Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[C:6](#[N:9])[CH:7]=[CH2:8].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>O>[CH2:1]([P:3]([CH2:8][CH2:7][C:6]#[N:9])(=[O:5])[OH:4])[CH3:2]
Reactant: C=CC#N
Reactant: CCP(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCC#N
Temperature: 100 °C
Yield: 82.9 %

Procedure:
564 g (6 mol) of ethylphosphonous acid (produced as in Example 1) are dissolved in 860 g of water and initially charged to a 5 l five-necked flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. After heating the reaction mixture to 100° C., 371 g (7 mol) of acrylonitrile and 500 g of a 5% strength sodium peroxodisulfate solution (1.5 mol % based on acrylonitrile) are added dropwise at atmospheric pressure over 1 h. The water is then distilled off in vacuo. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo and the residue is recrystallized from acetone to leave 732 g (83% of theory) of ethyl-(2-cyanoethyl)phosphinic acid as oil.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1>>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH:14]=1
Reactant: OCc1cccnc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: O=C(O)c1ccc(OCc2cccnc2)nc1
Yield: 66 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 66% yield starting from ethyl 6-chloronicotinate and pyridine-3-methanol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67-8.76 (m, 2 H), 8.54 (d, 1 H), 8.17 (dd, 1 H), 7.89 (d, 1 H), 7.42 (dd, 1 H), 6.98 (d, 1 H), 5.47 (s, 2 H); (APPI/APCI) m/z 231[M+H+].
Reaction SMILES: [CH3:1][S:2](=[O:19])([CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[CH3:8])=[N:3][C:4]([NH2:6])=[S:5].Br[CH:21]1[CH2:29][CH2:28][C:24]2=[N:25][O:26][N:27]=[C:23]2[C:22]1=O>CCO>[CH3:1][S:2](=[N:3][C:4]1[S:5][C:29]2[CH2:21][CH2:22][C:23]3[C:24]([C:28]=2[N:6]=1)=[N:25][O:26][N:27]=3)(=[O:19])[CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=1)[CH3:8]
Reactant: O=C1c2nonc2CCC1Br
Reactant: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=NC(N)=S
Solvent: CCO
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=Nc1nc2c(s1)CCc1nonc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)thiourea (J) (100 mg, 0.321 mmol) and 5-bromo-6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-one (76.6 mg, 0.353 mmol, 1.1 eq) were suspended in EtOH (1.6 mL). The reaction was stirred at room temperature for 2 h, and then heated to reflux for 1 h. The hot solution was filtered via a 0.45 μm nylon syringe filter and the filtrate was stored at −20° C. over night. 7-[(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)amino]-4,5-dihydro[1,3]thiazolo[4,5-e][2,1,3]benzoxadiazole (65) was obtained in form of slightly yellow crystals (70 mg, 0.163 mmol, 51%) as a 1:1 mixture of diastereomers (racemate) that were isolated by filtration, washed with a small amount of cold ethanol, and dried in the high vacuum. 1H-NMR (DMSO-d6, 400 MHz): δ=1.87 (d, J=6.9 Hz, 1.5H, CHCH3, diastereomer 1); 1.89 (d, J=6.9 Hz, 1.5H, CHCH3, diastereomer 2); 3.06-3.27 (m, 4H, CH2—CH2, diastereomers 1, 2); 3.42 (s, 1.5H, S—CH3, diastereomer 1); 3.43 (s, 1.5H, S—CH3, diastereomer 2); 5.34 (q, J=6.9 Hz, 1H, CHCH3, diastereomers 1, 2); 7.96 (d, J=7.7 Hz, 0.5H, pyr-C3-H, diastereomer 1), 7.98 (d, J=7.8 Hz, 0.5H, pyr-C3-H, diastereomer 2); 8.21-8.26 (m, 1H, pyr-C4-H, diastereomers 1, 2); 8.85 (d, 0.5H4J=1.6 Hz, pyr-C6-H, diastereomer 1); 8.86 (d, 0.5H, 4J=1.6 Hz, pyr-C6-H, diastereomer 2). 13C-NMR (DMSO-d6, 100 MHz): δ=13.3, 13.6 (CHCH3, two diastereomers); 17.9 (double peak, CH2, two diastereomers); 20.4 (double peak, CH2, two diastereomers); 36.4, 36.5 (S—CH3, two diastereomers); 60.8, 60.9 (CHCH3, two diastereomers); 119.4, 119.5 (pyr-C, two diastereomers); 120.3 (q, 2J (C—F)=271.5 Hz, CF3, two diastereomers), 131.6, 131.9; (pyr-C, two diastereomers); 132.0, 132.1 (Ar, two diastereomers), 132.4, 132.5 (Ar, two diastereomers); 138.0, 138.1 (pyr-C, two diastereomers); 145.0 (double peak, Ar, two diastereomers); 145.0, 145.1 (Ar, two diastereomers); 149.9 (double peak, pyr-C, two diastereomers); 151.2 (double peak, Ar, two diastereomers); 166.3, 166.6 (thiazole, two diastereomers). UPLC-MS (ESI+): mass calc'd for C16H15F3N5O2S2 (M+H+): 430.1, found 430.1, UPLC-MS (ESI+) mass calc'd for C16H13F3N5O2S2 (M−H+): 428.1, found 428.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([C:26]([OH:28])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)(=[O:13])=[O:12].C(N(C(C)C)C(C)C)C.O[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:40]([CH2:39][O:27][C:26](=[O:28])[C@@H:15]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:41]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc2ccccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](COC(=O)[C@@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc3ccccc3c2)C1
Reaction time: 15 h
Yield: 66.7 %

