Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:10]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:9][C:3]=1[CH:4]=[CH:5]C([O-])=O.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:10]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:9][C:3]=1[CH:4]=[CH2:5]
Reactant: COCCOCOc1cc(C=CC(=O)[O-])c(Cl)c(Cl)c1OCOCCOC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C=Cc1cc(OCOCCOC)c(OCOCCOC)c(Cl)c1Cl
Yield: 99.6 %

Procedure:
Using the procedure of Stage C of Example 40, 20 g of ester of Step B and 88 ml of diisobutylaluminium hydride were reacted to obtain 17.9 g of the expected product melting at 60° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH:4]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][CH3:21])[N:16]=[C:15](S(C)(=O)=O)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:6])[CH3:5]>CS(C)=O>[CH:4]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][CH3:21])[N:16]=[C:15]([C:1]#[N:2])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CCCc1cc(-c2cccc(C(C)C)c2)nc(S(C)(=O)=O)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCc1cc(-c2cccc(C(C)C)c2)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Sodium cyanide (65 mg, 1.32 mmol) was added at room temperature to 4-(3-isopropyl-phenyl)-2-methanesulfonyl-6-propyl-pyrimidine (211 mg) in DMSO (2 mL). The mixture was stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 7/3) to afford a pink oil which crystallised in pentane. After filtration, 4-(3-isopropyl-phenyl)-2-cyano-6-propyl-pyrimidine (164 mg) was obtained as an off white solid (mp=64° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[OH-].[Na+].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[O:16][CH2:15]1.Cl>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:15][CH:14]([OH:16])[CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8]
Reactant: COCCOCC1CO1
Reactant: COCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COCCOCC(O)COCCOC
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To ethylene glycol monomethyl ether (86.4 g, 2.27 moles), ground caustic soda (16.7 g, 0.83 moles) was added by several portions and caustic soda was dissolved by heating to 80° C. Ethylene glycol glycidyl methyl ether (50 g, 0.76 moles) was then added dropwise. After the completion of the dropwise addition, the solution was stirred for 2 hours and then air-cooled at room temperature. The solution was neutralized with hydrochloric acid and a salt was deposited by adding acetone, followed by filtration. Low-boiling materials were removed under reduced pressure to obtain 67 g (yield 85%) of 1,3-bis(2-methoxyethoxy)-2-propanol.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][N:11]=[C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)[C:14]=2[CH:15]=1
Reactant: COc1ccc2onc(C3CCN(C(C)=O)CC3)c2c1
Agent: Cl
Product: COc1ccc2onc(C3CCNCC3)c2c1

Procedure:
0.07 mol of 1-acetyl-4-(5-methoxy-1,2-benzisoxazolyl)piperidine and 110 ml of 6N HCl is refluxed for 6 hours and stand at room temperature to precipitate large amount of white deposit, which is recrystallized in ethanol to obtain 4-(5-methoxy-1,2-benzisoxazolyl)piperidine hydrochloride.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1.CCOC(C)=O>CN(C=O)C>[CH:1]1([O:6][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20]4[NH:28][C:27]5[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=5[CH:21]=4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(OC5CCCC5)nc34)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Similar to the method described in Example 103, cyclopentanol (0.18 mL, 2.02 mmol) was added to a suspension of NaH (60% w/w in mineral oil) (81 mg, 2.02 mmol) in DMF (2.0 mL) and the resulting light-yellow solution was stirred at RT for 10 min. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 75 mg, 0.25 mmol) was then added and the resulting dark red solution was stirred at RT for 5 min, then heated at 70° C. for 3 h. The mixture was cooled to RT and partitioned between EtOAc (70 mL) and saturated aq. NH4Cl (50 mL). The organic layer was separated, sequentially washed with water (20 mL) and brine (20 mL), and then dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography silica gel column, 10-100% EtOAc in hexanes over 25 min. then 100% EtOAc for 10 min.) to give 2-(2-(cyclopentyloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (30 mg, 0.09 mmol, 33.8% yield) as an amorphous yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.70 (br. s., 1H), 7.95-8.10 (m, 2H), 7.51-7.59 (m, 1H), 7.36-7.45 (m, 1H), 7.17 (d, J=2.0 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.57 (br. s., 1H), 5.44 (quin, J=4.4 Hz, 1H), 3.68 (t, J=6.7 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 2.02-2.16 (m, 4H), 1.84-1.98 (m, 2H), 1.67-1.80 (m, 2H). m/z (ESI, +ve ion) 348.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: Nc1cc(F)cnc1N
Reactant: CC(=O)C(C)Br
Solvent: CCO
Product: Cc1nc2c(N)cc(F)cn2c1C
Yield: 37.2 %

