Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:26])[N:12]([CH2:14]/[CH:15]=[CH:16]/[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC(=O)CC.CCOC(C)=O>[C:1]1([CH:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:26])[N:12]([CH2:14]/[CH:15]=[CH:16]/[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1C/C=C/c1cccc2[nH]ccc12
Reactant: CCOC(=O)CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1ccc2c(/C=C/Cn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 5-(diphenylmethyl)-1-[(2E)-3-(1H-indol-4-yl)-2-propen-1-yl]-2(1H)-pyridinone (80 mg), K2CO3 (80 mg) and benzyltriethylammonium chloride (8.8 mg) in 2-butanone (1 mL) was added ethyl bromoacetate (96 mg) at ambient temperature. The reaction mixture was stirred for 5 hours at 80° C. The resulting mixture was diluted with EtOAc and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=100:0-97:3) to give ethyl (4-{(1E)-3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]-1-propen-1-yl}-1H -indol-1-yl)acetate.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@H:5]([O:17][C:18](=[O:21])[CH2:19]Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[Si](C)(C)C>[Zn].CCOCC>[OH:2][C:3]1[CH2:4][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:17][C:18](=[O:21])[CH:19]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCOCC
Product: CCCCCCCCCCC[C@@H]1CC(O)=CC(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.5 %

Procedure:
In a flame-dried flask under N2 a mixture of 659 mg (10.1 mmol) zinc and 755 mg (1.99 mmol) (R)-3-[(bromoacetyl)oxy]tetradecanoic acid methyl ester in 10 mL 20% v:v Et2O:chlorotrimethylsilane was heated at reflux with rapid stirring for 20 min. The mixture was cooled to room temperature and suction filtered through a coarse fritted funnel, using a pad of celite, and washing with 10 mL Et2O. The homogenous filtrate was cooled in an ice/H2O bath and 10 mL tap H2O was added with stirring. After 10 min, the mixture was poured into 100 mL tap H2O and extraction with 3×50 mL Et2O was performed. The combined organic layers were washed with 50 mL brine and dried over MgSO4. The Et2O was removed by rotary evaporation giving 669 mg crude yellow solid. The solid was slurried in 9.0 mL hexanes for 30 min, followed by suction filtration through a medium fritted funnel. The product was dried under 25" vacuum at room temperature for 1.5 h, giving 120 mg (22%) (R)-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran-2-one as a white powder, mp=86°-7° C.
Reaction SMILES: C([Li])(CC)C.CN(CCN(C)C)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29].[CH2:30]([N:32]([C:35](=[O:41])[C:36](OCC)=[O:37])[CH2:33][CH3:34])[CH3:31]>CCOCC>[CH2:30]([N:32]([CH2:33][CH3:34])[C:35](=[O:41])[C:36](=[O:37])[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29])[CH3:31]
Reactant: CN1CCC2(C)c3cc(Br)ccc3N(C)C12
Reactant: CCOC(=O)C(=O)N(CC)CC
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCN(CC)C(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred (-78° C.) solution of sec-butyllithium (1.3M in cyclohexane; 6.6 ml) and TMEDA (1.3 ml) in anhydrous ether (4.0 ml) was added via canula under a N2 atmosphere a solution of 5-bromo-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (1.69 g), in anhydrous ether (4.0 ml). The solution was stirred at -78° C. for 2.5 hours and then added via canula, under N2, to a stirred (-78° C.) solution of N,N-diethylamino-oxo-acetic acid, ethyl ester (3.6 g) in diethyl ether (8.0 ml). The solution was stirred at -78° C. for 3 hours and gradually allowed to warm to room temperature over 2 hours. The mixture was quenched by the addition of an aqueous solution of saturated NH4Cl. The organic phase was separated and washed with two 50 ml portions of an aqueous solution of saturated NaHCO3, with brine, and dried (Na2SO 4). The crude residue was purified using preparative HPLC (silica gel, loading and eluting with 3% methanol in dichloromethane). The appropriate fractions were combined and concentrated to a foam which solidified upon trituration with hexane, to afford 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, diethyl amide.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.[CH2:24]([O:31][C:32](=[O:45])[NH:33][C:34]1[C:35]([OH:44])=[N:36][C:37]([CH2:40][CH2:41][CH:42]=[CH2:43])=[CH:38][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:45])[NH:33][C:34]1[C:35]([O:44][CH3:6])=[N:36][C:37]([CH2:40][CH2:41][CH:42]=[CH2:43])=[CH:38][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=CCCc1ccc(NC(=O)OCc2ccccc2)c(O)n1
Reactant: C[O+](C)C
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C=CCCc1ccc(NC(=O)OCc2ccccc2)c(OC)n1
Reaction time: 65 h
Yield: 90.7 %

