Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[C:17]1([C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:35][C:33](=[O:34])[NH:32]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=Cc1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc([N+](=O)[O-])c(O)c(C(F)(F)F)c2)N1
Temperature: 90 °C
Yield: 17.1 %

Procedure:
To a mixture of 4-hydroxy-3-nitro-5-(trifluoromethyl)benzaldehyde (Intermediate 79) (100 mg, 0.40 mmol), 1,2-diphenylethanone (83 mg, 0.40 mmol), urea (77 mg, 1.30 mmol) and conc. HCl (0.05 mL) in ethanol (1 mL) was heated at 90° C. for 37 hours. Solvent was removed under reduced pressure and the residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound 154 (31.2 mg, yield 30%) as yellow solid. 1H NMR (DMSO 300 MHz): δ 8.81 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.62 (s, 1H), 7.25-7.17 (m, 5H), 7.03-6.96 (m, 3H), 6.78 (d, J=7.2 Hz, 2H), 5.34 (s, 1H), MS (ESI): m/z 456.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1[CH:29]=[N:30][NH:31][C:32]=1[NH:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[CH3:27][C:28]1[CH:29]=[N:30][N:31]2[C:22]([CH2:23][CH2:24][CH3:25])=[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)[C:17](=[O:18])[N:33]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:32]=12
Reactant: Cc1cn[nH]c1NC1CCOCC1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Temperature: 180 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g), 4-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (0.4 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL) and N,N-diethylaniline (10 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 61%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]#[C:14][CH3:15].C(N(CC)CC)C>C(OCC)C>[CH2:18]([O:17][C:12]([C:13]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=2)=[N:2][O:1][C:14]=1[CH3:15])=[O:16])[CH3:19]
Reactant: CC#CC(=O)OCC
Reactant: O/N=C(\Cl)c1cccc(F)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2cccc(F)c2)noc1C
Temperature: 25 °C
Yield: 39.5 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-3-fluoro-benzenecarboximidoyl chloride (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0° C. followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (6.3 g, 39%) which was obtained as a white solid. MS: m/e=250.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)CCC1C(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A suspension containing (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (10.00 g, 0.044 mol, 1.0 equivalent), benzyl bromide (7.88 g, 0.046 mol, 1.05 equivalents), and potassium carbonate (15.20 g, 0.11 mol, 2.5 equivalents) in DMF (200 ml) was allowed to stir at 65° C. overnight. The reaction was allowed to cool to room temperature and the mixture was filtered through Celite. The solid was rinsed with ethyl acetate (100 ml) and the resulting filtrate was partitioned between ethyl acetate and saturated brine solution. The organic layer was washed with saturated brine (3×100 ml), dried over anhydrous Na2SO4 and concentrated iiz vacuo. The crude, colorless oil was chromatographed on silica to afford 5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester as a colorless oil (8.20 g, 0.026 mol, 59% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.36 (5H, broad s), 5.20 (2H, d), 4.64 (1H, dd), 2.44–1.96 (4H, m), 1.41 (9H, s). MS (LC-MS): Calculated for C17H21NO5 319.14. Found 320.19 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:9].[CH2:19]([O:26][C@H:27]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([C:39](O)=[O:40])[CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C)C=O.O>[CH2:19]([O:26][C@H:27]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C@H:29]([C:39](=[O:40])[NH:1][N:2]2[CH:6]=[CH:5][C:4]([Br:7])=[C:3]2[C:8](=[O:9])[NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
