Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)=[CH:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[H][H]>C1COCC1.[Pd]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH3:39])[CH3:40])(=[O:36])=[O:37])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)[CH2:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)C=C(c1ncco1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(c1ncco1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (45 mg, 0.08 mMol) was dissolved in 3.8 mL of THF and 0.9 mL of methanol added. 10% palladium on carbon (13 mg) was added and the reaction placed under 1 atm (balloon) of hydrogen atmosphere and stirred at room temperature for 18 hrs. The reaction was filtered through a plug of celite and the celite rinsed using dichloromethane. Removal of volatiles from the filtrate in vacuuo yield 47 mg of material which was purified by prep. HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software; % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=20 min; Flow rate=25 ml/min; Column=Waters Sunfire 19 mm×100 mm; Peak collection=10.09 min to 10.88 min. Obtained 33.7 mg (75%) of the title compound as a colorless solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20-1.31 (m, 1.1 H) 1.31-1.52 (m, 2.1 H) 1.66 (d, J=13.12 Hz, 1.1 H) 1.78 (d, J=9.16 Hz, 2.0 H) 1.93 (d, J=13.12 Hz, 1.1 H) 1.96-2.09 (m, 2.9 H) 2.82-2.98 (m, 2.2 H) 3.03-3.08 (m, 6.0 H) 3.11-3.19 (m, 1.0 H) 3.73-3.81 (m, 1.0 H) 3.84 (s, 1.3 H) 3.90 (s, 1.8 H) 3.97-4.02 (m, 0.9 H) 4.05 (dd, J=14.95, 5.80 Hz, 0.7 H) 4.75-4.85 (m, 0.4 H) 4.90 (d, J=14.95 Hz, 0.6 H) 6.84 (d, J=2.44 Hz, 0.4 H) 6.94 (dd, J=8.55, 2.44 Hz, 0.5 H) 6.97-7.01 (m, 1.2 H) 7.09-7.17 (m, 1.0 H) 7.32-7.49 (m, 2.0 H) 7.64 (s, 0.6 H) 7.69 (s, 0.4 H) 7.78-7.87 (m, 1.2 H) 7.90 (d, J=8.55 Hz, 0.4 H) 8.02 (s, 0.4 H) 8.42 (s, 0.5 H) 8.59 (s, 0.4H). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.02 min, purity 99%; Flow injection Mass Spectrometry: MS m/z 563(MH+), m/z 561(M-H)−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[O:27][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C@H:17]([OH:28])[C@@H:18]4[O:27][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 79.9 %

Procedure:
In 200 ml of tetrahydrofuran was dissolved 11.7 g of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one, followed by addition of 36 ml of a 1.0M solution of diisobutylaluminum hydride in toluene under ice-cooling. The mixture was stirred under ice-cooling for 15 minutes. Then, the reaction mixture was worked up in the same manner as Example 68 to recover 9.4 g of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3α-ol (yield: 80%) showing the following physical properties.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>CN(C=O)C.O>[C:2]([CH:3]([CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[CH2:9][CH3:10]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CCCC(Br)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C(=O)OCC)C(C(=O)CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of ethyl 3-oxopentanoate (7.21 mL; 50 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added potassium carbonate (7.6 g; 55 mmol), which has been dried at 120° C. for 12 h before using. After stirring for 15 min at room temperature, ethyl 2-bromovalerate (8.53 mL; 50 mmol) was slowly added under nitrogen and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was poured in water (240 mL) and neutralized by adding a solution of hydrochloric acid 6N. The product was extracted with diethyl ether (2×240 mL) and the combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by distillation under reduced pressure furnished 7.9 g (58%) of the title compound as a colorless liquid (bp. 130-135° C., 4 mbar, temperature of the oil bath 150° C.).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[C-:17]#[N:18].[Na+]>CCO.O>[F:14][C:13]([F:16])([F:15])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]=1[CH2:2][C:17]#[N:18]
Reactant: [C-]#N
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1CBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(C(F)(F)F)cccc1C(F)(F)F

