Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17](C=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][CH:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)[CH2:19][CH2:18]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=CC1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Reactant: NC1CCCCC1
Product: c1cc(N2CCC(NC3CCCCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 18 and cyclohexylamine.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To 3.44 g (187 mmol) (S)-1-Boc-3-pyrrolidinol in 15 ml THF are added 1.70 mL (21.6 mmol) of methanesulfonyl chloride at 0° C. The reaction mixture is stirred for 1 h. Water is added and it is extracted with EtOAc (3×). The organic layer is washed with an aq. NaHCO3 solution and dried over MgSO4. The solvent is removed in vacuo.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:6][CH:5]=1)([O-])=O.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([O:14][C@H:15]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]3)=[CH:6][CH:5]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])c3ccccc23)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(NS(=O)(=O)c3ccc(Cl)cc3)c3ccccc23)C1
Yield: 50.8 %

Procedure:
The compound was prepared from tert-butyl (3S)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (0.3 g, 0.9 mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield: 0.23 g (50%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (d, J=4.52 Hz, 9H) 2.15-2-34 (m, 2H) 3.54-3.74 (m, 4H) 5.05 (br s, 1H) 6.62-6.71 (m, 2H) 7.17-7.23 (m, 1H) 7.33 (d, J=8.53 Hz, 1H) 7.39-7.43 (m, 2H) 7.62-7.64 (m, 2H) 7.65-7.70 (m, J=6.02 Hz, 1H) 8.18 (d, J=8.53 Hz, 1H) MS (ESI+) for C25H27ClN2O5S m/z 520.2 (M+NH4)+, 447.0 (M−tBu)+. HPLC 100%, RT=2.772 min (System A1, 10-97% MeCN over 3 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: C=CCC(C)Oc1ccc(F)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C)Oc1ccc(F)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of methyl 5-fluoro-2-(pent-4-en-2-yloxy)benzoate (1.00 g, 4.20 mmol) in THF (10 mL) cooled to 0° C. was added dropwise lithium aluminum hydride (5.04 ml, 5.04 mmol) over 30 min. The resulting mixture was stirred at rt for 2 h. The reaction was diluted with 2 mL THF and cooled to 0° C. and quenched by the dropwise addition of brine. The mixture was further diluted with 5 mL EtOAc and the organic phase was decanted off, dried (Na2SO4), filtered and concentrated to give (5-fluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.80 g, 3.81 mmol, 91% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.04 (dd, J=8.7, 3.1 Hz, 1H), 6.93 (td, J=8.5, 3.1 Hz, 1H), 6.82 (dd, J=8.9, 4.3 Hz, 1H), 5.86 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.25-5.06 (m, 2H), 4.75-4.54 (m, 2H), 4.54-4.38 (m, 1H), 2.51 (dt, J=13.9, 6.7 Hz, 2H), 1.42-1.31 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([F:25])[CH:19]=1>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=2[OH:1])=[C:20]([F:25])[CH:19]=1
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: Nc1ccc(Cl)cc1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoic acid (1.68 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 4-chloro-2-fluorobenzenamine (1.1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1([CH2:22][CH3:23])[CH:11]([OH:12])[C:10](=[O:13])[N:9]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:8]1)=[O:6].[CH3:24]I.[NH4+].[Cl-]>C1COCC1>[CH3:3][O:4][C:5]([C:7]1([CH2:22][CH3:23])[CH:11]([O:12][CH3:24])[C:10](=[O:13])[N:9]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:8]1)=[O:6]
Reactant: CI
Reactant: CCC1(C(=O)OC)CN(c2c(C)cccc2C)C(=O)C1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1(C(=O)OC)CN(c2c(C)cccc2C)C(=O)C1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.8 %

