Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)[C:10]([OH:12])=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:31][CH:32]1[C:50](=[O:51])[N:34]2[C:35]([C:47]([OH:49])=[O:48])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH3:46])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12>C(OCC)(=O)C.O.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)[C:10]([NH:31][CH:32]1[C:50](=[O:51])[N:34]2[C:35]([C:47]([OH:49])=[O:48])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH3:46])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12)=[O:12]
Reactant: CON=C(C(=O)O)c1csc(C)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(C)n1
Temperature: 40 °C
Yield: 36.6 %

Procedure:
Phosphorus oxychloride (0.26 g.) was added under ice-cooling to dimethylformamide (0.15 g.) and the mixture was warmed at 40° C. for 1 hour. Ethyl acetate (1.5 ml.) was added thereto and to the mixture was at a time added 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (syn isomer) (0.3 g.) with stirring and ice-cooling, after which the resulting mixture was stirred for 20 minutes at 0° to 5° C. On the other hand, bis(trimethylsilyl)acetamide (1.2 g.) was added to a suspension of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.53 g.) in ethyl acetate (7 ml.) and the mixture was stirred at ambient temperature. To this solution was dropwise added the above obtained ethyl acetate solution at -20° C. and the mixture was stirred for 2 hours at -10° to -20° C. Water (20 ml.) was added to the reaction mixture below -25° C. and ethyl acetate (20 ml.) was added thereto, after which the mixture was stirred. An insoluble material was filtered off and the ethyl acetate layer was separated. Water (15 ml.) was added to the ethyl acetate layer and the mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with methylene chloride and methylene chloride in the aqueous layer was removed by bubbling of nitrogen gas. The aqueous solution was adjusted to pH 2.2 with 10% hydrochloric acid and precipitates were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.28 g.).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[C:10](Cl)([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11].O>O1CCOCC1>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11])[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCC[C@@H](N)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Yield: 34.3 %

Procedure:
D-Nle-OH (1.01 g) was dissolved in 30 ml of 10% NaCO3 and 10 ml of dioxan. While stirring, a solution of Fmoc-Cl (2.0 g) in 10 ml of dioxan was added to the solution. After stirring at room temperature for 2 hours, 400 ml of water was added to the mixture. The reaction mixture was extracted twice with 200 ml of ether to remove by-products. Ice was added to the aqueous phase and the mixture was neutralized with conc. hydrochloric acid. After extracting with ethyl acetate, the extract was washed with water. Crystallization from ether gave 933 mg of Fmoc-D-Nle-OH.
Reaction SMILES: O[C:2]([CH3:13])([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(S(F)(F)[F:20])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:20][C:2]([CH3:13])([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(O)CNC(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A solution of tert-butyl 2-hydroxy-2-methylpropylcarbamate (19.2 g, 101 mmol) in dichloromethane (500 mL) was stirred at −78° C. under a nitrogen atmosphere, and (diethylamino)sulfur trifluoride (DAST) (18.0 g, 112 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (150 mL) was added. The organic layer was then separated and washed sequentially with saturated aqueous sodium bicarbonate (150 mL), water (150 mL), and brine (150 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting oil was purified by automated flash chromatography (FLASH 65I cartridge, eluting with 10% ethyl acetate in hexane) to provide 13.7 g of tert-butyl 2-fluoro-2-methylpropylcarbamate as a light yellow oil that crystallized overnight.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]=2)=[CH:3][CH:2]=1.[H][H].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C.O=[Pt]=O>[NH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH2:7][CH:4]1[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]1
Reactant: c1cc(CCC2=NCCCCN2)ccn1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: C1CCNC(CCC2CCNCC2)=NC1
Yield: 76.7 %

Procedure:
The 4,5,6,7-tetrahydro-2[2-(4-pyridyl)ethyl]-1H-1,3-diazepine (1.9 g, 0.009M) and PtO2 (0.25 g) in ethanol (20 ml) and 2 NHCl (15 ml) was reduced at 45 psig of hydrogen. After the hydrogenation, the solvent was removed and the residue was crystallized from ethanol-ether to give 1.5 g of 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine (60% yield) as dihydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4].[Cl:13]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([Cl:13])=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccn(C(F)F)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nn(C(F)F)cc1Cl
Temperature: 50 °C

