Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 165 °C
Yield: 100.2 %

Procedure:
A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 77; 0.30 g, 1.07 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.23 g, 1.61 mmol), and DIEA (0.23 ml, 1.34 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 165° C. for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a yellow solid (0.41 g, 99%). NMR (400 MHz) 12.22 (s, 1H), 10.98 (s, 1H), 8.70 (d, J=7.2 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 6.22 (d, J=9.2 Hz, 1H), 6.17 (s, 1H), 5.27 (m, 1H), 1.89 (m, 1H), 1.52 (d, J=6.4 Hz, 3H), 0.95 (m, 2H), 0.64 (m 2H). MS: Calcd.: 382; Found: [M+H]+ 383.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2].[CH:13]1(C(O)C)CCCC[CH2:14]1>>[C:1]([O:4][CH:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH2:2][CH2:13][CH3:14]
Reactant: CC(O)C1CCCCC1
Reactant: CC(=O)OC(C)C1CCCCC1
Product: CCCC(=O)OC(C)C1CCCCC1

Procedure:
1-cyclohexylethan-1-yl acetate; 1-cyclohexylethan-1-ol;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][C:7]=1[NH2:8].[CH2:19](N(CCO)CCO)[CH2:20]O.[OH-].[NH4+]>C(O)(=O)C>[CH3:19][C:20]1[N:8]=[C:7]2[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=[C:2]2[N:1]=1
Reactant: CCOC(=O)c1cc(N)c(N)nc1C(=O)OCC
Reactant: OCCN(CCO)CCO
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2nc(C)nc-2[nH]c1C(=O)OCC
Temperature: 0 °C

