Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][CH2:36][CH2:37][CH2:38][S:39](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:41])=[O:40]>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][NH:11][S:39]([CH2:38][CH2:37][CH2:36][Cl:35])(=[O:41])=[O:40])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OC(C)(C)C

Procedure:
2-tert-Butoxycarbonylamino-3-octadecylcarbamoyloxypropylamine IVe2 is allowed to react by the same procedure as described in (4). m.p. 112°-115° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [NH3:1].[CH3:2][N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[N:5]=[C:4]1[CH3:12]>CO>[CH3:2][N:3]1[CH:7]=[C:6]([S:8]([NH2:1])(=[O:10])=[O:9])[N:5]=[C:4]1[CH3:12]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: N
Solvent: CO
Product: Cc1nc(S(N)(=O)=O)cn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A 7 mol/L solution of ammonia in methanol (2 mL) was added to 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (200 mg, 1.7 mmol) and the mixture was stirred at room temperature for 4 hours. The solvent in the reaction mixture was evaporated off under reduced pressure, and thereby 1,2-dimethyl-1H-imidazole-4-sulfonamide (Compound FG) (54 mg, yield: 60%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:7][C:8]=2[NH:9][C:10](=[O:12])[CH:11]=1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[N:7]=[C:8]3[C:3]([C:2]([CH3:1])=[CH:11][C:10](=[O:12])[NH:9]3)=[CH:4][CH:5]=2)[CH2:30][CH2:29]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: Cc1cc(=O)[nH]c2nc(OCCCC=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cc(=O)[nH]c2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
The crude 4-(5-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde from the previous reaction in 1,2-dichloroethane (30 mL) is treated with 1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.144 g, 4.20 mmol), followed by triethylamine (0.90 mL, 6.46 mmol) and sodium triacetoxyborohydride (0.955 g, 4.50 mmol). The cloudy yellow solution is stirred at room temperature for 1 hour. The mixture is quenched with H2O and saturated NaHCO3 solution and extracted with CH2Cl2. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to a yellow oil. The oil is purified by column chromatography (5:95 methano/vethyl acetate) to afford the title compound (0.97 g, 63% over 2 steps) as a white solid. mp 181–182° C. 1H NMR (CDCl3, 400 MHz): δ 7.57 (br s, 1H), 7.40 (d, 1H), 7.18–7.12 (m, 2H), 7.00–6.94 (m, 1H), 6.38 (d, 1H), 4.23 (t, 2H), 3.16–3.00 (m, 5H), 2.77–2.68 (m, 4H), 2.75–2.56 (m, 1H), 2.52–2.36 (m, 3H), 1.86–1.75 (m, 2H), 1.75–1.64 (m, 2H), 1.28 (d, 3H). MS ES: m/z=460.70, 462.58.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:32][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:31]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccccc2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 6-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.72 min.; [M+H]+: 403.01 g/mol.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24](O)=O>>[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[N:16]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(Cl)ccc3Cl)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 2,5-dichlorobenzoic acid: MS (ES) m/z 438 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OCC2CC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (400 mg, 1.18 mmol), anhydrous Cs2CO3 (769 mg, 2.36 mmol), and KI (40 mg, 0.24 mmol) in DMF (10 mL) is added bromomethylcyclopropane (229 μL, 2.36 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (30 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10-40% EtOAc in heptane) to give a pure product (10) as white solid (330 mg, 71%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][O:32][C@@H:33]1[C@@H:39]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])[O:38][C@H:35]([O:36][CH3:37])[C@@H:34]1[OH:51]>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][O:32][C@@H:33]1[C@@H:39]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])[O:38][C@H:35]([O:36][CH3:37])[C:34]1=[O:51]
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To an ice-cold suspension of Dess-Martin periodinane (50.0 g, 118 mmol) in anhydrous CH2Cl2 (350 mL) under argon (Ar) was added a solution of the compound from Step A (36.2 g, 75 mmol) in anhydrous CH2Cl2 (200 mL) dropwise over 0.5 h. The reaction mixture was stirred at 0° C. for 0.5 h and then at room temperature for 3 days. The mixture was diluted with anhydrous Et2O (600 mL) and poured into an ice-cold mixture of Na2S2O3.5H2O (180 g) in saturated aqueous NaHCO3 (1400 mL). The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 (600 mL), water (800 mL) and brine (600 mL), dried (MgSO4), filtered and evaporated to give the title compound (34.2 g) as a colorless oil, which was used without further purification in Step C below.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12](O)[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:12]1[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=1
Reactant: CCOc1cc(O)c2ccc(OC)c(C)c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(Cl)c2ccc(OC)c(C)c2n1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Ethoxy-7-methoxy-8-methyl-quinolin-4-ol (1.0 g, 4.3 mmol) was dissolved in POCl3 (21 mL) under a nitrogen atmosphere. The reaction was heated to 85° C. for 1 h. The reaction was cooled to 0° C. and ice was added slowly. After 30 min, pH was adjusted to 6 with 1N NaOH(aq). The solution was extracted with ethyl acetate (2×50 mL). The organic layers were dried with sodium sulfate, filtered and were concentrated. 4-Chloro-2-ethoxy-7-methoxy-8-methyl-quinoline (875 mg, 81%) was purified by silica gel chromatography to afford a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:16])[C:9]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>CN(C=O)C>[CH3:23][N:24]([CH3:29])[S:25]([N:6]1[C:5]2[CH:7]=[C:8]([Cl:16])[C:9]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:10][C:4]=2[N:3]=[C:2]1[Cl:1])(=[O:27])=[O:26]
Reactant: FC(F)(F)Oc1cc2nc(Cl)[nH]c2cc1Cl
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1c(Cl)nc2cc(OC(F)(F)F)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-Dichloro-5-trifluoromethoxy-1H-benzoimidazole (160 g, 0.59 mol, 1.0 equiv.) was dissolved in dry DMF (1.5 L) and then K2CO3 (98 g, 0.71 mol, 1.2 equiv.) and dimethylsulfamoyl chloride (85 g, 0.59 mol, 1.0 equiv.) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours to afford 2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic acid dimethylamide. Without isolation of 2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic acid dimethylamide, 1H-pyrazole-4-carboxylic acid ethyl ester (91 g, 0.65 mol, 1.1 equiv.) and K2CO3 (98 g, 0.71 mol, 1.2 equiv.) were added to the reaction mixture. The reaction mixture was stirred at 70° C. for 10 hours and cooled to room temperature, to afford 1-(6-chloro-1-dimethylsulfamoyl-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. To crude reaction mixture was added LiOH H2O (124 g, 2.95 mol, 5.0 equiv.) in 2.5 L water. The reaction solution was heated at 70° C. for 6 hours and then cooled to room temperature. Concentrated HCl was added to adjust pH=4.0. The precipitated solid was collected by filtration, washed with water and dried. The solid was recrystallized from hot EtOAc (˜3 L). After cooling to room temperature and filtration, the pure compound was obtained as a white solid (109 g, 0.31 mol, 54% over 3 steps). MS (ESI/CI): mass calcd. for C12H6ClF3N4O2, 346.0; m/z found, 347.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.79 (s, 1H), 13.06 (s, 1H), 8.91 (s, 1H), 8.33 (s, 1H), 7.79 (br d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30]OS(C)(=O)=O)[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:36]([F:39])([F:38])[F:37])[CH:10]=2)=[O:5])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:36]([F:39])([F:38])[F:37])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(COS(C)(=O)=O)cc1=O
Reactant: C1COCCN1
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CN2CCOCC2)cc1=O
Temperature: 45 °C
Reaction time: 3 h

