17][CH:16]=1)#[N:14]
Reactant: CONCc1ccc(C#N)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(C#N)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 99 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-cyanobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (99% yield): mp 148–149° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.72 (3H, s, OCH3), 4.86 (2H, s, NCH2), 6.39 (1H, s, CH), 7.46 (2H, m, aromatics), 7.63 (2H, m, aromatics). Anal. calcd. for C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C, 60.60; H, 4.91; N, 8.78.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=[C:7]3[C:6]2=[O:18])[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH:1]1([CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=[C:7]3[C:6]2=[O:18])[CH2:2][CH2:3]1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CC1CC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)N(CC1CC1)C2=O
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 48.6 %

Procedure:
N-Cyclopropylmethyl-4-nitrophthalimide (6.0 g, 24 mmol) in methanol (200 mL) was added dropwise over 30 min to a solution of sodium dithionite (27.0 g, 156 mmol) and sodium carbonate (13.0 g, 125 mmol) in water (200 mL) while the temperature was maintained at 70° C. The mixture was stirred at 70° C. for an additional 50 min before it was allowed to cool to room temperature. The reaction volume was then reduced to one-third by rotary evaporation. Water (400 mL) was added, and the suspension extracted with ethyl acetate (2×450 mL). The combined organic solutions were dried with anhydrous MgSO4. Solvent was then removed by rotary evaporation to afford 2.52 g (49%) of pure N-cyclopropylmethyl-4-aminophthalimide as a powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>O1CCOCC1.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>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[N:5]1[CH:6]=[C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[CH:3]=[N:4]1
Reactant: Brc1cnn(C2CCCCO2)c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1cc(-c2cnn(C3CCCCO3)c2)ccn1
Temperature: 80 °C
Yield: 68 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.025 eq, 4.22 mmol), 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1 eq, 0.17 mol, synthesis described in US2009/203705), sodium carbonate (675 mL, 2.0 M solution in water, 1.35 mol) and 4-pyridine boronic acid (1.2 eq, 0.21 mol) in dioxane (2000 mL) was heated under argon 41 h at 80° C. After that time, the reaction mixture was diluted with water (50 mL) and the volatiles were reduced in vacuo to a quarter of the volume. The crude was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over MgSO4 and evaporated. The obtained crude material was purified by bulb-to-bulb distillation (bp 130-135° C. at 0.02 mm Hg) and 26.37 g (68%) 4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]pyridine were obtained as slightly yellow viscuous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[Br:9]Br>[OH-].[Na+]>[Br:9][N:3]1[C:2]([CH3:8])([CH3:1])[CH2:6][O:5][C:4]1=[O:7]
Reactant: CC1(C)COC(=O)N1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)COC(=O)N1Br
Reaction time: 0.25 h

Procedure:
12.3 g (0.11 mol) 4,4-dimethyl-2-oxazolidinone was dissolved in 180 ml of 1 M sodium hydroxide and the resulting solution was cooled to 0°. 19.2 g (0.012 mol) bromine was added dropwise with stirring over 0.25 hr and the reaction mixture was stirred at 0° for an additional 0.75 hr. The N-bromamine separated from the reaction mixture as an orange colored solid. The solid was isolated by filtration and thoroughly washed with cold water. Trituration of this material in petroleum ether (30°-60°) gave 16.2 g (0.084 mol), 76%, 3-bromo-4,4-dimethyl-2-oxazolidinone (NBDMO), mp 118°-120°; uv (H2O) λmax 274 nm, ε= 201 M-1 cm-1 ; ir (KBr): 2985, 1725, 1370, 1290, 1200, 1165, 1040 and 740 cm-1 ; pmr (CDCl3) δ 4.27 (s, 2H) and 1.33 (s, 6H) ppm.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9]([S:28][CH2:29][CH2:30][C:31](Cl)=[O:32])([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)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>[OH-].[Na+]>[C:9]([S:28][CH2:29][CH2:30][C:31]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:32])([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:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1C(=O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 71.8 %

Procedure:
A solution of 1.51 g (0.01 mole) of L-proline in 20 mls of 2N NoOH is chilled in an icebath and treated with a total of 4.03 g (0.011 mol) of S-trityl-3-mercaptopropionyl chloride and 20 ml of 2N NaOH in 5 equal and alternate portions with vigorous intermittent shaking and cooling in an ice bath. The solution is kept at an alkaline pH by the addition of more alkali when necessary. Upon completion of the addition of the reagents, the reaction mixture is stirred for an additional 15 min. at room temperture and then acidified to Congo red with cooling by dropwise treatment with concentrated HCl. The reaction is placed in a refrigerator overnight. The resultant precipitate is recovered by filtration, washed several times with ice water and dried in a dessicator over phosphorus pentoxide. Recrystallization in EtOH/H2O gave 3.2 g (72%) of the desired product. The NMR and IR showed the required peaks.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:13][N:14]=[C:7]1[N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]2=[O:27].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH2:20]([N:6]1[C:5](=[O:27])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:1]([S:36]([CH3:35])(=[O:38])=[O:37])[S:36]([CH3:35])(=[O:38])=[O:37])[CH:3]=2)[N:8]2[C:12]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[N:13][N:14]=[C:7]12)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)c(=O)n(Cc1ccccc1)c1nnc(N3CCCC3)n21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1ccc2c(c1)c(=O)n(Cc1ccccc1)c1nnc(N3CCCC3)n21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.9 %

