Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C.O>[C:2]1([CH:1]=[CH:8][C:9](=[O:11])[CH:10]=[CH:20][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=CC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 146.0 g (1.0 mole) of benzalacetone and 122.0 g (1.02 mole) 4-tolualdehyde (Compound II-A) was dissolved in 750 ml ethanol, and the solution was diluted with 200 ml water. With stirring, at room temperature, all at once, 100 ml of 10% NaOH solution were added. After 1.5 hours the thick, cream precipitate was filtered off, resuspended in 1 liter 20% ethanol in water, refiltered, sucked dry and recrystallized from ethanol/ethyl acetate to give 180 g of 1-phenyl-5-(4-tolyl)-1,4-pentadiene-3-one (Compound IV-A). The product structure was confirmed by field desorption mass spectrometry (FDMS) and infrared (IR) spectrometry.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](O)=[O:25])(=[O:18])=[O:17])=[O:4].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:58]([N:60]([CH2:64][CH3:65])[CH2:61][CH2:62][NH2:63])[CH3:59].Cl>CN(C=O)C>[CH2:58]([N:60]([CH2:64][CH3:65])[CH2:61][CH2:62][NH:63][C:24]([C:20]1[S:21][CH:22]=[CH:23][C:19]=1[S:16]([NH:15][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:18])=[O:25])[CH3:59]
Reactant: CCN(CC)CCN
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccsc2C(=O)O)ccc2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCN(CC)CCNC(=O)c1sccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 463B (100 mg, 0.253 mmol) in DMF (2.0 mL) was treated with 4-methylmorpholine (111 μL, 1.012 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (192 mg, 0.506 mmol), stirred for one hour at room temperature, treated with N,N-diethylethylenediamine (71 μL, 0.506 mmol), stirred for 3 days at room temperature, treated with 1N HCl, and extracted twice with dichloromethane. The combined extracts were dried (MgSO4), filtered, concentrated, and purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 494 (M+H)+; (ESI(−)) m/e 492 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.06 (br s, 1H), 8.82 (t, 1H), 7.82 (d, 1H), 7.26 (d, 1H), 7.10 (d, 1H), 6.92 (d, 1H), 3.77 (s, 3H), 3.24-3.14 (m, 8H), 2.68 (br s, 2H), 2.55 (br s, 2H), 1.66 (quint, 4H), 1.21 (t, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:16])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>>[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:2]([CH3:1])[C:3](=[O:4])[C:5]3=[C:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:8][N:7]=[C:6]3[CH:16]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CNC(=O)c1c(C)noc1-c1ccccc1
Product: COC(=O)c1ccc(-c2cc3noc(-c4ccccc4)c3c(=O)n2C)cc1

Procedure:
This compound is obtained using 3-methyl-5-phenyl-isoxazole-4-carboxylic acid methylamide and 4-formyl-benzoic acid methyl ester in 15% as a beige solid. Mass spectrum: m/z (M+H)+: 361.2
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(F)cc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 6-fluoro-2(3H)-benzothiazolone (47.58 g) in 100% sulfuric acid (760 ml) was cooled at 0° to 5° C., and 98% fuming nitric acid (d=1.52; 18.79 g) was dropwise added thereto, followed by stirring at the same temperatur for 60 minutes. The reaction mixture was poured into ice-water. The precipitated crystals were collected by filtration, washed with water and dried to give 6-fluoro-5-nitro-2(3H)-benzothiazolone (48.48 g) as pale brown crystals. m.p., 180°-182° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:9].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>O1CCCC1>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[NH:9][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12]
Reactant: CC1CCCC(N)C1C
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC1CCCC(NCCCS(=O)(=O)O)C1C
Temperature: 25 °C

Procedure:
To a solution of 2,3-dimethylcyclohexylamine (10.0 g, 79.0 mmol) in tetrahydrofuran (60 mL) was slowly added a solution of 1,3-propane sultone (9.3 g, 75.0 mmol) in THF (20 mL). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with THF (50 mL) and acetone (50 mL). The solid was dissolved in 25% EtOH/water (150 mL), and treated with Dowex 50WX8 resin (15 g). The suspension stirred at room temperature for 5 minutes. The resin was removed by filtration. The filtrate was concentrated to dryness under reduced pressure; and the solid residue was suspended in acetone (100 mL). The solid material was collected by filtration, and dried in vacuo; affording compound DK (7.4 g, 43%). 1H NMR (D2O, 500 MHz) δ ppm 3.29 (m, 0.5H), 3.09 (m, 2H), 2.88 (t, 2H, J=7.3 Hz), 2.80 (m, 0.5H), 1.99 (m, 3H), 1.40 (m, 7H), 0.81 (m, 6H). 13C NMR (D2O, 125 MHz) δ ppm 62.85, 61.56, 59.88, 58.22, 48.26, 48.15, 44.29, 43.84, 43.59, 42.65, 42.01, 41.03, 37.34, 36.12, 34.73, 34.45, 33.88, 33.64, 29.39, 28.00, 26.50, 24.25, 24.02, 23.64, 22.42, 21.55, 21.45, 21.35, 19.38, 19.13, 18.82, 18.40, 14.38, 13.39, 4.59. ES-MS 248 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[C:13](O)(=O)[CH:14]([CH3:16])[OH:15]>Cl>[CH3:13][CH:14]([C:16]1[NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10]([N:12]=1)=[CH:9][CH:8]=[CH:7]3)[OH:15]
Reactant: Nc1cccc2cccc(N)c12
Reactant: CC(O)C(=O)O
Agent: Cl
Product: CC(O)C1=Nc2cccc3cccc(c23)N1
Reaction time: 2 h