Procedure:
A solution of 0.73 g (2.4 mmol) 2-bromomethyl-1,3-bis-trifluoromethyl-benzene and 0.183 g (3.7 mmol) sodium cyanide in 10 ml EtOH/H2O 6:1 (v/v) was hated to reflux for 3h. Then the reaction mixture was evaporated, the residue taken up in water and extracted with tert-butyl methyl ether. The combined extracts were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and evaporated. Purification by flash chromatography on silica gel with a gradient of 95:5 to 70:30% heptane/ethyl acetate provided (2,6-bis-trifluoromethyl-phenyl)-acetonitrile as colourless crystalline product of m.p. 84.5-86° C.: MS (EI): 253.0 (M.+ ), 234.1 ((M-F) .+), 233.1 ((M-HF)+.), 184.0 (((M-CF3)+.), 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:15][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1ccc2c(Cl)nccc2c1F
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc2c(F)nccc2c1F
Temperature: 140 °C
Yield: 73.7 %

Procedure:
To a solution of 1-chloro-5-fluoro-6-methoxyisoquinoline (0.5 g, 2.363 mmol) in DMSO (5 mL), was added CsF (0.718 g, 4.73 mmol). The mixture was heated to 140° C. for 2 h. The reaction was diluted with ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 30-50% DCM in hexanes. The product fractions were collected and the solvent was removed under vacuum to give 1,5-difluoro-6-methoxyisoquinoline (340 mg, 74% yield). MS m/z 196.2 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.CO.[CH3:16][NH2:17]>O>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([NH:17][CH3:16])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CN
Reactant: CCOc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CO
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])c(NC)n1
Reaction time: 1.5 h

Procedure:
In a stirred mixture consisting of 202.6 g (1 mole) of 2-chlor-6-ethoxy-3-nitropyridine and 500 ml of methanol, 202 g (2.6 mole) of a 40% monomethylamine solution is added drop by drop while stirring in the course of 90 minutes and at 25°-30° C. sump temperature. Subsequently, the mixture is again stirred for yet another 5 hours, is reacted with 650 ml of water, and then the product is filtered off by suction, is washed again with ample water and dried. Melting point 106°-7° C., Yield: 183.2 g (92.9% of theory).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10]Cl)=[O:9])[CH3:4].[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][C:8](=[O:9])[CH2:10][O:17][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:4]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COC(C)(C)C
Temperature: 0 °C

Procedure:
A suspension of sodium hydride (4.44 g, 60% dispersion in mineral oil) in dimethyl formamide (50 ml), at 0° C., was treated dropwise with ethyl-4-chloroacetoacetate (5 ml) and then with tert-butyl alcohol (7.08 ml). This mixture was maintained at 0° C. for 2 hours, then a further 2 hours at ambient temperature and then poured onto 2N hydrochloric acid/ice and then extracted four times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then with water, then with brine, then dried over magnesium sulfate and then evaporated. The resulting yellow oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol (1:9, v/v) to give 4-tert-butoxy-3-oxo-butyric acid ethyl ester (5.20 g) as a yellow oil. TLC (silica, 1:4, v/v ethyl acetate/petrol): RF=0.51. NMR (400 MHz, CDCl3): δ 1.21(9H, s), 1.28(3H, t), 3.55(2H, s), 4.19(2H, q).
Reaction SMILES: C([O:3][C:4](=[O:46])/[CH:5]=[CH:6]/[C:7]1[C:8]([CH3:45])([CH3:44])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[CH:21]1[C@:12]([CH3:43])([C@@:13]3([CH3:42])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)C.[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:35]([O:34][C:32]([C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:42])([CH2:14][CH2:15]2)[C@@:12]2([CH3:43])[CH:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:45])([CH3:44])[C:7](/[CH:6]=[CH:5]/[C:4]([OH:46])=[O:3])=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(/C=C/C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(/C=C/C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 104.4 %

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-benzyl 9-((E)-3-ethoxy-3-oxoprop-1-enyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (20 mg, 0.032 mmol) and 10 N sodium hydroxide (0.032 mL, 0.319 mmol) in dioxane (0.5 mL) and water (0.5 mL) was heated at 100° C. for 3 hours. The reaction mixture was neutralized with 1N HCl to pH=6 and extracted with ethyl acetate (3×4 mL). The extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (20 mg, 105%). This material was used in the next step without further purification. LCMS: m/e 597.68 (M−H)−, 2.50 min (method 6).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccccc1)c1cccnc1Cl