1-Amino-3-bromo-N-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide (1.5 g, 4.75 mmol), (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.99 g, 3.08 mmol) and diisopropylethylamine (2.8 ml, 16.08 mmol) were dissolved in dimethylformamide (30 ml) and the mixture cooled at 0° C. To this mixture, T3P (50% solution in ethyl acetate, 2.1 ml, 7.19 mmol) dissolved in DMF (5 ml) was dropwise added. Once the addition is over, the mixture was stirred at room temperature for 48 h. To this mixture, water was added and extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulphate, filtered and the solvents evaporated under reduced pressure. The residue was purified by flash chromatography (0% to 25% hexanes/AcOEt) to yield 1.42 g (74% yield) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)C(C)C)(C)C.Cl.[N:21]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[N:21]1([CH:26]2[CH2:31][CH2:30][N:29]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:28][CH2:27]2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1cn(C2CCNCC2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1N1CCC(n2ccnc2)CC1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A solution of 1-fluoro-2-nitro-benzene (0.32 mmol, 34 μL), N,N-diisopropylethylamine (1.6 mmol, 0.28 mL) and HCl salt of 4-Imidazol-1-yl-piperidine (0.53 mmol, 0.10 g) in ACN (2 mL) was irradiated using microwave for 10 minutes at a temperature of 180° C. The solution was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel to provide 4-Imidazol-1-yl-1-(2-nitro-phenyl)-piperidine (71 mg, 81% yield). To the solution of this nitro compound in EtOAc (15 mL) was added Pd on carbon (5% Pd, 55 mg). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide compound 41A (54 mg, 86% yield). HPLC-MS RT=0.63 minutes, mass calculated formula C14H18N4 242.15, observed LCMS m/z 243.30 (M+H).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:12])([F:11])[C:6]([O:8]CC)=O.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:15].Cl>C1(C)C=CC=CC=1.O>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:14](=[O:15])[CH2:13][C:6](=[O:8])[C:5]([F:4])([F:11])[F:12])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
216 g (4 mol) of anhydrous sodium methylate and 3.5 l of toluene are introduced into a 10 liter round-bottomed flask and, under vigorous stirring, 705 g (5 mol) of ethyl trifluoroacetate are then run in; the temperature rises slowly to 30° C. After cooling in an ice bath, a solution of 720 g (4 mol) of 3,4-dimethoxyacetophenone in 0.5 l of toluene is added dropwise to the reaction mixture; a white precipitate slowly forms. The mixture is next left stirred overnight and then heated to 50° C. for three hours. After cooling, 2 1 of water and 330 ml of concentrated hydrochloric acid are added, the organic phase is separated off after settling has taken place, dried over magnesium sulphate, filtered and evaporated to obtain 1060 g (96%) of a yellow solid melting at 87°-89° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCCCCCl)OCc1ccccc1
Yield: 85.2 %

