Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].O.O.O.O.O.O.[Br-].[Mg+2].[Br-]>CO>[CH3:1][O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Br-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2 g of sodium 3-acetoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate were dissolved in 20 ml of 35% v/v aqueous methanol, and 25 g of magnesium bromide hexahydrate were added to the solution. The resulting mixture was heated and stirred at 70° C. for 2 hours, after which it was treated as described in Example 2, to give 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylic acid in the form of a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([O:29][C:30](Cl)=[O:31])[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:30]([O:29][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 4.4 g 4-amino-piperidine-1-carboxylic acid benzyl ester hydrotrifluoroacetate and 5.3 ml triethylamine in 100 ml dichloromethane were added 1.8 ml butylchloroformate dropwise at 0° C. The suspension was stirred for 12 h, diluted with dichloromethane and washed with 0.1 M HCl and aqueous NaHCO3. The crude product was purified by flash chromatography on silica using ethyl acetate/heptan 1:2 as eluent.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]12[CH2:18][CH2:17][CH2:16][C:15]1([CH2:19][NH2:20])[CH2:14][CH2:13][CH2:12]2>>[N:11]12[CH2:18][CH2:17][CH2:16][C:15]1([CH2:19][NH:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:14][CH2:13][CH2:12]2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: NCC12CCCN1CCC2
Product: O=[N+]([O-])c1ccc(NCC23CCCN2CCC3)cc1
Yield: 74.4 %

Procedure:
p-Chloronitrobenzene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound as an oil in a yield of 74.4 %.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20].[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH:15][C:19](=[O:20])[CH2:18][O:17][CH3:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CCN)CCC2
Reactant: COCC(=O)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COCC(=O)NCCC1CCCc2ccc(OC)cc21

Procedure:
N-[2-(1,2,3,4-tetrahydro-7-methoxynaphthalen-1-yl)ethyl]amine was resolved according to the general procedure described in example 1 using L-tartartic add and was shown to have an enantiomeric excess of ≤99% by HPLC analysis. The HPLC analyses were carried out as described in example 3. The amine was converted to the amide according to General Procedure A using methoxyacetyl chloride. The final product was purified by reversed phase HPLC using acetonitrile/water to give a white solid. m.p.=58°-60° C.; 1H NMR (300 MHz, CDCl3) δ6.96 (d, J=8 Hz, 1H), 6.67 (s, 1H), 6.65 (m, 1H), 6.50 (bs, 1H), 3.86 (s, 2H), 3.76 (s, 3H), 3.43 (m, 2H), 3.38 (s, 3H), 2.79 (m, 1H), 2.66 (bm, 2H), 1.9-1.7 (bm, 4H), 1.67-1.63 (m, 2H); 3C NMR (75 MHz, CDCl3) δ169.44, 157.57, 141.26, 130.03, 129.24, 113.36, 111.82, 72.03, 59.17, 55.30, 36.94, 36.47, 35.66, 28.74, 27.52, 20.02; IR (KBr) 1658 cm-1 ; MS (DCI) m/e (MH)278; Analysis calc'd for C16H23N1O3 : C, 69.29; H, 8.36; N, 5.05; found: C, 69.17; H, 8.37; N, 4.92; [α] (20° C., 589 nm, CHCl3)=+6.96.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[NH:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([S:22][C:23]3[CH:24]=[C:25]([C:29]4([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[N:11]=1>>[CH3:3][N:4](/[CH:6]=[N:37]/[C:35]([C:29]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([S:22][C:19]3[CH:18]=[CH:17][C:16]([N:12]4[C:13](=[O:15])[NH:14][C:10]([CH3:9])=[N:11]4)=[CH:21][CH:20]=3)[CH:24]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)=[O:36])[CH3:5]
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C(N)=O)CCOCC4)c3)cc2)c(=O)[nH]1
Reactant: COC(OC)N(C)C
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)/N=C/N(C)C)CCOCC4)c3)cc2)c(=O)[nH]1

