Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1ccccc1Br
Product: O=c1cc(N2CCN(Cc3ccccc3Br)CC2)nc[nH]1

Procedure:
6-[4-(2-Bromo-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-bromobenzaldehyde. Mass spectrum (ES) MH+=349.
Reaction SMILES: C([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]([C:22]([OH:24])=[O:23])[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])C(C)C.[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44]([OH:46])=O)[C@@H:34]([CH3:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:11]([C@H:10]([C:22]([OH:24])=[O:23])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:44]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[C@H:34]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:43])=[O:46])[CH2:17][CH:18]([CH3:21])[CH3:19])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CCCCNCC(C)C)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nε-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-O-benzyl-L-threonine (93 mg, 0.3 mmol). The final product was triturated with ether to yield 195 mg (98%) of the desired material.
Reaction SMILES: S([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([Cl:13])[C:6]=1[OH:14])(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([Cl:13])[C:6]=1[OH:14])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(Cl)cc(S(=O)(=O)O)c(O)c1Cl
Product: Cc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl

Procedure:
The reaction of the 2-sulpho-4,6-dichloro-5-methylphenol, prepared in the second stage, with nitric acid in the third process stage to give 2-nitro-4,6-dichloro-5-methylphenol can be illustrated by the following equation: ##STR3##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH:21]([O:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:30][C:27]2[CH:26]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[NH:29][N:28]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (0.41 g, 2.1 mmol) and DIEA (0.31 ml, 1.8 mmol) in THF (10 ml) was added 5-isopropoxy-1H-pyrazol-3-amine (0.20 g, 1.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (DCM:EtOAc=2.5:1) to give the title compound as a yellow solid (0.19 g, 45%). MS: Calcd.: 298; Found: [M+H]+ 299.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[CH:7]1[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH:10]([O:22][CH3:23])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:74][C:75]1[S:79][C:78]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=2[F:86])=[N:77][C:76]=1[C:87](O)=[O:88])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CO>[NH2:74][C:75]1[S:79][C:78]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=2[F:86])=[N:77][C:76]=1[C:87]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[CH:7]1[CH2:8][CH2:9][C@H:10]([O:22][CH3:23])[C@@H:11]([NH2:14])[CH2:12][CH2:13]1)=[O:88]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: COC1CCC(c2c(N)cnn2C)CCC1NC(=O)OC(C)(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H]1CCC(c2c(NC(=O)c3nc(-c4ccccc4F)sc3N)cnn2C)CC[C@@H]1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 5-fluoro-2-methoxy-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)cycloheptylcarbamate (430 mg, 1.27 mmol) in MeOH (50 mL) was passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give an orange foam. This foam was then dissolved in MeOH (70 mL) and 10% palladium on carbon (45 mg) added. The mixture was then stirred under an atmosphere of H2 (400 psi) at room temperature for 3 hr, filtered through Celite® and the solvent removed under reduced pressure to give a complex mixture as an orange foam (378 mg) containing tert-butyl 5-(4-amino-1-methyl-1H-pyrazol-5-yl)-2-methoxycycloheptylcarbamate. To a solution of this mixture (378 mg, 1.13 mmol) in DCM (30 mL) was added DIPEA (1.0 mL, 5.74 mmol), PyBOP (1.5 g, 2.81 mmol) and 5-(tert-butoxycarbonyl-amino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid (418 mg, 1.24 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (150 mL) and washed with water (30 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (70-80% EtOAc/isohexane) gave a mixture of four diastereomers as a peach solid (240 mg) which were separated by preparative HPLC. Each diastereomer (25 mg, 0.03 mmol) was then stirred with HCl in dioxane (4 M, 0.95 mL, 3.80 mmol) in MeOH (1 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH, eluted with 7 N ammonia in MeOH to give 413 (Diastereomer 1) as an off-white solid (13 mg, 2% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.21 (td, J=7.7, 1.9 Hz, 1H), 7.79 (s, 1H), 7.38-7.32 (m, 1H), 7.26-7.21 (m, 1H), 7.16 (dd, J=11.4, 8.3 Hz, 1H), 6.09 (s, 2H), 3.84 (s, 3H), 3.36 (s, 3H), 3.11-2.99 (m, 2H), 2.91-2.84 (m, 1H), 2.13-2.02 (m, 2H), 1.98-1.91 (m, 2H), 1.85 (t, J=12.3 Hz, 4H), 1.58-1.46 (m, 2H). LCMS (ES+) m/z 459 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[OH:12].Cl.[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18]Cl)[CH3:15]>>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][O:12][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[NH2:9])[CH3:15]
Reactant: CCN(CC)CCCl
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Product: CCN(CC)CCOc1cc(N)ccc1OC

