Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].BrBr.C(=O)(O)[O-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:23][C:22]=1[CH2:33][OH:34].C(N(CC)CC)C>CCOCC.CC(C)=O>[Cl:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][C:1]([C:4]3[O:5][C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[CH:8]=3)=[O:3])[CH2:29][CH2:28]2)[CH:24]=[CH:23][C:22]=1[CH2:33][OH:34]
Reactant: OCc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(=O)c1cc2ccccc2o1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(CN1CCN(c2ccc(CO)c(Cl)c2)CC1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-acetylbenzofuran (3.2 g. 0.02) in ether (50 ml) was treated with bromine (3.2 g., 0.02 mole) portionwise at room temperature. The mixture rapidly decolorized to a light yellow solution that was poured into cold aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ether. The combined ether extracts were dried (K2CO3) and the ether was removed in vacuo, keeping the mixture cold. The gummy, off-white solid was dissolved in acetone (50 ml) and quickly added to a solution of 2-chloro-4-(1-piperazinyl)benzenemethanol (4.0 g, 0.0176 mole) and triethylamine (2.0 g, 0.902 mole) in acetone (200 ml). The mixture was stirred at room temperature for one hour, then cooled in an ice bath. The solid was collected, washed with ether, and air dried. Recrystallization from acetone-ethanol gave 3.7 g (55%), mp 169°-172°.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CCO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N)cc1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
Stannous chloride dihydrate (30.60 g, 135.6 mmol) was added to a solution of diethyl 2-methyl-2-(4-nitrophenyl)malonate (8.00 g, 27.1 mmol) in EtOH (100 ml) and stirred at reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken in water and basified with triethyl amine to adjust a pH˜8. The precipitated solid was filtered and washed with ethyl acetate. The separated organic layer from the filtrate was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 6.0 g (83%) of diethyl 2-(4-aminophenyl)-2-methylmalonate as brown oil.
Reaction SMILES: [P:1]([O-:37])([O:31][CH2:32][CH:33]([OH:36])[CH2:34]Cl)([O:3][C:4]([F:30])([F:29])[C:5]([F:28])([F:27])[C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:2].[Na+:38].C(O)C.[OH-].[Na+]>C(O)C>[P:1]([O-:37])([O:31][CH2:32][CH:33]1[O:36][CH2:34]1)([O:3][C:4]([F:30])([F:29])[C:5]([F:28])([F:27])[C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:2].[Na+:38]
Reactant: O=P([O-])(OCC(O)CCl)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=P([O-])(OCC1CO1)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCC(F)(F)F
Temperature: 70 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
20 g (0.030 mol) of sodium heptadecafluorodecyl 2-hydroxy-3-chloropropyl phosphate was charged into a reactor, to which 500 ml of ethanol was added, followed by agitation and heating to 70° C. to obtain a uniform mixture. Thereafter, the reaction system was cooled down to 30° C., to which was gradually added 16.9 g (0.030 mol) of a 0.0018 mol/g sodium hydroxide ethanol solution, followed by agitation for 4 hours while keeping the temperature. The HPLC analysis revealed the disappearance of a peak of the starting material with a peak for the resultant new product appearing. The resultant NaCl precipitate was removed by filtration and the ethanol was distilled off under reduced pressure to obtain 18.7 g (yield: 99%) of sodium heptadecafluorodecyl glycidyl phosphate.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[I:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1.O>ClCCl>[I:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(I)nc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(I)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 10 ml of triethylamine in 50 ml of dichloromethane under argon is added 3.2 g of 6-iodopyridine-3-carbonyl chloride. The mixture is stirred at room temperature for 16 hours and then poured into 100 ml of water. The organic layer is separated and washed with 2% HCl, water, saturated NaHCO3 and dried (Na2SO4). The solvent is removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1.O.O.[OH-].[Li+]>CO>[CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
Methyl 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazine-2-carboxylate (423 mg, 0.907 mmol) synthesized in Example (62c) was dissolved in methanol (10 mL), and water (2 mL) and lithium hydroxide monohydrate (76.2 mg, 1.82 mmol) were added, followed by stirring at 50° C. for 1 hour under nitrogen atmosphere. To the reaction solution, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: dichloromethane/methanol=0%-10%) to afford the desired compound (269 mg, yield 66%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:20]1(CCCS)[CH:25]=CC=C[CH:21]=1>>[CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][C:3]1[CH:25]=[CH:20][CH:21]=[CH:5][CH:4]=1
Reactant: SCCCc1ccccc1
Reactant: CCCCCSc1c[nH]nc1C1CN2CCC1CC2
Product: c1ccc(CCSc2c[nH]nc2C2CN3CCC2CC3)cc1
Yield: 11 %