Procedure:
A mixture of 2,3-diamino-5-fluoropyridine (0.3 g, 2.4 mmol) and 3-bromo-2-butanon (0.36 g, 2.4 mmol) in ethanol (20 ml) was refluxed for 10 h. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride and was treated with a bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified with column chromatography on silica gel with methanol:methylene chloride (1:20) as eluent to give 0.16 g (37%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[NH:29])[NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:16]([NH:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[NH:29])=[O:17])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
750 mg of 4-t-butoxycarbonyl-1-(4-nitrobenzyloxycarbonylamidino)piperazine [prepared as described in step (b) above] were dissolved in 10 ml of trifluoroacetic acid, and the resulting solution was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was dissolved in a mixture of ethyl acetate and water, and an aqueous solution of sodium hydrogen-carbonate was added thereto to make the mixture alkaline. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate three times. The ethyl acetate layer and all of the ethyl acetate washings were combined and concentrated by evaporation under reduced pressure, to obtain 530 mg of the title compound, as a powder.
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>ClCCl>[C:17]([O:14][CH2:13][C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])([CH3:16])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CC(C)(CO)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dichloromethane solution containing 2.52 g (0.011 mol) 2-carbobenzoxyamino-2-methyl-1-propanol and 1.17 g (0.015 mol) acetyl chloride was added dropwise with stirring 1.11 g (0.011 mol) triethylamine. The reaction was stirred at ambient temperature overnight and the dichloromethane was removed under reduced pressure. The triethylamine hydrochloride residue was triturated in anhydrous ether. Following filtration, the ether was removed under reduced pressure to afford 2.38 g (0.009 mol), 82%, crude 2-carbobenzoxyamino-2-methyl-1-propyl acetate as a pale yellow liquid, pmr (CDCl3) δ 7.2 (s, 5H), 5.4 (bs, 1H), 5.0 (s, 2H), 2.0 (s, 3H) and 1.2 (s, 6H) ppm.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:22]([N:24](CC)CC)[CH3:23].C(N)C.O1CCCC1>C(OC(=O)C)C.O>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:24][CH2:22][CH3:23])=[N:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: N#CC(NC(=O)c1sc(Br)nc1C(F)(F)F)c1cccs1
Agent: CCN
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNc1nc(C(F)(F)F)c(C(=O)NC(C#N)c2cccs2)s1
Yield: 73 %

Procedure:
1.0g of 2-bromo-4-trifluoromethyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide, 0.36ml of triethylamine and 0.50ml of ethylamine were added to 10ml of tetrahydrofuran and the reaction mixture was stirred under reflux for 4 hours. Water and ethylacetate were added thereto to separate the layers. The separated organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was recrystallized from the mixed solvent of n-hexane and ethylacetate to obtain 0.67g (Yield 73%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:25])(=O)=O>C(OCC)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([Cl:25])=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(O)cc(OC)cc1/C=C/c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1c(O)cc(OC)c(Cl)c1/C=C/c1ccccc1
Temperature: 0 °C
Yield: 85.2 %

Procedure:
Dissolve compound 7 (12 g, 0.042 mol) in anhydrous diethyl ether (150 ml), dropwise add in sulfuric chloride (11.2 g, 0.084 mol) at room temperature, when addition finishes, reflux the mixture for 3h, after completion of the reaction, cool the reaction mixture to 0° C., filter out the white solid precipitation to obtain the target product as a white solid (11.4 g, 85%). 1H NMR (400 MHz, CDCl3): 3.82 (s, 3H), 3.94 (s, 3H), 6.48 (d, J=16.0 Hz, 1H), 6.52 (s, 1H), 7.20 (d, J=16.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H),
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccnc(C(=O)c2ccc(F)cc2)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccnc(C(O)c2ccc(N)cc2)c1
Reaction time: 8 h
Yield: 113 %

