Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:13]CC2C=CC=CC=2)=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=2[CH:12]=1.[CH:21](Br)([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[OH:13][C:3]1[C:2]([O:1][CH:21]([CH3:23])[CH3:22])=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: CC(C)Br
Reactant: O=c1ccc2cc(O)c(OCc3ccccc3)cc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2ccc(=O)oc2cc1O
Reaction time: 2.5 h

Procedure:
50.0 g (186 mmol) 6-hydroxy-7-phenylmethoxy-2H-1-benzopyran-2-one, 36.3 ml (387 mmol) isopropylbromide, 51.5 g (373 mmol) potassium carbonate and 5.0 g potassium iodide are agitated in 500 ml DMF for 14 h at 80° C. After filtration the filtrate is evaporated and the product recrystallized from isopropanol, yield: 57.7 g (100%) 6-(1-methyl-ethoxy)-7-(phenylmethoxy)-2H-1-benzopyran-2-one. Of this 50.0 g (161 mmol) are agitated in 100 ml of glacial acetic acid and 90 ml concentrated hydrochloric acid for 2.5 h at 70° C. This is followed by evaporation and purification using column chromatography on silica gel (eluent: chloroform and methanol 98/2 H 95/5): 24.65 g (69%), fusion point 121°-122° C. (from isopropanol).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[NH:8]1[CH2:11][CH:10]([C:12]2[C:17]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2N2CCC(CO)CC2)C1
Agent: Cl
Solvent: CO
Product: OCC1CCN(c2nccnc2C2CNC2)CC1
Yield: 98 %

Procedure:
A solution of (36) (557 mg, 1.6 mmol) in 4N HCl/MeOH (20 mL) was stirred at RT for 30 min. The reaction mixture was concentrated to give (37) (450 mg, 1.58 mmol, yield 98%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C@@H:11]3[C:6]=2[CH:5]=[C:4]([O:17]C)[CH:3]=1.Cl.N1C=CC=CC=1>O.[OH-].[Na+]>[Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C@@H:11]3[C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1
Reactant: COc1cc(Br)c2c(c1)[C@H]1CN(C)CC[C@H]1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CN1CC[C@H]2COc3c(Br)cc(O)cc3[C@H]2C1

Procedure:
A mixture of 0.5 g (±)[4aR*,10bS*]-7-bromo-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-2H-[1]benzopyrano[4,3-c]pyridine and 5 g pyridine hydrochloride is heated under nitrogen at 200° for 20 minutes. The cooled reaction mixture is dissolved in water and basified with 6N NaOH. The aqueous phase is extracted with three 25 ml portions of CH2Cl2, the extracts are dried over Na2SO4, filtered, concentrated under reduced pressure, and flash chromatographed with methylene chloride/ammonia saturated methanol (10:1) to afford the title compound; m.p. HCl salt 259°-262°.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][N:14]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:15]2)C(=O)OC(C)(C)C>C(OCC)(=O)C>[F:23][C:20]([F:21])([F:22])[C:19]([N:14]1[CH2:15][CH:16]2[CH:11]([NH:3][CH3:2])[CH:12]([CH2:18][CH2:17]2)[CH2:13]1)=[O:24]
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(C(=O)C(F)(F)F)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC1C2CCC1CN(C(=O)C(F)(F)F)C2

Procedure:
Ethyl acetate (100 mL) saturated with HCl (g) was added, at 0° C., to a solution of tert-butyl methyl[3-(2,2,2-trifluoroacetyl)-3-azabicyclo[3.2.1]oct-8-yl]carbamate (see step (iv) above; 5 g, 15 mmol) in ethyl acetate (50 mL). The mixture was allowed to reach rt over the course of 3 h, after which time the solvent was evaporated. This gave 4 g (100%) of the sub-tide compound hydrochloride salt.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)NC1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][C:27]([CH3:37])([O:29][Si](CC)(CC)CC)[CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])([CH3:28])[CH3:37])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](SCCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 92.5 %

Procedure:
Under the same conditions as in Example 9, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-methyl-4-triethylsilyloxypentylthio)pregna-5,7,16-triene (55.7 mg, 0.0825 mmol), tetrahydrofuran (2 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1, developed once) to give the title compound as a colorless oil (34.1 mg, 92%).
Reaction SMILES: C([NH:3][C:4]1[CH:12]=[C:11]([C:13]#[N:14])[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]=1[CH3:15])=O.Cl.[OH-].[Na+]>O>[NH2:3][C:4]1[CH:12]=[C:11]([C:13]#[N:14])[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]=1[CH3:15]
Reactant: Cc1c(NC=O)cc(C#N)c2[nH]cnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N)cc(C#N)c2[nH]cnc12
Temperature: 80 °C

