Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12]N=C[CH:9]=2)[N:4]=1.[NH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[O:17].[CH3:26][N:27]1C(=O)CCC1>>[Cl:25][C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH2:15][NH:14][C:3]2[NH:7][N:6]=[C:5]([C:8]3[CH:9]=[N:27][CH:26]=[CH:12][CH:13]=3)[N:4]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CSc1nc(-c2ccncc2)n[nH]1
Reactant: NCC(=O)Nc1cccc(Cl)c1
Reactant: CN1CCCC1=O
Product: O=C(CNc1nc(-c2cccnc2)n[nH]1)Nc1cccc(Cl)c1
Temperature: 140 °C
Yield: 85 %

Procedure:
The sulfone from Step B (101 mg, 0.567 mmol) was dissolved in NMP (2 ml). To this solution 2-amino-N-(3-chlorophenyl)-acetamide (116 mg, 5 mmol) was added, and the mixture was heated at 140° C. for 12 h. The mixture was loaded directly onto an HPLC reverse phase column and purified by water to acetonitrile gradient in the presence of 0.1% trifluoroacetic acid. The aqueous phase was evaporated by lyophilization to yield the title compound as a fluffy white solid (166 mg, 85% yield). ES (MS): 345.12 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:18][C:15]([F:16])([F:17])[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 1c (15.15 g, 53.69 mmol) in CH2Cl2 (60 mL) was added trifluoroacetic acid (18 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation. Ether (100 mL) was added to the residue. The white solid was collected by filtration, washed with ether, and dried under vacuum. The crude compound 1d was used in the next reaction without further purification. MS m/z (M+H+) 183.1.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][N:8]=[C:7]([CH3:10])[CH:6]=1)=[C:2]=[O:3].[N+:11](=[C:13]1[N:17]=[CH:16][N:15]=[C:14]1[C:18]([NH2:20])=[O:19])=[N-:12]>CS(C)=O>[CH3:10][C:7]1[CH:6]=[C:5]([CH2:4][N:1]2[C:2](=[O:3])[N:17]3[CH:16]=[N:15][C:14]([C:18]([NH2:20])=[O:19])=[C:13]3[N:11]=[N:12]2)[O:9][N:8]=1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: Cc1cc(CN=C=O)on1
Solvent: CS(C)=O
Product: Cc1cc(Cn2nnc3c(C(N)=O)ncn3c2=O)on1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
5-Isocyanatomethyl-3-methyl-isoxazole (735 mg, 5.32 mmol) was diluted in DMSO (1.5 mL) and added to a solution of 5-diazoimidazole-4-carboxamide (250 mg, 1.83 mmol) in 2 mL DMSO. The reaction mixture was stirred at room temperature for 16 hours before the addition of sufficient ice water to cause precipitation of the crude product which was collected by vacuum filtration and washed with Et2O (1 reaction volume title compound as a yellow solid (503 mg, 98% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.86 (1H, s), 7.84 (1H, s), 7.71 (1H, s), 6.51 (1H, s), 5.64 (2H, s), 2.21 (3H, s).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[OH:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[CH2:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11]
Reactant: O=Cc1ccccc1O
Reactant: O=C1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Oc1ccccc1Cc1ccc2ccccc2c1O
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A solution of 1-tetralone (5.85 g, 0.040 mole) and salicylaldehyde (4.88 g, 0.040 mole) in t-butanol (400 mL) was treated with potassium t-butoxide (17.6 g, 0.160 mole) and heated at reflux for 16 hours. After cooling to room temperature, the solution was poured into stirred 1.0N hydrochloric acid. After isolation by extraction with ethyl acetate, the crude product was chromatographed with 4:1 petroleum ether/ether, to provide a tan solid. This was recrystallized (cyclohexane/chloroform) to give the title compound as white needles (5.24 g, 52%), mp 124°-125°.
