Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)([Cl:16])=O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Product: O=C(Cl)c1ccc(I)cc1[N+](=O)[O-]

Procedure:
4-Iodo-2-nitrobenzoic acid piperidine amide. A suspension of 4-iodo-2-nitrobenzoic acid (1.0 g, 3.4 mmol) in thionyl chloride (10 mL) was heated to reflux for 45 min. The reaction mixture became homogeneous. The mixture was cooled and concentrated in vacuo to give 4-iodo-2-nitrobenzoyl chloride as a yellow oil, which was used immediately in the following reaction. 1H NMR (500 MHz, CDCl3): 8.38 (d, J=1.6 Hz, 1H), 8.12 (dd, J=8.1, 1.6 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H). To a solution of 4-iodo-2-nitrobenzoyl chloride (3.4 mmol) in DCM (10 mL) at ambient temperature was added piperidine (1.3 mL, 13.1 mmol). The reaction mixture was stirred for 0.5 h then poured into 1 N HCl and extracted with DCM (2×). The combined organic extracts were dried (Na2SO4), and concentrated in vacuo affording the title amide as a white solid (1.2 g, 98%). MS (ESI): m/z 361 [M+H]+, 383 [M+Na]+. 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.51 (d, J=1.6 Hz, 1H), 8.01 (dd, J=8.0, 1.6 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 3.85–3.65 (bm, 2H), 3.16 (t, J=5.6 Hz, 2H), 1.90–1.35 (bm, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:15](O)=[O:16])[CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15]([CH:12]2[CH2:14][CH2:13]2)=[O:16])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(O)C1CC1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of (4-methyl-3-nitrophenyl)amine (304 mg) in DMF (3 mL) were added cyclopropanecarboxylic acid (258 mg), HATU (1.14 g) and iPr2NEt (1.55 g) successively, and the mixture was stirred at room temperature for 16 hr under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (15 mL) and the resulted mixture was washed with 1 M HCl (15 mL×2), saturated aqueous NaHCO3 (15 mL×2) and brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc-hexane (1:2) to give N-(4-methyl-3-nitrophenyl)cyclopropanecarboxamide (413 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][C:6]1=[O:16].CI.[C:19](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH3:19])[C:6]1=[O:16]
Reactant: O=c1[nH]c(=O)n(CCCBr)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)c2ccccc2n(CCCBr)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A mixture of 1-(3-bromopropyl)-2,4(1H, 3H)-quinazolinedione (2.83 g), methyl iodide (3 ml), anhydrous potassium carbonate (4.2 g) and N,N-dimethylformamide (25 ml) was stirred for 8 hours at ambient temperature. After the reaction mixture was diluted with cold water, the resultant mixture was extracted twice with chloroform. The chloroform layer was washed with water twice, and with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resultant oily residue was purified by subjecting to a column chromatography on silica gel (100 g) using chloroform for elution, to give 1-(3-bromopropyl)-3-methyl-2,4(1H)-quinazolinedione (1.85 g) as a crystal. m.p. 90°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>>[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[CH:24]([NH:23][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:13][C:12]=13)=[O:20])[CH2:25]2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: COc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Yield: 5 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamide was prepared from 2-(4-methoxyphenyl)benzoxazole-4-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 5% yield as an off-white solid: mp 108-109° C.; 1H NMR (500 MHz, CD3OD) δ 8.19 (dt, J=9.7, 2.8 Hz, 2H), 8.01 (dd, J=7.7, 0.9 Hz, 1H), 7.82 (dd, J=7.7, 0.9 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.14 (dt, J=9.7, 2.8 Hz, 2H), 4.25 (m, 1H), 3.91 (s, 3H), 3.47 (m, 1H), 3.02 (m, 2H), 2.91 (m, 2H), 2.77 (m, 1H), 2.12 (m, 2H), 1.80 (m, 3H); MS (ESI) m/z 378 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:5]=[C:4]2[N:23]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:24]=[C:25]([CH2:26][CH2:27]O)[C:3]=12.C(N(CC)CC)C.C[S:46](Cl)(=O)=O>ClCCl.C(OCC)(=O)C>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:23]2[C:4]3[C:3]4[C:25]([CH2:26][CH2:27][S:46][C:2]=4[N:7]=[C:6]([N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[N:5]=3)=[N:24]2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cn2nc(CCO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
