Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.N>C(O)C.O.C(O)(=O)C.[Fe]>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CSc1ncnc2cc([N+](=O)[O-])ccc12
Agent: [Fe]
Agent: N
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CSc1ncnc2cc(N)ccc12
Temperature: 50 °C
Yield: 93.8 %

Procedure:
Iron powder (325 mesh, 1.35 g, 52 mmol) was added portionwise to a stirred solution of 4-(methylthio)-7-nitroquinazoline (1.44 g, 6.52 mmol) in ethanol (130 ml), water (65 ml) and acetic acid (1.15 ml) at reflux over 1.5 hours. The mixture was cooled to 50° C., and a solution of ammonia (28%, 5 ml) was added. The precipitate was collected by suction filtration, washed with warm ethanol and the solvent was evaporated in vacuo. Purification by flash chromatography on by silica gel, eluting with 5% methanol in dichloromethane, yielded 4-(methylthio)-7-aminoquinazoline (1.17 g, 94% yield):
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[NH3:25]>>[ClH:1].[F:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]\[CH2:2][NH2:25])[S:7]1(=[O:24])=[O:23]
Reactant: Cc1ccc(N2c3ccccc3N(C/C=C\CCl)S2(=O)=O)c(F)c1
Reactant: N
Product: Cc1ccc(N2c3ccccc3N(C/C=C\CN)S2(=O)=O)c(F)c1
Product: Cl

Procedure:
In an analogous manner to general procedure V, 1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide was reacted with ammonia to provide (2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-en-1-amine hydrochloride:
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][Br:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[Br-:26].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:23][CH:22]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A solution of 29.4 g of triphenylphosphine in 200 ml of toluene is treated dropwise with 20.5 g of 4-chlorobenzyl bromide. The mixture is heated to 65° C. for 3 hours and then to boiling for 2 hours. After cooling to room temperature the precipitate is removed by filtration, washed with toluene and dried in a vacuum. The 4-chlorobenzyl-tri-phenylphosphonium bromide obtained is suspended in 500 ml of diethyl ether. The suspension is treated with 9.5 g of potassium tert.butylate while gassing with nitrogen, stirred at room temperature for a further 30 minutes and then treated dropwise at 20° C. with a solution of 19.8 g of trans-4'-(1,3-dioxolan-2-yl)-[1,1'-bicyclohexyl]-trans-4-carboxaldehyde in 250 ml of absolute diethyl ether. The reaction mixture is stirred at room temperature for a further 2.5 hours. Subsequently, the mixture is washed with 500 ml of semi-saturated sodium hydrogen carbonate solutions and with 300 ml of water, dried over sodium sulfate, fitted and concentrated. The residue is dissolved in 200 ml of hexane and 120 ml of methanol/water (vol. 4:1). The hexane phase is separated, washed with 40 ml of methanol/water (vol. 4:1), dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography on silica gel with hexane/ethyl acetate (vol. 9:1) gives trans-4-(1,3-dioxolan-2-yl)-trans-4'-(4-chlorostyryl)-[1,1'-bicyclohexyl].
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2=[C:7]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[S:8][C:9](S(C)=O)=[C:5]2[C:4](=[O:19])[CH2:3]1.[H-].[Na+].[CH:23]1([OH:27])[CH2:26][CH2:25][CH2:24]1>C1COCC1>[CH:23]1([O:27][C:9]2[S:8][C:7]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)=[C:6]3[CH2:18][C:2]([CH3:20])([CH3:1])[CH2:3][C:4](=[O:19])[C:5]=23)[CH2:26][CH2:25][CH2:24]1
Reactant: CS(=O)c1sc(-c2cc[nH]n2)c2c1C(=O)CC(C)(C)C2
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)c2c(OC3CCC3)sc(-c3cc[nH]n3)c2C1
Yield: 12 %

Procedure:
To a solution of 6,6-dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (178 mg, 0.59 mmol) in cyclobutanol (1 mL) and THF (3 mL) was added sodium hydride (70 mg of a 60% dispersion in oil, 1.76 mmol). After effervescence had ceased the mixture was heated at 95° C. for 2h before the solvent was evaporated. The residue was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (1:1) to give the title compound (22 mg, 12%) as a pale yellow solid. mp 202-204° C. Found: C, 62.48; H, 6.24; N, 8.49%. C17H20N2O2S .0.5(H2O) requires: C, 62.74; H, 6.50; N, 8.61% 1H NMR (360 MHz, CDCl3) δ 1.06 (6H, s), 1.60-1.76 (1H, m), 1.86-1.97 (1H, m), 2.37 (2H, s), 2.38-2.47 (2H, m), 2.50-2.60 (2H, m), 2.79 (2H, s), 4.76 (1H, pentet, J=7.2 Hz), 6.45 (1H, d, J=2.4 Hz), 7.62 (1H, d, J=2.4 Hz). MS (ES+) 317 (M+1).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[S:11][C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:28][CH2:27][NH:26][CH2:25]5)[CH:21]=[CH:20][C:17]=4[C:18]=3[N:19]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[CH:2]([N:5]1[C:9]([C:10]2[S:11][C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:28][CH2:27][N:26]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:25]5)[CH:21]=[CH:20][C:17]=4[C:18]=3[N:19]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNC3)ccc1-2
Agent: Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(S(C)(=O)=O)C3)ccc1-2