Procedure:
N,N-Dimethylformamide dimethyl acetal (15 mL) was added to 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxamide (2.0 g, 4.88 mmol) (example 10) and the reaction mixture was refluxed for about 2 hours. The solvent was evaporated under reduced pressure to obtain a light brown paste. Yield: 3.0 g.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:7]=1>CO.C(#N)C>[Cl:5][C:6]1[N:11]=[C:10]([NH:4][CH:1]([CH3:3])[CH3:2])[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:7]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: CC(C)N
Solvent: CC#N
Solvent: CO
Product: CC(C)Nc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A solution of isopropylamine (0.102 mL, 1.20 mmol) in methanol (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (104 mg, 0.40 mmol) in acetonitrile (2.0 mL). The reaction mixture was stirred overnight at rt. The mixture was purified by preparative HPLC yielding the title compound 63 mg (56%).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([NH2:20])[C:16]([O:18][CH3:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)(=[O:4])=[O:3].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])[C:25]([F:44])=[CH:24][N:23]=1>>[F:44][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])=[N:27][C:22]([NH:20][C:15]2[C:16]([O:18][CH3:19])=[CH:17][C:10]3[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CCS(C)(=O)=O)CC2
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1F
Product: COc1cc2c(cc1Nc1ncc(F)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCN(CCS(C)(=O)=O)CC2

Procedure:
The title compound was prepared from 3-(2-Methanesulfonyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2-Chloro-5-fluoro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.029 g, 25%). MP: 90-127° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.25 (d, 1H, J=8.8 Hz), 8.14 (s, 1H), 7.92-7.90 (m, 1H), 7.39 (s, 1H), 7.18 (d, 1H, J=1.8 Hz), 6.63 (s, 1H), 6.57 (d, 1H, J=1.8 Hz), 6.53 (dd, 1H, J=9.0 Hz and 1.9 Hz), 3.91 (s, 3H), 3.86 (s, 3H), 3.23-3.14 (m, 6H), 3.07 (s, 3H), 3.02 (t, 2H, J=6.3 Hz), 2.88-2.81 (m, 4H), 2.72-2.66 (m, 4H), 2.65-2.59 (m, 4H), 2.38 (s, 3H). MS: 614.27 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:11].C(N(CC)CC)C.[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[OH:11][C:5]1[CH:6]=[C:7]([NH:10][C:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:27])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:12]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)c1ccc(N)cc1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(NC(=O)N2CCOCC2)cc1O
Temperature: 25 °C
Yield: 15.6 %

Procedure:
A solution of 4-amino-2-hydroxy-benzoic acid methyl ester (1.0 g, 6 mmol) and triethylamine (0.8 mL, 6 mmol) in CHCl3 (25 mL) was treated with morpholine-4-carbonyl chloride (4.2 mL, 48 mmol) and stirred at reflux for 72 h. After cooling to room temperature, the solution was washed with 5% aqueous hydrochloric acid (25 mL), saturated aqueous sodium bicarbonate (25 mL), and brine (25 mL), dried over Na2SO4, and concentrated to an orange solid. The crude solid was triturated with CHCl3 (10 mL) to afford the product as an off-white solid (0.25 g, 15%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C(O[CH:16](OC(C)(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>CN(C=O)C>[CH3:16][N:17]([CH:19]=[C:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[NH:1][C:2]1=[O:10])[CH3:18]
Reactant: O=C1Cc2ncccc2N1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2cccnc21

Procedure:
This monomer was generated in situ (during library synthesis) from 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and dimethylformamide di-t-butylacetal in DMF.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@H:4]([C@@H:12]([CH3:14])[OH:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[C@@H:12]([CH3:14])[OH:13])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: C[C@@H](O)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C[C@@H](O)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-threoninamide (981 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1764 mg) in 2-propanol (10 mL) was added piperidinium acetate (755 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (560 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1[NH2:8].[N:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=O)=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[CH:25][CH:24]=1>>[CH2:9]([N:6]1[C:7]2[N:8]=[C:40]([CH2:39][C:36]3[CH:35]=[CH:34][C:33]([S:30]([NH:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)(=[O:31])=[O:32])=[CH:38][CH:37]=3)[NH:1][C:2]=2[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)Cc1ccc(S(=O)(=O)Nc2ccncc2)cc1
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(S(=O)(=O)Nc4ccncc4)cc3)nc21

Procedure:
Prepared from 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (30.6 mg, 0.1 mmol) and [4-(pyridin-4-ylsulfamoyl)-phenyl]-acetic acid. 4-[3-Butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-N-pyridin-4-yl-benzenesulfonamide was obtained as a colorless solid; 1H NMR (DMSO-d6, 300 MHz) δH 13.50 (s, 1H), 12.65 (broad s, 1H), 8.00–7.80 (m, 2H), 7.75–7.60 (m, 2H), 7.55–7.35 (m, 2H), 7.30–6.80 (m, 6H), 5.08 (s, 2H), 4.11 (s, 2H), 3.93 (t, J=7.3 Hz, 2H), 1.70–1.50 (m, 2H), 1.35–1.15 (m, 2H), 0.83 (t, J=7.1 Hz, 3H); FAB-HRMS m/e calculated for C28H27FN6O4S (M+H)+ 563.1877, found 563.1858.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][CH:13]([C:17]#[C:18][CH3:19])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]([OH:42])([CH3:41])[C:37]([F:40])([F:39])[F:38])=[CH:32][N:31]=1>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:30]3[N:31]=[CH:32][C:33]([C:36]([OH:42])([CH3:41])[C:37]([F:38])([F:39])[F:40])=[CH:34][N:35]=3)[CH:13]([C:17]#[C:18][CH3:19])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Reactant: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 140 °C
Yield: 48.1 %

