Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][N:5]=[C:4]([Br:7])[C:3]=1[Br:8].[F:9][S:10]([O:13][CH3:14])(=[O:12])=[O:11]>>[F:9][S:10]([O-:13])(=[O:12])=[O:11].[CH3:14][N+:5]1[S:6][C:2]([Br:1])=[C:3]([Br:8])[C:4]=1[Br:7]
Reactant: Brc1nsc(Br)c1Br
Reactant: COS(=O)(=O)F
Product: C[n+]1sc(Br)c(Br)c1Br
Product: O=S(=O)([O-])F
Yield: 88 %

Procedure:
Tribromoisothiazole (2.2 g, 0.007 mol) and 2.2 ml of methyl fluorosulfonate were heated at 65° for 10 min. under a nitrogen atmosphere. The resulting solid was washed with ether and benzene to yield 2.7 g (88%) of 2-methyl-3,4,5-tribromoisothiazolium fluorosulfonate, mp 121-129. Spectral data (NMR and IR) were consistent with the assigned structure.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[C:28]([O:32][C:33]([N:35]1[CH2:39][CH2:38][C:37]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)([C:40](O)=[O:41])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([C:37]2([C:40]([N:25]3[CH2:26][CH2:27][N:22]([C:20]4[C:21]5[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=5[N:17]=[CH:18][N:19]=4)[CH2:23][CH2:24]3)=[O:41])[CH2:38][CH2:39][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:34])[CH2:36]2)=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)C1
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)cc5)CCN(C(=O)OC(C)(C)C)C4)CC3)c21
Reaction time: 8 h
Yield: 58 %

Procedure:
DIPEA (35.5 mg, 0.275 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.69 mmol), 1-(tert-butoxycarbonyl)-3-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (26.9 mg, 0.082 mmol), and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5.0 mL) at room temperature. The resulting mixture was stirred overnight, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g), eluted by a mixture of MeOH and CH2Cl2 (1.5:98.5) to give tert-butyl 3-(4-chlorophenyl)-3-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)pyrrolidine-1-carboxylate as a clear oil (25 mg, 69%). LCMS (APCI+) [M-Boc+H]+ 526.1; Rt: 3.49.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1>C(O)C>[CH:8](=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccccc2)S1
Yield: 90.2 %

Procedure:
To a solution of 20 g (171 mmol) of 2,4-thiazolidinedione and 17.4 ml (171 mmol) of benzaldehyde in 350 ml of ethanol, 1.68 ml (17.1 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 31.67 g of the desired compound (90.4% yield, pale yellow crystals).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=3[Cl:45])[CH2:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+].O>C1COCC1.CO>[ClH:45].[Cl:45][C:36]1[C:37]([C:41]([F:42])([F:43])[F:44])=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][N:19]([CH2:20][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:18][CH2:17][CH2:16][O:15][C:11]1[CH:10]=[C:9]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cl
Product: O=C(O)C1(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 1(3-{3-[2-Chloro-3-trifluoromethyl-benzyl-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopropanecarboxylic acid ethyl ester (65 mg, 0.12 mmol) in THF (1 ml) and methanol (4 ml) was added lithium hydroxide (2N aq., 1 ml). The reaction was stirred at RT overnight. Acidic water was added to neutralize the solution and the organic products were extracted into ethyl acetate, washed with brine, dried (MgSO4), and evaporated. The residue was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% during 10 min, UV detection at 254 nm) to give 17 mg (27%) of the title compound as an oil. The oil was dissolved in methanol, and HCl in diethyl ether was added, the solvents were evaporated to form the hydrochloride salt as a solid. MS (ESI) 608.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[C:30]([F:36])[C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[C:20]([O:37][CH3:38])[N:19]=1>CN1C(=O)CCC1>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[C:34]2[C:29]=1[CH2:28][CH2:27][N:26]2[C:24]([C:22]1[CH:21]=[C:20]([O:37][CH3:38])[N:19]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:23]=1)=[O:25]
Reactant: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(Cl)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 25 °C

