Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=2[F:22])[NH:4][CH:3]=1.C([Li])CCC.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=2[F:22])[N:4]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc3[nH]cc(Br)c23)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Oc2ccnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3.23 g (8.87 mmol) of N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluorophenyl}acetamide are dissolved in 500 ml of THF and cooled to −78° C. 3.90 ml (9.76 mmol) of a 2.5M n-butyllithium solution are added, and the mixture is stirred for 15 min. 1.86 g (9.76 mmol) of p-toluenesulfonyl chloride are then added dropwise as a solution in 20 ml of THF. The reaction solution is allowed to warm to RT and stirred for one hour. Sodium bicarbonate solution is then added, and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.Cl.N1C=NC=N1.O>CN(C)C=O>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: Clc1ccnc2ccccc12
Reactant: c1nc[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(-n3cncn3)ccnc2c1

Procedure:
3.27 g of 4-chloro-quinoline, 1.38 g of 1H-1,2,4-triazole and 0.21 g of 1H-1,2,4-triazole hydrochloride are mixed in 10 ml of dimethyl-formamide for 1 hour at 80° C. The reaction mixture is added to 50 ml of water, neutralized with cc. aqueous ammonia, the precipitate is filtered, washed with water and recrystallized from 15 ml of ethanol. 2.47 g /63%/ of 4-(1H-1,2,4-triazole-1-yl)-quinoline (Substance 1) are obtained. M.p.:147°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])(=[O:12])=[O:11].Br[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:21][C:22]([OH:24])=[O:23])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccccc1NS(=O)(=O)c1ccccc1C
Product: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of N-(2-methoxy-phenyl)-2-methyl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]([O:21]C)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>>[C:27]([O:26][C:24](=[O:25])[CH2:23][C:18]([N:13]1[C:14]2[C:10](=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1)([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:19]([OH:21])=[O:20])([CH3:29])([CH3:30])[CH3:28]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)CC(C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product of step A (1.8 g, 3.4 mmol) and 3 N LiOH (410 mg, 17 mmol) was stirred at room temperature for 3 h. After the solvent was evaporated, the residue was dissolved in ethyl acetate (20 mL), and pH value adjusted to 6-7 with 1 M HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as colorless oil. LC/MS m/z=515.2[M+H]+.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH2:18][O:19][CH2:20][CH2:21][CH:22](CC)[CH2:23][CH2:24][CH3:25])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[ClH:28].OC(COC1C=CC([Cl:53])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:53].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[C:22]([Cl:1])[CH:23]=[CH:24][C:25]=1[Cl:28])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CCCC(CC)CCOC[C@@H](O)CNC(C)(C)Cc1ccc(OC)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(Cl)ccc2Cl)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M-15,.1), 280 (11), 279 (9), 278 (64), 276 (100), 163 (9), 161 (5), 121 (29) , 113 (8).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([CH2:21]O)[CH:18]=[C:19]([CH3:20])[C:14]=3[N:13]=[C:12]2[CH2:23][CH2:24][CH3:25])=[CH:6][C:5]=1[F:26].CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([CH2:21][N:42]=[N+:43]=[N-:44])[CH:18]=[C:19]([CH3:20])[C:14]=3[N:13]=[C:12]2[CH2:23][CH2:24][CH3:25])=[CH:6][C:5]=1[F:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(CO)cc2n1Cc1ccc(C(=O)OC)c(F)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2c(C)cc(CN=[N+]=[N-])cc2n1Cc1ccc(C(=O)OC)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
Intermediate (8a) (2.4 g, 6.5 mmol) was added to 125 mL of DCM followed by DIPEA (4.6 mL, 26.1 mmol) and 4-dimethylaminopyridine (80 mg, 653 μmol). Methanesulfonyl chloride (1.0 mL, 13.1 mmol) was then added at 0° C. and the mixture was warmed to room temperature. After 3 hours, the mixture was concentrated and the material redissolved in 40 mL DMF. Sodium azide (467 mg, 7.2 mmol) was added and the mixture was heated at 80° C. for 1 hour. The mixture was then cooled to room temperature. The solution was partitioned between EtOAc (100 mL) and 50 mL 10% LiCl (aqueous). The organic layer was concentrated and flash chromatographed 20-70% EtOAc:hexanes to yield Intermediate (8b) as a yellow oil (2.1 g). MS m/z: [M+H+] calcd for C21H22FN5O2, 396.2. found 396.0.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[OH:16])(=[O:7])=[O:6])[CH:2]=[CH2:3].[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:4][S:5]([C:8]1[C:9]([OH:16])=[C:10]([NH:15][C:26]([NH:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[Cl:17])=[O:27])[CH:11]=[CH:12][C:13]=1[Cl:14])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: C=CCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 29.1 %

