Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:44][C:45]1[C:46]([CH2:52][N:53]([CH3:55])[CH3:54])=[C:47](O)[CH:48]=[CH:49][CH:50]=1>C1COCC1>[ClH:44].[ClH:44].[CH2:1]([N:8]([CH2:9][CH2:10][O:11][C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([Cl:44])[C:46]=1[CH2:52][N:53]([CH3:54])[CH3:55])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)Cc1c(O)cccc1Cl
Reactant: CN(CCO)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)Cc1c(Cl)cccc1OCCN(C)Cc1ccccc1
Product: Cl

Procedure:
N-Benzyl-N-methylethanolamine (5.25 ml), triphenylphosphine (8.48 g) and diethyl azodicarboxylate (5.09 ml) were added to a solution of 3-chloro-2-(dimethylaminomethyl)phenol (6.0 g) in dry THF (200 ml) at ambient temperature with stirring under nitrogen. The mixture was stirred at ambient temperature for 24 hours and then evaporated to dryness under reduced pressure at 30° C. The residue was dissolved in 2M hydrochloric acid, washed with ethyl acetate, and then basified with concentrated sodium hydroxide solution. The mixture was extracted with dichloromethane to give an oil which was distilled under vacuum in a Kugelrohr. The higher boiling fraction which boiled at 140° C. at 0.01 mbar was dissolved in ether and treated with ethereal hydrogen chloride. The mixture was filtered and the solid collected was recrystallised from propan-2-ol to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-6-chloro-N,N-dimethylbenzylamine dihydrochloride, m.p. 238°-239° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)[CH2:7]C)=[O:5].NC1C=C([F:37])C(Br)=C2C=1C(=O)N(C)C2.NC1C=CC(Br)=CC=1C(N(CC)CC)=O>>[NH2:1][C:2]1[CH:14]=[C:13]([F:37])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[C:11]2[C:3]=1[C:4](=[O:5])[N:6]([CH3:7])[CH2:9]2
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CN1Cc2c(Br)c(F)cc(N)c2C1=O
Agent: CCN(CC)C(=O)c1cc(Br)ccc1N
Product: CN1Cc2c(c(N)cc(F)c2-c2cnn(CCCO)c2)C1=O

Procedure:
Prepared analogously to Compound 3C substituting 7-amino-4-bromo-5-fluoro-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 31D) for 2-amino-5-bromo-N,N-diethylbenzamide (Compound 3D). 1H NMR (CDCl3, 400 MHz): δ 7.75 (d, J=4.5 Hz, 2H), 6.41 (d, J=13.1 Hz, 1H), 4.46 (t, J=6.1 Hz, 2H), 4.39 (s, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.17 (s, 3H), 2.20-2.09 (m, 3H). MS (ESI): m/z=305.14 [M+H]+. UPLC: tR=0.95 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:26]=[C:27]([C:33]5[C:42]([CH3:43])=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=5[CH3:44])[CH:28]=[N:29][C:30]=4[O:31][CH3:32])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[C@H:13]2[CH3:49])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[F:51][CH:52]1[CH2:55][NH:54][CH2:53]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[F:51][CH:52]1[CH2:55][N:54]([C:21]2[N:20]=[C:19]([CH2:18][N:14]3[C@@H:13]([CH3:49])[C@@H:12]([C:4]4[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=4)[O:16][C:15]3=[O:17])[C:24]([C:25]3[CH:26]=[C:27]([C:33]4[C:34]([CH3:44])=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][C:42]=4[CH3:43])[CH:28]=[N:29][C:30]=3[O:31][CH3:32])=[CH:23][N:22]=2)[CH2:53]1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: FC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Yield: 100.9 %

Procedure:
To a solution of methyl 4-{5-[4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (INTERMEDIATE 50, 82 mg, 0.117 mmol) in THF (1.5 mL) was added 3-fluoroazetidine hydrochloride (39.2 mg, 0.351 mmol) and triethylamine (0.074 mL, 0.5927 mmol). The resulting mixture was subjected to microwave irradiation at 120° C. for 20 minutes (BIOTAGE microwave). The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (sodium sulfate), filtered and concentrated to give crude methyl 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (82 mg, 0.118 mmol). LCMS (M+H)+: 698.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[SH:19][CH:20](O)C.[C:23](=[O:26])([O-])[O-].[K+].[K+].O>CN(C)C=O.CCOCC>[OH:26][CH2:23][CH2:20][S:19][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(O)S
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(C(=O)c1ccc(SCCO)cc1)N1CCOCC1
Temperature: 95 °C

