Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[Na].[F:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[C:12]([F:18])[CH:11]=[CH:10][C:9]=1[C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:41])[CH2:26][C:27]2[N:28]([CH3:40])[N:29]=[C:30]3[C:35]=2[C:34](=[O:36])[N:33]([CH3:37])[C:32](=[O:38])[N:31]3[CH3:39])[S:22][CH:23]=1.[P:42]([O:54][CH2:55]I)([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C=O)C>[P:42]([O:54][CH2:55][N:20]1[C:19]([C:9]2[CH:10]=[CH:11][C:12]([F:18])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=2[F:7])=[CH:23][S:22][C:21]1=[N:24][C:25](=[O:41])[CH2:26][C:27]1[N:28]([CH3:40])[N:29]=[C:30]2[C:35]=1[C:34](=[O:36])[N:33]([CH3:37])[C:32](=[O:38])[N:31]2[CH3:39])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:43]
Reactant: Cn1nc2c(c1CC(=O)Nc1nc(-c3ccc(F)c(C(F)(F)F)c3F)cs1)c(=O)n(C)c(=O)n2C
Reactant: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na]
Solvent: CN(C)C=O
Product: Cn1nc2c(c1CC(=O)N=c1scc(-c3ccc(F)c(C(F)(F)F)c3F)n1COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared according to the general procedure as described in step 2 of method B for the preparation of phosphate derivatives by the reaction of sodium salt of N-(4-(2,4-difluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-2-(2,5,7-trimethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl)acetamide (500 mg, 0.93 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (489 mg, 1.39 mmol) dry DMF (5 ml) to yield 460 mg of product as a white solid. The title compound was also prepared according to the general procedure as described in method A by coupling of N-(4-(2,4-difluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-2-(2,5,7-trimethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl)acetamide (2.50 g, 4.86 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (5.95 g, 17.02 mmol) in the presence of sodium hydride (60% dispersion in mineral oil, 291 mg, 7.29 mmol) in dry DMF (25 ml) to yield 1.35 g of pure product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 1.44 (s, 18H), 3.34 (s, 3H), 3.51 (s, 3H), 3.92 (s, 3H), 4.74 (s, 2H), 6.44 (d, J=9.6 Hz, 2H), 7.09 (t, J=9.3 Hz, 1H), 7.51 (s, 1H), 8.45 (q, J=9.0 Hz, 1H). ESI (m/z): 736.56 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[N:20]=[C:21]([CH3:24])[O:22][C:23]5=4)[O:25][CH2:26]3)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 77.5 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.97 g, 4.92 mmole) were combined in 30 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 85% hexanelmethylene chloride to remove impurities and methylene chloride to elute the product, the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 196° C.) after evaporation of the solvent (0.21 g, 40%). MS (ESI) m/z 402(M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[C:11]([N:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[NH:26][CH2:25][CH2:24]2)[N:10]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[ClH:1].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[C:11]([N:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[N:26]([C:3](=[O:4])[CH2:2][Cl:1])[CH2:25][CH2:24]2)[N:10]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc2nc(N3CCN[C@@H]4CCCC[C@@H]43)nc(N)c2cc1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2nc(N3CCN(C(=O)CCl)[C@@H]4CCCC[C@@H]43)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of 0.26 g of chloroacetyl chloride in 6 ml of methylene chloride was added dropwise over 15 minutes at 0° C. to a stirred mixture of 0.5 g of the above intermediate 4A and 0.21 g of diisopropylethylamine in 15 ml of methylene chloride. After 4-hour stirring at room temperature and 72-hour resting in a refrigerator, the solid was collected by suction and purified by crystallisation from chloroform to give 0.12 g (33%) of the desired product; m.p. >270° C.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3][CH2:2]1.Cl[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>O>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[NH:7][C@H:4]1[CH2:5][CH2:6][C@H:1]([NH2:8])[CH2:2][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1ncccn1
Solvent: O
Product: N[C@H]1CC[C@H](Nc2ncccn2)CC1
Temperature: 160 °C

Procedure:
A stirred mixture of trans-1,4-cyclohexanediamine (1.50 g, 13.1 mmol) and 2-chloropyrimidine (500 mg, 4.37 mmol) was heated at 160° C. for 2 h then cooled to RT. The mixture was diluted with water, filtered, and the aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to afford 22A (235 mg, 28%). MS (ES): m/z=193 [M+H]+.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[CH3:14][C:15]1[C:19]([C:20]2[CH:21]=[C:22]([CH:39]=[O:40])[C:23]3[N:27]=[C:26]([O:28][CH2:29][CH3:30])[N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]=3[CH:38]=2)=[C:18]([CH3:41])[O:17][N:16]=1>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:39]([C:22]1[C:23]2[N:27]=[C:26]([O:28][CH2:29][CH3:30])[N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C:24]=2[CH:38]=[C:20]([C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[CH3:41])[CH:21]=1)=[O:40]
Reactant: CCOc1nc2c(C=O)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: Fc1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1nc2c(C(=O)c3c(F)cccc3F)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi (0.58 mL, 0.93 mmol) was added dropwise to a solution of 1,3-difluorobenzene (0.102 mL, 0.1 mmol) in THF (5 mL) cooled to −78° C. and allowed to stir for 1 hour. tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate (200 mg, 0.52 mmol) in THF was added and the reaction was allowed to stir for 5 mins at −78° C., quenched with ammonium chloride, extracted with EtOAc and concentrated. The crude was then taken up in DCM (2 mL), Des-Martin periodinane (290 mg, 0.78 mmol) was added and the reaction was allowed to stir for 15 mins. The reaction was quenched with sat. Na2S2O3, extracted with EtOAc, concentrated and purified by silica gel chromatography to give tert-butyl 4-(2,6-difluorobenzoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14]O)[CH2:9][CH:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][Cl:26])[CH2:9][CH:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1

Procedure:
24 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-hydroxy ethyl) piperazine are dissolved in 150 cc. of chloroform and added drop by drop to a solution of 15 g. of thionyl chloride in 150 cc. of chloroform. The mixture is boiled under reflux for 5 hours and the solvent is removed in a vacuum by heating the mixture in a water bath. Excess of absolute ethanolic hydrochloric acid is added and the remaining acid is distilled off. The crystalline residue obtained is recrystallized from absolute ethanol. Melting point 178°-195° C. (dec.); yield 30 g.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:16]=2[N:17]=1>>[BrH:1].[Br:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]3[CH:2]=[C:3]([C:5]4[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=4)[N:12]=[C:13]3[S:14][C:15]=2[CH:21]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1nc2ccc(Br)cc2s1
Product: Br
Product: Cc1ccc(-c2cn3c(n2)sc2cc(Br)ccc23)cc1
Yield: 24 %

Procedure:
The title compound is prepared from 2-bromo-4′-methylacetophenone and 2-amino-6-bromobenzothiazole using method B in 24% yield: mp 205-208° C.; 1H-NMR (DMSO-d6) 2.31 (s, 3H), 7.23 (d, 2H), 7.73 (m, 3H), 7.91 (d, 1H), 8.32 (s, 1H), 8.70 (s, 1H); HR-MS (EI) m/z 341.9822 (M+).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([CH3:35])([CH3:34])[C:14]([N:16]([CH3:33])[C:17]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O>O1CCCC1.FC(F)(F)C(O)=O>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[C:17]([N:16]([CH3:33])[C:14](=[O:15])[C:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=2)([CH3:34])[CH3:35])[CH:22]=1
Reactant: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1ccc(N)cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a solution of 950 mg (1.81 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2′-methyl-4-nitro-biphenyl-2-yl)isobutyramide in 12 ml tetrahydrofuran and 3 ml water 608 mg (10.87 mmol) iron powder and 3 drops trifluoroacetic acid were added. After heating at 85° for 3 hrs., the reaction mixture was cooled to room temperature and evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate 1:4) to give 890 mg (99%) N-(4-amino-2′-methyl-biphenyl-2-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as pale yellow crystals, MS (ISP):495.2(M+H)+.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:31]OCCOC.[N+](=C)=[N-]>C(O)(=O)C.CCOCC>[CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([O:28][CH3:31])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)O)CC2=O)c1
