Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([OH:12])=O)=[CH:8][C:7]([CH3:13])=[N:6]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[CH3:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][C:47]([CH3:48])=[C:26]([NH:25][C:10]([C:9]5[N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=[C:7]([CH3:13])[CH:8]=5)=[O:12])[CH:27]=4)=[N:35][N:34]3[CH:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: COCCn1nc(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: COCCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 75.8 %

Procedure:
In the same manner as in Example 259 and using 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylic acid (150 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (230 mg, 77%) was obtained as a pale-green solid.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[C:9]([S-:11])#[N:10].[Na+]>C(O)C>[S:11]([CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4])[C:9]#[N:10]
Reactant: N#C[S-]
Reactant: CC(=O)C(Cl)CCCl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)C(CCCl)SC#N
Yield: 86.7 %

Procedure:
A solution of 7.8 g (0.05 moles) of 3,5-dichloro-2-pentanone with 4.15 g (0.051 moles) of sodium rhodanide in 50 cm3 of ethanol is boiled for 2 hours under stirring. Then the procedure described in Example 1 is followed. 7.7 g (87%) of 3-thiocyanato-5-chloro-2-pentanone are obtained, which is identical in all respect with the product of Example 1 after distillation.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:17][C@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH2:21])=[O:20])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)#[N:2].C([O-])([O-])=[O:27].[K+].[K+]>CO.OO>[NH2:21][C:19](=[O:20])[C@H:18]([NH:17][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[C:3]([C:1]([NH2:2])=[O:27])=[N:4][CH:5]=1)[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: Cc1cccc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C#N)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: Cc1cccc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C(N)=O)c1

Procedure:
To a mixture of (R)-2-(5-cyano-6-(m-tolylamino)pyrazin-2-ylamino)-4-methylpentanamide in methanol (1 ml) was added K2CO3 (excess)) and H2O2 (50%, a few drops). After completion, it was concentrated and purified by preparative HPLC to give (R)-5-(1-amino-4-methyl-1-oxopentan-2-ylamino)-3-(m-tolylamino)pyrazine-2-carboxamide (6 mg). MS found for C18H24N6O2 as (M+H)+ 357.3, UV: λ=253.4, 304.5.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl.[Cl:11][CH2:12][C:13](=[NH:16])OC>CO>[ClH:11].[CH3:1][O:2][N:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:13](=[NH:16])[CH2:12][Cl:11])[CH2:6][CH2:5]1
Reactant: CON=C1CCNCC1
Reactant: COC(=N)CCl
Agent: Cl
Solvent: CO
Product: CON=C1CCN(C(=N)CCl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.5 %

Procedure:
2 ml of a methanolic solution containing 1.064 g of 4-methoxyiminopiperidine was added to a solution of 1.195 g of methyl 2-chloroacetimidate hydrochloride in 4 ml of absolute methanol, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off and the concentrate was mixed with anhydrous ether. The crystals which separated out were collected by filtration and washed with ether, giving 1.5 g of 2-(4-methoxyiminopiperidin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:20]([CH3:26])[CH2:21][C:22]([O:24]C)=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:20]([CH3:26])[CH2:21][C:22]([OH:24])=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CC(C)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Solvent: CCO
Product: CC(CC(=O)O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reaction time: 1 h