Procedure:
The title compound was prepared from 2-methoxy-5-nitrophenol and 2-diethylaminoethyl chloride hydrochloride using a similar procedure to Descriptions 1 and 2 (71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)[CH:3]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:22])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C)n1
Reactant: N
Solvent: CO
Product: Cc1cc(C)nc(Nc2cc(Cl)nnc2C(N)=O)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of ethyl 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (165 mg, 538 μmol) in methanol (1 mL) was added ammonia in methanol (4.72 g, 6 mL, 42.0 mmol) and the mixture stirred at 50° C. for 16 h. The mixture was then concentrated in vacuo to give 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (140 mg, 504 μmol, 94%) as a white solid. 1H NMR (400 MHz, DMSO-d) δ ppm 11.92 (s, 1H), 9.13 (s, 1H), 8.86 (s, 1H), 8.21 (s, 1H), 6.84 (s, 1H), 6.76 (s, 1H), 2.45 (s, 3H), 2.29 (s, 3H); MS (EI/CI) m/z: 277.9 [M+H].
Reaction SMILES: C([O-])(=O)C.[K+].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:18]3[C:22]4=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]4[N:20]=[C:19]3[CH2:29][CH3:30])[CH:15]=2)[N:10]=[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-])=O)[CH:8]=1.C(O)C>[C].[Pd].C(OCC)(=O)C.O.C(Cl)(Cl)Cl>[CH2:29]([C:19]1[N:18]([CH2:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH2:37])[CH:8]=[CH:7]3)[C:22]2=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]2[N:20]=1)[CH3:30]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3[N+](=O)[O-])cc(Cl)c2c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3N)ccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
To 2.04 g of a 5% palladium-carbon catalyst, 15 ml of water containing 10.2 g of potassium acetate was added. Then, a solution of 10.18 g (21.6 mmol) of 4-chloro-6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(nitrophenyl)quinoline obtained in Example 4 dissolved in 30 ml of ethyl acetate and 240 ml of ethanol at 70° C. was added thereto, and the thus-prepared mixture was stirred under a hydrogen atmosphere at 60° C. for 3 hours. After adding 150 ml of chloroform and 200 ml of water thereto, the thus-prepared mixture was filtered through celite. The resulting filtrate was separated out, and the organic layer obtained was concentrated to 95.0 g in an evaporator. After allowing to stand at 0° C., the crystals precipitated were collected by filtration. The resulting filtration residue was washed with 10 ml of ethanol three times and dried under reduced pressure at 40° C. to obtain 6.70 g of 2-{6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]quinolin-2-yl}aniline.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:30])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCSc3ccc(C4CCCCC4)cc3)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)ccc2N1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-cyclohexylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([S:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[CH:21]2>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([S:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:13]([C:12]3[C:2]([Cl:1])=[CH:3][C:4]4[S:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=4[CH:11]=3)=[O:15])[CH2:33][CH2:32]1)=[CH:21]2
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)cc2c1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCC(=O)N5)CC3)cc2c1

