Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCO[C:5]1[C:14](C)=[C:13](C)[C:12]2OC(C)(C)[CH2:9][CH2:8][C:7]=2[C:6]=1C=O.C([O-])(=O)C.[NH4+].[N+:26](C)([O-:28])=[O:27]>CCOC(C)=O>[N+:26]([CH:9]=[CH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:5][CH:6]=1)([O-:28])=[O:27]
Reactant: COCOc1c(C)c(C)c2c(c1C=O)CCC(C)(C)O2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C=Cc1ccccc1
Temperature: 80 °C

Procedure:
6-(Methoxymethoxy)-2,2,7,8-tetramethylchroman-5-carbaldehyde (500 mg, 1.7 mmol) and ammonium acetate (157 mg, 1.7 mmol) were taken up in nitromethane (11.6 mL) and the mixture was warmed to 80° C. for 1.5 hrs. After this time, the reaction was judged to be complete and the mixture was diluted in EtOAc (75 mL), washed once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient elution 0→15% EtOAc/Heptane) afforded the yellow solid nitrostyrene intermediate (500 mg). 1H NMR (CDCl3, 400 MHz) 8.30 (d, 2H), 7.80 (d, 2H), 4.82 (s, 2H), 3.76 (s, 3H), 2.78 (t, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 1.80 (t, 2H), 1.26 (s, 6H) ppm. The intermediate compound was dissolved in 5 mL THF and added dropwise over 30 min to a stirring suspension of LiAlH4 (400 mg, 10 mmol) in 3 mL THF at 0° C. After addition was complete, the mixture was stirred at 50° C. After 5 hr total, excess reagent was quenched by addition of 3 g sodium sulfate dodecylhydrate. The resulting suspension was stirred for 30 min, during which time the grey color turned to white. Subsequently, the suspension was filtered, and the filtrate concentrated in vacuo to provide 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine as a colorless oil, 450 mg. 1H NMR (CD3OD, 400 MHz) 4.84 (s, 2H), 3.60 (s, 3H), 2.80 (m, 4H), 2.70 (t, 2H), 2.14 (s, 3H), 2.06 (s, 3H), 1.78 (t, 2H), 1.22 (s, 3H), 1.20 (s, 3H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[N:19]([CH2:34][CH2:35][CH3:36])[C:20](=[O:33])[N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)[C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl>CCO>[CH3:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[CH3:31])[CH2:24][N:21]1[C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:37])=[O:3])=[CH:10][CH:11]=2)[N:19]([CH2:34][CH2:35][CH3:36])[C:20]1=[O:33]
Reactant: CCCn1c(CCCc2ccc(OC(C)(C)C(=O)OCC)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(CCCc2ccc(OC(C)(C)C(=O)O)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Yield: 89.1 %

Procedure:
A solution of 2-(4-{3-[1-(3,4-dimethyl-benzyl)-5-methyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester (0.124 g, 0.244 mmol) in EtOH (10 mL) was treated with aqueous 5 N NaOH (0.5 mL) and heated to reflux under N2 for 1 h. The reaction was cooled and the solvent removed in vacuo to give a residue that was acidified with aqueous 1 N HCl. The mixture was extracted with Et2O and water, the organic layer dried (MgSO4), and the solvent removed in vacuo to afford 0.104 g (89%) 2-(4-{3-[1-(3,4-dimethyl-benzyl)-5-methyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid. HRMS (ES+) m/z exact mass calcd for C29H39N2O4 [M+1] 479.2910, found 479.2917. 1H NMR.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][OH:5].BrCCC.[OH-].[Na+].[CH2:13]([C:15](C)=[O:16])[CH3:14]>[Cl-].[Na+].O>[CH2:15]([O:16][CH:4]([OH:5])[CH2:3][CH2:2][CH3:1])[CH2:13][CH3:14]
Reactant: OCCCCO
Reactant: CCC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCBr
Product: CCCOC(O)CCC
Temperature: 130 °C
Yield: 46.5 %

Procedure:
"PPAE-2" was prepared from the alkylation of 1,4-butane diol (1.25 kg, 13.9 moles) with bromopropane (0.5 kg, 4.1 moles) by addition of 50 wt-% sodium hydroxide (1 kg, 12.6 moles NaOH) at 65° C. and heating at 130° C. for two hours. The reaction mixture was cooled and methyl ethyl ketone (0.5 kg) and a 10 wt-% brine solution (1.1 kg) was added. Top phase (1.57 kg) was further washed with an additional 10 wt-% brine solution (1.1 kg). Top phase (940 g) was vacuum distilled to yield propoxybutanol (426 g, 86% yield), b.p. 112-118° C./14mm. Acetic anhydride (460 g) was added to the alcohol at 120° C. over one hour and heated at 130° C. for an additional hour. Acetic acid and excess acetic anhydride were distilled out to yield propoxy butyrate (585 g, 95% yield). The butyrate was fluorinated in perfluoromethyl morpholine using a tubular reactor described in U.S. Pat. No. 5,488,142 (Fall). After fluorination, excess methanol was added to provide methyl- 4-perfluoro-propoxybutyl acetate (604 g, 68% yield), b.p. 120-130° C. Saponification and decarboxylation was carried out by adding to the ester, sodium carbonate (23 g) and titration with sodium hydroxide (61 g) in methanol (380 g). Methanol was then removed after addition of"FC-71 FLUORINERT" electronic liquid, available from the 3M Co., St. Paul, Minn. (1.3 kg) under reduced pressure. The mixture was then heated up to 250° C. to yield perfluoropropoxyallyl ether (375 g, 75% yield), b.p. 58-62° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[F:10][C:11]1[C:12]([C:17]2([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18]2)=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.CN1C(=O)CCC1>O.C(OCC)(=O)C>[F:10][C:11]1[C:12]([C:17]2([CH2:21][NH:22][C:2]3[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=3)[CH2:20][CH2:19][CH2:18]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCC1(c2ncccc2F)CCC1
Reactant: N#Cc1ccc(Cl)nn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(NCC2(c3ncccc3F)CCC2)nn1
Temperature: 130 °C
Yield: 24.9 %

Procedure:
To a 20 dram vial was added 6-chloropyridazine-3-carbonitrile (1.0 g, 7.2 mmol, 1.0 equiv), (1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (1.36 g, 7.6 mmol, 1.05 equiv), triethylamine (2.1 mL, 14.4 mmol, 2.0 equiv), and NMP (2 mL). The reaction was heated at 130° C. for 12 h and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (1×20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20-30% EtOAc/hexanes) to give 507 mg (25%) of 6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carbonitrile. m/z=284 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]([C:11]2([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[O:17])[CH2:14][CH:13](O)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[C:30]1(=[O:44])[N:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40](O)=[O:41])[C:33](=[O:43])[CH:32]=[CH:31]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:16]([C:11]2([C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)=[O:10])[CH2:14][CH:13]([C:40](=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35][N:34]3[C:30](=[O:44])[CH:31]=[CH:32][C:33]3=[O:43])[CH2:12]2)=[O:17])=[CH:21][CH:22]=1
Reactant: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(O)C2)cc1
Reactant: O=C(O)CCOCCN1C(=O)C=CC1=O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(C(=O)CCOCCN3C(=O)C=CC3=O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of PMB-CB-OH (1.97 g, 4.91 mmol), 6-maleinimido-4-oxacaproic acid (1.57 g, 7.37 mmol) and triethylamine (2.04 ml, 8.64 mmol) is admixed with 2-chloro-1-methylpyridinium iodide (1.88 g, 7.37 mmol) in 30 ml anhydrous dichloromethane and stirred for three hours at room temperature. It is diluted with 140 ml dichloromethane, washed each time twice with 80 ml in hydrochloric acid, 80 ml water and once each time with 80 ml sodium chloride solution (saturated) and dried over magnesium sulfate. Subsequently the solvent is removed in a vacuum and the residue is purified by column chromatography (silica gel, chloroform/methanol 200:1). 2.89 g PMB-CB-1-Mal (99% of theory) is obtained as a colourless oil.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[C:17]([SH:21])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([S:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)S
Reactant: O=C1CCc2c(cccc2OCC2CO2)N1
Product: CC(C)(C)SCC(O)COc1cccc2c1CCC(=O)N2

Procedure:
Prepared analogous to Example 133 from 5-(2,3-epoxy-propoxy)-3,4-dihydro-carbostyril (m.p. 171°-173° C.) and tert. butyl mercaptan.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)#[N:14].N1CCCCC1>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[C:10](/[C:11]#[N:12])=[CH:19]\[C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1
Reactant: N#CCc1nc2ccccc2s1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#C/C(=C/c1ccc(C#N)cc1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzothiazole-2-acetonitrile (750 mg, 4.3 mmol) and 4-cyanobenzaldehyde (564 mg, 4.3 mmol) are dissolved in ethanol (20 ml). Piperidine (11 mg, 0.13 mmol) is added, and the reaction is stirred at room temperature for 2 hours. A precipitate is formed, which is filtered and washed with additional ethanol (5 ml). The solid is dried in a vacuum desiccator overnight and used without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][C:4]([CH3:11])([CH3:10])[C:5](OCC)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>CCOCC>[F:1][C:2]([F:13])([F:12])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5][OH:6]
Reactant: CCOC(=O)C(C)(C)CC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(CO)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4,4,4-trifluoro-2,2-dimethylbutanoate (1 g, 5.05 mmol) in ether (25 ml) under nitrogen was added LAH (1M solution in ether, 20.2 mmol) and allowed to stir at room temperature for one hour. Methanol was slowly added to R×n until bubbling stopped. The reaction was then suspended in ether and Water. The suspension was washed with Water, dried over sodium sulfate, filtered, and concentrated without heat to produce an oil 4,4,4-trifluoro-2,2-dimethylbutan-1-ol (75-1). 1H NMR (500 MHz, CDCl3) δ 3.4 (s, 2H), 2.20-2.01 (m, 2H), 1.05 (s, 6H). (M+H)+: observed=157.16, calculated=157.15
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=C1C.[OH-].[K+]>C(O)C.O>[NH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:8][NH:4][CH2:3][CH2:2][OH:1]
Reactant: CC1=NC(c2ccccc2)CN1CCO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(CNCCO)c1ccccc1

Procedure:
The hydroxyethylmethylphenylimidazoline produced in Example II in the amount of 30 g and 60 g potassium hydroxide, in 150 ml ethanol and 40 ml water, are refluxed for 24 hours. The solution is then concentrated by removal of the ethanol, and the residue is taken up in 50 ml of water.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:2].[CH:23](O)=[O:24]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH:23]=[O:24])[CH3:2]
Reactant: O=CO
Reactant: CCOC(=O)CNCc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)CN(C=O)Cc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 5.83 g of N-(4-benzyloxybenzyl)-glycine ethyl ester, 0.86 mL of formic acid, and 20 mL of xylene was refluxed for 2 hours using a Dean-Stark trap to remove the water produced in the reaction. After cooling, the reaction mixture was washed with 20% aqueous formic acid, water, saturated sodium bicarbonate solution, water, and brine. Finally the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to furnish 6.23 g of crude N-(4-benzyloxybenzyl)-N-formyl glycine ethyl ester, used in the following reaction without further purification.
Reaction SMILES: ClC1C=CC=C(F)C=1C(N[C@H](C(O)=O)CNC(C1CC1)=O)=O.[Cl:23][C:24]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:25]=1[C:26]([NH:28][C@H:29]([C:38]([OH:40])=[O:39])[CH2:30][NH:31][C:32]([CH:34]1[CH2:37][CH2:36]C1)=[O:33])=[O:27].ClC1C=CC=C(Cl)C=1C(N[C@H](C(O)=O)CNC(C1CCCC1)=O)=O.ClC1C=CC=C(F)C=1C(N[C@H](C(O)=O)CNC(C1CCCC1)=O)=O.ClC1C=CC=C(Cl)C=1C(N[C@H](C(O)=O)CNC(C1CCCCC1)=O)=O.ClC1C=CC=C(F)C=1C(N[C@H](C(O)=O)CNC(C1CCCCC1)=O)=O>>[Cl:45][C:41]1[CH:42]=[CH:43][CH:44]=[C:24]([Cl:23])[C:25]=1[C:26]([NH:28][C@H:29]([C:38]([OH:40])=[O:39])[CH2:30][NH:31][C:32]([CH:34]1[CH2:37][CH2:36]1)=[O:33])=[O:27]
Reactant: O=C(N[C@@H](CNC(=O)C1CCC1)C(=O)O)c1c(Cl)cccc1Cl
Agent: O=C(N[C@@H](CNC(=O)C1CC1)C(=O)O)c1c(F)cccc1Cl
Agent: O=C(N[C@@H](CNC(=O)C1CCCC1)C(=O)O)c1c(Cl)cccc1Cl
Agent: O=C(N[C@@H](CNC(=O)C1CCCC1)C(=O)O)c1c(F)cccc1Cl