Procedure:
2.4 g of methyl 3-(2-benzenesulphonamido-indan-5-yl)-butyrate are dissolved in 10 ml of ethanol, 2 ml of 15N sodium hydroxide solution are added, and saponification is carried out by boiling for 1 hour. The mixture is evaporated, the residue is dissolved in water, and the free acid is precipitated as a foamy material by adding hydrochloric acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si:28]([CH3:33])([CH3:32])[CH2:29][CH2:30]O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][Si:28]([CH3:33])([CH3:32])[CH2:29][CH2:30][O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: C[Si](C)(C)CCO
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a solution of 5-benzyloxy-2-(2-tert-butoxycarbonyl-vinyl)-benzoic acid (5.50 g, 15.5 mmol) in CH2Cl2 (100 mL) was added 2-trimethylsilyl-ethanol (3.67 g, 31.0 mmol), EDC (5.36 g, 27.9 mmol), and DMAP (3.67 g, 31.0 mmol). The resulting mixture was stirred at room temperature for 12 h, washed with aqueous NH4Cl (150 mL), and extracted with CH2Cl2 (100 mL). The combined organics were dried (Na2SO4) and concentrated. The residue was purified using silica gel chromatography (hexanes/EtOAc 9/1) to afford the title compound as an oil (5.90 g, 84%). 1H NMR (400 MHz, CDCl3): δ 0.07 (s, 9H), 1.14 (t, 2H, J=8.8 Hz), 1.52 (s, 9H), 4.41 (t, 2H, J=8.8 Hz), 5.10 (s, 2H), 6.20 (d, 1H, J=15.6 Hz), 7.13 (dd, 1H, J=3.0, 8.3 Hz), 7.34-7.44 (m, 5H), 7.50 (d, 1H, J=3.0 Hz), 7.53 (d, 1H, J=8.8 Hz), 8.41 (d, 1H, J=16.1 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C1(C)C=CC=CC=1.CS(C)=O>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:29](=[O:30])[NH:28][C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)[C:9]#[N:10]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
The solution of 4.9 g of the 1-methyl-β-oxo-2-pyrrolpropionitrile in 50 ml of toluene, 5 ml of dimethylsulfoxide and 4 g of triethylamine is treated with the solution of 5.7 g of p-nitrophenylisocyanate in the minimum amount of toluene while stirring. After standing overnight it is evaporated and the residue taken up in methanol. The solution is filtered, diluted with water and 6 ml of triethylamine, washed with ethyl acetate, and the washings extracted once with 5% aqueous sodium hydroxide. The combined aqueous solutions are acidified with 5 N hydrochloric acid and the precipitate collected. It is washed with water, triturated with methanol-ethanol and recrystallized from dimethylformamide, to yield the 1-methyl-β-oxo-α-(p-nitrophenylcarbamoyl)-2-pyrrolpropionitrile melting at 245°-250° with decomposition.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:23])[CH:5]3O[C:6]43[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]4.S(=O)(=O)(O)O.[N-:29]=[N+:30]=[N-:31].[Na+].Cl>CS(C)=O.O>[CH2:1]1[C@@H:3]2[C:4](=[O:23])[C:5]([N:29]=[N+:30]=[N-:31])=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC45OC4C(=O)[C@H]4CC4[C@]35C)[C@@H]1CCC2=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C(N=[N+]=[N-])C(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Temperature: 85 °C
Yield: 70 %

Procedure:
To a stirred solution of 1,2β-methylen-4,5-epoxyandrostane-3,17-dione (0.50 g, 1.59 mmole) in dry dimethylsulfoxide (7.5 ml) is added conc. sulfuric acid (0.11 ml) and sodium azide (1.4 g). The resulting reaction mixture is heated at about 85° C. during 3 hours, cooled, poured into a mixture of water (50 ml) and conc. hydrochloric acid (4 ml), and extracted with ethyl acetate (3×50 ml). The combined organic extracts are dried over sodium sulfate, filtered and evaporated in vacuo to yield a solid which is purified by flash column chromatography eluting with n-hexane-diethyl ether 6:4. There are obtained 0.378 g (70% yield) of 1,2β-methylen-4-azidoandrost-4-ene-3,17-dione [I, R=--N, R1 =R2 =H; (a) and (b)=single bonds]
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2O[C:12]([CH3:25])=[CH:13][C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][NH2:27]>CO>[CH:1]1([NH:7][C:8]([C:10]2[N:27]([CH3:26])[C:12]([CH3:25])=[CH:13][C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCCCC2)o1
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCCCC2)n1C
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of 3-benzyloxy-6-methyl-4-oxo-4H-pyran-2-carboxylic acid cyclohexylamide (1.40 g, 4.1 mmol) in 5 ml of methanol, methylamine solution (9 ml of 2M solution in methanol, 16 mmol) was added. The resulting solution was stirred at 70 to 75° C. for overnight under the pressure in a sealed tube. The solvent was removed under reduced pressure gave light yellow solid as a crude product. The material was purified by column chromatography (elution gradient: 100% ethyl acetate to 25% methanol in ethyl acetate) to give the titled compound as white solid (1.20 g, 83.0%).
Reaction SMILES: [S:1]1[C:5]23[CH:13]=[CH:12][CH:11]=[CH:10][C:6]2=[N:7][CH:8]=[CH:9][C:4]3=[C:3]([C:14]([OH:16])=O)[CH2:2]1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[S:1]1[C:5]23[CH:13]=[CH:12][CH:11]=[CH:10][C:6]2=[N:7][CH:8]=[CH:9][C:4]3=[C:3]([C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(O)C1=C2C=CN=C3C=CC=CC32SC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C1=C2C=CN=C3C=CC=CC32SC1)N1CCCCC1
Yield: 38.9 %

