Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2].C[Al](C)C.C1(C)C=CC=CC=1.CO[C:24](=O)[CH2:25][N:26]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:28]=[C:27]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>C(Cl)Cl.[OH-].[Na+].CO>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:24]1[CH2:25][N:26]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[N:28]=[C:27]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)[CH3:2]
Reactant: CCNc1ccncc1N
Reactant: COC(=O)Cn1cc(C(F)(F)F)nc1-c1nccs1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCn1c(Cn2cc(C(F)(F)F)nc2-c2nccs2)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N4-ethyl-pyridine-3,4-diamine (94 mg, 0.687 mmol) in CH2Cl2 (5 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (0.43 mL, 0.858 mmol), and the resulting mixture is stirred at room temperature for 1 h. Next, a solution of (2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetic acid methyl ester (100 mg, 0.343 mmol) in CH2Cl2 is added via cannula. The reaction mixture is then stirred at reflux overnight. After cooling to rt, it is treated with MeOH (˜1 mL). The mixture is further diluted with 0.5 N aq NaOH (10 mL) and then stirred vigorously for 30 min. The mixture is then extracted thrice with CH2Cl2 containing some (˜5%) MeOH, and the combined extracts are dried over K2CO3 and concentrated. The crude mixture of 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine and N-(4-amino-pyridin-3-yl)-2-(2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetamide is dissolved in AcOH (6 mL)), and the resulting solution stirred at reflux overnight. The reaction mixture is then concentrated, and the residue is dissolved in CH2Cl2 and washed with 0.5 N aq NaOH. The aqueous layer is reextracted once with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude residue is purified by preparative TLC. Developing with 15:1 CHCl3-MeOH affords 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 400 MHz) δ 9.10 (s, 1H), 8.47 (d, J=6.0 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J=3.2 Hz, 1H), 7.31 (d, J=5.6 Hz, 1H), 6.37 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:33][C:34]([C@H:36](OS(C(F)(F)F)(=O)=O)[CH3:37])=[O:35]>>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[C@H:36]([C:34]([OH:35])=[O:33])[CH3:37])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCCN1CCCC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(CCN1CCCC1)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-{[(2-pyrrolidin-1-ylethyl)amino]methyl}quinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-pyrrolidin-1-ylethyl)-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.27 (d, 3H); 1.83 (m, 4H); 2.86 (m, 8H); 3.44 (q, 1H); 3.84 (d, 1H); 3.94 (d, 1H); 4.01 (s, 3H); 7.25 (s, 1H); 7.33 (t, 1H); 7.53 (m, 1H); 7.63 (m, 1H); 8.42 (s, 1H); 8.48 (s, 1H); 9.78 (brs, 1H; Mass Spectrum: (M+H)+ 502.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1
Reactant: OCCO
Reactant: O=Cc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: c1cc(C2OCCO2)cs1
Yield: 96 %

Procedure:
To a mixture of thiophene-3-carbaldehyde (25.0 g), ethylene glycol (18.7 mL) and toluene (250 mL) was added p-toluenesulfonic acid monohydrate (2.13 g), and the mixture was stirred with heated under reflux for 7 hr while dehydrating using Dean-Stark (Dean-Stark) apparatus. Triethylamine (3.11 mL) was added to quench the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title compound (33.6 g, 96%) as a dark brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH2:30]([OH:32])[CH3:31]>O1CCOCC1.CN(C=O)C>[CH2:30]([O:32][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:31]
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with sodium hydride and ethanol in dioxane and DMF. ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=2.[BH4-].[Na+].O.[F:20][C:21]([F:26])([F:25])[C:22](O)=O>>[CH3:1][CH:2]1[CH:10]([CH2:11][CH2:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]1[CH2:22][C:21]([F:26])([F:25])[F:20]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCc1c(C)[nH]c2ccc([N+](=O)[O-])cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCC1c2cc([N+](=O)[O-])ccc2N(CC(F)(F)F)C1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 200 ml 2-neck round bottom flask, equipped with a magnetic stirrer and a cold water condenser, 4-nitrophenylhydrazine was dissolved in 75 mL concentrated hydrochloric acid and stirred at room temperature for 15 minutes. A solution of 2-hexanone (5 mL) in ethanol (25 mL) was added slowly and the reaction flask was heated in an oil bath at 105° C. for 18 h. The mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with EtOAc. The organic layer washed with saturated sodium bicarbonate solution, water, and brine solutions and evaporated to dryness. The oily residue was absorbed on silica gel and purified by silica gel chromatography with 20% EtOAc in Hexane solution to give 2-methyl-5-nitro-3-propyl-1H-indole. This indole product was dissolved in trifluoroacetic acid (10 mL) and 1 pellet sodium borohydride (0.7 g) was added and the reaction was stirred at room temperature for 18 h. Water (10 mL) was carefully added and the reaction mixture was extracted twice with EtOAc (15 mL). The organic layer washed with brine and dried over MgSO4, and purified by flash column chromatography on silica gel eluted with 20% EtOAc in hexanes to give 280 mg of 2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole.
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:40]2[CH2:41][CH2:42][CH:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=4)[NH:33][CH:32]=3)[CH2:38][CH2:39]2)=[O:25])[CH2:15][CH2:14]1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: C1COCCO1
Product: COc1ccc2[nH]cc(C3CCN(C(=O)NC4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1

Procedure:
The non-polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (338 mg, 1.0 mmole) was added to a solution of 5-methoxy-3-piperidine-4-yl-1H-indole (230 mg, 1.0 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml). It was obtained in a yield of 170 mg (36%) as a colourless solid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[S:25](=[O:33])(=[O:32])[N:24]=1>C1COCC1>[C:1]([N:5]1[C:9]([OH:10])=[C:8]([C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25](=[O:32])(=[O:33])[N:24]=2)[C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)CC(=O)N1Cc1ccc(F)cc1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)n1c(O)c(C2=NS(=O)(=O)c3ccccc32)c(=O)n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
step 5—To a solution of the pyrazolone 62a (300 mg, 1.1 mmol) in THF (5 mL) was added NaH (54 mg, 1.4 mmol). The reaction mixture was stirred at RT for 20 min, and 3-chloro-benzo[d]isothiazole 1,1-dioxide (270 mg, 1.4 mmol) was added. The reaction mixture was then stirred at RT for 2 h, quenched with saturated aqueous NH4Cl and extracted into ethyl acetate (2×). The combined organics were dried (MgSO4), filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase column chromatography eluting with acetonitrile/water which afforded 15 mg (3%) of III-2; LCMS RT 2.3 min, M−H.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][OH:11])=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:13][O:14][C:15]([C:17]1[S:21][N:20]=[C:19](O)[CH:18]=1)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:21][N:20]=[C:19]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:12])[CH:18]=1)=[O:16]
Reactant: CCCCc1noc(C)c1CO
Reactant: COC(=O)c1cc(O)ns1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)OC)sn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of 3-butyl-5-methyl-4-isoxazolyl-methanol (367 mg, 2.2 mmol) in THF (10 mL) was added 3-hydroxy-isothiazole-5-carboxylic acid methyl ester (345 mg, 2.2 mmol) and triphenylphosphine (622 mg, 2.4 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.04 mL, 2.4 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=9:1 to 0:1) afforded the title compound (518 mg, 77%) as a colourless liquid. MS: m/e=311.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](Cl)=[N:29][CH:28]=1>>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[N:29][CH:28]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 101 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) and methyl-6-chloronicotinate [CAS Reg. No. 73781-91-6]. MS (m/e)=501.0 [MH+].
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5]1([CH2:15][N:16]2[C:25](=[O:26])[C:24]3[N:23]([CH2:27][C:28]#[C:29][CH3:30])[C:22]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]4)=[N:21][C:20]=3[NH:19][C:17]2=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:5]1([CH2:15][N:16]2[C:25](=[O:26])[C:24]3[N:23]([CH2:27][C:28]#[C:29][CH3:30])[C:22]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]4)=[N:21][C:20]=3[N:19]([CH2:2][C:3]#[N:4])[C:17]2=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: N#CCBr
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2[nH]c(=O)n(Cc3cccc4ccccc34)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1cccc3ccccc13)c(=O)n2CC#N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
30 μl of bromoacetonitrile are added to a mixture of 0.20 g 1-(naphth-1-ylmethyl)-7-(but-2-ynyl)-8-(3-tert-butoxycarbonylamino-piperidin-1-yl)-xanthine and 0.10 g potassium carbonate in 3 ml of dimethylformamide. The reaction mixture is stirred for 3 h at 60° C. and then cooled to ambient temperature. Water is added and the precipitate is separated off and dried at 60° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([Cl:20])[N:18]=2)[C:13](C#N)=[CH:12]1.[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([Cl:20])[N:18]=2)[CH:13]=[CH:12]1
Reactant: Cc1cc(Cl)nc2c1c(C#N)cn2-c1ccc(C(C)C)cc1Br
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Cl)nc2c1ccn2-c1ccc(C(C)C)cc1Br
Yield: 80.2 %

Procedure:
A mixture of 52 mg of 1-(2-bromo-4-isopropylphenyl)-6-chloro-3-cyano-4-methyl-7-azaindole and 10 mL of 65% sulfuric acid was refluxed for one hour. The cooled solution was poured onto ice, and 17 mL of conc. ammonium hydroxide was added. The alkaline mixture was extracted with ethyl acetate. The extract was washed (brine), dried (Na2SO4), and evaporated. TLC of the residue on silica gel with 70:30 hexane-ethyl acetate showed a major new spot, Rf =0.58, with a trace of unchanged starting material (Rf 0.52). The crude product was purified by preparative TLC to give 39 mg of non-crystalline product, which slowly crystallized on standing. Mass spec. (m+H)+ =363.0247; calcd., 363.0264 (79Br, 35Cl).
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(N1CCOC(COC2C=CC=CC=2)C1)(=O)=O.[I:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[N:48](S(C1C=CC=CC=1)(=O)=O)[C:47]([C:61](OCC)=[O:62])=[C:46]2[S:66]([N:69]1[CH2:74][CH2:73][O:72][CH:71]([CH2:75][O:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH2:70]1)(=[O:68])=[O:67]>>[I:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[NH:48][C:47]([C:61]([NH2:7])=[O:62])=[C:46]2[S:66]([N:69]1[CH2:74][CH2:73][O:72][C@@H:71]([CH2:75][O:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[CH2:70]1)(=[O:68])=[O:67]
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCOC(COc3ccccc3)C2)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCOC(COc3ccccc3)C2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Product: NC(=O)c1[nH]c2ccc(I)cc2c1S(=O)(=O)N1CCO[C@@H](COc2ccccc2)C1

Procedure:
Using the same procedures described for Example 23, replacing the product from Step A of Example 22, ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, with ethyl(±)-5-iodo-3-{[2-(phenoxymethyl)morpholin-1-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the second-eluting enantiomer of ethyl 5-iodo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the titled compound after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 542.82 [M+H]+.
Reaction SMILES: BrCC(N[CH:6]1[C:28](=[O:29])[N:8]2[C:9]([C:25]([OH:27])=[O:26])=[C:10]([CH2:13][NH:14][C:15](=[O:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH2:11][S:12][C@H:7]12)=O.[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[SH:36]>>[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[S:36][CH:6]1[C:28](=[O:29])[N:8]2[C:9]([C:25]([OH:27])=[O:26])=[C:10]([CH2:13][NH:14][C:15](=[O:24])[C:16]3[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=3[Cl:22])[CH:11]([NH:14][C:15](=[O:24])[CH3:16])[S:12][C@H:7]12
Reactant: O=C(CBr)NC1C(=O)N2C(C(=O)O)=C(CNC(=O)c3c(Cl)cccc3Cl)CS[C@H]12
Reactant: Cn1ccnc1S
Product: CC(=O)NC1S[C@@H]2C(Sc3nccn3C)C(=O)N2C(C(=O)O)=C1CNC(=O)c1c(Cl)cccc1Cl
Yield: 60 %

Procedure:
1.0 g. of 7-bromoacetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-4-carboxylic acid and 0.23 g. of 1-methyl-2-mercapto-imidazole were reacted and worked up according to Example 15. Thus 0.67 g. (60%) of 7-(1-methylimidazole-2-ylthio)-acetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-4-carboxylic acid were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:28]1([NH:34][C:35]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:41]([C:40]5[CH:39]=[CH:38][C:37]([C:35](=[O:36])[NH:34][C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)=[CH:44][CH:43]=5)=[N:1][C:4]=4[CH:5]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Product: O=C(Nc1ccccc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 217 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-morpholinylbenzamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C31H27N5O3: 518.22; found: 518.03.
Reaction SMILES: [N:1]1([S:5]([NH:8][C:9]2[N:14]=[C:13]([S:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[N:12]=[C:11]([O:25][C@@H:26]([CH3:32])[C:27](OCC)=[O:28])[CH:10]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+]>C1COCC1>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][S:15][C:13]1[N:14]=[C:9]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:6])=[O:7])[CH:10]=[C:11]([O:25][C@@H:26]([CH3:32])[CH2:27][OH:28])[N:12]=1
Reactant: CCOC(=O)[C@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using 2-[[6-[(1-azetidinylsulfonyl)amino]-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2S)-propanoic acid, ethyl ester, (the product of step (0.28 g), THF (8 mL) and 2 M lithium borohydride in THF (0.57 mL). Purification was by column chromatography on silica using EtOAc/isohexane (2:3) as eluent to give the title compound as a white solid. Yield: 0.15 g
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH:22]([C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])C(O)=O)=[N:9]2)=[CH:4][CH:3]=1.[OH-:33].[Na+]>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]([OH:21])=[O:33])[CH2:22][C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCC(=O)C(C(=O)O)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A suspension of 30 mg of (±)-2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxoheptanoic acid in 4.7 cm3 of distilled water and 1.32 cm3 of a 0.1N aqueous sodium hydroxide solution is stirred at a temperature of approximately 20° C. for 72 hours. An insoluble product is removed by filtration and the filtrate is acidified to a pH=2 by addition of a 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with water and dried in air. 10 mg of (±)-2-{1-[(7-chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained whose characteristics are identical to those of the product of Example 1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C@H:8]3[CH2:11][CH2:12][NH:13][CH2:14][C@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])(=O)[C@H](C1C=CC=CC=1)O.C([O-])([O-])=O.[Na+].[Na+].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[Br:1][C:2]1[C:10]2[NH:9][C@H:8]3[CH2:11][CH2:12][N:13]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:14][C@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1N[C@H]1CCNC[C@@H]21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[C@@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@@H]2Nc3c(Br)cccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Alternative to the use of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (Compound of Formula 1C) free base, the reaction may also be done by starting with the (S)-mandelate salt of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole. A 100 mL round-bottomed flask is equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, and a N2 inlet on top of the addition funnel. The flask is charged with the S-mandelate starting material (5 g, 12.35 mmol), Na2CO3 (2.88 g, 27.17 mmol), and 25 mL of THF. To the yellow reaction mixture at 25° C. (heating block temperature) is added a solution of ethyl chloroformate (1.64 g, 15.11 mmol) in 5 mL of THF dropwise over ca 70 minutes. The batch is stirred at 25° C. for another 10 min, and is checked by HPLC. Less than 2% of the starting material is observed by HPLC, and the desired product is registered at ca. 98%. To the batch is added 12.5 mL of EtOH, and the batch is concentrated under reduced pressure to remove ca. 30 mL of solvent (mostly THF). To the batch is then added 37.5 mL of H2O, and the resultant mixture shows pH>9 by pH paper. The yellow mixture is then stirred at rt for ca. 1 h, and is filtered. The solid is rinsed with 25 mL of H2O. After drying in a vacuum oven at 58° C. for ca. 16 h, 3.9442 g of a yellow solid is obtained (98% yield). 1H NMR of the solid conformed, and showed no (s)-mandelic acid. HPLC analysis of the product shows the desired product at >99% purity. LC-MS showed a peak with M/e=326 (M+1).