Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.[C:23](O)(=[O:27])[C:24]([CH3:26])=[CH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>C(Cl)(Cl)Cl>[C:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)O
Reactant: O=C(O)c1ccc(OCCCCCCCCCCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 79.2 %

Procedure:
In 200 ml of chloroform were dissolved 15.0 g (48.6 mmol) of the compound (2), 60.0 g (697 mmol) of methacrylic acid, 2.0 g of p-toluenesulfonic acid, and 3.0 g of hydroquinone as polymerization inhibitor. The whole was refluxed for 13 hours under removing water formed. Then, after removal of solvent, the reaction mixture was poured into a plenty of ice-water, and the resulting precipitate was collected by filtration and dried after washing with water. The obtained white solid was recrystallized from acetone to obtain 14.5 g of p-(11-methacryloxyundecyloxy)benzoic acid (3) (yield: 78.9%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40]([O:42][CH3:43])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:37]1[CH2:38][CH2:39][N:34]([C:40]([O:42][CH3:43])=[O:41])[CH2:35][CH2:36]1
Reactant: COC(=O)N1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: COC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 13 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of methyl piperazine-1-carboxylate as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:10][C:11]1[N:12]=[C:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:14][C:15]=1[CH2:16][CH2:17]O.[OH-].[Na+]>O>[CH3:10][C:11]1[N:12]=[C:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:14][C:15]=1[CH2:16][CH2:17][O:2][N+:1]([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(-c2cccnc2)sc1CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2cccnc2)sc1CCO[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 41 %

Procedure:
3-[4-Methyl-5-(2-nitrooxy-ethyl)-thiazole-2-yl]-pyridine was prepared by drop-wise addition of 1.145 gr. of nitric acid (70%) to 1.78 grams of cooled sulfuric acid (95–98%) at 0–5° C., followed by addition of 4 grams (0.0181 moles) 2-(4-methyl-2-pyridin-3-yl-thiazole-5-yl)-ethanol over a time period of 30 minutes at 0–5° C. After the addition was completed the reaction mixture was stirred for 30 minutes at 0–5° C., and for one additional hour at room temperature. The reaction mixture was then added carefully to 25 ml of cold water. The water solution was turned basic with an aqueous 20% solution of sodium hydroxide and the aqueous phase was extracted with three portions of 75 grams of dichloromethane. The extracts were combined, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The nitration step was confirmed initially by thin-layer chromatography stained with diphenylamine as a marker for the nitrate ester moiety (FIG. 1). Chromatography of the crude product on silica gel (using ethyl acetate as eluent) gave 1.5 grams (41% yield) of Pet-12 as a pale yellow liquid having a purity of 99% as determined by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Br)c(F)c1)OCC
Temperature: 135 °C
Yield: 101.3 %

Procedure:
4-Bromo-3-fluorophenol (7 g, 0.03665 mol) and potassium carbonate (7.6 g, 0.055 mol) were dissolved in N,N-dimethylformamide (9 mL). 2-Bromo-1,1-diethoxyethane (8.5 mL, 0.055 mol) was added and the reaction mixture was stirred and heated to 135° C. for 7 h. The solvent was removed after the reaction was completed. The residue was dissolved in ethyl acetate and washed with 2M NaOH solution. The organic phase was dried over Na2SO4. The solvent was evaporated to yield 1-bromo-4-(2,2-diethoxyethoxy)-2-fluorobenzene as an oil (11.4 g, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16]([O:17][CH3:18])=[C:10]2[CH2:9]1)=O)(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[CH3:18][O:17][C:16]1[N:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:14]=[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=12
Reactant: CCOC(=O)Cn1nc2c(c1OC)CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1nc2c(c1OC)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of methylene chloride was dissolved 2.73 g (8.40 mmol) of ethyl 5-t-butoxycarbonyl-3-methoxy-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-acetate, and under ice-cooling, 10 ml of CF3CO2H was added to the solution and the mixture was stirred at room temperature for 2 hours.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][N:19]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([O:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCCC(Oc2ccnc(Cl)c2)C1
Yield: 84.5 %

Procedure:
Using the method of Example 3, Step A, tert-butyl 3-hydroxypiperidine-1-carboxylate (1.90 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9-46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide tert-butyl 3-(2-chloropyridin-4-yloxy)piperidine-1-carboxylate (2.50 g, 84% yield) as an oil. 1H NMR (CDCl3) δ 8.20 (d, 1H), 6.84 (s, 1H), 6.76 (d, 1H), 4.34 (m, 1H), 3.10-4.05 (bm, 4H), 1.50-2.05 (bm; 4H), 1.40 (bs, 9H).
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[K+]>[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:2])=[CH:17][CH:16]=1
Reactant: C=Cc1ccccc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: C=Cc1ccc(O)cc1
Temperature: 65 °C

