Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[CH2:20][CH2:21][CH3:22]>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=1
Reactant: CCCc1n(N)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 48 h

Procedure:
1.49 g (10 mmol) of 4-dimethylamino-benzaldehyde are added to a solution of 0.88 g (5 mmol) of 1,3-diamino-2-propyl-imidazolium chloride in 15 ml of glacial acetic acid. After leaving to stand at room temperature for 2 days the product is crystallized out by the addition of ether and then recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-propyl-imidazolium chloride of melting point 252°.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([OH:25])[C:14]=2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([O:35][CH3:36])[N:28]=1.Cl>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH3:36][O:35][C:29]1[N:28]=[C:27]([O:25][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:14]=2[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH:32]=[C:31]([O:33][CH3:34])[N:30]=1
Reactant: O=C(OCc1ccccc1)c1c(O)cccc1-c1ccccc1
Reactant: COc1cc(Cl)nc(OC)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(-c3ccccc3)c2C(=O)OCc2ccccc2)nc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
2.41 Grams of 60% sodium hydride in oil was suspended in 100 ml of N,N-dimethylformamide and to the suspension was added gradually 17.44 g of benzyl 6-phenylsalicylate dissolved in 50 ml of N,N-dimethylformamide. Then, the mixture was stirred at room temperature for 30 minutes. To the reaction system was added 10.01 g of 4-chloro-2,6-dimethoxypyrimidine in 50 ml of N,N-dimethylformamide and the reaction mixture was heated at 100°-110° C. with stirring for 3 hours. After cooling on standing, the reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with aqua. saturated sodium chloride solution three times and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue obtained was subjected to silica gel column chromatography (hexane/ethyl acetate (10:1-3:1, v/v) to obtain 21.55 g of benzyl 2-(2,6-dimethoxypyrimidine-4-yloxy)-6-phenylbenzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][CH:6]=1.[Li]CCCC.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1>[CH3:29][C:24]1([CH3:30])[C:25]([CH3:28])([CH3:27])[O:26][B:22]([C:2]2[CH:3]=[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][CH:6]=2)[O:23]1
Reactant: Brc1coc(-c2ccccc2)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2coc(-c3ccccc3)c2)OC1(C)C
Reaction time: 0.25 h
Yield: 19.1 %

Procedure:
To a solution of 4-bromo-2-phenylfuran (1.3 g, 5.8 mmol) in THF (15 mL) was added n-BuLi (2.5M, 2.8 mL, 7.0 mmol) at −78° C. The reaction mixture was kept at −55° C. for 15 min and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 7.0 mmol) was added at −78° C. The reaction mixture was stirred for 1.5 h and then poured into water/ice solution, extracted with petroleum ether (3×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford 4,4,5,5-tetramethyl-2-(5-phenylfuran-3-yl)-1,3,2-dioxaborolane as a red oil (300 mg, 19%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:29][CH3:30])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC2CCc3ccc([N+](=O)[O-])cc3C2)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.4 %

Procedure:
To a solution of 4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (485 mg, 1.25 mmol) and acetaldehyde (110 μL, 1.49 mmol) in dichloroethane (20 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (530 mg, 2.49 mmol, 2 eq.) in a single portion. The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica (10 g). This was placed on top of a flash column and eluted with 20% acetone in hexanes. The fractions containing product were pooled and concentrated to afford 4-{[ethyl-(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (430 mg).
Reaction SMILES: C(N1CCC[C@H](CNC2C=CC=CC=2)C1)(OC(C)(C)C)=O.C(N1CCC[C@H](CN(C2C=CC=CC=2)C(=O)CC)C1)(OC(C)(C)C)=O.[CH2:47]([N:55]1[CH2:60][CH2:59][CH2:58][CH:57]([CH2:61][N:62]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:63](=[O:66])[CH2:64][CH3:65])[CH2:56]1)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH2:47]([N:55]1[CH2:60][CH2:59][CH2:58][C@@H:57]([CH2:61][N:62]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:63](=[O:66])[CH2:64][CH3:65])[CH2:56]1)[CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCC(=O)N(CC1CCCN(CCc2ccccc2)C1)c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H](CNc2ccccc2)C1
Agent: CCC(=O)N(C[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Product: CCC(=O)N(C[C@@H]1CCCN(CCc2ccccc2)C1)c1ccccc1

