Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].[C:18]1([CH:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:32]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11](=[O:12])[C:10]4=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]4[C:8]3=[O:17])[CH2:28][CH2:27]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 5.4 ml of 1,5-dichloropentane was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1). The desired fraction was collected to yield 4.68 g of N-(5-bromopentyl)phthalimide as an oily substance. 4.68 g of N-(5-bromopentyl)phthalimide and 4.25 g of 4-(diphenylmethoxy)piperidine were dissolved in 30 ml of N,N-dimethylformamide; 2.42 g of potassium carbonate was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate-triethylamine (50:50:1). The desired fraction was collected to yield 6.67 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide as an oily substance. 6.6 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide was dissolved in 30 ml of ethanol; 0.694 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethyl acetate was added to the residue; the crystal precipitated was collected, dissolved in 15 ml of a 1 N aqueous solution of sodium hydroxide and 20 ml of water and extracted with ethyl acetate; the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the crystal obtained was collected to yield 3.29 g of the title compound.
Reaction SMILES: [H-].[Li+].[CH2:3](S)CC.C[O:8][C:9]1[CH:26]=[C:25]2[C:12]([C@H:13]3[C@H:22]([CH2:23][S:24]2(=[O:28])=[O:27])[C@:21]2([CH3:29])[C@H:16]([C:17]([CH3:31])([CH3:30])[CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)=[C:11]([C:32]([O-:34])=[O:33])[CH:10]=1>CN(P(N(C)C)(N(C)C)=O)C>[OH:8][C:9]1[CH:26]=[C:25]2[C:12]([C@@:13]3([CH3:3])[C@H:22]([CH2:23][S:24]2(=[O:28])=[O:27])[C@:21]2([CH3:29])[C@H:16]([C:17]([CH3:30])([CH3:31])[CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)=[C:11]([C:32]([OH:34])=[O:33])[CH:10]=1
Reactant: CCCS
Reactant: COc1cc(C(=O)[O-])c2c(c1)S(=O)(=O)C[C@H]1[C@H]2CC[C@H]2C(C)(C)CCC[C@]12C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A mixture of lithium hydride (0.88 g, 110 mmol), 1-propanethiol (11.7 mL, 133 mmol) in HMPA (20 mL) was prepared under N2. The mixture was stirred at room temperature for 30 min. To the mixture, (1R,10S,11S,16S)-5-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylate (64) (4.8 g, 11 mmol) in HMPA (10 mL) was added. The mixture was heated at 130° C. for 1 h. The mixture was cooled to room temperature and quenched with 1 M HCl, then extracted with EtOAc. The organic layer was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 10:1) to yield (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]-octadeca-2,4,6-triene-3-carboxylic acid (65) (4.2 g, 93%) as a white solid. 1H NMR (CD3OD): δ 7.18 (s, 1H), 6.88 (s, 1H), 3.45 (m, 1H), 2.83 (m, 1H), 2.10 (d, 1H), 1.82-1.35 (m, 10H), 1.20 (m, 2H) 1.00 (m, 5H), 0.89 (s, 3H), 0.85 (s, 3H). MS m/z 405 (C22H30NO5S−H+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][N:13]1[CH2:17][CH2:16][N:15]=[C:14]1SC.[NH2:20][NH2:21].C(O)(C)C>C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:12][N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:20][NH2:21]
Reactant: CSC1=NCCN1N
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCO
Product: NNC1=NCCN1N
Temperature: 25 °C

Procedure:
1-Amino-2-methylthio-2-imidazoline p-toluenesulfonate (2.123 g) in ethanol (4 ml) was treated with hydrazine (0.67 ml) and stirred at 25° C. for hours. Isopropyl alcohol (6 ml) was added and after stirring for 10 min the crystalline precipitate was filtered out and washed with isopropyl alcohol to give 1.55 g of 1-amino-2-hydrazino-2-imidazoline p-toluenesulfonate, melting point 168°-169° C.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9](CCN1CCC(C3C=CC=CC=3)CC1)[CH2:8][CH2:7]2.B(Br)(Br)Br>C(Cl)Cl>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCN(CCN1CCC(c3ccccc3)CC1)C2=O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C1NCCc2cc(O)ccc21
Reaction time: 16 h
Yield: 65.6 %