Procedure:
A solution of crude N-allyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (20 mg) and 2,3-dichlorophenylisocyanate (12 μL, 0.09 mmol) in 1 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), gave the desired product (10 mg, 29% for two steps). EI-MS (m/z) 450.2, 452.2, 454.1 (M−).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]=2[S:7](=[O:19])(=[O:18])[NH:6][C:5]=1[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21])=[CH:16][CH:15]=[CH:14][CH:13]=3.[CH3:28]I>CO>[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]=2[S:7](=[O:19])(=[O:18])[N:6]([CH3:28])[C:5]=1[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21])=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C(Nc1nccs1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
3.15 ml of 1 N sodium hydroxide (3.15 millimols) were added dropwise to a suspension of 1.12 gm (3 millimols) of 4-hydroxy-N-(2-thiazolyl) 2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide in 50 ml of methanol and 1.7 gm (12 millimols) of methyl iodide, whereby a reddish solution was formed. The solution was stirred at room temperature for 72 hours and was then evaporated to dryness in vacuo. The residue was triturated with water, filterd off and recrystallized from ethylene chloride, yielding 0.47 gm (40.5% of theory) of 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 249°-250° C (decomp).
Reaction SMILES: [Mg].[CH3:2]I.[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=O.O>C(OCC)C>[CH3:2][C:5]1[CH2:6][C:7]2[C:12]([CH:4]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CI
Reactant: O=C1Cc2ccccc2C1
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CC1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
50 ml of diethyl ether was added to 2.5 g of magnesium. A solution of 14.3 g of methyliodide in 50 ml of diethyl ether was added in 1 hour, with cooling with the aid of a water bath. Then the reaction mixture was stirred for 30 minutes at room temperature. A solution of 13.2 g of 2-indanone in 40 ml of diethyl ether was then added to this reaction mixture, followed by 30 minutes' stirring. 100 ml of water was then added. The organic layer was separated from the water layer. This water layer was washed twice, using 50 ml of dichloromethane, after which the combined organic layers were dried over magnesium sulphate. The filtrate obtained after removal of the drying agent through filtration was concentrated through evaporation to yield 14.0 g of residue. This residue was dissolved in 100 ml of toluene, after which 4 drops of concentrated sulphuric acid were added and the resulting reaction mixture was refluxed for 30 minutes. After cooling to room temperature, the mixture was washed once using 50 ml of water. The toluene was removed through evaporation, after which the residue was distilled under a vacuum. Yield: 4.0 g of 2-methylindene (30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8](C1C=CC=CC=1)=[C:7]2[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br>>[CH2:7]([C:8]1[N:9]=[N:10][C:11]2[C:6]([C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:36])([F:35])[F:25])[CH:28]=3)[CH:19]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:6]1[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Oc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: FC(F)(F)c1cccc(COc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenol and 3-trifluoromethylbenzyl bromide according the procedure of Example 14. MS (ES) m/z 504.8.
Reaction SMILES: [CH2:1]([C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[O:22])[CH:1]([C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:21]
Reactant: CCCCCCCCCCCCCC#N
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(C#N)C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 Moles of n-tridecyl cyanide and 0.5 moles of diethyl oxalate are mixed in 1,000 ml of dimethylformamide. To this solution is added with ice cooling 0.52 moles of potassium t-butoxide. The mixture is allowed to stir overnight at room temperature. Following evaporation (rotary evaporator under vacuum) of most of the dimethylformamide the residue is mixed with 3 liters of diethyl ether followed by the addition of 1 liter water. The mixture is acidified with concentrated hydrochloric acid to a pH of 3 and then the ether phase is separated. After washing the ether with water and drying the ether over magnesium sulfate evaporation of the ether affords 3-cyano-2-oxopentadecanoic acid ethyl ester. Recrystallization from petroleum ether at 30°-60° C. provides pure material.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[CH2:12](O)[CH2:13][OH:14].C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:4][CH2:5][C:6]1([CH2:7][CH2:8][CH:9]=[CH2:10])[O:14][CH2:13][CH2:12][O:11]1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: C=CCCC(=O)COC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCCC1(COC(C)=O)OCCO1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 15.6 g. (0.1 mole) of 1-acetoxy-5-hexen-2-one, 18.6 g. (0.3 mole) of ethylene glycol in 250 ml. of benzene containing 1.56 g. of p-toluene sulfonic acid monohydrate is heated to reflux using a Dean-Stark water separator. After 2 hours, the reaction mixture is shaken well with 250 ml. of cold water. The aqueous layer is washed with 3×25 ml. of ether. The combined organic layers are dried over anhydrous magnesium sulfate. Evaporation of the solvent gives 2-acetoxymethyl-2-(3-buten-1-yl)-1,3-dioxolane in 90% yield as a light brown oil. ##STR41##
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:15])=[O:14])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39](=[O:41])[CH3:40])=[CH:18][C:17]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:14])=[O:15])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1)C(N)=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCc2ccccc2)c1
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-succinamic acid tert-butyl ester (1.41 g, 3.10 mmol) in methylene chloride (100 mL) and Et3N (0.44 mL, 3.10 mmol) was added acetyl chloride (0.25 mL, 3.1 mmol). The reaction was stirred for 3 h. The solvent was removed and replaced with EtOAc (150 mL). The organic solution was washed twice with 5% citric acid, saturated NaHCO3, water, and brine. The solution was dried over MgSO4, filtered, and the solvent was removed. The resulting crude product was purified using silica gel flash chromatography (20% hexanes in EtOAc). (S)-3-(4-Acetylamino-2-benzyloxy-benzenesulfonylamino)-succinamic acid tert-butyl ester was obtained in 63% yield (0.96 g) as an off white foam. MS (APCI) m/z 490.2 (M−1).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:24]=[CH:23][C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(F)(F)F)cc2)C(N)C1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Product: NC(=O)c1ccnc2c(NC3CNCCC3c3ccc(C(F)(F)F)cc3)ncnc12