Reactant: COCCOC
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)OC)CC2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 415 mg. of N-decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)propenamide and 15 ml. of 1,2-dimethoxyethane is added a solution of 1.5 mmoles of diazomethane in 5 ml. of ether. The reaction mixture is stirred at room temperature for 16 hours, and then the excess diazomethane is decomposed by the addition of a few drops of acetic acid. The total solvents are removed by evaporation in vacuo, and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with 1 N sodium hydroxide, followed by water, followed by saturated sodium chloride solution, and then dried using sodium sulfate. Evaporation of the dried ethyl acetate solution in vacuo affords the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.O>C(O)(C)C>[CH2:15]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc2ccnn2c(Cl)c1CCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1nc2ccnn2c2c1CCN2Cc1ccccc1
Yield: 59.6 %

Procedure:
A solution of 1.15 g (5 mmoles) of 7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1,5-a]pyrimidine (prepared as described in Example 3), 643 mg (6 mmoles) of benzylamine and 2 ml of triethylamine dissolved in 5 ml of isopropanol was heated under reflux for 7 hours, with stirring. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was extracted with 5% by volume aqueous sulfuric acid, and the extract was made basic by the addition of sodium carbonate. The crystals which precipitated were collected by filtration and washed with water. They were then purified by column chromatography through silica gel (eluted with chloroform) and recrystallized from a mixture of ethyl acetate and chloroform, to afford 788 mg (yield 60%) of the title compound as colorless needles, melting at 130°-130.5° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]=[CH2:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].[OH-].[Na+].C1(O)C=CC=CC=1.Cl[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl>C(O)C.O>[CH2:25]([O:26][CH2:27][CH2:28][O:13][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:10][CH:11]=[CH2:12])[CH3:24]
Reactant: ClCCOCCCl
Reactant: C=CCc1cccc(CC=C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: O
Solvent: CCO
Product: C=CCc1cccc(CC=C)c1OCCOCC
Yield: 69 %

Procedure:
2,6-Diallylphenol (5.2 g, 0.03 mol) was diluted with 95% ethanol (50 ml). Sodium hydroxide (1.4 gm, 0.03 mol) was added to the phenol solution followed by 2-chloroethylether (3.8 gm, 0.035 mol). The reaction mixture was refluxed for 48 hrs, cooled, diluted with water, extracted with hexane and dried over MgSO4. Filtration of the MgSO4 and evaporation of the hexane gave 5.1 g of 2,6-diallylphenyl ethoxyethyl ether. MS m/z 246 (M+ calcd for C16H22O2=246). H NMR (300 MHz, CDCl3) d 1.30 (3, t, CH3), 3.40–3.55 (4, m, CH2 allyl), 3.65–3.75 (2,q, OCH2 methyl), 3.80 (q, 2, OCH2), 4.00(q, 2, OCH2), 5.05–5.25 (m, 4, CH2 vinyl), 5.90–6.20 (m, 2, CH vinyl), 7.05–7.20 (m, 4, CH2 vinyl), 7.05–7.20 (m, 3, aromatic). Oxidation of the product as described in Example 1 gave 2,6-di-(2,3-epoxypropyl)phenyl ethoxyethyl ether as an oil. MS m/z 278 (M+ calcd for C16H22O4=278). H NMR (300 MHz, CDCl3) d 1.25 (t, 3, CH30, 2.65–2.85 (m, 4, epoxypropyl CH2), 2.90–3.15 (m, 4, epoxypropyl CH2), 3.21–3.35(m, 2, epoxypropyl CH), 3.65 (q, 2, OCH2), 3.80 (q, 2, OCH2), 4.00 (q, 2, OCH2), 5.33 (s, 3, OCH3), 7.05–7.33 (m, 3, aromatic).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[C:19]([F:22])([F:21])[F:20]>C1CCCCC1>[CH:1]1([NH:4][C:10]2[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]([C:19]([F:20])([F:21])[F:22])=[C:6]([Cl:5])[C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: C1CCCCC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1NC1CC1

Procedure:
The compound was prepared by eacting cyclopropylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in cyclohexane to give the product having a melting point of 86° - 87°C.