Procedure:
Following the procedure for 395, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene hydrochloride salt and methanesulfonyl chloride gave 396 isolated as a pale orange solid (28 mg, 48%). LCMS: RT=11.27 min, [M+H]+=460. 1H NMR δ (ppm) (CDCl3): 8.33 (1 H, d, J=8.21 Hz), 7.90 (1 H, s), 7.05 (1 H, dd, J=8.24, 1.91 Hz), 6.94 (1 H, d, J=1.87 Hz), 5.93-5.83 (1 H, m), 4.42-4.36 (2 H, m), 3.79 (1 H, dd, J=9.53, 7.31 Hz), 3.61 (1 H, ddd, J=9.97, 8.27, 3.30 Hz), 3.50-3.31 (5 H, m), 2.86 (3 H, s), 2.41-2.32 (1 H, m), 2.15-2.03 (1 H, m), 1.61 (6 H, d, J=6.63 Hz)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:22])[CH2:10][CH2:11][O:12][CH2:13][C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:15].C(N(CC)CC)C.[Cl:30][C:31]1[C:40]2[C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:37]=[CH:36][C:35]=2[CH:34]=[N:33][CH:32]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:8][N:9]([CH3:22])[CH2:10][CH2:11][O:12][CH2:13][C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][N:19]([S:41]([C:39]2[C:40]3[C:31]([Cl:30])=[CH:32][N:33]=[CH:34][C:35]=3[CH:36]=[CH:37][CH:38]=2)(=[O:43])=[O:42])[CH2:18]1)=[O:15]
Reactant: CN(C)CCOCC(=O)N[C@H]1CCNC1
Reactant: O=S(=O)(Cl)c1cccc2cncc(Cl)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCOCC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
A solution of (S)-3-[2-[2-(Dimethylamino)ethoxy]acetyl]aminopyrrolidine trifluoroacetate (246 mg) prepared in Step F in dichloromethane (5 ml) was successively added with triethylamine (387 μl) and 4-chloro-5-isoquinolinesulfonyl chloride (145 mg) at 0° C., and the mixture was stirred at the same temperature for 45 minutes, and further stirred at room temperature for 15 minutes. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, and the organic layer was separated. The aqueous layer was extracted three times with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain the title compound (160 mg).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>C1C=CC=CC=1.ClCCl>[C:1]([NH:5][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([C:7]([F:6])([F:17])[F:18])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)N
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 429 %

Procedure:
To N-tert-butylamine (3.50 g, 0.0048 mol) in 75 mL of benzene was added 4-trifluoromethylbenzoyl chloride (5.00 g, 0.024 mol). The temperature was maintained below 15° C. during the addition and then the reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. The solvent was then stripped and the residue was dissolved in 75 mL of dichloromethane. This solution was washed with 5% hydrochloride acid (2×75 mL), water (2×75 mL), dried over MgSO4 and then the solvent was removed in vacuo to provide 5.05 g (85-9% yield) of the title compound, m.p. 146-148° C.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]I.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[I-:1].[I-:1].[CH2:2]([N+:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ICCCCCCCCI
Reactant: c1ccncc1
Product: [I-]
Product: c1cc[n+](CCCCCCCC[n+]2ccccc2)cc1
Temperature: 65 °C
Yield: 93 %

