Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)C(O[CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1>CC(C)=O>[N:29]1([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:27])[N:11]3[C:12]=2[C:13]([OH:15])=[O:14])[CH:33]=[CH:32][CH:31]=[N:30]1
Reactant: c1cn[nH]c1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cn3cccn3)CS[C@H]12

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (3.2 g., 6.9 mmole.) was dissolved in 50%-aqueous acetone (60 ml.). and treated with pyrazole (1.6 g., 24 mmole.), and the solution heated at 50° for 35 minutes. The acetone was removed under reduced pressure, and the aqueous residue was extracted with ether (9 × 20 ml.). After drying, the ether was evaporated and the solid residue recrystallised from aqueous alcohol (1.3 g., 47%), mp. 180°-185° (decomp) [α]D30 = 53.5° (c 1.01, ethanol), λmax (ethanol) 236 nm. (β 14,000), 261 nm. (ε = 8,250) (shoulder), νmax (Nujol) 3272 (--NH), 1773 (β-lactam), 1712 (--COOH), 1660 and 1532 cm-1 (--CONH--). (Found: C, 50.9; H, 4.2; N, 13.9; S, 15.7. C17H16N4S2O4 requires C, 50.5; H, 4.0; N, 13.9; S, 15.9%). N.M.R. (D2O, with NaHCO3) 2.30, 3.62, 2.41τ (-N-CH=CH-CH=N), Rf 0.37 (Systems B), 0.12 (System C).
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[CH:16]=[C:15]([N:17]=[C:18]=[O:19])[CH:14]=[C:13]([Cl:20])[N:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([N:17]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:18]2=[O:19])[CH:14]=[C:13]([Cl:20])[N:12]=1
Reactant: CCOC(=O)CNC
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: CN1CC(=O)N(c2cc(Cl)nc(Cl)c2)C1=O
Temperature: 5 °C
Reaction time: 96 h
Yield: 155.4 %

Procedure:
TEA (7.2 ml, 51 mmol) was added to a suspension of the HCl salt of sarcosine ethyl ester (3.4 g, 24.5 mmol) in dry DCM (80 ml). The formed triethylamine hydrochloride was filtered off and rinsed with DCM (20 ml). The filtrate was transferred into a 3-necked round bottom flask and cooled to 5° C. A solution of 2,6-dichloropyridin-4-yl isocyanate (10 g, 53 mmol) in DCM (25 ml) was added dropwise over 10 min while keeping the inner temperature below 10° C. After 96 h at RT, the reaction mixture was refluxed for 10 h. After cooling to RT, the solution was washed with brine, dried over MgSO4 and concentrated. The obtained amorphous solid was chromatographed over silica gel (eluent: cyclohexane/EtOAc 80/20 to 50/50) to yield the above titled compound as a white solid (9.9 g). mp=134° C. 1H NMR (CDCl3): 7.75 (2H, s), 4.07 (2H, s), 3.10 (3H, s).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[OH-].[K+].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCO>[C:5]([O:4][C:3]([NH:2][O:1][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:9])([CH3:8])([CH3:7])[CH3:6]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)OC(=O)NO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)ONC(=O)OC(C)(C)C

