Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[NH:9]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([OH:22])([C:16]([F:24])([F:23])[F:15])[C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[CH3:14]
Reactant: Cc1cc(=O)n(-c2ccc(F)cc2)[nH]1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(F)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(4-fluorophenyl)-3-methyl-5-pyrazolone (96 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (174 mg).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][N:6]=[C:7]([NH2:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1.N1C=CC=CC=1.O>C(Cl)Cl>[CH3:16][C:11]1[CH:10]=[C:9]([CH2:8][C:7]2[NH:17][S:1](=[O:2])[O:5][N:6]=2)[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CC(N)=NO)cc1C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CC2=NOS(=O)N2)cc1C
Reaction time: 3 h
Yield: 32 %

Procedure:
Thionyl chloride (17.7 mL, 0.24 mol) in methylene chloride (40 mL) was added dropwise to a solution of N'-hydroxy-2-(3,4-dimethylphenyl)ethanimidamide (10.8 g, 0.06 mol), methylene chloride (130 mL) and pyridine (9.8 mL, 0.12 mol) at 5° C. After 3 hours, the mixture was poured into water and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Recrystallization from ethyl ether afforded the desired product (4.3 g, 32%) as an off-white solid, m.p. 127°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C@H:13]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:12]1)(=[O:10])=[O:9].Cl.CN(C)CCCN=C=NCC.OC1[C:49]2[N:48]=N[NH:46][C:45]=2C=CC=1.C(N(C(C)C)C(C)C)C.NCC#N>CN(C)C=O>[C:45]([CH2:49][NH:48][C:16]([C@@H:14]1[CH2:15][CH:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH2:12][C@H:13]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:18])#[N:46]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCNC(=O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 97.4 %

Procedure:
To a mixture of (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-(4-chloro-phenoxymethyl)-cyclopentanecarboxylic acid (epimeric mixture, 50 mg) in dimethylformamide (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg), hydroxybenzotriazole (24 mg) and ethyldiisopropylamine (61 mg). After 45 min, aminoacetonitrile (8 mg) was added and the reaction mixture was stirred for 2 days then partitioned between ethyl acetate and an aqueous saturated solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with dichloromethane/methanol (19:1 v/v) as eluant to afford the title compound (53 mg, 97%) as light yellow oil. MS (EI): 467.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].[O:31]=[C:32]1[N:36]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[C:35]2[CH:43]=[CH:44][CH:45]=[CH:46][C:34]=2[NH:33]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(=O)([O-])O.[Na+]>ClCCl.O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:17]([N:40]1[CH2:39][CH2:38][CH:37]([N:36]2[C:35]3[CH:43]=[CH:44][CH:45]=[CH:46][C:34]=3[NH:33][C:32]2=[O:31])[CH2:42][CH2:41]1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(Cl)c(Cl)c1)C(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 56 %

Procedure:
Triethylamine (0.28 mL, 0.20 g, 2 mmol) was added to a stirred, cooled (0° C.) mixture of (S)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionic acid (prepared according to the method of Sugano. H, and Miyoshi. M, J. Org. Chem 1976, 41, 2352) (364 mg, 1 mmol), 4-(2-keto-1-benzimidazolinyl)piperidine (217 mg, 1 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (305 mg, 2 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 1h. Aqueous sodium hydrogen carbonate (saturated, 40 mL) and water (10 mL) were added and the mixture was extracted with dichloromethane (3×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×50 mL), aqueous sodium hydrogen carbonate (saturated, 2×50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (99:1) to give the title compound as a colorless foam (318 mg, 56%). m/e (ES+) 563 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][CH2:8][CH:9]1[CH2:13][CH:12]([OH:14])[C:11](=[O:15])[NH:10]1)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O>[OH:14][CH:12]1[C:11](=[O:15])[NH:10][CH:9]([CH2:8][CH2:7][C:6]([OH:16])=[O:5])[CH2:13]1
Reactant: CC(C)(C)OC(=O)CCC1CC(O)C(=O)N1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC1CC(O)C(=O)N1

