Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[CH:15]3[CH2:19][C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[NH:25][C:26]1[N:31]=[C:30]([N:32]([CH:42]2[CH2:44][CH2:43]2)CC2C=CC(OC)=CC=2)[C:29]2=[N:45][CH:46]=[C:47]([C:48]#[N:49])[N:28]2[N:27]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]([CH3:22])[CH:15]3[CH2:19][C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[CH2:12][CH2:13]2)=[CH:6][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[NH:25][C:26]1[N:31]=[C:30]([NH:32][CH:42]2[CH2:44][CH2:43]2)[C:29]2=[N:45][CH:46]=[C:47]([C:48]#[N:49])[N:28]2[N:27]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(N(C)C5CC(=O)N(C)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CN1CC(N(C)C2CCN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.2 %

Procedure:
To a round bottom flask charged with 2-((2-chloro-5-cyano-3-(4-(methyl(1-methyl-5-oxopyrrolidin-3-yl)amino)piperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (36.1 mg, 0.053 mmol) in dichloromethane (265 μl) was added anisole (28.9 μl, 0.265 mmol) and trifluoroacetic acid (204 μl, 2.65 mmol). The reaction mixture was stirred at room temperature ON. Excess TFA was removed by concentration in vacuo. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-100% B over 20 minutes, then a 0-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. 2-((2-Chloro-5-cyano-3-(4-(methyl(1-methyl-5-oxopyrrolidin-3-yl)amino)piperidin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (4.5 mg) was isolated.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][CH:9]([CH3:41])[CH2:10][CH2:11][NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:40])OC4C=CC=CC=4)[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14].CC(C)CCNC(N1C2C(=CC(OC3C=CN=C(NC(N4CCC(N5CCCC5)CC4)=O)C=3)=CC=2)C=C1)=O>CN(C)C=O>[CH3:41][CH:9]([CH3:8])[CH2:10][CH2:11][NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:40])[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14]
Reactant: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Reactant: OC1CCNCC1
Agent: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(O)CC4)c3)ccc21
Reaction time: 2 h
Yield: 60.8 %

Procedure:
N,N-dimethylformamide (2.5 ml) and 4-hydroxypiperidine (213 mg, 2.11 mmol) were added to a mixture (243 mg) of phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-carbamate and phenyl N-(4-(1-((3-methylbutyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate synthesized in Example 93; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by NH-silica gel column chromatography (ethyl acetate:methanol=10:1) to yield the title compound as white crystals (150 mg, 0.322 mmol).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=2[C:20](=[O:39])[CH2:21][CH2:22][C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][CH2:28][CH:29]3[O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[CH:25][CH:24]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(O[C:44](=[O:46])[CH3:45])(=O)C>N1C=CC=CC=1>[C:8]([O:3][C@@H:2]1[C@@H:4]([O:5][C:13](=[O:12])[CH3:14])[C@H:6]([O:7][C:4](=[O:5])[CH3:6])[C@@H:8]([CH2:10][O:11][C:2](=[O:3])[CH3:1])[O:9][C@H:1]1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:44](=[O:46])[CH3:45])[C:14]=1[C:20](=[O:39])[CH2:21][CH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][CH:29]2[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:25][CH:24]=1)(=[O:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCc1ccc2c(c1)C(OC1CCCCO1)CC2)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(OC(C)=O)c2C(=O)CCc2ccc3c(c2)C(OC2CCCCO2)CC3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 178.9 %

Procedure:
2'-(β-D-Glucopyranosyloxy)-6'-hydroxy-3-(1-tetrahydropyranyloxyindan-6-yl)propiophenone (1160 mg) is dissolved in pyridine (10 ml), and thereto is added acetic anhydride (1.63 g), and the mixture is stirred at room temperature overnight. The mixture is evaporated to remove the pyridine, and the residue is dissolved in ethyl acetate, washed with water, dried, and evaporated to remove the solvent to give 2'-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-acetoxy-3-(1-tetrahydropyranyloxyindan-6-yl)propiophenone (1438 mg). This product is dissolved in a mixture of acetic acid (20 ml), tetrahydrofuran (10 ml) and water (5 ml), and the mixture is stirred. The organic layer is collected, washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/acetone) to give 2'-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-acetoxy-3-(1-hydroxyindan-6-yl)propiophenone (1071 mg).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]3[CH2:26][CH2:25][C@:24]([CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:23][C:22]3=[O:38])[CH3:20])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[NH2:12]>O.C(O)(=O)C>[N:12]1[C:11]2[CH:10]=[CH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]([N:21]4[CH2:26][CH2:25][C@:24]([CH2:33][C:34]([OH:37])([CH3:35])[CH3:36])([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[O:23][C:22]4=[O:38])[CH3:20])=[CH:17][CH:18]=3)=[CH:7][C:6]=2[NH:5][N:1]=1
