Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1)[CH3:2].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:31][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[C:9]1[O:10][CH2:11][C:12]([CH3:14])([CH3:15])[N:13]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCc1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(C2=NC(C)(C)CO2)c(F)c1
Temperature: -70 °C
Reaction time: 8 h
Yield: 94529.8 %

Procedure:
The 4-ethylphenyloxazoline (2.03 g, 10 mmol) was dried in a vacuum oven at 60° C. for 2-3 hours, dissolved in 50 mL of dry THF, and charged to a 300 mL round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stir bar. The mixture was cooled under nitrogen to −70° C. in a dry ice/acetone bath. Butyl lithium in hexane (7.5 mL, 0.012 mmol) was added in two portions and warmed to −25° C. over 2 hours. The mixture was cooled again to 65° C. and N-fluorobenzenesulfonimide (3.79 g, 0.012 mmol) was added in three portions. The mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was quenched with 100 mL of saturated NH4Cl, and transferred to a separatory funnel with ethyl ether washes. 25% NaOH was added slowly and mixed until an aqueous phase with pH=10 was achieved. The aqueous phase was extracted with ether and the ether was washed with a small volume of water. The ether extracts were dried over MgSO4 and evaporated to give 2.51 g of 2-(2-fluoro-4-ethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole as a brown oil. In a second experiment, a rate of 70% fluorination was achieved (highest) with a reactant ratio of 1:1.5:1.5 oxazoline: BuLi: N-fluorobenzenesulfonimide. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.0 (d, 2H), 7.78 (t, 1H), 4.1 (s, 2H), 2.7 (q, 2H), 1.39 (s, 6H), 1.2 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])=[CH:23][CH:22]=2)[CH:5]=[C:6]([C:8]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[OH-].[Li+].CO.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])=[CH:23][CH:22]=2)[CH:5]=[C:6]([C:8]2([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: CCOC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(=O)O)CCOCC3)c2)cc1
Temperature: 0 °C
Yield: 9.6 %

Procedure:
A stirred mixture of ethyl 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (Example 2) (1.10 g, 25 mmol), an aqueous solution of lithium hydroxide (0.13 g, 30 mmol, 5 ml), methanol (15 ml) and THF (15 ml) was refluxed for 24 hr. The reaction mixture was neutralized with 1N hydrogen chloride. Volatiles were removed by evaporation under reduced pressure. The residue was suspended into a mixture of water (20 ml) and phosphate buffer (pH=7, 5 ml) and heated to reflux for 30 min. After cooling to 0° C., solids were collected by filtration, washed with water and then with ether and dried to constant weight under vacuum at 80° C. for 14 hr to afford the titled compound as white solids (0.98 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=O)[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:5][C:4]=2[N:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:8]1[CH2:7][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: Cc1ccc2c(n1)CC(c1ccccc1C)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(n1)CC(c1ccccc1C)CC2=NNC(=N)N
Yield: 78 %

Procedure:
A mixture of 2-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.3 g), aminoguanidine hydrochloride (0.26 g), concentrated hydrochloric acid (0.12 ml), water (0.12 ml) and ethanol (30 ml) was refluxed for 2.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid (2.5 ml), and the solvent was evaporated. The residue was washed with ethanol to give 5-guanidinoimino-2-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 88) (0.32 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH3:23])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1.P(N)([NH2:34])(=O)OC1C=CC=CC=1.[OH-].[Na+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH3:23])[C:15]=3[N:14]=[C:13]([NH2:34])[C:12]=2[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCc2c1c1cccc(OC)c1[nH]c2=O
Reactant: NP(N)(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccccc1N1CCc2c(N)nc3c(OC)cccc3c21
Temperature: 230 °C
Yield: 24.1 %