Procedure:
To a solution of t-butyl hydroxycarbamate (530 mg, 3.98 mmol) and potassium hydroxide (223 mg, 3.98 mmol) in EtOH (10 mL) was added ethyl 2-bromopropanoate (600 mg, 3.31 mmol) slowly at rt. The reaction mixture was heated at reflux overnight. White precipitate was filtered off and the filtrate was concentrated. The resulting residue was dissolved in ether, washed with water and brine, and dried over Na2SO4. Solvent was evaporated to afford the title compound as a clear oil which was used in the next step without further purification (825 mg, 100%). 1H-NMR (400 MHz, CDCl3) δ ppm 7.62 (s, 1H), 4.46 (q, 1H), 4.24 (q, 2H), 1.46 (d, 3H), 1.48 (s, 9H), 1.28 (t, 3H).
Reaction SMILES: C([O-])(=O)C.[Tl+3].C([O-])(=O)C.C([O-])(=O)C.[F:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:26])[C:22]([O:24]C)=[O:23])[CH:18]=[CH:17][C:16]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C.CCCCCC>[F:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:26])[C:22]([OH:24])=[O:23])[CH:18]=[CH:17][C:16]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Agent: CC(=O)[O-]
Agent: [Tl+3]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
Following the procedure of Example 2, the enol ether of the formula ##STR9## is reacted with thallium (III) acetate in an aqueous acetic acid/hexane mixture at 25° to 50° C. until methyl 2-(2-fluoro-4-biphenylyl)propionate is formed. This ester is isolated from the reaction mixture and hydrolyzed to 2-(2-fluoro-4-biphenylyl)propionic acid (generic name, flurbiprofen) by the described procedure.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([O:17]C)[C:8]3[CH:12]=[C:11]([Br:13])[S:10][C:9]=3[C:14]([O:15]C)=[C:4]2[CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:13][C:11]1[S:10][C:9]2[C:14]([OH:15])=[C:4]3[CH:3]=[C:2]([Br:1])[S:6][C:5]3=[C:7]([OH:17])[C:8]=2[CH:12]=1
Reactant: COc1c2cc(Br)sc2c(OC)c2cc(Br)sc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1c2cc(Br)sc2c(O)c2cc(Br)sc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2,6-Dibromo-4,8-dimethoxy-benzo[1,2-b:4,5-b′]dithiophene (500 mg, 1.22 mmol., 1.00 equiv.) and dichloromethane (12 mL) were added to a 50 mL schlenk flask. The mixture was cooled to −78° C. and boron tribromide was added (1.0 M solution in dichloromethane, 2.5 mL, 2.5 mmol., 2.1 equiv.) slowly. The mixture was stirred for 15 minutes at −78° C. before replacing the dry/ice acetone bath with an ice/water bath. The reaction mixture was left to warm to room temperature while stirring for 16 hours before cooling to 0° C. Water (dropwise at first, 150 mL total) and additional dichloromethane (50 mL) were added. The dichloromethane was removed on the rotary evaporator and the solid was collected by filtration. The solid was washed with water (25 mL) and dichloromethane (25 ml) to give a pale blue/green crude solid to be dried under vacuum and used in the next step without additional purification (287 mg). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 2H), 7.71 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:4]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:15]1([CH2:2][C:3]2[CH:8]=[N:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][N:4]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: BrCc1cnc(-c2ccccc2)cn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2cnc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using compound 71a (100 mg, 0.40 mmol), imidazole (109 mg, 1.60 mmol) and K2CO3 (276 mg, 2.00 mmol) in DMF according to Method B. Crude product was purified by flash chromatography on silica-gel using ethyl acetate as eluent. Light yellow solid. Yield: 69 mg, 73%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.50 (s, 2H), 7.24 (t, J=1.3 Hz, 1H), 7.33 (t, J=1.1 Hz, 1H), 7.64-7.74 (m, 3H), 7.86 (s, 1H), 8.17-8.23 (m, 2H), 8.63 (d, J=1.3 Hz, 1H), 9.18 (d, J=1.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=50.0, 119.2, 126.9, 129.1, 130.2, 130.3, 135.7, 137.5, 141.5, 142.3, 152.3; (ESI): m/z=236.91 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH2:21][CH2:22][CH3:23])[NH:13][C:12]2=[N:24][NH:25][CH:26]=[C:11]12)([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH2:21][CH2:22][CH3:23])[NH:13][C:12]2=[N:24][NH:25][CH:26]=[C:11]12
Reactant: CCCC1=C(C(=O)OCC)C(c2ccccc2[N+](=O)[O-])c2c[nH]nc2N1
Agent: [Pd]
Solvent: CO
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2N)c2c[nH]nc2N1
Reaction time: 3 h
Yield: 7.8 %

Procedure:
To a solution of ethyl 4,7-dihydro-4-(2-nitrophenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.68 g) in methanol (30 mL) was added 5% palladium-carbon (500 mg), and the mixture was stirred under 10 atm for 3 hours. After removing palladium-carbon by Celite filtration, the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (120 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23](F)=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35][O-:36].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([O:36][CH3:35])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1c(OC2CCN(C(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-(1-t-Butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (300 mg) was dissolved in 3 ml of DMF, followed by the addition of 32 mg of 55% sodium hydride under ice cooling. After the resultant mixture was stirred for 10 minutes, 72 mg of sodium methoxide was added. The mixture thus obtained was stirred further for 18 hours at room temperature. The reaction mixture was diluted with chloroform and then washed successively with 10% aq. citric acid solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness, whereby 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained. It was used directly in the reaction of the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[S:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:22])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)s1
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)s1

