Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[SH:8].CN(C=O)C.CS(O[CH2:19][CH2:20][CH:21]([C:29]1([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]1=[O:42])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=O)=O>C1COCC1>[CH3:45][CH:44]([CH3:46])[CH2:43][C:29]1([CH:21]([CH2:20][CH2:19][S:8][C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]1=[O:42]
Reactant: CC(C)CC1(C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: Sc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CC1(C(CCSc2cccs2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Sodium hydride (60%, 41 mg, 1.0 mmol) is added to a solution of thiophenethiol (118 mg, 1.02 mmol), THF (25 mL) and DMF (25 mL) at 0° C. The mixture is stirred for 30 minutes at 0° C. and a solution of tert-butyl α-[2-(methanesulfonyloxy)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (490 mg, 1.02 mmol) in THF (15 mL) is added. The solution is allowed to warm slowly and is stirred at room temperature overnight. Concentration, aqueous workup (EtOAc, MgSO4), and purification by flash chromatography (25% EtOAc/hexane) gives 361 mg (71%) of title compound as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[N:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:13][N:12]=[C:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: ON=C1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(ON=C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
The core molecule was synthesized following method A. Potassium t-butoxide (12 g, 110 mmol) was added in portions to a cooled (0° C.) solution of cyclopentanone oxime (9.9 g, 100 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 20 minutes and then 1-fluoro-4-nitrobenzene (14 g, 100 mmol) was added in portions. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to remove the DMF and then treated with water (300 mL). The precipitate was collected by filtration and washed with water to provide cyclopentanone O-(4-nitro-phenyl)-oxime (17 g). Cyclopentanone O-(4-nitro-phenyl)-oxime (14 g, 62 mmol) was dissolved in glacial acetic acid (40 mL) and 1.9 N hydrochloric acid (40 mL) was added. The reaction mixture was stirred at room temperature for 50 minutes and then concentrated. The solid was mixed with water (250 mL) and allowed to stand for 1 hour. The crude mixture was extracted with ethyl acetate and the combined organic phases were dried (Na2SO4) and concentrated. The crude material was dissolved in toluene (350 mL) and p-toluenesulfonic acid (2.0 g, 10 mmol) was added. The reaction mixture was heated to reflux for 4 hours and water was removed with a Dean-Stark trap. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na2SO4) and concentrated to give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (10 g). A mixture of give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (5.4 g, 27 mmol) and Raney nickel (˜5 g wet weight) in ethanol (50 mL) was hydrogenated at 50 PSI on a Parr shaker for 2 hours. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by column chromatography to provide 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (4.0 g). Mp 86.5-88.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CN(C=O)C.C(O)C.O>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1csc(Cc2ccncc2)c1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: C1=C(Cc2cccs2)CCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 106.3 %

Procedure:
To a stirred solution of 4-(thiophen-2-ylmethyl)pyridine (H) (3.1 g, 11.52 mmol) in DMF (10 mL) was added benzyl bromide (2.16 g, 12.67 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 100° C. for 3 h. Then the reaction mixture was cooled to 20-35° C., diluted with ethanol (30 mL) and NaBH4 (0.65 g, 17.28 mmol) was added slowly portionwise at 0° C. and then heated at 70-80° C. for 2 h. The reaction mixture was rotary evaporated, resultant residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using a mixture of 20% ethyl acetate/hexane as an eluent to get the desired compound as a light brown oily liquid (3.3 g, 67%); 1H NMR (400 MHz, DMSO-d6) δ 7.33-7.28 (m, 5H), 7.28-7.22 (m, 1H), 6.94 (dd, J=3.4, 5.4 Hz, 1H), 6.84-6.82 (m, 1H), 5.46 (s, 1H), 3.51 (s, 2H), 3.46 (s, 2H), 2.87 (s, 2H), 2.46 (t, J=5.9 Hz, 2H), 1.98 (s, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].[NH3:24]>C1COCC1>[NH2:24][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3]
Reactant: N
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(S(N)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-[(dipropylamino)carbonyl]benzoate (XXXVII, PREPARATION 11, 0.100 g, 0.300 mmol) in dry THF (3 mL) is added ammonia (7 N solution in methanol, 0.214 mL, 1.50 mmol). The mixture is stirred for 18 hours and solvent is then removed. The residue is partitioned between ethyl acetate and water. The organic phase is separate and washed with saline, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound, NMR (300 MHz, CDCl3) delta 8.45, 8.07, 8.01, 6.05, 3.93, 3.44, 3.09, 1.67, 1.52, 0.96 and 0.73; MS (ESI+) for C12H22N2O5S m/z (M+H)+=343.3.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2cccc(C#N)c2)n1
Product: Cc1cc(Cl)nc(/C=C/c2cccc(C#N)c2)n1
Yield: 99.4 %