Procedure:
To a solution of the title A compound of Example 1 (3.8 g, 21.5 mmol; 3,4-dihydro-6-methoxy-2-[2-(4-phenyl-1-piperidinyl)-ethyl]-1(2H)-isoquinolinone, monohydrochloride) in methylene chloride (50 mL) at −78° C. was added a solution of boron tribromide (1M, 53.7 mL, 53.7 mmol) under nitrogen. The reaction mixture was stirred at for 16 hours, quenched with saturated amminium chloride solution and extracted repeatedly with EtOAc. The organic layer was dried over MgSO4 and concentrated to give the crude product which was triturated with acetone to afford the title compound (2.3 g, 66% yield) as an off-white solid.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([F:36])=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([F:36])=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(F)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)c[nH]c34)no2)cc1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
Sodium hydroxide (25 mg) was added to a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D148) (875 mg) in THF (4 mL) and water (4 mL). The reaction mixture was stirred at 90° C. for 1 hour, and then at RT for another 24 hours. Then 0.5 M HCl was added until pH was about 6. The solvent was removed, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoic acid (E105) (101.6 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.63 (2H, t), 2.99 (2H, t), 4.98-5.04 (1H, m), 7.10 (1H, dd), 7.30 (1H, s), 7.56 (1H, d), 7.81 (1H, dd), 8.56 (1H, dd), 8.90 (1H, d), 11.11 (1H, s), 12.14 (1H, br s); δF (DMSO-d6, 376 MHz): −115.5; MS (ES): C23H19FN4O4 requires 434; found 435.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Yield: 5.8 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-cyanophenylboronic acid (73 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and the crude product was purified by reverse-phase prep LCMS to give the title compound (9.3 mg, 6%) m/z, 321.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2F)c1
Reactant: Clc1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3cccc(F)c32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[(2-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.88 (s, 3H), 5.11 (s, 2H), 6.22 (d, 1H), 6.61-6.67 (m, 1H), 6.82-6.89 (dd, 1H), 7.26-7.43 (m, 10H), 7.52 (d, 1H), 7.92 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: C1C2N[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=C(C(OCC)=O)N=1.[H-].[Na+].[CH2:21]([N:28]1[C:40]2[C:39]([CH3:41])=[N:38][C:37]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)C1C=CC=CC=1>CN(C=O)C>[C:6]1([CH2:5][CH2:4][CH2:21][N:28]2[C:40]3[C:39]([CH3:41])=[N:38][C:37]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36][C:35]=3[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: CCOC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3ccccc3n(CCCc3ccccc3)c2c(C)n1
Temperature: 25 °C
Yield: 75 %

Procedure:
Compound 10 (2.54 g, 10 mmol) was mixed with DMF (50 ml) and stirred at room temperature until the solution became clear. 60% NaH (1.2 g) was added and stirred for 5 minutes, followed by the addition of 1-bromine-3-phenyl propane (10 ml), and TLC track measurement. The mixture was reacted at room temperature for about 15 h. The subsequent steps were conducted according to those for synthesizing compound 58. Finally, white crystals (2.8 g, 75%) were obtained, mp 101-102° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)C(C)C)C.Cl[CH2:17][C:18](=[O:20])[CH3:19].[N:21]1([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[O:20]=[C:18]([CH3:19])[CH2:17][N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:26][CH2:25]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Yield: 58.6 %

Procedure:
Potassium carbonate (1.27 g, 9.22 mmol), N-ethyldiisopropylamine (0.80 ml, 4.61 mmol), and chloroacetone (1.22 ml, 13.83 mmol) were added to a solution of benzyl piperazine-1-carboxylate (2.03 g, 90.22 mmol) in acetonitrile(20 ml), and the mixture was heated under reflux for 2 hours. The insoluble substances were removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography(methylene chloride/methanol=100/1) to afford benzyl 4-(2-oxopropyl)piperazine-1-carboxylate (2.24 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [ClH:1].Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:4]2.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[ClH:1].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1)[CH2:4]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(OC2CN3CCC2CC3)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OC2CN3CCC2CC3)cc1

Procedure:
4-[(1-azabicyclo[2.2.2]oct-3-yl)oxy]benzenamine (Example 3) was acetylated with acetic anhydride in dry pyridine at -10° C. The crude product was converted into the hydrochloric salt to obtain N-[4-[(1-azabicyclo[2.2.2]-oct-3-yl)oxy]phenyl]acetamide hydrochloride. M.p. >250° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[N:8]=[C:9]([NH:17][C@H:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH2:22][C@H:18]([NH:17][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[N:8]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(-c2cc3ccccc3c(N[C@H]3CCNC3)n2)[nH]1
Reaction time: 1 h

Procedure:
To crude (S)-tert-butyl 3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate was added DCM (3 mL) and TFA (1 mL). The mixture was stirred for 1 hour and concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 5-30% ACN in water (acid mode) to give the title compound (8 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29]2[N:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[CH2:23]1>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[N:3]=[C:2]([N:22]2[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][N:34]=3)[CH2:23]2)[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccccc2Cl)nc1Cl
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Agent: Cl
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccccc4Cl)cc(C(F)(F)F)c3C#N)C2)nc1