Procedure:
Crude 2'-methyl-4'-(5-methyl-1,3,4-thiadiazol-2-yl)biphenyl-4-carboxylic acid (D73, 500 mg) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) afforded the title compound according to the general method of Example 1. Preparative HPLC afforded 10 mg of pure compound.
Reaction SMILES: [O:1]=[C:2]1[O:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:37](Br)[CH:38]=[CH2:39].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:39]([C@H:3]1[C:2](=[O:1])[O:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:4]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:38]=[CH2:37]
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@H]1C(=O)O[C@H](c2ccccc2)[C@H](c2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
10 g of tert-butyl (5S,6R)-2-oxo-5,6-diphenylmorpholine-4-carboxylate were dissolved in 200 ml of THF and cooled to −78° C. 63 ml of a 0.5 M solution of KHMDS in toluene were added dropwise and, after stirring for 10 min, 3.7 ml of allyl bromide were added dropwise. The mixture was allowed to warm from −78° C. to −20° C. over the course of 3 h, and the reaction was then stopped by adding 300 ml of a saturated ammonium chloride solution. 200 ml of ethyl acetate were added, and the phases were separated. The aqueous phase was extracted 3 times with 100 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo and the residue was stirred with diisopropyl ether.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.ClC(Cl)(Cl)C(=N)O[C:33]([CH3:36])([CH3:35])[CH3:34]>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:33]([CH3:36])([CH3:35])[CH3:34])[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Product: CC(C)(C)OCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 10 mmol of tert-butyl trichloroacetimidate are treated as described in Example 116. The title compound is crystallized in the form of the hydrogen maleate in ethanol and diethyl ether.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].[CH2:10]([N:17]=[C:18]=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[CH2:10]([NH:17][C:18]([NH:9][NH:8][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNC(=O)c1cccs1
Reactant: S=C=NCc1ccccc1
Solvent: CC#N
Product: O=C(NNC(=S)NCc1ccccc1)c1cccs1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a hot solution of 2-thiophencarboxylic acid hydrazide (5.0 g, 35 mmol) in acetonitrile (80 mL) was added neat benzyl isothiocyanate (4.7 mL, 35 mmol) via syringe. When the solvent started to boil, the reaction vessel was removed from the heat source and allowed to cool to room temperature. The resulting crystals were collected by vacuum filtration, washed with diethyl ether and air-dried to yield N-benzyl-2-(thien-2-ylcarbonyl)hydrazinecarbothioamide (9.11 g; 89%; (M+H)+−292.2).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:20])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[Br:21]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:20])[C:5]2[CH:11]=[C:10]([Br:21])[C:9](=[O:12])[N:8]([C@H:13]3[CH2:14][CH2:15][C@H:16]([OH:19])[CH2:17][CH2:18]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1ccc(=O)n2[C@H]1CC[C@H](O)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-amino-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (115 mg, 0.419 mmol) in dimethylformamide (2.0 mL) was added N-bromosuccinimide (75 mg, 0.42 mmol). After stirring for 1.5 hr at room temperature the solution was concentrated. The residue was slurried in methanol, filtered solids, and the filtrated was concentrated and purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-3%). Combined solids to afford the title compound (120 mg, 81%).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH2:9][NH2:10]>C(O)C>[CH:2]([C:3]1[NH:10][N:9]=[C:5]([NH2:6])[CH:4]=1)([CH3:8])[CH3:1]
Reactant: CC(C)C(=O)CC#N
Reactant: NN
Solvent: CCO
Product: CC(C)c1cc(N)n[nH]1
Yield: 103.3 %

Procedure:
A solution of 4-methyl-3-oxopentanenitrile (25 g, 225 mmol) and hydrazine (6.75 mL, 215 mmol) in ethanol (250 mL) was stirred at room temperature for 3 h, at which point LC/MS indicated exclusively product remained. The mixture was concentrated on a rotary evaporator followed by under high vacuum to give the desired product (27.8 g, 99%) as a yellow semisolid that was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][C:15]3([CH2:27][C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([NH:33][O:34]C5CCCCO5)=[O:32])[CH:24]=4)[O:19]3)[CH2:14][CH2:13]2)=[CH:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][C:15]3([CH2:27][C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([NH:33][OH:34])=[O:32])[CH:24]=4)[O:19]3)[CH2:14][CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CCCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(CN2CCCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NO)ccc2O3)c2ccccc21

Procedure:
(±)-(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (280 mg, 0.51 mmol) in DCM (5 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving after purification by preparative HPLC (±)-(E)-3-[1-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide (80 mg, trifluoroacetate salt) as a light brown solid.
Reaction SMILES: [I-].C(N1C=C[N+:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[C@@H:24]2[O:38][C@H:37]([CH2:39][O:40]C(C3C=CC(C)=CC=3)=O)[C@@H:26]([O:27]C(C3C=CC(C)=CC=3)=O)[CH2:25]2)=C1CCC)C1C=CC=CC=1.N.CO>O.CO>[NH2:11][C:14]1[N:22]=[C:21]([Cl:23])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C@@H:24]1[O:38][C@H:37]([CH2:39][OH:40])[C@@H:26]([OH:27])[CH2:25]1
Reactant: CCCc1n(Cc2ccccc2)cc[n+]1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Agent: N
Agent: [I-]
Solvent: O
Solvent: CO
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Yield: 108.9 %

