Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10].FC1C=CC=CC=1[CH:27]([CH2:30][CH2:31][N:32]([CH:36]([CH3:38])C)[CH:33]([CH3:35])C)C#N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:38][CH2:36][N:32]1[CH2:31][CH2:30][CH2:27][CH2:35][CH2:33]1)[C:9]#[N:10]
Reactant: CC(C)N(CCC(C#N)c1ccccc1F)C(C)C
Reactant: CC(C)N(CCC(C#N)c1ccccc1Cl)C(C)C
Product: CC(C)N(CCC(C#N)(CCN1CCCCC1)c1ccccc1Cl)C(C)C

Procedure:
When an equivalent quantity of α-(o-chlorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile prepared according to the first paragraph of Example 19, is substituted for α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile called for in Example 20 and the procedure detailed in the second paragraph of that example is substantially repeated, there is obtained α-(o-chlorophenyl)-α-[2-(diisopropylamino)ethyl]-α-(2-piperidinoethyl)acetonitrile, as an oil boiling at about 190°-195° C. at 0.3 mm. pressure.
Reaction SMILES: CC1C=CC([CH:6]=[S:7])=CC=1.[CH3:10][N:11]([CH3:13])[NH2:12].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cl-].[Na+].O.CC(C)=O.CCCCCC>[CH3:10][N:11]([CH3:13])[N:12]=[CH:20][C:14]1[CH:19]=[CH:18][C:17]([S:7][CH3:6])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C=S)cc1
Reactant: CN(C)N
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: O
Product: CSc1ccc(C=NN(C)C)cc1

Procedure:
7.44 g (48.9 mmol) of 4-methylthiobenzaldehyde and 4.0 ml (52.7 mmol) of 1,1-dimethylhydrazine are dissolved in toluene (50 ml) and heated to reflux for 2.5 hr. Brine is added to the reaction mixture after cooling, and the product is extracted with toluene. The toluene layer is condensed and the residue is applied to column chromatography on silica gel with acetone-hexane (1:20) as eluent. 9.07 g of a pale yellow oil are obtained (96%). 1H NMR (CDCl3), δ[ppm]: d 2.48 (s, 3H), 2.96 (s, 6H), 7.20 (s, 1H), 7.21 (d, 2H), 7.49 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][C:19]1(N)[CH2:24][CH2:23][N:22]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH2:21][CH2:20]1>CC(O)C.CO>[C:27]1([CH:25]([N:22]2[CH2:23][CH2:24][C:19]3([NH:16]/[C:13](=[N:12]/[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17][CH2:18]3)[CH2:20][CH2:21]2)[CH3:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(c1ccccc1)N1CCC(N)(CN)CC1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CO
Solvent: CC(C)O
Product: CC(c1ccccc1)N1CCC2(CC1)CN/C(=N\C(=O)c1nc(Cl)c(N)nc1N)N2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (1.7 g, 4.54 mmol) and 4-aminomethyl-1-(1-phenyl-ethyl)-piperidin-4-ylamine (Intermediate BM) (1.6 g, 4.59 mmol) in propan-2-ol (50 ml) is stirred at 80° C. for 16 hours. The reaction mixture is concentrated in vacuo and purified by column chromatography (basic alumina, 0-2% MeOH in DCM) to obtain pale yellow solid. The compound obtained is further dissolved in MeOH and precipitated by adding diethyl ether. The supernatant solvent mixture is decanted and the product is washed again with diethyl ether and dried under vacuum to afford the title compound as off-white solid; [M+H]+ 429
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[NH2:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=1>>[C:45]([C:44]1[CH:47]=[CH:48][C:41]([NH:40][C:32]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH:14]5[CH2:20][CH2:19][CH:18]4[CH2:17][O:16][CH2:15]5)[N:10]=3)=[CH:22][CH:23]=2)=[O:38])=[CH:42][CH:43]=1)#[N:46]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4C5CCC4COC5)n3)cc2)cc1
Yield: 46.5 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminobezonitrile (21 mg, 0.18 mmol) gave the title compound as off-white solid (14.3 mg, 46% yield). MS (ESI) m/z 513.5.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[O:23][CH2:24][C:25]#[N:26])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn]([N:43]=[N+:44]=[N-:45])(CCCC)CCCC)CCC>C(OCC)(=O)C.Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[O:23][CH2:24][C:25]3[NH:45][N:44]=[N:43][N:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCOc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(-c2nc(CCc3cccc(OCc4nnn[nH]4)c3)oc2-c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 20 h
Yield: 66.3 %

