Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:39]([C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=1)#[N:40]>>[C:39]([C:41]1[CH:46]=[CH:45][C:44]([O:1][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25](=[O:38])[N:7]3[C:8]=2[C:9]([O:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:43][CH:42]=1)#[N:40]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)COc4ccccc4)[C@H]3SC2)cc1

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and p-cyanophenol, to afford 270 mg of the title compound as a powder.
Reaction SMILES: [OH:1][C:2]1([C:12]#[N:13])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH2:3]1.[CH:14](Br)([CH3:16])[CH3:15].[H-].[Na+].O>CN(C)C=O>[CH:14]([O:1][C:2]1([C:12]#[N:13])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH2:3]1)([CH3:16])[CH3:15]
Reactant: CC(C)Br
Reactant: N#CC1(O)CC=CC2=C1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC1(C#N)CC=CC2=C1CCCC2

Procedure:
4-Hydroxy-5,6,7,8-tetrahydro-4-naphthonitrile (1.73 g, 10 mm), isopropyl bromide (0.78 g, 10 mM), and sodium hydride (0.24 g, 10 mM) in dimethyl formamide were stirred for 3 hours. Water was added and the mixture was extracted with ether. The ether was dried and evaporated to give the isopropyl ether (7).
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:1]([CH3:3])[CH3:2])=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)I
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 98.8 %

Procedure:
Isopropyl iodide (680 uL, 6.8 mmol) was added to a mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (1 g, 3 mmol) (Step 1) and potassium carbonate (940 mg, 6.8 mmol) in acetonitrile (20 mL). The reaction was heated at 60° C. overnight. The reaction was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product, (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-isopropoxyphenyl)propanoate (1 g, 90%) as a white solid. Analytical LCMS (M+H-Boc)+: m/z=237.9.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][CH3:43]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:44])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[S:42][CH3:43])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1ccccc1SC
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1SC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (8.26 g, 16.6 mmol) in anhydrous THF (50 mL) was added 2 M isopropylmagnesiumchloride in THF (18.4 mL, 36.8 mmol) at −40° C. It was then warmed to 0° C. and stirred at the same temperature for 30 minutes and then N-Methoxy-N-methyl-2-methylsulfanyl-benzamide (10.5 g, 49.8 mmol) was added in and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred overnight (18 h). It was then quenched with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography to provide 4-chloro-N-[5-chloro-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. Mass spectrum m/z: 486.9 (M+Na).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22].O>CC(CC)=O>[CH2:22]([O:1][C:2]1[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1)[CH:21]=[CH2:20]
Reactant: Cc1cc(=O)n2cccc(O)c2n1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: C=CCOc1cccn2c(=O)cc(C)nc12