Reaction SMILES: [CH2:1]([N:6]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:30]([OH:32])=[O:31])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N+](=[CH2:40])=[N-]>CO.C(OCC)C>[CH2:33]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:30]([O:32][CH3:40])=[O:31])[CH2:10]1)=[O:8])[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)[C@H](C(=O)O)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)[C@H](C(=O)OC)C1
Reaction time: 0.5 h

Procedure:
A solution of 368 mg (0.725 mmole) of (S)-4-(dipentylcarbamoyl)-1-(diphenylacetyl)piperazine-2-carboxylic acid (from Example 9) in 5 ml of methanol was treated at 0° C. with 20 ml of diazomethane solution in diethyl ether (prepared by the procedure above). The solution was strirred at 0° C. for 30 minutes and at 25° C. for 30 minutes. The excess diazomethane was destroyed by the dropwise addition of acetic acid until the solution became colorless. The resulting solution was concentrated in vacuo and the residue was chromatographed over an 85×2.5 cm LH-20 column and concentrated in vacuo to 225 mg (59%) of pale colored oil which was homogeneous by TLC (1:1 hexane-ethyl acetate, Rf =0.7).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:27](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:28].[CH:43]1([C:47]([NH:49][NH2:50])=[O:48])[CH2:46][CH2:45][CH2:44]1>O>[CH:43]1([C:47]([NH:49][NH:50][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[CH:10][C:11]([C:14]45[CH2:19][CH2:18][C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])([CH2:20][CH2:21]4)[O:16][CH2:15]5)=[CH:12][CH:13]=3)=[CH:6][CH:7]=2)=[O:48])[CH2:46][CH2:45][CH2:44]1
Reactant: NNC(=O)C1CCC1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cc4)cc3)(CC1)CO2
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: O
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(NC(=S)NNC(=O)C5CCC5)cc4)cc3)(CC1)CO2

Procedure:
The title compound was prepared analogous to Example 4, Step 2, starting from methyl 2-(4-(4′-aminobiphenyl-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (500 mg, 1.48 mmol) with 1,1′-thiocarbonyldipyridin-2(1H)-one (379 mg, 1.63 mmol) and cyclobutanecarbohydrazide (254 mg, 2.22 mmol). Water titration of the crude residue affords the title compound as off-white solid after drying (696 mg, 93% yield). LC/MS, ESI-MS(+): 508.4, RT: 1.29 (Condition E).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:9]=1.[CH3:29][N:30]([CH2:38][CH:39]=O)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(O)(=O)C.C([BH3-])#N.[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16][NH:17][CH2:39][CH2:38][N:30]([CH3:29])[C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:11]=[C:10]([C:21]([F:23])([F:24])[F:22])[CH:9]=1
Reactant: COc1ccccc1CCOc1cc(C(F)(F)F)nn1-c1cccc(C#N)c1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1CCOc1cc(C(F)(F)F)nn1-c1cccc(CNCCN(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a solution of 131 (85 mg, 0.219 mmol) in THF (0.4 mL) at 0° C. under nitrogen was added BH3 in THF (1.114 mL, 1.0M solution, 1.114 mmol). The reaction was stirred at room temperature for 1 hour then it was cooled to at 0° C. and quenched carefully with methanol. The mixture was concentrated, MeOH (1.5 mL), tert-butyl methyl(2-oxoethyl)carbamate (38.0 mg, 0.219 mmol) and acetic acid (25.1 μL, 0.439 mmol) were added and the mixture was stirred at room temperature for 1 h after which sodium cyanoborohydride (34.5 mg, 0.549 mmol) was added. After 16 h, the reaction was worked-up as usual and the residue was purified by silica gel chromatography (Biotage 12M, 0-5% MeOH/DCM) to give 132 (29.3 mg, 0.053 mmol, 24.34% yield) as clear oil. LRMS(ESI): (calc.) 548.6 (found) 549.2 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]O)=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]C(Br)(Br)Br>ClCCl>[Br:32][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