Procedure:
4-Hydroxy-5-oxo-2-pyrrolidinepropanoic acid t-butyl ester (1.87 g) and trifluoroacetic acid (1.2 g) in 10 ml of N,N-dimethylformamide was heated at 100° C. until disappearance of starting material by thin layer chromatography. After concentration under reduced pressure, the resulting solid is washed with acetone and filtered to give 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid. NMR (DMSOD6) and 12.14 (s, 1H), 7.96 (d, J=5 Hz, 1H), 5.37 (m, 1H), 4.00 (m, 1H), 2.60-1.09 (m, 6H). IR (cm-1) 3420, 3080, 2030, 2920, 1698, 1494, 1387, 1284.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][NH:7][CH3:8])[CH3:2].Cl[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12]>N1C=CC=CC=1>[O:12]=[C:11]([N:7]([CH3:8])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)(C)C(=O)Cl
Reactant: CCOC(=O)CCNC
Solvent: c1ccncc1
Product: CCOC(=O)CCN(C)C(=O)C(C)(C)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a solution of 61 g of N-methyl-β-alanine ethyl ester in 600 ml of dry pyridine there is added 82 g of ethyl 2-chloroformyl-2-methylpropionate. During the addition, which takes 30 minutes, the mixture is mechanically stirred and cooled with ice. Stirring is continued at 10° C for 30 minutes and then at 30° - 40° C for 1 hour. Next the pyridine is evaporated in vacuo, leaving a residue to which a small quantity of water is added, whereafter the mixture is extracted with ether. The extract is dried over magnesium sulphate and evaporated leaving the above-mentioned product as a liquid which is purified by distillation at reduced pressure. Yield 97 g (75%). Boiling point 134° - 136° C (1 mm). nD22 1.4565.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH3:23])[N:4]=1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N=C(OC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (3.19 g, 10.0 mmoles) in dry dichloromethane (15 ml) and pyridine (4 ml) was cooled to 0° C. and treated dropwise with ethyl chloroformate (1.2 ml, 12.0 mmoles) under argon. After the addition was completed, the cooling bath was removed and the reaction was allowed to stir at room temperature for 1 hour. It was then diluted with ethyl acetate and the resulting solution was washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was coevaporated with toluene to remove residual pyridine. The colorless solid obtained was subjected to high vacuum and used in the next reaction without further purification (3.81 g). For analytical purposes, a small amount of the compound was recrystallized from ether-hexanes to provide colorless solid, melting point 61.5°-64.5° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([C:12]([O:14]CC)=O)[CH2:10][C:9](=[O:11])[NH:8][CH2:7]1)C.[CH3:18][NH2:19]>>[CH3:18][N:19]1[C:4](=[O:3])[CH2:5][C:6]2([CH2:10][C:9](=[O:11])[NH:8][CH2:7]2)[C:12]1=[O:14]
Reactant: CN
Reactant: CCOC(=O)CC1(C(=O)OCC)CNC(=O)C1
Product: CN1C(=O)CC2(CNC(=O)C2)C1=O
Temperature: 220 °C

Procedure:
A solution of 20.3 g (0.084 mole) 3-ethoxycarbonyl-5-oxo-3-pyrrolidineacetic acid ethyl ester [J. Org. Chem. 46, 2757 (1981)]in 40 ml of 40% aqueous methylamine was stirred at room temperature overnight, then placed in an oil bath and gradually heated to 220° C. over 30 minutes allowing volatiles to distill from the open flask. The crude product was crystallized from ethanol to afford 12.56 g of the title compound, mp 201°-204° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.COC1C=CC(C[NH2:22])=CC=1.[Cl:25][C:26]1[C:27](I)=[C:28]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[C:29](Cl)=[O:30].CCN(CC)CC.Cl>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([Cl:35])[CH:34]=1)[C:11]1([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[NH:22][C:29]2=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1I
Reactant: COc1ccc(CN)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1NC2(CCNCC2)c2c(Cl)cc(Cl)cc21
Yield: 118.5 %