Procedure:
20.1 g (0.075 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholinopropan-1-one and 6.45 g (0.0825 mol) of mercaptoethanol in 100 ml of dimethylformamide are warmed to 95° C. 20.7 g (0.15 mol) of anhydrous potassium carbonate are then added. The suspension is stirred at 95° C. until the starting compound can no longer be detected. The reaction mixture is cooled and water is poured over it, and the product is taken up in ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The resulting oil is purified over a drying column, and crystallises after a little time.
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[S:44][C:45]5[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=5[C:47]=4[O:48][CH3:49])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:56][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:55]=[CH:54][C:33]([NH:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([C:43]3[S:44][C:45]4[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=4[C:47]=3[O:48][CH3:49])=[O:42])[CH2:39][CH2:40]2)=[CH:32][CH:31]=1
Reactant: COc1c(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)sc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1c(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)sc2ccccc12
Yield: 83 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl)(3-methoxy-1-benzothiophen-2-yl)methanone (0.148 g, 0.182 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.087 g, 0.151 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH2:12]([OH:14])[CH3:13].[ClH:15]>C(OCC)C>[ClH:15].[CH2:12]([O:14][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH3:13]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)c1cccc(C(C)=O)c1
Reaction time: 48 h

Procedure:
A solution of 7.25 g (0.05 mol) of 3-acetylbenzonitrile (Aldrich, Buchs, Switzerland; Cat. No. 29,221-4) in 150 ml of diethyl ether and 4.5 ml of ethanol is saturated at 0° C. with dry hydrochloric acid gas and then left to stand at 0° C. for 2 days. The product that has crystallized out is filtered off and the title compound is obtained after recrystallization from ethanol/diethyl ether, m.p. 110° C. (decomp.).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[O:6][C:5]1=[O:13])(=O)[CH3:2].[OH-].[Na+].C(=O)[C:17]1[CH:22]=[CH:21]C=[CH:19][CH:18]=1>>[C:2]1([CH:1]=[C:4]2[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[O:6][C:5]2=[O:13])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCC1CC(C(C)=O)C(=O)O1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCC1CC(=Cc2ccccc2)C(=O)O1

Procedure:
3-Phenylmethylene-5-butyldihydro-2(3H)-furanone was prepared by reacting 3-acetyl-5-butyldihydro-2(3H)-furanone with sodium hydroxide and benzaldehyde in accordance with the procedure described in Example I. The crude product (64.5% yield) was recovered by distillation of the reaction mixture at 25°-147° C. (0.04 mm/Hg) to remove light ends. The structure was confirmed by proton nuclear magnetic resonance spectroscopy. 1HNMR (CDCl3) δ7.5 (m,6H), 4.56 (pentet,1H),3.3 (ddd,1H) 2.8 (ddd,1H) 1.9-1.2 (m,6H), 0.86(t,3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[S:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48]>CN(C)C1C=CN=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:48][C:47]3[CH:49]=[CH:50][CH:51]=[C:45]([S:44][C:32]4[C:31]5[C:36](=[CH:37][C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[C:29]([O:28][CH3:27])[CH:30]=5)[N:35]=[CH:34][N:33]=4)[CH:46]=3)=[O:22])=[CH:11][C:10]([C:23]([F:24])([F:25])[F:26])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(F)cc4)c3)c2cc1OC
Yield: 25 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 171B (0.146 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.062 g, 25%). 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.79 (s, 1H), 8.68 (d, 1H), 7.78 (s, 1H), 7.68 (m, 2H), 7.45 (m, 4H), 7.37 (s, 1H), 7.33 (s, 1H), 7.27 (d, 1H), 6.87 (s, 1H), 4.33 (m, 2H), 4.02 (s, 3H), 3.76 (m, 2H), 3.34 (s, 3H); LC-MS (ESI) m/z 629 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: OCc1cc(Cl)ccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cc(Cl)ccn1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-Chloro-2-pyridinemethanol (1.0 g, 6.965 mmol) was dissolved in dichloromethane (25 cm3), heated to reflux and then treated slowly with a solution of thionyl chloride (1.50 cm3, d=1.631 gcm−3, 0.0206 mmol) in DCM (25 cm3). The reaction mixture was then stirred at 60° C. for 3 h, soon turning pink. After this time the DCM was evaporated off and the pale pink residue carefully neutralised with saturated sodium bicarbonate solution (40 cm3). The product was then extracted into DCM (3×30 cm3) and dried over sodium carbonate for 30 min. After filtration the product solution was then concentrated to a low volume and filtered through a short silica column (1:4 methanol/DCM as eluent), giving a pale yellow solution. This was then concentrated down to a red/brown oil, dried at 50° C., which was the desired product 4-chloro-2-chloromethylpyridine (934 mg, 83%); 1H NMR (CDCl3); δH 8.40 (d, 1H, J=5.5), 7.44 (d, 1H, J=1.5), 7.19 (dd, 1H, J=5.5, 1.5), and 4.58 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[C:2]#[CH:3].Br[C:15]1[C:16]([NH:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NC(C)C)(C)C>O1CCOCC1.[Pd](Cl)Cl.C(#N)C1C=CC=CC=1.C(#N)C1C=CC=CC=1.[Cu]I>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:13][N:4]1[CH2:1][C:2]#[C:3][C:15]1[C:16]([NH:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#CCN1CCc2ccccc2C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Solvent: N#Cc1ccccc1
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCc2ccccc2C1
Yield: 46.5 %

