Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([NH2:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:15]([S:22](Cl)(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:12][S:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])([CH3:11])[C:9]#[N:10])=[CH:13][CH:14]=1
Reactant: CC(N)(C#N)COc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C#N)(COc1ccc(Cl)cc1)NS(=O)(=O)Cc1ccccc1

Procedure:
suspension of 1-(4-chloro-phenoxy)-propan-2-one (3.7 g, 20 mmol), ammonium chloride (1.6 g, 29.2 mmol) and sodium cyanide (1.15 g, 23.3 mmol) in a solution of aqueous ammonia (100 ml, 28%) is stirred vigorously at room temperature for 20 hours. The aqueous phase is extracted repeatedly with ethyl acetate. The collected organic extracts are dried and the solvent is evaporated under reduced pressure to give the 2-(4-chlorophenoxy-methyl)-2-amino-propionitrile as a solid. c) A solution of 2-(4-chlorophenoxy-methyl)-2-amino-propionitrile (0.5 g, 2.4 mmol) and benzylsulfonyl chloride (0.5 g, 2.6 mmol) in pyridine (5 ml) is heated at +80° C. with stirring in the presence of DMAP (0.02 g) for about 16 hours. The reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate and the product is purified by flash chromatography (eluent: ethyl acetate/hexanes 1:3) to give the 2-(4-chlorophenoxy-methyl)-2-benzylsulfonylamino-propionitrile in form of a colorless solid, m.p. 120-121° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH3:17])[C:9](=[O:18])[C:8]([CH3:20])([CH3:19])[C:7]1=[O:21]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH3:17][N:10]1[C:11]2[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:12]=2[N:6]([CH3:5])[C:7](=[O:21])[C:8]([CH3:19])([CH3:20])[C:9]1=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)C(C)(C)C(=O)N(C)c2ccccc21
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)C(C)(C)C(=O)N(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 72 h

Procedure:
1.3 ml of nitric acid (65%) were cautiously added dropwise at 0° C. to 5.1 ml of acetic anhydride. The solution was added to a solution of 3.00 g of 2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-2,4-dioxo-1H-1,5-benzodiazepine in 6.5 ml of acetic anhydride and 2.1 ml of glacial acetic acid. The reaction mixture was left to stand at room temperature for 3 days, filtered, the residue was washed thoroughly with water, dried and recrystallized from ethanol. There were obtained 2.11 g of 2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-7-nitro-2,4-dioxo-1H-1,5-benzodiazepine, m.p. 224°-225° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1)([OH:3])=O.C(OC(=O)C)(=O)C>C1(C)C=C(C)C=C(C)C=1>[CH2:6]1[C:5]2([CH2:8][C:9](=[O:10])[O:11][C:1](=[O:3])[CH2:4]2)[CH2:7]1
Reactant: O=C(O)CC1(CC(=O)O)CC1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1cc(C)cc(C)c1
Product: O=C1CC2(CC2)CC(=O)O1
Temperature: 100 °C