2-(indol-3-yl)ethanol (623 mg, 3.86 mmol) was dissolved in dichloromethane (20 mL) and the solution was cooled to 0° C. Triphenylphosphine (1.12 g, 4.25 mmol) and tetra-bromomethane (1.41 g, 4.25 mmol) were then added thereto, followed by stirring for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography to afford the title compound (765 mg, 88%).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br-].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 145 °C
Reaction time: 7 h

Procedure:
In 24 L of dimethyl sulfoxide were suspended 14.5 kg (44.68 mol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 8.0 kg (29.88 mol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, 6.3 kg (59.43 mol) of sodium carbonate and 300 g (2.92 mol) of sodium bromide, which were then heated to 145±5° C. under a nitrogen atmosphere and stirred for 7 hours. After cooling to room temperature, 80 L of ethyl acetate and 80 L of water were added, followed by separation into two layers. The organic layer was washed with 40 L of water twice and concentrated under reduced pressure. To the residue was added 60 L of ethanol and concentrated until the total volume became 40 L under reduced pressure to yield a solution of crude ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate in ethanol. To the ethanol solution was added 2.4 kg of sodium hydroxide dissolved in 8 L of water. The reaction mixture was heated to 60±5° C. and stirred for 1 hour. The reaction mixture was cooled to 30±5° C. and adjusted to pH 10 or lower by the addition of 13 L of 3N hydrochloric acid, followed by the addition of 56 L of ethyl acetate. The mixture was adjusted to pH 6-7 by the addition of 13 L of 3N hydrochloric acid and 6 L of water was added thereto. The crystals formed were collected by filtration, washed with 40 L of a mixed solvent of water:ethanol:ethyl acetate (1:1:1), and dried to yield 13.5 kg of the title compound. HPLC purity area percentage 98.0%, Yield 80.1%.
Reaction SMILES: C([Cl:4])(=O)C.C(O)C.[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:23]=1>C(OCC)C>[ClH:4].[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH:23]=1
Reactant: CC(=O)Cl
Agent: Fc1cccc2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c12
Solvent: CCOCC
Solvent: CCO
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add dropwise acetyl chloride (2.3 mL, 32.4 mmol) to anhydrous ethanol (50 mL) and stir the solution for 10 min at ambient temperature and add to a solution N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine (10.7 g, 29.2 mmol) in diethyl ether. Concentrate the resulting solution under reduced pressure to give a yellow solid. Recrystallize the yellow solid from ethyl acetate/methanol to give the title compound: mp 163–164° C.; MS(m/e): 367 (M+1), 365 (M−1); Calculated for C19H18F4N2O HCl: Calcd: C, 56.65; H, 4.75; N, 6.90. Found: C, 56.45; H, 4.54; N, 6.90.
