Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[F:23])C1C=CC=CC=1>Br.CC(O)=O.O.C(=O)(O)[O-].[Na+]>[F:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8])=[O:24]
Reactant: O=C(Nc1ccccc1OCc1ccccc1)c1ccncc1F
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1ccccc1O)c1ccncc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Title compound 24 (4.40 g, 13.6 mmol) was dissolved in 33% HBr in AcOH (30 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and solid sodium bicarbonate (until alkaline) then extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude was triturated in 30% ethyl acetate in hexanes to afford the title compound 25 (2.36 g, 75%) as a beige solid. LRMS (ESI): (calc) 232.06 (found) 233.1 (MH)+.
Reaction SMILES: [CH:1]([OH:3])=O.OO.[C:6]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)C[CH2:9][CH2:8][CH:7]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][C:1]2=[O:3])=[CH:12][CH:13]=1
Reactant: O=CO
Reactant: Fc1ccc(C2=CCCC2)cc1
Agent: OO
Product: O=C1CCCC1c1ccc(F)cc1
Temperature: 40 °C
Yield: 69.8 %

Procedure:
A mixture of 80% formic acid (100 mL, 2618 mmol) and 30% hydrogen peroxide (23 mL, 149 mmol) was warmed at 40° C. for 10 min. The resulting solution was carefully added to 1-cyclopentenyl-4-fluorobenzene (24.155 g, 149 mmol) under stirring. The two-phase system was initially stirred at room temperature. After a certain period of time, a spontaneous exothermic reaction took place, and the temperature rose to about 50° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by careful addition of a saturated sodium bicarbonate solution. Ether was added and the content of the separatory funnel was vigorously shaken. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-(4-fluorophenyl)cyclopentanone (18.557 g, 104 mmol, 69.9% yield) as colorless oil. LC-MS (M+H)+=177.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.12-7.18 (2H, m), 6.98-7.04 (2H, m), 3.29 (1H, dd, J=11.6, 8.5 Hz), 2.42-2.54 (2H, m), 2.27 (1H, ddd, J=19.1, 10.5, 8.9 Hz), 2.12-2.20 (1H, m), 2.01-2.12 (1H, m), 1.87-1.99 (1H, m, J=11.7, 11.7, 8.2, 6.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=O.[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18].CCN=C=NCCCN(C)C>CN(C)C=O.C(OCC)C>[CH2:16]([N:19]([CH2:20][CH2:21][CH3:22])[C:13]([CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)=[O:15])[CH2:17][CH3:18]
Reactant: CCCNCCC
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)Cc1c[nH]c2ccc(OC)cc12
Reaction time: 12 h
Yield: 51.2 %

Procedure:
A solution of 5-methoxyindole-3-acetic acid (500 mg, 2.44 mmol) in 4.8 mL of N,N-dimethylformamide was added di-n-propylamine (0.60 mL, 7.2 mmol) and EDCI (1.90 g, 9.6 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 12 h, the reaction mixture was diluted with diethyl ether, and washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (360 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[CH:8]2)=[O:4].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O1CCOCC1>CCOCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(ccn2C)c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc([N+](=O)[O-])cc1)cn2C
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A solution of 1-methyl-1H-indole-5-carboxylic acid methyl ester (0.38 g, 2.0 mmol), prepared using procedures as described in Example 1, Ag2O (0.51 g, 2.2 mmol), 4-nitro-benzyl bromide (0.48 g, 2.2 mmol) and dioxane (6 mL) was heated to reflux for 25 hr, then more 4-nitrobenzyl bromide (0.48 g, 2.2 mmol) was added and the solution was heated at reflux an additional 4 days. After cooling to room temperature, the reaction mixture was diluted with ether (50 mL) and ethyl acetate (50 mL), washed with aq. NH4Cl (50 mL) and then brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:4) to provide of 1-methyl-3-(4-nitro-phenylmethyl)-1H-indole-5-carboxylic acid methyl ester (0.38 g, 58% yield). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.16 (d, 2H, J=8.3 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.45 (d, 2H, J=8.3 Hz), 7.35 (d, 1H, J=8.3 Hz), 6.90 (s, 1H), 4.25 (s, 2H), 3.94 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:13]=1[CH2:14][NH2:15].CCN(C(C)C)C(C)C.CCCCO>O>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:12]([O:11][CH3:10])[C:13]=1[CH2:14][NH:15][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(OC)c(CN)c(OC)c1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c(CNc2cc(Cl)ncn2)c(OC)c1
Temperature: 100 °C
Yield: 90.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (Aldrich, 1.48 g, 10.0 mmol), 2,4,6-trimethoxybenzylamine hydrochloride (2.33 g, 10.0 mmol), DIPEA (4.8 mL, 27.7 mmol), and n-BuOH (50 mL) was heated at 100° C. for 2 h. The mixture was cooled, diluted with water (200 mL) and the precipitated product was collected by vacuum filtration on a Büchner funnel. The product was washed with cold water, ether, and vacuum dried to give an off-white solid (2.8 g, 90%). 1H NMR (DMSO-d6) δ 8.28 (s, 1H), 7.38 (s, 1H), 6.49 (s, 1H), 6.25 (s, 2H), 4.34 (s, 2H), 3.77 (s, 9H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([Cl:18])[CH:15]=[N:14]2)=[C:9]([Cl:19])[CH:8]=1)[CH3:6])C.O.[NH2:22][NH2:23].C(Cl)Cl>CN(C)C=O>[Cl:19][C:9]1[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([NH:22][NH2:23])=[O:3])[CH:12]=[CH:11][C:10]=1[N:13]1[CH:17]=[C:16]([Cl:18])[CH:15]=[N:14]1
Reactant: NN
Reactant: CCOC(=O)C(C)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)NN)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reaction time: 2 h