Procedure:
2-Prop-2-ynyl-1,2,3,4-tetrahydro-isoquinoline (0.72 mmol), 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (0.86 mmol), Bis(benzonitrile)-palladium(II) chloride (0.02 mmol), copper (I) iodide (0.015 mmol), tri-tert-butylphosphine (0.04 mmol) and diisopropyl amine (0.86 mmol) in dioxane (4 ml) is stirred at room temperature for 2.5 h. After filtration, the reaction mixture is treated with saturated ammonium chloride. The mixture is extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a column of silica gel, which is eluted with following solvents: n-hexane:AcOEt=1:1 (v/v) and n-hexane:AcOEt=1:5 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo afford the title compound. yield 46.5%, Rf=0.31 (n-hexane:AcOEt=1:1).
Reaction SMILES: [I-:1].[I-].[CH3:3][N:4]1[CH:32]=[CH:31][CH:30]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:29])[C:22]2[CH2:23][N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[O:8])[CH2:5]1.[H][H]>C(O)C.O.[Pt]=O>[IH:1].[IH:1].[CH3:28][N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[CH:6]2[CH2:30][CH2:31][CH2:32][N:4]([CH3:3])[CH2:5]2)=[O:29])[CH2:23]1
Reactant: [I-]
Reactant: CN1C=CC=C(C(=O)NCCCCCCCCCCNC(=O)C2=CC=CN(C)C2)C1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O
Solvent: CCO
Product: CN1CCCC(C(=O)NCCCCCCCCCCNC(=O)C2CCCN(C)C2)C1
Product: I

Procedure:
1,10-Bis[N-(1-methylnipecotoyl)amino]decane dihydriodide (Example 28) was prepared in accordance with the procedure described by Lasslo et al for related compounds (Lasslo, Marine and Waller, J. Org. Chem., Vol. 21, pages 958-960 (1956); Lasslo and Waller, J. Org. Chem., Vol. 22, pages 837-838 (1957)). Thus, 12.0 g (0.018 mole) of 1,10-bis[N-(1-methylnicotinoyl)amino]decane diiodide was dissolved in a mixture of 125 ml of absolute ethanol and 125 ml of water, and subjected to hydrogenation (at maximum pressures of 45-50 psi and at ambient temperature) in the presence of 1.0 g of platinum oxide (Adams' catalyst). When hydrogen uptake ceased, the catalyst was removed by filtration and the solvent by distillation under reduced pressure. Subsequent to drying at 75° C./0.020 mm Hg for 2 hr, the residue constituted the analytical sample (11.8 g, 96.7%) with the properties described in Table 1. In other instances, the products so obtained were purified by recrystallization from appropriate solvents.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:11])=[O:10]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of 3-(2,5-dimethylphenylsulfonyloxy)-5-methylphenol (585 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a pale yellow oil (650 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.29 (s, 1H), 6.60 (s, 1H), 6.43 (s, 1H), 6.37 (s, 1H), 3.99 (t, J=6.0 Hz, 2H), 3.81 (m, 2), 2.70 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 1.98 (m, 2H), 1.63 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH3:20][N:21]([CH3:35])[C:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>C1COCC1>[O:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[C:25]1([OH:28])[CH2:26][CH2:27][C:22]([N:21]([CH3:20])[CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:24]1
Reactant: c1ccc2occc2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3o2)CC1
Temperature: -5 °C
Yield: 23.9 %