Procedure:
350 g crude (1-carboxymethyl-cyclopropyl)-acetic acid (2.2 mole, 92% purity, from step 1) are suspended in a mixture of 350 ml of mesitylene and 678 g of acetic anhydride (6.6 mole, 3 eq) and heated to 100° C. Upon reaching that temperature, the pressure is reduced to approximately 200 mbar and 45% of the solvent mixture are distilled off (distillation takes approx. 1 h). Then the mixture is slowly cooled to 0-5° C. and the precipitate is collected by filtration. The filter cake is washed with 87 ml of cold mesitylene and then dried in vaccuo at 40° C.
Reaction SMILES: OO.O[Li].O.C([C@@H]1COC(=O)N1[C:19](=[O:43])[C@H:20]([C@H:29]1[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:32]([CH3:42])([CH3:41])[CH2:31][CH2:30]1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)C1C=CC=CC=1.[O-:44]S([O-])=O.[Na+:48].[Na+]>C1COCC1.O>[Na+:48].[C:37]([O:36][C:34]([N:33]1[C:32]([CH3:42])([CH3:41])[CH2:31][CH2:30][C@H:29]1[C@H:20]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)[C:19]([O-:43])=[O:44])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Cl)c(F)c2)CCC1(C)C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)[O-])c2ccc(Cl)c(F)c2)CCC1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
30% H2O2 (0.159 mL, 1.65 mmol) was added to a solution of LiOH—H2O (0.055 g, 1.32 mmol) in 2:1 THF:H2O (40 mL). The mixture was stirred for 20 minutes and then cooled to 0° C. A solution of (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-chloro-3-fluorophenyl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.360 g, 0.660 mmol) in THF (3 mL) was next added slowly. Upon completion of the addition, the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was then recooled to 0° C., and 1M Na2SO3 (4 mL) was added. The reaction was stirred for 10 minutes at 0° C. and then warmed to room temperature and stirred for an additional 10 minutes. The reaction was then concentrated in vacuo to remove THF, and the resulting mixture was washed with EtOAc. The organic fraction was then dried over sodium sulfate, filtered and concentrated to give (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chloro-3-fluorophenyl)acetic acid sodium salt (0.24 g, 94%) as a powder. MS ESI (+) m/z 386 detected.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5](Br)=[C:6]([CH3:8])[N:7]=1.[SH:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:2][C:3]1[S:4][C:5]([S:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Sc1ncccn1
Reactant: Cc1nc(N)sc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)sc1Sc1ncccn1
Temperature: 90 °C
Yield: 57.8 %

Procedure:
A mixture of 2-amino-5-bromo-4-methylthiazole hydrochloride (1.15 g), 2-mercaptopyrimidine (0.6 g) and potassium carbonate (1.7 g) in N,N-dimethylformamide (20 ml) was heated at 90° C. for 3.5 hours with stirring. The reaction mixture was poured into ice water. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-methyl-5-(2-pyrimidinylthio)thiazole (0.65 g, yield: 58.0%).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:32]1[S:41][CH2:40][C@H:39]2[C@:34]([C:44]3[CH:49]=[C:48](Br)[CH:47]=[CH:46][C:45]=3[F:51])([CH2:35][O:36][C@@H:37]([CH2:42][F:43])[CH2:38]2)[N:33]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:51][C:45]1[CH:46]=[CH:47][C:48]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:49][C:44]=1[C@@:34]12[N:33]=[C:32]([NH2:24])[S:41][CH2:40][C@@H:39]1[CH2:38][C@H:37]([CH2:42][F:43])[O:36][CH2:35]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CF)C[C@H]2CS1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 85 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
2-Fluoropyridine-3-boronic acid (51.1 mg), tetrakis(triphenylphosphine)palladium (19.1 mg) and a 1 N sodium carbonate solution (363 μl ) were added to a solution of N,N-di(tert-butyloxycarbonyl)-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-fluoromethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (95 mg) in DMF (6.79 ml). After replacement with nitrogen, the mixture was stirred at 85° C. for two hours. After cooling to room temperature, the mixture was diluted with water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in dichloromethane (4.0 ml). TFA (1.0 ml) was added and the mixture was stirred at room temperature for three hours. Ice was added to the reaction mixture, followed by neutralization with a sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (59.0 mg).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](OCC)(=[O:13])[C:10]([O-])=[O:11]>>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][C:10](=[O:11])[C:9]1=[O:13]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: Nc1ccccc1N
Product: O=c1[nH]c2ccccc2[nH]c1=O

Procedure:
o-Phenylenediamine (10 grams) and ethyl oxalate (100 ml.) were mixed and the mixture was heated, with stirring, to reflux and refluxed for 30 minutes. The reaction mixture was then cooled and the resulting precipitate, the desired 2(1H), 3(4H)-quinoxalinedione, was separated by filtration. The product did not melt below 400° C. It was recrystallized from a mixture of dimethylformamide and water, yielding a purified product which did not melt below 405° C. The identity of the product was confirmed by NMR and IR. Elemental analysis showed
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(ON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of compound (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.193 g, 0.70 mmol) in dry DCM (20 mL) were added tert-butyl 3-(aminooxy)azetidine-1-carboxylate 36 (0.198 g, 1.05 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.142 g, 1.05 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.201 g, 1.05 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate 37 (0.15 g, 48%) as a clear thick oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CC(C)=O>[CH2:19]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCBr
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCC1(C(=O)OCC)CCCC1=O
Yield: 87.3 %