Reactant: C[C@@H](c1ccc(-c2ccc(N)c(N)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(-c2ccc3nn[nH]c3c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
A solution of NaNO2 (0.16 g) in water (2 mL) was added dropwise to an ice-cold solution of 3-[(S)-1-(3′,4′-diamino-biphenyl-4-yl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.43 g) in acetic acid (10 mL). The resulting mixture was stirred with cooling for 2 h and at room temperature for another 1 h. Then, water (100 mL) was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous NaHCO3 solution, water, and brine and dried (Na2SO4). The solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate/MeOH 98:2→80:20) to afford the title compound as a foam-like solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([O:26][CH3:27])[CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:19]([O:26][CH3:27])[CH:18]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Ic1ccncc1NCC1CCCCO1
Product: COc1cc(F)ccc1-c1ccncc1NCC1CCCCO1

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-((tetrahydro-2H-pyran-2-yl)methyl)pyridin-3-amine and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 3.5 hours at reflux. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) followed by EtOAc:MeOH (100:0 to 90:10). Brown oil (103%). MS (ESI): m/z=317.167 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]2[N:20]=[C:19]([NH2:21])[C:18]([NH2:22])=[C:17]([NH2:23])[N:16]=2)=[N:6]1.Cl[C:29]([O:31][CH3:32])=[O:30].O>N1C=CC=CC=1>[NH2:23][C:17]1[C:18]([NH:22][C:29](=[O:30])[O:31][CH3:32])=[C:19]([NH2:21])[N:20]=[C:15]([C:7]2[N:8]=[C:9]([C:10]3[S:11][CH:12]=[CH:13][N:14]=3)[N:5]([CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[F:1])[N:6]=2)[N:16]=1
Reactant: COC(=O)Cl
Reactant: Nc1nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc(N)c1N
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)Nc1c(N)nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc1N
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a suspension of 2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4,5,6-triamine (I-57, 0.31 mmol) in pyridine (2.0 mL) at 0° C. was treated with methyl chloroformate (1 equiv). After 30 min, additional portions of methyl chloroformate (3 equiv) were added and the reaction was stirred for 3 h. The reaction mixture was poured into water and the resultant tan solid was collected by filtration to afford methyl 4,6-diamino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-5-ylcarbamate (74% yield).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:12][S-:13].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:13][CH3:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(Br)cnc2[nH]ccc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.16 mmol) was combined with sodium thiomethoxide (151 mg, 2.16 mmol) and dissolved in N,N-dimethylformaldehyde (5 mL). The solution was at 80° C. for 15 hours when additional sodium thiomethoxide (75 mg, 1.08 mmol) was added. The solution was stirred for at 80° C. for 2 hours. Water (50 mL) was added to the reaction mixture, and the precipitate was collected by vacuum filtration to afford 5-Bromo-4-methylsulfanyl-1H-pyrrolo[2,3-b]pyridine (524 mg, 2.16 mmol, >99% yield) as a white solid. 1H-NMR [500 MHz, d6-DMSO] δ: 11.99 (s, 1H), 8.22 (s, 1H), 7.54 (d, 1H), 6.69 (d, 1H), 2.74 (s, 3H); MS [MH+] m/z: 243.0, 244.9
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>CCOCC.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2([OH:29])[CH2:25][CH2:24][CH:23]([CH:20]3[CH2:21][CH2:22][CH:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]3)[CH2:28][CH2:27]2)=[CH:3][CH:4]=1
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Reactant: Brc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCC1CCC(C2CCC(O)(c3ccc(Br)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
