Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].ClN1C(=O)CCC1=O.[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:31][C:30]([C:25]3[CH:26]=[C:27]([Cl:29])[CH:28]=[C:23]([Cl:22])[CH:24]=3)([C:32]([F:33])([F:35])[F:34])[O:8][N:7]=2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(C=NO)ccc1Br
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 35 °C
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
In a solution of 1.27 g of 4-bromo-3-nitrobenzaldoxime in 16 ml of N,N-dimethylformamide, 0.74 g of N-chlorosuccinic acid imide was added, and stirred at 35° C. for 90 minutes. Then, the reaction mixture was cooled with ice, 1.20 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 3 and 0.60 g of triethylamine were added, continued to stir at room temperature for 18 hours. After the completion of the reaction, the reaction mixture was poured in 50 ml of ice water, extracted with ethyl acetate (50 ml×2), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual solid was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:2 to 1:4 gradient), and 1.10 g of the aimed product was obtained as yellow crystal.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH2:18])[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:18][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Cc1csc([C@H](N)Cc2c[nH]c3ccccc23)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1csc([C@@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (R)-2-(1H-indol-3-yl)-1-(4-methylthiazol-2-yl)ethylamine (500 mg, 1.94 mmol) and 4-dimethylamino-4-phenylcyclohexanone (421 mg, 1.94 mmol) in anhydrous tetrahydrofuran (40 mL) was mixed with sodium sulphate (1.00 g) and stirred for 3 h at room temperature. After adding, acetic acid (291 mg, 287 μL, 4.85 mmol), sodium triacetoxyboron hydride (574 mg, 2.71 mmol) was added and the mixture stirred overnight at room temperature. The mixture was then filtered, the filtrate concentrated to low volume in a vacuum, the residue mixed with 1M potassium carbonate solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (876 mg) was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/methanol [95:5→9:1 and 1% ammonia in each case (33% in water)]. The non-polar diastereoisomer (450 mg) was purified once again by flash chromatography (38 g, 20×2.5 cm) with dichloromethane/methanol (300:9) and 1% ammonia (33% in water). The polar diastereoisomer (262 mg) was also purified once again by flash chromatography (18 g, 20×2.0 cm) with dichloromethane/methanol (24:1) and 1% ammonia (33% in water).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[N:7]([N:11](C)[C:12](=O)OCC)[CH:8]=[CH:9][CH:10]=1)=[O:5].O.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[N:7]([NH:11][CH3:12])[CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNn1cccc1C(=O)c1ccccc1Cl
Yield: 93.9 %

Procedure:
[2-(2-Chlorobenzoyl)-1H-pyrrol-1-yl]-methyl-carbamic acid, ethyl ester (39.2 g, 0.127 mol) was dissolved in 100 ml of ethanol and 200 ml of H2O containing sodium hydroxide (25 g, 0.625 mol). The reaction was refluxed for 18 hours followed by evaporation of the ethanol. The aqueous solution was extracted with three 300 ml portions of ethyl acetate, dried (MgSO4), filtered, and evaporated to give 28 g of an oil. This oil was distilled via Kugelrohr apparatus 125° (0.15 mmHg) to give 26.3 g of a solid. This solid was triturated with hexane to give 25.5 g (85%) of crystals, m.p. 56°-58°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].Br[CH2:13][CH2:14][CH:15]=[CH2:16]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][CH2:15][CH:14]=[CH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCOc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
To a solution of sodium 4-nitrophenolate (11 grams; 56 mmole) in dimethylformamide (50 ml.) is added 4-bromo-1-butene (5 g; 37 mmole). After 2.5 hours of heating at 100° C., the reaction mixture is diluted with 400 ml. of water and extracted with light petroleum ether. The ether extracts are re-extracted with cold 5% sodium hydroxide and then washed with water and dried over magnesium sulfate. This solution is evaporated under reduced pressure and the residual oil crystallized from petroleum ether at 0° to yield 4-(4-nitrophenoxy)-1-butene.
Reaction SMILES: [CH:1]1([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.[C:28]1(CCBr)C2C(=CC=CC=2)C=C[CH:29]=1>>[CH3:27][O:26][C:25]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][C:1]3[C:4]4[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:29]=[CH:28][CH:2]=3)[CH2:12][CH2:13]2)=[CH:18][C:19]2[O:23][CH2:22][CH2:21][C:20]=2[CH:24]=1
Reactant: BrCCc1cccc2ccccc12
Reactant: COc1cc2c(cc1N1CCN(CCC3Cc4ccccc43)CC1)OCC2
Product: COc1cc2c(cc1N1CCN(CCc3cccc4ccccc34)CC1)OCC2

