Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].O>OS(O)(=O)=O>[F:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
Fuming HNO3 90% (549.0 g, 7.84 mol corrected for 90% wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution of HNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice-water bath cooling over an hour. Upon complete addition, the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was complete by HPLC and the reaction mixture (brown solution) was poured over 10 minutes into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice. The yellow slurry was cooled to 14° C., stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven-dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55° C. under high vacuum overnight to yield 1035.9 g (75%) of compound 2 as a yellowish solid. HPLC was 98 a % (220 nm) and 100% (254 nm). 1H NMR (400 MHz, d6 DMSO) δ 8.44 (1H, apparent dt, J 1.9, 7, Ar—H). 19F NMR (376 MHz, d6 DMSO) δ −153.9, −131.5, −120.9. 13C NMR (100 MHz, d6 DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C—F, dt, J 251, 10), 148 (C—F, dd, J 265, 13), 154 (C—F, dd, J 265, 10), 163 (COOH). IR νmax/cm−1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (−) m/z 220 (M−1) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[O:6][CH2:7][CH:8]([OH:25])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:12][CH2:11]1>CO.[Pd].[C]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[O:6][CH2:7][CH:8]([OH:25])[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:14][CH2:15]1
Reactant: COc1cc(OCC(O)CN2CCN(c3ccccc3[N+](=O)[O-])CC2)cc(OC)c1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc(OCC(O)CN2CCN(c3ccccc3N)CC2)cc(OC)c1OC
Yield: 94 %

Procedure:
6 g (0124 mole) (±)-1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy-propyl]-4-(2-nitro-phenyl)-piperazine are dissolved in 300 ml of methanol and hydrogenated in the presence of 0.5 g Pd-carbon (10%) at room temperature. After filtering off the catalyst and removal of the solvent in vacuo it is recrystallized from ethanol. Yield: 94%. M.p. of the monohydrochloride: 181°-183° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]3[N:32]([CH3:33])[C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N:29]=3)[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])=O)(C)(C)C>C(Cl)Cl.CCOCC>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[O:14])[CH2:16][CH2:17]2)=[CH:22][C:23]=1[C:28]1[N:32]([CH3:33])[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]=1
Reactant: Cn1c(-c2cc(N3CCN(C(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)ccc2F)nc2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(-c2cc(N3CCN(C(=O)[C@@H]4CCCN4)CC3)ccc2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of (S)-2-{-4-[4-fluoro-3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.05 g, 0.10 mmol) in DCM (0.5 mL) 2M HCl in Et2O (2.0 mL) was added and the resulting suspension was stirred at room temperature overnight. The reaction was concentrated under reduced pressure then water (4.0 mL) was added and the mixture was concentrated again to afford 0.04 g of the title compound as chlorhydrate salt (86%).
Reaction SMILES: COC1C=C(N2CCP(C)(=O)CC2)C=CC=1N.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][P:44]([CH3:48])(=[O:47])[CH2:43][CH2:42]3)=[CH:37][C:36]=2[O:49][CH3:50])[C:31]([Cl:51])=[CH:30][N:29]=1.[S:52]1[CH:56]=[CH:55][CH:54]=[C:53]1[CH2:57][NH2:58]>>[Cl:51][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][P:44]([CH3:48])(=[O:47])[CH2:43][CH2:42]3)=[CH:37][C:36]=2[O:49][CH3:50])=[N:33][C:28]([NH:58][CH2:57][C:53]2[S:52][CH:56]=[CH:55][CH:54]=2)=[N:29][CH:30]=1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: NCc1cccs1
Agent: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(NCc2cccs2)ncc1Cl

Procedure:
The compound can be prepared as in Example 32 by reacting 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline with 2,4,5-trichloropyrimidine generating 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine. 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine is then reacted with 1-(thiophen-2-yl)methanamine as described in Example 32.
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[CH:41]=[CH:40][CH:39]=[CH:38][C:7]=1[CH2:8][N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=2[C:11]([C:22]#[N:23])=[C:10]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1.C(=O)([O-])[O-:43].[K+].[K+].OO>O>[NH2:23][C:22]([C:11]1[C:12]2[N:13]([CH3:21])[C:14](=[O:20])[N:15]([CH3:19])[C:16](=[O:18])[C:17]=2[N:9]([CH2:8][C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[Cl:5])[C:10]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:25]1)=[O:43]
Reactant: Cn1c(=O)c2c(c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(c(C(N)=O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.3 %