Procedure:
1,8-Diiodooctane (mmol) was added to a solution (30 mL) of dry pyridine, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated in a 93% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.11 (2H, d, C2&C6-H), 8.63 (1H, t, C4-H), 8.18 (2H, t, C3&C5-H), 4.59 (2H, t, C′1-CH2), 1.89 (2H, m, C′2-CH2), 1.28 (4H, m, C′3&4-CH2); 13C NMR (75 MHz, DMSO-D6) δ 145.3, 144.5, 127.9, 60.5, 30.6, 28.1, 25.2.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH2:29]([CH:31]1[CH2:33][O:32]1)[CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[OH:32][CH:31]([CH2:29][CH3:30])[CH2:33][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCC1CO1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)CC)c2ncnn12
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 2-ethyloxirane (1.17 mL), potassium carbonate (0.38 g) and N,N-dimethylacetamide (10 mL) was stirred in a sealed tube at 100° C. for 8 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.45 g, 75%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH:3]1([CH2:2][NH:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:5][CH2:4]1
Reactant: NCC1CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2 mL (23 mmol) of aminomethyl cyclopropane in 25 mL methylene chloride was added 4.8 mL (28 mmol) of diisopropylethyl amine. After 10 minutes of stirring, 4.49 g (23 mmol) of 4-fluorobenzene sulfonyl chloride was added and the mixture was allowed to stir for 4 hours. The reaction mixture was quenched with water and the organic layer was washed twice with 1N HCl, twice with water, dried over magnesium sulfate and then concentrated in vacuo. Then the solid was dried under vacuum to give 4.65 g of the title compounds as an off white solid; 1H NMR (CDCl3) δ 0.08-0.13 (m, 2H), 0.45-0.51 (m, 2H), 0.83-0.94 (m, 1H), 2.86 (t, J=6.9 Hz, 2H), 4.66-4.71 (m, 1H), 7.12-7.23 (m, 2H); MS (ES) m/z 218.23 (MH+); HRMS for C10H12FNO2S: 218.0637.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.[OH:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[CH:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[OH:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[CH:26][C:27]([NH:30][C:31]([N:2]3[CH2:7][CH2:6][C:5]4([C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:9](=[O:16])[O:8]4)[CH2:4][CH2:3]3)=[O:32])=[N:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1cnc(-c2cccc(O)c2)cn1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4cccc(O)c4)cn3)CC2)c2ccccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (40 mg), phenyl N-[5-(3-hydroxyphenyl)-2-pyrazinyl]carbamate (51 mg) and triethylamine (119 μL) in chloroform (5 mL) was stirred at 80° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL) and then dried over anhydrous Na2SO4. The concentration of the solvent left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) followed by recrystallization from ethyl ether-hexane to give the subject compound (24 mg) as colorless crystals (melting point 257-259° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Na+]>>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([S:11][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCSc1cc(C(=O)O)cc(N)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (5.2 g), n-pentyl bromide (5 ml), and 0.5 N sodium hydroxide is stirred at room temperature for 5 days. 5-Amino-3-n-pentylthio-4-phenoxybenzoic acid is precipitated by addition of 4 N hydrochloric acid (30 ml). After collection by filtration, recrystallisation from cyclohexane and drying, the compound is obtained from a melting point of 98° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].B(Br)(Br)Br.B(F)(F)F.[CH3:19][CH2:20][O:21]CC.C(O)(=O)C>O.ClCCl>[F:1][C:2]1[C:7]([OH:8])=[C:6]([C:20](=[O:21])[CH3:19])[CH:5]=[CH:4][C:3]=1[OH:10]
Reactant: COc1cccc(O)c1F
Reactant: CCOCC
Agent: BrB(Br)Br
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(O)c(F)c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
A solution of 2-fluoro-3-methoxy-phenol (0.5 g, 3.53 mmol) and dichloromethane is stirred at −78° C. A 1M solution of boron tribromide in dichloromethane (3.9 mL, 3.9 mmol) is added slowly and the mixture is stirred 10 min cold, then warmed to 0° C. and stirred 1 hr. The reaction is quenched with ice and stirred at room temperature overnight. The product is extracted with ethyl acetate (2×50 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting residue is combined with boron trifluoride diethyl etherate (1.3 mL, 10.3 mmol) and acetic acid (0.2 mL, 3.28 mmol) and heated to reflux 8 hr. The mixture is cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined extracts are dried over magnesium sulfate, filtered and concentrated to about 10 mL volume. The resulting mixture is diluted with hexanes (50 mL), cooled to 0° C., and filtered to give the title compound (310 mg, 58%) as a tan solid. MS ES 171 M+1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].I[CH2:20][CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18])[CH:21]([CH3:23])[CH3:22]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Temperature: 60 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A mixture of (R/S) 5-hydroxy-1-(oxan-2-yl)-1H-indazole-3-carbaldehyde (590 mg, 2.40 mmol, 1.00 equiv), 1-iodo-2-methylpropane (882.6 mg, 4.80 mmol, 2.00 equiv) and cesium carbonate (782 mg, 2.39 mmol, 1.00 equiv) and N,N-dimethylformamide (15 mL) was stirred under nitrogen overnight at 60° C. The reaction was cooled to room temperature then quenched by the addition of 50 mL of water/ice. The resulting mixture was extracted with 3×50 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 15-35% of ethyl acetate in petroleum ether to give 250 mg (35%) of (R/S) 5-iso-butoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a yellow solid. 1H NMR (300 MHz, CDCL3): δ 10.25 (s, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.16 (dd, J=9.0 Hz, 2.1 Hz, 1H), 5.83 (d, J=6.9 Hz, 1H), 4.05 (m, 1H), 3.83 (d, J=6.6 Hz, 2H), 3.80 (m, 1H), 2.60 (m, 1H), 2.15 (m, 3H), 1.80 (m, 3H), 1.08 (d, J=6.9 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.77 min, m/z=303.1 [M+H]+.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[C:18]([OH:20])=[O:19])=[CH:6][CH:5]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH2:3].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[C:18]([OH:20])=[O:19])=[CH:6][CH:5]=1.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[C:18]([OH:20])=[O:19])=[CH:6][CH:5]=1
Reactant: COc1ccc(CCCn2ccnc2C(=O)O)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O
Product: O=C(O)c1nccn1CCCc1ccc(O)cc1
Reaction time: 5 h