Procedure:
A mixture of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (535 mg, 3 mmol) and N-chloro-succinimide (1.22 g, 9.1 mmol) in N,N-dimethylformamide (5 ml) was heated at 50° C. overnight. The reaction mixture was cooled, poured into water (20 ml), then extracted with ethyl acetate. The organic layer was separated, washed with water, dried over sodium sulphate, finally evaporated at reduced pressure. The yellowish crude material was purified by chromatography on silica gel using a 3:1-mixture of cyclohexane and ethyl acetate as the eluent. The 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester was obtained as a white solid (540 mg, 84%); (calculated) C6H5ClF2N2O2 [210.57]; (found) [M]+=210.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:25]([CH3:27])[CH3:26])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:25]([CH3:26])[CH3:27])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(N(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1nc2ccc(Cl)cc2c(Cc2ccccc2Cl)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 12 step B from a mixture of 6-chloro-4-(2-chloro-benzyl)-2-dimethylamino-quinoline-3-carboxylic acid ethyl ester and 1N NaOH in ethanol. Pale yellow solid. LC-MS (ESI): 375 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.C[N:18](C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 72 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 10 g of 2,6-dichloro-5-fluoronicotinic acid in 30 mL of toluene, 8.5 g of thionyl chloride and 0.10 mL of N,N-dimethylformamide were added, and the mixture was stirred at 72° C. for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resultant residue was dropped to 30 mL of 25% ammonium water at −20° C. The temperature was increased to 5 C.°, and the mixture was stirred for 30 minutes. The solid was filtered off to obtain 9.9 g of 2,6-dichloro-5-fluoronicotinamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[Br:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([CH3:26])=[CH:18][CH:17]=1.C(O)(=O)C(O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Br:15][C:16]1[C:21]([C:22]([O:8][C:7]2[C:2]([Br:1])=[CH:3][CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]=2[F:9])=[O:23])=[C:20]([F:25])[C:19]([CH3:26])=[CH:18][CH:17]=1
Reactant: Cc1ccc(Br)c(C(=O)O)c1F
Reactant: CCCCCc1ccc(Br)c(O)c1F
Agent: CN(C)c1ccncc1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Product: CCCCCc1ccc(Br)c(OC(=O)c2c(Br)ccc(C)c2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
43.2 g (0.165 mol) of 6-bromo-2-fluoro-3-pentylphenol, 40.5 g (0.173 mol) of 6-bromo-2-fluoro-3-methylbenzoic acid and 3.52 g (29 mmol) of 4-(dimethylamino)pyridine were initially introduced in 300 ml of dichloro-methane, and a solution of 35.7 g (0.172 mol) of N,N-dicyclohexyl-carbodiimide in 80 ml of dichloromethane was added. The batch was stirred overnight at room temperature, and 4.16 g (33 mmol) of oxalic acid were subsequently added. After 1 hour, the precipitated solid was filtered off, and the filtrate was evaporated under reduced pressure. The crude product was filtered through silica gel with n-heptane/1-chlorobutane (1:1), giving 72.7 g (91% of theory) of 6-bromo-2-fluoro-3-pentylphenyl 6-bromo-2-fluoro-3-methylbenzoate as a colourless oil.
Reaction SMILES: C1(CCC(N(C)[C@H](C(N[C@H](C(N[C@H](C([NH:34][C@H:35]([C:47]([OH:49])=[O:48])[CH2:36][C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=O)CC(=O)N)=O)[C@H](CC)C)=O)C(C)C)=O)C=CC=CC=1.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC(=O)OCC1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC(=O)N.CC(C)C[C@H](N)C1NN=NN=1.CCN(C(C)C)C(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[NH2:34][C@H:35]([C:47]([OH:49])=[O:48])[CH2:36][C:37](=[O:46])[O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C(C)C)N(C)C(=O)CCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reaction time: 16 h