The above di-tert-butyl {4-chloro-3-(2-hydroxyethyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (8.5 g) was dissolved in dichloromethane (100 ml), triethylamine (4.5 ml) was added. Methanesulfonyl chloride (1.9 ml) was added under cooling in an ice bath, and the mixture was stirred at room temperature for two hours. The reaction solution was diluted with dichloromethane and ethyl acetate and washed with water. Then, the organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (100 mL), and sodium bisulfide monohydrate (1.5 g) was added under cooling in an ice bath. Then, the ice bath was removed and the mixture was stirred for one hour. Potassium carbonate (3.3 g) was added to the reaction mixture, followed by further stirring for 16 hours. Water (1000 ml) was added to the reaction mixture, followed by extraction with dichloromethane (500 ml) twice. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (6.0 g, 74%) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Cl:8][C:9]1[S:13][C:12]([S:14]([NH:17][C:18]2[C:23](Br)=[N:22][C:21]([Br:25])=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:11][CH:10]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC.C(OCC)(=O)C>[Cl:8][C:9]1[S:13][C:12]([S:14]([NH:17][C:18]2[C:23]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:22][C:21]([Br:25])=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1ccc(Cl)s1
Reactant: COCCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COCCOc1nc(Br)cnc1NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.17 h

Procedure:
2-Methoxyethanol (0.04 g) was added to a stirred suspension of sodium hydride (0.05 g of 60%) in 1,2-dimethoxyethane (5 mL). After 10 minutes, 5-chloro-N-(3,5-dibromo-2-pyrazinyl)-2-thiophenesulphonamide (0.2 g) was added. After 30 minutes, 5% aqueous citric acid and ethyl acetate were added. The organic layer was separated dried (MgSO4) and the solvent was evaporated. Chromatography on silica eluting with hexane/ethyl acetate gave the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17](O)=[O:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.C(Cl)(=O)C(Cl)=O.O[NH:29][C:30](=[NH:32])[CH3:31]>ClCCl.C(Cl)(Cl)Cl>[CH3:21][C:2]1([CH3:1])[CH:11]([N:12]2[C:16]([C:17]3[O:18][N:32]=[C:30]([CH3:31])[N:29]=3)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1
Reactant: CC(=N)NO
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1noc(-c2cncn2C2c3ccccc3C(=O)OC2(C)C)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.538 g, 1.88 mmol) (Example 23) is dissolved in dichloromethane (4 mL) and cooled to 0° C. Oxalyl chloride (0.41 mL, 4.702 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo. The residue obtained is redissolved in chloroform and N-hydroxyacetamidine (0.181 g, 2.44 mmol) is added. The reaction mixture is stirred at reflux for 72 h. The mixture is cooled to room temperature, washed with saturated solution of sodium bicarbonate and is extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane-ethyl acetate, 3:7) to give dimethyl-4-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-imidazol-1-yl]-isochroman-1-one as a white solid; MS (ESI) m/z 325.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.26 (s, 3 H), 1.61 (s, 3 H), 2.55 (s, 3 H), 6.94 (s, 1 H), 7.56 (d, J=7.1 Hz, 1 H), 7.63 (s, 1 H), 7.72 (td, J=7.6, 1.3 Hz, 1 H), 7.80 (td, J=7.6, 1.3 Hz, 1 H), 8.01 (s, 1 H), 8.30 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23]/[CH:24]=[CH:25]/[C:26](Br)=[O:27].[CH3:29][NH:30][CH3:31].O>C1COCC1>[CH2:20]([O:19][C:17]([C:16]1[C:9]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:26](=[O:27])/[CH:25]=[CH:24]/[CH2:23][N:30]([CH3:31])[CH3:29])[CH:3]=3)=[N:13][CH:12]=[N:11][C:10]=2[NH:14][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reactant: O=C(Br)/C=C/CBr
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NC(=O)/C=C/CN(C)C)c3)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (100 mg, 0.354 mmol) in THF (2 mL) was added (E)-4-bromobut-2-enoyl bromide (0.400 mmol) and the resulting reaction mixture was stirred for 1 hour at 0° C. Dimethylamine (0.886 mL, 1.77 mmol, 2 M in THF) was then added and the reaction mixture was sealed and stirred overnight. Water (10 mL) was added and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The reaction was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained. The water layer was neutralized with saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl-4-(3-{[(2E)-4-(dimethylamino)but-2-enoyl]amino}phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C21H24N5O3 [M+H]+: 394, found 394. 1H NMR (600 MHz, DMSO-D6) δ 13.0 (s, 1H), 10.2 (s, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 8.00 (s, 1H), 7.78 (d, 1H, J=8.21 Hz), 7.41 (t, 1H, J=8.21 Hz), 7.31 (d, 1H, J=7.63 Hz), 6.73 (dt, 1H, J=15.3, 5.87 Hz), 6.27 (d, 1H, J=15.3 Hz), 3.84 (q, 2H, J=7.04 Hz), 3.06 (d, 2H, J=5.87 Hz), 2.18 (s, 6H), 0.83 (t, 3H, J=7.04 Hz).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11][CH2:12][CH2:13]Br>C(O)C>[CH3:10][O:11][CH2:12][CH2:13][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: COCCBr