Procedure:
A mixture of 5-(formylamino)-4-methyl-1H-benzimidazole-7-carbonitrile (4.8 kg), water (46 L) and concentrated hydrochloric acid (17.8 kg) was agitated at about 80° C. for about 1½ h. After the mixture was cooled to about 25° C., a solution of 50% aqueous sodium hydroxide (17.1 kg) and water (64 L) was added. The mixture was cooled to about 25° C. over about 15 min. The mixtures was then filtered and the product was washed with water (50 L). The product was dried in a vacuum tray dryer at 45-50° C. and ca. 40 Torr.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[CH:18][C:17]([CH:23]3[CH2:25][CH2:24]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26].C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[ClH:26].[CH:20]1([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([CH:23]3[CH2:25][CH2:24]3)[CH:18]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,3,5-tribromopyridine (10 g), 1-Boc-piperazine (6 g) and potassium carbonate (20 g) was added 2-butanone (80 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g). To a mixture of 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1.3 g), tripotassium phosphate (38 g) and cyclopropylboronic acid (8.4 g) were added toluene (100 mL) and water (5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g). 4-(3,5-Dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (100 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), 4N hydrogen chloride/ethyl acetate (8 mL) was added, and the mixture was filtered to give the title compound (3.2 g).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:1]=[S:3]
Reactant: NCCCCCC(=O)O
Reactant: S=C=S
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCCCCN=C=S
Temperature: 25 °C
Reaction time: 44 h
Yield: 98 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 6-aminohexanoic acid (0.20 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 44 hours. The obtained reaction mixture was dropwise added to a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the obtained residue, a solvent mixture of hexane (3 mL) and ethyl acetate (3 mL) was added and thoroughly mixed, and an insoluble matter was filtered off. Then, the filtrate was concentrated under reduced pressure to dryness to obtain 6-isothiocyanatohexanoic acid as an orange oil (0.26 g, yield: 98%, and 1H-NMR spectrum showed no distinct by-product). LC-MS ES-172 (retention time: 19.3 min, condition 3).
Reaction SMILES: B(O)(O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:6]1[C:7]2[C:3](=[C:2]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc3[nH]ccc23)c2c(N)ncnc21
Temperature: 80 °C
Yield: 50 %

Procedure:
A solution of 1H-indol-4-yl-4-boronic acid (40 mg, 0.25 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.1 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA91 (14.6 mg, 50% yield). ESI-MS (M+H)+ m/z calcd 293.1, found 293.1.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C([BH3-])#N.[Na+]>>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][NH:3][O:2][CH3:1])=[CH:12][CH:11]=1
Reactant: CON=CCCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCCCc1ccc(F)cc1
Yield: 75 %

Procedure:
Reduction of 3-(4-fluorophenyl)-propionaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography on silica gel and distillation in vacuo (75% yield): bp 70-75° C./0.7 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CHCl3) δ (ppm): 1.85 (2H, m, CH2), 2.68 (2H, t, J=7.9 Hz, CH2), 2.95 (2H, t, J=7.1 Hz, CH2), 3.56 (3H, s, OCH3), 5.58 (1H, broad, NH), 6.99 (2H, m, aromatics), 7.17 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 97-100° C. Anal. calcd for C10H14FNO—HCl: C, 54.67; H, 6.88; N, 6.38. Found: C, 54.72; H, 6.71; N, 6.42.
Reaction SMILES: CC([Si](C)(C)[O:6][CH:7]([C:9]1[N:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=1)[CH3:8])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[OH:6][CH:7]([C:9]1[N:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 94.5 %

Procedure:
(+/−)-1,1-Dimethylethyl 4-{[6-(1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2-pyridinyl]oxy}-1-piperidinecarboxylate (1.16 g, 2.66 mmol) was dissolved in 25 mL of THF with stirring, Tetrabutyammonium fluoride (3.20 mL, 1M in THF, 3.20 mmol) was added via syringe. The reaction was stirred for 1 h and poured Into saturated ammonium chloride solution and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSC4, filtered, and concentrated in vacuo. Purification by flash chromatography gave 0.810 g (94%) of the title compound. 1H MMR (300 MHz, DMSO-d6) δ 7.69 (dd, J=8.1, 7.3 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.64 (d, J=8.1 Hz, 1H), 5.28 (d, J=4.9 Hz, 1H), 5.18 (m, 1H), 4.62 (m, 1H), 3.75-3.63 (m, 2H), 3.29-3.15 (m, 2H), 2.03-1.91 (m, 2H), 1.66-1.50 (m, 2H), 1.44 (s, 9H), 1.87 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([OH:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].[H-].[K+].[CH3:59][O:60][CH:61]([O:64][CH3:65])[CH2:62]Br>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH2:62][CH:61]([O:64][CH3:65])[O:60][CH3:59])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: COC(CBr)OC
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: [H-]
Agent: [K+]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OCC(OC)OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
Alternatively, a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (25 mg, Example 42, in 0.2 ml dry DME) is added to a stirring suspension of potassium hydride (1 equivalent in 0.5 ml DME) followed immediately by addition of a large excess of bromoacetaldehyde dimethyl acetal (0.2 ml). After 2 hours the mixture is quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organics are dried over magnesium sulfate and concentrated in vacuo. The product is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:10]([C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:19][CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:22][CH:21]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCN(CCOc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 60.3 %