Procedure:
Following a procedure similar to that described in Examples 4 and 5, (R)-N-(1-Boc-piperidin-3-ylmethyl)-aniline 28 was converted first to (R)-N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 29, and then to (R) N-(1-Phenethyl-piperidin-3-ylmethyl)-N-phenyl-propionamide 30 (LRMS 350).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:40][O:41][CH3:42])[C:4]([CH3:39])=[C:5]([C:28]([O:30]COC(=O)C(C)(C)C)=[O:29])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9]>C(OC(C)C)(C)C.O>[CH3:39][C:4]1[N:3]([CH2:40][O:41][CH3:42])[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])[C@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:5]=1[C:28]([OH:30])=[O:29]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: O
Solvent: CC(C)OC(C)C
Product: COCN1C(C)=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.1 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 590 mg of bis(pivaloyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 1 or 2, and 200 mg of Lipase PS was added thereto, followed by stirring at room temperature for 72 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 210 mg (yield: 44%) of (R)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl -4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl -3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCCC1.CO.O>[CH3:1][O:2][CH:3]([CH2:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Reaction time: 1.75 h
Yield: 96.3 %

Procedure:
To a solution of methyl 2-methoxy-3-(1-trityl-1H-imidazol-4-yl)propanoate (0.0592 g, 0.139 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.5 mL) was added 2N NaOH (0.278 mL) and the reaction mixture was stirred for 1.75 hrs. The organic solvents were removed and 1 N KHSO4 (5 mL) and ethyl acetate (10 mL) were added. The organic phase was washed with water (2×5 mL), then saturated sodium chloride (1×5 mL) and dried over MgSO4. The combined aqueous layers were re-extracted with DCM (2×10 mL), and dried over MgSO4—Solvent removal and drying in vacuo yielded 0.0552 g (96%) of 92.6% pure 2-methoxy-3-(1-trityl-1H-imidazol-4-yl)propanoic acid; retention time, 6.80 min.; column: Phenomenex Luna C18(2) (5 μm, 50×4.6 mm); gradient: 10% to 100% B in A over 10 min. at 1.25 mL/min. Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in AcCN. LC/MS: ESI (M+H)+=413.1. 1H-NMR (CDCl3, 500 MHz): δ 3.10-3.18 (m, 1H), 3.31-3.38 (m, 1H), 3.45 (s, 3H), 4.26-4.31 (m (1H), 6.86 (s, 1H), 7.04-7.11 (m, 6H), 7.37-7.47 (m, 9H), 8.16 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:47][O:48][CH:49]2[CH2:51][CH2:50]2)[C:8]([NH:10][C@@H:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:30])=[C:15]([CH2:18][S:19][C:20]4[N:25]([CH3:26])[C:24](=[O:27])[C:23](=[O:28])[NH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:47][O:48][CH:49]2[CH2:51][CH2:50]2)[C:8]([NH:10][C@@H:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([OH:31])=[O:30])=[C:15]([CH2:18][S:19][C:20]4[N:25]([CH3:26])[C:24](=[O:27])[C:23](=[O:28])[NH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Cn1c(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(N)n4)[C@H]3SC2)n[nH]c(=O)c1=O
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(N)n4)[C@H]3SC2)n[nH]c(=O)c1=O
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a suspension of benzhydryl 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (350 mg) in a mixture of anisol (0.5 ml) and methylene chloride (1.5 ml) was added trifluoroacetic acid (1 ml) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. The mixture was poured into diisopropyl ether (100 ml) and the resulted precipitate was collected. The precipitate was added to a mixture of ice-water and ethyl acetate and adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 3 with 6N hydrochloric acid. The precipitate was collected and dried over phosphorus pentoxide to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (157 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.O1CCCC1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:26][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)=[CH:3][CH:4]=2)=[O:9])=[CH:11]1
Reactant: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Temperature: 180 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
Into a pressure flask was added (6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 (3.5 g, 0.014 mol, prepared as described in Example 3), 4-(trifluoromethyl)benzylamine (30, 9.0 g, 0.051 mol), tetrahydrofuran (30.0 mL, 0.37 mol), palladium acetate (200.0 mg, 0.890 mmol) and 2-(di-t-butylphosphino)biphenyl (200.0 mg, 0.67 mmol). The reaction mixture was stirred at 180° C. overnight, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. To the residue was added acetic acid (15.0 mL) and H2O (5.0 mL). The reaction mixture was stirred at 100° C. for 5 hours and concentrated to remove the acetic acid. The residue was then treated with aqueous Na2HCO3 and extracted with ethyl acetate. The organic layer was washed, dried, concentrated and purified to give compound P-0017 (1.0 g, yield=18.5%) as a light yellow solid. MS (ESI) [M+H+]+=397.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][C:9]([NH:29][C:30]2[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[N:10][CH:11]=1
Reactant: COc1ccc(N)cn1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Nc1ccccc1)c1ccc(OC)cc1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Nc2ccc(OC)nc2)nc1Nc1ccccc1)c1ccc(OC)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(2-chloro-4-phenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (40 mg, 0.1 mmol) (from Example 12b supra) and 5-amino-2-methoxypyridine (37.2 mg, 0.3 mmol) (Aldrich) was heated at 110° C. for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and successively washed with saturated aqueous ammonium chloride solution (10 mL), water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 3-[2-(6-methoxy-pyridin-3-ylamino)-4-phenylamino-pyrimidin-5-yl]-2-(4-methoxy-phenyl)-propionic acid methyl ester as a dark-red solid which was used in the next step without further purification. (Yield 47.1 mg, 96.8%).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:52])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)C.[H-].[Na+].Br[CH2:56][CH:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>CN(C=O)C>[CH:57]1([CH2:56][N:23]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]4[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:51])[CH2:39]4)[CH:32]=3)[C:28]([F:52])=[CH:27][CH:26]=2)[C:21](=[O:22])[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:16]=2)[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: BrCC1CCCCC1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN(CC4CCCCC4)C(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1
Yield: 19.5 %