Procedure:
Treatment of 3-benzyl-1-{2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]purin-6-yl}-2-propylimidazolium iodide (0.83 g, crude) with NH3/MeOH (26%, 50 mL) at 60° C. followed by ion exchange chromatography (Dowex 1×2 [OH−], H2O/MeOH) by method 3 gave cladribine (0.31 g, quantitative). Recrystallization from EtOH gave a white solid (0.153 g, 54%), and the residue from the mother liquor was recrystallized from H2O to give a second crop (0.015 g, 59% total): mp>300° C.; UV (MeOH) max 212, 265 nm (∈ 24 000, 14 600), min 229 nm (∈ 2000); 1H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.83 (br, 2H), 6.26 (t, J=6.7 Hz, 1H), 5.32 (d, J=4.3 Hz, 1H), 4.97 (t, J=5.5 Hz, 1H), 4.38 (s, 1H), 3.85 (s, 1H), 3.57-3.61 (m, 1H), 3.48-3.53 (m, 1H), 2.62-2.67 (m, 1H), 2.25-2.29 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ 157.5, 153.6, 150.8, 140.5, 118.8, 88.6, 84.2, 71.4, 62.3, 38.0; HRMS m/z 285.0615 (M+ [C10H12ClN5O3]=285.0629). Anal. Calcd for C10H12ClN5O3: C, 42.04; H, 4.23; N, 24.51. Found: C, 41.87; H, 4.50; N, 24.39.
Reaction SMILES: C([N:8]1[CH:12]([C:13]2([CH3:17])[CH2:16][CH2:15][CH2:14]2)[CH2:11][C:10](=[O:18])[O:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:8][CH:12]([C:13]1([CH3:17])[CH2:16][CH2:15][CH2:14]1)[CH2:11][C:10]([OH:18])=[O:9]
Reactant: [H][H]
Reactant: CC1(C2CC(=O)ON2Cc2ccccc2)CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C(N)CC(=O)O)CCC1

Procedure:
A solution of racemic 2-benzyl-3-(1-methylcyclobutyl)isoxazolidin-5-one, 115a, (0.18 g, 1.28 mmol) in MeOH (2.9 mL) was shaken overnight under 50 psi hydrogen in the presence of 50 mg palladium hydroxide catalyst. The mixture was filtered through Celite and the volatiles were removed under reduced pressure to afford the desired product that was used without further purification: 1H NMR (400 MHz, MeOD) δ 3.42 (dd, J=11.0, 1.9 Hz, 1H), 2.26 (ddd, J=27.8, 16.7, 6.5 Hz, 2H), 1.86 (dddd, J=36.9, 26.3, 11.2, 7.6 Hz, 6H), 1.18 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:29]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]([F:29])=[O:11])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(c1ccccc1)C(NC(=O)OC(C)(C)C)C(=O)F
Reaction time: 1.5 h

Procedure:
To a solution of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid (838 mg, 3.0 mmol) in dichloromethane (10 mL) at −35° C. was added dry pyridine (255 μL, 3.15 mmol) and cyanuric fluoride (375 μL, 4.5 mmol) under an atmosphere of dry argon. The mixture was stirred for 1.5 hours while maintaining the temperature between −35 and −25° C. A small amount of ice was added to the reaction mixture and the mixture stirred vigorously for 15 minutes. The organic layer was decanted away from the aqueous solution and the aqueous layer extracted with dichloromethane (2×10 mL). The combined organic layers were washed with ice cold water (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give (1-fluorocarbonyl-2-phenyl-propyl)-carbamic acid tert-butyl ester which was used in the subsequent step without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=1)[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:29]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A mixture of (2R)-4-benzyl-1-[3,5-bis(trifluoro-methyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (5.20 g), ammonium formate (1.50 g) and 10% Pd charcoal (0.52 g) in ethanol (50 ml) was refluxed for 7.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified on a silica gel column eluting with a mixture of dichloromethane and methanol (20:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (2.67 g, 61.5%) as a syrup.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.C(OC(=O)C)C>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)C(=O)NCC2
Reaction time: 3.5 h
Yield: 105.2 %

Procedure:
10% Pd/C (100 mg) was added to a solution of 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (I-24a: 900 mg, 4.6875 mmol) in methanol (20 mL) at room temperature under nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 3.5 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was filtered; the filtrate was concentrated and dried to afford 800 mg of the crude product which was used in the next step without further purification.