Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([O:16][C:17](=[O:33])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][NH2:32])=[CH:25][CH:24]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:9]([O:16][C:17](=[O:33])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][NH:32][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:25][CH:24]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(NCCCCc1ccc(OCCNCc2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 42.8 %

Procedure:
Benzyaldehyde (0.74 ml, 7.31 mmol) was added to a solution of 4-[4-(2-aminoethoxy)phenyl]butylcarbamic acid benzyl ester (15) (5.00 g (˜50% purity by NMR), 7.30 mmol) dissolved in anhydrous dichloroethane (50 mL). The resulting solution was stirred at ambient temperature for 7 h. Sodium triacetoxyborohydride (4.10 g, 19.35 mmol) was added slowly and the reduction continued for 60 h. The reaction was quenched with aqueous sodium bicarbonate (50 mL) and then extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed sequentially with water and brine, and dried over anhydrous sodium sulfate. A white solid precipitated out during the drying and collected by dissolving it in dichloromethane and then filtering off the solid sodium sulfate. The filtrate was concentrated and dried under vacuum to give 16 (1.35 g, 43%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.45-1.62 (m, 4H), 2.54 (t, 2H), 3.07-3.22 (m, 4H), 3.88 (s, 2H), 4.10 (t, 2H), 4.73 (br, 1H), 5.09 (s, 2H), 6.79 (d, 2H), 7.04 (d, 2H), 7.28-7.39 (m, 10H); m/z (ESI) 433 [C27H32N2O3+H]+.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[CH2:36][CH2:37][NH2:38]>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH:32]2[CH2:33][CH2:34][CH2:35][N:31]2[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CN1CCCC1CCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC3CCCN3C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine by the procedure analogous to Example 1. MS (APCI, m/z): 454 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[C:24]([NH2:34])[N:23]=3)=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[NH2:34][C:24]1[N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=3)=[CH:16][CH:17]=2)[CH:27]=[C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:25]=1
Reactant: NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Methanesulfonyl chloride (0.040 mL, 0.52 mmol) was added to a solution of N4-(4-{[2-(aminomethyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine (Example 39, 0.20 g, 0.52 mmol) and DMAP (0.064 g, 0.52 mmol) in pyridine (8.0 mL) at 0° C. The mixture was allowed to warm to rt and was stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in DMF and purified by prep-HPLC to provide 82 mg of an off-white solid (27%). 1H NMR (CD3OD) 8 ppm 8.57 (1H, d, J=6.8 Hz), 8.00 (2H, s), 7.77-7.80 (2H, m), 7.63 (3H, d, J=7.4 Hz), 7.42 (1H, d, J=2.5 Hz), 7.29-7.33 (3H, P m), 6.58 (1H, s), 4.54 (2H, s), 3.04 (3H, s); MS ES 463 (M+H)+, calcd 463, RT=1.17 min.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]([CH3:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH:14]=[N:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[CH3:25][N:2]([CH3:1])[CH:3]([CH3:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH2:14][NH:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(OCC(C)N(C)C)c(C=NCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCC(C)N(C)C)c(CNCCc2ccccc2)c1
Yield: 74.7 %

Procedure:
N-[[2-[2-(Dimethylamino)propoxyl]-5-methoxyphenyl]methylene]benzeneethanamine (39.5 g) is reduced with 13.0 g of sodium borohydride in 200 ml of methanol following the procedure described in Example 1C yielding 29.7 g of the title compound, boiling point 205°-210° C. at 0.4-0.5 mm of Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15]S(C(F)(F)F)(=O)=O)[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:36]2[CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=[C:34]([C:33]([F:32])([F:48])[F:47])[CH:35]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 38 %

Procedure:
The title compound was prepared in 38% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 15, step (d)) under the conditions described in Example 15, step (e-f) using 3,5-bis-trifluoromethylphenylboronic acid in step (e).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:11]([O:10][C:2]([CH:3]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCCCCCCOc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCCOc1ccccc1)C(=O)OCC
Yield: 63 %