Procedure:
Under vigorously agitation, 31.2 g of ethyl 2-oxocyclopentane carboxylate was added to 84.5 g purity of 98%) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml Of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 57.54 ml (purity of 98%) of 1-bromo-n-hexane. Upon the completion of the addition, the reaction mixture was heated for reflux for 5 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 41.89 g of colorless liquid as a distillate cut of 156-160° C./23 mmHg was collected. Yield: 87.3%. MS: m/e 240(M+′), 212(M+′—CH2CH2), 195(M+′—OCH2CH3), 167(M+′—CO2CH2CH3), 156(base), 155, 127, 111.
Reaction SMILES: [Na].[Na].[C:3]([CH2:6][CH2:7][C:8]1[N:9]=[N:10][NH:11][C:12]=1[SH:13])([OH:5])=[O:4].CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O>>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:13][C:12]3[NH:11][N:10]=[N:9][C:8]=3[CH2:7][CH2:6][C:3]([OH:5])=[O:4])[CH2:28][S:27][C@H:22]12
Reactant: O=C(O)CCc1nn[nH]c1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na]
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3[nH]nnc3CCC(=O)O)CS[C@H]12

Procedure:
When an equivalent amount of 4-(2-carboxyethyl)-1,2,3-triazol-5-thiol disodium salt, prepared as in Example 8, is reacted with 7-aminocephalosporanic acid by the procedure of Example 8, 7-amino-3-[4-(2-carboxyethyl)-1,2,3-triazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15]I>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][CH2:14][C:13]([F:18])([F:17])[F:12])[N:6]=[C:5]2[I:11]
Reactant: FC(F)(F)CCI
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2CCC(F)(F)F
Yield: 46 %

Procedure:
The title compound was prepared in 46% yield from 5-fluoro-3-iodo-indazole and 1,1,1-trifluoro-3-iodopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.75-2.83 (2H, m), 4.60 (2H, t, J=7.2 Hz), 7.14 (1H, dd, J=2.0, 8.0 Hz), 7.26 (1H, td, J=2.4, 9.2 Hz), 7.34 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]2=[CH:4][CH:3]=1.[NH2:14][NH2:15]>C(O)C>[NH:14]([C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]2=[CH:4][CH:3]=1)[NH2:15]
Reactant: Clc1ccc2c(n1)CCCCCC2
Reactant: NN
Solvent: CCO
Product: NNc1ccc2c(n1)CCCCCC2
Temperature: 150 °C

Procedure:
2-chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine was treated with ethanol (20 mL) and anhydrous hydrazine (5 mL) in a sealed tube at 150° C. bath temperature for 7 h. Initial experiments showed that the addition did not proceed in boiling ethanol at atmospheric pressure. HPLC showed that the addition was incomplete, so the reaction mixture was heated at 150° C. for a further 7 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with 95% dichloromethane and 5% of a 2M solution of ammonia in methanol; 1H NMR (CDCl3, 300 MHz) 7.19 (d, 1H), 6.51 (d, 1H), 5.85 (br s, 1H), 3.77 (br s, 2H), 2.79 (m, 2H), 2.63 (m, 2H), 1.73 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 156.87, 158.54, 138.81, 126.67, 104.58, 34.72, 32.67, 31.45, 30.85, 26.41, 26.37; MS (ES) 192 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)O[N:10]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[S:24][N:10]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=[N+]([O-])c1ccc(C2CC(c3c(Cl)cccc3Cl)=NO2)cc1
Product: O=[N+]([O-])c1ccc(C2CC(c3c(Cl)cccc3Cl)=NS2)cc1

