Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9](Cl)=[O:10].[BrH:12]>ClCCl>[Br:12][CH2:3][C:9]([CH:5]1[CH2:6][CH2:7][CH2:8][O:4]1)=[O:10]
Reactant: O=C(Cl)C1CCCO1
Reactant: Br
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: O=C(CBr)C1CCCO1
Yield: 76.7 %

Procedure:
A stream of diazomethane (from N-methyl-N-nitrosotoluene-4-sulphonamide, 18.0g) in argon (P. Lombardi, Chem. and Ind., 1990, (21), 708) was passed into a solution of (RS)-tetrahydrofuroyl chloride [prepared from (RS)-tetrahydrofuroic acid (3.48g, 30mmol) as described in Example 2(a)] in dichloromethane (60ml) cooled in an ice bath. When the diazomethane addition was complete, 48% aqueous hydrogen bromide (5.6ml, 33.2mmol) was added. The mixture was stirred 0.25h then washed twice with water, dried, concentrated and flash chromaographed on silica gel eluting with 10% ethyl acetate in hexane to give the title compound as a pale yellow oil (4.44g, 77%); vmax (CH2Cl2) 1733, 1245, 1073 and 938cm-1 ; δH (CDCl3) 1.85-2.35 (4H, m), 3.85-4.05 (2H, m), 4.20 (2H, s), 4.54 (1H, dd, J 6.1, 8.2Hz). [Mass spectrum: +ve ion (ammonia) MNH4+ (210)].
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C.C([O-])=O.[NH4+]>[Pd].O>[N:11]1([CH2:14][CH2:15][O:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: NC(=O)COCCN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: NC(=O)COCCN1CCNCC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
II.2.1. 13.9 g (0.05 mol) of 2-(4-benzyl-1-piperazinyl)ethoxyacetamide prepared in Example I.2.1. and 139 ml of ethanol are introduced into a 250 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. 1.4 g o palladium on-charcoal (10% by weight) and 15.8 g of ammonium formate are then added. The mixture is heated at 30° C. for 30 minutes, and then at 40° C. for 1 hour, and again at 60° C. for 30 minutes. The mixture is allowed to cool to 40° C. and is filtered through diatomaceous earth (dicalite). The palladium is washed with ethanol. The filtrate is concentrated on a rotary evaporator under reduced pressure. 9.5 g (100%) of 2-(1-piperazinyl)ethoxyacetamide are obtained in the form of a colorless oil which crystallizes.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1C=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O)(=O)C>CO>[CH:13]1([NH:16][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:15][CH2:14]1
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: NC1CC1
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(NC2CC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 1-methylindole-2-carboxaldehyde (1.5 g, 10 mmole), cyclopropylamine (1.14 g, 20 mmole), and glacial acetic acid (0.6 mL, 10 mmole) in MeOH (30 mL) was added NaB3CN (0.69 g, 11 mmole). The reaction was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 10% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 65%) as a semi-solid: MS (ES) m/e 201 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:26][CH:9]1[CH2:10][CH2:11]2)=[O:7])(C)(C)C.Cl.[CH3:28][O:29][C:30]([NH:32][CH:33]([CH:37]([CH3:39])[CH3:38])C(O)=O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.O1CCOCC1>[CH3:28][O:29][C:30](=[O:31])[NH:32][CH:33]([C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:26][CH:9]1[CH2:10][CH2:11]2)=[O:7])[CH:37]([CH3:39])[CH3:38]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.0 g, 2.4 mmol) in methanol (20 mL) was added 4.0 M solution of HCl in dioxane (4.0 mL, excess). The mixture was stirred for 3 hours at 50° C. and concentrated under reduced pressure. The residue was treated with ether to remove excess HCl. The obtained white solid was dissolved in DMF (20 mL). To the solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (0.46 g, 2.6 mmol), HATU (1.0 g, 2.6 mmol) and N,N-diisopropylethylamine (2.5 mL, 14.4 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with 1 N NaOH solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (1.0 g, 89%). m/z 475.1, 477.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-])=O.[N+](C1C([N+]([O-])=O)=C(C=CC=1)C=O)([O-])=O>C(O)(=O)C.C(OCC)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(C=O)c(N)c1