Procedure:
Sodium (0.22 g, 9.6 mmol) was dissolved in EtOH (20 mL). Diethyl malonate (1.53 g, 9.6 mmol) in EtOH (5 mL) and 7-phenoxyheptyl bromide (2.36 g, 8.7 mmol) in EtOH (5 mL) were subsequently added at room temperature. The reaction mixture was refluxed for 8 h. After evaporation of the solvent, the residue was taken up in ethyl acetate (150 ml). The organic phase was washed with water (2×50 mL), and brine (50 mL), and dried over Na2SO4. The crude product was purified by Kugelrohr distillation to give ethyl 2-ethoxycarbonyl-9-phenoxynonanoate (1.92 g, 63%), bp 150-154° C./0.1 torr, 1H-NMR: 1.24 (t, 6H), 1.1-1.8 (m, 12H), 3.30 (t, 1H), 3.91 (t, 2H), 4.18 (q, 4H), 6.7-7.2 (m, 5H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](C2C=CC=CC=2)(O)[C:7]([OH:9])=[O:8])=[CH:2]1.CC(=O)OCC.[BrH:23]>C(O)(=O)C>[Br:23][CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: O=C(O)C(O)(c1ccccc1)c1ccsc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C(Br)c1ccsc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The (thiophen-3-yl)mandelic acid (8.60 g, 54.4 mmol) was dissolved in 100 ml of 30% HBr in acetic acid. The solution was stirred for 18 hours at RT. The clear black solution was poured onto 2.5 L of ice water and immediately extracted with Et2O (4×400 ml). The ether was dried over Na2SO4 and treated with decolorizing carbon. The Et2O was evaporated and the residue was azeotroped with toluene to remove residual acetic acid. The crude solid product was recrystalized from hexanes to yield 9.07 g. (75.%). EA, MS(FD).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:11][C:12]1([F:56])[CH2:17][CH2:16][CH:15]([C:18]2[C:27]3[CH:26]([OH:28])[CH2:25][C:24]([CH3:30])([CH3:29])[CH2:23][C:22]=3[N:21]=[C:20]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]4[N:42]=[CH:41][C:40]([OH:43])=[CH:39][N:38]=4)[CH2:33][CH2:32]3)[C:19]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:14][CH2:13]1>>[CH2:9]([O:8][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:43][C:40]1[CH:39]=[N:38][C:37]([N:34]2[CH2:33][CH2:32][CH:31]([C:20]3[C:19]([CH:44]([F:55])[C:45]4[CH:50]=[CH:49][C:48]([C:51]([F:52])([F:53])[F:54])=[CH:47][CH:46]=4)=[C:18]([CH:15]4[CH2:16][CH2:17][C:12]([F:11])([F:56])[CH2:13][CH2:14]4)[C:27]4[CH:26]([OH:28])[CH2:25][C:24]([CH3:30])([CH3:29])[CH2:23][C:22]=4[N:21]=3)[CH2:36][CH2:35]2)=[N:42][CH:41]=1)=[O:7])[CH3:10]
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 13 were performed except for using ethyl 5-bromovalerate instead of ethyl iodide, and from 85 mg (0.13 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 10, the crude title compound was obtained. The total amount of the obtained compound was used in Example (23-2).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:9][N:10]=1.CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([S:35]([N:38]([CH2:40][C:41]2[O:45][CH:44]=[C:43]([C:46]([OH:48])=O)[CH:42]=2)[CH3:39])(=[O:37])=[O:36])=[C:30]([CH3:49])[CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH3:49])[C:31]([S:35]([N:38]([CH2:40][C:41]2[O:45][CH:44]=[C:43]([C:46]([N:4]([CH3:3])[CH2:5][C:6]3[S:7][C:8]([CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:9][N:10]=3)=[O:48])[CH:42]=2)[CH3:39])(=[O:36])=[O:37])=[C:32]([CH3:34])[CH:33]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1nnc(CN2CCCC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3nnc(CN4CCCC4)s3)co2)c(C)c1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
N-methyl-1-[5-(pyrrolidin-1-ylmethyl)-1,3,4-thiadiazol-2-yl]methanamine dihydrochloride (25 mg, 0.087 mmol) was dissolved in DCM (5 mL), on addition of DIPEA (0.03 mL, 0.17 mmol). 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.09 mmol) and HOBt (17 mg, 0.12 mmol) were added and the resulting solution was cooled to 0° C. prior to the addition of EDCI (24 mg, 0.13 mmol). The mixture was stirred at ambient temperature for 7 h, quenched with saturated aqueous NaHCO3 (3 mL) and extracted with DCM (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by FCC eluting with 2% MeOH in DCM to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[CH2:16][O:17][CH2:18][O:19][CH3:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:16][O:17][CH2:18][O:19][CH3:20]
Reactant: COCOCc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COCOCc1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.6 %