Procedure:
In 5 ml of dimethylformamide were dissolved 458 mg of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid and 170 mg of piperidine, and 660 mg of DPPA (diphenylphosphorylazide) was added dropwise to the solution under ice-cooling. Then, 335 μl of triethylamine was added to the mixture and the resultant mixture was stirred overnight at room temperature. After the reaction was over, the reaction mixture was diluted with ethyl acetate and the solution was washed with an aqueous 5% citric acid solution, an aqueous 5% sodium hydrogencarbonate solution, and then a saturated aqueous sodium chloride solution and thereafter dried with sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (solvent: chloroform) and then recrystallized from a mixture of chloroform and ether to provide 230 mg (yield of 85%) of 1-(benzo[b]thieno[2,3-c]pyridine-3-carbonyl)-piperidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]=O)[C:11]3[O:15][CH:14]=[CH:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1.[NH2:19][OH:20].CO.N1C=CC=CC=1>CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]=[N:19][OH:20])[C:11]3[O:15][CH:14]=[CH:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cc(-c2ccc(O)cc2)cc2ccoc12
Solvent: CO
Solvent: CCOCC
Solvent: c1ccncc1
Product: ON=Cc1cc(-c2ccc(O)cc2)cc2ccoc12
Temperature: 68 °C
Reaction time: 0.08 h

Procedure:
To a 10 ml round bottom flask was added 5-(4-hydroxyphenyl)-benzofuran-7-carbaldehyde (76 mg, 0.32 mmol), hydroxylamine hydrochlorode (44.4 mg, 0.64 mmol), anhydrous MeOH (2 ml), and anhydrous pyridine (0.06 ml, 0.67 mmol). The reaction was then heated to 68° C. and the reaction was done in 5 minutes. The reaction was then cooled to room temperature, dilute with ether, and the layers separated. The ether layer was washed with water, dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to 20 mg (25%) of product as a yellow solid: 1H NMR (300 MHz, DMSO-d6): δ 6.86 (2H, d, J=8.5 Hz), 7.03 (1H, d, J=2.1 Hz), 7.51 (2H, d, J=8.5 Hz), 7.73 (1H, d, J=1.4 Hz), 7.84 (1H, d, J=1.6 Hz), 8.08 (1H, d, J=2.1 Hz), 8.45 (1H, s) 9.56 (1H, s), 11.57 (1H, s); MS (ESI) m/z 254 ([M+H]+).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:32][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(Cl)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-chlorophenol (6.40 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.3 mg, 26.9% yield) as a thick oil: 1H NMR 67 7.36 (s, 1H), 7.35–7.22 (m, 7H), 7.12 (m, 2H), 6.97 (apparent d, 1H, J=7.2 Hz), 6.77 (m, 2H), 5.23 (m, 1H), 3.18 (m, 2H), 2.70 (m, 2H), 2.50 (m, 2H), 2.40–1.80 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 491.4 (M+R)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzoic acid (4.9 g, 35.3 mmol), benzyl bromide (3.8 mL, 31.7 mmol), and cesium carbonate (17.2 g, 53 mmol) in DMF (50 mL) at room temperature was stirred for 24 hours, diluted with water, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI) m/e 248 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:14])[NH:10][C:11](=[O:13])[CH:12]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[CH:19]=[N+]=[N-])[CH3:16]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH:19]([C:18]([O:17][CH2:15][CH3:16])=[O:22])[CH:12]2[C:11](=[O:13])[NH:10][C:9]3=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1C=C(c2ccc(Br)cc2)C(=O)N1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C2C(=O)NC(=O)C21c1ccc(Br)cc1
Yield: 57.3 %