Procedure:
50.0 g of 20 percent poly(4-vinylpyridine) methanol solution from Ex. 1 (˜10.0 g of polymer) was placed in a 500 ml single neck flask and stripped of solvent on a rotary evaporator. To the dried polymer was then added 110 g of RO water and 10.0 g of con. hydrochloric acid. The mixture was stirred until a uniform pale yellow aqueous solution was obtained. This solution was then charged into a 500 ml three-necked round bottom flask equipped with a mechanical paddle stirrer, a nitrogen inlet, a pot thermometer, heating mantle and condenser. 0.6 g of potassium persulfate was then added followed by 30.0 g (˜0.288 moles) of styrene. The biphasic stirred mixture was then rapidly heated to 65° C. under nitrogen for 8 hrs. The final latex solids were determined to be 26.7 percent (theory 27.1 percent) or 98.5 percent conversion. A small portion of the final latex was coagulated in dilute potassium hydroxide solution for analysis. NMR indicated a composition of 25.8 percent poly(4-VP) and 74.2 percent polystyrene (theory 25 percent poly(4-VP) and 75 percent PS). Latex particle size was ˜182 nm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.C[O:27]B(OC)OC.O>O1CCCC1>[CH:12]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([OH:27])[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(O)cnc21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a mixture of EXAMPLE 338F (24.3 g) in tetrahydrofuran (500 mL) at −78° C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5 mL) was added, and the mixture was allowed to warm to room temperature over 1 hour. The reaction was poured into water, extracted three times with ethyl acetate, and the combined extracts were washed with brine and concentrated. The crude product was taken up in tetrahydrofuran (200 mL) at 0° C., and 1M aqueous NaOH (69 mL) was added, followed by 30% aqueous H2O2 (8.43 mL), and the solution was stirred for 1 hour. Na2S2O3 (10 g) was added, and the pH was adjusted to 4-5 with concentrated HCl and solid NaH2PO4. The solution was extracted twice with ethyl acetate, and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 5-25% ethyl acetate/hexanes.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18](=O)[CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22].CO.C([BH3-])#N.[Na+].C(Cl)[Cl:31]>>[ClH:31].[ClH:31].[NH2:22][CH2:21][CH2:20][NH:23][CH:18]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17]1
Reactant: NCCN
Reactant: ClCCl
Reactant: O=C1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cl
Product: NCCNC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 13 h
Yield: 32 %

Procedure:
A portion (0.20 g) of the compound obtained in Example 41 and ethylenediamine (0.54 ml) were suspended in a mixed solvent of methanol (3 ml) and methylene chloride (3 ml) and to the suspension was added sodium cyanoborohydride (61 mg). The mixture was stirred for 13 hours at room temperature and heated to reflux for further 20 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with three portions of methylene chloride. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride/methanol=19:1-9:1-4:1). The resulting brown foam was dissolved in a solution (3 ml) of 10% hydrochloric acid in methanol and the solution was concentrated. The concentrate was crystallized from ether to yield 93 mg (32%) of the titled compound as brown crystals.
Reaction SMILES: [OH:1][C@H:2]([CH2:16][OH:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15].C(NCCCCC1C=CC=CC=1OC[C@@H](O)CO)(OCC1C=CC=CC=1)=O>>[OH:1][C@@H:2]([CH2:16][OH:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: NCCCCc1ccccc1OC[C@H](O)CO
Agent: O=C(NCCCCc1ccccc1OC[C@@H](O)CO)OCc1ccccc1
Product: NCCCCc1ccccc1OC[C@@H](O)CO
Yield: 99 %

