Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:18])[S:5]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=1[CH3:17])(=[O:7])=[O:6].[CH3:19]I>CN(C)C=O>[CH3:18][N:4]([CH3:3])[S:5]([C:8]1[S:12][C:11]([N:13]([CH3:19])[C:14](=[O:16])[CH3:15])=[N:10][C:9]=1[CH3:17])(=[O:6])=[O:7]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)N(C)C)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1nc(C)c(S(=O)(=O)N(C)C)s1
Reaction time: 16 h
Yield: 81.6 %

Procedure:
6.0 g of sodium hydride (60% dispersion in mineral oil, 0.151 mol) were added dropwise at 0° C. to a solution of 36.2 g (0.137 mol) of N-{5-[(dimethylamino)-sulphonyl]-4-methyl-1,3-thiazol-2-yl}acetamide in dimethylformamide. Then 21.4 g (0.151 mol) of methyl iodide were added dropwise from a syringe. After TLC showed complete conversion, the mixture was quenched by adding a saturated ammonium chloride solution. The mixture was evaporated to dryness, and the residue was taken up with water, stirred for 16 h and filtered off. After the residue had been dried in vacuo it was further purified by chromotography on silica gel with toluene/ethyl acetate (15-66% ethyl acetate) as mobile phase. 31.0 g of a white powder were obtained (Rf=0.43 (toluene/ethyl acetate=1/2), yield 74%).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2([NH:14][C:15]([NH:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[CH2:12][CH2:11][CH2:10][CH:9]=[C:8]2[N:17]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:15](=[O:16])[NH:14]3)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)NC1(Cc2ccc(Br)cc2)CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C1NC2(Cc3ccc(Br)cc3)CCCC=C2N1c1cc(Cl)cc(Cl)c1
Yield: 66.8 %

Procedure:
A suspension of 1-[1-(4-bromo-benzyl)-2-oxocyclohexyl]-3-(3,5-dichlorophenyl)-urea (5.0 g) (0.0106 mol), K2CO3 (3.1 g) (2.1 eq) and molecular sieves 4A (15 g) in xylene (700 ml) was refluxed for 8 h. After cooling, the reaction mixture was filtered on paper, concentrated in vacuo, and the residue purified on SiO2 chromatography (eluent EtOAc/Cyclohexane-3/7) to yield 3a-(4-Bromo-benzyl)-1-(3,5-dichlorophenyl)-1,3,3a,4,5,6-hexahydro-benzimidazol-2-one (3.2 g) as a white solid. 1H NMR (CDCl3): 7.45 (2H, d), 7.20 (1H, m), 7.15 (2H, d), 7.05 (2H, m), 4.95 (1H, m), 3.0 (1H, d), 2.90 (1H, d), 2.5-2.1 (2H, m), 2.1-1.8 (3H, m), 1.8-1.6 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)=[C:4]([F:19])[CH:3]=1.[Cl-].[NH4+]>CO.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([NH2:16])[CH:9]=2)=[C:4]([F:19])[CH:3]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2F)cc1N
Temperature: 25 °C
Yield: 96 %

Procedure:
4′-chloro-4-ethyl-2′-fluoro-3-nitrobiphenyl (1.795 g, 6.45 mmol) is suspended in a mixture of methanol (20 ml) and water (4 ml). To this mixture is added zinc dust (2.95 g, 45 mmol) and a solution of ammonium chloride (1.04 g, 19 mmol) in water (4 ml), and once the addition is complete the mixture is heated at reflux for 3 hours. The mixture is cooled to room temperature, and filtered through a plug of diatomaceous earth. The filtrate is partitioned between ethyl acetate and water, and the organic extract is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 4′-chloro-4-ethyl-2′-fluorobiphen-3-ylamine (1.546 g), used without further purification in the next step.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:20])=[N:11][CH:12]=[C:13]([C:15]([F:18])(F)F)[CH:14]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>CN(C)C=O>[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=2)=[N:11][CH:12]=[C:13]([CH2:15][F:18])[CH:14]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)C(N)c1ncc(C(F)(F)F)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(OC)c(OC)c1)c1ncc(CF)cc1Cl