Procedure:
To a solution of 3-(4-bromophenyl)-1H-pyrrole-2,5-dione (3.45 g, 13.74 mmol) obtained in Step 1 of Intermediate IX, in toluene (50 mL) was added ethyldiazoacetate (4.27 mL, 41.23 mmol). The reaction mixture was heated to reflux for 18 h. After completion of the reaction as confirmed by TLC, solvent was removed in vacuo to afford crude product which was purified by column chromatography (silica gel, 4:6 EtOAc:Pet. ether) to afford the title compound as a yellow solid (2.66 g, 57%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([F:15])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[Cl:19][C:4]([C:3]1[C:2]([F:1])=[CH:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:7]=1[F:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cc(F)c(C(=O)O)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of 2,6-difluoro-4-(methoxycarbonyl)benzoic acid (1.6 gm, 7.4 mmol) in dichloromethane (25 mL), oxalyl chloride (2.33 gm, 18.5 mmol) was added at 0° C. followed by addition of dimethylformamide (1 mL). The resulting reaction mixture was stirred for about 3 hours at an ambient temperature. Solvents were evaporated to afford crude solid methyl 4-(chlorocarbonyl)-3,5-difluorobenzoate (1.6 gm, 94.11% Yield). The resulting product was used as such for next step.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:46]=[CH:45][C:11]([CH2:12][O:13][C:14](=[O:44])[CH:15]([N:17]2[C@H:20]([S:21][C:22]([S:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[S:23])[C@@H:19]([O:41][CH3:42])[C:18]2=[O:43])O)=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:47]1([P:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[N+](C1C=CC(COC(=O)C(N2[C@H](SC(SCCNC(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=S)[C@@H](OC)C2=O)Cl)=CC=1)([O-])=O>O1CCCC1.C(N(CC)CC)C>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14](=[O:44])[C:15]([N:17]2[C@H:20]([S:21][C:22]([S:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[S:23])[C@@H:19]([O:41][CH3:42])[C:18]2=[O:43])=[P:53]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)=[CH:45][CH:46]=1)([O-:7])=[O:6]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CO[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 24, 0.12 ml of thionyl chloride and 0.23 ml of triethylamine in 0.23 ml of absolute tetrahydrofuran are added to a solution of 640 mg of 2-[(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester in 4.5 ml of absolute tetrahydrofuran After reacting and working up, 0.54 g of triphenylphosphine is added to the crude 2-[(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester, obtained as intermediate, in 1.15 ml of absolute tetrahydrofuran. After working up and chromatography over silica gel, the title compound is obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2].[CH2:28]([CH2:30][NH2:31])[OH:29]>CS(C)=O>[C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([NH:31][CH2:30][CH2:28][OH:29])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: NCCO
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Solvent: CS(C)=O
Product: CCOCn1c(NCCO)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A mixture of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (4.45 g, 10.0 mmol) potassium carbonate (2.76 g, 20.0 mmol) and ethanolamine (1.22 g, 20.0 mmol) in dimethylsulfoxide (30 ml) was stirred at 80° C. for two hours. After cooling to room temperature, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate (3×25 ml). The combined extracts were washed with saturated aqueous sodium chloride solution, with water, and dried over magnesium sulfate. Concentration under reduced pressure provided (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-8-(2-hydroxyethylamino)-3-methylxanthine (3.95 g, 93% yield) as a beige powder.
Reaction SMILES: Cl[CH2:2]Cl.[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1(C)[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1>CCOCC>[CH3:2][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:17](=[O:18])[C:14]2[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: Nc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. dichloromethane (300 mL) solution of 25 mL (274 mmol) of aniline was added 16 mL (123 mmol) para-toluoyl chloride over 10 min. The mixture was stirred at room temperature for 0.5 h, treated with 200 mL of ether and filtered immediately. The filtrate was washed with 1 M HCl (2×50 mL), 0.1 M NaOH (2×50 mL), and saturated aqueous ammonium chloride, dried over Na2SO4 and concentrated. Para-methylbenzanilide (17.3 g) was obtained as a tan solid and used directly.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([NH:7][S:8]([C:11]1[C:12]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)=[N:13][C:14](S(C)=O)=[N:15][CH:16]=1)(=[O:10])=[O:9])=[O:6])[CH3:3].[CH3:28][NH2:29].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH3:28][NH:29][C:14]1[N:13]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[C:11]([S:8]([NH:7][C:5]([NH:4][CH:2]([CH3:3])[CH3:1])=[O:6])(=[O:10])=[O:9])=[CH:16][N:15]=1
Reactant: Cc1cccc(Nc2nc(S(C)=O)ncc2S(=O)(=O)NC(=O)NC(C)C)c1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CNc1ncc(S(=O)(=O)NC(=O)NC(C)C)c(Nc2cccc(C)c2)n1
Temperature: 45 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
N-[[(1-Methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]-2-(methylsulfinyl)-5-pyrimidinesulfonamide (1.39 g, 3.38 mmol) was suspended in water (20 mL) and aqueous methylamine (6 mL, 40 wt % in H2O) was added to form a homogeneous solution. The mixture was stirred for five hours at 45° C., then diluted with an equal volume of ethanol and the solvents removed under reduced pressure to give a solid residue. The residue was suspended in water (20 mL) and 1.0N sodium hydroxide was added until the solution became homogeneous. Aqueous acetic acid 10% was added dropwise to form a white solid precipitate. The solid was filtered, washed three times, and dried in a vacuum oven at 75° C. overnight to yield 1.12 g (2.96 mmol, 88%) of pure product, m.p. 206°-207° C., as a white solid.