Procedure:
A modified procedure of example I was used to assemble the protected tetrapeptide (SEQ ID NO:5) PhCH2CH2CO-N-Me-Val-Ile-Asn-Asp(OBzl)-OH wherein Boc-Asp(OBzl)-OH was linked to the photo-resin and HOBt/DCC was used for coupling Boc-Asn-OH. A solution of the protected tetrapeptide (375 mg, 0.54 mmol) and 3-methyl-1(S)-(5-1H-tetrazolyl)butylamine (375 mg, 1.25 mmol) in DMF (15 ml) was cooled to 0. DIPEA (284 mg) and then diphenylphosphoryl azide (760 mg) were added to the solution. The reaction mixture was stirred for 16 h at 0 and then partitioned between Et2O and H2O containing of few drops of concentrated NH4OH (pH=9.5). The aqueous phase was separated, washed with fresh Et2O and filtered through a 45 m membrane. The pH of the filtrate was adjusted to pH 6.5 by the addition of AcOH and again filtered through a 45 m membrane. The filtrate was loaded on a HPLC preparatory column. The column was eluted with a continuous gradient of 0.06% aqueous TFA in acetonitrile. The pure fractions as indicated by analytical HPLC were combined and lyophilized to give the corresponding Asp(OBzl) protected peptide (132 mg) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=O)[C@H:3]1[C@H:7]2[CH2:8][CH2:9][C@@H:4]1[C@H:5]([O:10][C:11](=[O:24])[C:12]([OH:23])([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:6]2.[NH2:35][CH2:36][C@@H:37]([C:46]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]2[C:47]=1[CH:48]=[CH:49][C:50](=[O:57])[NH:51]2)[O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[C:42]([Si:39]([CH3:41])([CH3:40])[O:38][C@H:37]([C:46]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]2[C:47]=1[CH:48]=[CH:49][C:50](=[O:57])[NH:51]2)[CH2:36][NH:35][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:2]([CH3:1])[C@H:3]1[C@H:7]2[CH2:8][CH2:9][C@@H:4]1[C@H:5]([O:10][C:11](=[O:24])[C:12]([OH:23])([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:6]2)([CH3:45])([CH3:44])[CH3:43]
Reactant: CN(CCCCCCCCC=O)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(CCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-[methyl-(9-oxo-nonyl)amino]bicyclo[2.2.1]hept-2-yl ester (max 0.73 mmol), 5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one (245 mg, 0.73 mmol), sodium triacetoxyborohydride (186 mg, 0.88 mmol), and acetic acid (2 drops) in dry 1,2-dichloroethane was stirred at ambient temperature overnight. The reaction mixture was partitioned between DCM and satd NaHCO3 (aq). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford a dark green/brown gum that solidified on standing, which was purified by preparative HPLC (system 2, 35% B+1% B/min). The fractions containing pure product were concentrated, neutralised with satd NaHCO3 (aq), and extracted with DCM. After concentration in vacuo a green/brown oil was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1.[CH2:13]([Mg]Br)CCCCC>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCCCCc1cc(C)ccn1
Reactant: CCCCCC[Mg]Br
Product: CCCCCCc1cc(C)ccn1