Procedure:
0.982 g (4.50 mmol) 1-Piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 500 mg (1.54 mmol) (2-chloro-6-methoxy-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone in 3.0 mL NMP were stirred for 12 h at 130° C. After the reaction mixture had cooled to RT the precipitate formed was filtered off and purified by preparative HPLC. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:7]=1.C(=O)([O-])O.[Na+]>CS(C)=O>[F:15][C:14]([F:17])([F:16])[CH2:13][O:12][C:8]1[N:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:11]=[CH:10][CH:9]=1
Reactant: [C-]#N
Reactant: FC(F)(F)COc1cccc(CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.5 %

Procedure:
Sodium cyanide (0.823 g, 16.8 mmol) is added to a solution of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (2.0 g, 7.63 mmol, Step-4) in DMSO (38 mL) and stirred at rt for 20 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (60 mL) and extracted with EtOAc (100 mL). The organic layer is washed with water (50 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on amine gel eluting with n-hexane/EtOAc (3:1) to give 1.13 g (69% yield) of the title compound as yellow oil.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[S:13][CH:14]=1)(OCC)=O)C.[H-].[Na+].[CH3:27][O:28][CH2:29][O:30][C:31]1[C:35]([CH:36]=O)=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.O>O1CCCC1>[CH3:27][O:28][CH2:29][O:30][C:31]1[C:35](/[CH:36]=[CH:9]/[C:10]2[N:11]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[S:13][CH:14]=2)=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1csc(-c2ccccc2C(=O)OC)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(-c2ccccc2C(=O)OC)n1
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
To a solution of methyl {4-[(diethoxyphosphoryl)methyl]-1,3-thiazol-2-yl}benzoate (4.7 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 1.1 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.8 g) was added to the reaction mixture, and the mixture was heated under reflux for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (30:70-60:40, v/v) to give methyl (4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazol-2-yl)benzoate as pale-yellow crystals (1.1 g, yield 20%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 134-135° C.
Reaction SMILES: [Mg].II.[CH:4]([C:7]1[CH:8]=[C:9](Br)[CH:10]=[CH:11][CH:12]=1)([CH3:6])[CH3:5].BrCCBr.[C:18](=[O:20])=[O:19].Cl>O1CCCC1.O>[CH:4]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[C:18]([OH:20])=[O:19])([CH3:6])[CH3:5]
Reactant: CC(C)c1cccc(Br)c1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
While stirring a solution of powdery magnesium (3.33 g, 137 mmol) and iodine (one crumb) in tetrahydrofuran (10 ml), a solution of 3-isopropylbromobenzene (10.91 g, 54.80 mmol) and 1,2-dibromoethane (10.3 g, 54.8 mmol) in tetrahydrofuran (100 ml) was dropwise added slowly. After completion of the dropwise addition, the mixture was stirred at 70° C. for 1 hr. The reaction solution was cooled to −78° C., and pulverized dry ice (10 g) was carefully added. The reaction solution was gradually warmed to room temperature with stirring. The reaction solution was diluted with water, acidified with conc. hydrochloric acid, and extracted twice with ethyl acetate. The solvent of the recovered organic layer was evaporated under reduced pressure to give a crude product of 3-isopropylbenzoic acid as a yellow liquid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](OCC)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][CH2:16][OH:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCOC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of (A) (14 g) in tetrahydrofuran (50 ml) was added to a solution of lithium aluminum hydride (2 g) in tetrahydrofuran (100 ml) under stirring. The mixture was refluxed for 3 hours and finally hydrolyzed by careful addition of water. After removal of inorganic salts by filtration, the filtrate was concentrated to give (B) as a viscous oil.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16].Cl>C1(C)C=CC=CC=1>[CH2:1]([NH:6][C:15](=[O:16])[O:17][CH2:18][Cl:19])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN
Reactant: O=C(Cl)OCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCNC(=O)OCCl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3.84 ml of n-pentylamine and 5.02 ml of triethylamine in 38 ml of toluene was added dropwise to 24 ml of a solution of 2.39 ml of chloromethyl chloroformate in toluene while cooling in an ice bath over a period of 15 min, and the mixture was stirred at room temperature for 15 hr. 1 N hydrochloric acid (60 ml) was added thereto, followed by separation. The organic layer was washed with 60 ml of a 5% aqueous sodium hydrogencarbonate solution and 60 ml of 20% brine, was dried over anhydrous magnesium sulfate, and was filtered. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give 3.31 g of chloromethyl N-pentan-1-ylcarbamate.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:27]1[N:28]=[C:29]([NH:32]C=O)[S:30][CH:31]=1)[C:5]([NH:7][CH:8]1[C:25](=[O:26])[N:10]2[C:11]([C:22]([OH:24])=[O:23])=[C:12]([CH2:15][S:16][C:17]3[S:18][CH:19]=[N:20][N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].P(Cl)(Cl)([Cl:37])=O>CO>[ClH:37].[CH3:1][O:2][N:3]=[C:4]([C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1)[C:5]([NH:7][CH:8]1[C:25](=[O:26])[N:10]2[C:11]([C:22]([OH:24])=[O:23])=[C:12]([CH2:15][S:16][C:17]3[S:18][CH:19]=[N:20][N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Product: Cl
Yield: 112.1 %

