Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH2:6][CH2:5]1.[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>C(#N)C>[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([C:11]([NH:10][C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:3][OH:2])[CH2:9][CH2:8]3)=[O:12])[CH2:14]2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: O=C(N[C@H]1CC[C@H](CO)CC1)[C@H]1CCCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)N[C@H]2CC[C@H](CO)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3S)—N-[trans-4-(hydroxymethyl)cyclohexyl]piperidine-3-carboxamide hydrochloride (170 mg, 0.61 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (138 mg, 0.61 mmol), and triethylamine (0.21 mL, 1.54 mmol) in acetonitrile (3 mL) was stirred at r.t. for 2 hours. After removal of solvent, the residue was loaded on flash column with methylene chloride and eluted with ethyl acetate-hexane. 110 mg final product was obtained. (Yield: 41%). LCMS: m/z 429.0 (M+H)+; 879.2 (2M+Na)+.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:37])[N:29]([CH2:33][C:34](=[O:36])[NH2:35])[CH:30]([CH3:32])[CH3:31])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:34]([CH2:33][N:29]([CH:30]([CH3:32])[CH3:31])[C:28]([C:26]1[N:27]=[C:23]([N:21]2[CH2:20][CH:19]([OH:18])[CH2:22]2)[S:24][CH:25]=1)=[O:37])(=[O:36])[NH2:35]
Reactant: CC(C)N(CC(N)=O)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)N(CC(N)=O)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 66.7 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]azetidine (6.52 g, 11.8 mmol) (obtained as described in Reference Example 49(3)) in anhydrous tetrahydrofuran (326 ml) was added a 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (14.2 ml, 14.2 mmol) in an ice bath, and the mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]-3-hydroxyazetidine (2.35 g, yield 67%) as a white solid.
Reaction SMILES: O.NN.[F:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]#[C:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=[CH:8][CH:7]=1.C(Cl)Cl>CCO>[F:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]#[C:13][CH2:14][CH2:15][NH2:16])[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC#Cc1cccc(CF)n1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: NCCC#Cc1cccc(CF)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
Hydrazine hydrate (1.0 mL, 5.2 mmol) was added to a solution of 2-(4(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.04 mmol) in EtOH (3 mL) and the reaction mixture was stirred for 4 hours at 50° C. The mixture was cooled down, DCM was added and the aqueous phase was extracted. The organic phase was washed with saturated solution of NaHCO3, dried over Na2SO4; filtered and concentrated to yield 117 mg (0.66 mmol, 630%) of 4(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:18])[F:19])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([N:36]4[CH2:37][CH2:38][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:35]4)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)O)c4)cc3N2)cc1OC
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c4)cc3N2)cc1OC
Yield: 51.8 %

Procedure:
Example ER-896388 was prepared in two steps from 3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoic acid (25 mg, 0.056 mmol) and commercially available tert-butyl piperazine-1-carboxylate (42 mg, 0.224 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl 4-(3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)piperazine-1-carboxylate (18 mg, 0.029 mmol, 52% yield). Then, this intermediate (16 mg, 0.026 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-896388 (14 mg, 98% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:27]([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([CH:24]5[CH2:26][CH2:25]5)=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:6]([CH3:8])[N:7]=2)[C:31]1=[O:35])(=[O:29])[CH3:28]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2C)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)c(C)n2)C1=O
Yield: 75.1 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (208 mg) described in Preparation Example 249 and 1-acetylimidazolidin-2-one (77 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (174 mg) was obtained.
