Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:22]1[CH2:28][S:25](=[O:27])(=[O:26])[O:24][CH2:23]1>CC(C)=O>[CH2:1]([N:17]1[CH:21]=[CH:20][N+:19]([CH2:23][CH2:22][CH2:28][S:25]([O-:27])(=[O:26])=[O:24])=[CH:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCn1ccnc1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCn1cc[n+](CCCS(=O)(=O)[O-])c1
Temperature: 25 °C

Procedure:
12.3 g of N-hexadecylimidazole was dissolved in 80 ml of acetone, and the mixture was cooled in an ice-water bath. Into the resultant, a solution in which 5.13 g of 1,3-propanesultone was dissolved in 80 ml of acetone was dripped, and after the dripping was completed, the resultant was stirred at room temperature. After the completion of the reaction, the resultant was filtered to obtain a precipitate. The precipitate was dried under reduced pressure, whereby 15.4 g of 3-(3-hexadecyl-1-imidazolio)-1-propanesulfonate (M-1) represented by the chemical formula (M-1) was obtained.
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH2:16]([O:18][C:19](=[O:31])[C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:21])[CH3:17].C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:31])[C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:21][C:11](=[O:13])[C:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])([CH3:10])[CH3:14])[CH3:17]
Reactant: CCOC(=O)[C@@H](N)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](COCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of BOC-α-methylalanine (3.05 g, 15 mmol), O-benzyl-L-serine ethyl ester hydrochloride (3.89 g, 15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl, 2.88 g, 15 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT, 2.04, 15 mmol) in methylene chloride (150 mL) is added triethylamine (1.52 g, 15 mmol). The mixture is stirred overnight and then concentrated in vacuo. The residue is re-dissolved in ethyl acetate and washed with water, 1 N HCl, water, and brine. The solution is dried over sodium sulfate and concentrated to yield N-[2-(BOC-amino)-2-methylpropionyl]-O-benzyl-L-serine ethyl ester of the formula
Reaction SMILES: ClC1C=CC(C2OC3C=CC=CC=3C=2)=CC=1.C(Cl)(=O)C1C=CC(OC)=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]3[CH:53]=[CH:52][CH:51]=[CH:50][C:38]=3[C:39]=2[C:40](=[O:49])[C:41]2[CH:46]=[CH:45][C:44]([O:47]C)=[CH:43][CH:42]=2)=[CH:31][CH:30]=1.Cl.N1C=CC=CC=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]3[CH:53]=[CH:52][CH:51]=[CH:50][C:38]=3[C:39]=2[C:40](=[O:49])[C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(Cl)cc3)oc3ccccc23)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: Clc1ccc(-c2cc3ccccc3o2)cc1
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1c(-c2ccc(Cl)cc2)oc2ccccc12

Procedure:
When 2-(4-chlorophenyl)benzofuran was acylated with p-anisoyl chloride as described in the procedure of Example 1 and the resulting 2-(4-chlorophenyl)-3-(4-methoxybenzoyl)benzofuran was demethylated with pyridine hydrochloride as previously described, 2-(4-chlorophenyl)-3-(4-hydroxybenzoyl)benzofuran was obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@@H:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:24]1([CH:13]([O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)[C@@H](O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC(C(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 9 h

Procedure:
A CH2Cl2 (200 mL) solution of p-toluenesulfonyl chloride (8.65 g, 45.4 mmol) was added dropwise to a cooled (−5° C.) CH2Cl2 (200 mL) solution of (S)-benzyl 2-hydroxy-2-phenylacetate (10.0 g, 41.3 mmol), triethylamine (5.75 mL, 41.3 mmol) and 4-dimethylaminopyridine (0.504 g, 4.13 mmol), while maintaining the temperature between −5° C. and 0° C. The reaction was stirred at 0° C. for 9 hours, and then stored in a freezer (−25° C.) for 14 hours. It was allowed to thaw to ambient temperature and washed with water (200 mL), 1N HCl (100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide benzyl 2-phenyl-2-(tosyloxy)acetate as a viscous oil which solidified upon standing (16.5 g). The chiral integrity of the product was not checked and that product was used for the next step without further purification. 1H NMR (DMSO-d6, δ=2.5, 500 MHz) δ 7.78 (d, J=8.6, 2H), 7.43-7.29 (m, 10H), 7.20 (m, 2H), 6.12 (s, 1H), 5.16 (d, J=12.5, 1H), 5.10 (d, J=12.5, 1H), 2.39 (s, 3H). RT=3.00 (Cond. III); >90% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C22H20NaO5S: 419.09. found 419.04.
Reaction SMILES: C(O)C.[C:4]1([NH:10][NH2:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(N(CC)CC)C>[C:4]1([NH:10][NH:11][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cl
Reactant: NNc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)NNc1ccccc1
Temperature: 0 °C
Yield: 86 %

Procedure:
Into 200 ml of ethanol were poured 21.6 g (0.2 mol) of phenylhydrazine and 30 ml of triethylamine, and 21.6 g (0.2 mol) of ethyl chloroformate was slowly added dropwise thereto. After the addition, the mixture was refluxed for 30 minutes and then poured into ice-water. The mixture was extracted with ethyl acetate, and the extract was concentrated and purified by column chromatography to obtain 31 g of N-phenyl-N'-ethoxycarbonylhydrazine as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:4](=[O:8])[CH:3]=1
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(N)cc1=O
Temperature: 78 °C
Yield: 41 %

Procedure:
To a solution of 4-aminopyridin-2(1H)-one (Molbridge)(0.9 g, 8.17 mmol) in DMF (30 mL) was added NaH (60%, 490 mg, 12.3 mmol). The mixture was stirred at room temperature for 30 min before (2-bromoethoxy) (tert-butyl)dimethylsilane (2.15 g, 8.99 mmol) was added. The reaction mixture was heated at 78° C. for 15 h. The mixture was cooled and poured into H2O (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with H2O (5×50 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (silica gel, 40+S, 0% to 10% MeOH in EtOAc) to give 4-amino-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyridin-2-one as a white solid (0.9 g, 41%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1>[CH2:24]([O:23][C:21]([CH2:20][N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(Oc2ccc(C3CCCN3)cc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CN1CCCC1c1ccc(Oc2ccccc2)cc1

Procedure:
To a solution of 23.9 parts of 2-(4-phenoxyphenyl) pyrrolidine in 80 parts of anhydrous benzene, there were quickly added 8.35 parts of ethyl bromacetate. The reaction mixture was then refluxed for 4 hours. After cooling and filtration, the residue was treated with 50 parts of water and 100 parts of ether. After decantation, then distillation, there were obtained 11.3 parts of 1-ethoxycarbonylmethyl-2-(4-phenoxyphenyl) pyrrolidine, B.P./0.1 mm Hg: 165° C., nD23 : 1.5524.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.Cl[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCNc1ccc(Cl)c(Cl)c1

Procedure:
In the manner given in Example 1, 3,4-dichloroaniline, 1-chloro-2-dimethylaminoethane hydrochloride, and sodium bicarbonate are heated to give N,N-dimethyl-N'-(3,4-dichlorophenyl)ethylenediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=2)=[CH:7][CH:8]=1)=[O:27]
Reactant: Nc1ccc(Oc2cccc(Cl)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2cccc(Cl)c2)cc1
Yield: 90 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(3-chlorophenoxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(3-chlorophenoxy)phenyl)propanamide (349 mg, 90%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:36]([NH:40][CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH:37]([CH3:39])[CH3:38]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: CC(C)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CNCC(C)C)C(C)C)ccc1OC

Procedure:
from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.52 mmol), isobutylamine (0.756 mL, 7.61 mmol) and NaBH4 (0.115 g, 3.04 mmol) and purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4, then CH2Cl2/MeOH (10% NH3 conc.) gradient from 9:1 to 8:2) to give the title compound as colorless oil. MS: 550.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.74 min.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25](Cl)[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25]([N:38]=[N+:39]=[N-:40])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(Cl)C(=O)OCc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 47 %

Procedure:
To a solution of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-chloroacetate (3.60 g.) in N,N-dimethylformamide (6 ml.) was added sodium azide (384 mg.) at 0° C., and the mixture was stirred at 0° C. for 50 minutes. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed twice with water and an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated to leave an oil (3.60 g.), which was chromatographed on silica gel (36 g.) with chloroform as an eluent to give an oil (1.71 g.) of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-azidoacetate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1.C(#N)C>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[NH:9][C:19]1=[O:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)[nH]c2cc(C(F)(F)F)cnc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of 1.91 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 3.24 g of carbodiimidazole and 10 ml of acetonitrile was stirred at 50° C. for 1 hour and at 80° C. for 2 hours. Water was poured into the cooled reaction mixture, and the precipitated crystal was obtained by filtration and dried to obtain 2.0 g of 3-methyl-6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:37][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-])=O)[C:22]=3[N:21]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:20]2=[O:36])[CH:13]=[CH:12]4)[C:5](=[O:38])[NH:4][C:3]1=[O:39].CCOC(C)=O>CO.[Pd]>[NH2:28][C:27]1[C:22]2[N:21]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:20](=[O:36])[N:19]([CH2:18][C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[CH:17][C:8]5[CH2:7][C@@:6]6([C:5](=[O:38])[NH:4][C:3](=[O:39])[N:2]6[CH3:1])[CH2:37][C:9]=5[CH:10]=4)[N:15]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)Cn1c(=O)n(Cc2ccc3cc4c(cc3n2)C[C@]2(C4)C(=O)NC(=O)N2C)c2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(=O)n(Cc2ccc3cc4c(cc3n2)C[C@]2(C4)C(=O)NC(=O)N2C)c2cccc(N)c21

Procedure:
A mixture of methyl (3-{[(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidin]-2-yl]methyl}-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step A (143 mg, 0.27 mmol) and 10% Pd/C (20 mg) was stirred vigorously in MeOH (3 mL) and EtOAc (5 mL) under an atmosphere of hydrogen (ca. 1 atm). Additional amounts of 10% Pd/C (20 mg) were added after 16 h and 24 h. After a total reaction time of 96 h, the mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z 501 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH:15][CH2:16][C:17]([NH2:26])([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH3:18])[CH2:6]1)[CH2:12]2)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[N:15]3[CH2:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)([CH3:18])[NH:26][C:28]3=[O:30])[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C12CC3CC(C1)C(NCC(C)(N)c1cccc(Cl)c1)C(C3)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(C1)C(N1CC(C)(c4cccc(Cl)c4)NC1=O)C(C3)C2
Reaction time: 4 h
Yield: 118.8 %

Procedure:
A solution of 4-[2-amino-2-(3-chloro-phenyl)-propylamino]-adamantane-1-carboxylic acid methyl ester (7.9 g) in 40 mL DCM was cooled to −20° C. and triphosgene (3.1 g) (separately dissolved in 10 mL DCM) was added to it drop wise followed by drop wise addition of triethylamine (6.57 mL). The reaction mixture was slowly brought to RT and left at stirring for 4 h. Reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and the DCM layer was separated. The aqueous layer was again extracted with DCM (2×). The combined DCM layers were dried over Na2SO4 and concentrated to afford the crude product, which was purified by column chromatography to give the desired 4-[4-(3-chloro-phenyl)-4-methyl-2-oxo-imidazolidin-1-yl] adamantane-1-carboxylic acid methyl ester (5.0 g) as a mixture of E/Z isomers as a white solid. MS (ES+): 403.4 (MH+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([N:8]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7].[NH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32].[OH-].[K+]>C(O)C>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([N:8]([C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:9][CH2:10][CH2:11][C:12]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:13])=[O:7]
Reactant: CC(C)(C)CC(C)(C)N(CCCC(=O)O)C(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)CC(C)(C)N(CCCC(=O)NCCC(=O)O)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(m-trifluoromethylbenzoyl)-4-[(1,1,3,3-tetramethylbutyl)amino]butyric acid and ethyl 3-aminopropionate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(m-trifluoromethylbenzoyl)-4-(1,1,3,3-tetramethylbutylamino)butyryl]-3-aminopropionic acid.
Reaction SMILES: [CH3:1][NH2:2].Cl.[OH-].[K+].[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[C:10]([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH:19]=O)[CH:9]=1>CO>[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[C:10]([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19][NH:2][CH3:1])[CH:9]=1
Reactant: COc1cc(C(CC=O)c2ccccc2)c2cc[nH]c2c1
Reactant: CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CNCCC(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
To a mixture of MeNH2·HCl (0.60 g, 9 mmol) and KOH (0.1 g, 1.8 mmol) in MeOH (5 ml) was added a solution of 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-propionaldehyde CXVIII (0.25 g, 0.89 mmol) in MeOH (6 ml) at RT. The resulting mixture was stirred at room temperature for 5 minutes and NaCNBH4 (21 mg, 0.33 mmol) was added. The reaction mixture was stirred for 45 minutes at room temperature and then quenched with HCl (1M, 50 ml). The resulting mixture was extracted with Et2O (25 ml), and the aqueous layer was basified until pH>12 by addition of a saturated solution of NaOH (50 ml). The aqueous layer was extracted with Et2O (35 ml). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) to afford [3-(6-Methoxy-1H-indol-4-yl)-3-phenyl-propyl]-methyl-amine compound CXIX (33 mg, 13% yield). MS (M+H)=295.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[C:5]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC(C)=O>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:10][CH:9]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2-c2ccc(CC(C)C)cc2)c1C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: Cc1noc(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3)cc2-c2ccc(CC(C)C)cc2)c1C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a solution of the compound of Example 43 (0.4 g, 1.0 mmol) and pyridine (0.082 mL, 1.0 mmol) in acetone (3 mL) was added benzoyl chloride (0.12 mL, 1.0 mmol). The mixture was stirred for 18 hours and concentrated. The residue was dissolved in methanol (50 mL) and a 5% solution of sodium hydrogen carbonate in water (10 mL) was added. The solution was stirred for 1 hour and the methanol was removed under vacuum. The aqueous residue was acidified to pH 3 with 6N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, and dried (magnesium sulfate). The residue was chromatographed on silica with (1:1) ethyl acetate:hexanes to afford 98 mg (19%) of the title compound as a tan solid, mp 207-211° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 90 %

Procedure:
To ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.2 g) was added conc. hydrochloric acid (5 ml), water (2 ml) and acetic acid (20 ml), and the mixture is refluxed for 2 hours. After cooling, the precipitated crystals are separated by filtration, and washed with water, ethanol and diethyl ether in this order to give 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) as a white crystal, m.p. 240°-243° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH3:3])[CH3:2].[N+:23]([O-])([OH:25])=[O:24]>CC(O)=O>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N+:23]([O-:25])=[O:24])=[CH:6][C:5]=1[O:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)(=[O:15])=[O:14])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(OS(=O)(=O)c2ccc(C)cc2)cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
To a solution of toluene-4-sulfonic acid 2-isopropyl-4-methoxy-phenyl ester (19.00 g, 59 mmol) in 118 mL AcOH was added 236 ml fuming HNO3 over 20 min. After 16 h the solution was pouring into a rapidly stirring slurry of 2 l of ice/H2O. After 15 min the precipitate was filtered, washed with H2O and dried under vacuum (50° C.) to give toluene-4-sulfonicacid 2-isopropyl-4-methoxy-5-nitro-phenyl ester (21.27 g, 98%) and toluene-4-sulfonic acid 2-isopropyl-4-methoxy-3-nitro-phenyl ester and as a pale yellow solid (7:1 inseparable mixture).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1.[NH:27]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]([NH2:34])[CH2:28]1>>[NH2:34][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][N:27]([CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:8][CH2:9]2)[CH2:28]1
Reactant: NC1CCCCNC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCO)CC3)cc12
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCC(N)C4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 150 from 4-isobutoxy-1H-indole-2-carboxylic acid [1-(2-hydroxy-ethyl)piperidin-4-yl]-amide, 190 and azepan-3-ylamine.