Reactant: CNCc1ccccc1
Solvent: CCO
Product: COCCN(C)Cc1ccccc1
Yield: 58 %

Procedure:
The synthesis of BnMO was carried out in a manner similar to that of BnEO (process 2) using N-methylbenzylamine (15 mL, 0.116 mol), bromoethyl methyl ether (12 mL, 0.116×1.1 mmol), and ethanol (200 mL) as a solvent. BnMO (12.09 g, 67.46 mmol, yield 58%) was obtained as a pale yellow clear liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)(=[O:33])=[O:32]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1

Procedure:
A suspension of 23.02 g (0.1 mol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 1 L of dichloromethane, and 42.0 ml (0.303 mol) of triethylamine is stirred at 0°-5° and 42.17 ml (0.33 mol) of chlorotrimethylsilane is added. The ice bath is removed and the mixture is stirred at room temperature for 1 hr. The hazy solution is cooled to 10° and 23.8 ml (0.31 mol) of methanesulfonyl chloride is added. The resulting solution is stirred at room temperature for 24 hours and the dichloromethane is evaporated under reduced pressure and 500 ml of water is added to the residue. The mixture is cooled to 10° and the solid is filtered, washed with water, acetonitrile, and ether, and dried to give 29.9 of 6-[4-(methylsulfonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>320°.
Reaction SMILES: S[C:2]1[CH:11]=[C:10](OC)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14]([O-])=[O:15].[Na+:17].OO.[S:20]([O-:23])([O-:22])=[O:21].[Na+].[Na+]>C(O)=O>[CH3:14][O:15][C:9]1[CH:10]=[CH:11][C:2]([S:20]([O-:23])(=[O:22])=[O:21])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1.[Na+:17]
Reactant: O=S([O-])[O-]
Reactant: O=C[O-]
Reactant: COC(=O)c1ccc(OC)cc1S
Agent: OO
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cc(OC)ccc1S(=O)(=O)[O-]
Temperature: 35 °C
Reaction time: 2 h
Yield: 731.7 %

Procedure:
A mixture of 50 g of the compound of Example 2, 34 g of sodium formate and 505 ml of formic acid was warmed to 35° C. and 90 ml of 30% hydrogen peroxide was added slowly over 0.75 hours. The reaction temperature was allowed to warm to 55° C. and held at 55° C. for 2 hours. The reaction mixture was cooled to ambient temperature and 7 g of sodium sulfite was added in portions to destroy excess hydrogen peroxide. The reaction mixture was concentrated in vacuo at 50° C. Toluene (250 ml) was added to the residue, and the suspension was concentrated in vacuo. Repeating this procedure gave 109 g of the title compound as a moist white solid, m.p. >280° C.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:29])[C:14]([C:15]([NH:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]3)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:30])[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:29])[C:14]([C:15]([NH:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]3)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:30])[CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)c2c(C)nn3c(OCc4c(F)cccc4F)cc(C)cc23)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC[C@H]3CC[C@H](C(=O)O)CC3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
90 mg (0.19 mmol, 1.0 eq.) of methyl trans-4-{[({7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]methyl}cyclohexanecarboxylate from Example 35 were dissolved in 5.5 ml of THF/methanol (5/1) and admixed with 1.3 ml of 1 N aqueous lithium hydroxide solution. The mixture was stirred at RT for 3 days. Subsequently, another 2 ml of 1 N lithium hydroxide solution were added and the mixture was stirred at 60° C. for 7 days. After cooling, the mixture was acidified to pH=3 with 1 N hydrochloric acid and freed of the organic solvents on a rotary evaporator. The resulting aqueous phase was extracted three times with dichloromethane and the combined organic phases were washed with water, then dried with sodium sulphate, filtered and concentrated. The residue was purified by means of thick-layer chromatography (eluent:dichloromethane/methanol=20/1). 46 mg of the target compound were obtained (53% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[C:20]([BH3-])#N.[Na+].C(O)=O.C=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][CH2:14]1
Reactant: [BH3-]C#N
