Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.[CH:26]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:28][CH2:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH:26]2[CH2:27][CH2:28]2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[N:14]=[CH:15][CH:16]=[N:17]2)=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Reactant: COC(=O)CNCc1ccc(-n2nccn2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1ccc(-n2nccn2)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of 79.5 g (323.2 mmol) of the compound of stage 3.2, 80.9 ml (581.6 mmol) of Et3N and 1.97 g (16.1 mmol) of DMAP in 1000 ml of CH2Cl2, a solution of 99.6 g (404 mmol ) of 4-cyclopropylmethoxy-benzenesulfonyl chloride in 150 ml of CH2Cl2 is added and stirred for 60 min. at 0-5° C. After stirring for additional 18 h at r.t., the reaction mixture is quenched with ice water and extracted with CH2Cl2. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by CC on silica gel (n-Hexane:AcOEt=4:1-2:1) to give the title compound as colorless solid; 1H-NMR (400 MHz, CDCl3): 0.35-0.45 (m, 2H), 0.65-0.75 (m, 2H), 1.25-1.35 (m, 1H), 3.58 (s, 3H), 3.87 (d, 2H, J=7.04 Hz), 3.94 (s, 2H), 4.52 (s, 2H), 6.99 (d, 2H, J=7.04 Hz), 7.37 (d, 2H, J=8.56 Hz), 7.81(s, 2H), 7.82 (d, 2H, J=7.04 Hz), 8.02 (d, 2H, J=8.56 Hz).
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[I:20]C1C=CC=CC=1N>>[I:20][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: Nc1ccccc1I
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Product: O=C(Nc1ccccc1I)C1CCCCC1
Yield: 84 %

Procedure:
This compound was prepared following the procedure described for compound 26A in example 26, except that 2-iodoaniline was used in place of 2-trifluoromethylaniline. Yield 84%.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:8][C:6]1[CH:7]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
5-Fluoro-2-nitrotoluene (1 mL, 8.20 mmol, commercially available from Aldrich), Boc-piperazine (1.68 g, 9.02 mmol, commercially available from Aldrich), anhydrous potassium carbonate (2.27 g, 16.40 mmol) and DMF (25 mL) were combined and heated to 50° C. for 24 hours. Upon allowing the reaction mixture to cool to room temperature, water was added to the reaction mixture and the resulting precipitate was filtered as product, washed with ether and dried under reduced pressure to give 2.21 g tert-butyl 4-(3-methyl-4-nitrophenyl)piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3), δ 7.96 (d, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 3.35 (m, 4H), 3.19 (m, 4H), 2.55 (s, 3H), 1.42 (s, 9H). MS (EI): 322 (MH+).
Reaction SMILES: [CH2:1]([N:8]([C:10]([NH:12][C:13]1[CH:14]=[N:15][N:16]([CH2:18][C:19]2[C:20]([CH3:25])=[N:21][O:22][C:23]=2[CH3:24])[CH:17]=1)=[O:11])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27](OCC)=[O:28].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[CH2:1]([N:8]1[C:10](=[O:11])[N:12]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[C:20]([CH3:25])=[N:21][O:22][C:23]=3[CH3:24])[CH:17]=2)[C:27](=[O:28])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)N(N)Cc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
1-benzyl-N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)hydrazinecarboxamide (2.00 g, 5.88 mmol), ethyl chlorformate (6.38 g, 58.77 mmol), and triethylamine (1.78 g, 17.63 mmol) in acetonitrile (50 mL) were heated at 100° C. for 48 hours. The mixture was cooled to 80° C., 1 M NaOH (aq) (5 mL) was added and the reaction mixture was stirred for 1 hour. The reaction was cooled to room temperature and concentrated on the rotpvap. The residue was dissolved in dichloromethane and filtered to remove salts and the solution was concentrated to afford 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (1.28 g, 60%) as a yellow oil. MS M+H calculated 367.14; found 367.2.
Reaction SMILES: Cl[C:2]([C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)([CH3:21])[CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][N:13]3[CH2:17][CH2:18][CH2:19][CH:12]3[C:11]=2[C:10]2[CH:9]=[C:8]([CH3:20])[CH:7]=[CH:6][C:5]1=2.[CH3:28][NH:29][CH3:30]>O>[CH3:28][N:29]([CH3:30])[C:2]([CH3:21])([C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)[CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][N:13]3[CH2:17][CH2:18][CH2:19][CH:12]3[C:11]=2[C:10]2[CH:9]=[C:8]([CH3:20])[CH:7]=[CH:6][C:5]1=2
Reactant: CNC
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(Cl)c2cnccn2)CCN2CCCC12
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(c2cnccn2)N(C)C)CCN2CCCC12
Temperature: 25 °C