Procedure:
To a cooled solution of 150 g 2-chloro-nicotinoyl chloride in 400 ml benzene there is added slowly 238 g AlCl3. After refluxing 2 hrs. the reaction mixture is added with stirring to a slightly acidic ice: water mixture. The organic layer is separated and the aqueous one is extracted with ethyl ether. The combined organic layers are washed with HONa 1N, then with water, and dried over Na2SO4. The excess benzene is distilled at water pump pressure in a rotary evaporator and the residual oil is distilled in vacuo. Yield: 157 g of title product, b.p. 123° C./0.05 mm; m.p. 35°-7° C.; UV (ethanol): λmax. 254 nm., ε: 17,180; Cl 15.97 (16.29).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([NH:9][CH3:10])[S:8][C:4]=2[CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]2[S:8][C:7]([NH:9][CH3:10])=[N:6][C:5]2=[C:11]([S:14]([Cl:13])(=[O:16])=[O:15])[CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: CNc1nc2ccc(Cl)cc2s1
Product: CNc1nc2c(S(=O)(=O)Cl)cc(Cl)cc2s1

Procedure:
A solution of 6-chloro-N-methylbenzo[d]thiazol-2-amine (500 mg, 2.53 mmol) in chlorosulfonic acid (5 mL) was stirred at 130° C. overnight. The solution was allowed to cool and slowly added to a large excess of ice. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chorography (silica gel) eluting with PE/EA=1:1 to get the title compound. 1H NMR (CHLOROFORM-d) δ: 7.95 (d, J=1.9 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 6.70 (br. s., 1H), 3.16 (d, J=4.3 Hz, 3H). LC-MS: m/z 297 (M+H)+
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].O.[NH2:30][NH2:31]>CO.CC1C=CC(S(O)(=O)=O)=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][C:3]([NH:30][NH2:31])=[O:2])[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: COC(=O)CCC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C(CCC(=O)NN)CCC2c2ccc(F)cc2)cc1
Yield: 83.3 %

Procedure:
To a stirred solution of (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester (1.5 g, 3.7 mmol) in MeOH (15 ml) was added hydrazine hydrate (0.54 ml, 11.1 mmol) and p-TsOH (10 mg) and the reaction mixture was heated under reflux conditions for 24 h. Evaporation and purification by column chromatography on silica gel (dichloromethane/MeOH 19:1) yielded (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid hydrazide (1.25 g, 83%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11])#[N:4].[CH2:12]([CH:14]1[O:16][CH2:15]1)Br>CN(C)C=O>[CH2:12]([O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[C:3]#[N:4])[CH:14]1[O:16][CH2:15]1
Reactant: N#C[C@@H]1CCCC[C@H]1O
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1CCCCC1OCC1CO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 60 mg, 1.59 mmol) was added to a solution of trans-2-cyanocyclohexanol in N,N-dimethylformamide (2.0 mL) and stirred for 10 minutes at room temperature. Epibromohydrin (0.22 g, 1.59 mmol) was then added and the reaction stirred for an additional 3 hours. The solution was partitioned between diethyl ether/water, and the layers separated. The ether layer was washed with water (3×100 mL) and dried over magnesium sulfate and evaporated to give 0.17 g of 2-cyanocyclohexyl glycidyl ether.
Reaction SMILES: [C:1]([N:20]1[C:24]([CH2:25]O)=[C:23]([CH3:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:42]([CH2:25][C:24]1[N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[N:22][C:23]=1[CH3:27])=[N+:43]=[N-:44]
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CN=[N+]=[N-]
Temperature: 60 °C

Procedure:
To a solution of 1-trityl-4-methyl-5-imidazolemethanol (3.7 g, 10 mmol) and DPPA (3.0 ml, 13 mmol) in THF (100 ml) was added DBU (2.0 ml, 13 mmol). The resulting solution was heated to 60° C. for 2 h. The solvents were removed in vacuo and the residue purified by flash chromatography (2:1 hexane/ethyl acetate) to give of the title compound. 1H NMR (CDCl3) d 1.42 (s, 3 H), 4.22 (s, 2 H), 7.10-7.35 (m, 16 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[CH3:9])[CH:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>>[CH3:9][N:8]([CH3:10])[C:4]1[CH:3]=[C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)c1cccc(Br)c1
Reactant: O=C1CCC2(CC1)OCCO2
Product: CN(C)c1cccc(C2(O)CCC3(CC2)OCCO3)c1