Procedure:
A mixture of 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetonitrile (1.60 g, 4.2 mmol) and tri-n-butyltin azide (1.45 g, 4.4 mmol) was stirred at 140° C. under an atomosphere of nitrogen. After 20 hours, the mixture was cooled, diluted with ethyl acetate (300 mL) and 1N HCl (200 mL) and the mixture stirred for 2 hours. The aqueous phase was removed and the organic phase added to 0.1M potassium fluoride solution. After stirring overnight, the organic layer was separated, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel using a mixture of chloroform and methanol (10:1) as eluent to give 5-[[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]methyl]-1H-tetrazole (1.18 g, 66%) after recrystallization from a mixture of hexanes and CH2Cl2 m.p. 138.5°-140° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[CH2:8](Cl)[CH:9]=[CH2:10]>>[CH2:10]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH:9]=[CH2:8]
Reactant: C=CCCl
Reactant: COC(CN)OC
Product: C=CCNCC(OC)OC

Procedure:
Aminoacetaldehyde dimethyl acetal was reacted with allyl chloride to give N-allyl-N-dimethoxyethyl amine, which was then acetylated with acetyl chloride to give N-allyl-N-dimethoxyethyl acetamide, according to the following reactions: ##STR3##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=S)[CH:18]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:20])=[CH:5][CH:4]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[N:22][OH:23])[CH:18]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:20])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(-c2cc(=S)c3cccc(C)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=NO)c3cccc(C)c3o2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of 2-(4-Methoxy-phenyl)-8-methyl-chromene-4-thione (160.0 mg, 0.57 mmol) in 3.5 mL of pyridine was added 118.4 mg (1.70 mmol) of hydroxylamine hydrochloride. The solution was stirred at 110° C. for 1 h. The solvent was removed under vacuum and the residue was treated with ice. The resulting slurry was filtered. The filter cake was washed with H2O and then dried overnight under vacuum to afford 137.0 mg (85.7% yield) of desired compound I-23 as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.89 (d, 2H), 7.71 (d, 1H), 7.35 (d, 1H), 7.15 (t, 1H), 7.09 (d, 2H), 7.00 (s, 1H), 3.84 (s, 3H), 2.44 (s, 3H) ppm. LC/MS: 282.1 (M+H), 280.0 (M−H), HPLC/Method A (Rt 6.268 min, 95.4% purity).
Reaction SMILES: [CH2:1]1[C:9]2[C:4]3=[C:5]([CH:10]=[CH:11][N:3]3[CH2:2]1)[CH:6]=[CH:7][CH:8]=2.C(Cl)(=O)C(Cl)=[O:14].CO.[C:20]([O:23][CH2:24]C)(=[O:22])[CH3:21]>O1CCCC1>[CH3:24][O:23][C:20](=[O:22])[C:21]([C:1]1[C:9]2[C:4]3=[C:5]([CH2:10][CH2:11][N:3]3[CH:2]=1)[CH:6]=[CH:7][CH:8]=2)=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1cc2c3c(c1)ccn3CC2
Reactant: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cn2c3c(cccc13)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1,2-dihydro-pyrrolo[3,2,1-hi]indole (112 mg, 0.78 mmol) in anhydrous tetrahydrofuran (3 ml) at 0° C. was added oxalyl chloride (71 μl, 0.82 mmol). The mixture was stirred at 0° C. for 1 hour. Methanol (1 ml) was added and the mixture was allowed to warm to room temperature. After 30 minutes ethyl acetate (100 ml) was added and the mixture washed with water (100 ml) and brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness to give (4,5-dihydro-pyrrolo[3,2,1-hi]indol-1-yl)-oxo-acetic acid methyl ester as a purple solid (153 mg). 400 MHz 1H NMR (CDCl3) δ: 8.32 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.08 (d, J=6.4 Hz, 1H), 4.60 (t, J=6.8 Hz, 2H), 3.95 (s, 3H), 3.84 (t, J=6.8 Hz, 2H); LCMS: 230 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[N:9][N:8]=1.Cl.[CH3:32][O:33][NH2:34].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([N:19]2[CH2:20][CH2:21][C:22](=[N:34][O:33][CH3:32])[CH2:23][CH2:24]2)=[N:9][N:8]=1
Reactant: CON
Reactant: COc1ccc(CNc2nnc(N3CCC(=O)CC3)c3ccc(C#N)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CON=C1CCN(c2nnc(NCc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc23)CC1
Yield: 48.7 %