Reaction SMILES: [CH2:1]([OH:13])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O:18]O)(C)(C)C.O.[OH-].[Na+]>C(Cl)Cl.C(CC(C)(C)C)(C)C.[Cl-].[Na+].O>[CH2:4]([C@H:3]1[O:18][C@H:2]1[CH2:1][OH:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(C)OO
Reactant: CCCCCCCCC/C=C\CO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCCC[C@H]1O[C@H]1CO
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
To a slurry of 500 mg of powdered 4A molecular sieves in 30 ml of dry CH2Cl2 at 0° C. under argon, was added 232 mg (0.82 mmole) of Ti(Oi-Pr)4 followed by 266 mg (1.14 mmole) of L(+)diisopropyl tartrate. The mixture was allowed to stir for 15 min. The mixture was cooled to -20° C. and a solution of 0.75 g (4.1 mmole) of cis-2-dodecene-1-ol in 5 ml of CH2Cl2, which has been dried over 3A molecular sieves for 15 min, was then added. After the catalyst had "aged" for 20 min, 2.15 ml of 3.8 M (8.17 mmole) tert-butyl hydroperoxide in isooctane was added slowly by syringe. The reaction was then allowed to stand in the freezer (-30° C.) for seven days. The mixture was then warmed to 0° C. and 5 ml of H2O was added with stirring. After 30 min, 1.5 ml of 30% NaOH in saturated brine was added and the mixture was allowed to stir 60 min longer. The organic layer was separated and the aqueous layer was washed twice with 20 ml of CH2Cl2. The combined organic layers were dried over MgSO4, filtered and evaporated to afford a sticky white solid. Recrystallization from Et2O:petroleum ether yielded 570 mg of a flocculent white solid mp 55-6° C. 1H NMR (CDCl3) δ 3.86 (ddd, 1, J=4, 8, 12 Hz), 3.7 (m, 1), 3.16 (dt, 1, J=4, 7 Hz) 3.0 (m, 1), 1.6-1.1 (m, 12), 0.88 (t, 3, J=7 Hz). Mass spectra EI; M-31 (--CH2OH), Calc. 169.1592, Found 169.1581.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
A mixture of 1-(3-bromo-phenyl)-ethanone (4.9 g, 24 mmol), 4-trifluoromethyl phenyl boronic acid (4.6 g, 24 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol), potassium phosphate (10 g, 49 mmol), 1,2-dimethoxyethane (50 mL) and water (10 mL) was heated to 80° C. under a blanket of nitrogen in a sealed tube. After 5 h, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a clear oil (5.6 g, 87%). MS (ESI): mass calcd. for C15H11F3O, 264.0; m/z found, 265.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.21 (t, J=1.6, 1H), 8.04-7.98 (m, 1H), 7.85-7.78 (m, 1H), 7.76-7.69 (m, 4H), 7.60 (t, J=7.7, 1H), 2.68 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[C@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-])=O)[CH2:6][C@@H:5]1[CH3:27])[CH3:2]>CCCCCCC.CCO>[NH2:24][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C@@H:7]1[CH2:8][C@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C@H:4]([O:3][CH2:1][CH3:2])[C@H:5]([CH3:27])[CH2:6]1.[NH2:24][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C@H:7]1[CH2:8][C@@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C@@H:4]([O:3][CH2:1][CH3:2])[C@@H:5]([CH3:27])[CH2:6]1
Reactant: CCO[C@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCCCCCC
Product: CCO[C@@H]1[C@H](C)C[C@H](c2ccncc2N)C[C@@H]1NC(=O)OC(C)(C)C
Product: CCO[C@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Yield: 33 %
Yield: 28 %

Procedure:
Method 6 was followed using (+/−)-tert-butyl (1R,5S,6S)-6-ethoxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate with Chiral HPLC (Heptane/EtOH=90/10, 20 mL/min, IC column) to yield tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-2-ethoxy-3-methylcyclohexyl)carbamate (33% yield, 99% ee) and tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-ethoxy-3-methylcyclohexyl)carbamate (28% yield, 99% ee). LC/MS (m/z)=350.2 (MH+), Rt=0.72 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][CH:30]1[CH2:48][C:34]2[C:35]3[NH:36][C:37](=[O:47])[C:38](=[O:46])[NH:39][C:40]=3[CH:41]=[C:42]([N+:43]([O-:45])=[O:44])[C:33]=2[CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[N+:43]([C:42]1[C:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:16])[CH2:48][C:34]=2[C:35]2[NH:36][C:37](=[O:47])[C:38](=[O:46])[NH:39][C:40]=2[CH:41]=1)([O-:45])=[O:44]
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1)C1CCNCC1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
N-t-butyloxycarbonylpiperidine-4-carboxylic acid (0.35 g, 1.5 mmol) and carbonyldiimidazole (0.24 g, 1.5 mmol) were refluxed in tetrahydrofuran (5 mL) for 15 min. The mixture was added to a solution of 9-amino-6-nitro-1,4,7,8,9,10-hexahydro-benzo[f]quinoxaline-2,3-dione (0.15 g, 1.5 mmol) in dimethylformamide (5 mL) and heated to 70° C. After 15 min, triethylamine (0.15 g, 1.5 mmol) was added and heating continued at 70° C. for 6 h. The solvent was removed by rotoevaporation in vacuo and the residue triturated with diethyl ether to form a solid. The solid was collected by filtration, washed with water and dried to give the crude product (0.23 g, 94% yield). For further purification, the solid was suspended and stirred in 2N HCl, and then filtered and dried. Anal. calc'd for C23H29N5O7.1.5 NaCl.H2O: C, 40.82; H, 4.57; N, 13.22; found-C, 40.35; H, 4.70:N, 12.91.