Procedure:
1-(2-Methoxyphenyl)-4-oxo-6-methoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (1.5 g) and phenyl phosphorodiamidate (2.5 g) were fused at 230° C. After 45 minutes the mixture was diluted with diphenyl ether (10 ml), further phenyl phosphorodiamidate (2 g) added, and heated for a further 15minutes at 230° C. Aqueous sodium hydroxide was added and the product extracted into dichloromethane. Chromatography (silica gel. 2.5-4%methanolic ammonia in dichloromethane) to remove unchanged starting material was followed by recrystallisation from ethanol/ethyl acetate to yield 1-(2-methoxyphenyl)-4-amino-6-methoxy-2,3-dihydropyrrolo[3,2-c]quinoline (0.36 g), m.p. 244°-247° (dec).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]3[CH:22]=[N:23][CH:24]=[C:17]23)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>>[N+:6]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:16]1[CH2:21][CH2:20][CH2:19][N:18]2[CH:22]=[N:23][CH:24]=[C:17]12)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(C2CCCn3cncc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccccc1C1CCCn2cncc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
0.055 ml of sulphuric acid is added slowly dropwise at 0° C. to 0.046 ml of nitric acid. The nitrating acid is subsequently added slowly dropwise at 0° C. to 0.69 mmol of 8-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine. The reaction mixture is subsequently stirred at 0° C. for 5 minutes and then poured into ice-water. The aqueous phase is rendered neutral with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3×). The combined organic phases are dried over magnesium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as a brown wax. Rf=0.25 (dichloromethane/ammonia (2M in EtOH) 97:3), Rt=5.10 (Gradient I).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:18]>ClCCl.O1CCOCC1>[ClH:18].[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N1CCC(N)CC1

Procedure:
To a solution of O-tert-butyl N-(1-acetylpiperidin-4-yl)carbamate (2.42 g) in dichloromethane (24 ml) was added 4N hydrogen chloride in dioxane (24 ml). The solvents were removed under reduced pressure. After rinse with diisopropyl ether, 1-acetyl-4-aminopiperidine hydrochloride (2.02 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:31]3[CH2:36][CH2:35][S:34][CH2:33][CH2:32]3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: C1CSCCN1
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCSCC3)C2)cc1
Temperature: 150 °C

Procedure:
5.00 g (12.1 mmol) of 3-methyl 1-(4-nitrophenyl) 5-(4-ethylphenyl)piperidine-1,3-dicarboxylate (Example 30A), 3.57 g (36.4 mmol) of thiomorpholine and 5.03 g (36.4 mmol) of potassium carbonate were added to 76 ml of DMF and heated in 5 portions at 150° C. for 1.5 h in a single-mode microwave (Emrys Optimizer). For workup, the reaction solutions were combined and filtered, and the residue was purified by means of preparative HPLC. Yield: 3.07 g (67% of theory)
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C@@H:30]2[C@H:35]([NH2:36])[CH2:34][CH2:33][O:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C@@H:30]2[C@H:35]([NH:36][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([C:5]([N:4]([CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:8][CH:9]=3)[CH2:34][CH2:33][O:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20]
Reactant: CC(C)N(C(=O)c1ccc(C(=O)Cl)cc1)C(C)C
Reactant: CCOc1cc([C@H]2COCC[C@H]2N)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)N(C(C)C)C(C)C)cc2)ccc1OC
Reaction time: 2 h

Procedure:
A solution of 1 equivalent 4-diisopropylcarbamoyl-benzoyl chloride (prepared from N,N-diisopropyl-terephthalamic acid and thionyl chloride) in dichloromethane is added dropwise at RT in the course of 10 min. to a solution of 1 equivalent of (3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-ylamine in dichloromethane and 1.1 equivalents of triethylamine. After stirring for about 2 h, the mixture is extracted with saturated sodium hydrogencarbonate solution, and the organic phase is washed a further two times with water and dried over sodium sulfate. The viscous residue remaining after concentration is purified by column chromatography on SiO2 (dichloromethane/ethyl acetate 85/15 vol/vol). The main product fraction concentrated in vacuo affords a brownish solid foaming residue which is used for the next reaction step without further treatment.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19].[OH-].[Na+]>CO.O>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:8]2([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[NH:19]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: O=C(C(=O)c1ccccn1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccccn2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 1 -phenyl-2-(2-pyridinyl)ethanedione (800 mg, 3.79 mmol) and 2-guanidinobenzimidazole (560 mg, 3.15 mmol) in methanol (20 mL) was treated with a solution of sodium hydroxide (40 mg, 1.0 mmol) in 1 mL of water. The title compound was isolated as pale yellow crystals (160 mg, 20% yield). 1H NMR (300 z, d6 -DMSO) δ 12.0 (br. s, NH, 1H) 11.5 (br s, NH, 2 H), 10.0 (br s, NH, I H), 8.6 br s, NH, 1 H), 8A1 (m, 2 H), 7.55 (t, J=6.9 Hz, 2 H), 7.30-7.10 (m, 8 H), 6.98 (dd, J=6.0, 3.1 Hz, 4 H); MS (ESI) m/z 526 [M+H+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[NH:13][C:14]3[CH:20]=[C:19]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:17][C:15]=3[N:16]=2)[NH:8][C:7]=1[CH3:29])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:9]3[NH:8][C:7]([CH3:29])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=3[CH3:11])[NH:13][C:14]=2[CH:20]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1c(C)[nH]c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)c(C)c1C(=O)O
Temperature: 25 °C
Yield: 74.9 %