Procedure:
Trimethyloxonium tetrafluoroborate (2.0 g, 13.5 mmol, 1.2 equiv) and 2,6-di-tert-butylpyridine (1.52 mL, 6.76 mmol, 0.6 equiv) were added to a solution of d1 (3.36 g, 11.26 mmol, 1 equiv) in CH2Cl2 (80 mL) at 23° C. The reaction mixture was stirred at that temperature for 65 h, then was partitioned between water (2×50 mL) and CH2Cl2 (2×200 mL) and combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (5% EtOAc in hexanes) to afford e1 (3.19 g, 91%) as colorless oil: IR (cm−1) 3432, 1733; 1H NMR (CDCl3) δ 2.42-2.49 (m, 2H), 2.73 (t, 2H, J=7.6), 3.96 (s, 3H), 4.94-5.07 (m, 2H), 5.20 (s, 2H), 5.80-5.94 (m, 1H), 6.71 (d, 1H, J=7.9), 7.11 (s, br, 1H), 7.32-7.43 (m, 5H), 8.16 (s, br, 1H); Anal. C18H20N2O3: C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li][CH:22](CC)C.CI>O1CCCC1>[Cl:1][C:2]1[C:7]([CH3:22])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: [Li]C(C)CC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a cold −78° C. solution of 4-chloro-1-[tris(1-methylethyl)silyl]-1H-pyrrolo[2,3-b]pyridine (3.24 mmol, prepared as described in Tetrahedron Lett. 2004, 45, 2317-2319), in dry tetrahydrofuran (22 mL) was added 1.4M sec-BuLi in hexanes (7.12 mmol) dropwise over 5 min. After 30 min, methyliodide (10.5 mmol) was added. After 45 min, the reaction mixture was quenched with saturated aqueous ammonium chloride (25 mL) and diluted with ethyl acetate (25 mL). The extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% hexanes) to give the title product as a white solid (86%). ESMS [M+H]+: 323.2
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1cc(Br)ccn1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Brc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 130 °C
Reaction time: 23 h
Yield: 60 %

Procedure:
A mixture of 2-amino-4-bromopyridine (5.00 g, 28.3 mmol), copper (I) bromide (207 mg, 1.44 mmol), 1,10-phenanthroline monohydrate (284 mg, 1.44 mmol) and benzonitrile (125 mL) was heated in a 380-mL autoclave to 130° C. and stirred for 23 h under 20 bar of air. After the autoclave was vented and opened (100% conversion, HPLC method cf. example 1.3), the dark brown reaction suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (40 mL) and dried to yield crude 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (4.74 g, 60%) as a green solid with 97.7% purity (HPLC area-%, HPLC method cf. example 1.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:20]([O-])=O)=[CH:12][C:13]=1[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:6]([O:8][CH2:9][CH3:10])=[O:7]>[Pd].C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([NH2:20])=[CH:12][C:13]=1[O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(OC)c(OCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(OC)c(OCC(F)(F)F)cc1N
Reaction time: 18 h
Yield: 92.7 %

Procedure:
A suspension of ethyl 3-methoxy-4-(2,2,2-trifluoroethoxy)-6-nitrobenzoate (24.0 g, 74.3 mmol) and 10% palladium on carbon (3.0 g) in a mixture of ethanol (100 ml) and ethyl acetate (750 ml) was stirred under an atmosphere of hydrogen for 18 hours. Removal of the catalyst by filtration, followed by solvent evaporation in vacuo yielded ethyl 3-methoxy-4-(2,2,2-trifluoroethoxy)-6-aminobenzoate (20.2 g, 93% yield) as a pale brown solid:
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([C:31]#[CH:32])=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C@@H:11]([NH:10][S:7]([C:5]2[S:6][C:2]([C:32]#[C:31][C:28]3[CH:29]=[CH:30][C:25]([CH3:33])=[CH:26][CH:27]=3)=[CH:3][CH:4]=2)(=[O:9])=[O:8])[C:12]([OH:14])=[O:13])=[CH:17]1
Reactant: C#Cc1ccc(C)cc1
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(Br)s1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#Cc2ccc(S(=O)(=O)N[C@H](Cc3c[nH]c4ccccc34)C(=O)O)s2)cc1
Temperature: 50 °C
Yield: 55.4 %