Procedure:
To a mixed solution of dimethyl sulfoxide (250 ml) and water (25 ml) were added tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (17.9 g) and potassium carbonate (4.7 g). In a water bath, an aqueous hydrogen peroxide solution (a 30-35% aqueous solution, 17 ml) was added dropwise and the resulting mixture was stirred at 25° C. for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed three times with water and then once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (15.6 g) as a light-yellow amorphous substance.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[C:10](OCC)=[O:11].[BH4-].[Na+]>C(O)C>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11]
Reactant: CCOC(=O)c1nc2cnccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl thiazolo[4,5-c]pyridine-2-carboxylate (R-3) (5 g, 24 mmol) in ethanol (100 mL) was added NaBH4 (0.9 g, 24 mmol) in portions at 0° C. The suspension was stirred at room temperature for 1 h, and then concentrated. The resulting residue was dissolved in EtOAc, washed with water. The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by chromatography on silica gel to give the title compound. MS (m/z): 167 (M+1)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH2:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([NH:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([C:8]3[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: COc1ccc(N)cc1-c1ccnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1ccnn1C(C)C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 3-chloro-4-fluoro phenyl isocyanate (0.075 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 47 as a colorless solid (0.090 g, 52%). LCMS m/z (%)=405 M+H+ (37Cl, 23) 403 M+H+ (35Cl, 60), 1H NMR (400 MHz, acetone-d6) δ: 8.3 (bs, 1H), 8.1 (bs, 1H), 7.82-7.796 (dd, J1=6.75 Hz, J2=2.58 Hz, 1H), 7.536 (d, J=2.67 Hz, 2H), 7.514 (d, J=2.67 Hz, 2H), 7.43 (d, J=1.57 Hz, 1H), 7.368 (d, J=2.65 Hz, 1H), 7.299 (d, J=1.23 Hz, 1H), 7.136 (t, 1H), 6.079 (d, J=1.69 Hz, 1H), 4.224 (m, 1H), 3.73 (s, 3H), 1.308 (d, J=6.61 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:19]([C:20](OCC)=[O:21])=[C:7]2[CH2:8][CH2:9][CH2:10][C:11]3[C:12](=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=3)[C:6]2=[N:5]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:18][S:17][C:14]1[N:15]=[CH:16][C:11]2[CH2:10][CH2:9][CH2:8][C:7]3[C:6]([C:12]=2[N:13]=1)=[N:5][N:4]1[CH2:3][CH2:2][O:1][C:20](=[O:21])[C:19]=31
Reactant: CCOC(=O)c1c2c(nn1CCO)-c1nc(SC)ncc1CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)-c1nn3c(c1CCC2)C(=O)OCC3
Temperature: 60 °C
Reaction time: 4 h
Yield: 49.6 %

Procedure:
To a solution of ethyl 2-(2-hydroxyethyl)-9-(methylsulfanyl)-2,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxylate 34.8 mg (0.1 mmol) in THF (3 ml) was added p-toluensulfonic acid 1.9 mg (0.01 mmol). The mixture was stirred at 60° C. for 4 hours. Upon completion, the volatiles were removed in vacuo, the residue was purified by flash chromatography eluting with EtOAc/hexane 5/5 to afford 15 mg of the title compound (50% yield).
Reaction SMILES: CS(C)=[O:3].[CH3:5][C@@:6]12[C@@H:14]([C:15]([CH2:17][OH:18])=[O:16])[CH2:13][CH2:12][C@H:11]1[C@@H:10]1[CH2:19][CH2:20][C:21]3[C@@:27]([CH3:28])([C@H:9]1[CH2:8][CH2:7]2)[CH2:26][CH2:25][C:23](=[O:24])[CH:22]=3>C(O)C>[CH3:28][C@@:27]12[C@H:9]3[C@@H:8]([OH:3])[CH2:7][C@:6]4([CH3:5])[C@@H:14]([C:15]([CH2:17][OH:18])=[O:16])[CH2:13][CH2:12][C@H:11]4[C@@H:10]3[CH2:19][CH2:20][C:21]1=[CH:22][C:23](=[O:24])[CH2:25][CH2:26]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Reactant: CS(C)=O
Solvent: CCO
Product: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Temperature: 32 °C
Reaction time: 0.25 h

