Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[CH3:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]([CH3:21])[CH2:23]1)=[O:18]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: CC1CNc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)n2C)c2ccccc21
Yield: 26.1 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 254 mg of 3-methylindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 96 mg of 3-methyl-2-[2-(3-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[S:8].[CH2:9]([Br:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[Br-:16].[CH2:9]([S:8][C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N+:2]=1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCCCC1=S
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: C[N+]1=C(SCc2ccccc2)CCCC1
Product: [Br-]
Reaction time: 3 h
Yield: 63.7 %

Procedure:
1-Methyl-2-piperidothione (1.29 g) was dissolved in acetone (10 ml) and treated with benzyl bromide (1.7 g). After allowing the mixture to stand for 3 hours at room temperature a solid formed and was filtered off, washed with acetone, and dried to give the title compound (1.9 g) mp 168°-7° C. (Found: C, 52.5; H, 6.3; N, 4.8. C13H18BrNS requires C, 52.0; H, 6.0; N, 4.7%).
Reaction SMILES: NC1C=CC=CC=1NC[N:10]1[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]1=[O:18].C(=O)CC.C(O)(=O)C>O1CCOCC1>[CH2:15]([CH:13]1[CH2:14][NH:10][C:11](=[O:18])[CH2:12]1)[CH2:16][CH3:17]
Reactant: CCCC1CC(=O)N(CNc2ccccc2N)C1
Solvent: CCC=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCC1CNC(=O)C1
Temperature: 25 °C
Yield: 33 %

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of (2-aminophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a29 (1 eq, 0.69 mmol, 170 mg), propionaldehyde (1.4 eq, 0.966 mmol, 56 mg, 71 μl), acetic acid (0.3 ml) and dioxane (4 ml) was heated at 65° C. during 40 h. After cooling to room temperature, the solvent was removed under vacuum and the crude product was purified by preparative thin layer chromatography (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4) to give of 1-[(2-propyl)-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 94 (65 mg, 33%).
Reaction SMILES: C1([Li])C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH:10]=1.I[CH2:24][CH:25]([CH3:27])[CH3:26].[I-]>C(OCC)C.C1CCCCC1.C(OCC)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:24][CH:25]([CH3:27])[CH3:26])[N:12]=[C:11]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH:10]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: CC(C)CI
Agent: [I-]
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: Cc1cc(CCC(C)C)nc(-n2c(C)ccc2C)c1
Temperature: -10 °C
Yield: 51.5 %

Procedure:
A solution prepared by the addition of 1.58 mL (2.85 mmol) of 1.8 M phenyllithium in 70:30 cyclohexane/diethyl ether to 4.0 mL of diethyl ether was stirred at -10° C. 4,6-Dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (500 mg, 2.5 mmol) was added as a solution in 1.7 mL of diethyl ether and the mixture was stirred 1h at -5 to -10° C. The red solution was then cooled to -45° C. and 0.354 mL (566 mg, 3.08 mmol) of 1-iodo-2-methylpropane was added in one portion. The reaction was warmed slowly to 10° C., stirring a total 2 h after addition of the iodide. The reaction was then quenched with 10 mL of saturated aqueous ammonium chloride and extracted with 30 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to give a yellow oil. Purification by flash column chromatography on silica gel, eluting with dichloromethane/hexane yielded 330 mg (52% yield) of 4-methyl-6-(3-methylbutyl)-2-(2,5-dimethylpyrrol-1-yl)pyridine as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[NH:54]1[CH:58]=[CH:57][C:56]([C:59](O)=[O:60])=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:56]2[CH:57]=[CH:58][NH:54][N:55]=2)=[O:60])[CH2:48]1
Reactant: O=C(O)c1cc[nH]n1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2cc[nH]n2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1H-pyrazole-3-carboxylic acid as the starting materials in 66% yield. LCMS for C27H27ClN9O2 (M+H)+: m/z=544.0.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-])=O>Cl>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: NCc1ccc(N)cc1
Temperature: 0 °C

Procedure:
A mixture of (II) (9,1 g), SnCl22H2O and 36% HCl (120 ml) was stirred under reflux for 1 h. After cooling to 0° C. the precipitate was filtered. The salt (Cl(H,H2NPhCH2NH2)½SnCL6) was decomposed with KOH and then extracted several times with dichloromethane. The combined organic layers were dried with Na2SO4. After evaporation of the solvent, the compound (III) was used in the next step without further purification.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[CH:16]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]2[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=2)[CH:36]=1>>[ClH:33].[ClH:33].[ClH:33].[ClH:33].[CH:1]1([N:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=4)[CH:16]=3)[CH2:12][CH2:13]2)[CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]3[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=3)[CH:36]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(NC4CCCCC4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)C4CCCCC4)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(Cyclohexylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (342 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (252 mg) were reacted in the same manner as described in Preparation Example 6. The title compound was obtained after converting the product to a tetrahydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C@@H:10]([C:34]([O:36]CC)=[O:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([C:29]([O:31]CC)=[O:30])[NH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:14][CH:13]=1)=[O:8].[OH-].[Na+].O>O1CCOCC1.CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C@@H:10]([C:34]([OH:36])=[O:35])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C@H:19]([C:29]([OH:31])=[O:30])[NH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][CH:17]=1)=[O:8]
Reactant: CCOC(=O)[C@@H](Cc1ccc(C[C@@H](NC(=O)c2ccccn2)C(=O)OCC)cc1)NC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@H](Cc1ccc(C[C@@H](NC(=O)c2ccccn2)C(=O)O)cc1)C(=O)O)c1ccccn1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a cooled (0° C.) solution of 1,4-bis-(2-(2-pyridylcarbonylamino)-2-ethyloxycarbonyl-(2R)-ethyl)-benzene (1.40 g; 2.70 mmol) in dioxane (4 ml) and EtOH (4 ml) an aqueous 2N NaOH solution (4 ml, 8.0 mmol) and water (2 ml) was added. The mixture was allowed to come to r.t. overnight. The solution was concentrated to approximately 5 ml under reduced pressure and the pH of the residual solution was adjusted to pH 3 by addition of aqueous 4N HCl, whereupon an oil separated. The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layer was dried (MgSO4), concentrated and the residue purified by: flash chromatography (chloroform/MeOH/HOAc 8/2/1) to yield 1,4-Bis-(2-(2-pyridylcarbonylamino)-2-carboxy-(2R)-ethyl)-benzene (1.1 g, 70%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[NH:22][CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:17][CH:16]=1)=[O:13]>ClCCl>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][NH:22][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:13])=[CH:20][CH:19]=1)=[O:29]
Reactant: C1CN(CC2CC2)CCN1
Reactant: CC(C)(C)CCNC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)CCNC(=O)c1ccc(OC(=O)N2CCN(CC3CC3)CC2)cc1
Reaction time: 16 h

Procedure:
The title product was prepared from 1-cyclopropylmethylpiperazine (0.35 mmol) dissolved in dichloromethane (5 ml). 4-(3,3-dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (method C) (5%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 2.43 min.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[C@H:13]([O:18][CH3:19])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:19][O:18][C@H:13]1[C@@H:14]([O:16][CH3:17])[CH2:15][NH:11][CH2:12]1
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1OC
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1CNC[C@H]1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a stirred solution of 3,4-cis-dimethoxy-pyrrolidine-1-carboxylic acid benzyl ester (16.95 g, 63.88 mmol) in 150 mL MeOH was added 1.3 g Pd on C (10% w/w). The mixture was stirred under H2 balloon at room temperature for 3 hours and filtered through celite. The filtrate was concentrated in vacuo, re-dissolved in CH2Cl2 and dried over Na2SO4. The solution was concentrated to give 8.3 g product as yellow oil (99% yield). 1H NMR (300 MHz, CDCl3) δ 3.80 (m, 2H), 3.47 (bs, 2H), 3.41 (s, 6H), 3.01 (bs, 2H).
Reaction SMILES: [C:1]1([C:7](=[O:18])/[CH:8]=[C:9](\[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](#[N:22])[CH2:20][CH3:21]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:20]([C:19]1[C:8]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:18])=[C:9]([CH3:10])[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:22]=1)[CH3:21]
Reactant: CCC#N
Reactant: C/C(=C/C(=O)c1ccccc1)Nc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCc1nn(-c2ccccc2)c(C)c1C(=O)c1ccccc1

Procedure:
According to AVV A, (Z)-1-phenyl-3-phenylamino-but-2-ene-1-one (237.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. After the dark-brown bluish raw product (330.0 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→60:40→0:100), the desired product was obtained in the form of a yellow oil (126.2 mg, 0.43 mmol, 43%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:30])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:30])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(S(C)(=O)=O)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: CS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2

Procedure:
tert-Butyl(1-{2-[6-(methylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate (Intermediate 100) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]2[CH2:21][O:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CCCCc2ccccc2O)c1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(CCCCc2ccccc2OCC2CO2)c1
Yield: 78.1 %

Procedure:
Following a procedure similar to that described in Example 1(a), 1.90 g of 2-[4-(3-methylphenyl)butyl]phenol (prepared as described in Preparation 10), 0.89 g of potassium t-butoxide and 1.08 g of epibromohydrin were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 1.83 g (yield 78%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[C:8]([N+:13]([O-])=O)[CH:7]=[CH:6][C:5]=2[CH3:16].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:13][C:8]1[CH:7]=[CH:6][C:5]([CH3:16])=[C:4]2[C:9]=1[C:10](=[O:12])[CH:11]=[C:2]([CH3:1])[O:3]2
Reactant: Cc1cc(=O)c2c([N+](=O)[O-])ccc(C)c2o1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)c2c(N)ccc(C)c2o1
Temperature: 25 °C

Procedure:
1.78 g (8.12 mmol) of 2,8-dimethyl-5-nitro-4H-chromen-4-one are heated with 9.16 g (40.6 mmol) of tin(II) chloride dihydrate in 70 ml of ethyl acetate at 70° C. overnight. After cooling to room temperature, the reaction mixture is brought to pH 9-10 with saturated sodium bicarbonate solution. After filtration through kieselguhr, the organic phase is separated off, and the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed in vacuo. 1.5 g (99% of theory) of the title compound are obtained.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:20])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)=[O:5])C.Cl>C1COCC1.O.C(OCC)(=O)C>[C:24]([O:23][C:21]([N:8]1[CH2:9][C@H:10]([C:11](=[O:20])[NH:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)[C@@H](C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ester obtained from step 2a (4.07 g; 10.3 mmol) is dissolved in a mixture of THF/water (1:1; 40 ml). LiOH monohydrate (0.947 g; 22.6 mmol) is added to the mixture and complete saponification is obtained after stirring for 18 h at 25° C. The mixture is acidified with 1N aq. HCl and diluted with ethyl acetate (100 ml). The organic phase is washed with brine (100 ml) and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. Yield: 3.28 g (86.7%), ESI-MS: m/z=367 [M−H]−, Cl-pattern
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:38]=[CH:37][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:38][CH:37]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](c2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)Cn1cncn1
Yield: 68 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4S)—N-(4-(4-fluorophenoxy)phenyl)-4-phenylpyrrolidine-2-carboxamide, gave Compound 78, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-phenylpyrrolidine-2-carboxamide (187 mg, 68%). 1H-NMR (400 MHz, CDCl3): σ 9.08 (s, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.46 (d, 2H), 7.40-7.37 (m, 2H), 7.33-7.29 (m, 2H), 7.04-6.99 (m, 2H), 6.96-6.92 (m, 4H), 5.04 (d, 2H), 4.96 (d, 1H), 4.06 (t, 1H), 3.96-3.86 (m, 1H), 3.61 (t, 1H), 2.90 (dd, 1H), 2.20-2.11 (m, 1H). MS (EI) for C27H24FN5O3. found 486.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][OH:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[O-][O-].[Mg+2].CO.C(OCC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]=[O:31])=[O:22])=[CH:33][CH:34]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CO)cc2)cc1
Agent: [Mg+2]
Agent: [O-][O-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C=O)cc2)cc1
Yield: 93.3 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-hydroxymethylphenyl)benzamide (225 mg) and magnesium dioxide (651 mg) in chloroform (10 ml) was refluxed for 3 hours and the solution was filtered through Celite. The filtrate was evaporated in vacuo to give a crude oil and the oil was subjected to silica gel column (1% methanol in chloroform). The product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-formylphenyl)benzamide (209 mg) as a white powder.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1>O1CCCC1.O>[CH2:9]([S:10][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: Cc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(SCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
To a suspension of sodium hydride (60% in oil, 512 mg) in tetrahydrofuran (45 mL) was added dropwise phenylmethanethiol (1.52 g) at room temperature, 2-bromo-4-methylpyridine (2.0 g) was added, and the mixture was stirred at 60° C. for 72 hr. The reaction mixture was diluted with water and extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane→hexane-ethyl acetate=24:1) to give the title compound as a brown oil (yield 1.40 g, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[CH:11]1[CH:12]=[CH:13][C:14]2[S:19][CH:18]=[CH:17][C:15]=2[CH:16]=1>>[S:19]1[C:18]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([Br:1])[CH:3]=2)=[CH:17][C:15]2[CH:16]=[CH:11][CH:12]=[CH:13][C:14]1=2
Reactant: c1ccc2sccc2c1
Reactant: Cc1ccc(C=O)cc1Br
Product: Cc1ccc(Cc2cc3ccccc3s2)cc1Br