Procedure:
4-[5-(6-Methanesulfonyloxymethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester 18 (123 mg, 0.214 mmol) was dissolved in dichloromethane (3 mL). Morpholine (47.3 μL, 0.537 mmol) was added via syringe. The mixture was stirred at 45° C. for 3 h. CH2Cl2 (50 ml) was added and the solution was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:05. 4-[5-(6-Morpholin-4-ylmethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester EHT 8935 was obtained (66 mg, 55%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:23][C:24]([C:26]1[O:27][C:28](Br)=[CH:29][C:30]=1[CH3:31])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([C:26]1[O:27][C:28]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:15])=[CH:29][C:30]=1[CH3:31])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(Br)oc1C(=O)NCc1ccccc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)oc1C(=O)NCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-5-bromo-3-methylfuran-2-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 22% yield: mp 191-192° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92 (t, J=6.2 Hz, 1H), 8.23 (d, J=7.9 Hz, 1H), 7.49-7.20 (m, 10H), 6.78 (s, 1H), 6.25 (dd, J=7.9, 2.7 Hz, 1H), 6.06 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.43 (d, J=6.2 Hz, 2H), 2.33 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.4, 160.7, 158.3, 143.7, 139.6, 137.1, 135.4, 134.5, 128.4, 128.3, 128.2, 128.0, 127.2, 126.7, 105.6, 101.8, 97.6, 69.9, 41.5, 11.0; MS (ES+) m/z 415.3 (M+1).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][C:10]([OH:12])=O)[C:4]=1[CH3:13])=[O:2].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][C:10]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:12])[C:4]=1[CH3:13])=[O:2]
Reactant: NCCN1CCCC1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Product: Cc1[nH]c(C=O)c(C)c1CC(=O)NCCN1CCCC1

