Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: CCOC(=O)c1ccc(-c2cc(OC)c(OC)c(OC)c2)nc1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (1.16 g) and ethyl 6-chloronicotinate (1.02 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:7][C:6]([C:5]2[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:8][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: COc1cc(OC)cc(C(=N)N)c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: COc1cc(OC)cc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)c1

Procedure:
The title compound, MS: m/e=405.4 (M+H+), was prepared from 3,5-dimethoxy-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][C:21]=1[CH3:22])[CH:18]=[CH:17][C:16]1[CH2:15][CH2:14][CH2:13][C:12](=[O:23])[C:11]2=1.[CH2:24](I)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34].O>C1C=CC=CC=1>[CH3:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][C:21]=1[CH3:22])[CH:18]=[CH:17][C:16]1[CH2:15][CH2:14][CH:13]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=[CH2:24])[C:12](=[O:23])[C:11]2=1.[CH3:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][C:21]=1[CH3:22])[CH:18]=[CH:17][C:16]1[CH2:15][CH2:14][CH2:13][C:12](=[O:23])[C:11]2=1
Reactant: C=CCCCCCCCCCI
Agent: CC(C)(C)[O-]
Agent: Cc1cc2ccc3c(c2cc1C)C(=O)CCC3
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C=CCCCCCCCCCC1CCc2ccc3cc(C)c(C)cc3c2C1=O
Temperature: 60 °C
Yield: 39 %

Procedure:
t-BuOK (3.6 g, 0.032 mole) was dissolved in 250 ml of dry benzene at 40°-50° C. To the stirred solution was added 6,7-Dimethyl-4-oxo-1,2,3,4-tetrahydrophenanthrene (3.6 g, 0.016 mole) in 50 ml of dry benzene and then, 10-undecenyl iodide (4.58 g, 0.016 mole) at 30° C. under N2. The mixture was heated to 60° C. for 2.5 hr under N2. After cooling the reaction mixture to room temperature, water was added. The whole mixture was extracted twice with diethylether. The combined diethylether solution was dried over anhydrous MgSO4. and then concentrated. Flash column chromatography of the residue on silica gel afforded 6,7-Dimethyl-4-oxo-3-(10-undecenyl)-1,2,3,4-tetrahydrophenanthrene as a sticky brown solid (2.36 g, 0.0063 mole, 39% yield) as a desired product, and unreacted 6,7-Dimethyl-4-oxo-1,2,3,4-tetrahydrophenanthrene (1.70 g, 47% recovered). 1H NMR (CDCl3)δ 1.29-1.62 (m,14H), 1.86-2.08 (m,4H), 2.21-2.35 (m,2H), 2.40 (s,3H), 2.46 (s,3H), 2.52-2.63 (m,1H), 3.07-3.13 (m,2H), 4.90-5.04 (m,2H), 5.75-5.89 (m,1H), 7.17 (d, J=8.2 Hz,1H), 7.53 (s,1H), 7.77 (d, J=8.2 Hz,1H), 9.10 (s,1H), IR (KBr) cm-1 2920, 2850, 1669, 1600, exact (EI) mass. calcd. for C27H36O: 376.2766, Found: 376.2766.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][OH:18]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][OH:18]
Reactant: Oc1cccc(Br)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCOc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromophenol (14) (36.38 g, 210.3 mmol) in acetone (175 ml) was added K2CO3 (0.033 g, 237 mmol) and 2-bromoethanol (20 ml, 283.3 mmol). The mixture was heated to reflux for 4 d under argon then cooled to room temperature. The solids were removed by filtration and the filtrate concentrated under reduced pressure. The residue was dissolved in diethyl ether (150 ml) and washed with water (100 ml), aqueous NaOH (10%, 100 ml, 3×50 mL, 5%, 200 ml), water (100 ml), and brine, dried over MgSO4 and concentrated under reduced pressure to give 2-(3-bromophenoxy)ethanol (15) as light brown oil. Yield (21.07 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J=7.8 Hz, 1H), 7.07-7.12 (m, 2H), 6.85 (ddd, J=7.8, 2.4, 1.3 Hz, 1H), 4.06 (m, 2H), 3.95 (m, 2H), 2.11 (t, J=12.3 Hz, 1H).
Reaction SMILES: Cl.[Sn](Cl)Cl.ClCCl.[N+:8]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([O-])=O>O>[N:21]1([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:16][C:11]=2[NH2:8])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: ClCCl
Solvent: O
Product: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Reaction time: 7 h
Yield: 83.2 %