Procedure:
The 5-(5-benzoylbenzimidazole-2-yl)-2,4-dimethylpyrrole-3-carboxylic acid ethyl ester (200 mg) obtained in Example 53 (2) was dissolved in ethanol (5 ml) and tetrahydrofuran (5 ml). To this solution was added a 4 N sodium hydroxide aqueous solution (10 ml), and the mixture was heated under reflux for 12 hours. After the starting material was disappeared, the reaction mixture was allowed to cool to room temperature, and neutralized with a 1 N hydrochloric acid solution. The precipitate was collected by filtration to afford 5-(5-benzoylbenzimidazol-2-yl)-2,4-dimethylpyrrole-3-carboxylic acid (139 mg, 75%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[OH:16][CH2:17][C:18]#[C:19][C:20]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)=[O:21].Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([O:16][CH2:17][C:18]#[C:19][C:20](=[O:21])[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)=[O:7]
Reactant: COc1cc(C(=O)C#CCO)cc(OC)c1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)C#CCOC(=O)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC

Procedure:
2.21 g (9.59 mmol) of 3,4,5-trimethoxybenzoyl chloride in 10 ml of methylene chloride and 1 ml of pyridine were o added simultaneously at 0° to a solution of 2.0 g (7.99 mmol) of 4-hydroxy-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one in 25 ml of methylene chloride. The reaction mixture was stirred at 0° for 30 minutes and at room temperature for 1.5 hours, Whereupon 30 ml of 0.5M hydrochloric acid and 100 ml of methylene chloride were added and the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated, and the residue was chromatographed on silica gel with ether. After recrystallization from ethyl acetate/hexane there was obtained 3-(3,4,5-trimethoxybenzoyl)-2-propynyl 3,4,5-trimethoxybenzoate of melting point 106°-108°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:20][C:21]1[S:25][C:24]([CH:26]=O)=[CH:23][CH:22]=1>[OH-].[K+].CCO>[Cl:20][C:21]1[S:25][C:24]([CH:26]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:23][CH:22]=1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccc(Cl)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)s2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 77.7 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g, 0.98 mmol) was reacted with 5-chlorothiophene-2-carboxaldehyde (0.215 g, 1.47 mmol) in 5 mL of 4% KOH in EtOH to afford 0.293 g (77%) of the title compound as a coarse cream solid, mp 143-144° C.: APCI-MS m/e 385.5 (M+ +1); 1H-NMR (CDCl3): δ 8.03 (1H, d, J=8.5 Hz), 7.81 (1H, s), 7.65 (1H, s), 7.10 (1H, d, J=3.9 Hz), 7.06 (1H, s), 7.02 (1H, s), 6.91 (1H, d, J=3.9 Hz), 6.80 (1H, dd, J=8.5 Hz, J=2.5 Hz), 6.66 (1H, d, J=2.5 Hz), 4.36 (2H, m), 4.26 (2H, m), 3.05 (2H, m), 2.93 (2H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:21][C:18]1[CH:17]=[N:16][C:15]([NH:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ncc(Br)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cnc(NC2CCCNC2)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (˜0° C.) solution of 3-(5-bromo-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (850 mg) in dry DCM (10 mL) was added slowly TFA (0.911 mL). The reaction mixture was stirred at RT for 20 h, 5 eq more of TFA (0.911 mL) was added and the stirring was continued for 2 h. The reaction was concentrated in vacuo to yield the title compound as a bis-trifluoroacetate salt, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[CH:3]1[C:13]([OH:15])=[O:14].[C:17]([CH:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[CH:18]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([O:15][CH:19]([C:17]#[CH:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)=[O:14]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(/C=C\C(=O)OCCF)C1C(=O)O
Solvent: ClC(Cl)Cl
Product: C#CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCCF)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step F of Example 9, (IR, cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid and α-ethynyl-3-phenoxy-benzyl alcohol were reacted to obtain α-ethynyl-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-fluoroethoxy) -1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20= +47° ±1.5° (c=1% in CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([OH:15])=O.[Cl-].[Al+3].[Cl-].[Cl-]>S(Cl)(Cl)=O.O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]2[C:4]=1[CH2:11][CH2:12][C:13]2=[O:15]
Reactant: COc1c(C)cc(C)cc1CCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1c(C)cc(C)c2c1CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A solution of 3-(2-methoxy-3,5-dimethylphenyl)propionic acid (8.80 g, 42.2 mmol) in thionyl chloride (80 mL) was refluxed for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1,2-dichloroethane (100 mL). To this solution was added anhydrous aluminum chloride (5.80 g, 43.5 mmol) gradually at 0° C. and the mixture was stirred at room temperature for 1.0 hour. After completion of the reaction, the reaction mixture was poured in iced water and extracted with 1,2-dichloroethane. The organic layer was washed serially with 1N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 6.90 g of the title compound. Yield 86%. Oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[S:18]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1cnccn1
Product: CN(C)CCNC(=S)NCCNCc1cnccn1