Procedure:
A suspension of fission yeast (S. pombe PE1) with a cell density of 3·107 cells/ml was prepared on a freshly grown culture using fresh EMMG (pH 7.4) as modified according to Ehmer et al. (Ehmer, P. B. et al., 1. Steroid. Biochem. Mol. Biol. 81, 173-179 (2002)). 492.5 μl of this cell suspension was admixed with 5 μl of inhibitor solution (50 μM of the compound to be tested in ethanol or DMSO) and incubated at 32° C. for 15 min. Controls were admixed with 5 μl of ethanol. The enzyme reaction was started by adding 2.5 μl of 11-deoxycorticosterone (20 μM, containing 1.25 nCi of [4-14C]11-deoxycorticosterone in Ethanol), followed by horizontal shaking at 32° C. for 6 h. The test was quenched by extracting the sample with 500 μl of EtOAc. After centrifugation (10,000 g, 2 min), the EtOAc phase was removed and evaporated to dryness. The residue was taken up in 10 μl of chloroform. The reaction of the substrate to form corticosterone was analyzed by HPTLC (see below).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:18][N:17]3[C:19]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[C:20]([CH3:25])[C:21]4[CH:22]=[CH:23][CH:24]=[C:15]([C:16]=43)[O:14]2)(=O)=O)=CC=1.[C-:35]#[N:36].[K+]>CS(C)=O>[C:35]([CH2:11][CH2:12][CH:13]1[CH2:18][N:17]2[C:19]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[C:20]([CH3:25])[C:21]3[CH:22]=[CH:23][CH:24]=[C:15]([C:16]=32)[O:14]1)#[N:36]
Reactant: [C-]#N
Reactant: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCOS(=O)(=O)c2ccc(C)cc2)O4)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCC#N)O4)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
13.7 9 of 2,3-dihydro-2-[2-(p-toluenesulfonyloxy)ethyl]-5-(4-methoxyphenyl)-6-methylpyrrolo[1,2,3-de]-1,4-benzoxazine (preparation see Example 1F)) were dissolved in 50 ml of hot dimethyl sulfoxide under a nitrogen atmosphere. 2.2 g of potassium cyanide were added to the reaction mixture heated at 80° C. and the mixture was stirred for a further 6 hours. For work-up, the reaction mixture was poured into ice-water after cooling. The resulting brown solid was filtered out and dissolved in dichloromethane. The organic solution was washed with water, dried and evaporated. The crude product remaining as a residue was purified by column chromatography using dichloromethane as an eluent. 9.1 g of 2,3-dihydro-2-(2-cyanoethyl)-5-(4-methoxyphenyl)-6-methyl-pyrrolo[1,2,3-de]-1,4-benzoxazine were obtained as a white solid having a melting point of 113° to 14° C.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]2[CH:22]=[CH:23][C:2]([N:35]3[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]3)=[N:3][C:4]=2[CH3:24])=[O:7])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 80 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 209 mg of 1-Boc-piperizine in 1 mL of BuOH. The reaction mixture was evaporated to afford tert-butyl 4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylate. 150 mg of tert-butyl 4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylate was treated with TFA (1 mL) containing trace amounts of H2O for 2 h. The reaction mixture was diluted with ethyl acetate, washed with 0.1N sodium hydroxide and brine, dried (MgSO4) and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamide. MS (Q1) 408.3 (M)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13]([CH:15]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23](=[O:35])[C:22]2=[O:36])[CH2:16][CH2:17][CH3:18])=[O:14])[CH3:11]>O1CCCC1>[C:31]([O:30][C:28]([NH:24][C:25]1[CH:26]=[CH:27][C:19]([CH:15]([CH2:16][CH2:17][CH3:18])[C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:20][C:21]=1[C:22](=[O:36])[C:23]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:35])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCCC(C(=O)OCC)c1ccc2c(c1)C(=O)C(=O)N2C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCCC(C(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
1.12 g of isoindoline are added to 3.5 g of 5-(1-ethoxycarbonylbutyl)-1-tertbutoxycarbonyl-2,3-dioxoindoline in 50 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The mixture is evaporated to dryness in vacuo and purified by column chromatography, giving 1.4 g (30%) of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-pentanoate; LC-MS retention time: 2.78 min (“nonpolar” gradient).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:4]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:37]=[CH:38][C:39]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:40]([CH:44]=1)[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:35][C:36]1[CH:37]=[CH:38][C:39]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:40]([C:41]([N:14]2[CH2:13][CH2:12][C@@H:11]3[C@@H:16]([N:9]([C:5]4[N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=[CH:7][N:6]=4)[CH2:10]3)[CH2:15]2)=[O:42])[CH:44]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN(c3nccc(C(F)(F)F)n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(4-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 27) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. For C20H17F4N7O, 447.40; m/z found 448.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][O:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[C:27](=[O:29])=[O:28].C(O)C.O>CCOCC.[Na].[Hg]>[CH3:1][CH:2]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][O:5][C:6]1[S:7][C:8]([C:27]([OH:29])=[O:28])=[CH:9][CH:10]=1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1cccs1
Reactant: O=C=O
Agent: [Hg]
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)s1
Temperature: 25 °C