Procedure:
Compound 73 was prepared in a similar fashion to the synthesis of compound 70 starting from compound 72 (1.67 g, 4.5 mmol). Amine 73 (1.06 g, 99%) was isolated as a white solid. 1H NMR (300 MHz, DMSO-d6) d 1.32 (m, 2H), 1.54 (m, 2H), 2.55 (m, 2H), 3.45 (m, 2H), 3.75 (m, 3H), 3.94 (m, 2H), 6.83 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].C[N:15]1CCOCC1.ClC(OCC(C)C)=O.[NH:29](N)[C@H:30]([C:35]([N:37]([CH3:40])[O:38][CH3:39])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33].Cl>C1COCC1.O1CCOCC1>[CH3:40][N:37]([C:35](=[O:36])[C@H:30]([CH2:31][CH:32]([CH3:33])[CH3:34])[NH:29][C:4](=[O:6])[C@H:2]([CH3:3])[N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH2:15])[O:38][CH3:39]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CON(C)C(=O)[C@H](CC(C)C)NN
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](C)N(N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Boc-Ala-OH (46 mmol) and N-methyl morpholine (46 mmol) in THF (20 ml) was added to a pre cooled solution of isobutyl chloroformate (46 mmol) in THF (30 ml) under nitrogen at between -10 and -15° C. over 30 minutes. The reaction was stirred at -10° C. for 1 hour after which time a solution of N-methyl morpholine (46 mmol) and HCl.H2N-Leu-N(OMe)Me (41.8 mmol) in 1,4-dioxane (20 ml) was added drop wise slowly. The reaction was left for 1 hour at -10° C. and then allowed to warm up to room temperature. After concentrating the solution under high vacuum, water (50 ml) and ethylacetate (200 ml) was added. The organic layer was then washed with 0.1 M citric acid solution (4×50 ml), then saturated sodium bicarbonate (4×50 ml), dried over magnesium sulphate and then concentrated under vacuum to give the product.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]([OH:11])(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:24]([OH:33])[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>C1COCC1.O>[C:7](=[O:11])([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])[O:33][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]
Reactant: O=C(CO)c1ccccc1
Reactant: CC(C)(C)O
Reactant: CC(C)(C)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Potassium tert-butoxide (0.543 g, 4.83 mM) and t-butyl alcohol (0.525 g, 7.08 mM) were stirred in 15 mL dry THF. The mixture was added to a suspension of carbonyldiimidazole (1.5 g, 9.26 mM) in 15 mL dry THF. The mixture was stirred at room temperature for about 14 h. Phenacyl alcohol (0.643 g, 4.73 mM) was added to the reaction mixture and stirred at 0° C. for 2 h. About 30 mL water was added to the mixture and the carbonate was extracted with (3×50 mL) dichloromethane. The carbonate was purified using 4:1 hexane ethyl acetate. Yield 0.429 g (38%) from 0.643 g phenacyl alcohol, yellow oil; 1H NMR (CDCl3, 400 MHz) δ1.50 (s, 9H), 5.23 (s, 2H), 7.43-7.59 (m, 3H), 7.88 (d, J=7 Hz, 2); 13C NMR (CDCl3, 400 MHz) δ192.3, 153.1, 134.1, 133.9, 128.8, 127.7, 83.0, 67.9, 27.7; FAB-MS, m/z (rel. intensity) 237 (M+1, 13),181 (100), 163 (14), 119 (21), 105 (49), 91 (21), 77 (9), 57 (73); HRMS calcd for (M+1) C13H17O4; 237.1127, found: 237.1135.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:9]=[C:8]([S:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].C(OCC)(=[O:30])C.[OH2:34]>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:30])=[O:34])[CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:23])([F:24])[F:22]
Reactant: CCOC(C)=O
Reactant: C[C@@](O)(C(=O)Nc1ccc(Sc2ccc(F)cc2)cc1Cl)C(F)(F)F
Reactant: O
Agent: OO
Solvent: CC(=O)O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1Cl)C(F)(F)F
Temperature: 100 °C
Yield: 72 %

Procedure:
Hydrogen peroxide (0.3 ml of a 30 wt. % solution in water) was added to a solution of (R)-N-[2-chloro-4-(4-fluorophenylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 188) (0.283 g) in glacial acetic acid (1.0 ml) and the mixture was stirred and heated at 100° C. for 80 minutes then allowed to cool. Ethyl acetate (40 ml) was added and the solution was washed with water (20 ml), saturated aqueous sodium hydrogen carbonate solution (20 ml) and brine and then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-25% ethyl acetate/hexane to give the title compound (0.261 g; 72%) as a solid Mp 131-133 ° C.; NMR: 1.6 (s, 3H), 7.46 (t, 2H), 8.0 (dd, 1H), 8.08 (m, 2H), 8.15 (d, 1H), 8.3 (d, 1H), 9.85 (brs, 1H); MS (ESP+): 426 (M+H)+.
Reaction SMILES: [N:1]1[CH2:2][CH2:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(#N)C.[Br:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[Br-:13].[CH2:14]([NH+:1]1[C:5]2=[CH:6][CH:7]=[CH:8][CH2:9][N:4]2[CH2:3][CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: C1=CC2=NCCN2C=C1
Solvent: CCOCC
Solvent: CC#N
Product: C1=CCN2CC[NH+](Cc3ccccc3)C2=C1
Product: [Br-]
Temperature: 25 °C