Procedure:
By the procedure of Example 40(a), treating N-(2-pyrazinylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate gives the title compound.
Reaction SMILES: C([O-])(O)=O.[Na+].C(#[N:8])C.[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15](Cl)=[O:16])([O-:11])=[O:10]>O>[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15]([NH2:8])=[O:16])([O-:11])=[O:10]
Reactant: CC#N
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The L-malic salt (5 mg, 14 μm) was dissolved in a mixture of 1 ml H2O, 3.5 mg (3 meq) NaHCO3, and 1 ml acetonitrile and 3.2 mg (14 μm) of 3,5-dinitrobenzoyl chloride was added and the reaction stirred for 16 hr at room temperature. After 5 ml H2O was added, the reaction was vacuum filtered and washed with H2O (2×1 ml portions), cold isopropanol (2×1 ml portions) and diethyl ether (2×2 ml) to isolate 2.5 mg of the 3,5-dinitrobenzamide, "DBN", (85 area % by gradient reverse phase HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH:24]=[CH2:25].C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:25][CH2:24][CH:23]=[CH2:22])[C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCBr
Reactant: CN(C)C(=O)c1c(O)cccc1OCc1ccccc1
Agent: BrCc1ccccc1
Product: C=CCCOc1cccc(OCc2ccccc2)c1C(=O)N(C)C

Procedure:
The title compound is prepared analogously to Example 1, step B, from 2-benzyloxy-6-hydroxy-N,N-dimethylbenzamide (Example 13, step C) except using 4-bromo-but-1-ene to replace benzyl bromide.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH2:20][O:21][C:22]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=4[CH:24]=3)(=[O:18])=[O:17])[CH2:12][C:11]2=[O:30])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>ClCCl>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2[CH:24]=[C:19]([S:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][C:8]4[CH:7]=[CH:6][C:5]([C:2](=[NH:3])[NH:4][C:40]([O:41][CH3:42])=[O:43])=[CH:32][CH:31]=4)[C:11](=[O:30])[CH2:12]3)(=[O:18])=[O:17])[CH2:20][O:21][C:22]=2[CH:28]=1
Reactant: COC(=O)Cl
Reactant: N=C(N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC(=N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1-(4-amidinobenzyl)-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone hydrochloride (99 mg) and triethylamine (0.084 ml) in dichloromethane (10 ml) was added dropwise a solution of methyl chlorocarbonate (0.023 g) in dichloromethane (2 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with dichloromethane, washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated. Precipitated crystals were washed with ether to give colorless crystals of the title compound (95 mg).