Product: O=C(N[C@@H](CNC(=O)C1CC1)C(=O)O)c1c(Cl)cccc1Cl

Procedure:
N-(2-chloro-6-fluorobenzoyl)-3-(cyclopropylcarbonyl)amino-L-alanine; N-(2,6-dichlorobenzoyl)-3-(cyclobutylcarbonyl)amino-L-alanine; N-(2,6-dichlorobenzoyl)-3-(cyclopentylcarbonyl)amino-L-alanine; N-(2-chloro-6-fluorobenzoyl)-3-(cyclopentylcarbonyl)amino-L-alanine; N-(2,6-dichlorobenzoyl)-3-(cyclohexylcarbonyl)amino-L-alanine; N-(2-chloro-6-fluorobenzoyl)-3-(cyclohexylcarbonyl)amino-L-alanine),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:22])[C:15]=4[NH:14][C:13](=O)[C:12]=3[CH2:11][CH2:10]2)=[C:5]([CH3:24])[CH:4]=1.P(Cl)(Cl)([Cl:27])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:22])[C:15]=4[N:14]=[C:13]([Cl:27])[C:12]=3[CH2:11][CH2:10]2)=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1ccc(N2CCc3c2c2cccc(C)c2[nH]c3=O)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(N2CCc3c(Cl)nc4c(C)cccc4c32)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(4-methoxy-2-methylphenyl)-4-oxo-6-methyl-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (1.0 g, 3.1 mmol) was dissolved in 10 ml of phosphoryl chloride (POCl3) and heated for 2 hours. The reaction mixture was stirred at room temperature for 30 minutes after cooling and addition of ice water. The reaction mixture was extracted with methylene chloride (20 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 786 mg of desired compound as an oil in 75% of yield.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][N:11]([C:13]([N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1)=[O:14])[CH3:12])=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[S:18]1[CH2:19][CH2:20][N:15]([C:13]([N:11]([CH3:12])[CH2:10][CH2:9][NH:8][CH3:6])=[O:14])[CH2:16][CH2:17]1
Reactant: CN(CCN(C)C(=O)N1CCSCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCN(C)C(=O)N1CCSCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-t-Butoxycarbonyl-N'-thiomorpholinocarbonyl-N,N'-dimethylethylenediamine (4.92 g) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (60 ml) under ice-bath cooling. After being stirred at ambient temperature for 30 minutes, the solution was concentrated in vacuo to give N-thiomorpholinocarbonyl-N,N'-dimethylethylenediamine hydrochloride (3.93 g) as an oil. Rf: 0.25 (chloroform:methanol:acetic acid, 8:1:1, V/V)
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)([CH3:7])[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:32]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[C:17]4[CH:35]=[CH:36][C:14]([CH:11]5[CH2:10][CH2:9][N:8]([C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[CH2:13][CH2:12]5)=[CH:15][C:16]=4[O:25][CH2:24][CH2:23][N:22]3[CH:21]=2)=[N:30][C:29]([CH3:31])=[N:28]1)([CH3:34])[CH3:33]
Reactant: CCOC(=O)C(C)(C)N1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)CO)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
A solution of 2-{4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionic acid ethyl ester (47 mg, 0.092 mmol) in anhydrous THF (3 mL) was cooled to 0° C. and treated with lithium aluminium hydride (1M solution in THF, 0.3 mL, 0.3 mmol), the mixture stirred and allowed to warm to RT before quenching by the addition of saturated aqueous sodium hydrogen carbonate. The resultant mixture was extracted twice with ethyl acetate, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to RPHPLC (C18 column, gradient 0 to 60% methanol in water+0.1% formic acid) to give 358 as a white solid (20 mg, 47%). LCMS: RT=2.74 min, [M+H]+=465. 1H NMR 400 MHz (DMSO-d) δ: 8.33 (1H, d, J=8.28 Hz), 8.26 (1H, s), 7.87 (1H, s), 7.05 (1H, dd, J=8.35, 1.77 Hz), 6.90 (1H, d, J=1.71 Hz), 5.82-5.81 (1H, m), 4.49 (4H, m), 3.38 (2H, s), 3.21 (2H, d, J=11.33 Hz), 2.58 (1H, t, J=11.87 Hz), 2.47 (2H, d, J=11.47 Hz), 2.26 (3H, s), 1.85 (2H, d, J=12.54 Hz), 1.72 (2H, m), 1.46 (6H, d, J=6.60 Hz), 1.07 (6H, s)
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([Cl:10])([Cl:9])=[CH2:8]>C(Cl)Cl>[Cl:9][C:7]([Cl:10])=[CH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: C=C(Cl)Cl