Procedure:
To a solution of 3.13 g (10 mmoles) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid ethyl ester in 20 ml of dimethyl formamide there are added dropwise, at room temperature, 15 ml of hydrazine hydrate. Stirring is continued for a further 2 hours at room temperature, followed by pouring on to ice, extraction with methylene chloride, drying of the organic phase and concentration. 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic hydrazide is obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].CC([N-]C(C)C)C.Cl[C:19]1[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]([CH3:27])[C:23](=[O:26])[C:24]=1[CH3:25]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:19]1[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]([CH3:27])[C:23](=[O:26])[C:24]=1[CH3:25]
Reactant: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Reactant: Nc1ccc(I)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)cn(C)c1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To the stirred solution of 2-fluoro-4-iodoaniline (470 mg, 1.94 mmol) in dry THF (4 mL) cooled to −78° C., was added LDA (2M in THF) (1.35 mL, 2.70 mmol) After vigorous stirring for 10 minutes at this temperature, a solution of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (160 mg, 0.792 mmol) dissolved in dry THF (8 mL) was added dropwise through a syringe. The dry-ice bath was removed after 1 hour, and the reaction was stirred for 16 hours at room temperature At this time, LC/MS indicated 23% of the title product and 33% of unreacted chloride in the reaction mixture. The same reaction mixture was continued to stir at room temperature for additional 24 hours. The mixture was then re-cooled to −78° C. under a dry-ice/acetone bath. Additional LDA (1.35 mL, 2.70 mmol) (2M in THF) was added to the reaction mixture and slowly warmed to room temperature in 16 hours until LC/MS showed the consumption of chloride material. The mixture was cooled to −5° C., and aqueous HCl (1N) (15 mL) was added. The solution was extracted with EtOAc (15 mL×3). The combined organic layers was dried (MgSO4) and concentrated to give a residue which was triturated with DCM to give a solid. The title compound was used for the next reaction without further purification. (165 mg, 52% yield).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1.[CH2:17](I)[CH3:18]>CN(C)C=O.ClCCl>[CH2:17]([O:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[CH3:18]
Reactant: CCI
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(C(C)C)ccc(CO)c1=O
Temperature: 70 °C
Yield: 37.5 %

Procedure:
60% oily sodium hydride (256 mg, 6.4 mmol) was added to a solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.13 g, 5.82 mmol) in dimethylformamide (5 ml) with stirring. Then, ethyl iodide (0.7 ml, 8.75 mmol) was added and the reaction mixture was heated at 70° C. for 3 hours. The reaction solution was diluted with dichloromethane, washed with water, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (2:3)] to give 485 mg of 2-ethoxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a pale yellow amorphous powder (yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([OH:25])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([O:25][CH3:34])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(C)(C)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 46.6 mg (0.1 mmole) of 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile in THF was cooled to −78° C. To this was added 0.3 mL of a 1M solution of NaHMDS in THF. After 10 minutes, 20 uL of iodomethane was added and the solution was allowed to warm to rt. The solution was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was filtered through silica gel using 10% ethyl acetate-hexane to afford the title compound; 1H-NMR (CDCl3) δ 1.07 (s, 3H), 1.14 (S, 3H), 2.28 (t, 1H, J=7.5 Hz), 2.74 (d, 1H, J=10.7 Hz), 2.82 (t, 1H, J=7.5 Hz), 3.10-3.16 (m, 2H), 3.19 (s, 1H), 3.62 (m, 1H), 4.29 (s, 1H), 6.67-6.73 (m, 3H), 7.21-7.4 (m, 8H);); Mass Spectrum: m/e=481 (M+1, 35Cl) and 483 (M+1, 37Cl).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N:32]1[N:33]=[C:34]([SH:37])[NH:35][CH:36]=1.Cl>CC(C)=O.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:10][S:37][C:34]1[NH:35][CH:36]=[N:32][N:33]=1)[CH2:22][CH:23]([CH3:24])[CH3:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: Sc1nnc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)C[C@@H](CSc1nnc[nH]1)NC(=O)OC(C)(C)C
Yield: 79.6 %