Reactant: COc1ccc([N+](=O)[O-])cc1N(C)C1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1N(C)C1CCN(C)CC1
Temperature: 27.5 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL three neck round bottom flask added 2-Methoxy-5-nitro-N-methyl-N-(piperidin-4-yl) phenylamine (1.93 grams, 7.33 mmol) obtained at step (III), followed by the addition of methanol (20 mL) and stirred at 25-30° C. for 5 minutes. Added sodium cyanoborohydride (0.548 grams, 8.80 mmol) and formic acid (1.08 mL, 22.01 mmol) and stirred the reaction mass for 10 minutes. The reaction mass was cooled to 0-5° C. in an ice bath and added formaldehyde (1.46 mL, 14.6 mmol, 30-50%) through syringe. Clear solution was obtained. The reaction mass was further stirred for 6 hours at 20-25° C. After completion of reaction (thin layer chromatography), solvent was distilled off under reduced pressure. To the residual oily mass, added water (100 mL) and basified to pH: 8 using saturated solution of sodium bicarbonate. The product was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain 1.96 grams of dark yellow colored oily mass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:21])[CH3:20])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:22](N=C(N(C)C)N(C)C)([CH3:25])([CH3:24])[CH3:23].BrCC(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][CH:22]([CH3:25])[CH3:24])[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:21])[CH3:20])=[CH:14][N:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(C)C)cnc1NS(=O)(=O)c1ccc(F)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
4-fluoro-N-(5-isopropyl-3-methylpyridin-2-yl)benzenesulfonamide (127 mg, 0.41 mmol) was dissolved in acetonitrile (3 mL) and to this solution was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.09 mL, 0.41 mmol). The mixture was allowed to stir at room temperature for 30 minutes, 1-bromo-2-methylpropane (0.09 mL, 0.83 mmol) was then added to the mixture and the reaction vessel sealed and heated by microwaves to 150° C. for 1 hour. The reaction mixture was concentrated in vacuo and the crude product extracted to the organic phase of an aqueous workup between ethyl acetate and water. The organic phase was then passed through a hydrophobic frit, concentrated in vacuo and purified by mass directed autoprep (formic acid modifier) to give the title compound (73 mg). LCMS (2 min, formic) Rt 1.44 min, m/z (ES+) 365 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([Cl:31])[CH:33]=2)[CH:6]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(Cl)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.34 g, 0.0008 mol) in DMF (10 mL), was added 3-chlorobenzyl bromide (0.25 g, 0.0012 mol) and powdered potassium carbonate (0.77 g, 0.0056 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.33 g in 77% yield. 1H NMR (CDCl3) δ 7.23 (d, 2H), 7.18 (m, 4H), 7.14 (m, 6H), 6.91 (d, 2H), 6.83 (d, 1H), 6.82 (d, 1H), 6.65 (s, 1H), 6.63 (d, 1H), 4.16 (t, 1H), 3.67 (s, 3H), 3.63 (t, 2H), 3.57 (s, 2H), 3.55 (s, 2H), 3.05 (d, 2H), 2.63 (t, 2H), 1.80 (t, 2H); 13C NMR (CDCl3) δ 173.3, 160.5, 144.7, 143.3, 136.6, 135.3, 130.8, 130.7, 130.3, 129.7, 129.6, 128.4, 128.3, 127.7, 122.7, 116.9, 114.5, 66.9, 61.1, 60.1, 53.5, 51.8, 51.1, 42.7, 28.2.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)Cl.C(N(CC)CC)C.[C:37](Br)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[N:19]([C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reactant: O=C(Br)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)n1c(=O)c(F)cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a solution of 0.50 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 20 ml of dioxane were added 0.75 ml of trimethylchlorosilane and 2.00 ml of triethylamine, and the mixture was stirred at room temperature for 2 hours. Then, the resulting mixture was left to stand at 60° C. for 30 minutes. To the reaction mixture were added 0.42 g of benzoyl bromide and 1.00 ml of triethylamine, and the mixture was left to stand at 60° C. for 1 hour. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate. Then, the solution was washed with saturated aqueous solution of sodium chloride. The ethyl acetate layer was separated and concentrated. The residue was dissolved in 30 ml of methanol and 0.5 ml of acetic acid was added thereto. The mixture was left to stand overnight. The solvent was distilled off and the residue was applied to a silica gel column to conduct gradient elution using chloroform and mixtures of methanol (up to 2%) and chloroform, giving 0.35 g of the title compound as a powder in a yield of 54%.