Procedure:
To a solution of 1-bromo-4-tert-butyldimethylsiloxy-2-methoxymethoxymethylbenzene (34.2 g, 94.8 mmol) in tetrahydrofuran (100 mL) was added tetrabutylammonium fluoride (1 mol/L in tetrahydrofuran, 50 mL), and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (2:1 hexane/ethyl acetate) to give 4-bromo-3-(methoxymethoxymethyl)phenol (25.9 g, quant).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][CH:9]=1>[Zn].C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:14][CH2:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCC=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Solvent: ClCCl
Product: COc1ccc(CCC=C(Br)Br)cc1
Reaction time: 2 h

Procedure:
A solution of 39.2 g. of zinc dust, 157 g. of triphenylphosphene and 200 g. of carbon tetrabromide in 500 ml. methylene chloride is stirred at room temperature for 25 hours. To the resultant solution is added 50 g. of 4-methoxyhydrocinnamaldehyde and stirring is continued for an additional 2 hours. The solution is diluted with 2 l. of pentane and the precipitate is filtered. The precipitate is stirred with 100 ml. methylene chloride, diluted with 400 ml. pentane, and again filtered. The organic solutions are combined and evaporated to yield 1,1-dibromo-4-(4-methoxyphenyl)-1-butene as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:12]([NH:19][CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH2:12]([N:19]([CH2:20][CH2:21][OH:22])[C:9](=[O:11])[CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(O)Cc1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1cccnc1Cl)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 102.7 %

Procedure:
To a solution of the compound (3.40 g) obtained in step 4, N-benzylethanolamine (4.53 g) and HOBt.H2O (4.60 g) in DMF (50 mL) was added WSC.HCl (5.80 g), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 80% ethyl acetate/hexane→2% methanol/ethyl acetate) to give N-benzyl-2-(2-chloropyridin-3-yl)-N-(2-hydroxyethyl)acetamide (6.20 g, 100%) as a pale-yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[N:12]=[C:11]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH:30]=2)[CH:10]=1.P([O-])([O-])([O-])=O>C(Cl)Cl>[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=2)[N:12]=[C:11]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32]([OH:34])=[O:33])[CH:30]=2)[CH:10]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC(=O)OC(C)(C)C)c2)c1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC(=O)O)c2)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
TFA (1.17 ml, 15.2 mmol) was added to a stirred solution of tert-butyl [4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-pyrazol-1-yl]acetate (330 mg, 0.76 mmol) in DCM (3.8 ml) at room temperature. The reaction mixture was stirred at 40° C. overnight. Upon cooling, the reaction mixture was poured into phosphate buffer pH 4 and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was triturated in Et2O to afford [4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-pyrazol-1-yl]acetic acid as a pale yellow solid. [M+H]+ 378. found, 378
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1>COCCO>[NH:14]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Solvent: COCCO
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1

Procedure:
4-Fluoro-3-nitrobenzoic acid (0.27 mol), an aniline (0.32 mol) and NMM (32.5 mL) in 2-methoxyethanol (750 mL) were stirred at reflux under argon for 24 h. The suspension was concentrated under reduced pressure and the residue was sonicated with 1M HCl (aq) over 1.5 h. The resultant orange solid was isolated by filtration, washed with water dried, then sonicated with t-butyl methyl ether, isolated by filtration and dried. Where necessary, the product was further purified by recrystallisation to yield the 4-anilino-3-nitrobenzoic acid: e.g. 4-(3-bromophenyl amino)-3-nitrobenzoic acid. (In some cases, for example with heteroaromatic anilines, NMN may be omitted from the reaction mixture).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][C:25]=2[CH3:30])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccc(N)c(C)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c(C)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-methoxy-2-methylaniline (53 mg, 0.39 mmol). The title compound was obtained as a solid (75 mg, 49% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.12(1H, s), 9.00 (2H, s), 8.63 (1H, m), 7.12 (1H, dd), 6.83 (1H, m), 6.76 (1H, m), 3.73 (3H, s), 2.14 (3H, s). MS m/z: 468.15, 470.12 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:12]I>O1CCCC1>[CH3:12][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCc2ccccc21
Temperature: 0 °C
Yield: 60.8 %