Procedure:
(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid was reacted with 1-(2-aminoethyl)pyrrolidine using General Amidation Procedure 1 to give 2-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide. MS m/z 278 [M+1].
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:6].CN(C=O)C.[F:24][C:25]([F:29])([F:28])[CH2:26]I>>[CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[C:13]([O:14][CH2:26][C:25]([F:29])([F:28])[F:24])=[CH:12][CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])(=[O:6])=[O:7]
Reactant: FC(F)(F)CI
Reactant: CN(C)C=NS(=O)(=O)c1c(O)cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=NS(=O)(=O)c1c(OCC(F)(F)F)cccc1[N+](=O)[O-]
Reaction time: 20 h

Procedure:
To a solution of N-(1-dimethylamino-methylidene)-2-nitro-6-hydroxy-benzenesulfonamide (847 mg, 3.1 mmol) in DMF (10 mL) NaH (135 mg, 55% dispersion in Nujol, 3.1 mmol) is added under argon. After stirring for 15 min 2,2,2-trifluoro-ethyl iodide (2777 mg, 12.4 mmol) is added, and stirring is continued for 20 h. Volatiles are evaporated under reduced pressure, and the residue is partitioned between EtOAc and water. The organic phase is washed with saturated brine, dried (Na2SO4) and evaporated. Chromatography of the residue (silica gel, hexanes/EtOAc/acetone 2:1:3) gives N-(1-dimethylamino-methylidene)-2-nitro-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([F:27])[F:26])=[CH:21][CH:20]=1>C1COCC1>[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([F:27])[F:26])=[CH:21][CH:20]=2)[C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: FC(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (232 mg, 5.31 mmol) was added to a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (762 mg, 3.54 mmol, intermediate G) in THF (7 mL) at 0° C. After 15 min, a solution of 1-(bromomethyl)-4-(difluoromethyl)benzene (980 mg, 4.43 mmol) in THF (7 mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was carefully quenched with several grams of ice pellets. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified using silica gel column chromatography (0-30% EtOAc/hexanes) to afford the desired product (440 mg, 35% yield) as a white solid: LCMS (M+H)+ 356.3; 1H NMR (500 MHz, chloroform-d) δ 7.49 (d, J=8.1 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 6.65 (br. t, J=1.0 Hz, 1H), 4.56-4.44 (m, 2H), 4.38 (t, J=7.5 Hz, 1H), 3.27 (ddd, J=9.7, 8.7, 3.4 Hz, 1H), 3.13 (dt, J=9.7, 7.4 Hz, 1H), 2.36-2.27 (m, 1H), 1.98-1.90 (m, 1H), 0.96 (br. s., 9H), 0.22-0.20 (m, 3H), 0.20-0.18 (m, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:7]=1[C:8](OC)=[O:9])[CH3:5]>C(O)CCC>[CH2:4]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:7]=1[C:8]([NH:2][NH2:3])=[O:9])[CH3:5]
Reactant: NN
Reactant: CCc1c(C(=O)OC)ccc(O)c1C
Solvent: CCCCO
Solvent: O
Product: CCc1c(C(=O)NN)ccc(O)c1C
Yield: 68 %

