Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH:9]([C:15]#[N:16])C(OCC)=O)[CH2:2]2.[Na].C([O:23][N:24]=O)CC(C)C>C(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9](=[N:24][OH:23])[C:15]#[N:16])[CH2:2]2
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)C(C#N)C1CN2CCC1CC2
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl (1-azabicyclo[2.2.2]octan-3-yl)cyanoacetate (10 g, 45 mmol) was added to a solution of sodium (1.04 g, 45 mmol) in absolute ethanol (60 ml). The mixture was stirred for 15 min. at room temperature and isoamylnitrite (7.9 ml, 60 mmol) was added. The reaction mixture was stirred for 18 h at 60° C. Evaporation of the reaction mixture gave crude title compound, which was used without further purification.
Reaction SMILES: O=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1C=CC=CC=1>[S:23]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=S)N1
Yield: 191.1 %

Procedure:
To a solution of t-butyl pyroglutamate (1a) (10.12 g, 54.6 mmol) in benzene (250 mL), was added Lawesson's reagent (11.05 g, 27.3 mmol). The mixture was stirred at reflux for 15.5 h, then concentrated. The resultant residue was purified by flash chromatography (0 to 2 to 3 to 4% MeOH/CHCl3) to afford 10.50 g (95%) of the title compound, 1b. 1H NMR (300 MHz, CDCl3) δ7.27 (br s, 1H), 4.46-4.39 (m, 1H), 3.03-2.84 (m, 2H), 2.58-2.46 (m, 1H), 2.37-2.23 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([CH3:19])([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:20])[C:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:33][CH:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH2:24]2)[C:10]1=[O:18])([CH3:8])[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CC(C)(C)OC(=O)C(C)(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc2c1C(Cn1c(=O)n(C(C)(C)C(=O)OC(C)(C)C)c3ccccc31)CN2C
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
To a mixture of 2-methyl-2-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid tert-butyl ester (130 mg, 0.47 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (250 mg, 0.73 mmol) in DMF (2.5 mL) was added K2CO3 (200 mg, 1.45 mmol). The mixture was stirred at 100° C. for 4 hours. The mixture was diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 30% EtOAc in Hexane as the eluent to afford the desired 2-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-2methyl-propionic acid tert-butyl ester (138 mg, 68%).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[C:10]([O:36][C:37]2[CH:38]=[C:39]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[F:56])[C:40]([Cl:49])=[CH:41][C:42]=2[C:43]2[CH:48]=[CH:47][N:46]=[N:45][CH:44]=2)=[CH:11][C:12]([F:35])=[C:13]([S:15]([N:18](CC2C=CC(OC)=CC=2OC)[C:19]2[S:20][CH:21]=[N:22][N:23]=2)(=[O:17])=[O:16])[CH:14]=1>CO>[Cl:8][C:9]1[C:10]([O:36][C:37]2[CH:38]=[C:39]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[F:56])[C:40]([Cl:49])=[CH:41][C:42]=2[C:43]2[CH:48]=[CH:47][N:46]=[N:45][CH:44]=2)=[CH:11][C:12]([F:35])=[C:13]([S:15]([NH:18][C:19]2[S:20][CH:21]=[N:22][N:23]=2)(=[O:17])=[O:16])[CH:14]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccccc4F)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(-c3ccccc3F)c(Cl)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
Hydrogen chloride in dioxane (4M, 1.5 mL, 6.00 mmol) was added to a solution of 5-chloro-4-(6-chloro-2′-fluoro-4-(pyridazin-4-yl)biphenyl-3-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 92, 220 mg, 0.27 mmol) in methanol (1.5 mL) and the reaction stirred at room temperature for 18 hours. The mixture was evaporated to dryness and dissolved in dimethylsulfoxide (4.0 mL) and methanol (2.0 mL). The resulting precipitate was filtered, washed with methanol (2.0 mL) and the filtrate purified by preparative HPLC using a Phenomenex Luna C18 5 u 110 A 21.2×150 mm using acetonitrile:water as eluent to give the title compound (92 mg, 56%) as a beige coloured solid.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:27])[N:25]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=472.2.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3]1.C(Cl)Cl.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>>[F:1][C:2]1([F:15])[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3]1.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]