Procedure:
A mixture of 32 g (0.2 mole) of 1,8-diaminonaphthalene and 32 g (0.3 mole) of 85% lactic acid in 400 ml of 4N hydrochloric acid is refluxed for 18 hr. The separated solid is filtered and converted to the free base by treatment with dilute ammonia for 2 hr. The new solid is filtered and recrystallized twice from 95% ethanol to give the product, α-methyl-2-perimidinemethanol, as yellow crystals, m.p. 205°-206° dec.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.C[O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH:41]=O>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:41]3[C:36]4[C:35](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:34](=[O:33])[O:43]3)=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COC(=O)c1ccccc1C=O
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C1OC(=O)c2ccccc21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.50 mmol) in THF (3.0 mL) under nitrogen atmosphere at 0° C. was added isopropylmagnesium chloride (0.60 mL, 1.2 mmol, 2 M in THF). The mixture was then stirred for 30 min at 0° C. and 2-formyl-benzoic acid methyl ester (164 mg, 1.0 mmol) was added. The aqueous layer was stirred at room temperature overnight, quenched with saturated aqueous ammonium chloride, and followed by sodium bicarbonate to pH ˜6. The mixture was extracted with ethyl acetate, dried, and concentrated to provide 4-chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. The crude residue was used directly in the next step.
Reaction SMILES: CC([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])(C)C.[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl.O>O1CCCC1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)CCSc1ccc(O)c(C(C)(C)C)c1
Temperature: 12.5 °C
Reaction time: 3 h

Procedure:
2.0 g of the aldehyde of Example 4 was dissolved in 20 ml of dry tetrahydrofuran under argon and added to 8.5 ml of 2 M isopropylmagnesium chloride in tetrahydrofuran that had previously been added under argon gas to a flask that had been dried in vacuo overnight. Reaction temperature was maintained at 10-15° C. with an ice bath. When addition was complete, the reaction mixture was allowed warm to room temperature and stirred for 3 hours. 2 N hydrochloric acid (2 ml) was added followed by 50 ml of water and the mixture extracted with ethyl acetate three times. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed in vacuo after filtration and the crude product chromatographed on silica to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[CH2:19]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.O>[CH2:19]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=[CH:10][CH:9]=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Yield: 62 %

