Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=2[O:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(Nc2nc(Cl)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 2,4-dimethoxyaniline by a procedure similar to Example 28 (92% yield). 1H NMR (CDCl3): 8.59 (d, J=8.7 Hz, 1H), 8.22 (s, broad, 1H), 7.75-7.81 (m, 3H), 7.52 (ddd, J=8.4, 6.6 and 2.1 Hz, 1H), 6.52-6.59 (m, 2H), 3.95 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: CS([Cl:5])(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:18]=[CH:19][CH2:20]O)[S:16][CH:17]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:5][CH2:20][CH:19]=[CH:18][C:15]1[S:16][CH:17]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC=Cc1nc(-c2ccc(F)cc2)cs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-c2csc(C=CCCl)n2)cc1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
258 μl (3.3 mmol) of methanesulfonyl chloride were slowly added to 265 mg (1.12 mmol) of 3-(4-(4-fluorophenyl)thiazol-2-yl)prop-2-en-1-ol and 456 mg (4.5 mmol) of triethylamine in 10 ml of dichloromethane at room temperature and the mixture was stirred for 3 h. After standing at room temperature over the weekend, the mixture was extracted with a sodium hydrogencarbonate solution. Evaporation of the organic phase yielded 280 mg of the title compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([N+:26]([O-:28])=[O:27])([CH3:25])[CH2:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O>C(N(CC)CC)C>[CH2:1]([NH:8][CH2:13][CH2:12][CH2:11][C:10]([CH3:25])([N+:26]([O-:28])=[O:27])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCCC(C)(C)[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Product: CC(C)(CCCNCc1ccccc1)[N+](=O)[O-]
Temperature: 70 °C

Procedure:
To a stirred mixture of benzylamine (9 ml) and triethylamine (5.5 ml) was added 4-methyl-4-nitro-1-tosyloxypentane (11.9 gm). The mixture was then heated to 70° C. for 2 hrs. The mixture was cooled and partitioned between ethyl acetate and water, the ethyl acetate solution was washed twice with water, then with brine and dried over magnesium sulphate. The solution was evaporated and the product isolated by column chromatography of the residue using gradient elution (Kieselgel; 1:1 60/80 petroleum ether:ethyl acetate going to ethyl acetate). Yield 6.89 gm.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:29])[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14](=[O:28])[C@H:15]([CH3:27])[NH:16]C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC.[BrH:35]>C(O)(=O)C>[BrH:35].[CH:1]1([NH:7][C:8](=[O:29])[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14](=[O:28])[C@H:15]([CH3:27])[NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2 g (0.005 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline cyclohexylamide were dissolved in 10 ml of 4-N hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 1 hour. 100 ml of dry ether were then added. An oil precipitated and was allowed to settle. The solution was decanted off, the oil washed with 100 ml of ether, dissolved in the minimum volume of methanol and an excess of ethyl acetate added. Crystallisation soon took place and there were obtained 1.75 g (100%) of L-alanyl-L-proline cyclohexylamide hydrobromide of melting point 233°-236° C.
Reaction SMILES: [NH2:1][C:2]1[N:30]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:31]1([C:34]([NH:1][C:2]2[N:30]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2n1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (100 mg, 0.24 mmol) in N,N-dimethylacetamide (2.0 mL) was added cyclopropanecarbonyl chloride (33 μL, 0.36 mmol), and the mixture was stirred at room temperature for 4 hr. Cyclopropanecarbonyl chloride (15 μL, 0.17 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (150 mL), washed with 1N hydrochloric acid (15 mL), 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and fractions containing the desired product were concentrated under reduced pressure and the residue was recrystallized from ethyl acetate, hexane and diisopropyl ether to give the title compound (108 mg, 92%) as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (103 mg, 0.38 mmol), 2,5-dimorpholinoaniline (100 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.095 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-2-(2-fluorophenyl)-3-methyl-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.29 (1H, d, J=8.6 Hz), 7.93 (1H, d, J=8.2 Hz), 7.68-7.76 (1H, m), 7.65 (1H, td, J=7.4, 1.6 Hz), 7.40-7.55 (3H, m), 7.34 (1H, t, J=7.4 Hz), 7.19 (1H, t, J=9.0 Hz), 7.11 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.8, 2.9 Hz), 6.06-6.20 (1H, m), 3.85-4.00 (4H, m), 3.67-3.80 (4H, m), 3.01-3.17 (4H, m), 2.88-3.00 (4H, m), 2.21 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=499.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Br:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20]>C1COCC1>[Br:13][C:14]1[C:15]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: COc1ccc(CO)cc1
Reactant: Cc1ccnc(Cl)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2nccc(C)c2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-bromo-2-(4-methoxybenzyloxy)-4-methylpyridine was prepared by the procedure described in J. Med. Chem., 2008, 51, 3065. A pressure vessel was charged with anhydrous THF (25 ml) and sodium hydride (1.44 g, 36.18 mmol, 60% dispersion). To this stirred mixture was added portionwise a solution of 4-methoxybenzyl alcohol (5.0 g, 36.18 mmol) in anhydrous THF (15 ml). After addition was complete, the mixture was stirred at room temperature for 30 minutes and a solution of 3-bromo-2-chloro-4-picoline (4.97 g, 24.08 mmol) in anhydrous THF (15 ml) was added. The vessel was sealed and the reaction mixture was heated at 75° C. for 6 hours. Upon cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water, sat'd NaCl(aq.), dried over MgSO4, filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes: EtOAc) gave the title compound as a clear oil which crystallized on standing (6.71 g, 90%).