Procedure:
By the method of Asian. J. Chem., 2000, 12, 1358-1360, (±)3-(2,6-dichlorophenyl)-5-(4-nitrophenyl)-2-isoxazoline can be treated with diphosphorus pentasulfide followed by aqueous quench to produce (±)-3-(2,6-dichlorophenyl)-5-(4-nitrophenyl)-2-isothiazoline. The nitrophenyl group can be reduced to the corresponding aniline with tin dichloride or iron powder and ammonium chloride. The aniline, in turn, can be treated with 2,2-dichloroacetyl chloride and triethylamine to yield (±)-2,2-dichloro-N-[4-[3-(2,6-dichlorophenyl)-5-(2-isothiazolinyl)]phenyl acetamide.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH2:10][N+:11]([O-])=O)[CH2:3][C:4]1([CH3:9])[O:8][CH2:7][CH2:6][O:5]1.[H][H]>[Pt].C(O)C>[CH3:1][C:2]([CH3:14])([CH2:3][C:4]1([CH3:9])[O:5][CH2:6][CH2:7][O:8]1)[CH2:10][NH2:11]
Reactant: CC(C)(C[N+](=O)[O-])CC1(C)OCCO1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CC(C)(CN)CC1(C)OCCO1
Reaction time: 24 h
Yield: 101.1 %

Procedure:
A Parr hydrogenation vessel was charged with 2-(2,2-dimethyl-3-nitropropyl)-2-methyl-[1,3]dioxolane (23.1 g, 113 mmol), 5% platinum on carbon catalyst (3.0 g) and ethanol (250 mL); placed on a Parr shaker; and the system pressurized to 50 psi (3.4×105 Pa) hydrogen. After shaking for 24 hours, the reaction mixture was filtered through CELITE filter agent and concentrated under reduced pressure to provide 2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propylamine (19.8 g) as an oil that was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([O:38][CH2:39][O:40][CH3:41])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH:17]=O)[CH:15]=3)[N:8]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:53][NH:54][CH3:55].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([O:38][CH2:39][O:40][CH3:41])[CH2:35][CH2:36][CH2:37]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:54]([CH3:55])[CH3:53])[CH:15]=3)[N:8]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CC=O)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CCN(C)C)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetaldehyde (14C) (300 mg, 0.490 mmol) in tetrahydrofuran (3.267 mL) was added sequentially acetic acid (0.056 mL, 0.980 mmol), sodium sulfate (139 mg, 0.980 mmol) and dimethylamine (0.368 mL, 0.735 mmol). The reaction was stirred for 0.5 hours at ambient temperature, and sodium triacetoxyborohydride (208 mg, 0.980 mmol) was added in a single portion. The reaction was stirred overnight and then quenched by the addition of saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated, and the aqueous layer was extracted with addition ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS ESI(+) m/z 641.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>C1COCC1>[CH3:35][N:34]1[C:27]2[N:28]([C:29](=[O:31])[N:30]=[C:25]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([O:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=4)=[C:9]([CH:12]=3)[C:10]#[N:11])[CH:26]=2)[CH2:32][CH2:33]1
Reactant: N#Cc1cc(CO)ccc1Oc1ccnc(C(F)(F)F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (12.28 mg, 0.307 mmol), 5-(hydroxymethyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile (60.2 mg, 0.205 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one (38 mg, 0.205 mmol).
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].CI.[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][NH:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:12][CH:11]=1>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][N:19]([CH3:1])[C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.9 %

Procedure:
1.18 g of sodium bicarbonate and 0.876 ml of methyl iodide were added, whilst ice-cooling, to a solution of 3.3 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methoxycarbonylpyrrolidine [prepared as described in step (9) above] dissolved in 30 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography over silica gel (eluted with a 1:2 by volume mixture of ethyl acetate and benzene), to afford 968 mg of the title compound as an oil.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.O>CS(C)=O>[C:1]1([S:7]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 120 °C
Yield: 79.6 %

Procedure:
Sodium phenylsulfinate (16.4 g, 0.1 mol) and 4-fluorobenzaldehyde (12.4 g, 0.1 mol) were combined in dimethylsulfoxide (100 mL) and heated at 120° C. for 4 days. The cooled reaction was poured into water. The resulting crystals were filtered off and washed with water, then dissolved in ethyl acetate/dichloromethane, dried and concentrated in vacuo until crystallisation ensued. The mixture was diluted with isohexane and the crystals filtered off and washed with further isohexane to yield 4-(phenylsulfonyl)benzaldehyde (19.6 g, 80%). δH (500 MHz, d6 DMSO): 10.06 (1H, s), 8.16 (2H, d, J=8.3 Hz), 8.09 (2H, d, J=8.3 Hz), 7.99 (2H, d, J=7.7 Hz), 7.71 (1H, t, J=6.9 Hz), 7.63 (2H, t, J=7.7 Hz).