Procedure:
Diethyl 5,6-diamino-2,3-pyridinedicarboxylate (10.38 g, 0.041 mol) is stirred under an N2 atmosphere in 100 mL glacial acetic acid, to give a clear orange solution. Trietbylorthoacetate (TEOA), (0.19 mol ) is then added and the mixture is heated to reflux for 15 hours. The cooled solution is poured into ice water and neutralized with ammonium hydroxide. The solution is extracted with ethyl acetate, the combined organic layers washed with brine. dried over Na2SO4, filtered and concentrated to an oil. The oil is taken up in ethyl acetate and the desired product is precipitated by the addition of hexanes in two crops of beige solid, totalling 8.11 g (71.3%), having a melting point of 164°-165° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][N:6]([C:8]([NH:10][CH2:11][CH3:12])=[NH:9])[N:5]=[CH:4]1)[CH3:2].CCN(C(C)C)C(C)C.Cl[S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])(=[O:25])=[O:24]>C(Cl)Cl>[CH2:11]([NH:10][C:8](=[N:9][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])(=[O:25])=[O:24])[N:6]1[CH2:7][CH:3]([CH2:1][CH3:2])[CH:4]=[N:5]1)[CH3:12]
Reactant: CCNC(=N)N1CC(CC)C=N1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=NS(=O)(=O)c1cccc(C(=O)O)c1)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
Under N2 atmosphere, 1.0 g 4,N-diethyl-4,5-dihydro-pyrazole-1-carboxamidine was dissolved in 15 mL dry DCM, and 1.14 mL DiPEA and 1.31 g of 3-(chlorosulfonyl)benzoic acid were added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was purified by flash chromatography (first column with DCM/MeOH/acetic acid 84:15:1; second column with DCM/MeOH/NH4OH 84:15:1) to yield 0.08 g (4%) of an off-white powder. 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.4 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H), 1.38-1.62 (m, 2H), 3.02-3.18 (m, 1H), 3.27-3.62 (m, 3H), 3.89-4.17 (m, 1H), 6.94 (s, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 8.49 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8]O)=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[N:3]=1.[CH2:44]=[O:45].Cl>O1CCOCC1>[C:6]([CH:11]1[CH:10]([C:6]2[C:7]3[CH2:8][O:45][CH2:44][NH:1][C:2]=3[N:3]=[C:4]([C:23]3[C:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)=[CH:27][CH:26]=[CH:25][C:24]=3[O:39][CH2:40][CH:41]3[CH2:43][CH2:42]3)[CH:5]=2)[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])([CH3:10])([CH3:7])[CH3:5]
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Reactant: C=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3C(C)(C)C)c3c(n2)NCOC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a stirred solution of tert-butyl 3-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-1-piperidinecarboxylate (0.501 g, 0.850 mmol) in 1,4-dioxane was added 37% formaldehyde solution (5.000 mL) and 1N HCl (5.000 mL). The mixture was stirred at room temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate/hexane=3/2) to give 1,1-dimethylethyl (tert-butyl)-3-{7-[2-[(cyclopropylmethyl)oxy]-6-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl}-1-piperidinecarboxylate as a colorless foam (0.319 g, yield; 62%).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])([C:6]1[S:7][C:8](F)=[C:9]([F:12])[C:10]=1[F:11])[OH:5].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:3][C:4]([C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])([C:6]1[S:7][C:8]([Br:1])=[C:9]([F:12])[C:10]=1[F:11])[OH:5]
Reactant: OC(F)(c1sc(F)c(F)c1F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OC(F)(c1sc(Br)c(F)c1F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (0.698 g) was added to a solution of 1 (1.80 g, 4.16 mmol) in CH2Cl2 (15 mL). After stirring overnight at room temperature, the mixture was neutralized with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3×20 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo (1.90 g, 89%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.CC1C=CC(S(O[CH2:46][CH:47]2[CH2:50][O:49][CH2:48]2)(=O)=O)=CC=1>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][N:1]([CH2:46][CH:47]6[CH2:50][O:49][CH2:48]6)[CH:5]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Product: c1cc(N2CCCNCC2)nc(-n2ncc3cnc(-c4cnn(CC5COC5)c4)cc32)c1
Yield: 51 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and oxetan-3-ylmethyl 4-methylbenzenesulfonate, 158 was obtained as a yellow solid (38 mg, 51%) over two steps. 1H-NMR (500 MHz, CD3OD) δ (ppm): 9.16-9.19 (m, 1H), 8.86-8.77 (m, 3H), 8.43-8.47 (m, 1H), 7.66-7.73 (m, 1H), 7.18-7.26 (m, 1H), 6.63-6.66 (m, 1H), 4.81-4.83 (m, 2H), 4.60-4.64 (m, 2H), 3.75-3.97 (m, 7H), 3.61-3.64 (m, 1H), 3.46-3.48 (m, 1H), 3.10-3.12 (m, 1H), 2.88-2.90 (m, 1H), 1.98-2.07 (m, 2H); MS (ESI) m/z: 431 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4]([C:13]([OH:15])=O)=[CH:3]1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:38][CH2:39][CH2:40][N:41]1[CH:45]=[CH:44][C:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[C:48]([Cl:54])[CH:47]=2)=[N:42]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:54][C:48]1[CH:47]=[C:46]([C:43]2[CH:44]=[CH:45][N:41]([CH2:40][CH2:39][NH:38][C:13]([C:4]3[NH:5][N:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2](=[O:1])[CH:3]=3)=[O:15])[N:42]=2)[CH:53]=[CH:52][C:49]=1[C:50]#[N:51]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(=O)n(-c4ccccc4)[nH]3)n2)cc1Cl
Yield: 17.3 %

Procedure:
5-Oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carboxylic acid (0.05 g; 0.24 mmol), HOBt (0.049 g; 0.37 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.07 g; 0.37 mmol) were added to 2.5 ml of DCM. To this a mixture of 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.06 g; 0.24 mmol) and DIPEA (0.064 ml; 0.37 mmol) was added dropwise and the mixture was stirred overnight after which 10 ml of DCM was added. The mixture was washed with 3×5 ml of water and the combined water phases were extracted with 2×5 ml of DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The product was purified with flash chromatography using DCM/MeOH as gradient eluent. The combined fractions gave 18 mg of the product. 1H-NMR (400 MHz; d6-DMSO): δ 1.23 (s, 1H), 3.65-3.70 (m, 2H), 4.37 (t, 2H), 5.83 (s, 1H), 6.97 (d, 1H), 7.31-7.35 (t, 1H), 7.45-7.49 (t, 2H), 7.76 (d, 2H), 7.85-7.89 (m, 2H), 7.94-7.96 (m, 1H), 8.09 (d, 1H), 8.28 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C(N(CC)CC)C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[Cl-].[Na+]>>[CH:27]1([NH:30][C:11](=[O:13])/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][CH2:28]1
Reactant: O=C(O)/C=C/CCc1ccccc1
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=C(/C=C/CCc1ccccc1)NC1CC1
Yield: 85 %