Procedure:
6-(2-Chloro-2-pyrazin-2-yl-propyl)-9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (500 mg, 1.31 mmol) in 40% dimethylamine in water (30 mL) was heated at 100° C. for 3 h. The reaction mixture was cooled at RT and extracted with EtOAc (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 62 mg of dimethyl-[1-methyl-2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethyl]-amine. 1H NMR (CD3OD, TFA salt): δ (ppm): 8.06 (s, 1H), 7.48 (s, 1H), 7.21 (s, 1H), 7.17 (d, 1H), 7.00 (d, 1H), 4.98 (t, 1H), 4.28 (d, 2H), 3.6 (m, 3H), 3.39 (m, 2H), 3.2 (m, 1H), 3.15 (s, 6H), 2.8 (m, 1H), 2.7 (m, 1H), 2.39 (s, 3H), 2.17 (m, 3H). Chiral HPLC separated the racemate into diastereomers II-6a-d.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28].CCN(C(C)C)C(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[C:25]([Cl:24])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:34])=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)ccn(C)c2=O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
To a suspension of 4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride salt (34 mg, 0.1 mmol) and 2,6-dichlorobenzoyl chloride (25 mg, 0.12 mmol) in dichloromethane (2 mL) was added DIEA (174 μL, 1.0 mmol) at room temperature. After 5 min, a clear solution was obtained which was stirred for 72 h. Then, the mixture was concentrated, the residue was dissolved in ethyl acetate (25 mL), was washed with 0.5 N HCl (25 mL), saturated NaHCO3 solution (25 mL), brine solution (15 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave crude product, which was purified by silica gel chromatography using a Biotage (40 s) column, to afford 23 mg (49% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C24H22Cl2N2O4 (M+Na) 495.0850. found 495.0859. f) Preparation of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[NH2:24][C:22]([C:21]1[CH:20]=[C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])[S:18][C:17]=1[NH:16][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1)=[O:23]
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CCOC(=O)c1cn2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc2n1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (430 mg, 1.92 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (400 mg, 1.28 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.CO[C:25]([CH3:27])=[CH2:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH:25]([CH3:27])[CH3:26])=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reactant: C=C(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2) (0.30 g, 1 mmol) in dry 1,2 DCE (5 mL) was added sequentially 2-methoxypropene (0.141 mL, 1.5 mmol), acetic acid (0.056 mL, 1 mmol) and sodium triacetoxyborohydride (0.313 g, 1.5 mmol). Further 1,2 DCE (5 mL) was added and the reaction mixture was stirred under argon at room temperature for 16 hours. Saturated NaHCO3 (15 mL) was added and reaction mixture stirred for a further 1 hour. The aqueous layer was then extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material was purified by column chromatography eluting with 0-100% ether/petroleum ether to give the title compound (0.265 g). δH (CDCl3, 400 MHz) 7.09 (2H, d), 6.54 (2H, d), 4.16 (1H, br.s), 3.78 (1H, d), 3.61 (1H, sp), 3.49 (1H, s), 3.42 (2H, m), 3.28 (1H, d), 3.08 (1H, td), 2.75 (1H, d), 2.59 (1H, d), 1.95 (1H, dd), 1.94 (1H, m), 1.45 (9H, s), 1.20 (9H, m). MS (AP+): 370.3 (MNa+), 248.3, no molecular ion (MH+) observed.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:49][O:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:10]([NH:12][CH:13]2[C:47](=[O:48])[N:15]3[C:16]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[C:17]([O:20][S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].ClC1C=CC=C(C(OO)=[O:67])C=1>C(Cl)Cl>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:49][O:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:10]([NH:12][CH:13]2[C:47](=[O:48])[N:15]3[C:16]([C:31]([O:33][CH:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:32])=[C:17]([O:20][S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:22])=[O:23])[CH2:18][S:19](=[O:67])[C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c4csc(NC=O)n4)[C@H]3SC2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c4csc(NC=O)n4)[C@H]3S(=O)C2)cc1