Reaction SMILES: O1CCCC1.[CH:6]([OH:9])([CH3:8])[CH3:7].[H-].[Na+].[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39]Br>O>[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39][O:9][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)O
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To 2 ml of dehydrated tetrahydrofuran solution containing 1 ml of isopropanol was added 155 mg of sodium hydride (55% dispersed material in mineral oil), the mixture was stirred at room temperature for 20 minutes, then, 272 mg (0.48 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was further added to the mixture, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 176 mg of the title compound as a colorless oil. (Yield: 67%)
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:25]([O:27][CH2:28][C:29]#[CH:30])=[O:26]>>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:25]([O:27][CH2:28][C:29]#[CH:30])=[O:26])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[NH:16]1
Reactant: C#CCOC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Product: C#CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Yield: 9.5 %

Procedure:
Following the procedure used in example 16 and starting from (3aS,7aS)-3-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-one (HCl salt, 181 mg, 0.51 mmol) and prop-2-ynyl chloroformate (0.050 mL, 0.51 mmol), the title compound (19.40 mg, 9.50%) was obtained after purification by preparative LC/MS (high pH). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.29-1.47 (m, 5H), 1.49 (s, 3H), 1.76-2.01 (m, 8H), 2.29-2.44 (m, 2H), 2.82 (t, J=9.96 Hz, 5H), 2.90 (d, J=10.55 Hz, 2H), 3.03 (d, J=6.64 Hz, 1H), 3.68 (t, J=9.57 Hz, 2H), 4.06-4.17 (m, 1H), 4.27 (d, J=19.53 Hz, 2H), 4.52 (s, 1H), 4.69 (s, 1H), 4.76 (s, 1H). MS (M+1): 403.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH2:18][N:17]2[N:13]([C:14](=[O:38])[CH:15]([NH:19][C:20](=[O:37])/[C:21](/[C:25]3[N:26]=[C:27]([NH:30]C(OCC=C)=O)[S:28][CH:29]=3)=[N:22]\[O:23][CH3:24])[CH2:16]2)[C:12]=1[C:39]([O:41]CC=C)=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([SnH](CCCC)CCCC)CCC.Cl>C(#N)C.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O>[CH2:1]([O:8][C:9]([C:11]1[CH2:18][N:17]2[N:13]([C:14](=[O:38])[CH:15]([NH:19][C:20](=[O:37])/[C:21](/[C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:22]\[O:23][CH3:24])[CH2:16]2)[C:12]=1[C:39]([OH:41])=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)NC2CN3CC(C(=O)OCc4ccccc4)=C(C(=O)OCC=C)N3C2=O)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CC#N
Product: CO/N=C(\C(=O)NC1CN2CC(C(=O)OCc3ccccc3)=C(C(=O)O)N2C1=O)c1csc(N)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, allyl 3-(benzyloxycarbonyl)-7-(R,S)-[2-(2-(allyloxycarbonylamino)thiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-8-oxo-1,5-diazabicyclo[3,3.0]octa-2-ene-2-carboxylate (340 mg, 0.54 mmol) was suspended in a mixture of acetonitrile (10 ml) and diethyl ether (5 ml) then palladium(II) acetate (6.1 mg, 0.027 mmol,) and triphenylphosphine (56.7 mg, 0.216 mmol,) were added. Acetone (20 ml) was added and the resultant solution was stirred for 30 minutes at room temperature then cooled to 0° C. Tri(n-butyl)tin hydride (0.3 ml, 1.1 mmol) was added and the solution was stirred for 1.5 hours at room temperature. 12N hydrochloric acid (0.09 ml, 1.1 mmol) was added and the solution was concentrated in vacuo. The resultant residue was dissolved in methylene chloride, diethyl ether was added to effect precipitation and the precipitate was collected by filtration to give 3-(benzyloxycarbonyl)-7-(R,S)-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-8-oxo-1,5 -diazabicyclo[3.3.0]octa-2-ene-2-carboxylic acid: n.m.r. (90 MHz, DMSO-d6): δ 2.60-4.14 (m, 5), 3.76 (s, 3), 4.64-5.20 (m, 2), 5.04 (s, 2), 7.12 (br. s, 2), 7.24 (br. s, 5), 9.01 (br. d, 1, J=7); i.r. (KBr): 3417, 1696, 1662, 1617, 1521, 1442, 1396, 1380, 1331, 1272 cm-1 ; u.v. (EtOH); λmax =231 (ε=15547), 329 (ε=11296); m.p. d>160° C.°, f.a.b.m.s. (m/e) M+1=501.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
To a mixture of ethyl N-Boc-piperidine-4-carboxylate (0.5 mol) and ethyl acetate (3 mol) t-BuOK (1.5 mol) was added in some portions at 0 C. The mixture was stirred at room temperature for 3 h (monitored by TLC), concentrated up to a half of volume, diluted with water (200 mL) and extracted with ether. Organic layer was dried over sodium sulfate and evaporated in vacuo. Purification by column chromatography (silica gel, ethyl acetate/hexane) afforded 4-(2-ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (78 g, 52%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Cc1ccc2cc(N)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2cc(NS(=O)(=O)c3cc(Cl)ccc3Cl)ccc2n1