Procedure:
To 250 mg of toluene-4-sulfonic acid (S)-2-tert-butoxycarbonylamino-4-methyl-pentyl ester in 2.5 ml acetone and 0.5 ml water were added 112 mg of potassium carbonate, followed by the addition of 75 mg 4H-1,2,4-triazole-3-thiol. The reaction was heated in a microwave reactor for 5 min to 100° C. The pH was then adjusted to 7 by the addition of 2 M aqueous hydrochloric acid and the mixture was extracted with ethyl acetate twice. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. 161 mg (80%) of [(S)-3-Methyl-1-(4H-[1,2,4]triazol-3-ylsulfanylmethyl)-butyl]-carbamic acid tert-butyl ester were obtained.
Reaction SMILES: [C:1]1([C:7]([CH:9]=[N+]=[N-])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C@:13]12[C@@H:33]([OH:34])[CH2:32][C@@:31]3([CH3:35])[C@@H:23]([CH2:24][C@@H:25]([OH:37])[C@:26]3([OH:36])[C:27](=[O:30])[CH2:28][OH:29])[C@@H:22]1[CH2:21][CH2:20][C:19]1[C@:14]2([CH3:39])[CH2:15][CH2:16][C:17](=[O:38])[CH:18]=1>CO>[F:12][C@:13]12[C@@H:33]([OH:34])[CH2:32][C@@:31]3([CH3:35])[C@@H:23]([CH2:24][C@@H:25]([O:37][CH2:9][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH2:8])[C@:26]3([OH:36])[C:27](=[O:30])[CH2:28][OH:29])[C@@H:22]1[CH2:21][CH2:20][C:19]1[C@:14]2([CH3:39])[CH2:15][CH2:16][C:17](=[O:38])[CH:18]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: C=C(C=[N+]=[N-])c1ccccc1
Solvent: CO
Product: C=C(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 2-phenyl-3-diazo-1-propene prepared as described above is diluted with 150 ml of cold methanol and stirred well at 0°C as 13 g of 9-fluoro-11β ,16α ,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions. The slurry is stirred for 1 hour at 0°C and filtered to give 9.6 g of the title compound. The filtrate is stirred at room temperature for 1 hour with 4 g of the cycloborate and the resulting solution is cooled to 0°C and filtered to give 4.2 g of the title compound. The filtrate is evaporated in vacuo and the residue is dissolved in 400 ml of 3:1 ether-methanol and cooled to -10°C to give a further 3.0 g of material. A small sample recrystallized from acetone-hexane has a melting point of 161°-163.5°C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)=[CH:10][CH:9]=[CH:8][CH:7]=2>O1CCOCC1.C(OCC)C>[F:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCNCC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
50 cm3 of a solution of hydrogen chloride in dioxane at a concentration of 4M were added cautiously to a solution of 8.7 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate in 150 cm3 of anhydrous dioxane, and the temperature was maintained below 30° C. during the addition. After stirring for 18 hours in the region of 20° C., the suspension was diluted with 250 cm3 of diethyl ether, filtered and washed with 5 times 50 cm3 of diethyl ether, and the solid was dried in a desiccator under reduced pressure (2 kPa) and at a temperature in the region of 20° C. The solid was taken up in 50 cm3 of water and aqueous 5N sodium hydroxide solution was added so that the pH was at about 10, and the mixture was then extracted with 5 times 100 cm3 of diethyl ether. The organic phases were combined, dried over magnesium sulfate, taken up with plant charcoal (3S), filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. 4.7 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]piperidine-4-carboxylate were obtained in the form of a viscous orange-colored oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29]1([CH2:35][C:36]([Cl:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[N:12]([C:36](=[O:37])[CH2:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cl