Procedure:
NaH (60% dispersed in mineral oil, 50 mg, ˜2.0 mmol) was added slowly to a cooled (0° C.) solution of 1-(2,6-dimethylphenyl)-3-ethyl-4-hydroxy-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step b, 146 mg, 0.5 mmol) in THF (5 mL). After stirring for 5 min, MeI (62.5 μL, 1 mmol) was added and the resulting reaction mixture was slowly warmed to room temperature and stirred further for 12 h. Saturated aqueous NH4Cl solution (10 mL) was added, and the solution was extracted with EtOAc (3×25 mL). The combined organic layer were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2, 10→50% EtOAc/hexanes) to give 1-(2,6-dimethylphenyl)-3-ethyl-4-methoxy-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (70 mg, 46% yield). LC-MS: Rt (retention time): 2.31, 2.44 min (two diastereomers), MS: (ES) m/z 306.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: CCO
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
5,6-Dichloronicotinic acid (4.90 g) was dissolved in ethanol (40 mL), and thionyl chloride (2.0 mL) was added thereto under ice-cooling. The mixture was refluxed for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give ethyl 5,6-dichloronicotinate (4.85 g) as a white solid.
Reaction SMILES: [P](I)I.Cl[C:5]1[N:6]=[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[N:22]=1.I>>[NH:23]([C:7]1[C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[N:22]=[CH:5][N:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1nc(Nc2ccccc2)c2nc(Cl)nc(Nc3ccccc3)c2n1
Agent: I
Agent: I[P]I
Product: c1ccc(Nc2ncnc3c(Nc4ccccc4)ncnc23)cc1
Reaction time: 1 h

Procedure:
12 gm. of phosphorus diiodide (P2I4) were added in small portions to a suspension, heated on a steam bath, of 3.8 gm. (0.01) 2,6-dichloro-4,8-dianilino pyrimido-pyrimidine in 40 cc. hydrogen iodide (d=1.7) in the course of about half an hour. Heating was continued for one hour. The mixture was then cooled and the precipitated crystals were filtered off on a vacuum filter. The precipitate was extracted with 200 cc. of hot dioxane. 2.8 gm. of red, brilliant rhombic crystals remained after extraction. The yield was about 90% of the theoretical yield. The crystals were twice recrystallized from dimethyl formamide, whereby very slightly yellowish, small needles having a melting point of 255-256° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC>O>[NH2:16][CH2:15][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncccc1OCc1ccccc1
Agent: CNC
Solvent: O
Product: NCc1ncccc1OCc1ccccc1

Procedure:
Heat 75 gm of 3-benzyloxy-2-phthalimidomethylpyridine under reflux for one hour in 550 ml of a 40% aqueous dimethylamine solution. Cool the resulting reaction mixture to room temperature, then dilute it with 550 ml water and extract with dichloromethane. Wash the dichloromethane extract with brine and dry over anhydrous sodium sulfate. Filter the dried reaction mixture and remove the solvent dichloromethane from the filtrate under reduced pressure, yielding 2-aminomethyl-3-phenylmethoxypyridine, BP 145°-155°/0.5 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1[OH:20].B(F)(F)F.CCOCC>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:18]1[CH:19]=[C:13]([Cl:12])[C:14]([OH:20])=[CH:15][C:16]=1[OH:17])=[O:11]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C(O)Cc1ccccc1Br
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(Cc1ccccc1Br)c1cc(Cl)c(O)cc1O
Reaction time: 2 h

Procedure:
This compounds was synthesised in the same manner as described above. 2-Bromophenylacetic acid (5 g, 23.3 mmol), 4-chlororesorcinol (3.36 g, 23.3 mmol), boron trifloride etherate (20 ml). After standing for two hours a brown precipitate formed (7.4 g, 93.3%); Rf 0.4 hexane/ethyl acetate (70/30). This was shown to be the required product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][C:25]([NH2:27])=[O:26].O>O1CCCC1>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH2:24][C:25]([NH2:27])=[O:26])[C:11]3=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2cc(OCc3ccc(F)cc3)ccc21
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
A mixture of 5-(4-fluoro-benzyloxy)-isoindole-1,3-dione (100 mg, 0.37 mmol), sodium hydride (55% in mineral oil, 18 mg, 0.42 mmol) and 2-bromoacetamide (61 mg, 0.44 mmol) in dry tetrahydrofuran (5 mL) at 0° C. was stirred at room temperature for 3 h and then heated at 50° C. for 1 h. After cooling to 0° C., water (2 mL) was added and the product extracted with ethyl acetate. The organic extracts were then washed with brine and dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, heptane-CH2Cl2 2:3 then CH2Cl2— 2N NH3-MeOH 99:1: to 4:1) to afford the title compound (78 mg, 65%) as a white solid.
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15](N2N=CC=N2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[CH3:32][C@:33]1(NC2C=NC(C(F)(F)F)=CN=2)[CH2:37]CC[C@@H]1N.C1(C2C(C(O)=O)=NC=CC=2)CC1.C(N(CC)CC)C>>[CH:37]1([C:15]2[C:10]([C:8]([NH:7][C@H:3]3[CH2:4][CH2:5][CH2:6][C@:2]3([CH3:1])[NH:21][C:22]3[CH:27]=[N:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][N:23]=3)=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:33][CH2:32]1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Agent: O=C(O)c1ncccc1C1CC1
Solvent: CCN(CC)CC
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1C1CC1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 48 mg, 0.15 mmol), 3-cyclopropylpyridine-2-carboxylic acid (Intermediate 16; 33 mg, 0.20 mmol) and triethylamine (0.077 ml, 0.55 mmol) except this was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) followed by column chromatography (silica, 0-2.5% methanol/DCM) to afford the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.CCOC(C)=O.CCCCCCC>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4F)c3c2CC1
Yield: 42.9 %