Reaction time: 0.08 h
Yield: 51.7 %

Procedure:
To a solution of 2,5-dichlorobenzenesulphonyl chloride (163 mg, 0.664 mmol) in dichloromethane (4 mL) was added pyridine (130 μL, 1.58 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoline (100 mg, 0.632 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (120 mg, 52%), single spot at Rf 0.68 (ethyl acetate). mp 124.6-125.0° C., HPLC purity 99+% (tR 2.22 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.98 (1H, d, 2.2 Hz), 7.94 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=8.9 Hz), 7.57 (1H, d, J=2.2 Hz), 7.45-7.35 (3H, m), 7.27-7.24 (2H, m), 2.68 (3H, s). LCMS: 365.10 (M−). FAB-MS (MH+, C16H12Cl2N2O2S): calcd 367.0075, found 367.0074.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)[CH3:2].CN(C)C(=N)N(C)C.[F:24][C:25]([F:32])([F:31])[C:26](OCC)=[O:27]>CO>[CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH:10][C:26](=[O:27])[C:25]([F:32])([F:31])[F:24])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: CO
Product: CCOc1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reaction time: 48 h

Procedure:
O-Ethyl-L-tyrosine (IV, EXAMPLE 3, 20.9 g, 100 mmol) is suspended in methanol (100 mL), tetramethylguanidine (TMG) (12.5 mL, 100 mmol) is added, followed by ethyl trifluoroacetate (14 mL, 120 mmol). The mixture is stirred at 20-25 deg for 48 hr and the resulting mixture is concentrated to remove most of the methanol and excess ethyl trifluoroacetate. The residue is dissolved in water (40 mL), added hydrochloric acid (100 mL of 1.0 M) to adjust the pH<3. The mixture is stirred at 20-25° for at least 2 hr, then filtered. The precipitate is suspended in water (50 mL), stirred for 0.5 hr, then filtered. This wash process is repeated once. Then the precipitate is dried in oven at 55° for 48 hr to give the title compound, NMR (DMSO-d6) δ12.9, 9.72, 7.15, 6.82, 4.46, 3.98, 3.15, 2.92 and 1.31; CMR (DMSO-d6) δ171.8, 157.6, 157.7, 130.3, 129.0, 116.1, 63.2, 54.6, 35.1 and 15.0; FMR (DMSO-d6) δ-74.7; HRMS (FAB) calculated for C13H14F3NO4 [M+1]=306.0953, found=306.0952.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].Cl>N1C=CC=CC=1.C(Cl)Cl>[OH:1][C@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC[C@H](O)CO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CC#N)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
(3S)-3,4-Dihydroxybutyronitrile (161.8 g, 1.6 mol) was dissolved in pyridine (260 ml). To the resulting solution, a solution of tosyl chloride (396.6 g) in methylene chloride (1.6 liters) was added at 0° C. and stirred at 0° C. for 5 hours. Then, the pH of the mixture was adjusted at 2 with 6N hydrochloric acid, and the mixture was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated off. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain (3S)-3-hydroxy-4-p-toluenesulfonyloxybutyronitrile (85.9 g). Yield, 70 %.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11]C(=O)C(F)(F)F)=[C:4]([CH:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[C:3]=1[F:23].O1CCOCC1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[C:3]=1[F:23]
Reactant: O=C(Nc1c([N+](=O)[O-])cc(Br)c(F)c1C1CCCO1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1c([N+](=O)[O-])cc(Br)c(F)c1C1CCCO1
Yield: 98.6 %

Procedure:
A reaction flask was charged with N-(4-bromo-3-fluoro-6-nitro-2-tetrahydrofuran-2-yl-phenyl)-2,2,2-trifluoro-acetamide (18) (242.3 g, 604.1 mmol), 1,4-dioxane (1.212 L), aqueous 2 M sulfuric acid (362.4 mL, 724.9 mmol), and stirred at reflux for 5 days (HPLC showed 98% conversion). Allowed to cool, diluted with EtOAc, neutralized with saturated aqueous NaHCO3, separated the layers, and re-extracted the aqueous phase with EtOAc (2×). The combined organic phase was washed with brine (2×), dried over MgSO4, filtered and concentrated in vacuo giving 19 as a greenish brown solid (181.7 g, 94% yield; 95% HPLC purity). The product was carried to the next step without further purification. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 305.20 (3.63 min). 1H NMR (300 MHz, CDCl3) δ 8.35 (d, J=7.3 Hz, 1H), 7.45 (s, 2H), 5.23-5.16 (m, 1H), 4.23-4.14 (m, 1H), 3.93-3.84 (m, 1H), 2.31-1.96 (m, 4H) ppm.