Procedure:
Concentrated hydrochloric acid (12.2 ml, 146 mmol) and anhydrous tin dichloride (12.7 g, 67.2 mmol) were sequentially added at 0° C. to a dichloromethane solution (10 ml) of 1-[2-nitro-4-(trifluoromethyl)phenyl]piperidine (6.13 g, 22.4 mmol), obtained as described in Referential Example 1-1B. The resulting mixture was stirred for seven hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (200 g, hexane/ethyl acetate=15/1). Thus, 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (4.55 g, 83.0%) was yielded as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[CH3:24][S:25](O)(=[O:27])=[O:26].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH2:20][CH2:21][CH2:22][O:23][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)O
Reactant: O=c1c(CCCCO)c(O)c2cccnc2n1-c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CS(=O)(=O)OCCCCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 55 °C

Procedure:
4-Hydroxy-3-(4-hydroxybutyl)-1-phenyl-1,8-naphthyridin-2(1H)-one (10 g.) was dissolved, with stirring, in Eaton's Reagent (10% P2O5 in methanesulfonic acid; 50 ml.) under a nitrogen atmosphere. The solution was heated to 55° C. where it was held for 31/2 hr. It was then cooled and poured into a water/ice mixture. After stirring for several hours, the aqueous mixture was extracted (3×) with ethyl acetate (250 ml. each). The organic extract was separated, dried (Na2SO4), filtered and evaporated. The residue was stirred with a small volume of cold isopropanol and filtered to yield a brown solid, the mono-mesylate, which was used without further purification in Example 7.
Reaction SMILES: C([NH:11][C@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14][CH2:13]1)(OCC1C=CC=CC=1)=O.Br.C(=O)=O>C(O)(=O)C>[NH2:11][C@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14][CH2:13]1
Reactant: O=C(N[C@@H]1CSc2ccccc2NC1=O)OCc1ccccc1
Agent: Br
Agent: O=C=O
Solvent: CC(=O)O
Product: N[C@@H]1CSc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A mixture of 6.2 g (18.9 mmol) of 3(S)-[(carbobenzyloxy)amino]-2,3 dihydro-1,5-benzothiazepin-4(5H)-one and 25 mL of a 30% HBr solution in acetic acid was stirred at room temperature for 1 hour. There was noticeable evolution of carbon dioxide gas (CO2) and the initial suspension gradually went into solution. After solution was obtained, a heavy precipitate was formed. The precipitate was filtered, and the solid triturated with 75 mL of NaHCO3 and 75 mL of ethyl acetate. The ethyl acetate layer was dried and evaporated. The residue was triturated to yield 1.7 g of product as a white solid. Neutralization of the filtrate and extraction yielded an additional 1.15 g of product. The two solids were combined to yield 2.85 g (78%) of 3-(S)-amino-2,3-dihydro-1,5-benthiazepin-4(5H)-one.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([NH:31]C=O)[CH:5]=[C:6]([CH2:22][P:23]([O:28]CC)([O:25]CC)=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(OCC1C=CC=CC=1)=O.[ClH:35]>>[ClH:35].[ClH:35].[NH2:31][CH:4]([CH:5]=[C:6]([CH2:22][P:23]([OH:28])([OH:25])=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[C:3]([OH:34])=[O:2]
Reactant: CCOP(=O)(CC(=CC(NC=O)C(=O)OC)CCCCNC(=O)OCc1ccccc1)OCC
Agent: Cl
Product: NCCCCC(=CC(N)C(=O)O)CP(=O)(O)O

Procedure:
0.5 g (1.0 mmol) of 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is heated under reflux in 5.0 ml of 6N hydrochloric acid for 6 hours. Concentration to dryness by evaporation yields 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid dihydrochloride in the form of a rubber-like solid which is recrystallised from acetonitrile; m.p. 128° (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Into a stirred solution of 5.00 g (16.0 mmol) of tert-butyl 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-carboxylate in 100 ml of 1,4-dioxane at 0° C. was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3×80 mL of dichloromethane and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 2.85 g (87.5% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.09 (d, 1H, J=8.4 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 6.35–6.25 (m, 1H), 3.58 (apparent q, 2H, J=3.0 Hz), 3.14 (t, 2H, J=5.6 Hz), 2.54–2.46 (m, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24]([O:28][CH3:29])(=[O:27])[CH2:25][SH:26]>>[CH3:29][O:28][C:24](=[O:27])[CH2:25][S:26][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:23])=[N:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCOCC2)CC1
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCOCC2)C2CCC(C)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea (Example 203) and methyl thioglycolate.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17]>C(N(CC)CC)C>[CH3:29][C:26]([C:21]1[CH:22]=[C:23]([S:25][CH2:6][CH2:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[O:7])[CH:24]=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[C:20]=1[OH:30])([CH3:27])[CH3:28]
Reactant: C=CC(=O)N(CC)Cc1ccncc1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CCN(Cc1ccncc1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared according to the method of Example 4 from N-ethyl-N-(4-pyridinylmethyl)-2-propenamide (1.5 g, 0.00788 mole,), 2,6-bis(1,1-dimethyl-ethyl)-4-mercaptophenol (2.06 g, 0.00867 mole,) and triethylamine (1 ml) to provide 3.0 g of product, m.p. ca. 121°-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[CH3:20])[CH3:11].[S-:21][C:22]#[N:23].[K+].BrBr>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([CH3:20])=[CH:15][C:16]2[N:17]=[C:22]([NH2:23])[S:21][C:18]=2[CH:19]=1)[CH3:11]
Reactant: N#C[S-]
Reactant: Cc1cc(N)ccc1OC(C)c1c(Cl)ccc(F)c1Cl
Agent: BrBr
Agent: [K+]
Product: Cc1cc2nc(N)sc2cc1OC(C)c1c(Cl)ccc(F)c1Cl
Yield: 17.5 %

