Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.[H-].[Na+].[CH3:12]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:12])=[CH:4][N:3]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Cl)nc1
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
To a solution of 2-chloro-5-hydroxymethylpyridine (1 g, 6.97 mmol) in THF (34.8 ml) was added sodium hydride (60% wt) (0.418 g, 10.45 mmol). The reaction was stirred for 10 minutes and treated with methyl iodide (0.653 ml, 10.45 mmol). The reaction was stirred at ambient temperature for 4 hrs. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic portion was concentrated and purified in 10-40% EtOAc/Heptanes to give the title compound (880 mg, 5.58 mmol, 80% yield) as a tan solid. MS m/z=157.9 (M+H).
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:13].[N-:14]=[N+:15]=[N-:16].[Na+].O>CC(C)=O>[N:14]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:13])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: [O-][n+]1c(Cl)ccc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=Nc1ccc2ccccc2[n+]1[O-]

Procedure:
In this example, 2.00 grams (0.009 mol) of 2-chloroquinoline N-oxide hydrochloride and 2.00 grams (0.031 mol) of sodium azide were added to and dissolved in 50 ml. of water and 100 ml. of acetone and the resulting solution stirred for 72 hours at 25° C. A solid separated and was collected by filtration. Recrystallization of this solid from benzene gave 2-azidoquinoline N-oxide in a yield of 1.01 grams or 58% of theory having a melting point of 103.5° C. to 104.5° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>ClC1N=C(Cl)C=C(C2C=CC=CC=2)N=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Clc1cc(-c2ccccc2)nc(Cl)n1
Product: N#Cc1ccc(-c2ccc(Br)cc2)cc1

Procedure:
4-bromo-4′-cyanobiphenyl was synthesized by the same method as in syntheses of 2,4-dichloro-6-phenylpyrimidine in the above (3-1-1), except that 4-bromoiodobenzene was used in place of 2,4,6-trichloropyrimidine and that 4-cyanophenylboronic acid was used in place of phenylboronic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][C:27]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][C:27]=1[O:35][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Oc1cc2cc[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 95 °C
Yield: 47.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (282 mg, 0.662 mmol), 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.994 mmol) was heated at 95° C. for 3 hours. After cooling, the residue was poured in water (12 ml) and the pH was adjusted to 8. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by preparative column chromatography on C18 silica eluting with 60% methanol in aqueous ammonium carbonate (2 g ammonium carbonate/liter saturated with CO2). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether and the solid was filtered, dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (147 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:11])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Reactant: Cc1ccc(N)cc1Br
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Br

