Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:19])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([F:18])[C:10]([C:13]([O:15]CC)=[O:14])=[N:11][CH:12]=1.Cl.O1CCOCC1>C1COCC1>[F:19][CH:4]([F:3])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([F:18])[C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: CCOC(=O)c1ncc(OCC(F)F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)c1ncc(OCC(F)F)cc1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 229.8 %

Procedure:
Sodium hydroxide (2 M in water, 2.43 mL, 4.86 mmol) is added to a solution of ethyl 5-(2,2-difluoroethoxy)-3-fluoro-pyridine-2-carboxylate (242 mg, 0.97 mmol) in THF (10 mL). The reaction is stirred at room temperature for 5 days. The reaction is quenched by the addition of 4 M HCl in dioxane (1.25 mL, 5 mmol) and the solution is concentrated to give the crude title compound (493 mg, 229%). ES/MS (m/e): 222.0 (M+1).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([N:27]([CH3:39])[C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)[CH3:18])=[O:15])[CH3:2].I([O-])(=O)(=O)=[O:41].[Na+].I([O-])(=O)(=O)=O>CC(C)=O.O>[CH2:1]([S:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([N:27]([CH3:39])[C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)[CH3:18])=[O:15])=[O:41])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCSCCCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)CCCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a stirred solution of 20-(11-(ethylthio)-undecanoyloxy)-4-methyl-5α-4-azapregnan-3-one (0.056 g, 0.1 mM) in acetone (5 mL) at room temperature was added a solution of sodium periodate (0.033 mg, 0.154 mM) in water (3 drops). After prolonged stirring with additional portions of the periodate added (0.046 g total) over 3 days, the solvents were removed in vacuo, and the residue extracted with methylene chloride. The methylene chloride was removed in vacuo, and the resulting residue was flash chromatographed on silica gel (30% acetone/methylene chloride eluant) to give the title compound as a glaze. MS M+ calculated for C34H59NO4 S, mw=577.90; observed m/e 577.
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)/[C:10](=[N:17]\[NH:18][C:19]([NH2:21])=[O:20])/[C:8]1=[O:9])([CH3:3])[CH3:2].C1(C)C=CC=CC=1>CN(C)C=O>[CH:22]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)/[C:10](=[N:17]/[NH:18][C:19]([NH2:21])=[O:20])/[C:8]1=[O:9])([CH3:24])[CH3:23]
Reactant: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)N(CCN1C(=O)/C(=N\NC(N)=O)c2ccccc21)C(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
1.10 Grams of (E)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone was suspended in a mixture of ml of dry toluene and 20 ml of dry N,N-dimethylformamide, and the suspension was stirred for 3 hours at 120° C. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from benzene-hexane to obtain 0.84 g of (Z)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 189°-191° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C@H:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:36])[C:33]=1[CH:34]=O)[C:28]([OH:30])=[O:29].C(O)(=O)C>CO>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][O:16][C@H:11]([CH2:10][N:9]2[C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=[C:34]2[C:33]2[C:32]([F:36])=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=2[F:24])[CH2:12]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=Cc1c(F)cc(C(=O)O)cc1F
Reactant: Cc1ccc(NC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c(N)c1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)nc(-c1c(F)cc(C(=O)O)cc1F)n2C[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
A mixture of (R)-tert-butyl 2-((2-amino-4-methylphenylamino)methyl)morpholine-4-carboxylate (600 mg, 1.87 mmol), 3,5-difluoro-4-formylbenzoic acid (347 mg, 1.87 mmol) and acetic acid (0.534 ml, 9.33 mmol) in methanol (15.0 ml) was stirred for 1.5 hr at room temperature. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, eluting with mixtures of EtOAc and heptane, to afford (R)-4-(1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3,5-difluorobenzoic acid (750 mg, 82%) as an oil. The oil was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; particle size: 5 μm). MS m/z 488.4 [M+H]+ (ESI), Rt 1.56 min.
Reaction SMILES: [CH:1]1([CH:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH:19]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][N:16]([S:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=4)(=[O:42])=[O:41])[CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2-Dicyclohexyl-N-((3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)acetamide from Example 53 (101 mg, 0.304 mmol), triethylamine (0.042 mL, 0.304 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.049 mL, 0.304 mmol) were combined in dichloromethane (2 mL). A catalytic amount of N,N-dimethylaminopyridine was added. The reaction was stirred at room temperature for 1 hour, LCMS showed product, and TLC showed no more starting material. The reaction was quenched with aqueous sodium bicarbonate and the aqueous layer was separated. The organic layers was concentrated to give a precipitate. The precipitate was washed with water and ether and dried under a stream of nitrogen to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.49 (d, J=6.3, 1H), 8.34 (s, 1H), 8.19 (d, J=7.9, 1H), 7.93 (d, J=7.8, 1H), 7.73 (t, J=7.8, 1H), 4.46-4.38 (m, 1H), 3.73 (dd, J=3.4, 9.3, 1H), 3.17 (dd, J=2.8, 9.7, 1H), 3.07 (ddd, J=6.4, 12.0, 23.6, 3H), 2.49 (dd, J=8.0, 15.9, 1H), 2.12 (t, J=7.2, 1H), 2.02-1.77 (m, 8H), 1.73 (dd, J=5.3, 9.0, 4H), 1.68-1.58 (m, 3H), 1.52 (ddd, J=3.2, 12.5, 14.7, 1H), 1.43 (ddd, J=3.1, 12.6, 15.0, 1H), 1.37-1.03 (m, 9H); MS (ESI+) m/z 541 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:28]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:29][CH2:30][CH2:31][N:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OC(=O)C)C>[CH2:39]([N:28]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][N:32]([CH2:33][CH2:34][O:35][C:8](=[O:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:36][CH2:37][O:38][C:8](=[O:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCN(CCO)CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCN(CCOC(=O)Nc1ccccc1)CCOC(=O)Nc1ccccc1