Procedure:
6-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-methyl-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 3.12 g of 4-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-methylaniline, 3.86 g of potassium thiocyanate and 0.509 cm3 of dibromine. We obtain 0.644 g of 6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-methyl-1,3-benzothiazol-2-amine in the form of a yellow-coloured solid, which has the following characteristics:
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([CH3:34])([NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])[CH3:5].[Li+].[OH-]>>[CH3:34][C:4]([NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])([CH3:5])[C:3]([OH:35])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC(C)(C)C(=O)O)ccc21
Yield: 88.7 %

Procedure:
2-Methyl-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionic acid (88 mg) was prepared by following General Procedure E starting from 2-methyl-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionic acid methyl ester (102 mg), and LiOH (0.5 ml, 2.0 N solution in water). LC/MS: m/z 495.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]([N:33]1[CH2:40][CH:39]([OH:41])[CH2:38][C@H:34]1[C:35](O)=[O:36])(=[O:32])[CH3:31].CN1CCOCC1.ClC(OC)=O>C(O)(C)C.C(O)(=O)C.ClCCl>[C:30]([N:33]1[CH2:40][CH:39]([OH:41])[CH2:38][C@H:34]1[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:36])(=[O:32])[CH3:31]
Reactant: CC(=O)N1CC(O)C[C@H]1C(=O)O
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: CC(=O)N1CC(O)C[C@H]1C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 84.8 %

Procedure:
A suspension of 172.5 g (0.75 mol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 312 ml (2.23 mol) of triethylamine, and 11.8 L of dichloromethane is stirred at 10° and 290 ml (2.28 mol) of chlorotrimethylsilane is slowly added. The resulting mixture is stirred overnight at room temperature. A mixture of 273 g (1.58 mol) of N-acetyl-4-hydroxy-L-proline and 3.5 L of dichloromethane is stirred at -15° and 177.5 ml (1.61 mol) of N-methylmorpholine is added during a 20 min period followed by 250 ml of dichloromethane as a wash. The mixture is stirred at -13° for 15 min and 125.5 ml (1.62 mol) of methyl chloroformate is added over a 25 min period at -14° followed by 150 ml of dichloromethane as a wash. The mixture is stirred at -15° for 40 min and the above silylated nicotinic acid is added over a period of 60 min at -17° followed by 500 ml of dichloromethane as a rinse. The mixture is stirred for 1 hr and 40 min as the temperature rose to 1°. The mixture is stirred overnight with ice bath cooling as the temperature rose to 16° and 135 ml of glacial acetic acid is added followed by 135 ml of isopropanol. The reaction mixture is concentrated to 4 L under reduced pressure and the solid filtered, washed with dichloromethane and dried to give 245 g of 6-[4-(N-acetyl-4-hydroxy-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])[CH2:4][CH:3]=1.[O:15]([C:22]1[N:27]=[C:26]([CH2:28]Br)[CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[CH3:1][C:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:11][CH2:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:27]=2)=[O:10])[CH2:4][CH:3]=1
Reactant: CC1=CCN(C(C(=O)O)C(C)C)CC1
Reactant: BrCc1cccc(Oc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1=CCN(C(C(=O)OCc2cccc(Oc3ccccc3)n2)C(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The resulting 2-(4-methyl-1,2,5,6-tetrahydro-1-pyridyl)-3-methylbutanoic acid (7.0 mmol) is combined with (6-phenoxy-2-pyridyl)methyl bromide (7.0 mmol) and potassium carbonate (14.0 mmol) in 15 ml dimethylformamide, and the mixture is stirred at RT, under nitrogen, for 20 hours. The solution is brought up in ether, washed with water (3×) and brine, and dried over sodium sulfate to give (6-phenoxy-2-pyridyl)methyl 2-(4-methyl-1,2,5,6-tetrahydro-1-pyridyl)-3-methylbutanoate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:22]([OH:24])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH2:32]([O:39][C:40](=[O:48])[CH2:41][CH2:42][NH:43][C:44](=[O:47])[CH2:45][NH2:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40](=[O:48])[CH2:41][CH2:42][NH:43][C:44](=[O:47])[CH2:45][NH:46][C:22](=[O:24])[CH:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N#Cc1ccc(CC(NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: NCC(=O)NCCC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC(NC(=O)OCc2ccccc2)C(=O)NCC(=O)NCCC(=O)OCc2ccccc2)cc1