Procedure:
To a suspension of 1.08 g (60% reagent, 27 mmol) of sodium hydride in 20 ml of tetrahydrofuran (THF), stirred in an ice bath, was added dropwise 6 ml (6.7 g, 27 mmol) of triethyl 4-phosphonocrotonate. The resulting mixture was stirred for an additional 1 hour in the cooling bath and a solution of 4.2 g (18 mmol) of 1-benzylindol-3-carboxaldehyde in 25 ml of water. This mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layer was washed with two 25 ml portions of brine, dried (magnesium sulfate) and concentrated on a rotary evaporator to give an oil. Purification on a dry column (25% ethyl acetate in hexane) followed by crystallization (acetone-ether) gave 3.7 g of product as orange crystals, m.p. 110-112. MS (EI): 331 (M+), 240 (M+--C7H7), 167 (M+--C7H7 --CO2C2H5). NMR spectrum (CDCl3) shows a triplet centered at δ1.26 (J=7 Hz), a singlet at δ5.21, a doublet centered at δ5.8 which is the signal of the olefinic proton adjacent to the carbonyl group. The remainder of the proton signals cluster around 7.25 ppm.
Reaction SMILES: [BH4-].[Na+].[H][H].[Si:5]([O:12][CH:13]([C:27]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:28]=1[CH3:36])[CH:14]([CH2:23][N+:24]([O-])=O)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:24][CH2:23][CH:14]([CH:13]([C:27]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:28]=1[CH3:36])[O:12][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(O[Si](C)(C)C(C)(C)C)C(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(N)cc1C(O[Si](C)(C)C(C)(C)C)C(CN)CC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Adapting literature known protocols (Osby and Ganem, Tetrahedron Lett., 1985, 26(52), 6413-6416), a mixture of nickel(II) dichloride hexahydrate (NiCl2.6H2O) (1.19 g, 5.0 mmol) in methanol (MeOH) (80 mL) is sonicated to effect complete dissolution. Solid sodium borohydride (NaBH4) (567 mg, 15.0 mmol) is added in small portions upon a black precipitate (Ni2B) is generated immediately and hydrogen gas is generated (exotherm!). After about 30 min, a solution of tert-butyl 4-(tert-butyl(dimethyl)silyl)oxy-4-(2-methyl-5-nitro-phenyl)-3-(nitromethyl)butanoate (17c) (4.69 g, 10.0 mmol) in MeOH (20 mL) is added followed by portion-wise addition of more NaBH4 (1.13 g, 30.0 mmol) at room temperature. The reaction is monitored by TLC and/or LCMS till completion. The reaction mixture is filtered over Celite® 545 and the filter residue is washed with additional MeOH. The combined filtrates are evaporated to dryness under reduced pressure using a rotary evaporator. The crude tert-butyl 3-(aminomethyl)-4-(5-amino-2-methyl-phenyl)-4-(tert-butyl(dimethyl)silyl)oxy-butanoate (17d) is used directly in the next step without further isolation and purification procedures.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=O)=O)=CC=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of 2-fluoro-4-chloro-5-hydroxynitrobenzene (7.1 g, 37.1 mmol) and potassium carbonate (5.1 g, 37.1 mmol) in acetonitrile (300 ml) was stirred for 2 hours at a refluxing temperature. Cyclopentyl p-toluenesulfonate (10.3 g, 40.8 mmol) was added thereto, followed by stirring further for 2 hours under refluxing. After completion of the reaction, the solvent was distilled off under reduced pressure from the reaction mixture, 1N hydrochloric acid (800 ml) was added thereto, and the mixture was extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with an aqueous solution of sodium bicarbonate and water, dried, and the solvent was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxynitrobenzene as a yellow solid (8.93 g, 34.3 mmol, 92.6% yield).
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].CS(O[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O.O>CN(C)C=O>[CH3:3][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5]1=[O:13])=[CH2:1]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCCCCOS(C)(=O)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCCCCNC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
5.9 g (135 mmol) of a 55% sodium hydride dispersion in mineral oil are washed oil-free with hexane and subsequently covered with 100 ml of dimethylformamide. To this suspension are added dropwise at room temperature 22.3 g (128 mmol) of 1-(1-methylvinyl)benzimidazolin-2-one in 100 ml of dimethylformamide. After stirring at room temperature for 2 hours 55.0 g of tert.-butyl [6-[(methylsulphonyl)oxy]hexyl]carbamate in 100 ml of dimethylformamide are added dropwise and the reaction mixture is stirred at room temperature for 18 hours. Thereafter. the reaction mixture is poured into 1 l of water and extracted with 750 ml of methylene chloride. The organic extract is washed with water, dried over potassium carbonate and evaporated. The thus-obtained residue is chromatographed on 950 g of silica gel with methylene chloride/hexane, methylene chloride and a 95:5 mixture of methylene chloride and isopropanol as the elution agent, whereby there are obtained 45.3 g of tert.-butyl [6-[3-(1-methylvinyl)-2-oxo-1-benzimidazolinyl]hexyl]carbamate as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:10])[CH3:9].Cl[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][C:13]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:10])[CH3:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Yield: 99.4 %