Procedure:
5-Phenyl-2E-pentenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.5 eq, cyclopropylamine 1.5 eq, quench with 10% sodium chloride solution, yield=85%.
Reaction SMILES: Cl[C:2]1(Cl)[CH2:7][O:6][CH2:5][CH2:4][O:3]1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[NH2:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:9][C:10]1[CH:11]=[C:12]([N:13]2[CH2:2][CH2:7][O:6][CH2:5][C:4]2=[O:3])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: ClC1(Cl)COCCO1
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(N2CCOCC2=O)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 66 h
Yield: 83 %

Procedure:
12.8 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) are added to a solution of 10.0 g (65.7 mmol) of 3-methyl-4-nitroaniline in 250 ml of acetonitrile, and the mixture is stirred at 80° C. for 66 hours. The reaction solution is cooled to room temperature, 42.8 g (131 mmol) of caesium carbonate are added, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is filtered, the residue is washed well with acetonitrile, and the filtrate is evaporated. The residue is recrystallised from a little acetonitrile, giving 12.8 g (83%) of 4-(3-methyl-4-nitrophenyl)morpholin-3-one as yellowish solid. ESI 236. 1H-NMR (d6-DMSO): δ=2.54 (s; 2H), δ=3.82 (t, J=5 Hz; 2H), 4.00 (t, J=5 Hz; 2H), 4.25 (s; 2H), 7.57 (m; 2H), 8.04 (d, J.=8 Hz; 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(#N)C>[CH2:35]([O:34][C:32]([C:31]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:6][N:7]2[CH:30]=1)=[O:33])[CH3:36]
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)c1cn2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)ccc2n1
Yield: 40.5 %

Procedure:
Compound 22 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.105 g (0.53 mmol) of ethyl 3-bromo-2-oxopropionate in 4 mL of acetonitrile. 0.05 g of the expected product is obtained in the form of a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>ClCCl>[O:48]=[S@@:17]1[C@@H:12]2[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:38](=[O:39])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[O:27])=[C:15]([O:18][S:19]([C:22]([F:24])([F:25])[F:23])(=[O:21])=[O:20])[CH2:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)C[S@](=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethanesulphonyloxy)ceph-3-em-4-carboxylate (1.0 g, 1.7 mmol) in dichloromethane (25 ml) was treated with a solution of m-chloroperbenzoic acid (70%) (0.45, 1.8 mmol) in dichloromethane (15 ml). After stirring at room temperature for 30 min the solvent was evaporated and the residue crystallised from dichloro-methane/hexane to give the title compound (775 mg, 75%); m/z (3-NOBA sodium) 625 (MNa+); νmax (KBr) 1793, 1736, 1649 cm-1 ; δH (CDCl3) 3.47 (1H, dd, J 18.4, 1.4 Hz), 3.63 (1H, d, J 15.6 Hz), 3.66 (1H, d, J 15.6 Hz), 3.81 (3H, s), 3.87 (1H, d, J 18.4 Hz), 4.53 (1H, dd, J 4.8, 1.4 Hz), 5.20 (1H, d, J 11.7 Hz), 5.36 (1H, d, J 11.7 Hz), 6.07 (1H, dd, J 4.9, 9.8 Hz), 6.75 (1H, d, J 9.8 Hz), 6.89 (2H, d, J 8.6 Hz), 7.25-7.36 (7H, m).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:36][CH2:35][CH2:34][CH2:33][O:32][CH3:31])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: COCCCN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: COCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 20.9 mg (0.23 mmol) of 3-methoxypropylamine are reacted together by general method E. 29.8 mg (44.5% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:30]=[CH:29][C:11]3[N:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:13]([C:15]4[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=4[C:17]([NH:19][NH2:20])=[O:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[N:36]#[C:37]Br>O1CCOCC1.O>[NH2:36][C:37]1[O:18][C:17]([C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[C:13]2[N:12]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:11]3[CH:29]=[CH:30][C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)=[CH:9][C:10]=3[N:14]=2)=[N:19][N:20]=1
Reactant: N#CBr
Reactant: CC(C)(C)n1c(-c2ccccc2C(=O)NN)nc2cc(-c3cnc(N)nc3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)n1c(-c2ccccc2-c2nnc(N)o2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a vial is added 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-benzoic acid hydrazide (43 mg, 0.107 mmol) in 1,4-dioxane (2 mL), followed by the addition of NaHCO3 (13 mg, 0.155 mmol) in water (0.5 mL), then cyanogen bromide (13 mg, 0.123 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. The residue is loaded to a silica gel column. The column is eluted with 0-8% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford the title compound (30 mg, 66%) as an off-white solid. LCMS (ESMS): m/z 427.76 (M++1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[CH:9]1)[CH3:2].[C:20]([O:24][C:25](=[O:43])[C@H:26]([CH2:41][SH:42])[NH:27][S:28]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:23])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([S:42][CH2:41][C@H:26]([NH:27][S:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:25]([O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:43])[C:11]=2[CH:10]=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCCn1ccc2c(Cl)nc(C)nc21
Reactant: CC(C)(C)OC(=O)[C@H](CS)NS(=O)(=O)c1cccc2ccccc12
Product: CCOC(=O)CCCn1ccc2c(SC[C@H](NS(=O)(=O)c3cccc4ccccc34)C(=O)OC(C)(C)C)nc(C)nc21