Procedure:
7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (10.8 g.) was added to methanol (200 ml.), and phosphorus oxychloride (7.2 g.) was dropwise added thereto with stirring and ice-cooling at 2° to 9° C. After stirring for 1.5 hours at the same temperature, the reaction mixture was concentrated under reduced pressure on a water bath of 25° to 28° C. to the volume of 100 ml. To the residue was added ether (300 ml.) with stirring and ice-cooling. Precipitates were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (12.3 g.). This powder (12.3 g.) was suspended in water (100 ml.) and dissolved by adjusting pH of the suspension to 7.5 by addition of a saturated aqueous solution of sodium bicarbonate. To the solution was added ethyl acetate (100 ml.), and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with cold water and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (6.1 g.). The aqueous layer in the mother liquor was separated and stirred under cooling after addition of sodium chloride. Precipitates were collected by filtration to give the same object compound (3.8 g.). Total yield (9.9 g.). This compound was identified with the compound obtained in the foregoing Examples by I.R. and N.M.R. spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:13]#[N:14].[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)C(C#N)CCO2
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(CNC(C)=O)CCO2

Procedure:
The nitrile obtained in Step A (200 mg; 1.05 mmol) is solubilised in the reactor of a Parr apparatus in 15 ml of acetic anhydride. Raney nickel (60 mg; 30% by weight) and also sodium acetate (1.5 eq; 1.58 mmol; 130 mg) are added. The reactor is placed under hydrogen pressure of 580 psi at 50° C. for 12 hours. When the reaction is complete, filtration over Celite and then rinsing with AcOEt are carried out. The product is purified by flash chromatography on silica gel (eluant: AcOEt (100%)). The white solid obtained is recrystallised from a pentane-ether mixture.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8][CH2:9][C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8][CH2:9][C:10]([Cl:21])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CSC(c1ccccc1)c1ccccc1
Product: O=C(Cl)CSC(c1ccccc1)c1ccccc1

Procedure:
2-[(Diphenylmethyl)thio]acetic acid (III), on reaction with thionyl chloride yielded the corresponding 2-[(diphenylmethyl)thio]acetylchloride (IV), which on reaction with ammonia produced 2-[(diphenylmethyl)thio]acetamide (I) which on oxidation with hydrogen peroxide resulted in modafinil (II).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[NH4+].[Cl-]>C1COCC1>[O:6]1[CH2:7][CH2:8][O:9][CH:5]1[CH2:4][CH2:3][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[C:11]([F:10])([F:20])[F:21])[OH:15]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: BrCCC1OCCO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCC1OCCO1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.7 %