Procedure:
NaH (15 g, 375.00 mmol) was added in several batches to a chilled (0° C.) solution of indoline (30 g, 252.10 mmol) in tetrahydrofuran (400 mL). Methyl iodide (53 g, 373.24 mmol) was then added dropwise with stirring, while maintaining the temperature of 0° C. The resulting solution was stirred at room temperature for 15 hours, then quenched by the addition of ethanol (200 mL). The mixture was concentrated, water (400 mL) was added, and the product was extracted with methylene chloride (3×200 mL). The organics were combined, dried (Na2SO4), filtered and concentrated to provide 20.4 g (60%) of 1-methylindoline as a brown liquid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[H-].[Na+].[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][Cl:22])([O-:18])=[O:17].Cl>CO.CCOCC>[ClH:22].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N+:16]([O-:18])=[O:17])=[CH:9][CH:8]=1
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=[N+]([O-])c1ccccc1COc1ccc(Cc2ncc[nH]2)cc1

Procedure:
Analogously to Example 1, a crude ether is obtained from 1.74 g. of 4-(1-imidazolylmethyl)-phenol, 300 mg. of sodium hydride suspension, and 1.72 g. of 2-nitrobenzyl chloride. This crude ether is dissolved in methanol and combined with an excess of methanol which contains hydrogen chloride until the mixture shows an acidic reaction. After the solvent has been removed by evaporation under vacuum, the residue is dissolved in methylene chloride and mixed with ether until the onset of crystallization, thus obtaining 925 mg. of [4-(1-imidazolylmethyl)-phenyl]-(2-nitrobenzyl)-ether, hydrochloride, which melts at 156°-158° after another recrystallization from isopropanol.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([F:29])=[N:23][C:24]=2Cl)(=O)C.[O:30]([CH2:37][C@H:38]([NH2:40])[CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>O1CCOCC1>[F:29][C:22]1[N:23]=[C:24]([NH:40][C@H:38]([CH3:39])[CH2:37][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[N:26]=[CH:27][N:19]([C:20]=2[N:21]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(F)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@@H](N)COc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](COc1ccccc1)Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 28.1 %

Procedure:
9-(2,3,5-Tri- O-acetyl-β-D-ribofuranosyl)-6-chloro-2-fluoro-9H-purine (1.03 g, 2.38 mmol) PCT Publication No. WO 938206, (R)-1-phenoxy-2-propylamine (0.36 g, 2.38 mmol) and triethylamine (0.29 g, 0.28 mmol) in dioxan (20 ml) were stirred at room temperature for 18 h. The reaction mixture was filtered and evaporated to a residue which was purified by flash chromatography. The resultant 2',3',5'-tri- O-acetyl-2-fluoro- N-[(R)-1-phenoxy-2-propyl]adenosine was deprotected using methanolic ammonia to provide the title 2-fluoro- N-[(R)-1-phenoxy-2-propyl]adenosine (0.28 g, 23%)(after column chromatography), mp 148°-150° C.; 1H NMR (DMSO-d6)δ 1.33 (3H, d, -3.59 (1H, m, H-5'a), 3.63-3.71 (1H, m, H-5'b), 3.92-3.99 (2H, m, H-4' and --C--H), 4.10-4.18 (2H, m, H-3' and --C--H), 4.51 (1H, q, H-2'), 4.61 (1H, m, --CH3C H--), 5.06 (1H, t, 5'-OH), 5.22, 5.48 (2H, 2d, 2' and 3'-OH), 5.82 (1H, d, H-1'), 6.89-6.97 (3H, m, Ar--H), 7.25-7.30 (2H, t, Ar--H), 8.39 (1H, s, H-8), 8.49 (1H, d, N--H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[S:8]([O:1][C@@H:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1OCC[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A suspension of (R)-α-hydroxy-γ-butyrolactone (3.5 g, 34.3 mmol), tosyl chloride (10.0 g, 52.6 mmol), and K2CO3 (2.23 g, 16.2 mmol) in dry CH2Cl2 (50 mL) was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate washed with 1M phosphate buffer pH=7 (2×50 mL), 3 M NaCl (aq.) (1×50 mL), dried with Na2SO4, filtered and evaporated to dryness to give the crude product. The crude product was triturated by PE40/60 (50 mL) and stirred for 30 minutes. The precipitate formed was isolated by filtration and washed with PE40/60 to remove trace amounts of tosyl chloride, to give 7.7 g (87%) of enantiopure (R)-α-tosyloxy-γ-butyrolactone. [α]36525=−9.9°.