Temperature: 35 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
To a nitrogen purged 5 liter 4-neck flask fitted with a condenser, mechanical stirrer, addition funnel, and temperature probe, was added 325 mesh iron dust, which can be obtained from Aldrich, Milwaukee, Wis. (220 g, 3.9 mol, 8 equiv), water (800 mL), and glacial acetic acid (5 mL). Over the next hour, some frothing occurred and the temperature rose to 28° C. In a separate container, 2,4-dinitrobenzaldehyde (97 g, 0.49 mol, 1 equiv) was dissolved in 1:1 glacial acetic acid/ethyl acetate (800 mL). 2,4-Dinitrobenzaldehyde can be purchased from Aldrich, Milwaukee, Wis. About 5 mL of the 2,4-dinitrobenzaldehyde solution was added dropwise to the iron mixture, which led to a dissipation of the frothing. The reaction mixture was warmed to 35° C. with a steam bath. Without further heating, the remaining dinitrobenzaldehyde solution was added at such a rate as to maintain the temperature below 50° C. The addition was completed after 6 hours. The reaction mixture was diluted with water (1 L) and diatomaceous earth (BNL Fine Chemicals and Reagents, Meriden, Conn.) was added (100 g). The reaction mixture was stirred an additional 3 hours at which point the temperature had dropped to 25° C. The solids were removed by filtration. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×400 mL). The extracts were then used to wash the solids from the initial filtration. The organic layers were combined and washed with water (400 mL) and saturated aqueous NaHCO3 (3×400 mL). The combined organic layers were dried over MgSO4 and Darco G-60® (activated charcoal; BNL Fine Chemicals and Reagents, Meriden, Conn.) (10 g). After filtration to remove the drying agents, the organic layers were concentrated in vacuo to a slurry and diluted with 1 L of hexanes. The precipitated solids were collected by suction filtration and dried in air to give 2,4-diaminobenzaldehyde (48 g, 71%) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:40])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29](C([O:35][C:36](C)(C)C)=O)[N:28]=[CH:27]4)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5].[C:41]([OH:47])([C:43](F)(F)F)=O.C(Cl)[Cl:49]>>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:1])[CH3:40])[CH:12]=[CH:11][CH:10]=4)[N:22]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1.[CH3:36][O:35][CH2:43][C:41]([Cl:49])=[O:47]
Reactant: ClCCl
Reactant: CN(C)CC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Reactant: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Product: COCC(=O)Cl

Procedure:
To tert-butyl 5-(2-(3-(2-(dimethylamino)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (560 mg, 1.04 mmol) was added a solution of 1:1 TFA:CH2Cl2 (6 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ethyl ether and drops of CH2Cl2 to afford 2-methoxyacetyl chloride N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(dimethylamino)acetamide. (325 mg, 0.74 mmol, 71%)
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([O-:11])=O.[NH4+:12]>C(OCC)(=O)C.CO.[Pd]>[NH2:12][C:4]1[C:3]([O:11][CH3:9])=[C:2]([CH:7]=[C:6]([C:2]([CH3:7])([CH3:3])[CH3:1])[CH:5]=1)[C:1]#[N:8]
Reactant: [NH4+]
Reactant: O=C[O-]
Reactant: N#Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(N)cc(C(C)(C)C)cc1C#N
Temperature: 25 °C
Yield: 153.6 %

Procedure:
The above benzonitrile (100 mg, 0.427 mmol) was dissolved in 1:1 ethyl acetate/methanol (10 mL) in a nitrogen-flushed flask. Ammonium formate (270 mg, 4.27 mmol) and palladium on carbon (30 mg, 10% wet) were added and the mixture was heated to reflux for 30 min. The reaction was cooled to room temperature and filtered through a pad of diatomaceous earth, eluting with ethyl acetate. The ethyl acetate was evaporated under vacuum. The resulting residue was purified by chromatography on silica gel (1:1 ethyl acetate/hexanes) to afford the title compound, (67 mg, 77%) as a colorless oil.