Procedure:
Method 6 General Experimental: Magnesium (230.0 mmol, 5.6 g) in TBF (200 ml), under an argon atmosphere, was treated with 2-(2-bromoethyl)-1,3-dioxolane (200.0 mmol, 23.5 ml), slowly, keeping the internal temperature below 35° C. with the aid of an ice bath. After completion of the addition, the mixture was held at room temperature for an additional 1 h. 2-Trifluoromethyl benzaldehyde (100 mmol, 13.2 ml) in THF (100 ml) was cooled to −78° C. under an argon atmosphere, then treated with the freshly formed Grignard reagent prepared above. After completion of the addition, the solution was allowed to warm to room temperature, then held at room temperature overnight. The reaction mixture was then poured into saturated aqueous NH4Cl (200 ml), and extracted with ethyl acetate (2×150 ml). The combined organics were washed with brine (2×75 ml), then concentrated under reduced pressure to give 32.8 g of 3-[1,3]dioxolan-2-yl-1-(2-trifluoromethyl-phenyl)-propan-1-ol, which may be used without further purification. 1H NMR (CDCl3) δ7.78 (1H, d, J=7.7), 7.62-7.52 (2H, m), 7.34 (1H, t, J=7.6), 4.92 (1H, t, J=4.0), 4.00-3.81 (5H, m), 1.90-1.80 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].CN(C)CCCN=C=NCC.Cl.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[CH2:12][C:10]#[N:11]
Reactant: Nc1ccc(F)cc1Cl
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCC(=O)Nc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
A mixture of 2-chloro-4-fluoroaniline (3.55 g, 24.3 mmol), cyanoacetic acid (2.48 g, 29.2 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide•hydrochloride (7.01 g, 36.5 mmol), 1H-1,2,3-benzotriazol-1-ol (4.94 g, 36.5 mmol), triethylamine (5.10 mL, 36.5 mmol) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hr. The mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a basic silica gel pad. The solvent was evaporated under reduced pressure, and the obtained residue was washed with hexane and collected by filtration to give the title compound (2.84 g, 54%) as a white solid.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C(Cl)=O.[CH:14]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[NH:18]1)([CH3:16])[CH3:15].[Li]CCCC>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH:14]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5])([CH3:16])[CH3:15]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
To a stirred solution of pentanoic acid (5.98 g, 58.6 mmol) in CH2Cl2 (100 mL) and 10 drops DMF was added oxalyl chloride (5.64 mL, 64.4 mmol) dropwise over 5 min and the solution stirred for 2.75 h, at which time all bubbling subsided. The solution was concentrated in vacuo. In a separate flask, to a cold (−78° C.), stirred solution of (S)-4-isopropyloxazolidin-2-one (7.56 g, 58.6 mmol) in THF (280 mL) was added n-BuLi (2.5M in hexane, 23.42 mL, 58.6 mmol) dropwise via addition funnel over 20 min (temperature never exceeded −68° C.). After stirring 10 min, the above acid chloride dissolved in THF (50 mL) was added via addition funnel over 25 min. After the addition was complete, the reaction mixture was allowed to warm to room temperature as bath warmed and stirred overnight. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to an amber oil. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hex/EtOAc, REDISEP® SiO2 120 g, applied as a DCM solution) to give Preparation 4A (6.51 g, 52%) as a colorless oil: 1H NMR (400 MHz, chloroform-d) δ ppm 4.44 (1H, ddd, J=8.16, 3.51, 3.39 Hz), 4.27 (1H, t, J=9.00 Hz), 4.21 (1H, dd, J=9.00, 3.01 Hz), 2.99 (1H, ddd, J=16.60, 8.50, 6.50 Hz), 2.86 (1H, ddd, J=16.60, 8.50, 6.78 Hz), 2.31-2.44 (1H, m), 1.56-1.72 (2H, m), 1.39 (2H, sxt, J=7.43 Hz), 0.94 (3H, t, J=7.28 Hz), 0.92 (3H, d, J=7.03 Hz), 0.88 (3H, d, J=6.78 Hz); HPLC: RT=2.497 min (CHROMOLITH® SpeedROD 4.6×50 mm (4 min grad) eluting with MeOH/H2O/0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[C:10]2([C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>O1CCCC1>[C:1]([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][O:16][C:43](=[O:45])[CH3:44])[C:10]2([C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CO)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (0.3 g, 0.56 mmol) in tetrahydrofuran (2 mL) at 0° C. was added pyridine (44 mg, 0.56 mmol) and acetyl chloride (44 mg, 0.56 mmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, saturated aqueous CuSO4, brine, dried over MgSO4, and concentrated to give as rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester as a yellow oil (0.24 g, 74%)