Procedure:
Preparation in analogy to example 6c from 282 mg of 4-(4-chloro-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-butyric acid ethyl ester (example 2a) and 440 mg of N-(naphthalene-1-sulfonyl)-(R)-cysteine-tert-butyl ester. Yield: 110 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=5)=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol) in N-methylpyrrolidone (3 mL) was added pyridine-2-carbonylchloride hydrochloride (107 mg, 0.60 mmol), and the mixture was stirred at room temperature for 18 hr. A 5% aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→80/20) and crystallized from ethyl acetate to give the title compound (131 mg, yield 63%) as a white solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]2[CH3:31])=[O:24])[CH:20]=[C:19]([Cl:32])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:32][C:19]1[CH:20]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]2[CH3:31])=[O:24])[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1
Reactant: CC1CCCCN1C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCCCN1C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 5 h

Procedure:
A solution of {2-[3-chloro-5-(2-methyl-piperidine-1-carbonyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.065 g) in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 5 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.061 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [N:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:21]([CH2:28][CH2:29][CH3:30])[CH2:22][C:23]([O:25]CC)=[O:24].[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:18]=[CH:19][C:4]([N:1]2[C:21]([CH2:28][CH2:29][CH3:30])=[C:22]([C:23]([OH:25])=[O:24])[N:3]=[N:2]2)=[CH:5][CH:6]=1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCc2ccccc2)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
4-Azido-N-benzylbenzamide obtained in Example 58a) and ethyl 3-oxohexanoate (1.08 ml, 6.44 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (487 mg, 6.44 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 10 min, and then at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a grayish white powder (1.71 g, 4.70 mmol, 91.3%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)([O-])O.[K+].[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O.CC(C)=O>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(CN)OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(CNC(=O)c1ccc(Br)cc1)OC
Reaction time: 0.5 h

Procedure:
A solution of 24 mmol aminoacetaldehyde dimethylacetal was dissolved in 30 ml of water and treated with 25 mmol of potassium hydrogencarbonate. A solution of 23 mmol of 4-bromobenzoyl chloride in 50 ml of acetone was slowly added under stirring over a period of 30 min. The acetone was evaporated and the aqueous phase was extracted 3 times with ethyl acetate to yield the crude title compound as a slightly brown solid.