Procedure:
To 2.0 g. of 2,3-dihydroimidazo[1,2-a]pyridine in 40 ml. of dry acetonitrile is added 3.42 g. of α-bromotoluene and the resulting mixture heated to reflux overnight. The solution is cooled to room temperature and treated with 30 ml. of diethyl ether. The precipitated solid is filtered and recrystallized from acetonitrile, 1.64 g., m.p. 143°-145° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:11]([O-:13])=[O:12].[Na+]>C(O)C.O>[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[C:8]=1[N+:11]([O-:13])=[O:12].[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[C:8]=1[N:11]=[O:12]
Reactant: O=N[O-]
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)cc(C)c1N=O
Product: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 143.3 %

Procedure:
[3,5-Dimethyl-4-nitrophenol was synthesized by the reference procedures (U.S. Pat. No. 4,564,640)] 750 ml of Concentrated hydrochloric acid was added to a solution of 3,5-dimethylphenol (80.6 g) in 750 ml of 95% ethanol. The mixture was cooled to 0° C. in an ice/methanol bath. While maintaining the temperature of the reaction mixture below 5° C., a solution of NaNO2 (69.0 g) in 150 ml of water was added dropwise to the reaction mixture. The mixture was stirred at 0° C. for more than an hour and then poured into 9 liters of water. The aqueous mixture was filtered to give a yellow solid which was recrystallized from hot methanol and filtered to give 71.45 g of 3,5-dimethyl-4-nitrosophenol as a yellow solid. Mp. 180-181° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([SH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[C:16](/[C:25](/I)=[CH:26]/[C:27](=O)[C:28]2[NH:29][CH:30]=[CH:31][CH:32]=2)=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.[H-].[Na+].[H][H]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:25]2[CH:26]=[C:27]([C:28]3[NH:29][CH:30]=[CH:31][CH:32]=3)[C:18]3[C:19](=[O:24])[NH:20][C:21]4[C:17]=3[C:16]=2[C:15]([F:14])=[CH:23][CH:22]=4)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](S)C1
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC[C@H](Sc2cc(-c3ccc[nH]3)c3c4c(ccc(F)c24)NC3=O)C1
Temperature: 120 °C

Procedure:
To a mixture of (S)-3-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester (from Example 55 above) (1.35 g, 5.81 mmol) and (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (100 mg, 0.20 mmol) was added NaH (48 mg, 2.01 mmol) in small portions at room temperature. After the evolution of hydrogen ceased, the mixture was heated to 120° C. for 1 hour then cooled and partitioned between ethyl acetate and water. The water layer was extracted with ethyl acetate (3×) and the combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC (silica gel, 25% ethyl acetate in hexanes) followed by a precipitation out of THF with excess of pentane to give (S)-3-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid. (Yield 57 mg; 62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[F:14][C:15]([F:26])([F:25])[CH2:16]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][C:15]([F:26])([F:25])[F:14])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 0 °C

Procedure:
Under an atmosphere of nitrogen a solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.31 mmol) in N,N-dimethylformamid (2 ml) was treated at room temperature with sodium hydride (55% dispersion in oil, 64 mg). After the gas formation had ceased, the suspension was cooled to 0° C. and trifluoro-methanesulphonic acid 2,2,2-trifluoro-ethyl ester (364 mg, 1.57 mmol) was added. After stirring at room temperature for 2 hours about 50% of the starting material was left. Another 364 mg of trifluoro-methanesulphonic acid 2,2,2-trifluoro-ethyl ester were added and after 30 minutes the reaction was complete. For the workup, the reaction mixture was treated with a saturated solution of sodium carbonate, then extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulphate, and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a 3:1-mixture of heptane and ethyl acetate as the eluent. The 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester was obtained as a white solid (216 mg, 70% of theory). MS (ISP): m/z=236.3 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[N:24]3[CH:25]=[N:26][CH:27]=[C:23]3[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[N:24]3[CH:25]=[N:26][CH:27]=[C:23]3[CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1)=[O:11]
Reactant: OCc1ccc(C2CCCc3cncn32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccc(C2CCCc3cncn32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.16 ml of dimethylsulfoxide in 16 ml of methylene chloride is cooled to -70° under nitrogen and 0.17 g of oxalyl chloride is added dropwise. The reaction mixture is stirred for 30 min and 0.24 g of 5-(p-hydroxymethylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 4 ml of methylene chloride is added slowly. The reaction mixture is stirred for 2 h at -70°, 0.8 ml of triethylamine is added dropwise, and the reaction mixture is allowed to warm slowly to room temperature. The reaction mixture is diluted with 20 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated to yield the title compound which is purified by conversion to the fumaric acid salt, m.p. 131°.