Procedure:
A solution of 1.0 g of N-2-naphthylsulfonyl-(D)-tryptophan in 20 ml of DMF is treated with 0.5 ml of ethyldiisopropylamine. After the addition of 0.6 g of t-butyl (S)-3-hydroxymethyl-1-piperidinecarboxylate (Example 3c) and 1.1 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate the reaction mixture is stirred for 15 hours. The solvent is evaporated and the residue is taken up in water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried and evaporated. Chromatography over silica gel with ethyl acetate gives 1.0 g of N-(2-naphthylsulfonyl)-D-tryptophan (S)-l-t-butyoxycarbonyl-3-piperidinylmethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[S:11]1[CH2:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]2[S:11][C:12](=[O:17])[NH:13][C:14]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 31.7 %

Procedure:
4-Methoxybenzaldehyde (20.4 g, 150 mmol), thiazolidine-2,4-dione (21.1 g, 180 mmol), piperidine (12.8 g, 150 mmol) and ethanol (150 mL) were mixed and refluxed for 18 hours. After allowed to stand for cooling, the precipitated crystals were collected by filtration. These were washed with ethanol, and then dried to obtain 11.2 g (32%) of the title compound as yellow crystals. Moreover, the filtrate was made acidic with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, washed with ethanol and water, and then dried to additionally obtain 18.1 g (51%, totally 83%) of the title compound as yellow crystals.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[CH3:50][C:51]1[S:52][C:53]([CH2:56][NH2:57])=[CH:54][N:55]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:53]4[S:52][C:51]([CH3:50])=[N:55][CH:54]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1ncc(CN)s1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1ncc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)nc2C)s1
Yield: 45 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (2-methylthiazol-5-yl)methanamine, the title compound was obtained as a colorless solid in 45% yield: mp 213-215° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.07-7.01 (m, 3H), 6.29 (br s, 1H), 4.62 (d, J=5.3 Hz, 2H), 4.46 (s, 2H), 4.10-4.05 (m, 2H), 3.48-3.43 (m, 2H), 2.71 (s, 3H), 2.61 (s, 3H); MS (ES+) m/z 446.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>C(OCC)C>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:14](=[O:16])[C:13]([NH:12][C:10]3[CH:9]=[CH:8][C:6]4[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=4[CH:11]=3)=[O:17])[CH2:26][CH2:25]2)=[CH:30][CH:31]=1
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4c(c3)OCC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and 4-(4-methylbenzyl)-piperidine [J Org. Chem., 64,3763. (1999)] according to the method described in Example 1c. Melting Point: 228-231° C. (diethylether)
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].C(N(CC)CC)C.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19]1([S:25]([O:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])[CH3:8])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)=CCC[C@@H](C)CCO
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCCC(C)CCOS(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 109.6 %