Reactant: CC(C)(C)OC(=O)NC1CCC(F)(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3,3-difluorocyclopentylcarbamate and DCM/TFA (50%, 7 mL) was stirred at 25° C. for 30 min. The reaction mixture was concentrated down and dried in vacuo to afford the title compound as an orange semi-solid, TFA salt (0.51 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 1.69-1.88 (m, 1 H) 2.00-2.22 (m, 3 H) 2.22-2.38 (m, 1 H) 2.56 (d, J=6.32 Hz, 1 H) 3.71 (d, J=5.31 Hz, 1 H) 8.20 (br. s., 3 H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]2[NH:14][C:13](=[O:15])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.CC(O)=O>CN(C)C=O>[C:3]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:4]=[CH:5][C:6]([CH2:9][C@H:10]2[N:14]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:13](=[O:15])[CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)CC[C@H]2Cc2ccc(-c3ccccc3)cc2)cc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Under N2, sodium hydride (55%, 6.9 g, 158 mmol) is added to the mixture of (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (3a, R1=H) (36 g, 143 mmol) in 400 mL dry dimethylformamide at r.t., then 4-methoxybenzyl chloride (24.7 g, 158 mmol) is added. The reaction mixture is heated to 55° C. and stirred for 3 h. Cooled to r.t., 5 mL AcOH is added, and stirred for another 15 min, then dimethylformamide is removed, the residue is redissolved in 400 mL ethyl acetate, washed with water, dried with sodium sulfate. The solvent is removed, the residue is redissolved in 100 mL tert-butylmethylether, cooled to 0° C. and stirred for 5 h, filtered, and dried to afford (S)-5-biphenyl-4-ylmethyl-1-(4-methoxy-benzyl)-pyrrolidin-2-one (3a, R1=p-methoxybenzyl). 1HNMR (400 MHz, CDCl3): 1.78 (m, 1H, 3-CHH), 1.90 (m, 1H, 3-CHH), 2.28 (m, 2H, 2-CH2), 2.59 (dd, 1H, 5-CHH), 3.05 (dd, 1H, 5-CHH), 3.80 (s, 3H, OCH3), 3.98 (d, 1H, CHH), 5.05 (d, 1H, CHH), 6.80˜7.40 (13H, m, aromatic).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)COC(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)OCC(C)C)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and isobutyl chloroformate, there is obtained ethyl N-isobutoxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 366 (11), 337 (13), 293 (20), 263 (88), 194 (100);
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)Cc1nc(N)sc1C
Product: COC(=O)Cc1nc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 4-biphenylsulfonyl chloride as described in the synthetic METHOD B to give a white solid (22:1 mg) with purity >90%. LCMS (pos) m/z 403.0.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1>>[CH3:16][C:17]1[N:18]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]3)[CH:19]=[CH:20][N:21]=1
Reactant: O=C1CCCc2cc(OCCCl)ccc21
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1CCOc1ccc2c(c1)CCCC2=O
Yield: 66 %

Procedure:
According to the method of Example 1, Step 2, 6-(β-chloroethoxy)-1-tetralone (0.208 g, 0.93 mmol) and 2-methylimidazole (0.137 g, 1.67 mmol) were reacted to provide the title compound (0.166 g, 66%) as a cream colored solid: CI-MS m/e 270 (M+), 271 (M++1);
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1>C(O)C>[C:2]([NH:3][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[S:14])#[N:1]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
The suspension of monosodium cyanamide (2.1 g, 32.6 mmol) in absolute ethanol (50 mL) was slowly treated with 4-fluorophenylisothiocyanate (5.0 g, 32.6 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (4.1 g), m.p. >270° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH:24]=[CH:23][N:22]([CH2:25][CH3:26])[C:14]=3[N:15]=[C:16](S(C)(=O)=O)[N:17]=2)=[CH:7][CH:6]=1>CS(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH:24]=[CH:23][N:22]([CH2:25][CH3:26])[C:14]=3[N:15]=[C:16]([C:1]#[N:2])[N:17]=2)=[CH:7][CH:6]=1