Procedure:
A mixture of 1.19 g 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-oxopiperidino]-6-phthalazine carbonitrile, 354 mg methoxyamine hydrochloride, 1.2 g sodium carbonate, and 10 ml ethanol was heated under reflux for 2 hr. After cooling, saline was added to the reaction solution which was then extracted with ethyl acetate. It was dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated, and the resulting residue was purified by silica gel column chromatography to give 620 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(methoxyimino)piperidino]-6-phthalazine carbonitrile. This product was dissolved in a mixed solvent of methanol and ethanol, and recrystallized by adding 0.35 ml of 4 N hydrochloric acid/ethyl acetate to give 388 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(methoxyimino)piperidino]-6-phthalazinecarbonitrile hydrochloride.
Reaction SMILES: C=O.[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([C:13]([OH:15])=[O:14])[CH2:5]1.N1CCCC[CH2:17]1.[CH3:22][O:23][C:24](=[O:32])[C@H:25]([CH2:30][SH:31])[NH:26][C:27](=[O:29])[CH3:28]>C(O)C>[C:27]([NH:26][C@H:25]([C:24]([O:23][CH3:22])=[O:32])[CH2:30][S:31][CH2:17][CH:5]1[C:4](=[O:3])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1[C:13]([OH:15])=[O:14])(=[O:29])[CH3:28]
Reactant: C1CCNCC1
Reactant: COC(=O)[C@H](CS)NC(C)=O
Reactant: O=C1CC(C(=O)O)c2ccccc21
Agent: C=O
Solvent: CCO
Product: COC(=O)[C@H](CSCC1C(=O)c2ccccc2C1C(=O)O)NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.7 %

Procedure:
After 37% formalin (0.088 ml, 1.08 mmol) was added to a mixture of 3-oxo-1-indanecarboxylic acid (191 mg, 1.08 mmol) and piperidine (92.3 mg, 1.08 mmol), the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated. Ethanol (3 ml) and N-acetyl-L-cysteine methyl ester (80 mg, 0.45 mmol) were added to the residue. The mixture was heated to reflux for 10 minutes and then concentrated in vacuo. The residue was purified by silica gel column chromatography (100 ml, chloroform:methanol:acetic acid=30:1:0.5) to give Compound (6A) (62 mg, yield: 15.7%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=[N:9]1.[Cl:16][C:17]1[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[CH:21][N:22]=1>ClCCl.CN(C)C=O>[NH2:24][C:18]1[N:19]=[C:20]([NH:23][C:13]([C:12]2[N:8]([CH3:7])[N:9]=[CH:10][CH:11]=2)=[O:15])[CH:21]=[N:22][C:17]=1[Cl:16]
Reactant: Nc1cnc(Cl)c(N)n1
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nccc1C(=O)Nc1cnc(Cl)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
Oxalyl chloride (0.288 ml, 3.32 mmol) was added to a suspension of 1-methyl-1H-pyrazole-5-carboxylic acid (0.279 g, 2.21 mmol) in dichloromethane (5 ml) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.16 g, 1.11 mmol) and the mixture heated at 60° C. for 3 hours before cooling to room temperature and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluting with ethylacetate:heptane 1:1, to afford the product as a pale solid (100 mg).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=P(Cl)(Cl)Oc1ccc(Br)cc1

Procedure:
One embodiment of the invention provides a method of preparing AZT-5′-(para-bromophenyl methoxyalaninyl phosphate) in a single reaction vessel without purification of the intermnediates formed. Phosphorous oxychloride is reacted with a para-bromophenol moiety to form para-bromophenyl phosphorodichloridate. Without purification, the para-bromophenyl phosphorodichloridate is contacted with alanine methyl ester to produce para-bromophenyl methoxyalaninyl phosphorochloridate. Without purification, the para-bromophenyl methoxyalaninyl phosphorochloridate is reacted with AZT.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: BrCCOC1CCCCO1
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)c(OCCOC2CCCCO2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 2-fluoro-5-nitrophenol (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.4 mL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H2O (5×'s to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes—1:1 hexanes:EtOAc to provide 2-(2-(2-fluoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII.
Reaction SMILES: [NH2:1][C@@H:2]([C:9]([NH:11][OH:12])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C=O.O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([N:11]([C:9](=[O:10])[C@@H:2]([CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)[NH2:1])[OH:12])=[O:23])([OH:18])=[O:17]
Reactant: N[C@H](Cc1c[nH]cn1)C(=O)NO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H](Cc1c[nH]cn1)C(=O)N(O)C(=O)c1ccccc1C(=O)O
Reaction time: 4 h
Yield: 44.9 %