Procedure:
A solution of citronellol 6 (30.0 g, 192 mmol) in 400 mL CH2Cl2 was allowed to stir at 0° C. under N2 in a 1 L round bottom flask. Triethylamine (60 mL, 430 mmol) was added in one portion, followed by DMAP (2.0 g, 1.64 mmol). Finally, benzenesulfonyl chloride (30 mL, 240 mmol) was added dropwise via syringe. After the mixture was stirred for 2 h at 0° C., it was partitioned between petroleum ether and, sequentially, 3 M aqueous HCl, water, and brine. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo at 30° C. Removal of residual solvent under high vacuum yielded citronellyl benzenesulfonate (62.4 g, 110% of theoretical) as a clear yellow oil, TLC Rf(10% MTBE/petroleum ether)=0.41. 1H NMR (CDCl3) (δ): 7.92 (m, 2H), 7.66 (m, 1H), 7.56 (m, 2H), 5.03 (m, 1H), 4.09 (m, 2H), 1.91 (m, 2H), 1.68 (m, 1H), 1.67 (s, 3H), 1.57 (s, 3H), 1.52 (m, 1H), 1.44 (m, 1H), 1.24 (m, 1H), 1.11 (m, 1H), 0.81 (d, J=6.49 Hz, 3H); 13C NMR (CDCl3) (δ): u: 136.1, 131.4, 69.2, 36.6, 35.5, 25.1; d: 133.6, 129.1, 127.7, 124.2, 28.7, 25.6, 18.9, 17.5; IR (cm−1): 2914, 1449, 1360, 1188, 944.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[C:14]2[CH:15]=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:7][N:6]=1.[Br:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].O>CN(C)C=O>[Br:26][C:27]1[CH:34]=[C:33]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][C:12]([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[C:13]3[C:5]([C:4]([F:24])([F:3])[F:25])=[N:6]2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: FC(F)(F)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Reactant: N#Cc1ccc(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1Br
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
Sodium hydride (0.183 g, a 55% dispersion in paraffin liquid) was added to a solution of compound (1d) (0.940 g) in N,N-dimethylformamide (hereinafter referred to as DMF, 6 mL) at room temperature, followed by stirring for 30 min. Subsequently, 2-bromo-4-fluorobenzonitrile (0.838 g) was added to the reaction solution, followed by stirring at 60° C. for 1 hr. After cooling, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline in this order and was dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (1e) (0.56 g, 38%) as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[C:12]([CH2:14][CH3:15])[C:10]([NH2:11])=[C:9]([CH2:16][CH3:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[Ca+2].[C:24](Cl)(Cl)=[S:25]>C(Cl)Cl>[CH:1]1([C:7]2[CH:8]=[C:9]([CH2:16][CH3:17])[C:10]([N:11]=[C:24]=[S:25])=[C:12]([CH2:14][CH3:15])[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1cc(C2CCCCC2)cc(CC)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C2CCCCC2)cc(CC)c1N=C=S

Procedure:
231 g of 4-cyclohexyl-2,6-diethyl-aniline in 300 ml of methylene chloride are added dropwise at 10°-15° C. to a suspension of 600 ml of methylene chloride, 500 ml of water, 200 g of calcium carbonate and 140 g of thiophosgene. The mixture is then heated to the boil, until the evolution of gas has ended. The batch, when cold, is filtered to remove solids, and the methylene chloride layer is dried over calcium chloride and fractionated; boiling point 175°-179° C./1.5 mm Hg; yield 251 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:25](O)=[O:26])[C:12]2[C:17]([CH3:18])=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C:13]=2[N:14]=1.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.[C:42]([N:49]1[CH2:54][CH2:53][NH:52][C:51]([CH3:56])([CH3:55])[CH2:50]1)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>ClCCl.C(N(CC)C(C)C)(C)C>[C:45]([O:44][C:42]([N:49]1[CH2:54][CH2:53][N:52]([C:25]([C:11]2[C:12]3[C:17]([CH3:18])=[N:16][N:15]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:13]=3[N:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[F:1])[CH:10]=2)=[O:26])[C:51]([CH3:56])([CH3:55])[CH2:50]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)O)c12
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)C)c12
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a suspension of 6-(2-fluoro-4-Hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg) in dry dichloromethane (3 mL), N,N-diisopropylethylamine (70 μL), 2-bromo-1-ethylpyridinium tetrafluoroborate (221 mg) and 1-Boc-3,3-dimethylpiperazine (87 mg) were added. The solution was stirred for 30 min. Upon complete conversion, the solution is evaporated in vacuo and 3 mL of 30% sodium methoxide in methanol were added. The mixture was stirred for 30 min, the pH was adjusted to 5 by addition of 2M hydrochloric acid. Ethyl acetate was added and the organic layer was extracted with saturated sodium bicarbonate, 20% aqueous ammonium chloride solution and multiple times with water. The organic layer was dried over sodium sulfate and evaporated to dryness to give 132 mg (58%) of the title compound.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.COC1C=CC(C[N:52]2[C:56]3[CH:57]=[CH:58][C:59]([NH2:61])=[CH:60][C:55]=3[N:54]=[CH:53]2)=CC=1.COC1C=CC(CN2C3C=C(N)C=CC=3N=C2)=CC=1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:61][C:59]3[CH:58]=[CH:57][C:56]4[NH:52][CH:53]=[N:54][C:55]=4[CH:60]=3)=[N:3][CH:4]=[C:5]([CH2:34][N:35]3[CH2:36][CH2:37][N:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:39][CH2:40]3)[CH:6]=2)[N:9]=1
Reactant: COc1ccc(Cn2cnc3cc(N)ccc32)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: COc1ccc(Cn2cnc3ccc(N)cc32)cc1
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc3[nH]cnc3c2)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 246 using 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and a mixture of 1-(4-methoxybenzyl)-1H-benzo[d]imidazol-5-amine and 1-(4-methoxybenzyl)-1H-benzo[d]imidazol-6-amine regioisomers, and was isolated as yellow amorphous solid (5.5%). m/z (ESI, +ve ion) 495.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.29 (1H, br. s.); 12.04 (1H, br. s.); 8.72 (1H, d, J=2.5 Hz); 8.39 (1H, br. s.); 8.25 (1H, d, J=2.3 Hz); 8.11 (1H, s); 7.80-7.86 (1H, m); 7.72 (1H, br. s.); 7.51 (1H, br. s.); 7.37 (1H, br. s.); 3.50 (2H, s); 3.11 (4H, d, J=4.5 Hz); 2.87 (3H, s); 2.50 (4H, s); 2.47 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1F
Temperature: 70 °C
Reaction time: 20 h
Yield: 50.6 %