Procedure:
To a solution of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-tosyloxy-3-cephem-4-carboxylate (syn isomer) (3.2 g) in methylene chloride (20 ml) was added m-chloroperbenzoic acid (1.62 g) at ambient temperature. The mixture was stirred for an hour. The resulting solution was concentrated under reduced pressure and the residue was subjected to column chromatography on silica gel (eluent: benzene-ethyl acetate) to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-tosyloxy-3-cephem-4-carboxylate-1-oxide (syn isomer), 0.6 g).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:8](=O)[C:9]1[CH:23]=[CH:22][C:12]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1)[CH2:4][C:5](O)=[O:6].CN(C(O[N:33]1[N:41]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.NN>C1COCC1>[CH3:1][O:2][C@H:3]1[C:8]([C:9]2[CH:23]=[CH:22][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:41][NH:33][C:5](=[O:6])[CH2:4]1
Reactant: CO[C@H](CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CO[C@@H]1CC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1
Reaction time: 0.17 h

Procedure:
140 mg (430 μmol) (R)-3-methoxy-4-oxo-4-(2-phenyl-benzoxazol-6-yl)-butyric acid are combined at RT with 190 mg (500 μmol) HATU, 200 μl (1424 μmol) TEA and 2 ml DMF. The mixture is stirred for 10 min, then 431 μl (431 μmol) hydrazine 1M in THF are added. The mixture is stirred for a further 2 h at RT, then extracted with DCM and phosphate buffer (pH7). The org. phase is dried and evaporated down. The residue is purified by RP-HPLC.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[S:9][CH:10]=1)C.[Li+].[OH-]>C1COCC1.O>[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:25])=[O:3])[N:7]=1)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(=O)Nc1nc(CC(=O)OCC)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)Nc1nc(CC(=O)O)cs1

Procedure:
In a first step, (2-amino-thiazol-4-yl)-acetic acid ethyl ester is coupled to dodecanoyl chloride as described in the method of Example 334 to provide (2-Dodecanoylamino-thiazol-4-yl)-acetic acid ethyl ester as a crude solid. In a second step, the crude solid of (2-Dodecanoylamino-thiazol-4-yl)-acetic acid ethyl ester was deprotected using LiOH (2-fold excess) in THF/H2O to provide the title compound as a crude solid, which was used directly without further purification or characterization.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12](I)[CH:13]=[C:8]2[N:7]=1)C.C([Sn](CCCC)(CCCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)CCC.C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:34][O:33][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:16][N:15]1[C:9]2=[N:10][CH:11]=[C:12]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH:13]=[C:8]2[N:7]=[C:6]1[NH2:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccccn5)cnc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12.7 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.250 g, 0.42 mmol), 2-(tributylstannyl)pyridine (0.235 g, 0.63 mmol), copper(I) iodide (0.040 g, 0.21 mmol) and triethylamine (0.130 g, 1.26 mmol) in N,N-dimethylformamide (5 mL) was added bis(triphenylphosphine)palladium(II) dichloride (0.018 g, 0.042 mmol). The mixture was irradiated in a microwave reactor at 140° C. After 1.5 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated. The residue was purified by prep-HPLC to afford 0.025 g (13%) of the product as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=4.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.5 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.84-7.76 (m, 1H), 7.74-7.72 (m, 1H), 7.32-7.29 (m, 1H), 7.12 (d, J=6.0 Hz, 1H), 7.00-6.77 (m, 3H), 6.82 (d, J=8.5 Hz, 1H), 6.83-6.74 (m, 1H), 5.24 (s, 2H), 4.96 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H) ppm; (M+1)=469.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:16][CH2:17][CH2:18][OH:19]>COCCOC>[C:7]([NH:6][C:5]1[CH:10]=[CH:11][C:2]([S:1][CH2:16][CH2:17][CH2:18][OH:19])=[CH:3][CH:4]=1)(=[O:9])[CH3:8]
Reactant: OCCCCl
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(SCCCO)cc1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A mixture of 16.7 g (0.1 mole) of p-mercaptoacetanilide, 4 g of sodium hydroxide, 40 ml of water, 40 ml of 1,2-dimethoxyethane, and 0.39 g (0.11 mole) of 3-chloropropanol is heated in a steam bath with stirring for 30 minutes. Two liquid phases are formed, and TLC indicates that the reaction is substantially complete. The mixture is distilled in vacuo to remove 1,2-dimethoxyethane, and the oily mixture which separates is triturated with cold water until it solidifies. The crude product is recrystallized from ethanol to obtain a by-product: the disulfide derived from the starting mercapto compound. The ethanol filtrate is concentrated, and the residue is triturated with ether-hexane to obtain 15.7 g of the desired product. Recrystallization from ethyl acetate-hexane gives 11.8 g of 3-(p-acetamidophenylthio)propanol which shows the correct IR and NMR spectra.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:20]2[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1
Reactant: COc1cccc(OCCCl)c1
Reactant: c1ccc(-c2cccnc2N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(OCCN2CCN(c3ncccc3-c3ccccn3)CC2)c1
Yield: 77 %