Procedure:
Triethylamine (0.28 ml) was added to a solution of ethyl 2-(3-chloro-5trifluoromethyl-2-pyridyl)glycinate (1 g; prepared in a similar manner to the starting material for Example 3) in dimethylformamide (10 ml) with stirring followed by 3,4-dimethoxybenzoyl chloride (0.70 g), the mixture was stirred for 45 minutes and evaporated. The residue was extracted with ethyl acetate and the extracts worked up to give the title product, m.p. 40-3° C. (Compound 601)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:30]([O-:32])=[O:31])[C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:30]([O-:32])=[O:31])[C:27]=1[O:28][CH3:29])[C:22]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:23]
Reactant: NCCc1ccccc1
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NCCc2ccccc2)cc([N+](=O)[O-])c1OC

Procedure:
A solution of 1.49 g of 2-phenylethylamine in 100 ml of methylene chloride is treated with 1.26 g of triethylamine. A solution of 3.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 100 ml of methylene chloride is added dropwise thereto while stirring, whereupon the mixture is stirred for a further 15 minutes. The organic phase is then extracted twice with 50 ml of ice-water each time, dried over sodium sulfate and evaporated in a water-jet vacuum. After recrystallization from methylene chloride/n-hexane there is obtained 3,4-dimethoxy-5-nitro-N-phenethylbenzamide in the form of pale beige needles of m.p. 121°-122°.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1.O>C(#N)C>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][NH:3][CH2:1][CH3:2])=[CH:9][CH:10]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCN
Solvent: O
Solvent: CC#N
Product: CCNCc1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
65-70% ethylamine solution (70 g, 1 mol), acetonitrile 50 mL were added into a three necked round bottom flask mounted with pressure-equalizing dropping funnel and thermometer. The solution was stirred in ice bath for 15 min to control the temperature near 0° C. Then, 2-chloro-5-(chloromethyl)pyridine (16.10 g, 0.10 mol) in 25 ml acetonitrile was added by pressure-equalizing dropping funnel in 3.5 hrs with a speed of 3 drop/min. After completion, water was added and the reaction mixture was extracted with DCM. The organic phase was collected, thereby obtaining 14 g N-((6-chloropyridin-3-yl)methyl)ethanamine as oil with 70% yield. GC-MS: m/z (%)=170 ([M]+, 20), 155 (80), 126 (100), 114 (10), 90 (12).
Reaction SMILES: C(O[N:6]([C:10]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:12][CH:11]=1)[C:7](C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:7][NH:6][C:10]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(N(OC(C)(C)C)C(C)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cccc(NC)n1
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a solution of ethyl 2-{6-[(tert-butoxy)-N-methylcarbonylamino]-2-pyridyl}acetate (3.56 g, 12.1 mmol) in dichloromethane (15 ml) was added trifluoroacetic acid (8 ml). The reaction was stirred for 16 h. The solvent was removed under vacuum and the crude product was chromatographed over silica gel to yield 2.2 g (100%) of Ethyl 2-[6-(methylamino)-2-pyridyl]acetate.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[NH2:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:23][C:24]45[CH2:33][CH:28]6[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]6)[CH2:25]4)[CH2:31]5)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)NC12CC3CC(CC(O)(C3)C1)C2
Yield: 91.5 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and 3-aminoadamantan-1-ol hydrate (0.129 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(3-hydroxyadamantan-1-yl)acetamide as a white solid (0.275 g, 90.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14]2)=O)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C([O-])=O.[NH4+:34]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:34]=[C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14]3)[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1cccc(Cl)c1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: Clc1cccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)c1
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 96.3 %

Procedure:
A mixture of N-[2-(3-chlorophenyl)-2-oxoethyl]-4-(phenylmethyl)-2-morpholinecarboxamide (350 mg, 0.939 mmol) and ammonium trifluoroacetate (615 mg, 4.69 mmol) was stirred for 2.5 hours at 150° C. Water (150 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (200 mL). The organic phase was dried (Na2SO4), filtered, and concentrated to afford the title compound (320 mg) as a brown oil. LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].[CH2:23]([O:25][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27])[CH3:24].[Sn]>C1(C)C=CC=CC=1.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>[CH2:26]([O:25][C:23]([C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8])=[CH2:24])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Sn]
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(OC[C@@H]2CCCN2)cnc1Cl
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (500 mg, 1.28 mmol) in toluene (10.0 mL) was added (1-ethoxyvinyl)tributyltin (489 mL, 1.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.-45 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with hexane/EtOAc 2:1 and 1:1 to afford an oil (568 mg, >100%; some tin reagent contamination). MS (CI/NH3) m/z 383 (M+H)+. 1H NMR (CDCl3, 300 MHz)δ 1.25-1.45 (m, 3H), 1.47 (s, 9H), 1.55-1.71 (m, 1H), 1.98-2.07 (m, 3H), 3.32-3.45 (m, 1H), 3.87-3.96 (m, 2H), 4.05-4.21 (m, 3H), 4.43-4.47 (m, 2H), 7.26-7.34 (m, 1H), 8.03-8.06 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S([Cl:35])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:35][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCN(Cc1ccccc1)Cc1ccoc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCCN(Cc1ccccc1)Cc1ccoc1
Yield: 77.2 %