Procedure:
To a 20 mL vial was added 1-((6-chloro-3-pyridinyl)sulfonyl)-3-(1-propyn-1-yl)piperazine (1.70 g, 7.47 mmol, Example 240, Step 4), diisopropylethylamine (4.20 mL, 24.2 mmol), and NMP (8.0 mL), and 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (1.4 g, 6.37 mmol, Intermediate E). The vial was sealed and heated at 140° C. for 9 h. The reaction mixture was cooled to rt and partitioned between EtOAc (200 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (2×75 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (120 g of silica, 10 to 50% EtOAc in hexanes) to afford 2-(2-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (1.5 g) as a light yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>CN(C=O)C>[C:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)#[N:22]
Reactant: N#Cc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#N)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (3.49 g, 17.3 mmol) was dissolved in DMF (35 ml) and cooled to 0° C. NaH (1.19 g, 24.8 mmol) was added in small portions over 20 minutes. The reaction was stirred for 30 minutes at 0° C. and 3-fluorobenzonitrile (3.1 ml, 29.0 mmol) added. The reaction was allowed to warm to r.t. over 1 h, stirred for a further 16 h and then quenched by addition of water. The reaction mixture was separated between water (500 ml) and DCM (2×500 ml). The combined organics were washed with water (500 ml), dried through a phase separator and evaporated in vacuo. Purification by flash silica gel chromatography using a 100 g Biotage column with a gradient of 5-40% EtOAc in heptane yielded the title compound as a white solid. Yield: 4.2 g (81%). 1H NMR (400 MHz, CDCl3) δ 7.34 (t, 1H, J=7.9 Hz), 7.21 (d, 1H, J=7.7), 7.14-7.08 (m, 2H), 4.46 (m, 1H), 3.67 (m, 2H), 3.33 (m, 2H), 1.90 (m, 2H), 1.72 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].C[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(OCC)C>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:10]1[NH:9][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: Cn1cccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 92.7 %