Procedure:
A stirred mixture of 1-(2-chloroethoxy)-3-methoxybenzene (0.65 g, 3.5 mmol), 1-[3-(2-pyridyl)-2-pyridyl]piperazine (0.7 g, 2.9 mmol) and K2CO3 (3.5 mmol) in DMF was refluxed overnight. After cooling, the mixture was evaporated to dryness and H2O (20 mL) was added to the residue. The aqueous phase was extracted with AcOEt (2×30 mL). The collected organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/AcOEt, 9:1, as eluent) to afford pure compound in 77% yield.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[C:9](Cl)=[N:10][CH:11]=1.[OH:14][CH2:15][CH:16]1[O:20]C(C2C=CC=CC=2)[N:18]([CH:27]([CH3:29])[CH3:28])[CH2:17]1>COCCOC>[NH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[C:9]([O:14][CH2:15][CH:16]([OH:20])[CH2:17][NH:18][CH:27]([CH3:29])[CH3:28])=[N:10][CH:11]=1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Reactant: NCCc1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)NCC(O)COc1ncc(CCN)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12 g of sodium hydride dispersion (55% strength) are added in portions to 44 g of 5-(2'-aminoethyl)-2,3-dichloro-pyridine and 55 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine, dissolved in 500 ml of 1,2-dimethoxyethane, whilst cooling with ice at 0°-10° C. The reaction mixture is then stirred for 2 hours at room temperature and 16 hours under reflux. Working up gives crude 5-(2'-aminoethyl)-3-chloro-2-[3'-isopropyl-2'-phenyloxazolidinyl-(5')]-methoxy-pyridine, which is hydrolysed without further purification, analogously to Example 37, to give 5-(2'-aminoethyl)-3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine (boiling point 165°-185° C./0.06 mm Hg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
Reflux a mixture of 53.5 mL (0.504 mol) of 1-fluoro-4-nitrobenzene, 99.14 g(0.555 mol) of 1-benzylpiperazine, and 76.7 g (0.555 mol) potassium carbonate in acetonitrile for about 17 h. Cool the mixture to room temperature and dilute with methylene chloride and filter. Concentrate thefiltrate in vacuo. Dissolve the residue in methylene chloride and wash withwater. Dry the organic layer with anhydrous sodium sulfate and concentrate in vacuo to give the title compound. NMR (DMSO-d6): δ=2.59(t,4),3.42(t,4), 3.57(s,2), 6.80(d,2) 7.34(m,5) and 8.11(d,2) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)Cl>ClCCCl>[Br:12][CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1csc(CBr)n1
Temperature: 70 °C
Yield: 8 %

Procedure:
A mixture of ethyl-2-methylthiazole 4-carboxylate (500 mg, 2.9 mmol), N-bromosuccinimide (877 mg, 4.9 mmol), and benzoyl peroxide (5-10 mg ) in 1,2-DCE (3 mL) was heated at 70° C. for 85 h. After cooling to room temperature, DCM (10 ml) was added and washed with water (3 times). The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by preparative chromatography to yield the above-titled compound (58 mg). 1H NMR (CDCl3): 8.23 (1H, s), 4.77 (2H, s), 4.43 (2H, q), 1.42 (3H, t).
Reaction SMILES: F[O:2][C:3]([O:6]F)([F:5])[F:4].[F:8][C:9]([F:13])=[C:10]([F:12])[F:11]>N#N>[F:4][C:3]1([F:5])[O:6][C:9]([F:13])([F:8])[C:10]([F:12])([F:11])[O:2]1
Reactant: FOC(F)(F)OF
Reactant: FC(F)=C(F)F
Agent: N#N
Product: FC1(F)OC(F)(F)C(F)(F)O1
Temperature: -80 °C

Procedure:
Into a multineck glass reactor equipped with: magnetic entrainment mechanical stirrer, reflux cooler, thermocouple, inner plunging pipes for introducing the reagents, and maintained at a temperature of -80° C., there were simultaneously fed-after having introduced 75 ml of FC 75-0.5 l of bis(fluoroxy)difluoromethane at a flowrate of 0.3 l/h diluted with N2 (0.5 l/h) and 5.0 g of tetrafluoroethylene (3.0 g/h).