Procedure:
When in Example 3, 1-bromo-3,7,11,15-tetramethylhexadecane is substituted for 1-bromohexadecane, 2-(3,7,11,15-tetramethylhexadecyloxy)thiophene is obtained. A solution of 38.1 g (0.1 mole) of 2-(3,7,11,15-tetramethylhexadecyloxy)-thiophene in 50 ml of anhydrous ether is added over a 4 hour period to 6.0 g of sodium amalgam in 100 ml of hydrous ether at reflux temperature (36°-39° C) under slight nitrogen pressure. The mixture is refluxed an additional 2 hours, then cooled to room temperature and carbonated by adding freshly crushed dry ice after which 20 ml of ethanol is added dropwise followed by the addition of 50 ml of water. The aqueous solution is separated from the ether layer, filtered and acidified with hydrochloric acid to precipitate 5-(3,7,11,15-tetramethylhexadecyloxy)-2-thiophenecarboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[C-:25]#[N:26].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:25]([CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1)#[N:26]
Reactant: O=c1cc(CCl)n(Cc2ccccc2)cc1OCc1ccccc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: N#CCc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Yield: 27.7 %

Procedure:
To a suspension of 2.0 g (6 mmol) of 2-(chloromethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone in 20 ml of acetonitrile was added 3.9 g (60 mmol) of potassium cyanide and 0.1 g of 18-crown-6; the mixture was heated to reflux for 2.5 hours. The salts were filtered off by suction, and the filtrate was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel using ethyl acetate/methanol (8:2) as eluent; yielding 0.55 g of the title compound, melting point 175°-180° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH2:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>C(O)C>[CH:21]1([CH2:20][NH:2][C@H:3]([C:11]([NH2:13])=[O:12])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)[C@H](Cc1ccccc1)NCC1CC1
Yield: 39.1 %

Procedure:
To 100 ml. of anhydrous ethyl alcohol were added 8 grams (0.04 mole) of L-phenylalanine amide hydrochloride. To the mixture then were added 13.4 grams (0.16 mole) of solid anhydrous sodium bicarbonate and 6.44 grams (0.048 mole) of bromomethylcyclopropane. The mixture was refluxed for seven hours and then was evaporated in vacuo to an oil. The oil was dissolved in ethyl acetate, and the ethyl acetate solution was extracted with water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to an oil. The oil was applied to a 3×50 cm. column of Grace and Davison grade 62 silica gel in chloroform. The product was eluted with a gradient of chloroform containing up to 5 percent methanol. The product was isolated according to the thin-layer profile of the fractions collected to give 3.41 grams (39 percent) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].C1(C)C=CC=CC=1.[C:29]([OH:49])(=[O:48])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][C@@H:40]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[OH:41]>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].[C:29]([O-:49])(=[O:48])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][C@@H:40]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[OH:41]
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Solvent: Cc1ccccc1
Product: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)[O-]
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a vial was added retinol in toluene (54% retinol; 1.852 g; 1.0 g retinol; 3.49 mmol), ricinoleic acid (80%; 1.250 g; 4.19 mmol; 1.2 equiv), and Novozym 435 (1 g). The mixture was sealed and stirred at room temperature for 21 h to afford 83% conversion of retinol to 1b.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH2:38])[CH2:33]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(Cl)cccc2Cl)nc1C(=O)O
Product: Nc1sc(-c2c(Cl)cccc2Cl)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(2,6-dichlorophenyl)thiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (9 mg). 1H NMR (500 MHz, DMSO) δ 9.21 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.69-7.60 (m, 2H), 7.56 (dd, J=8.9, 7.3 Hz, 3H), 7.04 (d, J=5.3 Hz, 1H), 3.08 (d, J=8.1 Hz, 1H), 2.97 (d, J=11.9 Hz, 1H), 2.79 (d, J=9.0 Hz, 1H), 2.56 (dd, J=21.5, 11.0 Hz, 1H), 2.48-2.41 (m, 1H), 1.66 (d, J=14.0 Hz, 2H), 1.54 (d, J=10.1 Hz, 1H), 1.11 (d, J=9.8 Hz, 1H). ESIMS m/z=463.1 (M+1).