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C(=O)C=C(Cl)Cl
Temperature: 25 °C
Yield: 1.7 %

Procedure:
To a solution of 53.5 gm (0.5 mole) of isobutyryl chloride and 45 gm (0.27 mole) of ferric chloride in 50 ml of methylene chloride cooled to 50°, and maintained below 10°, was added, with stirring, 53.2 gm (0.55 mole) of vinylidene chloride over a 1 hour period. After the addition, the reaction mixture was allowed to warm to room temperature for 3 hours before being poured over 100 gm of crushed ice. The layers were separated, and the organic solution was washed three times with 50-ml portions of water before being dried over magnesium sulfate. After being filtered, the solution was diluted with 50 ml of methylene chloride. The diluted solution was washed twice with dilute aqueous potassium carbonate and then with water before being distilled under reduced pressure, yielding 1.4 gm of crude 1,1-dichloro-4-methyl-1-penten-3-one; b.p., 41°-62°/4.1-4.7mm. The presence of the dichloroketone was established by gas chromatographic analysis, complimented by the mass spectrum of the gc component believed to be the dichloroketone, the mass spectrum of which showed a parent peak at m/e 166 and a fragmentation pattern consistent with 1,1-dichloro-4-methyl-1-penten-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetate (1 eq) was dissolved in dichloromethane (10 ml/mmol), cooled, and trifluoroacetic acid (13 eq) was added slowly at room temperature. After stirring for 2 h at room temperature, the reaction mixture was concentrated to small volume under vacuum and dried. The crude product was used in the next stage with no further purification. Yield: quantitative
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirring solution of 4,6-dichloro-5-nitropyrimidine (1.5 g, 7.73 mmol, CAS RN 4316-93-2), 2-methylphenyl boronic acid (1.16 g, 8.5 mmol), potassium carbonate (3.2 g, 23.2 mmol) and tetrakis-triphenylphosphine palladium(0) (447 mg, 0.30 mmol) in dioxane (50 mL) was heated under Argon atmosphere to 80° C. After 3 hours, the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles gave a brown solid. Column chromatography on silica gel (50-75% ethyl acetate in n-hexane) provided the title compound gave 4-chloro-5-nitro-6-o-tolylpyrimidine (621 mg, 32%).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1])=[CH:11][CH:10]=1
Reactant: C#CC(C)(C)O
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)C#CC(C)(C)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
Too pre-cooled, −78° C. stirred solution of 2-methylbut-3-yn-2-ol (4.3 g, 0.04 mol) in dry THF (150 mL) n-BuLi (39.9 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The mixture was stirred for 30 min at −78° C., and then a solution of 4-methoxy-benzaldehyde (5 g, 0.037 mol) in dry THF (30 mL) was added to reaction mixture and stirring was continued for an additional 40 min at −78° C. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain crude material. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 1-(4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (6.3 g, 78%) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9](Cl)=[N:10][OH:11].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)=[N:10][OH:11]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)CCOc1cccc(C(Cl)=NO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)CCOc1cccc(C(=NO)n2cncn2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To 100 ml of 1,2-dimethoxyethane were added 2.0 g (7.8 mmol) of 3-(3,3-dimethylbutoxy)benzohydroximoyl chloride, 1.9 g (27.5 mmol) of 1,2,4-triazole, and 1.5 g (10.9 mmol) of potassium carbonate. The mixture was stirred for 8 hours at about 50° C. After the resultant mixture was allowed to sit and cool naturally, the solvent in the mixture was removed. The residue was purified by column chromatography, thus obtaining the desired product of 1.2 g (yield: 46% ) .