Procedure:
This compound was obtained using the same experimental procedure as per 4-methyl-2-pentyl-pyridine (see above), using hexyl magnesium bromide instead of pentyl magnesium bromide. The product was obtained with similar yield and purified in the same way.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:36]=[C:6]2[N:7]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:8]([CH3:25])=[C:9]([C:23]#[N:24])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=3[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]2[N:4]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>N1C=CC=CC=1>[C:23]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=2[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]2[N:4]=[C:3]([NH:2][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])[N:36]=[C:6]2[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:8]=1[CH3:25])#[N:24]
Reactant: O=C(Cl)C1CC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)n2nc(NC(=O)C3CC3)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7S)-2-amino-7-[4-cyano-2-(methylsulfonyl)phenyl]-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (16 mg, 30 μmol) was dissolved in abs. pyridine (1 ml). At room temperature, cyclopropanecarbonyl chloride was added in two portions (in each case 3.7 mg, 36 μmol, 1.2 eq.). Once HPLC showed substantial conversion (12 h), the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Macherey & Nagel Gravity C18 column, 21×300 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (11.2 mg, 66% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][N:12](C=O)C>[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:12]1[C:11]2=[N:7][CH:8]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]2[CH:10]=[CH:9]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2[nH]ncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: N#Cc1cnc2[nH]ccc2c1
Temperature: 80 °C
Yield: 75 %

Procedure:
A mixture of bromide 24 (10.0 g, 50.8 mmol), ZnCl2 (3.58 g, 30.5 mmol), and Pd(PPh3)4 (3.52 g, 3.05 mmol) in DMF (110 mL) was heated at 80° C. overnight. The solvent was evaporated and the residue separated by silicagel chromatography (100 g column) using hexane:ethyl acetate as eluent (gradient elution). The resulting solid was partitioned between water (200 mL)/CH2Cl2 (100 mL) and the aqueous phase extracted with more CH2Cl2 (4×100 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the product as a white solid (5.48 g, 75%), which was used for subsequent reactions without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(F)(F)F)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (203 mg, 0.70 mmol) and 3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K38) (256 mg, 0.70 mmol) according to the general procedure M. Obtained as an off-white solid (290 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[CH3:55][N:56]1[CH2:59][CH:58]([NH2:60])[CH2:57]1>ClCCl>[CH3:24][C:9]1([CH3:25])[CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[NH:11][CH:10]1[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:19])[NH:60][CH:58]2[CH2:59][N:56]([CH3:55])[CH2:57]2)[CH:16]=1
Reactant: CN1CC(N)C1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CN(C)C3)c1)N2
Reaction time: 1 h
Yield: 109.2 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (100 mg, 0.29 mmol) in dichloromethane (6.7 mL) was added N-hydroxybenzotriazole (59.7 mg, 0.44 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (169.7 mg, 0.88 mmol), followed by 4-methylmorpholine (89.5 mg, 0.88 mmol) and the resultant mixture was stirred at room temperature for 40 min. Then 1-methylazetidin-3-amine (30.5 mg, 0.35 mmol) was added to the flask and the reaction mixture was stirred for an additional 60 min, LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 129 mg of methyl 3,3-dimethyl-2-(3-(1-methylazetidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was washed with ether to afford 103 mg desired product as a white powder, yield: 85.8%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.C(#N)C.[C:32]([O:36][C:37]([NH:39][C:40]1[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43])=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:32]([O:36][C:37]([N:39]([C:40]1[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: COc1ccc(Cn2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1)C(=O)OC(C)(C)C

Procedure:
A mixture of 5-[4′-(bromomethyl)biphenyl-2-yl]-1-(p-methoxybenzyl)-1H-tetrazole (compound 5a, 9.25 g, 21.2 mmol), acetonitrile (107 ml), methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate (compound 19a, 6.43 g, 21.7 mmol) and potassium carbonate (3.00 g, 21.7 mmol) was heated under reflux for 6 hr under a nitrogen atmosphere. The reaction was monitored by TLC (eluent: toluene/ethyl acetate (4:1)). The reaction mixture was cooled, and filtered, and the cake was washed with acetonitrile (35 mL). The filtrate was concentrated under reduced pressure at 35° C. or lower to give a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene/ethyl acetate (100:0-4:1)), and the fraction was concentrated. To the residue was added chloroform (about 30 ml), and the mixture was concentrated. The operations were repeated four times. The residue was dried under reduced pressure in a bath at 40° C. to give methyl 2-(N-tert-butoxycarbonyl-N-{(2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate (compound 20a) as a yellowish brown amorphous solid (9.83 g (71.1%)).