Procedure:
2-(4-fluorobenzoyl)-4-methylpyridine (1.6 g) and sodium azide (2.4 g) were suspended in dimethylsulfoxide (15 ml) under nitrogen atmosphere 90° C., and the mixture was heated with stirring overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was dissolved in tetrahydrofuran (50 ml), and to the solution was added aluminum lithium hydride (0.66 g) under ice-cooling, and the mixture was stirred overnight at room temperature under nitrogen atmosphere. To the solution were added water (0.66 ml), 15% aqueous solution of sodium hydroxide (0.66 ml) and water (1.98 ml) under ice-cooling, the mixture was stirred and dried over anhydrous magnesium sulfate. After filtration, the solvent of the filtrate was distilled off, to give (4-aminophenyl)(4-methylpyridin-2-yl)methanol (1.8 g) as pale yellow crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][OH:22])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][O:22][CH2:37][C:36]4[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(CBr)cc1
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccc2c(c1)OCO2
Product: COc1ccc(COCc2c(-c3ccccc3)c3cc(Br)ccc3c(=O)n2Cc2ccc3c(c2)OCO3)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 240 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (250 mg) and 4-methoxybenzylbromide. Colorless crystals (240 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1.[O:14]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:14])[CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: OC1=CCCSc2ccc(Cl)cc21
Reactant: C1COCCO1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=S1CCC=C(O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: The solution of 6.4 g of 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin in 65 ml of dry methanol and65 ml of dry dioxane is treated dropwise at 0° in 1 hour with the solution of 7.0 g of sodium metaperiodate in 65 ml water. The mixture is stirred at 0° for two hours after the addition period and then allowed to warm to room temperature for overnight. It is filtered and the solid rinsed with 30 ml of methanol. The combined filtrate and wash is concentrated to a smaller volume and treated with 40 ml of water. The mixture is extracted with chloroform, the extract separated, washed with water, dried and evaporated, to yield the 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin-1-oxide boiling at 154-157/0.25 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([Mg]Br)[CH3:12]>C(OCC)C>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([CH2:11][CH3:12])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCC(C)(O)c1cccc(O)c1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 3 M solution of ethylmagnesium bromide in diethyl ether (1.5 ml) as starting materials, the title compound (124.9 mg) was obtained in the same manner as that of Reference Example 69.
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:15][CH2:14]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].N12CCCN=C1CCCCC2>O1CCOCC1>[CH:13]1([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccccc1CC(Cl)C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1C=CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
To 1 g (4.25 mmol, purity 96%) of 1-(2-chloro-2-cyclopropylethyl)-2-nitrobenzene in 20 ml of dioxane is added 0.65 g (4.25 mmol) of 1,8-diazabicyclo(5.4.0)undec-7-ene, and the mixture is stirred at room temperature for 12 h. Subsequently, the solvent is concentrated under reduced pressure and the residue is admixed with ethyl acetate and water. After the organic phases have been removed and the solvent has been concentrated by evaporation, 0.7 g (79% of theory) of 1-[2-cyclopropylvinyl]-2-nitrobenzene is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54]O)[CH:49]=1>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:54][C:50]3[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1cccnc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2cccnc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 12 %

Procedure:
1,4-Diethylazodicarboxylate (205 gL) is added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41, triphenylphospine (341 mg), and 3-pyridylmethanol (243 μL) in THF (10 mL). The reaction mixture is stirred at room temperature for 20 h and then the resulting suspension is filtered. The crude product is purified by recrystallization from ethanol to afford 63 mg (12%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[N:3]=1.CS(C)=O.C(N(C(C)C)CC)(C)C.[CH3:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1>C(OCC)(=O)C>[C:9]([C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:25]([CH3:24])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[N:5]=1)#[N:10]
Reactant: N#Cc1nc(N)nc(Cl)n1
Reactant: CNc1cccc(C)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N(C)c2nc(N)nc(C#N)n2)c1