Procedure:
Yet another process, described in Scheme 3, comprises reacting 3-bromo-4-methyl-aniline with 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester to obtain N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide. The latter is reacted with 4-(3-pyridyl)-2-pyrimidine amine (which is obtained by reacting cyanamide with 3-dimethylamino-1-pyridin-3-yl-propenone) to obtain Imatinib
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[C:34]([CH3:47])=[C:35](/[CH:41]=[CH:42]/[C:43]([O:45]C)=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:19]=[C:20]([C:28]([F:30])([F:29])[F:31])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[C:34]([CH3:47])=[C:35]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccc(OC)c(-c2ccc(N3CCC3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1C
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CCC(=O)O)c(C)c1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl (2E)-3-{3-[6-(azetidin-1-yl)-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxy-2-methylphenyl}prop-2-enoate (118 mg, 0.178 mmol) in methanol (2371 μl) was added palladium on carbon (10%) (59 mg, 0.178 mmol). This mixture was placed under a balloon of hydrogen gas and purged three times with vacuum, then allow to stir at 45° C. for 1.5 hours. LC/MS indicated complete conversion to desired product. The mixture was then diluted with filtered though a plug of Celite®. The residue was concentrated to furnish the desired product as a 53/47 mixture of atropisomers. To a solution of this mixture (98 mg, 0.147 mmol) in dioxane (1996 μl) and water (499 μl) was added lithium hydroxide (35.3 mg, 1.472 mmol). The reaction was stirred at room temp for 5 hours until complete. The mixture was then concentrated in vacuo and purified on reverse phase HPLC (C-18 column, 0-90% acetonitrile in water). The pure mixture of atropisomers was then separated on a Chiral SFC (Chiralcel AD-H column, 10% EtOH in CO2). To provide both atropisomers. Atropisomer A: Mass spectrum (ESI) 652.3 (M+1). 1H NMR (500 MHz, CDCl3) (atropisomers) δ 7.85 (s, 1H), 7.73 (s, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.32 (d, J=8.4 Hz, 1H), 5.69 (d, J=8.7 Hz, 1H), 4.55 (m, 1H), 4.43 (d, J=15.8 Hz, 1H), 4.10 (m, 4H), 3.72 (m, 1H), 3.65 (s, 3H), 2.97 (m, 2H), 2.64 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 2.00 (s, 3H), 0.71 (d, J=6.6 Hz, 3H). Atropisomer B: Mass spectrum (ESI) 652.3 (M+1). 1H NMR (500 MHz, CDCl3) (atropisomers) δ 7.84 (s, 1H), 7.68 (s, 2H), 7.20 (d, J=7.9 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.32 (d, J=7.6 Hz, 1H), 5.51 (d, J=8.0 Hz, 1H), 4.62 (d, J=15.9 Hz, 1H), 4.22 (m, 1H), 4.09 (m, 4H), 3.73 (m, 1H), 2.95 (m, 2H), 2.64 (t, J=7.5 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H), 2.02 (s, 3H), 0.68 (d, J=6.3 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:18][C@@H:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>CCOC(C)=O.CC(O)C>[CH:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[C:5]([O:4][CH2:3][C@H:2]([OH:1])[CH2:18][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@H]3CO3)c12
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC[C@@H](O)COc2cccc3[nH]c4ccccc4c23)c(OC)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
To a solution of (R)-(−)-4-(2,3-Epoxypropoxy)-carbazole (7 g, 0.029 mole) in EtOAc/IPA (40/80 mL) was added 2,4-dimethoxybenzylamine (8.7 mL, 0.058 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was concentrated to half its volume, and cooled to room temperature to give a colorless solid. The solid was filtered, re-dissolved in EtOAc (60 mL) by refluxing, concentrated to 40 mL and the colorless precipitate formed on cooling to room temperature, was filtered and dried. Recrystallization of the residue obtained from the filtrate was repeated until maximum amount of the solid was recovered. The combined solid was triturated with diethylether by stirring for 6 hours, followed by filtration to afford 5.5 g (46% yield) of the desired compound as a colorless solid with m.p: 152-153° C. 1H NMR (400 MHz, CDCl3): δ 2.17 (s 1H), 2.86-2.92 (m, 1H), 2.99-3.02 (m, 1H), 3.74-3.86 (m, 8H), 4.18-4.32 (m, 3H), 6.38-6.44 (m, 2H), 6.67 (d, 1H, J=8.0 Hz), 7.04 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.18-7.41 (m, 4H), 8.09 (s, 1H), 8.21 (d, 1H, J=8.0 Hz). MS m/z: 407.1 (M+1). Chiral purity: 99.99%
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[O:9][N:8]=1)=[O:5].[CH3:24]I>C[O-].[Na+]>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([N:6]([CH3:24])[C:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[O:9][N:8]=1)=[O:5]
Reactant: O=C(Nc1cc(-c2ccc(Cl)cc2)on1)c1c(Cl)cccc1Cl
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Product: CN(C(=O)c1c(Cl)cccc1Cl)c1cc(-c2ccc(Cl)cc2)on1
Reaction time: 0.25 h