Procedure:
Phenyl isocyanate (3.85 g.) is added to a warm solution of N,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine (5.0 g.) in ethylacetate (20 ml.) and the mixture heated to reflux for one hour. The mixture is cooled, then taken to dryness under reduced pressure. The residue is triturated with carbon tetrachloride, filtered, and the filtrate evaporated to dryness. Ethyl acetate (25 ml.) is then added, the mixture cooled, filtered, washed with ethylacetate and dried in vacuo; m.p. 54°-6° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1
Reactant: COc1ccc(-c2cccc(N)c2)cn1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 84% yield: LCMS (ESI) m/z 403 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[CH2:16][CH2:15][CH2:14][N:5]1[C@@H](C(Cl)(Cl)Cl)[O:7][C:8]2=O.[NH3:17]>CO>[CH3:1][O:2][CH2:3][C@@:4]1([C:8]([NH2:17])=[O:7])[CH2:16][CH2:15][CH2:14][NH:5]1
Reactant: COC[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Reactant: N
Solvent: CO
Product: COC[C@@]1(C(N)=O)CCCN1
Reaction time: 48 h

Procedure:
A mixture of (3R,7aR)-7a-methoxymethyl-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (0.6 g) and 7M ammonia in methanol (6 ml) is stood at room temperature for 2 days in a sealed vessel. The reaction mixture is then evaporated to give the title compound as a pale yellow oil which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[S:25])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ncccc1OCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccccc1)Nc1ncccc1OCc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(4-chlorobenzyloxy)pyridine (3.37 g, 0,014 mol), phenyl isothiocyanate (2.33 g, 0,017 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 4.36 g (82%), m.p. 162°-164 ° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([CH3:24])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[NH:36][C:37]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([CH3:24])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[O:38]
Reactant: Cc1nc2nccc(Oc3ccc(N)c4ccccc34)c2[nH]c1=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: Cc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c4ccccc34)c2[nH]c1=O