Procedure:
Following the general procedure outlined in Example 66, 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (47.3 mg, 0.0662 mmol), NaH (6.62 mg, 0.262 mmol) and (bromomethyl)cyclohexane (0.0150 mL, 0.108 mmol) in DMF (1.0 mL) were reacted to give the desired product (7.9 mg, 19.6%). EI-MS m/z 611 (M−H)+.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[C:13]([O:21]C)(=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>CO>[CH3:19][O:18][C:16](/[C:15](=[CH:8]/[C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([CH3:4])[CH:6]=1)/[CH2:14][C:13]([OH:21])=[O:20])=[O:17]
Reactant: Cc1cccc(C=O)c1
Reactant: COC(=O)CCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(=C/c1cccc(C)c1)CC(=O)O

Procedure:
To a solution of sodium methoxide (1.4 g) in methanol (20 ml}was added a mixture of 3-methylbenzaldehyde (2.4 g) and dimethyl succinate (3.5 g) and the mixture was refluxed for 3 hours. After the reaction mixture was concentrated in vacuo, water was added to the resulting residue and the mixture was washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with diethyl ether. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated under reduced pressure to give 3.8 g of
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Br[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1.BrC1SC=CC=1>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Brc1ccsc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: Brc1cccs1
Product: COc1ccc(Nc2ccsc2)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
Reaction of 4-methoxy-2-nitroaniline (X:R=4-OMe) and 3-bromothiophene (XI:R′=3-Br) as described above for Example 55, but for only 6 hours, gave 4-methoxy-2-nitro-N-(3-thienyl)aniline (XIV:R′=4-OMe, 3-thienyl) (71%): mp (EtOAc/petroleum ether) 121-123° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13](=O)[CH2:14][C:15]([O:17]C)=O.[CH3:20][NH:21][NH2:22]>C(O)C>[OH:17][C:15]1[N:21]([CH3:20])[N:22]=[C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH:14]=1
Reactant: COC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: CNN
Solvent: CCO
Product: Cn1nc(CN2C(=O)c3ccccc3C2=O)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.3 %