Procedure:
2,6-Dichloro-N-(5-(4-chlorophenyl)-3-isoxazolyl)benzamide (1 gram prepared according to the teaching of synthesis route III and Example 15) and sodium methoxide (160 milligrams in 100 ml. methanol) were placed in a reaction vessel and stirred for about 15 minutes. Excess methyl iodide was added and the reaction mixture was then heated to reflux for 4 hours. Upon cooling a solid formed which was filtered and then recrystallized from ethanol. NMR analysis confirmed that the final product was a mixture of exo- and endo-alkylated isoxazole, m.p.=175°-178° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:27])=O>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:3][CH2:4][CH2:5][C:6]([Cl:27])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)Cl
Yield: 99.6 %

Procedure:
Under a nitrogen atmosphere, one drop of pyridine was added to 10 g of 5,9,13,17-tetramethyloctadecanoic acid and 20 ml of methylene chloride, and 5.2 g of thionyl chloride was added dropwise thereto at room temperature. After the completion of dropwise addition, the mixture was refluxed for 1 hour and concentrated under reduced pressure to obtain 10.5 g of 5,9,13,17-tetramethyloctadecanoic acid chloride.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:22])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[NH:19][N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:23](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[I:1][C:2]1[C:3](=[O:22])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[N:19]([CH3:23])[N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccn1c(=O)[nH]nc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
To an ice-cooled solution of 7-iodo-8-phenyl-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione in DMF (2 mL) was added cesium carbonate (73 mg, 0.224 mmol) and iodomethane (0.021 mL, 0.336 mmol). The mixture was allowed to warm to RT and stirred for 1.5 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was isolated and extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (25.5 mg, 51%, over 2 steps) as a yellow solid. LCMS (Method A): RT=3.98 min, [M+H]+=420.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:38].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:38])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=CCCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NCCCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-]
Reaction time: 1.5 h
Yield: 21.5 %

Procedure:
In this example, 5 m moles of 4-benzyloxy-2-(10-formyldecyl) quinoline-N-oxide is dissolved in methanol, and 50 m moles of ammonium acetate and 15 m moles of sodium cyanoborohydride are added thereto with ice cooling. Then, the mixture is stirred for 1.5 hours. After the reaction, the solvent is removed therefrom by distillation, and then the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate, and the solvent is removed therefrom by distillation. The residue is purified by silica gel column procedure, whereby the captioned compound is obtained as colorless crystals (yield: 21.5%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=[CH:15][C:7]1=[N:6]2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]([NH:33][C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[O:18])[CH:14]=[CH:15][C:7]1=[N:6]2
Reactant: Cc1sc(C)c2c(=O)n3cc(C(=O)O)ccc3nc12
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(C)c2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc12
Temperature: 105 °C
Yield: 62.6 %

Procedure:
A mixture of 0.6 g (0.0022 mol) of 1,3-dimethyl-10-oxo-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (Example 48) and 0.84 g (0.005 mol) of 1,1' carbonyldiimidazole (Aldrich Chemical Company) in 90 ml of dimethylformamide is stirred and heated in a wax bath at 105° C. for eighty five minutes under nitrogen. The mixture is allowed to stand at room temperature for thiry minutes and then 0.225 g (0.0022 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the mixture heated at 105° C. for three and one-half hours. The solvent is evaporated and the residue suspended in hot methanol, cooled and 0.71 g of crude product is collected. This material is dissolved in hot pyridine, activated charcoal (Darco G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 0.47 g of 1,3-dimethyl-10-oxo-N-1H-tetrazol-5-yl- 10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide with pyridine (1:0.2); mp >300° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]3[C:20]4[CH2:21][NH:22][CH2:23][CH2:24][C:25]=4[C:26]([CH3:29])([CH3:28])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]3[C:20]4[CH2:21][N:22]([CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:23][CH2:24][C:25]=4[C:26]([CH3:28])([CH3:29])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: CN(C)C(=O)CCl
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)N(C)C)CC1