Procedure:
Compound 25 was prepared following general synthesis scheme 9 wherein 4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [417 (M+H)], 1H NMR (400 MHz, DMSO-d6) δ 9.77 (d, 1H), 8.99 (d, 1H), 8.93-8.82 (m, 1H), 8.82-8.70 (m, 1H), 8.65 (d, 1H), 8.36 (d, 2H), 8.16 (d, 1H), 7.48 (t, 4H), 5.37-5.21 (m, 1H), 3.75-3.42 (m, 1H), 3.26-3.06 (m, 1H), 2.02 (d, 1H).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH2:11][CH3:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][CH:15]([N:17]1[C:21]([NH2:22])=[CH:20][CH:19]=[N:18]1)[CH3:16]>C1C=CC=CC=1>[CH3:14][CH:15]([N:17]1[C:21]2[N:22]=[C:9]([CH2:10][CH2:11][CH3:12])[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:20]=2[CH:19]=[N:18]1)[CH3:16]
Reactant: CC(C)n1nccc1N
Reactant: CCCC(=O)CC(=O)C(=O)OCC
Solvent: c1ccccc1
Product: CCCc1cc(C(=O)OCC)c2cnn(C(C)C)c2n1
Temperature: 62 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
To a solution of ethyl 2,4-dioxoheptanoate (446 mg, 2.397 mmol) in benzene (5 mL) was added 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and the mixture was stirred at 62° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (Silica gel, gradient of 0 to 100% EtOAc/hexanes) to give 370 mg (56%) of product. LCMS E-S (M+H)=276.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.12 (m, 3H), 1.46-1.54 (m, 3H), 1.58-1.70 (m, 6H), 1.82-1.96 (m, 2H), 2.91-3.02 (m, 2H), 4.51 (q, J=7.2 Hz, 2H), 5.28-5.44 (m, 1H), 7.58-7.68 (s, 1H), 8.27-8.40 (s, 1H)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[S:17]([N:20]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH2:24][O:23][CH2:22][C@H:21]2[CH2:32][C:33]#[N:34])(=[O:19])=[O:18])[CH:10]=[CH:9][CH:8]=1.Cl>CN(C=O)C>[NH:1]1[C:33]([CH2:32][C@H:21]2[N:20]([S:17]([C:15]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:16]=3[N:7]=[CH:8][CH:9]=[CH:10]4)(=[O:19])=[O:18])[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH2:24][O:23][CH2:22]2)=[N:34][N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2COC[C@H]1Cc1nnn[nH]1
Temperature: 125 °C
Reaction time: 48 h
Yield: 27.5 %