Procedure:
Prepared in the same manner as the product of Example 3 but using 2-(naphth-1-yl)-1-bromoethane instead of 2-(benzocyclobutan-1-yl)-1-bromoethane.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:23](=NOC)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=1[NH:49][NH2:50].C(O)(=O)C>COCCO>[CH2:33]([C:32]1[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][CH:17]=2)=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:49]([C:41]2[CH:42]=[C:43]([N+:46]([O-:48])=[O:47])[CH:44]=[CH:45][C:40]=2[Cl:39])[N:50]=1)[CH2:34][CH2:35][CH3:36]
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=NOC)C(=O)OCC
Agent: Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 105 °C
Reaction time: 20 h
Yield: 49.5 %

Procedure:
A mixture of 3.07 g (5.79 mmol) of ethyl 3-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2-methoxyimino-4-oxooctanoate (from Step F), 5.00 g (22.3 mmol) of 2-chloro-5-nitrophenylhydrazine hydrochloride [prepared from 2-chloro-5-nitroaniline according to H. Stroh and G. Westphal, Chem. Ber., 96, 184 (1963)], 55 mL of glacial acetic acid, and 25 mL of 2-methoxyethanol was stirred under N2 at 105° C. for 20 hours. The cooled mixture was concentrated in vacuo and the residue was partitioned between 200 mL of 0.2N HCl and 200 mL of ethyl acetate. The organic layer was washed with H2O (200 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatography of the residue twice on silica gel (first column eluted with 2% MeOH in CH2Cl2, second column eluted with 1% MeOH in CH2Cl2) to provide 1.71 g (47%) of the title compound as a viscous, orange oil; homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 598 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.87 (t, J=7.3 Hz, 3H), 1.06 (t, J=7.1 Hz, 3H), 1.34 (m, 2H), 1.59 (m, 2H, partially obscured by H2O peak), 2.62 (t, J=7.8 Hz, 2H), 4.10 (s, 2H), overlapping 4.14 (q, J=7.0 Hz, 2H), 4.24 (s, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.32 (dd, J=7.5, 1.3 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.49 (m, 1H), 7.58 (m, 1H), 7.66 (d, J=8.8 Hz, 1 H), 8.14 (dd, J=7.9, 1.3 Hz, 1H), 8.26 (dd, J=8.8, 2.7 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:28][C:20]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=2[F:18])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A mixture of the bromide 41 (5.1 g, 20.5 mmol), potassium carbonate (5.65 g, 4 mmol) and 2-fluoro-4-nitrophenol (4.82 g, 30.7 mmol) was heated at 190° C. in diphenyl ether (25 ml) for 3 hrs. After cooling to room temperature it was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (eluent EtOAc:hexane, 3:1) to afford title compound 42 as a yellow solid (5.4 g, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.55 (d, J=5.28 Hz, 1H), 8.46 (dd, J=2.5 and 10.4 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.72 (t, J=8.4 Hz), 6.99 (d, J=5.47 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].Cl.[CH3:7][CH:8]1[CH2:10][NH:9]1>O>[NH2:5][CH:3]([CH3:4])[CH2:2][NH:1][CH2:7][CH:8]([NH2:9])[CH3:10]
Reactant: CC1CN1
Reactant: CC(N)CN
Agent: Cl
Solvent: O
Product: CC(N)CNCC(C)N
Temperature: 110 °C
Yield: 24 %