Procedure:
The above-titled compound was prepared by reacting 8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N,N-dimethylacetamide according to the method of Example 3.
Reaction SMILES: [Li+].[I-].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11].O>C(OCC)C>[CH3:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(C)=O
Reactant: CCCCC=O
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCC/C=C/C(C)=O

Procedure:
A solution of 7.73 g (58 mM) of anhydrous LiI and 1.47 ml (20 mM) of acetone in 35 ml of diethyl ether was heated to gentle reflux. To this solution was added dropwise a solution of 1.59 ml (15.0 mM) 1-pentanal in 5 ml diethyl ether over 10 minutes. The solution was then heated at reflux for 6 hours. After the solution was cooled to ambient temperature water was added and the layers separated. The ether phase was washed once with brine and dried over anhydrous MgSO4. The diethyl ether was removed by distillation at atmospheric pressure followed by distillation of the residue. There was obtained 0.52 g (27%) of a highly mobile colorless liquid. 1H NMR (CDCl3):6.80δ (dt,1H,JHH =7Hz, 16Hz), 6.01δ (d,1H,JHH =16Hz), 2.20δ (s,3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:6]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[I-].[Na+].[ClH:31].[C:32]1([C:38]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[ClH:31].[C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:6]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:41]2[CH2:42][CH2:43][C:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:39][CH2:40]2)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1

Procedure:
9 g (20 mmol) 5-acetyl-1,4-dihydro-2,6-dimethyl-3-(6-bromohexanoyl)4-(3-nitrophenyl) -pyridine are reacted first with 6 g (40 mmol) sodium iodide, as described for starting compound B, and then with 11 g (38 mmol) 4,4-diphenylpiperidine hydrochloride. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=1/1. The product thus obtained is taken up in 20 ml acetonitrile. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 4 g (31%). M.p. 136° C. decomp. (acetonitrile).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:12])[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(O)(=O)C.Br.[H][H]>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH3:12])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)CCCc2ccc(F)cc2)c1
Reactant: [H][H]
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(CCCc1ccc(F)cc1)c1cc(O)cc(O)c1
Reaction time: 17 h

Procedure:
Fifty grams of the above-prepared 2-(3,5-dimethoxyphenyl)-5-(p-fluorophenyl)pentane, 450 ml. of acetic acid and 180 ml. of 48% HBr in water were mixed. While cooling, the mixture was saturated with hydrogen gas (approximately one-half hour). The reaction was placed in an 87° bath and stirred for 17 hours. The reaction was then concentrated in vacuo and the residue neutralized with K2CO3 and NaHCO3, extracted with ether, treated with charcoal and MgSO4 and filtered to yield 45 g. of 2-(3,5-dihydroxyphenyl)-5-(p-fluorophenyl)pentane as a brown oil which distills at 180°/0.01 mmHg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C1C(=O)N([Br:26])C(=O)C1>CO.C(Cl)Cl.[Pd]>[Br:26][C:5]1[CH:6]=[C:7]([S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.3 %

Procedure:
A solution of 250 mg (0.918 mmol) of 4-(4-nitro-benzenesulfonyl)-morpholine in MeOH (15 mL) was treated with 20 mg of 10% Pd/C (Degussa type E101-NE/W, Aldrich, 50% by weight water) under H2 (1 atm). The mixture was stirred at RT for 1.5 h and filtered through Celite. The filter cake was washed with MeOH, and the filtrate was concentrated in vacuo. The residue was taken up in CH2Cl2 (10 mL), cooled to 0° C., and treated with 124 mg (0.698 mmol) of NBS at that temperature for 25 min. The mixture was diluted with CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3 (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 40-50% EtOAc-hexane afforded 50.0 mg (17%) of the title compound as a pale tan solid: Mass spectrum (ESI, m/z): Calcd. for C10H13N2O3SBr, 321.0 (M+H), found 320.9/322.8.