Product: O=C(Cc1ccccc1)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Temperature: 4 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a mixture of 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (118 mg) and pyridine (64 mg) in N-methyl-1-pyrrolidone (2 ml) was added phenylacetyl chloride (65 mg) under nitrogen atmosphere with ice cooling. After stirring for 1 hour at 4° C., the reaction mixture was poured into cold water. The separated oil was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtain oil was dissolved in 10% methanolic hydrogen chloride (1 ml). The resulting clear solution was concentrated in vacuo. The residue was crystallized from ethyl acetate to give 7-(4-fluorophenyl)-2-phenylacetyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine hydrochloride (130 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:45]=[CH:44][CH:43]=[CH:42][C:8]=1[CH2:9][N:10]1[C:18]2[C:17](=[O:19])[NH:16][C:15]([C:20]3[CH:25]=[C:24]([S:26]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=3[O:36][CH2:37][CH3:38])=[N:14][C:13]=2[C:12]([CH2:39][CH2:40][CH3:41])=[N:11]1>N1C=CC=CC=1>[NH3:6].[CH2:37]([O:36][C:21]1[CH:22]=[CH:23][C:24]([S:26]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)(=[O:28])=[O:27])=[CH:25][C:20]=1[C:15]1[NH:16][C:17](=[O:19])[C:18]2[N:10]([CH2:9][C:8]3[CH:42]=[CH:43][CH:44]=[CH:45][C:7]=3[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:11]=[C:12]([CH2:39][CH2:40][CH3:41])[C:13]=2[N:14]=1)[CH3:38]
Reactant: CCCc1nn(Cc2ccccc2N)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCc1nn(Cc2ccccc2NS(C)(=O)=O)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Product: N
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
Methanesulphonyl chloride (31 μl, 0.40 mmol) was added to a stirred, ice-cooled solution of the title compound of Example 52 (150 mg, 0.27 mmol) in pyridine (3 ml) and the mixture stirred at room temperature for 2 hours, then evaporated under reduced pressure. The residue was treated with water (10 ml) and the resulting suspension extracted with dichloromethane (40 ml in total). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give an orange oil which was purified by chromatography on silica gel, using ethyl acetate:methanol:0.880 aqueous ammonia (94:5:1) as eluant, to provide the title compound (62 mg) as a white foam. Found: C, 54.03; H, 5.87; N, 14.70. C29H37N7O6S2 requires C, 54.10; H, 5.79; N, 15.23%. δ (CDCl3): 1.02 (3H, t), 1.66 (3H, t), 1.90 (2H, m), 2.28 (3H, s), 2.50 (4H, m), 2.96 (2H, t), 3.10 (7H, m), 4.39 (2H, q), 5.79 (2H, s), 7.18 (2H, m), 7.36 (1H, m), 7.60 (1H, d), 7.72 (1H, d), 7.83 (1H, d), 8.80 (1H, s), 9.68 (1H, s), 10.95 (1H, s). LRMS: m/z 644 (M+1)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:32]O)[N:18]([CH2:19][C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:21]=3)[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[ClH:3].[Cl:3][CH2:32][C:17]1[N:18]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:21]=2)[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc2ccccc2c2c1nc(CO)n2Cc1cc(-c2ccc(F)cc2)no1
Solvent: ClCCl
Product: Cl
Product: Nc1nc2ccccc2c2c1nc(CCl)n2Cc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.5 %

Procedure:
The methods described in Examples 30 and 31 were repeated on a larger scale to provide (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-2-yl)methanol. The reaction described in Example 31 was heated at reflux and was complete within three hours. Thionyl chloride (0.45 mL, 6.17 mmol) was added dropwise to a suspension of (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-2-yl)methanol (1.2 g, 3.08 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 1.8 hours. The volatiles were removed under reduced pressure, and the residue was combined with material from another run, triturated with a mixture of ethanol and diethyl ether, and isolated by filtration to provide 1.54 g 2-(chloromethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(#N)C>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([O:12][CH3:13])=[O:14])=[CH:8][CH:9]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Nc1ccc(CCO)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Yield: 89.4 %

Procedure:
6.0 g (30.7 mmole) methyl N-[4-(2-hydroxyethyl)phenyl]carbamate was dissolved in acetonitrile. 6.17 g (61 mmole) triethylamine and 7.0 g (61 mmole) methanesulfonyl chloride were added. The mixture was stirred until completion, then the solvent was evaporated in vacuo, water was added to the residue and the product was extracted with dichloromethane to give 7.5 g (yield 89.4%) of 4-[(methoxycarbonyl)amino]phenethyl methanesulfonate.