Reaction SMILES: [O:1]=[C:2]([CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11]C1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].O1C2(CCC(C(O)=O)C2)OCC1.O1C2(CCC(C(O)=O)CC2)OCC1>>[O:1]=[C:2]([CH:9]1[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:11]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Agent: O=C(O)C1CCC2(C1)OCCO2
Agent: O=C(O)C1CCC2(CC1)OCCO2
Product: CCOC(=O)CC(=O)C1CCC2(C1)OCCO2

Procedure:
Ethyl 3-oxo-3-(1,4-dioxaspiro[4.4]nonan-7-yl)propanoate was synthesized in a manner similar to the synthesis of ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate, but with 1,4-dioxaspiro[4.4]nonane-7-carboxylic acid substituted for 1,4-dioxaspiro[4.5]decane-8-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O>O1CCCC1.[H][H]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Reactant: [H][H]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2

Procedure:
57.4 g of the product of Example 15a were dissolved in 400 ml of tetrahydrofuran and hydrogenated with hydrogen for 5 hours at 30° C. at 50 bar in the presence of 4 g of catalyst (palladium on charcoal, 10% strength by weight). The mixture was then subjected to filtration, the solvent was removed and the residue was distilled under a high vacuum. This gave 37 g of product (=63% of theory) having a boiling point of 83° C. at 0.07 mbar. 19F-NMR: -59.0 and -84.6 ppm. 1H-NMR: 2.98 ppm.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>CO.C(Cl)(Cl)Cl>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)c1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccc(C(C)C)cc3)s2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosulfonyl-2-(4-isopropylphenyl)thiophene (260 mg, 0.87 mmol) with 5-amino-4-bromo-3-methylisoxazole (161 mg, 0.91 mmol) yielded after flash chromatography using 10% MeOH/CHCl3 a pale brown solid (265 mg) which was further purified using preparative HPLC to give the pure sulfonamide as a light tan colored solid, m.p. 114-116° C.
Reaction SMILES: [N+](C1C=CC(C2C3C=C4OCOC4=CC=3CC(C)NN=2)=CC=1)([O-])=[O:2].ClCCl.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCCCC(O)=O>>[CH:37]1([NH:36][C:35]([NH:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:2])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCC(=O)O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of a.2.5. g (7.68 mmol) portion of the product of Example 26 in 40 ml of anhydrous dichloromethane 4.75 g (23 mmol) of dicyclohexylcarbodiimide and 2.88 g (23 mmol) of n-valeric acid were added and the reaction mixture was maintained at 25° C. under intermittent stirring for 24 hours. Then the N,N'-dicyclohexylurea formed as by-product was filtered, the filtrate was evaporated under reduced pressure, the residue was mixed with 2×40 ml of distilled water, decanted and the wet product was left to solidify under 50 ml of 50% ethanol. The solid compound was filtered, washed with 2×10 ml of 50% ethanol and dried at 80° C. The raw product obtained was recrystallized from 24 ml of ethanol and the crystals were dried at 100° C. to yield 2.20 g (70%) of the aimed product as a yellow powder, m.p.: 145°-147° C.