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-3-methylpyrido[2,3-b]pyrazin-2(1H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a slightly yellow solid (28 mg, 42%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1=Cc2ccc(CCCCOC3CCCCO3)cc2Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1=Cc2ccc(CCCCO)cc2Cc2ccccc21
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A solution of ethyl (±)-3-[4-(2-tetrahydropyranyloxy)-1-butyl]-5H-dibenzo[a,d]cycloheptene-10-acetate (456.0 mg, 1.04 mmole) and p-toluenesulfonic acid monohydrate (60 mg, 0.31 mmole) in absolute EtOH (10 mL) was stirred at RT. After 2 hr, the reaction was quenched with 5% NaHCO3 (1 mL) and concentrated to remove the EtOH. The residue was diluted with H2O (2 mL) and extracted with CH2Cl2. Drying (MgSO4), concentration, and silica gel chromatography (1:1 EtOAc/hexanes) gave the title compound (342.4 mg, 93%) as a colorless oil: TLC (1:1 EtOAc/hexanes) Rf 0.49; 1H NMR (250 MHz, CDCl3) δ 6.85-7.25 (m, 7 H), 4.34 (d, J=15.1 Hz, 1 H), 4.08-4.30 (m, 2 H), 3.75-3.95 (m, 2 H), 3.53-3.72 (m, 2 H), 3.33 (dd, J=15.1, 4.1 Hz, 1 H), 2.95 (dd, J=15.1, 9.4 Hz, 1 H), 2.40-2.75 (m, 4 H), 1.45-1.80 (m, 4 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 353 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:23]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1cccnc1
Product: CN(C)CCN(C(=O)c1cccnc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and nicotinic acid chloride
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:16]1[CH2:15][N:14]([C:11]2[S:12][CH:13]=[C:9]([C:7]([N:4]3[CH2:3][CH2:2][S:1][CH2:6][CH2:5]3)=[O:8])[N:10]=2)[CH2:17]1)(=[O:26])[CH3:24]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCSCC3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCSCC3)cs2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 61.7 %

Procedure:
To a solution of 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (709 g, 1.95 mmol) (obtained as described in Reference Example 25(3)) in dimethylformamide (20 ml) was added potassium thioacetate (1.34 g, 11.7 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:n-hexane:methylene chloride (1:1:1) as the eluant to afford 3-acetylthio-1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)azetidine (413 mg, yield 64%) as a pale brown solid.
Reaction SMILES: O.[Na].[Na].[Na].[C:5]([C:8]1[N:9]=[N:10][NH:11][C:12]=1[SH:13])([OH:7])=[O:6].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.O.Cl>CC(C)=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[C:5]([OH:7])=[O:6])[CH2:28][S:27][C@H:22]12
Reactant: O=C(O)c1nn[nH]c1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3[nH]nnc3C(=O)O)CS[C@H]12

Procedure:
4-Carboxy-1,2,3-triazole-5-thiol trisodium salt hydrate (4.4 g., 20 mmol.) was added to a stirred suspension of 4.08 g. (15 mmol.) of 7-aminocephalosporanic acid in 30 ml. of water and 15 ml. of acetone. The reaction mixture was quickly acidified to pH 7.3 with dilute hydrochloric acid, then heated at 65° for 4.5 hours. The mixture was cooled (ice bath), brought to pH 2.4 with dilute hydrochloric acid and the precipitate was collected, washed with water and acetone and dried in vacuo over phosphorus pentoxide to give the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[C:7]=1[C:8]([OH:10])=[O:9]>O>[CH3:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(C)c1C(=O)O
Solvent: O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
271 ml of 98 percent nitric acid are initially taken at -5° C. and 106 g (0.55 mol) of the 2-methyl-6-acetamidobenzoic acid prepared in 1. are added in portions. After stirring at 10° C. for one hour, the reaction mixture is poured into a mixture of 540 g of ice and 270 ml of water. The deposited precipitate is filtered off with suction, washed with water and dried under reduced pressure at 50° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Oc1cc(Br)cc(F)c1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Fc1cc(Br)cc(OC2CCCCO2)c1F
Yield: 64.6 %