Procedure:
To 3.52 g of 9-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one in 100 ml of pure ethyl methyl ketone is added 3.31 g of micronized anhydrous potassium carbonate and 2.90 g of allyl bromide. The mixture is stirred and heated under reflux for about 6 hours and then cooled. To the mixture is added 20 ml of water and the whole stirred vigorously, filtered with suction, the water layer separated, the organic layer washed with saturated aqueous sodium chloride, dried, and concentrated. The residue is recrystallized from heptane to give 9-[ (allyl)oxy]-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one, m.p. 113°-115°.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:18]Cl>C(O)(=O)C>[Cl:18][C:14]1[CH:15]=[CH:16][C:8]2[C:7](=[O:17])[NH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[C:9]=2[CH:13]=1
Reactant: ClCl
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(=O)c2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A mixture of 11.15 g of 5H-dibenz[b,e]azepin-6,11-dione and 600 ml of glacial acetic acid is heated on a steam bath until the solid dissolves. To the solution (70° C.) is added chlorine gas. chlorine is bubbled through the solution until a precipitate begins to form. The mixture is allowed to cool to room temperature and is filtered to give 7.3 g of product, m.p. 290° C. to 295° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[N:13]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36])[CH3:33].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][N:40]([S:28]([C:25]2[CH:24]=[CH:23][C:22]([CH:7]([C:8](=[O:21])[NH:9][C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[N:13]=4)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:39][CH2:38]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(S(=O)(=O)Cl)cc3)sc2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)Nc3nc4ccc(OC)nc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Title compound E, 4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl chloride (120 mg, 0.2499 mmol) was dissolved in dichloromethane. To this was added a solution of piperidine-4-carboxylic acid ethyl ester (38 μL, 0.2499 mmol) and diisopropylethylamine (87 μL, 0.4998 mmol) in dichloromethane. The reaction was stirred at room temperature for 1 hour, then concentrated. The residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford a yellow oil. The crude was then purified via column chromatography 10-90% ethyl acetate in hexanes to afford the desired product as a yellow foam (107 mg, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J=7.07 Hz, 3 H) 1.10-1.22 (m, 2 H) 1.50 (d, J=2.78 Hz, 2 H) 1.49 (br. s., 1 H) 1.63 (dd, J=14.91, 7.83 Hz, 2 H) 1.62 (br. s., 1 H) 1.81 (dd, J=13.64, 3.79 Hz, 3 H) 1.95 (t, J=7.07 Hz, 2 H) 1.91 (d, J=7.83 Hz, 1 H) 2.21-2.31 (m, 2 H) 2.53 (td, J=11.43, 2.91 Hz, 2 H) 3.61-3.71 (m, 3 H) 4.00 (s, 3 H) 4.09 (q, J=7.07 Hz, 2 H) 6.80 (d, J=8.84 Hz, 1 H) 7.52 (d, J=8.59 Hz, 2 H) 7.74-7.84 (m, 3 H) LC/MS 601.3 (M+1) 599.4 (M−1)
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.CN([C:23]([CH:25]=[CH2:26])=O)C.FC(F)(F)C(O)=O>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:6]1[C:2]2=[N:1][CH:23]=[CH:25][CH:26]=[C:3]2[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5]1
Reactant: C=CC(=O)N(C)C
Reactant: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Reaction time: 72 h

Procedure:
The solution obtained from 3A) is treated with 61.25 ml (60.77 g, 0.613 mol) of dimethylaminoacrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid and boiled under argon for 3 days. The solvent is then evaporated in vacuo, the residue is added to 2 l of water and the mixture is extracted three times with 1 l of ethyl acetate each time. The combined organic phases are dried using magnesium sulphate and concentrated in a rotary evaporator. The residue is chromatographed on 2.5 g of silica gel and eluted with a toluene/toluene-ethyl acetate=4:1 gradient. Yield: 91.6 g (49.9% of theory over two steps).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A mixture of 2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (4.06 g, 20.0 mmol) and dibenzylamine (5.0 g, 25.4 mmol) was stirred at 80° C. overnight. EtOH (50 mL) was added, and stirred at room temperature. The mixture was filtered to give white solid (4.5 g).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][C:38]1[C:39]([CH3:44])=[N:40][O:41][C:42]=1[CH3:43]>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][C:38]3[C:39]([CH3:44])=[N:40][O:41][C:42]=3[CH3:43])[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: Cc1noc(C)c1CCl
Product: Cc1ccccc1N1C(=O)N(Cc2c(C)noc2C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=609.0 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 4-(chloromethyl)-3,5-dimethylisoxazole.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][Li])[CH2:5][CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:27]=[CH:26][C:19]2[N:20]=[C:21]([S:23](Cl)=[O:24])[NH:22][C:18]=2[CH:17]=1>C1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:27]=[CH:26][C:19]2[N:20]=[C:21]([S:23]([CH2:12][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]4[C:11]=3[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5]4)=[O:24])[NH:22][C:18]=2[CH:17]=1
Reactant: [Li]Cc1cccc2c1N(C)CCC2
Reactant: COc1ccc2nc(S(=O)Cl)[nH]c2c1
Solvent: c1ccccc1
Product: COc1ccc2nc(S(=O)Cc3cccc4c3N(C)CCC4)[nH]c2c1
Yield: 3.6 %

Procedure:
(1-Methyl-1,2,3,4-tetrahydroquinolin-8-yl)methyl lithium (18.3 g) was dissolved in benzene (150 ml). After adding (5-methoxy-2-benzimidazolyl)sulfinyl chloride (20.1 g) thereto, the mixture was refluxed for 2 hours. The resulting lithium chloride was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give 8-(5-methoxy-2-benzimidazolyl)sulfinylmethyl-1-methyl-1,2,3,4-tetrahydroquinoline (1.1 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=1)=O>O1CCOCC1>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1
Reactant: Cc1cc(C(=O)CBr)ccc1O
Reactant: NC(N)=S
Solvent: C1COCCO1
Product: Cc1cc(-c2csc(N)n2)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.3 %