106 g (0.45 mol) of 1,4-dibromobenzene are initially introduced in 400 ml of Et2O at −45° C., and 275 ml (0.45 mol) of n-BuLi (15% soln. in hexane) are metered in. After 30 min at this temperature, a solution of 100 g (0.45 mol) of 4′-propylbicyclohexyl-4-one in 200 ml of Et2O is added dropwise, and the mixture is warmed to 0° C. After 1 h, water and dil. hydrochloric acid are added to the batch, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and subsequently dried using sodium sulfate. The solution is concentrated to completion, and the residue is used without further purification for the following reaction.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]([CH3:43])([CH2:41]C)[CH2:13][C:14]1[N:15]=[C:16]([C:25](=[O:40])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[N:17]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:18]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:54])(=O)=O)=CC=1>O1CCCC1>[CH3:11][C:12]([CH3:43])([CH3:41])[CH2:13][C:14]1[N:15]=[C:16]([C:25](=[O:40])[CH:26]([F:54])[C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[N:17]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:18]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)C(F)c1ccc(-c2ccc(F)cn2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Lithium hexamethyldisilazide (1 M in tetrahydrofuran) (92 mL, 0.09 mmol) was added to a −78° C. solution of 4-(2,2-dimethylbutyl)-2-{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (35 mg, 0.08 mmol) in tetrahydrofuran (2 mL). After stirring at −78° C. for 10 min, a solution of N-fluorobenzenesulfonimide (36 mg, 0.11 mmol) in tetrahydrofuran (1 mL) was added. The reaction was allowed to warm to ambient temperature, quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{fluoro[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO[C:21](OC)([CH3:23])[CH3:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO>C(Cl)Cl>[CH2:6]([O:5][C:3]([CH:2]1[CH2:8][CH:9]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[O:18][C:21]([CH3:23])([CH3:22])[O:1]1)=[O:4])[CH3:7]
Reactant: COC(C)(C)OC
Reactant: CCOC(=O)C(O)CC(O)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C1CC(CC(=O)OC(C)(C)C)OC(C)(C)O1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 1-ethyl 6-tert.-butyl 2,4-dihydroxyadipate (1.6 g, 6.1 mmol) in methylene chloride (60 ml), dimethoxypropane (1.672 ml, 78 mmol) and pyridinium p-toluenesulfonate (251 mg, 1 mmol) were added and stirred under reflux conditions for one hour, followed by further stirring at 50° C for one hour while azeotropically removing methanol with methylene chloride. To the mixture, methylene chloride (60 ml) was added and stirred at 50° C. for one hour to remove methylene chloride. After adding water, the mixture was extracted with methylene chloride. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=7:1) to give pure 2-ethoxycarbonyl-4-tert.-butoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane (1.23 g, 4.06 mmol). Yield, 67%.
Reaction SMILES: C(OP(C[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([Cl:23])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=O)OCC)C.ClC1N=C(Cl)C(C(F)(F)F)=CN=1.[CH2:40]([P:43](C1C=CC(N)=CC=1)([CH2:45][CH2:46][CH3:47])=[O:44])[CH2:41][CH3:42]>>[Cl:23][C:21]1[C:20]([C:24]([F:25])([F:26])[F:27])=[CH:19][N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([P:43]([CH2:45][CH2:46][CH3:47])([CH2:40][CH2:41][CH3:42])=[O:44])=[CH:15][CH:14]=2)[N:22]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CCCP(=O)(CCC)c1ccc(N)cc1
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: CCCP(=O)(CCC)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1

Procedure:
The title compound was prepared according to the procedure for diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using 2,4-Dichloro-5-trifluoromethylpyrimidine (101.6 mg, 0.4681 mmol) and 4-(dipropylphosphoryl)aniline (Compound 198B: 116 mg, 0.515 mmol). This was purified on an ISCO Combiflash unit (0-5% MeOH/DCM) to isolate 75 mg of the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.3 Hz, 6H), 1.30 (br. s., 2H), 1.46 (br. s., 2H), 1.76-2.00 (m, 4H), 7.69 (dd, J=10.1, 8.6 Hz, 2H), 7.84 (dd, J=8.7, 1.9 Hz, 2H), 8.87 (s, 1H), 10.89 (s, 1H). MS (ES+): m/z=406.04 (100) 408.01 (35) [MH+]. HPLC: tR=4.01 min (ZQ3, polar—5 min)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=S)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N=C=NC(C)C)(C)C.[NH2:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([N:29]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])=[CH:25][C:24]=1[NH:42][CH2:43][CH2:44][CH:45]1[O:49][CH2:48][CH2:47][O:46]1>O1CCCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:42]([CH2:43][CH2:44][CH:45]3[O:46][CH2:47][CH2:48][O:49]3)[C:24]3[CH:25]=[C:26]([C:27]([N:29]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])=[O:28])[CH:40]=[CH:41][C:23]=3[N:22]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=C=S)cc1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCC2OCCO2)c1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCC2OCCO2)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