Procedure:
A suspension of 1.1 g (0.0037 mole) of 1-[3-(4-methoxyphenyl)propyl]imidazole-2-carboxylic acid hydrochloride in 100 ml of CH2Cl2 at 5° was treated with a solution of 2.8 g (0.011 mole) of BBr3 in 7 ml of CH2Cl2. The mixture was allowed to warm to 22°, and stirred for 5 hr. Methanol was cautiously added, and when a virgorous reaction was over, all solvents were evaporated. A residue was dissolved in 10 ml of H2O and the pH was adjusted to 3.5 with aqueous NaHCO3. The product crystallized, was filtered, washed with H2O and dried. Recrystallization from methanol gave 1-[3-(4-hydroxyphenyl)propyl]imidazole-2-carboxylic acid, hemihydrate, 0.65 g (71%), mp 136° (dec).
Reaction SMILES: [CH2:1]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CC=C.C[N+]1([O-])CC[O:22]CC1.[CH3:26][C:27]([CH3:29])=[O:28]>O>[OH:22][CH2:26][CH:27]([OH:28])[CH2:29][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C=CCCCCCCCCCN1CCCCC1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Solvent: O
Product: OCC(O)CCCCCCCCCN1CCCCC1
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
A solution of N-(10-undecenyl)piperidine (3.1 g, 13 mmol), 4-methylmorpholine-N-oxide (1.84 g, 15.7 mmol) and potassium osmate dihydrate (13 mg) in acetone (64 mL) and water (16 mL) were stirred for 6 hours. The reaction was quenched by the addition of 25 mL of a saturated solution of sodium sulphite and stirred for 15 minutes. The reaction mixture was then extracted with ethyl acetate (4×100 mL), the combined organic extract was dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 10% methanol/ethyl acetate eluant to yield 2.5 g (83.4% yield) N-(11,10-dihydroxyundecyl)piperidine (inventive compound no. 1622).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]1.S(Cl)([Cl:18])(=O)=O.C(Cl)Cl>C(Cl)(Cl)Cl>[Cl:18][CH:7]([C:8](=[O:10])[CH3:9])[C:6]([N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:12][CH2:13][CH3:14])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCN(CC1CC1)C(=O)CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCN(CC1CC1)C(=O)C(Cl)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of N-cyclopropylmethyl-N-propyl-3-oxo-butanamide (scheme 2: (H)) (900 mg, 4.57 mmoles) in chloroform (30 mL) at 0° C. was treated with sulfuryl chloride (1M in methylene chloride, 5.48 mL, 5.48 mmoles). The mixture was stirred at room temperature for 30 minutes and then poured into methylene chloride and washed with 5% sodium bicarbonate solution, brine, and dried over Na2SO4. The solution was concentrated in vacuo and the crude product used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:14])([CH3:13])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:20]([O:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:13])([CH3:14])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.8 %

Procedure:
To a stirred solution of intermediate 25, ethyl 3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (2.68 g, 10 mmol) and benzyl bromide (1.43 mL, 12 mmol) in DMF (40 mL) was added K2CO3 (2.07 g, 20 mmol). After stirring 48 h at ambient temperature, the reaction mixture was diluted with ether (100 mL), then washed with water (3×30 mL) and brine (20 mL). The organic layer was dried (Na2SO4/activated carbon), filtered and concentrated to give a yellow solid. Trituration with hexanes/ether (9:1) afforded the title compound as an off-white solid (2.79 g, 78% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 7.48-7.45 (2H, m), 7.37-7.30 (3H, m), 5.25 (2H, s), 4.33 (2H, q, J=7.3 Hz), 4.05-3.99 (4H, m), 1.62 (6H, s), 1.29 (3H, t, J=7.3 Hz). HRMS (M+H) calcd for C19H23N2O5: 359.1607; found: 359.1611. Anal calcd for C19H22N2O5: C, 63.67; H, 6.18; N, 7.81; found: C, 63.63; H, 6.16; N, 7.78.