Procedure:
A mixture of 3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.738 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium (0.23 g, 0.20 mmol) in dimethoxyethane (5.0 mL) and a solution of 2-fluorophenylboronic acid (0.336 g, 2.4 mmol) in dimethoxyethane (5.0 mL) and sodium carbonate (2 M, 7.0 mL) were reacted in a manner similar to Preparation 1. Column chromatography (silica gel, 20-50% EtOAc/heptane) afforded 0.33 g (43%) of the title compound as a solid: mp 241-244° C.; 1H NMR (400 MHz, CDCl3) δ 8.20, 8.04, 7.31, 7.15, 7.04, 3.96, 3.83, 3.62, 3.42, 3.14, 2.84, 2.71-2.69, 2.47, 2.31; IR (drift) 3236, 1603, 1501, 1485, 1469, 1456, 1434, 1249, 1217, 795, 786, 759, 746, 733, 706 cm−1; MS (EI) m/z 384 (M+); HRMS (FAB) calcd for C25H21FN2O+H: 385.1716, found: 385.1721; Anal. Calcd for C25H21FN2O: C, 78.10; H, 5.51; N, 7.29. Found: C, 77.61; H, 5.60; N, 7.14.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:3]1=2.[OH-].[Na+]>>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:27][C:4]2[C:3]3[C:2]([CH3:1])([CH3:36])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(C#C[Se]c2cc(OCc3ccc(Cl)cc3)c3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2c(OCc3ccc(Cl)cc3)cc([Se]C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
In a manner similar to that of Example 1g, by reacting 300 mg (0.5 mmol) of methyl 4-[5,5,8,8-tetramethyl-4-(4-chlorobenzyloxy)-5,6,7,8-tetrahydro-2-naphthylselanylethynyl]benzoate with 110 mg of sodium hydroxide. A white crystallized solid is obtained (m=210 mg; yield=72%, m.p.=255° C.).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=3)[CH:18]=2)[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Sn](Cl)Cl>>[NH2:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][O:23][C:19]1[CH:18]=[C:17]([CH:12]([CH2:11][NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:13]([O:15][CH3:16])=[O:14])[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C(CNS(=O)(=O)c1ccccc1)c1cccc(OCc2cccc([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Product: COC(=O)C(CNS(=O)(=O)c1ccccc1)c1cccc(OCc2cccc(N)c2)c1

Procedure:
Corresponding to Example 3d, 442 mg of (8e) were treated with tin-(II) chloride. A yellowish solid was obtained (yield: 387 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][NH:12][C:11]1=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:11]1=[O:21]
Reactant: O=c1[nH]cc(-c2ccccc2)n1Cc1ccccc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(Cc2ccccc2)c1=O