Procedure:
10.0 g methyl 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-oxo-butyrate are dissolved at 60° C. in 200 ml of ethanol and 1.94 g methylhydrazine are added. The reaction mixture is cooled and stirred further at ambient temperature. After 5 hours the precipitated substance is suction filtered and washed with ethanol. 7.91 g of the product are obtained as a powder.
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(F)(F)F)CC3)C=2)C=1)(C)CCC(O)=O.C(O)(C(F)(F)F)=O.[N+:37]([C:40]([C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:61][C@H:62]3[CH2:67][CH2:66][C@@H:65]([C:68]([F:71])([F:70])[F:69])[CH2:64][CH2:63]3)[C:53]=2[C:57]([F:60])([F:59])[F:58])[CH:48]=1)([CH3:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])([O-])=O>>[NH2:37][C:40]([C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:61][C@H:62]3[CH2:63][CH2:64][C@@H:65]([C:68]([F:69])([F:70])[F:71])[CH2:66][CH2:67]3)[C:53]=2[C:57]([F:59])([F:60])[F:58])[CH:48]=1)([CH3:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44]
Reactant: CC(CCC(=O)O)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CCC(=O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1
Yield: 46 %

Procedure:
4-Amino-4-[5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid was synthesized as per 4-amino-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid (Example 282) in 46% yield (as TFA salt), using 4-nitro-4-[5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid as starting material. MS: m/z=500.10 [M+Na]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.23 (br. s., 1H), 8.52 (br. s., 3H), 8.23 (d, J=9.3 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.77 (dd, J=9.3, 2.0 Hz, 1H), 7.71 (d, J=9.3 Hz, 1H), 5.07-5.13 (br. s., 1H), 2.39-2.59 (m, 2H obscured), 2.21-2.34 (m, 2H), 1.93-2.17 (m, 4H), 1.56-1.78 (m, 9H).
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:11][NH:10][C@H:9]([CH2:12][OH:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.II>O1CCCC1.C(OCC)(=O)C.CCCCCC.O>[CH2:20]([O:27][C:28]([N:10]1[CH2:11][C@H:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][C@H:9]1[CH2:12][OH:13])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC[C@@H]1C[C@@H](C2CCCCC2)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1C[C@H](C2CCCCC2)C[C@H]1CO

Procedure:
To a solution of (2S-trans)-4-cyclohexyl-2-pyrrol idinemethanol(45 g) in tetrahydrofuran (400 ml) was added potassium carbonate solution (18.7 g, 120 ml water and cooled to -2° C. (Benzyloxy)carbonyl chloride (37.7 ml) was added dropwise to the well stirred reaction mixture, keeping the inside temperature between -2° and 0° C. After the addition (20 minutes), the reaction mixture was stirred for 15 minutes at 0° C. and poured into crushed ice and water (500 ml). The organic layer was separated after saturation with sodium chloride and the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic phase was washed with 5% hydrochloric acid (2×100 ml), water (1×100 ml) and brine (1×100 ml). Evaporation of the solvents after drying over anhydrous sodium sulfate furnished a colorless thick oil, 78.1 g. TLC showed a single spot at Rf =0.7 with very faint shadow at origin and at solvent front (silica gel, ethyl acetate-hexane, 4:1, UV and iodine). [α]D =-21.0°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH2:18][O:19][C:20](/[C:22](/Cl)=[N:23]\[OH:24])=[O:21].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.Cl>[CH2:18]([O:19][C:20]([C:22]1[CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH:9]=2)[O:24][N:23]=1)=[O:21])[CH3:17]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cccc(NC(=O)OC(C)(C)C)c2)on1
Reaction time: 16 h
Yield: 69.7 %

Procedure:
(3-ethynyl-phenyl)-carbamic acid tert-butyl ester (2.48 g, 0.0114 mole) and ethyl chlorooximidoacetate (3.82 g, 0.0252 mole) were mixed in THF (12 mL) and triethylamine (3.98 mL, 0.0286 mole) was added slowly. The mixture was stirred for 16 hours and then diluted with ethyl acetate (100 mL) and aqueous 1N HCl (50 mL). The two layers were separated and the aqueous layer extracted with ethyl acetate (2×50 mL). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified by flash chromatography (10–15% ethyl acetate/Hexane) to provide the titled compound (2.64 g, 50% yield).