Reaction SMILES: [OH2:1].Cl.Cl.O.Cl.Cl.NC1N=CN=C2C=1N=CN2[C@@H]1O[C@H](C(O)=O)[C@@H](N[C:27](=[O:39])[C@H:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[NH2:29])[C@H]1O>Cl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C@@H:28]([C:27]([OH:39])=[O:1])[NH2:29])=[CH:36][CH:35]=1
Reactant: O
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Agent: Cl
Product: COc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
A suspension of dihydrochloride monohydrate of FR-48736 substance [1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid dihydrochloride monohydrate] (300 mg) prepared by Example 98 in 6N hydrochloric acid (20 ml) was refluxed for 12 hours. The resulting solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in water (30 ml) and the solution was adjusted to pH 7 with 1N sodium hydroxide. Then, the solution was applied to a column of Diaion HP 20 (200 ml). The column was washed with water (400 ml) and eluted with a mixture of methanol and water (3:7, 200 ml). The solvent was evaporated under reduced pressure. The residue was chromatographed on a cellulose column and eluted with a mixture of acetonitrile and water (8:2). The fractions containing the object compound were combined and the solvent was evaporated under reduced pressure to give O-methyl-L-tyrosine (30 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:22][C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc(I)ccn1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccnc(C)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 4-iodo-2-methylpyridine (0.07 mL, 0.59 mmol) according to the general procedure IF to give 62 mg (44%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5): Rf=0.50 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 8.48-8.46 (m, 1H), 7.48-7.45 (m, 2H), 7.25-7.20 (m, 4H), 3.67 (s, 3H), 2.98 (t, J=7.8 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H), 2.56 (s, 3H); 13C NMR (CDCl3) δ 173.1, 158.6, 149.3, 142.0, 132.1, 131.8, 128.6, 125.1, 122.7, 120.3, 93.4, 86.9, 51.8, 35.4, 31.0, 24.5; ESI-MS m/z 302.1 (M+Na+).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[Cl:12])=[O:3].[N+:13]([O-])([OH:15])=[O:14]>>[CH3:1][C:2]([NH:4][C:5]1[C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[Cl:12])=[O:3]
Reactant: CC(=O)Nc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nitric acid (30 ml) is cooled to -5°, and N-methylcarbonyl 2,3-dichloroaniline (9.8 g, 48 mmol) is added to the acid in small portions, with the temperature maintained at -5° or lower. After the addition is complete, the reaction is stirred for 1 hour at +5°. The reaction is then added dropwise to about 150 g of ice-water mixture. The resulting solid is collected by filtration and purified by prep. TLC (developing with 30% ethyl acetate/hexane). The least polar component is isolated to give N-methylcarbonyl 2,3-dichloro-6-nitroaniline.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5]CC)C>Cl>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:3])([OH:5])[OH:8])=[CH:11][CH:12]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOP(=O)(Cc1ccc(C(=O)c2ccccc2)cc1)OCC
Agent: Cl
Product: O=C(c1ccccc1)c1ccc(CP(=O)(O)O)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A mixture of 4.8 g of 4-benzoylbenzyl bromide and triethylphosphite was heated at 125° C. for 0.5 hours and cooled to room temperature. The resulting oil was purified by flash chromatography (70% ethyl acetate/hexanes) to afford 3.2 g of diethyl 4-benzoylbenzylphosphonic acid, as an oil. A mixture of 3.2 g (9.6 mmol) of diethyl 4-benzoylbenzylphosphonic acid and 40 ml of concentrated hydrochloric acid was refluxed for 7 hours and cooled to room temperature. The two phase mixture was partitioned between 125 ml of water and 400 ml of EtOAc, the EtOAc layer was dried over Na2SO4, filtered and evaporated to give 0.7 g of product; m.p. 172°-175° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1.C1(C)C(C)=CC=CC=1.N([C:25]1[NH:26][CH2:27][CH2:28][N:29]=1)[N+]([O-])=O>CC(C)=O>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[Cl:10])[CH:3]([OH:12])[CH2:2][NH:1][C:25]1[NH:29][CH2:28][CH2:27][N:26]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCC(O)c1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1ccc(Cl)c(Cl)c1
Temperature: 160 °C

Procedure:
To a stirred solution of 8 parts of α(aminomethyl)-3,4-dichlorobenzyl alcohol in 4.5 parts of xylene are added 5.2 parts of 2-(nitramino)-2-imidazoline. The whole is heated in an oil-bath at a temperature of about 160°C. till a clear melt is obtained (about 15 minutes). After cooling to about 60°C., the melt is dissolved in acetone and allowed to crystallize. The precipitated product is filtered off and recrystallized from 20 parts of 4-methyl-2-pentanone, yielding 3,4-dichloro-α-(2-imidazolin 2-ylaminomethyl)benzyl alcohol; m.p. 148°C.