Procedure:
Compound 49G was prepared following the procedure as described for the synthesis of compound 49B (see Scheme 10) using 3-phenyl-1-propanethiol as reagent. Subsequent purification by flash chromatography (EtOH) afforded compound 49G.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:20][CH3:21])([CH3:19])[C:16](O)=[O:17])[N:13]=2)=[N:6][CH:7]=1.C[N:30]1[CH2:35][CH2:34]O[CH2:32][CH2:31]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.N1CCCC1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:20][CH3:21])([CH3:19])[C:16]([N:30]3[CH2:35][CH2:34][CH2:32][CH2:31]3)=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(C)(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)O
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: ClCCl
Product: COC(C)(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
In a 20 mL scintillation vial, 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoic acid (0.087 g, 0.187 mmol) was dissolved in CH2Cl2 (5 mL) and DMF (2 mL) and N-methylmorpholine (0.031 mL, 0.281 mmol), followed by addition of 1-hydroxybenzotriazole. The mixture was cooled to 0° C. and EDCI (0.0467 g, 0.244 mmol) was added. The resulting mixture was agitated for 30 minutes and pyrrolidine (0.020 g, 0.28 mmol) was added. The mixture was then agitated overnight, diluted with 50 mL of CH2Cl2 and washed with citric acid solution and sodium bicarbonate solution, dried and evaporated to give crude product which was purified by chromatography on silica gel, eluting with 50-70% ethyl acetate/Hexane, to provide the title compound (0.079 g, 79% yield) as white solid. 1H NMR (DMSO-d6 δ 1.23 (s, 3H), 1.66-1.80 (m, 4H), 3.03-3.63 (m, 9H), 7.01 (m, 1H), 7.16-7.46 (m, 7H), 8.25 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:16][CH2:17][CH3:18])=[N:13][C:14]=2[CH3:15])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[Mg+].[Br-].[CH2:22](OCC)C.O>O1CCCC1>[CH3:15][C:14]1[N:13]=[C:12]([CH2:16][CH2:17][CH3:18])[N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=[C:2]([CH3:22])[C:3]=12
Reactant: CCCc1nc(C)c2c(Cl)nc3ccccc3n12
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc(C)c2c(C)nc3ccccc3n12
Reaction time: 8 h

Procedure:
2.6 g 4-Chloro-3-methyl-1-propyl-imidazo(1,5-a)quinoxaline (10 mmol) were dissolved in 50 ml tetrahydrofuran. At room temperature 12 ml 3 M MeMgBr solution in diethylether (36 mmol) was added, followed by 8 hours stirring. After complete reaction, controlled by TLC, 0.5 ml water were added and diethylether was distilled off. The residue was distributed between 100 ml dichloromethane, 25 ml water and 25 ml 10% aqueous ammonia. The organic layer was filtered off, and distilled to dryness. The residue (2.5 g) was chromatographed on silica gel with 5% MeOH/CH2Cl2.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[OH:27])=[C:8]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:9]2=[N:10][C:11]=1[CH3:12])C.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:29]([O:28][CH:5]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[OH:27])=[C:8]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:9]2=[N:10][C:11]=1[CH3:12])[C:4]([OH:31])=[O:3])[CH3:30]
Reactant: CCOC(=O)C(OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1O)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1O)CCCC3
Temperature: 60 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
To a stirred solution of Ethoxy-[4-(2-hydroxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl]-acetic acid ethyl ester (20 mg, 45 μmols) in ethanol (1 mL) and tetrahydrofuran (1 mL) was added the sodium hydroxide (2N aqueous, 0.5 mL, 20 eq) and the reaction was stirred at 60° C. for 5 hours. The reaction was concentrated in vacuo until all organic solvents had been removed, the aqueous residue was then acidified with hydrochloric acid (2N aqueous) to pH 2. A pale yellow solid, 4 mg (16% yield) was filtered off and analysed and found to contain ethoxy-[4-(2-hydroxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl]-acetic acid. LC-MS (12 min acidic) 5.04 mins 47-43% pure by UV, ES+/APCI+ 412, ES−/APCI− 410; 5.80 mins 12-13% pure by UV, ES+/APCI+ 412, ES−/APCI− 410.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1>O.C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[CH2:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[N:3]=1
Reactant: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC1
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)CC1
Reaction time: 8 h
Yield: 32.8 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(4-methyl-1-piperazinyl)(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1688 g, 0.258 mmol) was taken up in water (2 mL) and acetic acid (8 mL). The reaction was left to stir overnight. Purification by RP-HPLC provided [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4-methyl-1-piperazinyl)(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.0483 g, 25%). LCMS: (M+H)+=571.2.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f52) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:24])[CH2:6][C@H:5]1[OH:25])=[N+]=[N-].N[C@@H]1CCN(CCN2C3C(=C(F)C=C(F)C=3)C=CC2=O)C[C@@H]1C(OC)=O>>[NH2:1][C@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:24])[CH2:6][C@H:5]1[OH:25]
Reactant: [N-]=[N+]=N[C@H]1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)C[C@H]1O
Agent: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Product: N[C@H]1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)C[C@H]1O

Procedure:
Cis(±)1-{2-[4-azido-3-hydroxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one (Intermediate 43) (190 mg, 0.54 mmol) was hydrogenated as described for Intermediate 34, for 3 hours, to give the product as a colorless oil, 175 mg (quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[Br:14][C:15]1[CH:26]=[CH:25][C:18]2[C:19](Cl)=[N:20][S:21](=[O:23])(=[O:22])[C:17]=2[CH:16]=1>C(#N)C>[Br:14][C:15]1[CH:26]=[CH:25][C:18]2[C:19]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]3[C:4]([CH3:13])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)=[N:20][S:21](=[O:23])(=[O:22])[C:17]=2[CH:16]=1
Reactant: O=S1(=O)N=C(Cl)c2ccc(Br)cc21
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: CC#N
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2cc(Br)ccc21

Procedure:
A slurry of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (252 mg, 1.04 mmol) and 6-bromo-3-chlorobenzisothiazole 1,1-dioxide (U.S. Pat. No. 4,490,527) (292 mg, 1.04 mmol) in 15 ml acetonitrile was heated under dry nitrogen until nearly completely dissolved, when the above compound precipitated as the hydrochloride salt, yielding 360 mg (66%), m.p. 224°-232° C. IR(KBr) 1620, 1300, 1160, 650 cm-1.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=[O:17])[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].C[O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.O.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:4][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=[O:17])[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:1])[CH3:3].[NH:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[C:21]([OH:27])=[O:20]
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN1
Reaction time: 20 h

Procedure:
26-1 (9.20 g) was dissolved in 90 ml of THF, adding 50 ml of H2O, followed by 21 ml of 2.0N LiOH in portions over a period of 2 hr. The solution was let stir 20 hr and the reaction was worked up by addition of dil. KHSO4 to neutrality, evacuation of solvent under reduced pressure to give a thick paste to which was added 200 ml of H2O in portions with stirring, followed by dil. KHSO4 to acidity (pH<2). After stirring for 1 hr, the solid was isolated by filtration, washing with H2O twice, and drying in vacuo to give 6.45 g (72% yield overall) of intermediary Boc-D-cyclohexylglycine-proline. Evaporation of the filtrate to a volume of <100 ml afforded 26-2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:12]([SH:23])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10].II>>[C:17]1([C:14]2[N:13]=[C:12]3[S:23][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:9](=[O:10])[C:11]3=[CH:16][N:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NCc1ccccn1)c1cnc(-c2ccccc2)nc1S
Agent: II
Product: O=c1c2cnc(-c3ccccc3)nc2sn1Cc1ccccn1
Yield: 81.6 %

Procedure:
Using the procedure of Example 20, 2.0 g (6.20 mmol) of 4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid (pyridin-2-ylmethyl)-amide were treated with 1.73 g (6.82 mmol) of iodine to give 1.62 g of the title compound after recrystallization from isopropanol, mp 154-156° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:18])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: CN1CCN(Cc2ccc(O)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2F)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 44.5 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.50 g, 11.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 29B (1.3 g, 5.8 mmol) in DMF (25 mL) was added drop-wise over 10 minutes. The mixture was stirred for 20 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.7 g, 6.9 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. for six days and then cooled to RT. Water and some aqueous NaOH was added and the mixture was extracted three times with EtOAc. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 0.98 g (45%) of 29C as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.28 (s, 3H), 2.28-2.72 (bm, 8H), 3.52 (s, 2H), 3.91-4.03 (m, 2H), 4.22-4.33 (m, 2H), 4.76-4.89 (m, 1H), 6.39-6.52 (m, 2H), 7.19-7.28 (m, 1H).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[S:31]1[N:35]=[CH:34][C:33]([C:36]([NH:38][NH2:39])=O)=[N:32]1>ClCCl.C(OCC)(=O)C>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:36]([C:33]3[CH:34]=[N:35][S:31][N:32]=3)=[N:38][N:39]=[C:26]2[CH2:25]1)=[O:23]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1cnsn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2cnsn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (144 mg, 0.756 mmol) was added under argon to a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (200 mg, 0.687 mmol) in dry dichloromethane (DCM) (1.7 ml). The reaction mixture was stirred at room temperature for 1 h—everything dissolved. 1,2,5-thiadiazole-3-carbohydrazide (I119)(119 mg, 0.824 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and 1-butanol (1.700 ml) was added to the residue. The resulting reaction mixture was stirred at reflux for 5 h. The reaction mixture was diluted with ethyl acetate (I25 mL) and washed with water (2×25 mL), sat. NaHCO3 (25 mL) and brine (2×25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by MDAP (basic method). The resulting residue was triturated with Et2O and dried 3 days at 50° C. under vacuum. The resulting solid was triturated with n-hexane and dried at 50° C. under vacuum for 20 h. The resulting solid was triturated again with n-hexane and dried at 50° C. under vacuum overnight to afford the desired product in 37.5 mg as a white powder.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=1)=[N+:2]=[N-:3].[CH2:19]([Sn:23]([C:32]#[C:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].C1(C)C=CC=CC=1>>[F:18][C:15]([F:16])([F:17])[C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=1)[CH2:4][N:1]1[C:33]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:32]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[N:3]=[N:2]1
Reactant: CCCC[Sn](C#CN1CCOCC1)(CCCC)CCCC
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1
Temperature: 100 °C
Yield: 66 %

Procedure:
Add 1-azidomethyl-3,5-bis-trifluoromethyl-benzene (1.21 g, 4.5 mmol) to a solution of 4-tributylstannanylethynyl-morpholine in toluene (5 mL) (1.20 g, 3.0 mmol). See Berger, D., et al., Helv. Chim. Acta (1996) 79(I): 179-91. Flush with N2, seal in reaction vessel, and heat at 100° C. overnight. Concentrate, dissolve residue in CHCl3, dry over MgSO4, concentrate. Purify by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford the title compound (710 mg, 66%); MS(IS) 669 (M+1); TLC: Rf=0.53 (25% EtOAc/hexanes).