Reaction SMILES: C(C([N:7]([C:14]1[CH:19]=[CH:18][C:17](CC#N)=[C:16]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:15]=1)C(C(C)(C)C)=O)=O)(C)(C)C.C(C(NC1C=CC(CC#N)=C(OCC(F)(F)F)C=1)=O)(C)(C)C.[ClH:51].[C:52]([OH:55])(=[O:54])[CH3:53]>>[ClH:51].[NH2:7][C:14]1[CH:19]=[CH:18][C:17]([CH2:53][C:52]([OH:55])=[O:54])=[C:16]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])[CH:15]=1
Reactant: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1ccc(CC#N)c(OCC(F)(F)F)c1
Reactant: CC(=O)O
Agent: CC(C)(C)C(=O)Nc1ccc(CC#N)c(OCC(F)(F)F)c1
Agent: Cl
Product: Nc1ccc(CC(=O)O)c(OCC(F)(F)F)c1

Procedure:
A ~3:1 mixture of 4-(N,N-di-(tert-butylcarbonyl)amino)-2-(2,2,2-trifluoroethoxy)phenylacetonitrile and 4-(tert-butylcarbonylamino)-2-(2,2,2-trifluoroethoxy)phenylacetonitrile (1.1 g) from Step 5 above was refluxed in a 1:1 mixture of acetic acid and concentrated aqueous HCl for 3 h. The solvents were removed under reduced pressure. The residue was dissolved in water and the solvent was evaporated under reduced pressure to remove residual acetic acid. 4-Amino-2-(2,2,2-trifluoroethoxy)phenylacetic acid hydrochloride was obtained as a colorless gum (HPLC retention time=4.2 min (method A)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.NN.Cl>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: NN
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.5 %

Procedure:
5-Methylisatin (15.0 g) and 60 mL of hydrazine hydrate were heated at 140 to 160° C. for 4 hours. Thin layer chromatography (ethyl acetate:hexane 1:2, silica gel) showed no starting material remaining. The reaction mixture was cooled to room temperature, poured into 300 mL of ice water and acidified to pH 2 with 6N hydrochloric acid. After standing at room temperature for 2 days the precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 6.5 g (47% yield) of 5-methyl-2-oxindole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1I)[C:5]#[N:6].[C:11]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C(O)C.[O-]CC.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.O>[C:11]1([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[F:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: N#Cc1ccc(I)c(F)c1
Reactant: OB(O)C1=CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N#Cc1ccc(C2=CCCCC2)c(F)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a mixture of 3-fluoro-4-iodobenzonitrile (1.53 g), 1-cyclohexen-1-yl-boronic acid (938 mg), bis(triphenylphosphine)palladium(II) dichloride (435 mg) and ethanol (9.75 mL), sodium ethoxide (about 20%, solution in ethanol, 5.75 mL) was added and the mixture was stirred at 90° C. for 15 minutes under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into water and three extractions were conducted with chloroform. The combined organic layers were washed with saturated brine and passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-75:25) to give the titled compound as a pale yellow oil (980 mg).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][OH:55]>CN(C)C=O>[OH:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: OCCOCCOCCCl
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CN1CCN(CCOCCOCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (129 mg, 0.25 mmol) (Example 22(a)) was dissolved in dimethylformamide (1 ml). Sodium iodide (7.5 mg, 0.5 mmol) , triethylamine (76 mg, 0.75 mmol) and 2-[2-(2-chloroethoxy)-ethoxy]ethanol (85 mg, 0.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred at ambient temperature for 90 minutes, the temperature was then raised to 100° C. and kept there for 1 hour. The solvent was evaporated, and the residue was dissolved in dichloromethane (2 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the organic phase and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (4 ml). The aqueous solution was acidified, the water was evaporated and the title compound was isolated as a hygroscopic white powder. Yield 77 mg (64%). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[S:20][C:13]=13)=[CH:6][CH:5]=2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[CH:28]=[CH:27][C:24]([CH2:25][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:23][CH:22]=4)[S:20][C:13]=13)=[CH:6][CH:5]=2
Reactant: C1COCCN1
Reactant: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(C=O)cc5)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(CN6CCOCC6)cc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 4-[7-(2-methyl-1H-Indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde(60 mg, 0.156 mmol) and morpholine (82 mg, 0.939 mmol) by a procedure analogous to example 89. RP18-HPLC RT: 4.652 minutes; API MS: 454.59 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[O:15][C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])[N:19]=[CH:18][C:17]=3[N:30]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH:11]([OH:13])[CH3:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[O:15][C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])[N:19]=[CH:18][C:17]=3[N:30]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCCC(C)O)c(F)c3)nc2cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CCOc1ccc(-c2nc3cnc(OC[C@H](C)NC(C)=O)cc3o2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