Procedure:
Into a 500 mL flask, 180 mL of de-ionized water was placed. To this, 120 mL of 1,2-diaminopropane (1.39 mol) was added and a condenser was fitted to the flask. 50 mL (0.507 mol) of hydrogen chloride (37%) was added dropwise and the reaction allowed to subside before adding 10 mL of 2-methylaziridine (0.142 mol). The solution was then heated to 110° C. for 25 hours. The solvent and excess 1,2-diaminopropane were then removed by vacuum distillation. The crude product was then distilled under vacuum (approximately 40 torr) with a boiling point of 110° C. The yield was 24% with 4.541 g obtained. The purity was determined by NMR, showing multiplets at 2.71, 2.35 and 0.91 ppm which corresponded to those in a commercial sample. There was an additional peak at 2.11 ppm which may be due to a structural isomer of the product.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[N:8]=C[N:6]3[CH:11]=[N:12][N:13]=[C:5]3[C:4]=2[CH:3]=1>CO.C(Cl)Cl>[Cl:1][C:2]1[S:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][CH:11]=[N:12][N:13]=2)[CH:3]=1
Reactant: Clc1cc2c(ncn3cnnc23)s1
Solvent: CO
Solvent: ClCCl
Product: Nc1sc(Cl)cc1-c1nnc[nH]1
Temperature: 60 °C

Procedure:
To a stirring mixture of 8-chlorothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (60 mg, 0.285 mmol) in MeOH (10 mL) was added N-methylethyl 1,2-diamine (106 mg, 1.4 mmol). The resulting mixture was warmed to 60° C. for 1 hr. The reaction mixture was cooled to rt and then diluted with DCM. This mixture was then washed several times with a saturated NH4Cl solution. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 5-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine. This amine was taken directly to the next coupling reaction without further purification. Retention time (min)=1.227, method [1], MS(ESI) 201.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[O:21]=[C:22]1[NH:26][C:25]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[C:24]([C:34](O)=[O:35])[S:23]1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:34]([C:24]2[S:23][C:22](=[O:21])[NH:26][C:25]=2[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[O:35])[CH2:6][CH2:7]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Yield: 26.5 %

Procedure:
Prepared as Example 1 using (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.158 g) and 2-oxo-4-(pentafluoroethyl)-2,3-dihydro-1,3-thiazole-5-carboxylic acid (0.130 g) to yield the title compound as a colourless solid (0.074 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:38][N:39]([CH3:48])[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42]Cl>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[N:39]([CH3:48])[CH3:38])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3N(C)C)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 46.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-(dimethylamino)benzyl chloride (0.51 g) as starting materials, 5-benzyloxy-N-({1-[(2-(dimethylamino)phenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g) was obtained.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Reactant: COc1ccc(N)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCn1c(=O)ccc2cnc(Nc3ccc(OC)cc3)cc21
Reaction time: 8 h
Yield: 57 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol) and p-anisidine (160 mg, 1.3 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (1.2 mL, 1.8 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a brown residue that was purified by silica gel chromatography eluting with 1:1 EtOAc hexanes then EtOAc. The product fractions were pooled and concentrated to a solid that was crystallized to give 1-ethyl-7-(4-methoxyphenylamino)-1H -[1,6]naphthyridin-2-one (87 mg, 57%): mp (2-propanol) 165-166° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][S:7][CH2:8][CH2:9][O:10][P:11]([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])=[O:12])[NH2:5].C(N(C(C)C)CC)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][S:7][CH2:8][CH2:9][O:10][P:11]([N:13]([CH2:14][CH2:15][Cl:16])[CH2:17][CH2:18][Cl:19])([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])=[O:12])[NH:5][S:38]([CH3:37])(=[O:40])=[O:39]
Reactant: COC(=O)[C@@H](N)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)NS(C)(=O)=O
Reaction time: 8 h