Procedure:
The product is produced as described in example 1 from 1.8 g of NaH (80% suspension in mineral oil), 15 g of 1-benzyl-5-phenyl-4-imidazolin-2-one, 120 cc. of DMF, 14.2 g of 8-bromocaprylic acid methyl ester and 1.8 g of NaJ.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1)=O.CC(C[AlH]CC(C)C)C>ClCCl.CCCCCC>[OH:2][CH2:3][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: COC(=O)c1coc2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: OCc1coc2ccccc12
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a stirring solution of 650 mg (3.69 mmol) of Benzofuran-3-carboxylic acid methyl ester, prepared as in Intermediate 18, in 25 mL dichloromethane at -78° C. is added dropwise over 5 min a solution of 9.22 mL (9.22 mmol, 2.5 equiv) of a 1.0M solution of DIBAL-H in hexane. The resulting solution is allowed to slowly warm to RT over a 4 h period then quenched by careful addition of 5 mL of H2O. The reaction mixture is poured into 100 mL of EtOAc and extracted with 1N HCl (1×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent afforded 444 mg of the title compound as a pale yellow oil: 1H NMR (CDCl3, 300 MHz) δ7.66 (d, 1H), 7.60 (s, 1H), 7.49 (d, 1H), 7.29 (m, 2H), 4.82 (d, 2H), 1.70 (m, 1H); Rf =0.17 in hexane/EtOAc 5/1.
Reaction SMILES: [N+:1]([C:4]1[C:13]([OH:14])=[CH:12]C=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1C(OC)=O)([O-:3])=[O:2].[C:19]([O:22][CH2:23]C)(=[O:21])[CH3:20].C(Cl)Cl>>[OH:14][C:13]1[CH:12]=[C:20]([C:19]([O:22][CH3:23])=[O:21])[C:6](=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1C(=O)OC
Solvent: ClCCl
Product: COC(=O)c1cc(O)c([N+](=O)[O-])cc1C(=O)OC

Procedure:
A mixture of dimethyl 4-hydroxyphthalate (25.0 g, 0.119 mol) and concentrated sulfuric acid at 0°-5° C., is treated dropwise with nitric acid (90%, 6.10 mL, 0.142 mo)), stirred for 10 minutes, poured into ice water and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated in vacuo to give the title product mixture as a viscous yellow oil, 29.7 g (98.0%), identified by NMR spectral analysis. Flash chromatography (silical gel, 2% ethyl acetate/methylene chloride) of the mixture gives dimethyl 4-hydroxy-5-nitrophthalate as a yellow solid 3.70 g, mp 82°-85° C. and dimethyl 3-nitro-4-hydroxyphthalate as a pale yellow solid, 3.80 g, mp 108°-111° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.[C:34]([C@H:38]([O:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49](=[O:53])[CH:50]([NH2:52])[CH3:51])[CH2:45][CH2:44]1)[C:39]([OH:41])=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C)CCCN=C=NCC>CN(C)C=O>[C:34]([C@H:38]([O:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49](=[O:53])[CH:50]([NH:52][C:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:3]([NH2:2])=[N:4][CH:5]=[CH:6]3)=[O:15])[CH3:51])[CH2:45][CH2:44]1)[C:39]([OH:41])=[O:40])([CH3:36])([CH3:35])[CH3:37]
Reactant: Nc1nccc2cc(C(=O)O)ccc12
Reactant: CC(N)C(=O)N1CCC(O[C@H](C(=O)O)C(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc2c(N)nccc2c1)C(=O)N1CCC(O[C@H](C(=O)O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.3 %

Procedure:
To a solution of 0.33 g (1-amino-6-isoquinolinyl)carboxylic acid hydrochloride in 20 mL of N,N-dimethylformamide were added 0.34 g hydroxybenztriazole, 0.504 mL N-methylmorpholine, 0.525 g tert-butyl (S)-[[1-(2-amino-1-oxopropyl)piperidin-4-yl]oxy]acetic acid hydrochloride and 0.425 g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide After stirring at room temperature for three days the mixture was concentrated. Dichloromethane and 1% aqueous sodium hydrogencarbonate were added to the residue and the organic layer was separated. The aqueous layer was washed four times with dichloromethane, the combined organic layers dried (sodium sulfate) and concentrated. The residue was purified by chromatography (silica gel, dichloromethane/methanol: 10/1 v/v followed by a purification using silica gel, ethyl acetate/methanol: 10/1 v/v) to give 0.619 g of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH2:15])[CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@H:13]([NH:15][C:23]2[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:14]1
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The crude amine from step 1, cesium carbonate (2.500 g, 1.535 mmol), 2-chloro-3-nitropyridine (394 mg, 2.488 mmol), and dry dimethylsulfoxide (5 mL) were added and the reaction mixture was stirred at 120° C. for 2 hours. The reaction was cooled and partitioned between water (100 mL), saturated sodium bicarbonate (20 mL) and ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-nitropyridin-2-yl)cyclobutane-1,3-diamine (580 mg, 1.699 mmol, 75% yield) as light-yellow solid.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH2:43][CH2:44][O:45][CH3:46])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCNC(=O)CCl
Product: CCN(Cc1ccc(OCCNCCOC)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 13.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methoxyethyl)acetamide (14 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (3.5 mg) was obtained.