Procedure:
Preparation of4-nitro-2-trichloroacetyl-1-methylpyrrole(15). To a well stirred solution of trichloroacetylchloride (1 kg, 5.5 mole) in 1.5 liters of ethyl ether was added dropwise over a period of 3 hours a solution of N-methylpyrrole (14) (0.45 kg, 5.5 mole) in 1.5 liters of anhydrous ethyl ether. The reaction was allowed to stir for an additional 3 hours and quenched by the dropwise addition of a solution of 400 g of potassium carbonate in 1.5 liters of water. The layers were separated and the ether layer was concentrated in vacuo to provide 2-trichloroacetyl pyrrole (1.2 kg, 5.1 mole) as a yellow crystalline solid. which can be purified by recrystallization from benzene, but is sufficiently pure to be used without further purification. To a cooled (−40° C.) solution of 2-trichloroacetyl pyrrole (1.2 kg, 5.1 mole) in acetic anhydride (6 liters) flask equipped with a mechanical stirrer was added 440 ml of filming nitric acid over a period of I hour while maintaining a temperature of −40° C. The reaction was carefully allowed to warm to room temperature and stirred an additional 4 hours after which the mixture was cooled to −30° C. and isopropyl alcohol (6 liters) was added. The solution was stirred at −20° C. for 30 minutes during which time a white precipitate formed. The solution was allowed to stand for 15 minutes and the resulting precipitate collected by vacuum filtration to provide (15) (0.8 kg, 54% yield). TLC (7:2 benzene/ethyl acetate) Rf 0.7; 1H NMR (DMSO-d6) δ8.55 (d, 1 H, J=1.7 Hz), 7.77 (d, 1 H, J=1.7 Hz), 3.98 (s, 3 H); 13C NMR (DMSO-d6) δ173.3, 134.7, 133.2, 121.1, 116.9, 95.0, 51.5; IR (KBr) 1694, 1516, 1423, 1314, 1183, 1113, 998, 750; FABMS m/e 269.936 (M−H 269.937 calc. for C7H5N2O3Cl3).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:21].O>CC#N>[CH3:17][O:16][CH2:15][CH2:14][N:4]1[C:5](=[O:13])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[CH3:19])=[CH:28][CH:27]=2)[C:3]1=[O:18]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Solvent: CC#N
Solvent: O
Product: COCCN1C(=O)C(Nc2ccc(NC(C)=O)cc2)=C(c2ccccc2)C1=O
Temperature: 140 °C
Yield: 45.6 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.26 mmol, 70 mg) and 4-aminoacetanilide (0.53 mmol, 79 mg) was dissolved in dry CH3CN (2 mL) and the reaction mixture was subjected twice to microwave heating single node 140° C. for 10 min. 0.3 mL Water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 45 mg (45%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.17 (bs, 1H), 7.78 (bs, 1H), 7.24-7.09 (m, 5H), 7.04-7.00 (m, 2H), 6.73-6.68 (m, 2H), 3.73 (t, J=5.7 Hz, 2H), 3.59 (t, J=5.7 Hz, 2H), 3.33 (s, 3H), 2.01 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)=[N:5][CH:4]=1)#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C>CO>[OH:23][B:14]1[C:13]2[CH:24]=[C:9]([O:8][C:6]3[S:7][C:3]([C:1](=[NH:2])[NH:27][OH:28])=[CH:4][N:5]=3)[CH:10]=[C:11]([CH3:25])[C:12]=2[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15]1
Reactant: NO
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C#N)s3)cc(C)c21
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=N)NO)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(6-(5-cyanothiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2.5 g, 7 mmol, 1 eq.) and hydroxylamine hydrochloride (1.21 g, 17.4 mmol, 2.5 eq.) in methanol was added triethylamine (3.41 ml, 24.5 mmol, 3.5 eq.). After stirring at room temperature overnight, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and then washed with water. The organic layers were collected, dried with Na2SO4 and evaporated to give the crude product as a yellow solid. The crude was used in subsequent steps without further purification.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=1>>[Cl:23][C:17]1[CH:16]=[C:15]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: N#Cc1ccc(N)cc1Cl
Product: N#Cc1ccc(S(=O)(=O)Cl)cc1Cl

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-amino-2-chloro-benzonitrile.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[N:41][CH:42]=2)O1>>[N:23]1([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[N:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Product: COC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Yield: 35 %

Procedure:
Compound 15a (1.50 g, 3.24 mmol) was subjected to Suzuki coupling conditions with methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate using the reaction conditions described in Example 1, Step G to obtain compound 15b as a yellow solid (600 mg, 35% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H24N6O4: 497.2 (M+H). Found 497.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:26](Br)[C:27]#[CH:28].O>CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)=[CH:10][C:5]2[N:6]([CH2:28][C:27]#[CH:26])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3[nH]c(=O)oc3cc2Cl)c1=O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1c(=O)oc2cc(Cl)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
0.20 g (0.58 mmol) of 3-(6-chlorobenzoxazolin-2-on-5-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 10 ml of DMF, and 0.026 g (0.65 mmol) of 60% sodium hydride was added thereto at room temperature, followed by stirring for 0.5 hour. Further, 0.09 g (0.76 mmol) of propargyl bromide was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.17 g (yield: 78%) of the desired product. Melting point: 187-189° C. H-NMR (400 MHz, CDCl3) δ value: 2.38(1H,t), 3.72(3H,s,), 4.60(2H,d), 6.80(1H,d), 7.18(1H,s), 7.37(1H,s), 7.43(1H,d)ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])[CH:23]=[C:22]([Cl:32])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][C:17](=O)[CH2:16]2)=[CH:11][CH:10]=1.Cl.[CH3:34][O:35][NH2:36]>N1C=CC=CC=1>[CH3:34][O:35][N:36]=[C:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[C:22]([Cl:32])=[CH:23][C:24]([O:26][CH2:27][CH:28]=[C:29]([Cl:30])[Cl:31])=[CH:25][C:2]=3[Cl:1])=[CH:14][CH:13]=2)[CH2:16]1
Reactant: O=C1CCCC(c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)C1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCCC(c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)C1

Procedure:
109 mg of 3-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-cyclohexanone and 21 mg of O-methylhydroxylamine hydrochloride are stirred in 5 ml of pyridine at 85° C. for 3 hours. The reaction mixture is concentrated and the residue is stirred with tert-butyl methyl ether and 0.5N hydrochloric acid. After concentration of the organic phase and purification over silica gel, the title compound is obtained in the form of a colourless oil.