Procedure:
2,4-Difluoronitrobenzene (8.0 g) was dissolved in N,N-dimethylformamide (110 ml) and the solution was admixed with 1H-1,2,4-triazole (3.47 g) and potassium carbonate (6.95 g) and the mixture was stirred under a nitrogen atmosphere at 70° C. for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the ethyl acetate layers were combined and washed 5 times with water and then with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:1.3). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield 1-(3-fluoro-4-nitrophenyl)-1H-1,2,4-triazole (5.29 g) as yellow powdery crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:4][CH:3]=1.[CH3:36][C@@H:37]1[O:39][C@H:38]1[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[OH:39][C@@H:38]([CH3:40])[C@H:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:6][CH:7]=1)[CH3:36]
Reactant: C[C@@H]1O[C@H]1C
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ccnn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O[C@H](C)[C@H](C)O)cc2)c2ccnn12
Yield: 54 %

Procedure:
To a solution of 4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.92 g) in N,N-dimethylformamide (10 mL) were added trans-2,3-epoxybutane (1.8 mL) and then cesium carbonate (2.0 g), and the mixture was stirred at 100° C. for 15 hr. The mixture was allowed to cool, to the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.57 g, 54%).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40])[C@@H:3]1[OH:45].N1C=CC=CC=1.[C:52](Cl)(=[O:57])[CH2:53][CH2:54][CH2:55][CH3:56]>C(Cl)(Cl)Cl>[CH3:56][CH2:55][CH2:54][CH2:53][C:52]([O:36][CH2:35][C:33]([C@:11]1([OH:37])[CH2:12][C:13]2[C:18](=[C:17]([OH:19])[C:16]3[C:20](=[O:21])[C:22]4[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:23]=4[C:24](=[O:25])[C:15]=3[C:14]=2[OH:32])[C@@H:9]([O:8][CH:6]2[O:7][CH:2]([CH3:1])[CH:3]([OH:45])[CH:4]([NH:38][C:39]([C:41]([F:44])([F:42])[F:43])=[O:40])[CH2:5]2)[CH2:10]1)=[O:34])=[O:57]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](OC2CC(NC(=O)C(F)(F)F)C(O)C(C)O2)C1)C(=O)c1c(OC)cccc1C3=O

Procedure:
A solution containing 5.0 mg. of N-trifluoroacetyladriamycin dissolved in 0.5 ml. of anhydrous pyridine was treated with 18 microliters of valeroyl chloride, which was added in small portions over a two-day period. The reaction was monitored by thin layer chromatography and when the presence of N-trifluoroacetyladriamycin could no longer be observed, the reaction mixture was diluted with 10 ml. of chloroform. The chloroform solution was extracted three times with pH 4 gaseous buffer and once with pH 7 buffer. The dried chloroform solution was then evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel G with chloroform:methanol:water (120:20:1 by volume) as the solvent system. The major orange-colored band was removed and washed free of silica gel with a mixture of methanol and ethyl acetate. Upon evaporation of the methanol and ethyl acetate, 2.19 mg. of N-trifluoroacetyladriamycin-14-valerate was obtained. This material was idential by spectral and chromatographic comparison with samples of N-trifluoroacetyladriamycin-14-valerate prepared by the earlier described methods.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[Br:16]N1C(=O)CCC1=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[C:11]([Br:16])[C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O)c(Br)cc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 99.9 %

Procedure:
To a mixture of methyl((3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (10 g) in THF (dry) (192 mL) was added N-bromosuccinimide (8.55 g) at 0° C. The mixture was gradually warmed to room temperature and stirred at room temperature for 1.5 day. The mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (13.78 g).