Procedure:
For the preparation of the ester starting material, N-(benzyloxycarbonyl)-3-(p-cyanophenyl)-DL-alanine and N-glycyl-β-alanine benzyl ester trifluoroacetate are coupled to give N-[N-[N-(benzyloxycarbonyl)-3-(p-cyanophenyl)-DL-alanyl]glycyl]-β-alanine benzyl ester, m.p. 134°-135° C. Therefrom with hydrogen sulphide and triethylamine in pyridine there is obtained N-[N-[N-(benzyloxycarbonyl)-3-[p-(thiocarbamoyl)phenyl]-DL-alanyl]glycyl]-β-alanine benzyl ester m.p.150°-151° C. Reaction with methyl iodide in acetone, subsequent reaction with ammonium acetate in methanol and treatment with benzyl chloroformate and triethylamine in THF give N-[N-[N-(benzyloxycarbonyl)-3-[p-[N-(benzyloxycarbonyl)-amidino]phenyl]-DL-alanyl]glycyl]-β-alanine benzyl ester, MS: 694 (100, M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[CH2:3][CH2:2]1.[OH-].[K+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CCOC(C)=O>[Cl:15][CH2:16][C:17]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:18]
Reactant: COc1cccc(NC2CC2)c1
Reactant: O=C(Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cccc(N(C(=O)CCl)C2CC2)c1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a mixture of cyclopropyl(3-methoxyphenyl)amine (1.52 g, 9.3 mmol), KOH (1.57 g dissolved in 8 mL H2O) and EtOAc (15 mL) at 0° C. was added dropwise, with vigorous stirring, chloroacetyl chloride (1.12 mL, 14.0 mmol). The mixture was stirred for additional 30 minutes, washed with water (3×350 mL), concentrated and purified on silica gel (CH2Cl2/hexane, 1:1) to provide 2-chloro-N-cyclopropyl-N-(3-methoxy-phenyl)acetamide as a solid (1.80 g, 81%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:17][C:16]=2[F:34])[N:7]=1)=[O:5])C.CO.[Li+].[OH-]>>[C:30]([O:29][C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:8]2[C:9]([CH2:11][CH2:12][CH3:13])=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]2)=[C:16]([F:34])[CH:17]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reaction time: 8 h
Yield: 101.2 %

Procedure:
1-(2′-t-Butoxycarbonyl-3-fluorobiphenyl-4-ylmethyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (758 mg, 1.6 mmol) was diluted with MeOH (10 mL, 0.2 mol), and LiOH (233 mg, 4.9 mmol) was added. The mixture was stirred overnight then concentrated to dryness. The residue was dissolved in DCM and water and the aqueous layer was neutralized with AcOH. The water layer was extracted with DCM and the combined organic layers were washed with saturated aqueous NaCl and dried over Na2SO4. The crude product was purified by flash chromatography (EtOAc in hexanes) to yield the title compound (710 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[C:13]([CH3:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2].CN.C[CH2:29][N:30](CC)CC.CN(C=O)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[N:10]=[C:11]([NH:30][CH3:29])[N:12]=[C:13]([CH3:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cc2c(C)nc(S(C)=O)nc2n(C2CCCC2)c1=O
Agent: CN
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1cc2c(C)nc(NC)nc2n(C2CCCC2)c1=O
Yield: 72.2 %

Procedure:
A solution of example 87 (16.0 g, 0.044 mol), methylamine (10.15 g, 0.088 mol, 27% in EtOH), Et3N (8.9 g, 0.088 mol) and a catalytic amount of DMF in acetonitrile (60 mL) was refluxed for 48 hours under a N2 balloon. TLC (petroleum ether/EtOAc 1:2) indicated the starting material was consumed completely. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc from 15:1 to 4:1) to yield the crude product. Re-crystallization from CH2Cl2/petroleum ether (10 mL/150 mL) afforded pure title compound (10.5 g, 72.2%) as a white solid.