Procedure:
1 ml of butanol and 4.5 ml of hydrazine hydrate are added to 1.88 g of methyl 2-ethyl-4-hydroxy-3-methylbenzoate in a screw-lid vial, and the mixture is stirred at 100° C. until the hydrazide formation is complete. The cooled reaction mixture is poured onto water, the precipitate is filtered off with suction and dried. Purification by recrystallisation from water/1 -propanol gives 1.28 g of 2-ethyl-4-hydroxy-3-methylbenzohydrazide as colourless crystals (68%); MS-FAB (M+H+)=1.95.1; Rf (polar method): 0.99 min.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:16])[CH2:14][CH3:15]>>[N+:10]([C:3]1[CH:4]=[C:5]([CH:6]=[N:16][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:9][C:2]=1[NH:10][CH2:3][CH2:2][CH3:9])([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCN
Product: CCCN=Cc1ccc(NCCC)c([N+](=O)[O-])c1

Procedure:
(a-1) A solution of 40 parts of 4-chloro-3-nitrobenzaldehyde and 338 parts of 1-propanamine was stirred and refluxed for 1.50 hour. The reaction mixture was evaporqted, yielding 53.7 parts of 2-nitro-N-propyl-4-[(propylimino)methyl]benzenamine as a residue (int. 1).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)([O-:34])=[O:33]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N+:32]([O-:34])=[O:33])[CH:24]=1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccccc1[N+](=O)[O-]
Yield: 21.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-nitrophenylboronic acid (31 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with 30% ethyl acetate/hexanes and then by RP HPLC to afford the product as a white solid (12 mg, 21%). MS m/e 452.18 (M+H+)
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17]([CH3:51])([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:33][CH2:32]2)=[C:26]([C:47]([O:49][CH3:50])=[O:48])[CH:25]=1)=[O:21])[CH3:18]>C(Cl)Cl>[CH3:18][C:17]([CH3:51])([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])[CH2:33][CH2:32]2)=[C:26]([C:47]([O:49][CH3:50])=[O:48])[CH:25]=1)=[O:21])[CH3:16]
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N(c1ccc(CNC(=O)OC(C)(C)C)cc1C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 96 h
Yield: 47.8 %

Procedure:
2.08 g of DIEA and then 1.745 g of ethyl chloroformate are added to a solution of 1.6 g of benzyl 4-{[4-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 5.2 in 11 ml of DCM. The mixture is stirred at AT for 4 days. It is evaporated under reduced pressure. The residue is taken up in 10 ml of pyridine (10 ml) and 0.7 g of ethyl chloroformate is added. The mixture is stirred at AT for 4 h 00. It is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (10/90, v/v) as far as (30/70, v/v), to give 0.875 g of the expected product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][NH:4][C:3]1=[O:6].O.[C:8]1([CH2:14][C:15](O)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1>[C:8]1([CH2:14][C:15]([NH:1][C@H:2]2[CH2:5][NH:4][C:3]2=[O:6])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: N[C@H]1CNC1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@H]1CNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
(S)-3-Amino-2-azetidinone (0.86 g) is suspended in 40 ml of tetrahydrofuran and 5 ml of water is added. A solution of phenylacetic acid (1.36 g) in 10 ml of tetrahydrofuran is added, followed by N-ethyl-N'-(3-dimethylamino)propylcarbodiimide, hydrochloride (1.92 g). The solution is adjusted to pH 4 by the addition of 2N hydrochloric acid and stirred for 1 hour at room temperature. The tetrahydrofuran is removed by evaporation and the remaining suspension is filtered to yield 1 g of (S)-3-[[(phenylmethyl)carbonyl]amino]-2-azetidinone, melting point 182° C., dec.