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])=[CH:10][CH2:11]1)[C:7](=[O:14])[CH2:6][CH:5]2[CH3:15])([CH3:3])=[CH2:2].[Li]C.[CH3:18]COCC.[NH4+].[Cl-]>C1COCC1>[C:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])=[CH:10][CH2:11]1)[C:7]([CH3:18])([OH:14])[CH2:6][CH:5]2[CH3:15])([CH3:3])=[CH2:2]
Reactant: CCOCC
Reactant: C=C(C)C12CC=C(C)C(C1)C(=O)CC2C
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C12CC=C(C)C(C1)C(C)(O)CC2C
Temperature: 5 °C
Reaction time: 5 h

Procedure:
At 5° C., a soln. of 1 g of 5-isopropenyl-4,8-dimethylbicyclo[3.3.1]non-7-en-2-one (4.9 mmol) in 15 ml THF was treated dropwise with 21 ml 1.4M MeLi in Et2O (29.4 mmol, 6 eq.). The reaction mixture was stirred 5 h at 5° C., warmed to 25° C. overnight, poured into aq. sat. NH4Cl soln., and extracted with Et2O. The org. phase was washed with aq. sat. NaCl soln., dried, and concentrated. FC (SiO2, hexane/Et2O 9:1) of the crude (1.2 g, starting material/OH exo/OH endo 17:65:18)gave 0.2 g of starting material (20%), 0.5 g 8A (46%), 0.25 g 8A/8B (1:1, 23%), and 0.1 g 8B (9%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:9]([N:6]1[CH2:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: CCc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
A solution of 4-ethylpyridine (3.0 g, 28 mmol) in anhydrous dimethylformamide (10 ml) was treated with benzyl bromide (3.7 ml, 31 mmol) and the mixture was stirred at room temperature for two hours. The reaction mixture was diluted with absolute ethanol (60 ml), treated with sodium borohydride (1.3 g, 35 mmol) and stirred at reflux for one hour. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed with 1:1 hexane/ethyl acetate as eluant to give the title compound (1.92 g, 34% over two steps) as a colourless oil; δH (CDCl3) 1.00 (3H, t, J 7.5 Hz, CH2CH3), 1.94-2.12 (4H, m, CH2CH3 and tetrahydropyridinyl CH2), 2.55 (2H, t, J 6.3 Hz, tetrahydropyridinyl CH2), 2.90-3.00 (2H, m, tetrahydropyridinyl CH2), 3.58 (2H, s, PhCH2N), 5.32-5.40 (1H, m, tetrahydropyridinyl 5-H), and 7.20-7.40 (5H, m, ArH); m/z (CI+, NH3) 202 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:36])=[CH:17][N:18]2[CH:33]([CH3:35])[CH3:34])=[O:13].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:36])=[CH:17][N:18]2[CH:33]([CH3:34])[CH3:35])=[O:13]
Reactant: COC(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)cn(C(C)C)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C(=O)O)cc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 50 °C
Yield: 38.7 %

Procedure:
To a solution of methyl 4-[4-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-3-methyl-1-(1-methylethyl)-1H-indol-6-yl]benzoate (30 mg, 0.062 mmol) in MeOH (2 mL) and THF (1 mL) was 3 N NaOH (0.031 mL, 0.185 mmol). The reaction was heated at 50° C. for 12 h, at which time it was allowed to cool to ambient temperature and treated with acidic ice water to bring pH to 6. The solid was filtered and washed several times with water and an 8:2 mixture of acidic (pH2) ice water:MeOH. Purification by reverse phase Gilson HPLC (10-80%, acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes) provided the title compound (12 mg, 0.024 mmol, 39.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (br. s., 1 H) 11.48 (br. s., 1 H) 8.23 (t, J=5.05 Hz, 1 H) 8.02 (d, J=8.34 Hz, 3 H) 7.87-7.94 (m, 4 H) 7.38 (s, 1 H) 7.32 (d, J=1.52 Hz, 1 H) 5.87 (s, 1 H) 4.91 (quin, J=6.63 Hz, 1 H) 4.36 (d, J=4.80 Hz, 2 H) 2.24 (s, 3 H) 2.18 (s, 3 H) 2.11 (s, 3 H) 1.44 (d, J=6.57 Hz, 6 H). MS (ES) [M+H]+ 486.1.