Procedure:
In analogy to example 12c), by heating (E)-3-[2-(4-hydroxy-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile (1 g, 4.21 mmol) in POCl3 (7.7 ml, 84.3 mmol) at 130° C. for 4.5 h there was obtained (E)-3-[2-(4-chloro-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile (1.07 g, 99%) as an orange solid. EI mass spectrum, m/e: 255 (M calculated for C14H10ClN3: 255).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35].C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:27][C:28]1[CH:29]=[C:30]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCc1nc(C)n(-c2ccc(OC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (3-fluoro-4-methoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in tetrahydrofuran (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.24 g, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.[CH3:14][Sn](C)(C)C.C(Cl)(Cl)Cl>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2c(c1)CCN2
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Temperature: 140 °C
Reaction time: 12 h
Yield: 74.1 %

Procedure:
To a solution of 7-bromo-5-nitroindoline (0.65 g, 2.7 mmol) in 10 mL of DMF were added tetramethyltin (1.0 mL, 7.3 mmol) and bis(triphenylphosphine) palladium(II) chloride (0.10 g) in a portion and resulting mixture was stirred in sealed tube for 12 h at 140° C. The reaction mixture was concentrated in vacuo, providing a dark oily residue which was subjected to column chromatography (CHCl3, neat) to yield 0.35 g (2.0 mmol, 74%) of the desired product.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:10]([O:12]CC)=[O:11])=[CH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[S:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of ethyl 2-tert-butylthiazole-5-carboxylate (1.16 g, 5.44 mmol) in THF (10 mL) was added lithium hydroxide (0.45 g, 10.9 mmol) in water (5 mL) and the mixture was stirred for 16 h at RT. Solvents were removed under vacuum, and the thick liquid was diluted with water (5 mL) and acidified with 2M HCl solution to pH 4 to 5. The product precipitated, was filtered, washed with water (2×5 mL) and dried to provide 2-tert-butylthiazole-5-carboxylic acid as white solid (0.55 g, 55% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1H), 1.39 (s, 9H); MS (ESI) m/z: 186.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14]C(=O)C)[CH:5]=[CH:6][C:7]=1[C:8]([CH2:10][N+:11]([O-:13])=[O:12])=[O:9].[OH-].[Na+].C(O)(=O)C>O>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH2:10][N+:11]([O-:13])=[O:12])=[O:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(=O)Nc1ccc(C(=O)C[N+](=O)[O-])c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(C(=O)C[N+](=O)[O-])c(Cl)c1
Temperature: 80 °C

Procedure:
A mixture of 12.2 g (47.5 mmol) of N-[3-chloro-4-nitromethylcarbonylphenyl]acetamide prepared in Example 12, 11 g (274 mmol) of sodium hydroxide pellets and 161 ml of water is heated at 80° C. for 1 hour. After cooling, the reaction medium is diluted with 900 ml of water and acidified to pH 5 by adding acetic acid. The precipitate formed is recovered, washed with water and air-dried before being recrystallized from ethyl acetate (Yield=276).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.S(O[CH2:22][CH:23]1[CH2:27][CH2:26][CH:25]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[O:24]1)(C1C=CC(C)=CC=1)(=O)=O.COCCOCCOCCOC.[OH-].[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][N:8]2[CH2:28][CH:25]3[O:24][CH:23]([CH2:27][CH2:26]3)[CH2:22]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Reactant: NCCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOCCOC
Product: Clc1ccc(CCN2CC3CCC(C2)O3)cc1
Temperature: 180 °C
Reaction time: 3 h