Reaction SMILES: [Cl:1][C:2]1[S:32][C:5]2[C:6]3([CH2:16][CH2:15][N:14]([CH2:17][C:18]4[C:19]([CH3:31])=[N:20][N:21]([C:23]5[N:30]=[CH:29][CH:28]=[CH:27][C:24]=5[CH:25]=[O:26])[CH:22]=4)[CH2:13][CH2:12]3)[O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:48][N+:49]#[C-:50])(=O)=O)=CC=1>CO>[Cl:1][C:2]1[S:32][C:5]2[C:6]3([CH2:12][CH2:13][N:14]([CH2:17][C:18]4[C:19]([CH3:31])=[N:20][N:21]([C:23]5[C:24]([C:25]6[O:26][CH:50]=[N:49][CH:48]=6)=[CH:27][CH:28]=[CH:29][N:30]=5)[CH:22]=4)[CH2:15][CH2:16]3)[O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nn(-c2ncccc2-c2cnco2)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 65 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a screw-cap test tube containing 2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)nicotinaldehyde (0.120 g, 0.25 mmol) in methanol (2.5 mL) are added potassium carbonate (0.104 g, 0.75 mmol) and p-toluenesulfonylmethyl isocyanide (0.054 g, 0.28 mmol) under nitrogen. The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and is stirred in a preheated oil bath at 65° C. for 3 hr. with the aid of a magnetic stirrer. The mixture is diluted with methanol and purified using a 2 g SCX cartridge. The solvent is evaporated in vacuo. The resulting residue is purified by normal phase Isco chromatography eluting with hexane/ethanol (5-30%) to give 0.093 g of the title compound. MS (m/z): 518 (M+1)
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])(C)(C)C.CN1CCCN(C)C1=O.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]
Reactant: Brc1cccs1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]C(C)(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: OCCCCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-bromothiophene (0.341 g, 2.09 mmol) in tetrahydrofuran (30 ml) under argon at -78° was added t-butyl lithium (2.53 ml of a 1.7M solution) followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.268 g, 2.09 mmol). To this mixture was added 1-bromo-8-t-butyldimethylsiloxyoctane (0.615 g, 1.90 mmol in tetrahydrofuran (10 ml). After gradual warming followed by stirring at room temperature for 18 hours, the mixture was concentrated, taken up in ethyl ether and washed consecutively with cold 10% hydrochloric acid, saturated sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. To this residue in tetrahydrofuran (20 ml) at 0° was added tetrabutylammonium fluoride (8.4 ml of a 1.0M solution). After stirring for 16 hours at room temperature the mixture was concentrated, taken up in ethyl ether and washed with 10% hydrochloric acid, saturated sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. Further purification by flash chromatography (silica, 30% ethyl acetate/hexane) give the desired alcohol.
Reaction SMILES: [CH3:1][CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[NH2:9][C:10]([NH2:12])=[O:11]>C(O)C.Cl>[OH:11][C:10]1[N:12]=[C:6]([CH3:7])[C:2]([CH3:1])=[C:3]([CH3:4])[N:9]=1
Reactant: NC(N)=O
Reactant: CC(=O)C(C)C(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1nc(O)nc(C)c1C

Procedure:
To 3.65 g (32 mmol) of 3-methyl-2,4-pentanedione in ethanol (15 ml) was added urea (1.92 g; 32 mmol) followed by 3 drops concentrated HCl. This mixture was refluxed under N2 overnight (12 hours). Upon cooling a solid separated which was filtered off and washed with cold ethanol and ethyl ether. Drying on the pad gave an off-white tlc pure solid. NMR (d6 -DMSO, δ from TMS): 1.94(S, 5-CH3), 2.22(S, 4, 6 -CH3S), 5.47 (br S, OH). Mass spectroscopy showed M+ at m/e 138.