Procedure:
A solution of benzo[b]furan (1.50 g, 12.7 mmol) in dry THF (50 ml) was cooled to −8° C. under a stream of argon. Tert-butyllithium (15.2 mmol, 10.2 ml of a 1.5 molar pentane solution) was added dropwise in such a way that a reaction temperature of −5° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2½ hours at −5° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (2.76 g, 12.7 mmol) in dry THF (15 ml) was added dropwise at 0° C. The mixture was stirred for 1 hour at 0° C. and then 4 days at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (30 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out by flash chromatography with cyclohexane/ethylacetate (V:V=7:3) over silica gel. 1.02 g 1-benzofuran-2-yl-4-dimethylamino-4-phenylcyclohexanol with a melting point of 134–137° C. were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:23])[C:13]2[N:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1)[CH3:2].S(=O)(=O)(O)O.[N+:29]([O-])([OH:31])=[O:30]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:29]([O-:31])=[O:30])=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:23])[C:13]2[N:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1)[CH3:2]
Reactant: CCCc1ccnc2c(=O)[nH]c(-c3ccccc3OCC)nc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCc1ccnc2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77 %

Procedure:
A solution of 2-(2-ethoxyphenyl)-8-n-propylpyrido-[3,2-d]pyrimidin-4(3H)-one (Preparation 8; 0.80 g, 0.0026 mol) in a mixture of concentrated sulphuric acid (5.4 ml) and concentrated nitric acid (0.20 ml) was stirred at ambient temperature for 4.5 hours. The mixture was then poured cautiously into stirred ice/water (50 g) and the resulting mixture extracted with a methanol:dichloromethane mixture (1:9, 3×50 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum, and the residue crystallised from ethyl acetate:methanol to give the title compound as an off-white solid (0.71 g, 77%), m.p.257°-259° C. Found: C,61.28; H,5.11; N,15.60. C18H18N4O4 requires C,61.01; H,5.12; N,15.81%.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:6]=[C:5]([O:13][CH3:14])[CH:4]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:13][C:5]1[CH:4]=[C:3]([CH2:2][N:25]2[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]2)[C:11]2[O:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(CBr)c2c(c1)C(=O)CO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)CO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.8 %

Procedure:
A solution of 7-(bromomethyl)-5-methoxybenzofuran-3(2H)-one (0.040 g, 0.16 mmol) in methylene chloride (2.0 mL) was added with 1-tert-butoxycarbonylpiperazine (0.032 g, 0.17 mmol), and triethylamine (0.021 g, 0.20 mmol), and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl 4-[(5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.008 g, 14%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(O)(C)C>O>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Solvent: O
Solvent: CC(C)O
Product: CC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a 0.33 g. sample of 5-amino-2-nitro-3-phenylbenzofuran is added 1 ml. of acetic anhydride, and the mixture is heated for 5 minutes on a steam bath. About 10 ml. of isopropanol is added, and the mixture is again heated on a steam bath to dissolve the solid. It is then saturated with hot water and cooled to provide yellow needles of 5-acetamido-2-nitro-3-phenylbenzofuran, m.p. 204°-207° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1.C(OCC)C>ClCCl>[CH3:1][C:2]1([CH3:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:27])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2ccccn2)c2ccccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)C=C(c2cccc[n+]2[O-])c2ccccc2O1
Yield: 2 %

Procedure:
1.61 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of dichloromethane at room temperature and 2.0 g of m-chloroperbenzoic acid were added. After 1 hour the mixture was washed with sodium bisulphite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/ethanol/formic acid (40:4:1) for the elution. The product was obtained as an oil which solidified upon trituration with diethyl ether. Recrystallization from toluene gave 0.034 g of 2-(2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 148°-150° C.