Procedure:
p-Chlorophenethylamine (0.643 mole, 100 grams) was added to a mixture of 2,5-bis(tosyloxymethyl)tetrahydrofuran (0.214 mole, 99.6 grams) and 200 ml of Ansul 161 (triethylene glycol dimethyl ether) and stirred the reaction mixture for 3 hours at 180° C. The reaction mixture was cooled to room temperature and neutralized with a methanolic sodium hydroxide solution (0.429 mole, 17.14 grams NaOH in 200 ml CH3OH) while stirring for 15 minutes. The solvents and excess starting amine were distilled from the reaction mixture under aspirator pressure. The residue was filtered collecting the sodium p-toluenesulfonate. The filtrate was distilled collecting one fraction (terminal pot temperature 280° C./0.1 mm Hg). The distillate which solidified was recrystallized from methanol obtaining 3-(p-chlorophenethyl)-8-oxa-3-azabicyclo(3.2.1)octane.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[C:11]([C:9]1[CH:8]=[N:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Reactant: CC(C)(C)c1cnn2c(Br)cnc2n1
Product: CC(C)(C)c1cnn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1
Yield: 48 %

Procedure:
This compound was prepared in 48% yield as described in the final paragraph of Example 2, step d, but using 7-bromo-3-tert-butylimidazo[1,2-b][1,2,4]triazine instead of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine, and using 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine (prepared as described in Example 3, step f) instead of 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile: 1H NMR (360 MHz, CDCl3) δ 1.50 (9H, s), 7.34 (1H, m), 7.44 (1H, dd, J 4.9, 8.1 Hz), 7.94-8.02 (2H, m), 8.19 (1H, dd, J 2.5, 7.4 Hz), 8.21 (1H, s), 8.59 (1H, s), 8.66 (1H, d, J 4.82 Hz), 8.88 (1H, s); MS (ES+) m/z 348 [M+H]+. Anal. Found: C, 66.95; H, 5.15; N, 19.00%. Required for C20H18FN5.0.75H2O: C, 66.56; H, 5.45; N, 19.41%.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23](N1CCCC1)[CH2:22][CH2:21]2>C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]3[CH2:3][CH2:2][C:1](=[O:4])[NH:5][C:23]=3[CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: C=CC(N)=O
Reactant: Brc1ccc2c(c1)CCC(N1CCCC1)=C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: O=C1CCC2=C(CCc3cc(Br)ccc32)N1

Procedure:
17.5 g of acrylamide and 0.65 g of p-toluenesulphonic acid were added to 35.5 g of 1-(6-bromo-3,4-dihydro-2-naphthyl)pyrrolidine. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. The reaction mixture was treated with 250 ml of chloroform. whereupon the insoluble constituents were filtered off. There was obtained 8-bromo-1,4,5,6-tetrahydrobenzo[f]-quinolin-3(2H)-one of melting point 227°-228°. After recrystallization from ethanol the product exhibits a melting point of 230°-231°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([CH3:27])[CH:19]=2)=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: Cc1cccc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 60 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and m-tolylboronic acid. Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 2.3 (s, 3H), 3(t, 2H), 7.18 (d, 1H), 7.34 (t, 1H), 7.42 (m, 4H), 7.6 (dd, 2H). MS (M+H, 310).
Reaction SMILES: [N+:1]([C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:16]([OH:18])=O)([O-:3])=[O:2].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:30]([NH2:36])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20]>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:30]([N:36]2[C:16](=[O:18])[C:5]3[C:6](=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:9])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1C(=O)O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: Cc1ccccc1
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc([N+](=O)[O-])c([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 48.8 %