A solution of N-((2S)-1-((2-(3-fluoro-4-(3-hydroxybutoxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide (300 mg) and Dess-Martin reagent (914 mg) in DMF (30 mL) was stirred at room temperature for 15 hr. To the mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was stirred at room temperature for 10 min. Water was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (165 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:26][C:27]([O:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)=[O:28].O>CN(C)C=O.C(OCC)(=O)C>[NH:26]([C:27]([O:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:11][C:10]([C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[O:12])=[CH:36][CH:37]=1)=[O:28])[NH:25][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: CC(=O)Nc1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NNC(=O)OCCc1ccc(O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(C(=O)Oc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
To a suspension of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (466.2 mg, 2.504 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added 1,1′-carbonyldiimidazole (405.7 mg, 2.502 mmol), and the mixture was stirred at 50° C. for 2.5 hr. tert-Butyl 2-(4-hydroxyphenyl)ethyl hydrazine-1,2-dicarboxylate (594.8 mg, 2.001 mmol) was added, and the mixture was stirred at 50° C. for 18 hr. Water (40 ml) and ethyl acetate (40 ml) were added to the reaction mixture and the mixture was stirred, stood still and then partitioned. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 40 g, hexane:ethyl acetate=6:4→5:5). The fractions containing the object product were concentrated under reduced pressure and the obtained solid was suspended in a mixture of hexane (40 ml) and tert-butyl methyl ether (20 ml). The suspension was filtered and dried under reduced pressure to give 2-[4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}oxy)phenyl]ethyl tert-butyl hydrazine-1,2-dicarboxylate (539.2 mg, 1.161 mmol, yield 58.0%) as a white solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([O:22][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(O)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with pivalyl chloride there is obtained 3,4-bis(pivalyloxy)phenyl tert-butylaminomethyl ketone, which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride. The ketone intermediate and the alcohol product obtained in this manner are identical with the ketone and the alcohol described above in Example 5A and 5B, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:19]=[CH:18][C:10]([CH:11]=[N:12][C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.CO.C(OCC)(=O)C>[Pt].O>[CH3:17][C@H:13]([NH:12][CH2:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)[C:14]([NH2:16])=[O:15]
Reactant: C[C@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Agent: [Pt]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
An autoclave is loaded with (S)-2-[4-(3-fluorobenzyloxy)benzylidene-amino]propanamide (16.0 g; 0.053 mol), prepared as described above, and wet (50% H2O) Pt/C 5% (1.7 kg: Engelhard S.r.l., Rome, Italy) and methanol (90 mL) is added thereto. The autoclave is purged from air with nitrogen and then hydrogen is introduced at 5.0 bars. The reaction is kept at 5.0 bar and at 35° C. for 1 hour. After cooling to room temperature and elimination of the catalyst by filtration, the solvent is distilled off under reduced pressure until a residue of approximately 30 g is obtained. To this residue a mixture of ethyl acetate (150 mL) and H2O (110 mL) is added and the heterogeneous mixture is heated to 40° C., until two clear phases are obtained. These two phases are separated and the aqueous layer is extracted with 50 mL of ethyl acetate at 40° C. The organic phases are collected and evaporated to dryness. The procedure is repeated twice by adding every time 90 mL of ethyl acetate to make the product anhydrous. 95 mL of n-heptane are then added slowly and under stirring to the residue. The mixture is then maintained under stirring for 3 hours at 20° C. The solid formed is collected by filtration, washed with n-hetpane (15 mL) and dried under reduced pressure to give 15.2 g (94.8% yield) of safinamide with a HPLC purity of 99.8 (area %, see Example 17A) and a content of (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide lower than 0.005% by weight measured by HPLC (see Example 17B).