Reactant: CCn1ccc2c(Nc3ccc(Cl)cc3)nc(S(C)(=O)=O)nc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCn1ccc2c(Nc3ccc(Cl)cc3)nc(C#N)nc21
Temperature: 90 °C

Procedure:
Sodium cyanide (0.103 g) was added to a solution of the product from step (iii) (0.37 g) in dimethylsulphoxide (10 ml) and heated at 90° C. for 48 h. The mixture was partitioned between ethyl acetate and water, the organics dried (MgSO4) and evaporated under reduced pressure. The residue was purified by RPHPLC eluting with 29-95% acetonitrile in aqueous trifluoroacetic acid. Yield 0.14 g
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].CO[CH:7](OC)[CH2:8][N:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)S(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[F:27][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[CH:20]=[N:9][CH:8]=[CH:7]2
Reactant: COC(CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Fc1ccc2cnccc2c1
Reaction time: 8 h
Yield: 29.8 %

Procedure:
41.6 g of AlCl3 were suspended in 400 mL of dichloromethane. At room temperature, a solution of 22.95 g N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl-benzenesulfonamide (2) in 150 ml of dichloromethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the layers were separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were then washed twice with sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75 g) was purified by silica gel chromatography to yield 2.74 g of compound 3. Rt=0.30 min (Method C). Detected mass: 148.1 (M+H+).
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([O-:34])=[O:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].[CH2:40]([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[OH:1][CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([O:34][CH3:40])=[O:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)[Si](OCCC1(CCOc2ccccc2C(=O)[O-])CCCCC1)(c1ccccc1)c1ccccc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1OCCC1(CCO)CCCCC1
Reaction time: 2 h

Procedure:
To a solution of methyl 2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]benzoate (synthesized in Example 35) (547 mg) in tetrahydrofuran (4 mL) was added a 1M tetrabutyl ammonium fluoride/tetrahydrofuran solution (1 mL) at room temperature. The solution was then stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (2:1)] to give the title compound (226 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18](=[O:24])[NH:19]2.N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[NH:19][C:18]1=[O:24]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 51.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 74 mg 4-methyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 80 mg (52%) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:33]([N:36]([CH:39]([CH3:41])[CH3:40])[CH2:37][CH3:38])([CH3:35])C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:10][C:5]3[CH:6]=[CH:40][C:39]([N:36]4[CH:33]=[CH:35][CH:38]=[CH:37]4)=[CH:41][CH:4]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(-n4cccc4)cc3)C2)c1
Reaction time: 8 h
Yield: 185.8 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (44.4 mg, 0.10 mmol) in CH3CN (5 ml) was added 1-[4-Bromomethyl) phenyl]-H-pyrrole) (35.1 mg, 0.15 mmol) and diisopropylethylamine (35 μl, 0.20 mmol). The reaction was microwaved at 150° C. for 1 hour, then continued at room temperature overnight, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (56 mg, 94%). Calcd for C37H41F3N2O2 (M+H) 602.73, Found 603.5
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.B1([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]3)=[N:35][CH:34]=2)OC(C)(C)C(C)(C)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:34]=[N:35][C:36]([N:39]6[CH2:40][CH2:41][NH:42][CH2:43][CH2:44]6)=[CH:37][CH:38]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N5CCNCC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 118.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-(4-boc-piperazine)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 1.97 min (Method A); M+H=455 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.30-8.25 (m, 1H), 8.14-8.11 (m, 1H), 8.07-8.01 (m, 1H), 7.90-7.84 (m, 1H), 7.62-7.56 (m, 1H), 7.46-7.41 (m, 1H), 6.95-6.89 (m, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 3.53-3.46 (m, 4H), 2.86-2.76 (m, 4H), 1.95 (s, 3H))