Procedure:
To a stirring solution of N-acetylpiperazine (5.10 g, 40.0 mmol) in acetonitrile (100 mL) was added 1-(4-nitrophenoxy)-2-bromoethane (10.0 g, 40.0 mmol), K2CO3 (15 g, 108 mmol), and NaI (0.90 g, 6.0 mmol). The mixture was stirred under nitrogen at 70° C. for 24 hours, cooled, and concentrated. The residue was partitioned between ethyl acetate/10% aqueous K2CO3. The organic phase was dried and concentrated to afford crude product which was purified by flash column chromatography (5% CH3OH/CH2Cl2) to afford 7.07 g (61%) of 1-acetyl-4-[2-(4-nitrophenoxy)ethyl]piperazine as a semisolid: 1H NMR (CDCl3): δ8.20 (d, J=9.6 Hz, 2H), 6.95 (d, J=9.6 Hz, 2h), 4.20 (t, J=6.0 Hz, 2H), 3.65 (m, 2H), 3.50 (m, 2H), 2.85 (t, J=6.0 Hz, 2H), 2.55 (m, 6H), 2.08 (s, 3H).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[C:32]([C:33]#[N:34])=[C:31]([SH:35])[N:30]=[C:29]([CH3:36])[CH:28]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:35][C:31]3[N:30]=[C:29]([CH3:36])[CH:28]=[C:27]([CH3:26])[C:32]=3[C:33]#[N:34])=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cc1cc(C)c(C#N)c(S)n1
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc(C)cc(C)c3C#N)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 4,6-dimethyl-2-mercaptonicotinonitrile was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.53-1.71 (m, 8H) 2.01 (s, 3H) 2.06 (m, 2H) 2.34 (m, 1H) 2.37 (s, 3H) 2.58 (m, 2H) 2.83 (d, J=17.9 Hz, 1H) 2.93 (d, J=15.0 Hz, 1H) 3.80 (s, attenuation due to proximity to H2O peak) 6.98 (s, 1H) 7.02 (d, J=8.2 Hz, 1H) 7.11 (d, J=5.0 Hz, 1H) 7.23 (d, J=1.9 Hz, 1H). MS (APCI) calcd for C27H29ClN2O4S: 513.06; found M=513.1.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH:5]([CH2:7][CH2:8][CH3:9])O.[CH2:11]([SH:15])[CH:12]([SH:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:13][CH:12]1[CH2:11][S:15][C:4]([CH2:3][CH2:2][CH3:1])=[C:5]([CH2:7][CH2:8][CH3:9])[S:14]1
Reactant: CCCC(=O)C(O)CCC
Reactant: CC(S)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC1=C(CCC)SC(C)CS1

Procedure:
The method of Example 4 was followed, using butyroin (12 g), propane-1,2-dithiol (9 g) and p-toluenesulfonic acid (0.5 g). 2,3-Dihydro-2-methyl-5,6-dipropyl-1,4-dithiin was obtained as a greenish liquid, boiling range 76°-85°/0.055 mm, yield 7.5 g (35%). NMR (CDCl3) 0.92 δ (triplet), 1.25-2.4 δ (complex overlapping doublet, multiplet, and quartet) 2.6-3.6 δ (complex multiplet).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([NH2:33])[CH:29]=[N:28]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH:11]3[CH2:15][NH:14][CH2:13][CH:12]3[CH2:23]2)=[N:7][C:2]([NH:33][C:30]2[CH:29]=[N:28][N:27]([CH3:26])[C:31]=2[CH3:32])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Cc1c(N)cnn1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cnn1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (579.1 mg, 1.55 mmol) and 1,5-dimethylpyrazol-4-amine hydrochloride (446.8 mg, 3.03 mmol) in dioxane (10 mL) was added trifluoroacetic acid (862.8 mg, 7.57 mmol). The reaction mixture was stirred at 100° C. overnight and adjusted to pH=10 with a saturated Na2CO3 solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM=1/10) to give the title compound as a beige solid (105.6 mg, 19.6%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=2[Cl:24])=[N:3][CH:4]=1
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cc(Cl)ccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,5-dichlorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.8 Hz), 8.34 (1H, d, J=2.6 Hz), 8.27–7.99 (3H, m), 7.46–7.43 (3H, m), 7.35 (1H, d, J=2.3 Hz), 7.29–7.25 (1H, m), 5.44–5.34 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=6.9 Hz).