Procedure:
3-[[2-[[Bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-L-alanine methyl ester, 400 mg (0.8 mmol), was dissolved in 4 mL anhydrous tetrahydrofuran, and 550 μL (3.2 mmol) diisopropylethylamine added, followed by methanesulfonyl chloride, 181 mg (1.6 mmol). The reaction mixture was purged with argon and stirred overnight. After adding a further 275 μL (1.6 mmol) diisopropylethylamine, then tris(2-aminoethyl)amine-polystyrene resin, 480 mg (1.6 mmol), the mixture was agitated for 6 hours, then filtered and the filtrate evaporated to dryness under vacuum, giving N-(methanesulfonyl)-3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-L-alanine methyl ester, 397 mg. Purity was verified with ELSD and identity verified with 1H and 31P NMR.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3].C(NC1C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1)(=O)C.N12CCCN=C1CCCCC2.[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:4][C:5](=[O:15])[C:6](=[N+:29]=[N-:30])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Cc1ccc(F)c(F)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C=CCOC(=O)C(=[N+]=[N-])c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
(3,4-Difluoro-phenyl)acetic acid allyl ester (64 g) was dissolved in acetonitrile (400 mL) and 4-acetamidobenzenesulfonyl azide (p-ABSA, 87 g, 0.36 mol) was added and the mixture stirred at room temperature for 15 min. The mixture was then cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 58.6 mL) was added dropwise at 0° C. during 30 min. The mixture was allowed to warm up to rt (room temperature) and stirred at rt for 4-20 h (until TLC showed completion of reaction). Saturated ammonium chloride (500 mL) was added and the organic phase was separated from the water phase. The water phase was extracted with diethylether (3×200 mL) and the four combined organic phases were dried (Magnesium sulphate) and evaporated in vacuo. The resulting solid was extracted with a 50:50 mixture of diethylether/pentane (3×200 mL). The combined ether phases were evaporated in vacuo (keep temperature below 40°) and purified by flash column chromatography (silicagel, eluent: 10:90 mixture of diethylether/pentane). The yellow fractions were combined and evaporated in vacuo (keep temperature below 40°) to give 70 g diazo-(3,4-Difluoro-phenyl)acetic acid allyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][Br:14])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccn(C(=O)OC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc(CBr)n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
3-methyl pyrazole 1-carboxylic acid tert-butyl ester (4.0 g, 21.95 mmol) was dissolved in 73 mL of CCl4. N-bromosuccinimide (5.47 g, 30.73 mmol) and benzoyl peroxide (744 mg, 3.07 mmol) were added. This solution was warmed to reflux for 5.5 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and saturated NaHCO3 solution. The phases were separated, and the organic phase was extracted with brine, dried over Na2SO4, filtered and concentrated to give a yellow oil. Purification by column chromatography (SiO2, ISCO chromatography system, elution with 5 to 10% ethyl acetate in hexanes) provided 3-bromomethyl pyrazole 1-carboxylic acid tert-butyl ester (53-2) as a pale yellow oil (2.94 g, 51% yield). 1H NMR was consistent with desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:20])C>S(=O)(=O)(O)O>[OH:20][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC(F)(F)C(F)F)cc[n+]([O-])c1C
Agent: O=S(=O)(O)O
Product: Cc1c(OCC(F)(F)C(F)F)ccnc1CO
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Concentrated sulfuric acid (two drops) was added to a solution of 2,3-dimethyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine-1-oxide (2.6 g) in acetic anhydride (8 ml). The mixture was stirred at 110° C. for 4 hours, which was then concentrated. The residue was dissolved in methanol (20 ml), to which was added sodium hydroxide (1.2 g) dissolved in water (5 ml). The mixture was stirred at room temperature for 30 minutes, which was concentrated. To the residue was added water, and the mixture was subjected to extraction with ethyl acetate. The extract was dried on magnesium sulfate, followed by removal of the solvent by evaporation. The residue was chromatographed on a column of silica gel (50 g), eluted with chloroform-methanol (10:1), and recrystallized from isopropyl ether to yield 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine as yellow crystals, m.p. 67°-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](O)=[S:12])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:23][N:22]([CH3:21])[C:11]([C:6]1[NH:7][C:8]2[C:4]([C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[S:12]
Reactant: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared from 5-chloro-3-phenylthioindole-2-carboxylic acid (1.0 g, 3.30 mmol)) N,O-dimethylhydroxylamine hydrochloride (0.64 g, 6.6 mmol), triethylamine (1.0 mL, 7 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.6 mmol) in dimethylformamide according to the general procedure described in Example 1 for the preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide.