Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)=[CH:18][CH:17]=2)[N:3]=1.[Br:30][CH2:31][CH2:32]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[CH:20][CH:21]=3)[CH:5]=2)=[CH:9][CH:10]=1
Reactant: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(O)cc4)nc(N)n3)cc2)ccn1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(OCCBr)cc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C

Procedure:
To a solution of Step 2 product (1 equiv) in DMF is added 1,2-dibromoethane (1 equiv) and K2CO3 (3 equiv). The mixture is refluxed overnight. After cooling to rt, the mixture is diluted with EtOAc and washed sequentially with 1N NaOH, water and brine. The organic layer is dried (Na2SO4) and concentrated to afford a crude product which is to be used in next step without further purification.
Reaction SMILES: C([O:8][C:9]([Cl:12])(Cl)Cl)(OC(Cl)(Cl)Cl)=O.[Si:13]([O:20][CH:21]1[CH2:24][NH:23][CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[Si:13]([O:20][CH:21]1[CH2:24][N:23]([C:9]([Cl:12])=[O:8])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of ditrichloromethyl carbonate (2.38 g, 8.02 mmol, 1.50 equiv) in dichloromethane (20 mL) was added a solution of 3-[(tert-butyldimethylsilyl)oxy]azetidine (1 g, 5.34 mmol, 1.00 equiv) in dichloromethane (5 mL) dropwise with stirring at 0° C. over 30 min. Stirring was continued for 30 min whereupon a solution of triethylamine (810 mg, 8.00 mmol, 1.50 equiv) in dichloromethane (5 mL) was added dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined, washed with 2×40 mL of sodium chloride (sat.), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). Purification afforded 1.3 g (97%) of 3-[(tert-butyldimethylsilyl)oxy]azetidine-1-carbonyl chloride as a light yellow liquid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:17])=[C:13]([CH:16]=1)[C:14]#[N:15].C1(C)C=CC=CC=1.O>CCOC(C)=O>[Cl:17][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cc(N)ccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(Cl)c(C#N)c1
Yield: 91.8 %

Procedure:
Acetic anhydride (2.79 mL, 29.5 mmol), 5-amino-2-chloro-benzonitrile (3.00 g, 19.7 mmol), N,N-dimethylaminopyridine (0.241 g, 1.97 mmol), and toluene (50 mL) were combined and heated to reflux for 1.5 h. The reaction mixture was cooled, and water and EtOAc (150 mL) were added. The solid remaining in the mixture was collected and set aside. The aqueous layer was extracted once more with EtOAc, and the combined layers were washed with brine. The reserved precipitate was then dissolved in EtOAc, which was washed with brine. All organic layers were combined, dried, filtered, and concentrated. The residue was triturated with DCM/hexanes to yield the titled compound (3.52 g, 92% yield). This compound did not yield MS data. 1H NMR (400 MHz, CDCl3): 7.92 (d, J=1.0 Hz, 1H), 7.57 (dd, J=2.1, 1.2 Hz, 2H), 2.17 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CCBr)CCO1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 50 °C
Yield: 63.3 %

Procedure:
A mixture of N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate, (0.2 g, 0.571 mmol) and anhydrous potassium carbonate (0.316 g, 2.284 mmol) in DMF (2.5 ml) was heated at 50° C. for 1 hour. The mixture was cooled to room temperature and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (0.152 g, 0.685 mmol) was added and the mixture heated at 50° C. for 18 hours. The mixture was quenched with water (2 ml) and then extracted with DCM (2×5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing down under a stream of nitrogen. DMSO:MeOH (1:1) was added to the residue and the resulting precipitate was collected by filtration, washed with methanol and dried in vacuo to give the title compound as a white solid (136 mg).
Reaction SMILES: C([C:3]1[C:4]([C:9]([OH:11])=O)=[C:5]([NH2:8])[S:6][CH:7]=1)C.C([O-])=O.[NH4+].[CH:16]([NH2:18])=O>>[N:8]1[C:5]2[S:6][CH:7]=[CH:3][C:4]=2[C:9]([OH:11])=[N:18][CH:16]=1
Reactant: CCc1csc(N)c1C(=O)O
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: Oc1ncnc2sccc12

Procedure:
Ethyl 2-amino-3-carboxythiophene 2 is refluxed with ammonium formate and formamide to give the cyclized intermediate 3 which is then treated with thionyl chloride to afford the chloro derivative 4. Boc-protected aminopiperidine 5 is reductively alkylated with a variety of arylaldehydes 6 to provide the corresponding intermediates 7. Deprotection of 7 with trifluoroacetic acid treatment yields the free amine intermediate 8. Reflux of a mixture of the key intermediates 4 and 8 in i-propanol or acetonitrile in the presence of triethylamine yields the final compound 1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:22][C:23]([CH3:29])([CH3:28])[C:24]([NH:26][CH3:27])=[O:25]>>[CH3:28][C:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24](=[O:25])[NH:26][CH3:27])[CH3:29]
Reactant: CNC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (Example 78 b) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (EI): m/e=397.1 [M+H]+.
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([OH:5])=O.[CH:15]1([NH:22][C:23]([NH2:25])=[S:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:22][C:23]2[S:24][CH:2]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=3)[C:3](=[O:5])[N:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Product: O=C1N=C(NC2CCCCCC2)SC1Cc1ccc(O)c(O)c1

Procedure:
Synthesis was performed from (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]([CH3:45])([CH2:43][CH3:44])[CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[CH2:18][C:17]([F:20])([F:19])[CH2:16][N:15]1C(OC(C)(C)C)=O)=O>C(OCC)(=O)C.O>[CH3:45][C:7]([CH3:6])([CH2:43][CH3:44])[CH2:8][C:9]1[N:5]=[C:12]([C:14]2([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=4)=[CH:31][CH:30]=3)[CH2:18][C:17]([F:20])([F:19])[CH2:16][NH:15]2)[NH:11][CH:10]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CC(F)(F)CN2)n1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (947 mg, 12.3 mmol) was added to an ambient temperature solution of tert-butyl 2-{[(4,4-dimethyl-2-oxohexyl)amino]carbonyl}-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate (138 mg, 0.25 mmol) in xylenes (10 mL). After stirring in a sealed tube at 160° C. for 1 h, the reaction mixture was diluted with ethyl acetate and water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by chromatography over silica eluting with 0-100% ethyl acetate/hexane followed by high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid. The residue was dissolved in trifluoroacetic acid (1 mL). After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to afford the title compound. (M+H) found: 443.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=[C:11]([C:14]([C:16]3[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=3)=[O:15])[CH:12]=2)[N:7]=[C:6]([O:23][CH3:24])[C:5]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1>CO>[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=[C:11]([CH:14]([C:16]3[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=3)[OH:15])[CH:12]=2)[N:7]=[C:6]([O:23][CH3:24])[C:5]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=1
Reactant: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(C)cc(C(O)c3cncn3C)cc2c(Cl)c1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (0.016 g, 0.422 mmol) was added in one portion to a suspension of (4-chloro-2-methoxy-8-methyl-3-(3-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.1 g, 0.211 mmol, Intermediate 15: step d) in MeOH (3 mL). The mixture was stirred at room temperature overnight, then filtered, rinsing the solids with MeOH and H2O. The solid product was dried under reduced pressure to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (s, 1H), 7.57-7.69 (m, 1H), 7.41-7.53 (m, 4H), 7.30-7.41 (m, 1H), 6.76 (s, 1H), 5.94-6.15 (m, 1H), 4.35 (s, 2H), 4.09 (s, 3H), 3.60 (s, 3H), 2.67 (s, 3H), 2.58 (m, 1H). MS (EI) 476 [M+H]+.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)(=O)=O.[NH3:17].C1COCC1>>[C:11]1([C:9]2[N:10]=[C:5]([NH2:17])[N:6]=[N:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N
Reactant: CS(=O)(=O)c1nncc(-c2ccccc2)n1
Solvent: C1CCOC1
Product: Nc1nncc(-c2ccccc2)n1
Yield: 73 %

Procedure:
5-Phenyl-1,2,4-triazin-3-amine (1.70 g, 73%) was prepared from 3-(methylsulfonyl)-5-phenyl-1,2,4-triazine (3.20 g, 13.6 mmol) and 0.5 M ammonia in THF (100 mL, 500 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: C(OC([N:8]1[CH2:39][CH2:38][CH:37]([CH2:40][CH3:41])[C@H:9]1[C:10]([N:12]1[CH2:36][CH2:35][CH2:34][C@H:13]1[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH2:25][NH:26]C(OC(C)(C)C)=O)=[O:15])=[O:11])=O)(C)(C)C.Cl>O1CCOCC1>[CH2:40]([CH:37]1[CH2:38][CH2:39][NH:8][C@@H:9]1[C:10]([N:12]1[CH2:36][CH2:35][CH2:34][C@H:13]1[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH2:25][NH2:26])=[O:15])=[O:11])[CH3:41]
Reactant: CCC1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CCN[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN

Procedure:
To a stirred solution of diastereomer A of 1-(tert-butoxycarbonyl)-3-ethylprolyl-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-L-prolinamide (34 mg, 0.06 mmol) from the previous step in dioxane (2.0 mL) at ambient temperature was added an excess of 4.0 N solution of HCl in dioxane. The reaction was monitored for completeness by LCMS. The solvent was removed in vacuo to give the HCl salt of 3-ethyl-L-prolyl-N-[2-(aminomethyl)-5-chlorobenzyl]-L-prolinamide as a pale yellow oil. LCMS RT=0.74 min. LCMS (M+H)=393.3. 1H NMR (CD3OD, 400 MHz): δ 8.93 (m, 1H), 7.51 (s, 1H), 7.42-7.37 (m, 2H), 4.54-4.47 (m, 2H), 4.41-4.31 (m, 2H), 4.23 (s, 2H), 3.78-3.70 (m, 1H), 3.64-3.52 (m, 1H), 3.50-3.45 (m, 1H), 3.44-3.34 (m, 1H), 2.43 (br m, 1H), 2.34-2.27 (m, 1H), 2.16-1.67 (br m, 6H), 1.53-1.45 (m, 1H), 1.03 (t, J=7.4 Hz, 3H). Diastereomer B (37 mg, 0.06 mmol) was deprotected in similar fashion to afford the HCl salt of 3-ethyl-L-prolyl-N-[2-(aminomethyl)-5-chlorobenzyl]-L-prolinamide as a yellow oil. LCMS RT=0.73 min. LCMS (M+H)=393.3. 1H NMR (CD3OD, 400 MHz): δ 8.95 (m, 1H), 7.52 (s, 1H), 7.43-7.40 (m, 2H), 4.55 (d, J=15.6 Hz, 1H), 4.44 (dd, J=3.2 Hz, 8.8 Hz, 1H), 4.37 (d, J=15.2 Hz, 1H), 4.31 (d, J=4.8 Hz, 1H), 4.25 (s, 2H), 3.84-3.81 (m, 1H), 3.66-3.59 (m, 1H), 3.57-3.46 (m, 1H), 3.42-3.35 (m, 1H), 2.41-2.38 (m, 1H), 2.31-1.84 (m, 6H), 1.71-1.66 (m, 1H), 1.56-1.50 (m, 1H), 1.04 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])=[N:6][CH:7]=1.[CH:44]1(B(O)O)[CH2:46][CH2:45]1.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:44]1([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=3)[C:17]([CH3:42])=[C:16]4[CH3:43])=[O:12])[CH3:9])=[N:6][CH:7]=2)[CH2:46][CH2:45]1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(Br)cn3)cc12
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(C4CC4)cn3)cc12
Temperature: 100 °C

Procedure:
A high-pressure vial was filled with the (S)-tert-butyl 4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (50 mg, 0.078 mmol), cyclopropylboronic acid (8 mg, 0.09 mmol, 1.2 equiv), Pd(OAc)2 (12 mg, 0.055 mmol, 0.7 equiv), (Cy)3P (8.7 mg, 0.031 mmol, 0.4 equiv), K3PO4 (49 mg, 0.23 mmol, 3 equiv), in toluene-water (10%). The reaction mixture was heated at 100° C. for 3 h under microwaves. The mixture was evaporated in vacuo to obtain the crude which was purified by prep. HPLC (MeOH/Acetonitrile/water) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH:33]C(=O)C(F)(F)F)[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[OH-].[Na+].O.Cl>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Yield: 47.5 %

Procedure:
A solution of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g.) in a 0.1 N aqueous solution of sodium hydroxide (10.5 ml.) was warmed at 45° C. for 6 hours. Water (15 ml.) and ethyl acetate (30 ml.) were added to the reaction mixture and the resulting mixture was adjusted to pH 3.5 with 10% hydrochloric acid. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 5.0 with an aqueous solution of sodium bicarbonate. The aqueous solution was subjected to column chromatography on Amberlite XAD-2 (20 ml.)(prepared by Rohm & Haas Co.) using 10% ethanol as developing solvent. The eluate containing object compound was collected and lyophilized to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.12 g.).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=O)[CH2:3][C:4]([OH:6])=[O:5].[Cl-].C([O:21][C:22](=[O:33])CCCCCCCC(O)=O)C.C(OC(=O)C=C(C)C)C>>[CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:22]([OH:33])=[O:21])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CCCCCCCC(=O)O
Reactant: CC(CCCCCCCCC(=O)O)CC(=O)O
Agent: CCOC(=O)C=C(C)C
Agent: [Cl-]
Product: CC(CCCCCCCCCC(=O)O)CC(=O)O

Procedure:
The starting material 3-methyl-tridecanedioic acid (m.p.68.5°-69.5° C.) is prepared, under the conditions described in Example 1 for the preparation of 3-methyldodecanedioic acid, from azelaic acid ethyl ester chloride and dimethylacrylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][N:20]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:25][CH:22]1[CH2:23][CH2:24][N:20]([CH3:19])[CH2:21]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CN1CCC(N)C1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: COc1ccc2nc3cc(Cl)ccc3c(NC3CCN(C)C3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and 1-methylpyrrolidin-3-amine, the title compound was obtained; MS (Found M+1=356)
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[C:3]=1[CH3:15].CCN=C=NCCCN(C)C.[O:27]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:15][C:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[NH:1][C:32]([CH:29]1[CH2:30][CH2:31][O:27][CH2:28]1)=[O:33]
Reactant: O=C(O)C1CCOC1
Reactant: Cc1c(N)ccc2sc3ccccc3c12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(NC(=O)C2CCOC2)ccc2sc3ccccc3c12

Procedure:
2-Amino-1-methyldibenzothiophene (Method 10; 0.337 g, 1.58 mmol), 4-(dimethylamino)pyridine (0.213 g, 1.74 mmol), EDAC (0.334 g, 1.74 mmol) and tetrahydro-3-furoic acid (0.167 ml, 1.74 mmol) were stirred in DCM (20 ml) at reflux under an argon atmosphere for 64 h. The product was purified by flash chromatography eluting with DCM-5% methanol/DCM. Evaporation of the appropriate fractions gave the product as a white solid. NMR: 9.77 (brs, 1H), 8.44 (m, 1H), 8.04 (m, 1H), 7.82 (d, 1H), 7.52 (m, 2H), 7.36 (d, 1H), 4.00 (m, 1H), 3.76 (m, 3H), 3.27 (m, 1H), 2.68 (s, 3H), 2.15 (q, 2H); m/z 313.
Reaction SMILES: C1CO[C:3]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)([CH2:4][CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)[C@H:9]([CH2:29][C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][CH:31]=3)[CH2:8]2)[O:2]1.[ClH:48]>C(OCC)(=O)C>[ClH:48].[F:45][C:42]1[CH:43]=[CH:44][C:39]([C:3](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([C:24]([F:26])([F:25])[F:27])[CH:15]=3)[C@H:9]([CH2:29][C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][CH:31]=3)[CH2:8]2)=[CH:40][CH:41]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCC2(c3ccc(F)cc3)OCCO2)C[C@H]1Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(CCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of (2R)-4-[4,4-ethylenedioxy-4-(4-fluorophenyl)butyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (210 mg) in ethyl acetate was added 4N hydrogen chloride in ethyl acetate solution (0.5 ml) and the whole was stirred at room temperature for 23 hours. The solution was evaporated in vacuo. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether to give (2R)-4-[4-(4-fluorophenyl)-4-oxobutyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine hydrochloride (183.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)([OH:21])[CH3:22])[C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1Cc2[nH]c3ccc(Cl)cc3c2CN1C
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1Cc2c(c3cc(Cl)ccc3n2CC(C)(O)c2cccnc2)CN1C
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To a solution of 8-chloro-2,3-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.13 mmol) in 4 mL of DMF was added sodium hydride (256 mg, 6.40 mmol) at 0° C., and stirred for 10 min. 3-(2-methyloxiran-2-yl)pyridine (432 mg, 3.20 mmol) was added and the mixture was stirred at RT for 12 h. The reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice cold water and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product, which was crystallized in n-hexane to obtain 350 mg of 1-(8-chloro-2,3-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.72 (s, 1H), 8.47 (d, 1H), 7.52 (d, 1H), 7.23 (s, 1H), 6.94 (m, 3H), 4.10 (dd, 2H), 3.65 (m, 1H), 3.40 (m, 1H), 2.86 (m, 2H), 2.38 (s, 3H), 2.36 (m, 1H), 1.62 (s, 3H), 1.07 (d, 3H). Separation by chiral HPLC provided diastereomers II-147a-b.