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].[P:25](=O)([OH:28])([OH:27])[OH:26]>>[CH:22]1([N:14]2[C:3]3[C:2](=[CH:1][C:6]([F:7])=[C:5]([N:8]4[CH2:9][CH2:10][N:11]([P:25]([OH:28])([OH:27])=[O:26])[CH2:12][CH2:13]4)[CH:4]=3)[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[CH2:23][CH2:24]1
Reactant: O=P(O)(O)O
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(P(=O)(O)O)CC3)c(F)cc2c1=O

Procedure:
To a stirred solution of 2.34 g of the product of Example 40 in 25 ml of methylene chloride under argon was added 2.57 g of N,O-bis(trimethylsilyl)triflouroacetamide and then (after 10 minutes) 2.68 g of bromotrimethylsilane. After 17 hours, the solution was evaporated to dryness at 40° C./0.02mm. The evaporation was then repeated twice after redissolving the residue in 25 ml portions of methylene chloride. A solution of the residual solid in 25 ml of methylene chloride was added to a stirred solution of 1 ml of water in -00 ml of acetone and then stirred for 15 minutes, to hydrolyze silyl ester groups. The resulting solid was collected and washed with acetone to give 2.24 g of cream-colored solid, m.p. 246°-252° (dec.); 31P-NMR (in DMSO with 5% triethylamine) δ 9.34 compared to δ 0.54 (at 50° C.) for a salt of ciprofloxacin with an equimolar amount of phosphoric acid, and δ0 0.35 for phosphoric acid. The product was soluble in 0.1 M phosphate buffer, pH 7.5, unlike ciprofloxacin.
Reaction SMILES: [S:1]([O:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].[NH2:23]Cl.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:23][N:14]1[CH:15]=[CH:16][C:12]([O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])=[C:13]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: NCl
Reactant: COC(=O)c1[nH]ccc1OS(=O)(=O)c1ccc(C)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(OS(=O)(=O)c2ccc(C)cc2)ccn1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Solid methyl 3-(tosyloxy)-1H-pyrrole-2-carboxylate (1.33 μm, 4.50 mmole) was added in portions to an ice-cooled suspension of NaH (60% in mineral oil, 234 mg, 5.85 mmole) in dry DMF (15 mL) under a dry N2 atmosphere. Upon completion of the addition, the reaction was removed from the bath and left stirring at RT. After 1 hr, a solution of NH2Cl (59 mL; 0.1 M in Et2O prepared according to J. Chem. Soc. C, 1971, 824; 5.85 mmole) was added and the reaction was left stirring for 1.3 hr. It was then cooled to −5° C. and an aqueous solution of Na2S2O4 (20 mL, 1.0 M) was slowly added over 5 min. Water (60 mL) was added and the bath was removed. After 10 min, this was extracted with EtOAc (2×200 mL) and the organic extracts were washed with brine and dried (Na2SO4). Removal of the solvents followed by flash chromatography on silica gel using step gradient elution (hexane:EtOAc from 100:0 to 70:30) afforded the title compound (1.22 gm, 88% yield) as a solid. 1H NMR (CDCl3): 2.39 (s, 2H), 3.62 (s, 3H), 5.44 (s, 2H), 5.76 (m, 1H), 6.73 (m, 1H), 7.26 (m, 2H), 7.66 (m, 2H); MS: 311 (M+H)+; HPLC Ret Time: 1.28 min (YMC Xterra S7 3.0×50 mm column, 2 min gradient, 5 mL/min).