Procedure:
Analogously to the preparation of Example 20, 60 mg (0.19 mmol) of 2-chloro-6-(2-chlorophenyl)-4-(trifluoromethyl)pyridine-3-carbonitrile and 47 mg (0.19 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) were used to obtain, after separation by means of preparative HPLC (method 13), 61 mg (67% of theory) of the product in solid form.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])C.[OH-].[Li+]>C1COCC1.O>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:9][CH2:8][N:7]([C:5](=[O:6])[C:4]([OH:27])=[O:3])[CH2:12][CH2:11]3)[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1OC1CCCC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[4-(3-cyclopentyloxy-4-methoxyphenyl)piperidin-1-yl]-2-oxo-acetic acid ethyl ester (14.1 mmol, 5.3 g) in THF (140 mL) was added aqueous lithium hydroxide solution (1.0M; 17.6 mmol, 17.6 mL) in one portion at room temperature and the resulting homogeneous solution stirred overnight. The precipitated solution was diluted with H2O (150 mL) and the THF was removed in vacuo. The aqueous phase was diluted with saturated NaHCO3 (400 mL), and acidified with 2N HCl. The aqueous phase was then extracted with EtOAc (3×400 mL) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The product was triturated with Et2O/hexane to yield the title compound as a white solid, mp=112°-113° C. (10.8 mmol, 3.74 g, 76%).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])=[CH:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[CH2:17]1.C(OCC)(=O)C.CC(C)=O>CO.[Pd]>[ClH:1].[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[CH2:17]1
Reactant: Cc1ccccc1C(=CCOCCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1C
Agent: [Pd]
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(CCOCCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1C
Yield: 26.4 %

Procedure:
The acid prepared in Example 31 (0.75 g, 1.7 mmol) was dissolved in methanol (25 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (35% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a residue which was treated with a mixture of ethyl acetate and acetone and filtered to give a solid which was recrystallised from toluene to give 0.20 g (26%) of the title compound as a solid. TLC: rf=0.39 (SiO2 ; methanol/dichloromethane=1 1).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)[CH3:2].[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=3)[CH:20]=[CH:19]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1ccc(CCl)cc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: CCc1ccc(Cn2ccc3ccc(CC(=O)O)cc32)cc1

Procedure:
The titled compound (24 mg) as a reddish brown solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 4-ethylbenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=O)[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:23]([CH2:25][C:26]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([C:52]([O:54][CH3:55])=[O:53])[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH3:24].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([N:23]([CH2:25][C:26]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([C:52]([O:54][CH3:55])=[O:53])[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH3:24])=[O:12])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CNCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
254 mg of Z-Sta-OH (see stage 1.12), 297 mg of H-Sar-His-Lys(Boc)-OMe, 97 mg of HOBt×H2O and 196 mg of DCCI are dissolved, in this sequence, in 3 ml of DMF and the whole is left to stand for 20 hours at room temperature. The DCH which has crystallised out is filtered off, the filtrate is concentrated to dryness, heated for 1 hour at 60° in 7 ml of methanol/glacial acetic acid/H2O (94:3:3), and this solution is again concentrated to dryness. The oily residue is purified by chromatography over 75 g of silica gel (Merck No. 60, 230-400 mesh) by elution with CHCl3 /MeOH (9:1). The pure fractions are dissolved in ethyl acetate, washed with NaHCO3 solution and with H2O and, by concentration of the organic phase, Z-Sta-Sar-His-Lys(Boc)-OMe is obtained in amorphous form (honey); Rf (F)=0.15; Rf (I)=0.5.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1>CN1C(=O)CCC1.O.C(OCC)(=O)C>[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:13][CH:14]=1
Reactant: c1cn[nH]c1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2cccn2)nn1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
To a solution of pyrazole (3.69 g, 25 mmol, 1.0 equiv) in NMP (25 mL) was added sodium hydride (60% dispersion in mineral oil, 1.5 g, 38 mmol, 1.5 equiv). The mixture was stirred for 15 min, followed by the addition of 3,6-dichloropyridazine (3.02 g, 25 mmol, 1.0 equiv). The reaction mixture was stirred for 1.5 h and then diluted with water (50 mL) and ethyl acetate (100 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (3×50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give 3.89 g of 3-chloro-6-(1H-pyrazol-1-yl)pyridazine as a crude tan solid that was used directly in the next step.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[OH-].[K+].C1C[O:17][CH2:16]C1.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl>O.CCOC(C)=O>[O:11]1[C@@H:3]2[CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C@@H:2]2[NH:1][C:16]1=[O:17]
Reactant: C1CCOC1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1N[C@H]2c3ccccc3C[C@H]2O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
To a solution of (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (500 mg, 3.35 mmol) in water (20 mL) at 0° C. was added potassium hydroxide (1128 mg, 20.1 mmol) followed by THF (20 mL) and the reaction was stirred at 0° C. for 20 minutes. Bis(trichloromethyl) carbonate (995 mg, 3.35 mmol) was added and the reaction was stirred at 0° C. for 2 hours. The reaction was poured into EtOAc and the organic phase washed with 1N HCl, 1N NaOH and brine. After drying over MgSO4, concentration yielded (3aS,8aR)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (574 mg, 97.8% yield) as a white solid.