Procedure:
A solution of (2-isopropoxy-5-methanesulfonyl-phenyl)-piperazin-1-yl-methanone trifluoro-acetic acid (compound 2.4, 80 mg) 2-chloro-5-nitro-pyridine (29 mg), potassium carbonate (50 mg) in 1-butanol (3 mL) was stirred at 120° C. for 20 hours. After such time the solution was concentrated in vacuo, and purified by column chromatography (SiO2) to yield the title compound as white foam (81 mg). MS (m/e): 449.1 (M+H+, 100%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[Cl:32]>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([S:33]([NH:2][C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]3)=[CH:5][CH:4]=2)(=[O:34])=[O:35])[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 0.5 g (1.9 mmol) of the hydrochloride salt of 1-(4-amino-phenyl)-piperidine-4-one (which was obtained in Example 224) in 10 mL of anhydrous methylene chloride was added 0.99 mL (5.7 mmol) of diisopropylethyl amine. After 10 minutes of stirring, 0.51 g (2.1 mmol) of 3,4-dichlorobenzene sulfonyl chloride was added and the mixture was allowed to stir overnight. The reaction mixture was quenched with water and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed twice with water, twice with brine, dried over sodium sulfate and then concentrated in vacuo. The residue was then purified by flash chromatography (10% EtOAc in hexanes to 50% EtOAc in hexanes) and the title compound was collected as 0.25 g of a yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.55 (t, J=6.09 Hz, 4H), 3.58 (t, J=6.03 Hz, 4H), 6.33 (s, 1H), 6.60-6.88 (m, 2H), 6.95-7.00 (m, 2H), 7.50 (d, J=1.47 Hz, 2H), 7.78-7.79 (m, 1H); MS (ES) m/z: 398.8 (MH+); HRMS found for C17H16Cl2N2O3S: 398.0227.
Reaction SMILES: [CH2:1]([C:4]1[CH:49]=[C:48]([Cl:50])[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:47]=[CH:46][C:15]([CH2:16][CH:17]([C:27]([N:29]([CH2:33][C:34]3[CH:39]=[C:38]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:37]=[CH:36][C:35]=3[Cl:45])[CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[C:6]([Cl:51])[CH:5]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:61].[Na+].OO>CCOC(C)=O.C1COCC1>[Cl:45][C:35]1[CH:36]=[CH:37][C:38]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:39][C:34]=1[CH2:33][N:29]([CH:30]1[CH2:32][CH2:31]1)[C:27](=[O:28])[CH:17]([CH2:16][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][O:8][C:7]2[C:6]([Cl:51])=[CH:5][C:4]([CH2:1][CH2:2][CH2:3][OH:61])=[CH:49][C:48]=2[Cl:50])=[CH:47][CH:46]=1)[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: C=CCc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3cc(CCCOC)ccc3Cl)C3CC3)cc2)c(Cl)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCc1ccc(Cl)c(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(CCCO)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a THF solution (0.04 M) of tert-butyl {2-{4-[2-(4-allyl-2,6-dichlorophenoxy)ethoxy]benzyl}-3-[[2-chloro-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]-3-oxopropyl)carbamate from Example 122, Step 5 (1 eq.) was added 9-borabicyclo[3.3.1]nonane (0.5 M THF solution, 2.6 eq.) dropwise at 0° C. The resulting solution was warmed slowly to RT over 16 h. The reaction was quenched at 0° C. with the dropwise addition of ethanol. Then, NaOH (1 N aqueous solution, 4 eq.) and H2O2 (30% w/w aqueous solution, 12 eq.) were added. After 1 h of stirring at 0° C. and another 4 h of stirring at RT, the reaction mixture was diluted with EtOAc. The organic layer was separated, washed with water, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex:EtOAc→EtOAc), revealed the title compound.
Reaction SMILES: [C:1](O)(=O)C.C(N)=N.[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][C:18]2[N:23]=[C:22]([NH:24][C:25]3[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=3)[C:21]([NH2:33])=[CH:20][CH:19]=2)[CH3:16])=[N:13][CH:14]=1>C(O)C.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][C:18]2[N:23]=[C:22]3[N:24]([C:25]4[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:1]=[N:33][C:21]3=[CH:20][CH:19]=2)[CH3:16])=[N:13][CH:14]=1
Reactant: CC(=O)O
Reactant: COc1ncccc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)ccc1N
Agent: N=CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ncccc1-n1cnc2ccc(N[C@@H](C)c3ccc(F)cn3)nc21
Temperature: 85 °C
Yield: 84 %

Procedure:
Formamidine acetate (141 mg, 1.35 mmol) was added to a solution of N6-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]N2-(2-methoxypyridin-3-yl)pyridine-2,3,6-triamine in ethanol (Preparation 22c) and the resulting mixture was heated at 85° C. for 5 hours. The reaction was cooled down and diluted with ethyl acetate (50 mL), washed with brine (2×100 mL) and water (50 mL), dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by flash chromatography (9:1 hexanes/ethyl acetate to 100% ethyl acetate) to give the title compound (104 mg, 84%, two steps) as a green oil.
Reaction SMILES: OC[C@@H](N[C:11](=[O:25])[C@@:12]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:27]>O1CCOCC1>[CH3:24][C@:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:25])=[O:27]
Reactant: O=S(=O)(O)O
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)CC[C@@](C)(C(=O)O)c1ccccc1
Yield: 97 %

Procedure:
To a solution of Example 39A (4.26 g, 12.55 mmol) in 1,4-dioxane (15 mL) was added 4M sulfuric acid (15 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo and partitioned between water and methylene chloride. The methylene chloride layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.70 g, 97%). 1H NMR (300 MHz, CDCl3): δ ppm 0.88 (m, 6 H) 1.09 (m, 2 H) 1.52 (m, 4 H) 1.99 (m, 2 H) 7.35 (m, 5 H).