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[C:11]([CH3:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][Mg]Cl)=[CH:19][CH:18]=1.Cl>CCOCC>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:11]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:14])([CH3:12])[CH3:13])=[CH:19][CH:18]=1
Reactant: COc1ccc(C[Mg]Cl)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)Cc1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Diethylisopropylidenemalonate (6.686 ml, 34.09 mmol) was dissolved in 300 ml Et2O and cooled to −78° C. 4-Methoxybenzylmagnesium chloride (150.000 ml, 37.50 mmol) was added and stirring was continued for 5 h. The temperature was warmed up to 0° C. The reaction was hydrolyzed with 0.5 M HCl and extracted 3×EtOAc. Glass col. Chromatography (10-50% EtOAc in Hex.) provided diethyl 2-(1-(4-methoxyphenyl)-2-methylpropan-2-yl)malonate. MS m/z: 323.1 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:7]([C:6]([OH:13])=[O:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@H](N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
23.5 mg of L-N-[(2R or S)-5-ethylthio-2-(1-naphthylmethyl)pentanoyl]norleucine tert-butyl ester was dissolved in 0.2 ml of dichloromethane, and 0.1 ml of trifluoro acetic acid was added thereto. The mixture was stirred at room temperature for four hours. Then, the reaction solution was concentrated under reduced pressure to obtain 20.7 mg of L-N-[(2R or S)-5-ethylthio-2-(1-naphthylmethyl)pentanoyl]norleucine as colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
1-Benzylpiperidin-4-one (10 g, 53.0 mmole) was added to the stirred suspension of sodium hydride (1.8 g, 53.0 mmole) in tetrahydrofuran (50 ml) at 10° C. The reaction mixture was stirred for 15 min, benzyl bromide (9.0 g, 53.0 mmole) was added at 10° C. The resulting mixture stirred at room temperature for 4 hr and concentrated to dryness. The residue was triturated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1,3-dibenzylpiperidin-4-one. Yield 1.8 g (13%), C19H21NO, m/z 280 (M+1), PMR (CDCl3): 2.22-2.62 (4H, m, H2 & H6), 2.86 (2H, m, H5), 3.2 (1H, dd, H3, j=12 Hz), 3.45 (2H, m, CH2Ar), 3.68 (2H, m, N—CH2Ar), 7.1-7.4 (10, m, ArH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
A solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-6-oxo-piperidin-1-yl}-but-2-ynyloxy)-acetic acid methyl ester (35 mg, 0.084 mmol) in toluene (2 mL) was added via cannula to a round-bottomed flask containing hydrido(triphenylphosphine)copper(I) hexamer (164 mg, 0.084 mmol) at −40° C. under nitrogen. The reaction was allowed to warm to rt and stirred for 3 h. The reaction was quenched with NH4OH/NH4Cl (1:1, 5 mL) and extracted with EtOAc (3×7 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20% →50% EtOAc/CH2Cl2, gradient) followed by preparative thin layer chromatography (silica, 80% EtOAc/CH2Cl2) afforded 12 mg (34%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[NH2:8].[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:9][N:4]1[C:3](=[O:10])[C:2]2[N:1]=[C:17]([C:14]3[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=[N:5]1
Reactant: Cn1ncc(N)c(N)c1=O
Reactant: O=Cc1ccncc1
Solvent: O=[N+]([O-])c1ccccc1
Product: Cn1ncc2[nH]c(-c3ccncc3)nc2c1=O
Temperature: 190 °C
Yield: 42 %

Procedure:
0.560 g of 4,5-diamino-2-methyl-2H-pyridazin-3-one and 0.535 g of 4-pyridinecarbaldehyde were added to 10 ml of nitrobenzene, and the mixture was heated at 190° C. under a nitrogen atmosphere for three hours. The reaction solution was cooled down, and the precipitate was collected by filtration to give 0.381 g of the title compound.