Procedure:
To the mixture of sodium azide (48 mg, 0.75 mmol) and ammonium chloride (40 mg, 0.75 mmol) in dry DMF (5 mL) was added compound 24 (100 mg, 0.25 mmol) under a nitrogen atmosphere. The mixture was stirred at 125° C. for 48 hr. The cooled reaction was poured into ice water and acidified to pH=1 with 1N HCl. The mixture was concentrated in vacuo and purified by Prep-HPLC to obtain compound 25 (30 mg, 27% yield). LCMS (m/z): 437.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:44]=[C:45]([N+:47]([O-])=O)[CH:46]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:43])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8])([O-])=O>CN(C)C=O.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:44]=[C:45]([NH2:47])[CH:46]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:43])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N)cc(C(=O)OCCCCCCOC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 90.7 %

Procedure:
18.80 g (0.027 Mol) of 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-dinitrobenzoate are dissolved in a mixture of 350 ml of N,N-dimethylformamide and 25 ml water. 44.28 g (0.164 Mol) ferric chloride hexahydrate are added. 17.85 g (0.273 Mol) Zinc powder are added portionwise within 40 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 400 g silica gel using toluene:ethyl acetate (2:1) as eluant yielded 15.39 g (91%) of 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-diaminobenzoate as yellowish crystals.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[OH-].[K+].NC1C2CCN(CC2)C1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:31]([S:34](=[O:37])(=[O:36])[NH2:35])=[CH:30][C:26]=1[C:27]([Cl:29])=[O:28]>O.O1CCCC1>[OH2:24].[ClH:29].[NH2:35][S:34]([C:31]1[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[C:26]([CH:30]=1)[C:27]([NH:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1)=[O:28])(=[O:36])=[O:37]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)Cl
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NC1CN2CCC1CC2

Procedure:
A solution of 3-aminoquinuclidine dihydrochloride (2.5 g, 0.0126 mole) in 25 ml of water was treated with approximately 5 g of KOH and the resultant slurry/solution taken to complete dryness on the rotary evaporator at 50°/35 mm. The dry residue was carefully extracted by repeated triturations with warm tetrahydrofuran until a total volume of 130 ml had been collected and dried over magnesium sulfate. This solution of 3-aminoquinuclidine base was treated with a solution of 2-methoxy-5-sulfamylbenzoyl chloride (2.92 g, 0.0117 mole) in 50 ml of dry tetrahydrofuran by dropwise addition under nitrogen. The resultant very turbid solution was refluxed gently for about 30 min, then freed of tetrahydrofuran by allowing it to evaporate. The residue was taken up in 90% ethanol containing a few drops of ethereal hydrogen chloride, filtered and chilled. The solid produced was then recrystallized again to yield 4.3 g (97%), m.p. 233°-234° C. NMR, MS, and IR were in support of the structure proposed.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12])=[O:4].[CH3:13][C:14]([CH3:19])([CH2:17]O)[CH2:15][OH:16].O>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][C:3]1([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[CH3:12])[O:16][CH2:15][C:14]([CH3:19])([CH3:17])[CH2:13][O:4]1
Reactant: CC(C)(CO)CO
Reactant: Cc1ccc(C)c(C(=O)CCl)c1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(C)c(C2(CCl)OCC(C)(C)CO2)c1

Procedure:
0.5 mol of 2-chloro-1-(2,5-dimethylphenyl)ethanone, 104 g [1 mol] of 2,2-dimethyl-1,3-propanediol (neopentyl glycol) and 9.5 g [0.05 mol] of p-TsOH hydrate are boiled in 500 ml of xylene with a water trap until the formation of water ceases (about 4 hours). 200 ml of water and 30 ml of xylene are added to the reaction mixture at room temperature. A better phase separation is achieved by adding 50 ml of saturated aqueous NaCl solution. The organic phase is then extracted again with 100 ml of water and 100 ml of saturated aqueous NaCl solution, dried and concentrated.