Procedure:
The title compound is prepared as a white solid (13 mg, 24% yield) following Scheme 3 and in analogy to Example 53 using 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (22 mg, 0.09 mmol, 1.0 eq) and 1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30 mg, 0.09 mmol, 1.0 eq) as starting materials.
Reaction SMILES: C(O[C:4](=[O:35])[CH2:5][CH2:6][CH2:7][N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([C:11]1([CH3:26])[CH2:14][CH2:13][N:12]1[C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[O:10])C.[NH3:36]>CO>[C:4]([CH2:5][CH2:6][CH2:7][N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([C:11]1([CH3:26])[CH2:14][CH2:13][N:12]1[C:15](=[O:25])[CH2:16][C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[O:10])(=[O:35])[NH2:36]
Reactant: CCOC(=O)CCCN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Reactant: N
Solvent: CO
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CCCC(N)=O)Cc2ccc(Cl)cc2)c1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 4-((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-butyric acid ethyl ester, Intermediate 146 (1 eq.) in MeOH was added an aqueous solution of NH3 (20% in water). The reaction was stirred at 60° C. for 15 h then cooled to 20° C. The solvents were evaporated under reduced pressure and the crude was purified by preparative LCMS to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (3-carbamoyl-propyl)-(4-chloro-benzyl)-amide.
Reaction SMILES: [CH3:1][P:2](=[O:7])([CH:5]=[CH2:6])[CH:3]=[CH2:4].[C:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1.O>[CH3:1][P:2]1(=[O:7])[CH2:5][CH2:6][N:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=CP(C)(=O)C=C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCP(C)(=O)CC2)CC1
Yield: 46.5 %

Procedure:
A solution of methyl divinyl phosphine oxide (140 mg, 1.21 mmol) and 1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) in 1:1 THF/water (3 mL) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired compound as a white solid (178 mg, 38% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]2[C:9]([CH:10]=1)=[C:8]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([CH3:21])=[C:6]2[C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([O:32][CH3:33])[CH:24]=1.F[C:36](F)(F)C(O)=O>>[CH3:33][O:32][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[N+:29]([O-:31])=[O:30])[C:22]([C:6]1[N:5]2[C:9]([CH:10]=[C:2]([NH:1][CH3:36])[CH:3]=[CH:4]2)=[C:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:7]=1[CH3:21])=[O:34]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(N)ccn23)ccc1[N+](=O)[O-]
Product: CNc1ccn2c(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)c(C)c(C(=O)OCc3ccccc3)c2c1
Yield: 78 %

Procedure:
This compound is obtained according to the same method as the compound of Example 49 by deprotection of the amino functional group of 849 mg (1.48 mmol) of benzyl [7-[(N-tert-butoxycarbonyl)(N-methyl)amino]-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]carboxylate with trifluoroacetic acid. 549 mg of an orange-coloured powder are obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[F:27][C:28]([F:40])([F:39])[O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34]>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([O:29][C:28]([F:27])([F:39])[F:40])[CH:31]=2)[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(OC(F)(F)F)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-(trifluoromethoxy)-benzoic acid
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]([C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:26]([C:24]3[S:25][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=3)(=[O:27])=[O:28])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)s1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.43 g of 5-tert-butyl-thiophene-2-sulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted three times with 30 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was chromatographed on 50 g of Kieselgel 60 with ethyl acetate/hexane (1:2) as the eluent. The product-containing fractions were concentrated and the residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.20 g of 5-tert-butyl-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide separated as yellowish crystals after neutralization with concentrated hydrochloric acid and repeated boiling.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].Br[C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:32]=[S:28]1(=[O:31])[CH2:29][CH2:30][CH:25]([C:16]2[C:15]3[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=[C:13]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]=[O:2])[CH:4]=4)[CH:14]=3)[NH:18][CH:17]=2)[CH2:26][CH2:27]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of (3-formylphenyl)boronic acid (0.121 g, 0.808 mmol), 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (0.150 g, 0.404 mmol) and Potassium carbonate (0.168 g, 1.212 mmol) in 1,4-Dioxane (1.796 mL)/Water (0.898 mL) was degassed with nitrogen for several minutes and PdCl2(dppf) (0.030 g, 0.040 mmol) was added. The mixture was heated at 100° C. for 5 minutes in the microwave on ‘high’ absorption setting. The aqueous layer was removed via pipette and the reaction mixture was filtered through a 500 mg Stratospheres PL Thiol SPE cartridge, eluting with 10 mL of DCM/MeOH (1:1). Crude LCMS shows the desired compound as major peak. Concentrated under nitrogen to obtain 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(3-formylphenyl)-1H-indole-7-carboxamide (0.160 g, 0.404 mmol, 100% yield).
Reaction SMILES: [CH2:1]([O:3][P:4](C#CC1N(C2C=CC(F)=CC=2)C2C(C=1C(C)C)=CC=CC=2)([CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].P(OCC)(OCC)[O:37][CH2:38][CH3:39]>>[CH2:38]([O:37][P:4]([O:3][CH2:1][CH3:2])([CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:39]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)CC(=O)CP(=O)(C#Cc1c(C(C)C)c2ccccc2n1-c1ccc(F)cc1)OCC
Product: CCOC(=O)CC(=O)CP(=O)(OCC)OCC
Temperature: 115 °C
Yield: 66.9 %