Procedure:
The above 3-bromo-4-methylbenzaldehyde and thianaphthene were treated in a manner similar to Reference Example 7 to give (Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-methylbenzene as a colorless solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[CH2:21][C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[C:22](=[O:24])[CH2:21][C:12]2[CH:13]=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCNCc2ccccc2)c(CC(=O)O)cc1OC
Solvent: Cc1ccccc1C
Product: COc1cc2c(cc1OC)CC(=O)N(Cc1ccccc1)CC2

Procedure:
A stirred suspension of 4.1 suspension of 4.1 g of the benzylamino acid obtained in Example 22 was refluxed in 75 ml. of xylene under a Dean-Stark trap for 24 hours, at the end of which time a clear solution had resulted. Distillation of the xylene in vacuo left the above-named product as shining white plates, m.p. 141°-142°. A sample of the cyclic lactam recrystallized from toluene melted at 141°-142°.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]C)=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:5]1[C:6]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 65.6 %

Procedure:
Methyl ether 84 (0.15 g, 0.33 mmol) was treated with BBr3 in CH2Cl2 to give the crude product as a yellow viscous oil, which was purified by reverse phase preparation HPLC on Agilent 1100 to afford 95 mg (65%) of the title compound (85) as pale yellow solid. mp 128-130° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.74 (t, J=7.3 Hz, 3H), 1.10-1.25 (m, 2H), 1.35-1.45 (m, 2H), 2.50-2.60 (m, 2H), 6.25 (d, J=16.1 Hz, 1H), 6.55 (d, J=8.6 Hz, 2H), 6.96 (dd, J1=9.0 Hz, J2=2.0 Hz, 1H), 7.08-7.18 (m, 3H), 7.18-7.28 (m, 3H), 7.33 (d, J=8.6 Hz, 2H), 7.46-7.58 (m, 2H), 7.59 (d, J=9.0 Hz, 1H). LCMS (ESI): m/z 439 (M+H)+, m/z 437 (M−H)−. Anal. Calc for C29H26O4.0.4H2O: C, 78.15; H, 6.06. Found: C, 78.03; H, 6.00.