Procedure:
In a 20 ml balloon flask, we resuspend 0.55 g (1.5 mmol) of 7-amino-4-benzyl-1-(pyrrolidin-1-yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (described in example 225) in 10 ml methylene chloride. We add 0.42 ml (3.0 mmol) of triethylamine then 0.24 ml (3.0 mmol) of methanesulfonyl chloride. The obtained solution is shaken for 24 hours at ambient temperature. After cooling down, the obtained solution is washed in water, dried on Na2SO4 then evaporated under vacuum. The crude mixture of the 2 obtained compounds (0.85 g) is chromatographied on silica column by elution with the mixture CH2Cl2 99/CH3OH 1/NH4OH 0.1. The fractions containing the first product by elution order are joined and evaporated under vacuum to give 0.65 g of 4-benzyl-7-(N,N-dimethylsulfonylamino)-1-(pyrrolidin-1-yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=2)=[CH:13][N:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Br)cn1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(-c2cccc(S(C)(=O)=O)c2)cn1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[2-(5-bromo-pyridin-2-yl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-methylsulfonylphenylboronic acid in analogy to Example 1b): MS (ISP): 535.1 and 536.1 (M+H)+, 479.1 and 481.0 ((M-isobutene)+H)+ (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]1([OH:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: BrCCCCCBr
Product: Nc1ccc(Br)cc1C1(O)CCCCC1

Procedure:
1-(2-Amino-5-bromo-phenyl)cyclohexanol was prepared, according to the procedure of Example 1 using 2-amino-5-bromobenzoic acid and the Grignard reagent prepared from 1,5-dibromopentane, as a clear oil: 1H-NMR (DMSO-d6) δ7.07 (d, 1H, J=2.3 Hz), 7.03 (dd, 1H, J=8.4, 2.4 Hz), 6.55 (d, 1H, J=8.6 Hz), 5.49 (s, 2H, D2O exchangeable), 5.00 (s, 1H, D2O exchangeable), 2.01 (d, 2H, J=1.8 Hz), 1.66-1.77 (m, 2H), 1.44-1.61 (m, 4H), 1.16-1.34 (m, 2H); MS (ESI) m/z 270/272 ([M+H]+, 98%/100%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>ClCCl>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:24](=[O:27])[CH:25]=[CH2:26])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 101.2 %

Procedure:
To a solution of 390 mg (1.6 mmol) D-Proline benzyl ester hydrochloride and 0.47 ml (3.4 mmol) triethylamine in 20 ml dichloromethane at 0° C. was added dropwise 0.2 ml (2.4 mmol) acryloyl chloride and stirring continued for 24 h at room temperature. The reaction mixture was then washed sequentially with water, 1M hydrochloric acid and once more with water, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford 420 mg (100%) of the title compound (R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester as a colorless oil.
Reaction SMILES: Cl.[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:3].Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:10][CH2:11]1)[CH3:3]
Reactant: Brc1ccccn1
Reactant: CCN(CC1CCNCC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC1CCN(c2ccccn2)CC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Temperature: 165 °C
Yield: 15.3 %

Procedure:
A mixture of ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-4-ylmethyl-amine hydrochloride salt (30 mg, 0.064 mmol), 2-bromopyridine (0.62 μL, 0.64 mmol), and triethylamine (26 μL, 0.19 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 30 minutes at 165° C. The crude mixture was purified by HPLC to provide compound A126 as a white solid (5 mg, 15%). Exact mass calculated for C25H28FN7O2S 509.2, found 510.5 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:7]=1[CH:8]=O)[CH2:2][CH2:3][CH3:4].C1(P(=[CH:37][C:38]([O:40][CH3:41])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O>[CH3:41][O:40][C:38](=[O:39])[CH:37]=[CH:8][C:7]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C(F)(F)F)ccc1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 90 %

Procedure:
2-Butoxy-4-trifluoromethyl-benzaldehyde (420 mg) was reacted with methyl (triphenylphosphoranylidene)acetate (679 mg) at 110° C. overnight as described above to yield title compound (464 mg) after column chromatography (Hex/EtOAc=20/1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[C:4]([N+:20]([O-:22])=O)[CH:3]=1.[H][H]>CN(C)C=O.[Ni]>[Br:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[NH:12][C:13](=[O:14])[C:15](=[O:16])[N:20]([OH:22])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2ccccc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: O=c1[nH]c2c3ccccc3c(Br)cc2n(O)c1=O
Yield: 65.1 %

Procedure:
A solution of 4-bromo-1-ethoxalylamino-2-nitronaphthalene (0.20 g, 0.5 mmol) in 20 ml of N,N-dimethylformamide was hydrogenated at room temperature and atmospheric pressure in the presence of a small amount of Raney-Ni. After the hydrogen uptake was complete, the mixture was filtered. The filtrate was evaporated to dryness and the residue was triturated with water and hot ethanol to give 100 mg (62%) of the title compound. M.p. >200° C. dec.; IR (KBr): 1690 cm-1 ; MS (m/e): 306 (M+, 2%), 308 ((M+2)+, 2%).