Procedure:
The title compound was prepared as a white solid from 1-bromo-3-dimethylamino-benzene (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][O:15][CH2:16][CH:9]1[CH2:10][N:11]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:12]2)C1C=CC=CC=1.[H][H]>CCO.CO.[Pd]>[C:20]1([S:17]([N:11]2[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][O:15][CH2:16]3)[CH2:12]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Yield: 89 %

Procedure:
To a solution of 112e (3.0 g, 8.37 mmol) in EtOH (100 ml) was added Pd/C (0.5 g) in MeOH (30 ml). The reaction mixture was hydrogenated at atmospheric hydrogen at 50° C. for overnight. Then, the catalyst was filtered off, washed with ethanol, and the solvent was evaporated to give 112f as a colorless solid (2.0 g, 90%) MS: [M+H]+: 268
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30]Br.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH2:30][N:7]2[C:2]([OH:1])=[C:3]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C:4](=[O:16])[N:5]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:8])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 10.1 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (example 11a, 357 mg, 1.03 mmoles), 3,4-dichlorobenzyl bromide (193 uL, 1.13 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) in dimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3 mL) for 3 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water—0.1% TFA, 20-100%) and crystallization from ethanol-water gave the title compound (50 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (s, 1 H), 10.11 (t, J=5.68 Hz, 1 H), 7.59 (dd, J=5.18, 3.16 Hz, 2 H), 7.24-7.34 (m, 6 H), 5.01 (s, 2 H), 5.02 (s, 2 H), 4.14 (d, J=5.81 Hz, 2 H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:53]=[CH:52][C:51]2[CH2:50][CH:49]([C:54](O)=[O:55])[CH2:48][CH2:47][C:46]=2[N:45]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:54]([CH:49]1[CH2:48][CH2:47][C:46]2[N:45]=[C:44]([C:43]([F:58])([F:42])[F:57])[CH:53]=[CH:52][C:51]=2[CH2:50]1)=[O:55])[CH3:4]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: O=C(O)C1CCc2nc(C(F)(F)F)ccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([C@@H](C)NC(=O)C2CCc3nc(C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Yield: 73.9 %

Procedure:
A 2 mL vial was charged with (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (14 mg, 0.049 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (17 mg, 0.044 mmol). A solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (6.0 mg, 0.024 mmol) and N,N-diisopropylethylamine (21 uL, 0.12 mmol) in N-methylpyrrolidinone (0.4 mL, 4 mmol) was added, and the mixture stirred to dissolution. After 40 min the mixture was filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (8.4 mg, 72%). 1H NMR (400 MHz, CD3OD) δ 7.73 (app t, J=8.3 Hz, 1H), 7.53 (dd, J=3.8, 8.0 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.14 (dd, J=1.4, 11.7 Hz, 1H), 5.19 (app pentet, J=7.0 Hz, 1H), 3.17-2.94 (m, 4H), 2.98 (s, 3H), 2.82-2.71 (m, 1H), 2.32 (s, 3H), 2.23-2.12 (m, 1H), 2.07-1.89 (m, 1H), 1.47 (d, J=7.0 Hz, 3H); m/z=474.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.O.C(=O)(O)[O-].[Na+].[F:27][C:28]([F:36])([F:35])[C:29]([F:34])([F:33])[C:30](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)=[CH:6][C:5]2[NH:19][C:30]([C:29]([F:34])([F:33])[C:28]([F:36])([F:35])[F:27])=[N:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 49.7 %

Procedure:
A solution of 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (200 mg, 0.66 mmol) in pentafluoropropanoic acid (2 ml) was stirred overnight at 80° C. in an oil bath. The solution was poured into water (50 ml), adjusted pH to 8 with sodium bicarbonate (sat) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 8% ethyl acetate in petroleum ether to produce 5-chloro-2-(pentafluoroethyl)-6-[4-(trifluoromethyl)phenoxy]-1H-1,3-benzodiazole as a white solid (141.7 g, 49.7%).