Procedure:
2-(Benzyl-(3-furylmethyl)amino)ethanol (6.5 g, 28 mmol), triethylamine (5.9 ml, 42 mmol), 4-dimethylaminopyridine (250 mg, 2.1 mmol) and tosyl chloride (6.4 g, 34 mmol) were stirred at room temperature for 17 hours in dichloromethane (260 ml). The reaction solution was mixed with dichloromethane, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 5.4 g of crude 1-chloro-2-(benzyl-(3-furylmethyl)amino)ethane. The crude 1-chloro-2-(benzyl-(3-furylmethyl)amino)ethane (1.8 g) was dissolved in anhydrous tetrahydrofuran (35 ml) and cooled to 0° C. In an atmosphere of argon, n-butyl lithium hexane solution (14 mmol) was added thereto to carry out 2 hours of the reaction at room temperature. The reaction solution was mixed with 1 N sodium hydroxide aqueous solution, the reaction product was extracted with dichloromethane, and then the organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 1.1 g (5.1 mmol, 73% in yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Cl.Cl[C:18]1[N:19]([C:23]2[CH2:27][CH2:26][CH2:25][N:24]=2)[CH2:20][CH2:21][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:18]3[N:19]([C:23]4[CH2:27][CH2:26][CH2:25][N:24]=4)[CH2:20][CH2:21][CH:22]=3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Clc1ccc2c(c1)Oc1ccccc1N2
Reactant: ClC1=CCCN1C1=NCCC1
Agent: Cl
Product: Clc1ccc2c(c1)Oc1ccccc1N2C1=CCCN1C1=NCCC1

Procedure:
Reaction of 3-chlorophenoxazine with 2-chloro-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 3-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOXAZINE HYDROCHLORIDE, m.p. 262.5°-270° C. (dec.) (corr.), from ethanol-ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].Cl.N1C=CC=CC=1>CC(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Yield: 74.9 %

Procedure:
A stirred mixture of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile (10.7 g, 40 mmol), 3-chloro-4-fluoroaniline (7.0 g, 48 mmol), pyridine hydrochloride (4.6 g, 40 mmol), and 200 ml of 2-propanol was heated to reflux temperature and maintained for 1 h. The 2-propanol was evaporated off, and the residue was stirred in water with potassium bicarbonate (pH˜8). The resulting solid was filtered, washed with water and 5:1 hexane-DCM, and dried. Recrystallization from EtOH gave 11.3 g of yellow solid, mp 259-263°; ms 377.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[O:4][N:3]=1.[I:12]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[I:12][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)Cc1cc(C)no1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1onc(C)c1I
Temperature: 65 °C
Yield: 72.4 %