Procedure:
Thiourea (79.8 mg, 1.05 mmol) was added to a solution of 2-bromo-1-(4-hydroxy-3-methylphenyl)ethanone (200 mg, 0.87 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 25° C. for 24 h. The resulting suspension was filtered and the solid was washed with 1,4-dioxane and dried under reduced pressure. The solid was suspended in water (30 mL), pH 7 buffer solution (15 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were successively washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 1:1) to give the title compound (180 mg, 100% yield).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3](=[O:10])[CH2:2][S:15][C:12]([CH3:14])([CH3:13])[CH3:11])[CH3:9]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(C)(C)S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)CSC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-chloroacetoacetate (7.5 mL, 51.9 mmol), 2-methyl-2-propanethiol (5.6 mL, 49.7 mmol), triethylamine (10.8 mL, 77.4 mmol), and catalytic tetrabutylammonium bromide were dissolved in THF (250 mL) and stirred at room temperature overnight. Silica gel was added, and the mixture was concentrated and filtered over a plug of silica gel to obtain the desired product (B-1), which was used without further purification.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])=[CH2:2].Cl.[NH2:32][OH:33].C([O-])([O-])=O.[K+].[K+]>CCO>[OH:33][NH:32][C:28]([C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]3=[O:30])=[N:15][C:16]=2[CH:27]=1)=[NH:29]
Reactant: NO
Reactant: C=C(C)n1c(=O)n(Cc2nc3cc(C#N)ccc3n2CCC(C)C)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=C(C)n1c(=O)n(Cc2nc3cc(C(=N)NO)ccc3n2CCC(C)C)c2ccccc21
Yield: 26.1 %

Procedure:
2-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (110 mg, 0.275 mmol) was treated with hydroxylaminehydrochloride (57 mg, 0.275 mmol), K2CO3 (55.3 mg, 0.4 mmol) and heated to reflux in EtOH(10 ml) for 6 h. The solvent was removed and the residue dissolved in CH2Cl2 and washed with H2O. The solvent was removed to give 31 mg (26%) of N-hydroxy-2-(3-isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:10])([CH3:9])[C:7]#[N:8].[NH2:11][OH:12]>CCO>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:10])([CH3:9])[C:7]([NH:11][OH:12])=[NH:8]
Reactant: NO
Reactant: CC(C)(C#N)COCCCl
Solvent: CCO
Product: CC(C)(COCCCl)C(=N)NO
Reaction time: 18 h

Procedure:
3-(2-Chloroethoxy)-2,2-dimethylpropanenitrile (6.1 g, 37.7 mmol) was placed together with 50% aqueous hydroxylamine (3.1 g, 37.7 mmol) in 60 mL EtOH and warmed at 75-80 C with stirring for 18 h. The solution was concentrated and then concentrated further with EtOH and vacuum dried to leave (9.4 g, ˜80% pure) of the title compound as a gum. 1H NMR (300 MHz, CDCl3) δ: 1.17 (s, 6H), 3.40 (s, 2H), 3.58-3.73 (m, 4H), 5.16 (s, 2H). LC/MS (M+H): 195.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)[N:6]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C)C=O>[CH3:22][O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([N:7]1[C:8]([CH3:10])=[CH:9][C:5]([O:4][CH2:3][CH2:2][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:6]1)[CH:20]=[CH:19]2
Reactant: C1COCCN1
Reactant: COc1ccc2cc(-n3nc(OCCCl)cc3C)ccc2c1
Solvent: CN(C)C=O
Product: COc1ccc2cc(-n3nc(OCCN4CCOCC4)cc3C)ccc2c1
Yield: 61 %