Procedure:
To 2-amino-4-chloro-6-cyano-[1,3,5]triazine (Prepared in an analogous way to Intermediate 3, 46 mg, 296 μmol) was added 1 mL anhydrous DMSO, diisopropylethylamine (77 μL, 444 μmol) and N-methyl-m-toluidine (40 mg, 326 μmol). The mixture was heated at 90 C for 2 h, allowed to cool and diluted with 10 mL ethyl acetate. The mixture was then extracted with water (10 mL), 0.5 M HCl (3×10 mL), water (10 mL) and saturated brine (10 mL). The organic layer was dried further over anhydrous sodium sulfate and evaporated to give the desired product which was used directly without further purification or characterization (42 mg, 59%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]=[C:8]1[C:13]2[CH:14]=[CH:15][C:16]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)=[C:17]([CH2:18][CH2:19][CH3:20])[C:12]=2[O:11][C:10]([CH2:43][CH2:44][C:45](OCC)=[O:46])([CH2:36][CH2:37][C:38](OCC)=[O:39])[CH2:9]1>O1CCCC1>[OH:7][CH:8]1[C:13]2[CH:14]=[CH:15][C:16]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)=[C:17]([CH2:18][CH2:19][CH3:20])[C:12]=2[O:11][C:10]([CH2:36][CH2:37][CH2:38][OH:39])([CH2:43][CH2:44][CH2:45][OH:46])[CH2:9]1
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCCO)(CCCO)CC2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a stirred suspension of 319 mg (8.40 mmol) of LiAlH4 in 12 ml of tetrahydrofuran (THF) at 0° C. was added a solution of 1.00 g (1.68 mmol) of the title product of Example 42 in 5 ml of tetrahydrofuran. After one-half hour, the mixture was permitted to warm to room temperature, and stirred further for two hours. The reaction was then quenched by sequentially adding 320 μl of water, 320 μl of 15% aqueous sodium hydroxide, and 960 μl of water. The formed salts were removed by filtration, and the solvent removed under reduced pressure to give the title compound (770 mg) as a white solid, m.p. 123°-123.5° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1.Cl[CH:14]([NH:20][OH:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C1COCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[O:21][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NOC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 8 h

Procedure:
To a mixture of 1-(trifluoromethyl)-4-vinylbenzene (2.0 g, 11.27 mmol), a compound of formula (20) and ethyl 2-chloro-2-(hydroxyamino)acetate (2.11 g, 13.52 mmol), a compound of formula (21), in anhydrous THF was added a solution of triethylamine (3.0 ml) in tetrahydrofuran was added dropwise at room temperature. The mixture was stirred overnight under N2. The white precipitate thus formed was filtered off, and washed twice with tetrahydrofuran (10 ml). The solvent was removed from the filtrate under reduced pressure, and the residue partitioned between water/ethyl acetate (20 ml:20 ml v/v), extracting three times with 20 ml of ethyl acetate. The combined organic layers were washed with aqueous ammonium chloride, and dried over MgSO4, to provide ethyl 5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-3-carboxylate, a compound of formula (22).
Reaction SMILES: [C:1]([C:4]1[C:8]2[C:9](=O)[CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][C:7]=2[O:6][CH:5]=1)(=[O:3])[NH2:2].[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[C:1]([C:4]1[C:8]2/[C:9](=[N:24]/[NH:23][C:20]([NH2:22])=[NH:21])/[CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][C:7]=2[O:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: N=C(N)NN
Reactant: NC(=O)c1coc2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: CCO
Product: N=C(N)N/N=C1\CC(c2ccccc2)Cc2occ(C(N)=O)c21
Temperature: 90 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a mixture of 3-carbamoyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.24 g) and aminoguanidine hydrochloride (104 mg) were added ethanol (20 ml) and 6N hydrochloric acid (0.081 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. Precipitated crystals were washed with ethanol and isopropylether, and dried to give (E)-3-carbamoyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 107) (0.28 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:15]2[CH2:16][CH2:17][C:18]3[CH2:19][CH2:20][C:21]([F:23])=[CH:22][C:13]([C:14]=32)=[CH:12][N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:23][C:21]1[CH2:20][CH2:19][C:18]2[CH2:17][CH2:16][N:15]3[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][CH:12]=[C:13]([C:14]=23)[CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C1=NC=C2C=C(F)CCC3=C2N1CC3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To an ice-cooled solution of [(S)-1-(5-fluoro-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen-1-yl)ethyl]carbamic acid tert-butyl ester (252.6 mg, 0.7576 mmol) in DCM (8 mL) was added TFA (2 mL) and the mixture was stirred at RT for 1.5 h. Toluene was added and volatiles were removed under reduced pressure, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a light pink solid (144.5 mg, 82%). LCMS (Method J): RT 1.93 min [M+H]+ 234