Reaction SMILES: ClC1[CH:7]=[CH:6][C:5]([CH:8]([NH:27][C:28]2[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=2)[C:9]2[C:10]([C:24](O)=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH2:37]([Cl:39])Cl.CO>>[Cl:39][C:37]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:13]=3[CH3:14])[C:24](=[O:25])[N:27]2[C:28]2[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(C(=O)O)c(C(Nc3cc(C)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C)cc1
Reactant: ClCCl
Solvent: CO
Product: COc1ccc(Cn2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2cc(C)c(=O)n(C)c2)C3=O)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid (Step 27.2). tR: 4.54 min (HPLC 1); tR: 1.03 min (LC-MS 2); ESI-MS: 489 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CCCCCC.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-nitrobenzyl bromide (1.00 g, 4.63 mmol) and diethyl malonate (0.741 g, 4.63 mmol) in 30 ml of hexane was added potassium carbonate (0.640 g, 4.63 mmol) and 18-Crown-6 (0.012 g, 0.05 mmol). After stirred at 80° C. for 18 hours, the mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with water, then with brine, and concentrated under reduced pressure to obtain crude diethyl (2-nitrobenzyl)malonate.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[CH3:23][C@@H:24]1[CH2:28][O:27][C:26](=[O:29])[NH:25]1>>[CH3:21][C:20]1[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([C:4]3[CH:3]=[C:2]([N:25]4[C@H:24]([CH3:23])[CH2:28][O:27][C:26]4=[O:29])[S:6][CH:5]=3)=[O:8])[CH2:10][CH2:11]2)=[N:16][CH:17]=[C:18]([CH3:22])[CH:19]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3csc(Br)c3)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3csc(N4C(=O)OC[C@H]4C)c3)CC2)c(C)c1
Yield: 57.7 %

Procedure:
Using (5-bromothiophen-3-yl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 244 and (R)-4-methyloxazolidin-2-one (34 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (65 mg) was obtained.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[I-].[Na+]>C1C=CC=CC=1>[CH2:35]([CH:20]1[C:19](=[O:24])[CH2:18][C:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[O:22][C:21]1=[O:23])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3ccccc3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.7 %

Procedure:
DBU (28.6 ul, 0.191 mmol) was added to a solution of 6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (55 mg, 0.174 mmol, described below) in benzene (1.9 ml), under an atmosphere of argon. Benzyl bromide (21 ul, 0.174 mmol) was then added. The reaction mixture was stirred at room temperature for 20 minutes, followed by the addition of 5 crystals of sodium iodide. The reaction mixture was stirred for a further 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (9.0 mg).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[NH2:25]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:23]=[C:22]([Cl:21])[CH:28]=[C:27]([Cl:29])[CH:26]=2)=[O:13])[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 22.5 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3,5-dichloroaniline (1.87 g, 11.7 mmol) in 15 mL of pyridine. The crude product was recrystallized from ethanol, then ethyl ether to yield 0.78 g of the title compound, mp 235-236° C.