Procedure:
A solution of 3-(2-chloroethoxy)-5-methyl-1-(6-methoxynaphthalen-2-yl)-1H-pyrazol (0.63 g, 2 mmol) and morpholine (0.96 g, 8 mmol) in dimethylformamide (10 ml) was heated to 95° C., in a nitrogen atmosphere, during 20 hrs. Next, it was cooled, the DMF was evaporated in a rotavapor and water and dichloromethane was added to the residue. The organic phase was washed with water and, subsequently, it was extracted with HCl 2N several times. The collection of acidic waters was basified by the addition of NaOH 20% and it was extracted with dichloromethane, which was dried over Na2SO4, filtered and evaporated, thereby leaving a residue of 448 mg of 4-{2-[1-(6-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine (yield: 61%) in the form of a colourless oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(Cl)[Cl:21].Cl>O1CCOCC1>[ClH:21].[CH:1]1([CH2:4][NH:5][C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@H]1CC[C@H](O)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CC[C@H](NCC2CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl (cyclopropylmethyl)(trans-4-hydroxycyclohexyl)carbamate (0.857 g, 3.2 mmol) in a solution of methylene chloride (6 mL) and 4.0 M of hydrogen chloride in 1,4-dioxane (3 mL) was stirred at r.t. 2 hours. Concentration yielded 0.658 g of trans-4-[(cyclopropylmethyl)amino]cyclohexanol hydrochloride (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:23][C:24]2[C:25]([NH2:33])=[CH:26][C:27]3[O:31][CH2:30][O:29][C:28]=3[CH:32]=2)=CC=1>>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:9]=2[CH:10]=1)=[N:33][C:25]1[CH:26]=[C:27]2[O:31][CH2:30][O:29][C:28]2=[CH:32][C:24]=1[CH:23]=3
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Product: COc1cc2c(cc1OC)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 80.9 %

Procedure:
Using the procedure of Example 1, 5,6-dimethoxyindan-1-one (192 mg, 1 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (255 mg, 1 mmol) to yields 7,8-dimethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (260 mg, 81% of theory).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][C@@H:9]([CH3:10])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:10][C@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@H]2[C@@H]1OC[C@@H]2O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1 h

Procedure:
Methanol (1.25 mL) was added dropwise to a mixture of 10% palladium on charcoal (20 mg) and bicyclic alcohol (108) (49 mg, 0.177 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1 hour then filtered through celite in vacuo. The filter cake was washed with ethanol (10 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with diethyl ether (3×3 mL) to obtain the crude (3R,3aR,6S,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (107) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[O-:10][CH2:11][CH3:12].[Na+].C(O)C>O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][CH3:12])=[N:4][CH:3]=1
Reactant: COc1cncc(Br)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(Br)cc1OC

Procedure:
As shown in step 5-i of Scheme 5,5-bromo-2-chloro-3-methoxypyridine (1.0 g, 4.5 mmol, prepared in the same manner as Compound 1003 in Example 2 starting with 3-bromo-5-methoxypyridine) was treated with a sodium ethoxide/ethanol solution (5.05 mL, 21% w/v, 13.5 mmol) and the reaction mixture microwave irradiated at 100° C. for 20 minutes. Water was added and the ethanol evaporated under reduced pressure. The resulting aqueous solution was extracted with DCM and ether, followed by drying the combined extracts over MgSO4. After filtration, removal of the volatiles under reduced pressure provided 5-bromo-2-ethoxy-3-methoxypyridine (Compound 1016), 0.72 g, 69% yield): ESMS (M+H) 232.32/234.23. As shown in step 5-ii of Scheme 5, Compound 1017 (ESMS (M+H) 218.32/220.23) was prepared in the same manner as Compound 1016, using sodium methoxide in methanol instead of sodium ethoxide in ethanol.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:20]([C:19]1[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=1)[OH:21])[CH3:5])[CH3:2]
Reactant: Cc1ccc(C=O)cc1
Reactant: C#CCOC(C)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
A solution of 5 g (33 mmol) of 1-(1-ethoxyethoxy)-2-propyne in 84 ml of tetrahydrofuran was treated at -78° under argon with 24.4 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 4.6 ml (33 mmol) of 4-methylbenzaldehyde in 34 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0° , stirred at 0° for a further 1 hour and then treated with 60 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by chromatography on 500 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-1-(4-methylphenyl)-2 -butyn-1-ol.