4-acetylphenyl isothiocyanate (1.1 g, 1.2 eq) and diisopropylcarbodiimide (1.95 g, 3 eq) are successively added to a solution of 4-amino-3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)benzamide (2 g, 1 eq) in tetrahydrofuran (50 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Water (100 ml) and dichloromethane (200 ml) are added to the residue obtained. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 4:6) produces the expected compound in the form of a white foam (1.8 g; 66% yield).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])=[CH:18][C:17]=1[C:29]([F:32])([F:31])[F:30]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:27]=[CH:28][C:16]([F:15])=[C:17]([C:29]([F:31])([F:32])[F:30])[CH:18]=1)[CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
In accordance with the above reaction formula (1), the compound of the present invention was prepared. First, after 4.2 g (0.039 mole) of benzylamine and 3.1 g (0.039 mole) of pyridine were dissolved in 50 ml of toluene, 11.0 g (0.039 mole) of 2-(4-fluoro-3-trifluoromethylphenoxy)butanoic chloride was gradually added dropwise to the solution under stirring at room temperature. After dropwise addition, the mixture was further stirred for 3 hours at room temperature, and the reaction mixture was then washed with a diluted hydrochloric acid, diluted sodium hydroxide and water with the order. After the toluene layer was dehydrated with anhydrous sodium sulfate, toluene was distilled out under reduced pressure. Resulting crude crystal was recrystallized from toluene to give 12.8 g (Yield: 92 %) of N-benzyl-2-(4-fluoro-3-trifluoromethylphenoxy)butanoic amide having a melting point of 75 to 76 ° C. as colorless needle crystals. Elemental analysis
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([CH3:15])[C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:28])[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([CH3:15])[C:6]=1[C:7]([C:19]1[C:20]([CH3:28])=[CH:21][C:22]([O:26][CH3:27])=[C:23]([O:24][CH3:25])[C:18]=1[O:17][CH3:16])=[O:9])(=[O:3])[CH3:2]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: CC(=O)Oc1ccc(Br)c(C)c1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC(C)=O)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1C (6.83 g, 25 mmol), 3,4,5-trimethoxytoluene (4.56 g; 25 mmol), P2O5 (15.0 g) and dichloromethane (100 ml) is stirred at room temperature for 16 hours. Subsequently, the dichloromethane is distilled off and the residue is diluted with water and ethyl acetate. The organic phase is washed with water and concentrated. The residue is purified by preparative HPLC with acetonitrile:water 9:1 as eluent yielding the pure product as a yellow oil, 1.1 g, (10.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[SH:11].Cl[CH2:17][C:18]([OH:20])=[O:19].[OH-].[K+].Cl>CN(C)C=O.O>[C:18]([CH2:17][S:11][C:7]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:14]=[C:13]([F:15])[CH:12]=2)[CH:10]=[CH:9][N:8]=1)([OH:20])=[O:19]
Reactant: Fc1cc(F)cc(Cn2ccnc2S)c1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CSc1nccn1Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
1-(3,5-Difluorobenzyl)-2-mercaptoimidazole (2.26 g, 0.010 mole) and chloroacetic acid (0.95 g, 0.010 mole) were dissolved in a mixture of dimethylformamide (10 ml) and water (0.5 ml), and potassium hydroxide (1.12 g, 0.020 mole) in water (10 ml) was added dropwise with stirring at ambient temperature over 30 minutes. Stirring at ambient temperature was continued for five hours. The solution was then diluted with water (10 ml) and acidified with concentrated hydrochloric acid. A trace of precipitate formed. The mixture was filtered and the pH of the filtrate was adjusted to 5.5 with concentrated ammonium hydroxide and the mixture was extracted with three portions of methylene chloride. Concentration of the combined extracts gave a clear, heavy oil which was triturated with boiling ether. A white crystalline solid formed which was filtered and recrystallized from ethyl acetate hexane to give 1.18 g (42% yield) of 2-(carboxymethylthio)-1-(3,5-difluorobenzyl)imidazole, mp 101°-103° C.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][C:10]2[N:14]3[C:15]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:16]=4[N:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18](=[O:20])[CH2:19][C:13]3=[N:12][N:11]=2)=CC=1.Br.[OH-].[Na+]>C(O)(=O)C>[OH:8][CH2:9][C:10]1[N:14]2[C:15]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:16]=3[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18](=[O:20])[CH2:19][C:13]2=[N:12][N:11]=1
Reactant: COc1ccc(COCc2nnc3n2-c2ccc(Cl)cc2N(c2ccccc2)C(=O)C3)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1Cc2nnc(CO)n2-c2ccc(Cl)cc2N1c1ccccc1

Procedure:
3.1 g of 1-[(p-methoxybenzyloxy)-methyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 30 ml acetic acid, at 25°, is stirred with 24 ml 48% aqueous hydrobromic acid for 20 minutes. The reaction is neutralized with 30% aqueous sodium hydroxide and extracted with chloroform. The organic phase is separated, washed with water, dried and the solvent evaporated to give the title compound.