Procedure:
The title A compound of Example 3 (41.0 g, 0.174 mol) was dissolved in (EtO)3P (150 mL, 0.87 mol) and heated at 115° C. (bath temperature) for 18 hours and then cooled to room temperature. The excess (EtO)3P was distilled off at reduced pressure (1 mm Hg, 45° C. bath temperature). The resulting brown residue was purified by chromatography on silica gel, isopropanol:hexane (1:9), to give the title compound as a pale yellow liquid (31 g, 67%).
Reaction SMILES: Cl.[CH2:2]([O:4][N:5]=[C:6]([C:33]1[N:34]=[C:35]([NH:38]C=O)[S:36][CH:37]=1)[C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:28]([OH:30])=[O:29])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]>CO>[CH2:2]([O:4][N:5]=[C:6]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:28]([OH:30])=[O:29])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 64.1 %

Procedure:
Conc. hydrochloric acid (0.54 g.) was added dropwise at ambient temperature to a suspension of 7-[2-ethoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.7 g.) in methanol (70 ml.), and the resulting mixture was stirred for 4.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and water (30 ml.) was added to the residue. The mixture was adjusted to pH 7.2 with a saturated aqueous solution of sodium bicarbonate, and an insoluble material was filtered off. The filtrate was washed with ethyl acetate (25 ml.) and then in turn adjusted to pH 5.5, 4.5 and 3.8, and in turn washed with ethyl acetate at each pH. The aqueous layer was adjusted to pH 1.7, and precipitates were collected by filtration, washed with water (200 ml.) and dried under reduced pressure to give 7-[2-ethoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl- 1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.65 g.).
Reaction SMILES: [CH2:1]([NH:10][CH3:11])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:13][C:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:14]([CH2:13][N:10]([CH2:1]/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:11])=[CH:15][CH2:16]1
Reactant: CNC/C=C/c1ccccc1
Reactant: ClCC1=CCOc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C/C=C/c1ccccc1)CC1=CCOc2ccccc21
Reaction time: 24 h

Procedure:
1.15 g of trans-N-cinnamyl-methylamine in 20 ml of dimethylformamide are slowly added dropwise with stirring to 1.4 g of 4-chloromethyl-2H-1-benzopyrane and 0.8 g of sodium carbonate in 40 ml dimethylformamide. Stirring is continued for 24 hours at room temperature, the resulting mixture evaporated under vacuum and the residue taken up in ethylacetate/water. The organic phase is separated, washed with 1% tartaric acid, saturated NaHCO3 and saturated NaCl, dried over MgSO4 and concentrated by evaporation. After purification by chromatography on kieselgel (eluant toluene/ethylacetate 10/1) the title compound is obtained.