Procedure:
A 500-mL flask was charged with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (7.0 g, 35 mmol), 4-methoxy-benzylamine (4.8 g, 35 mmol) and 120 mL of toluene. The mixture was heated to reflux for 12 h. The yellow-orange solution was allowed to cool to ambient and then evaporated. The residue was used directly in the next step without further purification. It was dissolved in 150 mL of toluene. Then 3,5-dichloro-2-iodobenzoyl chloride (9.4 g, 28 mmol) and Et3N (4.5 g, 44 mmol) was added. The mixture was heated to reflux overnight. The mixture was acidified with 0.5 N aq HCl, and the layers were separated. The organic layer was washed with brine, dried and concentrated to give the crude product. It was purified by column chromatography (PE:EtOAc=15:1) to give the desired product (9.0 g, 42%).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10](OC)=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.[O:35]1[CH2:40][CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36]1>>[O:35]1[CH2:40][CH2:39][CH:38]=[C:37]([C:10]2[CH:9]=[C:8]([F:24])[C:7]3[O:6][C:5]4[C:14](=[CH:15][C:2]([C:31]5[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:3][CH:4]=4)[C@@:13]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:12]=3[CH:11]=2)[CH2:36]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: OB(O)c1cccnc1F
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCCOC3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in method A7 above, but using intermediate 20B, 2-fluoropyridin-3-ylboronic acid and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: C([S:3]([C:6]1[CH:13]=CC([N+]([O-])=O)=C[C:7]=1C#N)(=[O:5])=[O:4])C.F[C:18]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=1[C:20]#[N:21].[CH3:29]C(S)(C)C.C1C=C(Cl)C=C(C(OO)=O)C=1>>[C:6]([S:3]([C:18]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=1[C:20]#[N:21])(=[O:5])=[O:4])([CH3:13])([CH3:29])[CH3:7]
Reactant: CC(C)(C)S
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Agent: O=C(OO)c1cccc(Cl)c1
Product: CC(C)(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Yield: 88 %

Procedure:
Using a procedure analogous to that used to prepare 6A, 2-fluoro-5-nitrobenzonitrile (2.50 g, 15.6 mmol) was reacted with tert-butylthiol and oxidized with mCPBA to afford 10A (3.14 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9 H), 7.88 (d, J=8.79 Hz, 1 H), 8.37 (dd, J=8.35, 2.64 Hz, 1 H), 8.55 (d, J=2.64 Hz, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7])#[N:2].Cl.[NH2:32][OH:33].C(N(CC)CC)C>CCO>[NH2:2][C:1](=[N:32][OH:33])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7]
Reactant: NO
Reactant: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C#N)c2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C(N)=NO)c2)cc1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-N2-(4-isopropylbenzoyl)-4-hydroxy-1,2-benzenediamine (445 mg, 1.11 mmol) and absolute EtOH (30 mL) was added hydroxylamine hydrochloride (125 mg, 1.80 mmol) followed by triethylamine (0.3 mL, 2.15 mmol). The resulting mixture was heated to 80° C. for 2 h, cooled to room temperature, and filtered to give the title compound as a solid (238 mg, 0.55 mmol, 50%); NMR(300 MHz, d6-DMSO): δ9.92 (s, 1H), 9.76 (s, 1H), 9.69 (s, 1H), 9.53 (s, 1H), 8.23 (s, 1H), 7.84 (m, 4H), 7.49 (m, 1H), 7.29 (m, 4H), 6.65 (d, J=9.0, 1H), 5.85 (s, 2H), 2.92 (m, 1H), 1.19 (s, 3H), 1.17 (s, 3H); MS(FD): 432.2.
Reaction SMILES: C1(N=[C:8]([OH:24])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([OH:13])=[S:12])C=CC=CC=1.[OH-:25].[Na+].Cl>>[C:18]1([C:17]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=[S:12])[C:9]=2[C:8]([OH:24])=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OC(=S)c1cccc(-c2ccccc2)c1C(O)=Nc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1c(C(O)=S)cccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
99.4 g (0.3 mol) of 3-phenylthiophthalic acid N-phenylimide are suspended in 1,326 ml of a 20% sodium hydroxide solution and the suspension is heated at 100° C. for 30 minutes, with stirring. After cooling, the alkaline suspension is acidified with 672 ml of 37% hydrochloric acid, with stirring. After one hour, the fine suspension is filtered with suction and the material on the suction filter is suspended, while still wet, in 882 ml of 37% hydrochloric acid and the resulting suspension is refluxed for one hour. The reaction mixture is cooled, the resulting fine suspension is filtered with suction and the product is dried at 80° C./13,000 Pa. 69.4 g (85% of theory) of 3-phenylthiophthalic acid are obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].N#N.F[C:11](F)(F)[C:12](O)=O.[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:6]([O:5][C:1]([C:2]12[CH2:25][N:24]([CH2:30][C:12]3[CH:11]=[CH:20][CH:19]=[CH:18][CH:23]=3)[CH2:17][CH:3]1[CH2:25][N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:30]2)=[O:4])[CH3:7]
Reactant: O=C(O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C#CC(=O)OCC
Agent: N#N
Solvent: C1CCOC1
Product: CCOC(=O)C12CN(Cc3ccccc3)CC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 10 h
Yield: 915 %

Procedure:
To the ethyl propynoate (Aldrich, 3.96 g, 40 mmol) in THF (200 mL) in a 3-neck, 3-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at 0° C. was added trifluoroacetic acid (TFA) (Aldrich, 0.3 mL, 4 mmol). Benzyl(methoxymethyl)trimethylsilylmethylamine (Aldrich, 23.7 g, 100 mmol) in 50 mL THF was added dropwise via addition funnel over 30 minutes with the reaction temperature being maintained below 5° C. After the addition was complete, the mixture was allowed to warm slowly to ambient temperature and then was stirred for 10 h. The mixture was concentrated and the residue was dissolved in 500 mL EtOAc. It was washed with 2×50 mL saturated NaHCO3 and 25 mL brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50% hexanes-EtOAc) to give 14.5 g of the title compound (36.6 mmol, 91% yield). MS (DCl/NH3) m/z 365 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[O:19][CH2:20][C@@H:21]([CH:23](O)[CH3:24])[N:22]=1)=[CH:5]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[O:19][CH2:20][C@H:21]([CH2:23][CH2:24][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:22]=1)=[CH:5]2
Reactant: C1COCCN1
Reactant: Cc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](C(C)O)CO3)cc2c1
Product: Cc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@@H](CCN4CCOCC4)CO3)cc2c1

Procedure:
The compound obtained in Example 104 and morpholine were reacted according to the procedures as Preparation 33 and Example 15 in the order to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]1([N:34](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:34][C:28]1([CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)CCCCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N)CCCCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(aminomethyl)-N,N-dibenzylcyclohexanamine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CDCl3) δ ppm 8.02-7.99 (dd, J=1.2 Hz, 8.0 Hz, 1 H), 7.65-7.63 (d, J=7.6 Hz, 1 H), 7.48-7.46 (m, 2 H), 7.34-7.25 (m, 3 H), 5.86 (s, 1 H), 5.64 (s, 1 H), 5.10 (s, 2 H), 4.56 (s, 2 H), 3.55 (s, 2 H), 3.05-3.04 (d, J=4.8 Hz, 2 H), 2.41 (s, 3 H), 1.98 (s, 4 H), 1.56 (m, 10 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25](Cl)=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2.[NH3:29]>>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25]([NH2:29])=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(=O)Cl)cccc4c3)ccc21
Reactant: N
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(N)=O)cccc4c3)ccc21
Yield: 88 %

Procedure:
Utilizing a procedure analogous to that of Example 16(b), 671 mg (1.7 mmol) of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)naphthoyl chloride were reacted with 10 ml of aqueous ammonia (32%) to provide 560 mg (88%) of the expected amide, having a melting point of 175°-6° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:46])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:46])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-octylaminocarbonyl)-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate in trifluoroacetic acid/methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH2:13].C(N(CC)CC)C.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of 2-amino-4-nitro-benzoic acid methyl ester (5.00 g, 25.5 mmol) in methylene chloride (75 mL) was added triethylamine (4.13 g, 40.8 mmol) followed by 4-trifluoromethoxy-benzoyl chloride (6.87 g, 30.6 mmol). This mixture was allowed to stir overnight at ambient temperature. The mixture was filtered, partitioned against brine, the layers were separated, and the aqueous layer was extracted with one portion of ethyl acetate. The organics were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was recrystallized from ethyl acetate (250 mL) to give 4-nitro-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (6.83 g, 70%) as pale-yellow crystals. 1H NMR (500 MHz, DMSO-d6); δ 11.53 (s, 1H), 9.20 (d, 1H), 8.19 (d, 1H), 8.10 (d, 2H), 8.07 (dd, 1H), 7.63 (d, 2H), 3.91 (s, 3H).