Procedure:
A mixture of 3,4-dinitrophthalic acid (4.63 g, 18.1 mmol) and 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (4.94 g, 18.1 g) in toluene (70 mL) was heated to reflux for 15 hours. The water was removed by a Dean-Stark trap. To the reaction mixture was added ethyl acetate (150 mL). The organic layer was extracted with water, sodium hydrogen carbonate (sat), brine (100 mL each), and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (300 mL) to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-dinitroisoindoline-1,3-dione as an orange solid (4.35 g, 49% yield): mp, 122.0-124.0° C.; 1H NMR (CDCl3) δ 1.47 (t, J=6.9 Hz, 3H, CH3), 2.93 (s, 3H, CH3), 3.65 (dd, J=3.9, 14.3 Hz, 1H, CHH), 3:86 (s, 3H, CH3), 4.10 (q, J=6.9 Hz, 2H, CH2), 4.56 (dd, J=11.4, 14.1 Hz, 1H, CHH), 5.90 (dd, J=3.9, 11.1 Hz, 1H, NCH), 6.84 (d, J=8.0 Hz, 1H, Ar), 7.07-7.11 (m, 2H, Ar), 8.16 (d, J=8.2 Hz, 1H, Ar), 8.60 (d, J=7.9 Hz, 1H, Ar); 13C NMR (CDCl3 ) δ 14.66, 41.66, 49.57, 53.38, 55.98, 64.61, 111.61, 112.42, 120.64, 123.93, 126.18, 127.85, 131.93, 136.74, 138.10, 142.45, 148.77, 150.17, 161.57, 163.47; Anal Calcd for C20H19N3O10S+0.1 ethyl acetate: C, 48.78; H, 3.97; N, 8.37. Found: C, 48.50; H, 3.77; N, 8.07. (HNMR showed the sample contained ˜10% eq of ethyl acetate).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[C:1]([NH:8][C@H:9]([C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (210 μl) was condensed with Boc-3-cyclohexyl-L-alanine (590 mg, manufactured by Bachera Fein Chemikalien AG, Switzerland) to give N-(Boc-3-cyclohexyl-L-alanyl)morpholine (702 mg) as a colorless oily product (yield 95%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (210 mg) to yield the title compound (compound 75; 379 mg) as a colorless oily product (yield 76%).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:15])([F:14])[C:6]1[NH:10][N:9]=[CH:8][C:7]=1[C:11]([O-:13])=[O:12].CO.Cl>O.C1COCC1>[F:15][C:5]([F:4])([F:14])[C:6]1[NH:10][N:9]=[CH:8][C:7]=1[C:11]([OH:13])=[O:12]
Reactant: O=C([O-])c1cn[nH]c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cn[nH]c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of lithium hydroxide hydrate (1.265 g, 30.2 mmol) in water was added to a solution of ethyl 1-(((+/−)cis)-2-allylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a racemate (0.996 g, 3.02 mmol) in THF and MeOH and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting turbid solution was diluted with water to provide a clear solution. The pH was adjusted to 1 by adding 1 M HCl and the mixture was stirred vigorously for 30 min. The resulting precipitate was collected by vacuum filtration to provide 1-(((+/−)-cis)-2-allylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid as a racemate (D60) as a white solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:18][C@H:19]([CH2:35][OH:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([NH:18][C@H:19]([CH:35]=[O:36])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:26]=1)([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(OCc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccc(OCc2ccccc2)cc1

Procedure:
Analogously to Example 21 B) 1)c), a solution of 3.5 ml of (49 mmol) of DMSO in 60 ml of methylene chloride is added at -60° C. to 4.76 g (37.5 mmol) of oxalyl chloride in 33.6 ml of methylene chloride. The addition of 8.94 g (25 mmol) of N-Boc-(p-benzyloxyphenylalaninol) in 150 ml of methylene chloride, 14 ml (100 mmol) of triethylamine in 30 ml of methylene chloride and aqueous working up (extraction of the aqueous phases with ethyl acetate) yields the crystalline title compound: TLC Rf (A)=0.71; 1H-NMR (200 MHz, CDCl3): 1.44 (s, 9 H), 3.06 (d, J=6 Hz, 2 H), 4.39 (m, 1 H), 6.86-6.98 and 7.03-7.15 (2m, each 2 H), 7.30-7.48 (m, 5 H), 9.62 (s, 1 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)=[O:12])[O:8][N:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CO>[Cl:21][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:9]2[O:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:10]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: C1CCNC1
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1cc(OCCCBr)no1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cc(OCCCN2CCCC2)no1
Yield: 92.4 %

Procedure:
A solution of 3-(3-bromopropoxy)-N-(3-chloro-4-fluorophenyl)isoxazole-5-carboxamide (38 mg, 0.10 mmol), and pyrrolidine (100 μL, 1.20 mmol) in tetrahydrofuran (1.5 mL) was stirred at room temperature for 4 h. The reaction was diluted with methanol and purified by preparative LCMS to give the desired product (34 mg, 92%). MF=C17H20ClFN3O3; LCMS calculated for C17H20ClFN3O3 (M+H)+: m/z=368.