Reaction SMILES: [NH2:1]CC(C)(C)CO.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18](Cl)(=[O:20])=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C(Cl)Cl>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18]([NH2:1])(=[O:20])=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CC(C)(CN)CO
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
A solution of 3.16 g (30.6 mmol) of 3-amino-2,2-dimethylpropanol in 10 mL of CH2Cl2 was added at once to a solution of 2.40 g (10.2 mmol) of 4-nitrophenylmethanesulphonyl chloride (Lee, et al., Journal of the American Chemical Society 1987, 109, 7472-7; Macor, et al., Tetrahedron Letters 1992, 33, 8011-4) in 40 mL of CH2Cl2. The mixture was stirred at rt for 15 min, the solvent was removed in vacuo and the residue was redissolved in 50 mL of EtOAc. The solution was washed with three 50-mL portions of 1.0 N HCl and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane/EtOAc 1:1) afforded N-3-hydroxy-2,2-dimethyl-propyl)-(4-nitrophenyl)-methanesulfonamide as a white solid (0.84 g, 27%): 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.78 (d, J=6.4 Hz, 2H), 3.11 (d, J=5.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 4.52 (s, 2H), 7.02 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); APCI−MS: m/z 301 (M−H)−. A mixture of 0.66 g (2.2 mmol) of N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitro-phenyl)-methanesulfonamide and ˜0.06 g Pd/C 10% in 50 mL of MeOH was shaken on a Parr hydrogenator for 3.5 h. The catalyst was removed via filtration, and 0.273 mL (3.28 mmol) of conc. HCl was added. The solvent was removed in vacuo, and the solid residue was redissolved in 20 mL of EtOH and added to 0.486 g (1.98 mmol) of 8-dimethylaminomethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. The mixture was heated to reflux for 4.5 h and cooled to ambient tempurature. The solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven at 70° C. to afford the title compound as a yellow solid (0.66 g, 70%): mp 229-230° C. (dec); 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.73 (d, J=6.4 Hz, 2H), 3.08 (d, J=5.3 Hz, 2H), 4.27 (s, 2H), 4.43 (t, J=5.3 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 8.03 (d, J=12.3 Hz, 1H), 9.24 (s, 1H), 10.84 (s, 1H), 11.04 (d, J=12.3 Hz, 1H); ESI−MS: m/z 471 (M−H)−. Anal. Calcd for C22H24N4O4S2.0.5 H2O: C, 54.87; H, 5.23; N, 11.63; S, 13.32. Found: C, 54.90; H, 5.26; N, 11.68; S, 13.25.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]([F:25])([F:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[C:9]([CH3:26])[CH:8]=1.[B:27](OC)([O:30]C)[O:28]C>C1COCC1>[Si:17]([O:16][CH2:15][C:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([B:27]([OH:30])[OH:28])=[CH:8][C:9]=1[CH3:26])([F:25])[F:24])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COB(OC)OC
Reactant: Cc1cc(Br)cc(C)c1C(F)(F)CO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)cc(C)c1C(F)(F)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
n-BuLi (1.6 M in hexanes, 1.236 ml, 1.977 mmol) was added to a solution of Intermediate 7C (500 mg, 1.318 mmol) in THF (5 ml) at −78° C. After 45 min, trimethyl borate (0.295 ml, 2.64 mmol) was added and the cooling bath was removed. The reaction mixture was warmed to rt, diluted with diethyl ether (300 mL), washed with 1.0 HCl, water and brine and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0 to 100% ethyl acetate in hexane over 30 min using a 12 g Isco column). Intermediate 7D (370 mg, 82% yield) was obtained as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm −0.03-0.02 (m, 6H) 0.82-0.88 (m, 9H) 2.57-2.63 (m, 6H) 4.10 (t, J=12.92 Hz, 2H) 7.86 (s, 2H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].CC(=O)OCC>O>[OH:13][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(N)cc1C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4.27 g 5-amino-2-methylbenzoic acid (see below), 6 ml concentrated sulfuric acid and 10 ml water, 50 ml ice are added, and a solution of 2.1 g sodium nitrite in 15 ml water is added drop wise, maintaining a temperature of the reaction mixture below 7° C. After stirring this mixture for further 30 min, it is added drop wise to a refluxing mixture of 20 ml concentrated sulfuric acid and 20 ml water. The resulting mixture is held under reflux for further 10 min and stirred over night allowing the temperature to cool down to RT. The mixture is portioned between water and EA, the phases are separated, the organic phase is dried over MgSO4, and the solvent is removed under reduced pressure. For further purification the remaining crude product is solved in diethyl ether, and the organic phase is washed with water, dried over MgSO4, and the solvent is removed under reduced pressure, resulting in 5-hydroxy-2-methylbenzoic acid as the product, which is used for the next step without further purification.