Procedure:
D-Histidine hydroxamic acid (1.9 g, 11.2 mMol) was dissolved in dimethylformamide (75 ml) and water (100 ml). Phthalic anhydride (1.65 g, 11.2 mMol) was added, the solution stirred 4 hours, evaporated to an oil which was crystallized from water/ethanol, and crystallized again from water to yield 1.6 g, m.p. 175° (dec.) of N-(2-carboxybenzoyl)-D-histidine hydroxamic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=O)[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3>CCOCC.C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COc1ccc2c(=O)c3ccccc3oc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)Oc1ccccc1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a suspension of lithium aluminum hydride (0.524 g, 13.8 mmole) in Et2O (30 ml) at 0° was added, dropwise, a solution of xanthone 8 (1 g, 4.42 mmole) in toluene (25 ml). The resulting mixture was stirred at room temperature for 30 min, then refluxed vigorously for 17 hrs. After cooling in an ice bath, the reaction was quenched carefully with EtOAc (1.5 ml), MeOH (1.5 ml) and finally with dilute HCl solution until the aqueous layer was acidic. The reaction mixture was partitioned between 10% EtOAc-hexanes and water. After the organic layer was separated, the aqueous layer was extracted two more times with 10% EtOAc-hexanes. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4 and filtered through a silica gel plus. After concentration of the filtrate, 3-methoxy-9H-xanthene 9 (0.806 g, 86%) was isolated as a slightly yellow solid: m.p. 72-74° C.; 1H NMR (CDCl3): delta 7.13-7.20 (2H, m), 6.98-7.06 (3H, m), 6.58-6.62 (2H, m), 3.97 (2H, s) and 3.79 (3H, s); 1R (CHCl3): 3000, 2935, 2836, 1625, 1596, 1520, 1480, 1455, 1438, 1275, 1227, 1150, 1119, 1092, 1031, 962 and 837 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([N:17]1[CH2:24][CH:23]2[C:25]([CH3:27])([CH3:26])[CH:19]([CH2:20][NH:21][CH2:22]2)[CH2:18]1)[CH2:14][CH2:15][CH3:16]>ClCCl>[ClH:12].[CH2:13]([N:17]1[CH2:18][CH:19]2[C:25]([CH3:26])([CH3:27])[CH:23]([CH2:22][N:21]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:20]2)[CH2:24]1)[CH2:14][CH2:15][CH3:16]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCN1CC2CNCC(C1)C2(C)C
Solvent: ClCCl
Product: CCCCN1CC2CN(S(=O)(=O)c3ccc(C#N)cc3)CC(C1)C2(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of 2.5 g of 4-cyanobenzenesulfonyl chloride in 20 ml of dichloromethane was added dropwise with ice-cooling to a solution of 2.37 g of 7-(n-butyl)-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane in 30 ml of dichloromethane. The ice-cooling was then removed, and the reaction mixture was stirred at room temperature for one hour. The hydrochloride of the title compound was thereupon deposited as a white precipitate. The crystals were filtered out with suction and dried at 60° C. in a vacuum drying oven. 2.5 g of 7-(n-butyl)-3-[(4-cyanophenyl)sulfonyl]-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane hydrochloride having a melting point of 98° to 99° C. were obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[C:8]([Cl:20])[CH:7]=2)[CH2:2]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34](OCC)=[O:35])=[N:31][N:30]=2)=[CH:25][CH:24]=1>>[Cl:20][C:8]1[CH:7]=[C:6]([CH:19]=[CH:18][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)[O:5][CH:3]1[CH2:4][N:1]([C:34]([C:32]2[O:33][C:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[N:30][N:31]=2)=[O:35])[CH2:2]1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Reactant: CN1CCN(Cc2ccc(OC3CNC3)cc2Cl)CC1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCN(C)CC5)c(Cl)c4)C3)o2)cc1
Yield: 64 %