Procedure:
To a sealed tube fitted with magnetic stirrer was charged methyl (3-methyl-1,2-oxazol-5-yl)acetate (0.9 g, 5.8 mmol) and N-iodosuccinimide (2.61 g, 11.6 mmol) in 10 mL trifluoroacetic acid. The reaction mixture was heated at 65° C. for 3 h. The RM was quenched with NaHCO3 solution (25 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (30 mL) and saturated brine solution (30 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown solid (1.18 g, yield: 72.4%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:8])=[N:4][S:5][C:6]=1[Cl:7].C(=O)([O-])[O-].[K+].[K+].[CH2:15](I)[CH3:16].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:8][CH2:15][CH3:16])=[N:4][S:5][C:6]=1[Cl:7]
Reactant: Oc1nsc(Cl)c1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nsc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
To a mixture of 4,5-dichloro-3-hydroxyisothiazole (17.00 g, 0.100 mol) and potassium carbonate (13.82 g, 0.100 mol) in dry DMF (80 ml) was added dropwise a solution of ethyl iodide (8.84 ml, 0.110 mol) in dry DMF (20 ml). The mixture was stirred 18 hours at ambient temperature. Water (500 ml) was added and the mixture was extracted with ether (3×400 ml). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product (18.35 g). The crude product was distilled to give 4,5-dichloro-3-ethoxyisothiazole (14.63 g, 74%, b.p. 64°-66°/0.1 mm). TLC (2% methanol/chloroform, silica): Rf=0.72.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55](=[O:59])[CH:56]([NH2:58])[CH3:57])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:41]1[C:42]2[C:37](=[N:36][C:35]3[C:44]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55]([CH:56]([NH:58][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:57])=[O:59])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:38]=[CH:39][CH:40]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)cc1C(=O)O
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 47.8 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dichlorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1nc2cccc([N+](=O)[O-])c2n1
Reactant: FCc1cccc(Br)n1
Product: O=[N+]([O-])c1cccc2nn(CCC#Cc3cccc(CF)n3)nc12
Yield: 40909.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (92 mg, 0.48 mmol) and 2-but-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole (95 mg, 0.44 mmol, Example, 160(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 59 mg (0.18 mol, 42%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-nitro-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>C(O)C>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCc1ccc(F)cc1F
Solvent: CCO
Product: O[C@H](CNCc1ccc(F)cc1F)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 2,4-difluorobenzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=96%, [M+H]+=429.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[C:11]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10][CH:9]=1.Cl[CH2:29][C:30]1[CH:49]=[CH:48][C:33]([O:34][CH2:35][C:36]2[N:37]=[C:38]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:39][C:40]=2[CH3:41])=[C:32]([O:50][CH3:51])[CH:31]=1>O>[CH3:51][O:50][C:32]1[CH:31]=[C:30]([CH:49]=[CH:48][C:33]=1[O:34][CH2:35][C:36]1[N:37]=[C:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:39][C:40]=1[CH3:41])[CH2:29][N:19]1[C:20]2[CH:8]=[CH:9][CH:10]=[C:11]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:12]=2[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCOC(=O)COc1cccc2[nH]c3ccccc3c12
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
18 mg of sodium hydride (60%) was added to N,N-dimethylformamide (5 mL) solution of 107 mg of ethyl 2-(9H-carbazole-4-yloxy)acetate, and stirred at room temperature for 20 minutes. Thereafter, 144 mg of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole was added thereto, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The combined extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was crystallized from methanol, isolated by filtration, and washed with methanol. The residue was dried under reduced pressure, and 107 mg of the subject compound was prepared as white crystal.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]([N:14]([CH2:18][C:19]1[CH:20]=[C:21]([CH:54]=[CH:55][CH:56]=1)[C:22]([NH:24][C:25]1[S:26][C:27]2[CH2:53][CH2:52][CH2:51][CH2:50][C:28]=2[C:29]=1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([C:45]([OH:47])=[O:46])=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)=[O:31])=[O:23])[CH:15]([CH3:17])[CH3:16])=[O:13])([O:6]CC)=[O:5])[CH3:2].Br[Si](C)(C)C.C(Cl)(Cl)Cl>O>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][C:12]([N:14]([CH2:18][C:19]1[CH:20]=[C:21]([CH:54]=[CH:55][CH:56]=1)[C:22]([NH:24][C:25]1[S:26][C:27]2[CH2:53][CH2:52][CH2:51][CH2:50][C:28]=2[C:29]=1[C:30]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:45]([OH:47])=[O:46])=[CH:48][CH:49]=2)=[CH:37][CH:38]=1)=[O:31])=[O:23])[CH:15]([CH3:17])[CH3:16])=[O:13])([OH:6])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCC(=O)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1)C(C)C)OCC
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOP(=O)(O)CCCC(=O)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A mixture of 180 mg of 4-[2-(4-{[(2-{[3-({[4-(diethoxyphosphoryl)butanoyl](isopropyl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoic acid, 0.040 mL of bromotrimethylsilane, and 3.6 mL of chloroform was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 42 mg of 4-(2-{4-[({2-[(3-{[{4-[ethoxy(hydroxy)phosphoryl]butanoyl}(isopropyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoic acid.