Procedure:
A solution of 5-bromo-2,3-difluorophenol (2.75 g, 13.16 mmol), 3,4-dihydro-2H-pyran (2.39 mL, 26.3 mmol) and PPTS (0.165 g, 0.658 mmol) in DCM (10 mL) was stirred for 1 h at rt. At this time, analytical HPLC showed that the reaction was complete. The reaction was concentrated in vacuo. The crude oily product was chromatographed [SiO2; continuous gradient of EtOAc/hexane (0% to 20% over 15 min)] to give the title compound (2.5 g, 8.5 mmol, 65% yield) as a clear oil. 1H NMR (CDCl3) δ: 7.17 (dt, J=6.4, 2.2 Hz, 1H), 6.99 (ddd, J=8.8, 6.2, 2.4 Hz, 1H), 5.45 (t, J=3.0 Hz, 1H), 3.88 (td, J=11.0, 3.0 Hz, 1H), 3.72-3.62 (m, 1H), 2.11-1.82 (m, 3H), 1.80-1.59 (m, 3H); 19F NMR (CDCl3) δ: −135.00, −158.84.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([CH:12]=[O:13])=[N:7]2.[OH-:19].[Na+].OO.Cl>CO.OO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([C:12]([OH:19])=[O:13])=[N:7]2
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a slurry of 5-bromo-3-(tert-butylamino)quinoxaline-2-carbaldehyde (306a) (250 mg, 0.81 mmol) in MeOH (0.4 mL) and NaOH 1.0 N (1.62 mL, 1.62 mmol) was added two drops H2O2 30% in water (0.10 mL, 1.01 mmol) from a pasteur pipette. The reaction was stirred rapidly at RT and became a yellow/orange solution. Additional 0.05 mL 30% aq H2O2 was added. After 30 min, additional 0.05 mL 30% aq H2O2 was added. After 30 min, the reaction mixture was treated with ice, acidified to pH <2 with 1.0 N HCl, and diluted with 10 mL water. The orange suspension was filtered, rinsing with 10 mL of water to give 5-bromo-3-(tert-butylamino)quinoxaline-2-carboxylic acid (0.26 g, 0.80 mmol, 99% yield) as an orange solid. m/z (ESI, +ve ion) 324.0/326.0 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[C:7](\[NH:11][C:12]([CH:14]1[CH2:16][C:15]1([CH3:18])[CH3:17])=[O:13])/[C:8]([OH:10])=[O:9].[SH:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].C([O-])([O-])=O.[Na+].[Na+]>O>[C:22]([C:21]1[C:20]([S:19][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[C:7](\[NH:11][C:12]([CH:14]2[CH2:16][C:15]2([CH3:18])[CH3:17])=[O:13])/[C:8]([OH:10])=[O:9])=[N:28][CH:27]=[CH:26][CH:25]=1)([OH:24])=[O:23]
Reactant: O=C(O)c1cccnc1S
Reactant: CC1(C)CC1C(=O)N/C(=C\CCCCBr)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC1C(=O)N/C(=C\CCCCSc1ncccc1C(=O)O)C(=O)O

Procedure:
A solution of 600.0 mg (1.89 mmole) of (+) Z-7-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid, 267.0 mg (1.72 mmole) of 2-mercaptonicotinic acid and 400.6 mg (3.78 mmole) of Na2CO3 in 3.0 ml of H2O was stirred under N2 at room temperature.
Reaction SMILES: [F:1][C:2]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH3:19][C:20]([S@:23]([NH:25][CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:18])([F:1])[C:14]([F:17])([F:16])[F:15])=[CH:6][CH:7]=1)[CH3:12])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(=O)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (3.2 g, an off-white solid) from 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanone (3.0 g, 11.0 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].[Cl-].[Na+]>>[P:7]([C:1]1[CH:6]=[C:5]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:4]=[CH:3][CH:2]=1)([OH:9])([OH:8])=[O:10]
Reactant: O=P(O)(O)c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Product: O=P(O)(O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 140 °C

Procedure:
The preparation was undertaken as a modification of the process for forming 3-carboxybenzenesulfonyl chloride as reported in J. Chem. Soc. (C), page 11 et seq. (1968) by R. J. W. Cremlyn. Phenylphosphonic acid was added in portions to chlorosulfonic acid; about 10 moles of chlorosulfonic acid per mole of phenylphosphonic acid were employed. The initial mixing step was exothermic, causing the temperature of the mixture to rise to about 90° C. After completion of the addition of the phenylphosphonic acid to the chlorosulfonic acid, the reaction mixture was heated to about 140° C. for about two hours. Reaction proceeded according to the equation ##STR5## Attempts to lower the molar ratio of chlorosulfonic acid: phenylphosphonic acid, by addition of sodium chloride (to remove sulfuric acid from the reaction mixture), caused uncontrollable frothing.