Procedure:
Using a similar protocol as described in Example 16 employing 49A (2.7 g, 9.1 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (2.5 g, 10.0 mmol) as starting materials afforded 2.9 g (64%) of 49 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.28 (s, 3H), 2.3-2.7 (m, 8H), 3.56 (s, 2H), 3.88 (s, 3H), 4.32 (dd, 1H), 4.63 (dd, 1H), 4.74 (dd, 1H), 5.05 (m, 1H), 5.11 (m, 1H), 6.67 (dd, 1H), 6.78 (d, 1H), 7.02 (d, 2H), 7.39 (d, 1H), 8.09 (d, 2H), MS (APCI+) m/z 498 [M+H]+, LC purity: 95%.
Reaction SMILES: [H][H].[N+:3]([CH2:6][CH2:7][OH:8])([O-:5])=[O:4].Cl.C(NCCC)CC.[CH2:17]([CH2:22][C:23]([O-])=O)[CH2:18][CH2:19][CH2:20][CH3:21]>>[N+:3]([C:6]1[CH2:7][O:8][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)([O-:5])=[O:4]
Reactant: [H][H]
Reactant: O=[N+]([O-])CCO
Reactant: CCCCCCC(=O)[O-]
Agent: Cl
Solvent: CCCNCCC
Product: O=[N+]([O-])C1=Cc2ccccc2OC1

Procedure:
The compounds of this invention are prepared by various means. The compounds of this invention wherein R3 is hydrogen, R1 is hydrogen, ethyl or propyl, cyclopropylmethyl or cyclobutylmethyl and R2 is --CH2 cycloalkylC3-8, alkylC2-8, --(CH2)q --R4, or --CH2CH2O(CH2)rCH3 are prepared by refluxing one equivalent of a salicyl aldehyde of formula C-1 (see Chart 1) with one and one-half equivalents of 2-nitroethanol in amylacetate in the presence of one and one-half equivalents of din-propylamine hydrochloride followed by azeotropic distillation for 12 hours in a Dean-Stark apparatus to give the 3-nitrochromene of formula C-3. The 3-nitrochromene is reduced with cyanoborohydride or zinc and HCl to give the 3-aminochromane of C-4. The 3-aminochromane of C-4 can be acylated with an appropriate acid halide, e.g., acid chloride, of the formula RyCOhalide wherein Ry is alkylC1-7, --(CH2)tR4 wherein t is 1 or 2, cycloalkylC3-8 or --CH2O(CH2)mCH3 wherein R5 and m have the meanings in Formula I to give the chromane amides of formula C-5. Also the aminochromane of formula C-4 can be treated with methyl iodide to give the compound of formula C-6 wherein R14 is hydrogen and R15 is methyl or can be treated with formaldehyde in water in the presence of NaBH3CN and a few drops of glacial acetic acid at pH5 to give the corresponding dimethylated compounds. The compounds of formulas C-5 and C-6 can be converted to the corresponding compounds of formulas C-7 and C-8 wherein R is F, Cl, CF3, NR5R6, NR7C(=O)R8, NR9C(=O)OR10, or NR11C(=O)NR12R13 as follows:
Reaction SMILES: OC(C1C=CC(C[N:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[CH:11]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[CH:21]=2)=CC=1)(C)C.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([OH:45])([CH3:44])[CH3:43])=[CH:38][CH:37]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[OH:45][C:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[N:10][C:11]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([OH:31])[C:27]([F:29])([F:28])[F:30])[CH:21]=2)=[CH:37][CH:38]=1)([CH3:44])[CH3:43]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: CC(C)(O)c1ccc(CN2C=CC=C(C(=O)O)C2Oc2cccc(C(O)C(F)(F)F)c2)cc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2cccc(C(O)C(F)(F)F)c2)cc1

Procedure:
To a stirred solution of N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenoxy]-nicotinic acid (0.400 grams, 1.28 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.232 grams, 1.40 mmole), and 1-hydroxybenzotriazole hydrate (0.189 grams, 1.40 mmole) in dry dimethylformamide (5 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.294 grams, 1.54 mmole) and stirred over night. The mixture poured into 100 ml water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2.5% methanol/methylene chloride (0.550 g). 1H NMR (CDCl3) d 1.54 (6H, s), 3.53 (1H, d), 4.66 (2H, d), 4.92 (1H, m), 7.46-7.15 (9H, m), 8.12 (1H, m), 8.16 (1H, dd) 8.62 (1H, dd). MW 313.25 MS (m/e) 313 (M+).