Procedure:
46.5 g (0.3 mole) of 6-chlorohexanoic acid and 35.6 g of benzyl alcohol in 500 ml of toluene are heated in the presence of 1 g of p-toluenesulphonic acid, using a water separator. When the reaction has ended, the mixture is washed with 5% strength sodium bicarbonate solution and water, dried with sodium sulphate and concentrated and the residue is distilled, 61.5 g (85% of theory) of benzyl 6-chlorohexanoate of boiling point 163° to 165°/4 mm being obtained.
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH3:9])[CH2:4][C:5]([OH:7])=O)[CH3:2].S(Cl)(Cl)=O.[CH3:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[C:16]=1[NH2:28].C(=O)(O)[O-].[Na+].[Cl-].[Na+].O.O>C(#N)C>[CH3:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[C:16]=1[NH:28][C:5](=[O:7])[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:8][CH3:9]
Reactant: Cc1cc(N2CCOCC2)cc(C)c1N
Reactant: CCC(CC)CC(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CCC(CC)CC(=O)Nc1c(C)cc(N2CCOCC2)cc1C
Temperature: 110 °C
Yield: 30.6 %

Procedure:
3-Ethylpentanoic acid (0.79 g) and thionyl chloride (0.44 mL) were mixed in acetonitrile (10 mL) and heated to 110° C. for 5 minutes in a sealed microwave process vial. 2,6-Dimethyl-4-morpholin-4-yl-phenylamine (1.25 g) dissolved in acetonitrile (10 mL) was added to the reaction mixture and heated to 150° C. for 15 minutes in a sealed microwave process vial. Saturated aqueous sodium bicarbonate/brine/water (1:1:1, 50 mL) was added to the crude mixture and it was extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was recrystallized from hot toluene, and the product was collected by filtration, washed with cold toluene and dried in vacuo to furnish 0.59 g (30% yield) of the title compound as an off-white solid. LC-MS (m/z) 319 (MH+); tR=2.04, (UV, ELSD) 98%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.87 (t, 6H), 1.35 (qui, 4H), 1.76 (m, 1H), 2.07 (s, 6H), 2.20 (d, 2H), 3.05 (t, 4H), 3.71 (t, 4H), 6.62 (s, 2H), 8.94 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH:27]1[C:40]2[CH:39]([C:41](O)=[O:42])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:41]([CH:39]1[C:40]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:42])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)C1c2ccccc2Oc2ccccc21)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with xanthene-9-carboxylic acid under the conditions described in example 86 to yield the desired product.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][CH2:15][N:16]([CH2:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([O:39]C(C)(C)C)=[O:38])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:7])(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl.CCOCC>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH2:17][N:16]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:44])[CH2:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38])=[O:31]
Reactant: COc1ccc(CN(CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(CCC(=O)N2CCC[C@@H]2C(=O)O)CCC(=O)N2CCC[C@@H]2C(=O)O)cc1OC
Reaction time: 16 h
Yield: 87 %

Procedure:
To a stirred solution of 150 mg (0.24 mmol) (R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(3,4-dimethoxy-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after trituration in ether, 130 mg (87%) of the title compound as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.C(Cl)(C(Cl)=O)=O.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1/[CH:12]=[CH:13]/[C:14]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[O:16]
Reactant: NCCCCCCO
Reactant: O=C(O)/C=C/c1ccccc1Sc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccccc1Sc1ccc(Cl)cc1Cl)NCCCCCCO
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
A suspension of the acid (284 mg, 0.87 mmol) from Example 1B in 5 mL of methylene chloride was stirred with (COCl)2 (84 μL, 0.97 mmol), and one drop of DMF under nitrogen atmosphere for 90 minutes. The solvent was then removed under vacuum. The residue (COCl)2 was removed with benzene (2×) in vacuo. To a separate flask, previously filled with 6-amino-1-hexanol (12 mg, 0.10 mmol), Hunig's base (22.8 μL, 0.13 mmol) and DMAP (1.1 mg, 0.008 mmol) in 2.0 mL of CH2Cl2, the acid chloride (30 mg, 0.087 mmol) in 1.0 mL of CH2Cl2 was then dropped in slowly. After 30 minutes, the reaction mixture was poured into 3N HCl and extracted with ethyl aceetate (EtOAc). The organic layer was washed with brine, dried with Na2SO4, condensed under reduced pressure. The crude product was purified by preparative TLC to give 21.0 mg (90%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.31-1.48 (m, 4H), 1.48-1.70 (m, 4H), 3.37 (q, J=6.7 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H), 5.63 (br s, 1H), 6.36 (d, J=15.9 Hz, 1H), 6.71 (d, J=9.3 Hz, 1H), 7.05 (dd, J=2.4, 8.7 Hz, 1H), 7.31-7.49 (m, 4H), 7.65 (dd, J=2.1, 7.5 Hz, 1H), 7.99 (d, J=15.9 Hz, 1H). MS (DCI/NH3)(M+NH4)+ at m/z 441, 443, 445.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][C:10](Cl)=[O:11].[CH:13]([N:16]=[C:17]=[S:18])([CH3:15])[CH3:14]>>[CH:1]1([N:7]2[C:10](=[O:11])[CH2:9][S:18]/[C:17]/2=[N:16]\[CH:13]([CH3:15])[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: CC(C)N=C=S
Reactant: NC1CCCCC1
Product: CC(C)/N=C1\SCC(=O)N1C1CCCCC1

Procedure:
3-Cyclohexyl-2-[(Z)-isopropylimino]-thiazolidin-4-one is prepared starting from cyclohexylamine, chloroacetyl chloride and isopropylisothiocyanate following Method B. LC-MS: tR=0.83 min, [M+1]+=241, 1H NMR (CDCl3): δ 4.30 (tt, J=3.6, 12.0 Hz, 1H), 3.69 (s, 2H), 3.37 (hep, J=6.4 Hz, 1H), 2.40-2.25 (m, 2H), 1.84-1.75 (m, 2H), 1.64-1.50 (m, 2H), 1.40-1.20 (m, 4H), 1.14 (d, J=6.4 Hz, 6H).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH:47]1([CH2:53][CH2:54][OH:55])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[Cl:17][C:18]1[C:19]([O:55][CH2:54][CH2:53][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCCC1CCCCC1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-cyclohexylethanol, the title compound was obtained as a colorless solid (0.09 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz, 1H), 4.17 (t, J=6.6 Hz, 2H), 2.87 (s, 6H), 1.76-1.60 (m, 7H), 1.54-1.42 (m, 1H), 1.28-1.11 (m, 3H), 1.02-0.90 (m, 2H); MS (ES−) m/z 405.1, 407.1 (M−1).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9].C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:9][C:8]1[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:7]=1[CH3:6])=[O:4]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CCl
Reaction time: 20 h

Procedure:
Chloroacetyl chloride (4.0 g) in methylene chloride (25 ml) was cooled via an ice bath to 0° C. A solution of 2,6-dimethylaniline (4.25 g) and triethylamine (5 ml) in methylene chloride (25 ml) was added dropwise over 1 hour and the resulting solution stirred and allowed to come to room temperature for a 20 hour period. 10% Hydrochloric acid was added and the layers were separated. The organic layer was washed with 1N hydrochloric acid and water, dried over sodium sulfate, filtered and the solvent removed to give a solid which was recrystallized from benzene. The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:8]([NH:9][C:10](=[O:14])[C@@H:11]([OH:13])[CH3:12])[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3]1.C(N(CC)CC)C.Cl[C:29](OC1C=CC([N+]([O-])=O)=CC=1)=[O:30].[F:41][C:42]([F:49])([C:45]([F:48])([F:47])[F:46])[CH2:43][NH2:44]>C1(C)C=CC=CC=1>[CH3:1][C@@H:2]1[C@H:8]([NH:9][C:10]([C@@H:11]([O:13][C:29](=[O:30])[NH:44][CH2:43][C:42]([F:49])([F:41])[C:45]([F:48])([F:47])[F:46])[CH3:12])=[O:14])[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3]1
Reactant: C[C@H](O)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2O[C@@H]1C
Reactant: NCC(F)(F)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2O[C@@H]1C
Reaction time: 8 h

Procedure:
In an inert atmosphere and under exclusion of moisture, a solution of 95 mg (0.34 mmol) of (S)—N-((6R,7S)-6,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2-hydroxy-propionamide in 1 ml of toluene was treated with 0.57 ml (0.41 mmol) of triethylamine and 70.9 mg (0.34 mmol) of 4-nitrophenyl chloroformate at room temperature. After stirring at room temperature during the weekend, 0.374 ml (0.34 mmol) of 2,2,3,3,3-pentafluoropropylamine were added and stirring was continued overnight. The solvent was removed by distillation and the crude product was chromatographed on silica gel using a gradient of a 1:3- to 3:1-mixture of ethyl acetate and heptane as the eluent. There were obtained 28 mg (18% of theory) of the title compound as a colourless oil, MS m/e (%): 454.4 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[O:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[O:36])=[CH:33][CH:32]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: NC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cc(-c3ccc(C(N)=O)cc3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 42.8 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (1.0 g mg, 2.3 mmol), 4-bromobenzamide (690 mg, 3.45 mmol) and cesium carbonate (2.25 g, 6.9 mmol) in water (6 mL) and N,N-dimethylformamide (20 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (88 mg, 0.12 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by column chromatography (7:3 hexanes/ethyl acetate to ethyl acetate, then ethyl acetate to 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to give 4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (423 mg, 43%) as a brown solid: ESI MS m/z 429 [M+H]+.