Procedure:
In a round bottom flask was added crude (R)-2-(5-Bromo-thiophene-2-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid (3) (60 mg, 0.14 mmol), p-tolyl acetylene 4 (480 mg, 0.41 mmol), PdCl2P(PPh3)2 (10 mg, 0.015 mmol), copper(I)iodide (2 mg, 0.01 mmol) and triethylamine (0.025 g, 0.25 mmol) and then dissolved in dry DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was then heated at 50° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate and washed with a solution composed of NaCl/NaHCO3/(NH4)2CO3/water (1:1:1:1) (×3), water, and then dried over sodium sulfate (Na2SO4). The crude product was purified using a SAX column to provide to give the desired (R)-3-(1H-Indol-3-yl)-2-(5-p-tolylethynyl-thiophene-2-sulfonylamino)-propionic acid 5 (0.036 g, 55%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[O:11])[C:5]=1[OH:26])=[N+]=[N-]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)=[O:11])[C:5]=1[OH:26]
Reactant: [N-]=[N+]=Nc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Reaction time: 4.5 h
Yield: 76.4 %

Procedure:
To 0.14 g of 4-azido-3-hydroxy-N-para-phenoxyphenylpicolinamide (obtained from the compound of the Preparation Example according to the methods described in Examples a) to g)) dissolved in a mixture of ethanol/ethyl acetate, 1:2, there is added a spatula tip of 10% palladium on carbon. Hydrogenation is carried out at 20 bars pressure and ambient temperature for 4-5 hours. After filtration, concentration and chromatography of the residue in ethyl acetate, there is obtained 0.099 g of a white solid (MP : 197° C.).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:12][C:10](=[O:11])[C:6](=[C:7]([CH3:9])[CH3:8])[CH2:5][CH2:4]1.[OH-:13].[K+]>>[C:10]([OH:11])(=[O:13])[CH2:12][C@@H:3]([CH2:4][CH2:5][CH:6]=[C:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CC(C)=CCC[C@@H](C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44.3 g of HCl gas (measured by determining the weight gain) were passed into 187.2 g (1.045 mol) of technical (85% pure) (R)-pulegone (or R-(+)-p-menth-4(8)-en-3-one) while cooling in ice. After the reaction solution had stood overnight, it was poured into 2.0 l of 5% strength KOH solution and stirred at RT (=room temperature) for 2 h. It was subsequently extracted 5 times with 200 ml of diethyl ether each time. The extract contains pulegone and isopulegone, which can be reused. On addition of concentrated HCl to the aqueous phase (to pH=2), the citronellic acid separated out as a yellowish oil. The acid was extracted by shaking 5 times with 200 ml of diethyl ether each time, the organic phase was dried with Na2SO4 and, after the solvent had been stripped off, was distilled under reduced pressure (boiling point 105°-110° C. under 0.04 mbar). 84.6 g (0.486 mol=45.5% of theory) and, on reuse of the extracted ketones under similar conditions conditions [sic], a further 44.4 g (0.255 mol) of (R)-(+)-citronellic acid were obtained as a clear liquid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:22]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:29])[CH:22]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)Cc1cccnc1)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 3.20 ml (23.0 mill) was added to a methylene chloride 40 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 1.74 g (9.18 mill) and 3-pyridylacetic acid hydrochloride 1.76 g (10.1 mill) and stirred at 0° C. for 30 min. WSC 2.47 g (12.9 mill) was added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 46 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After the drying agent was removed by filtration, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(3-pyridylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 60 ml solution of lithium aluminum hydride 0.77 g (20.3 mill) and refluxed under heating for 3 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrate in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1-5:1) to obtain the product as yellowish oily material.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(OCC)C.C(=O)([O-])O.[Na+]>[Br:15][CH2:13][C:12]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[C:2]=1[F:1])=[O:14]
Reactant: [Br-]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1F
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1cccc(C(F)(F)F)c1F
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 1-[2-fluoro-3-(trifluoromethyl)phenyl]ethanone (5.07 g, 24.6 mmol) in diethyl ether (15 mL) was added phenyltrimethylammonium tribromide (9.62 g, 25.6 mmol), and the mixture was stirred overnight. The reaction mixture was diluted with diluted aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (6.95 g, 99%) as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][C:7]3[CH:9]=[C:10]([OH:14])[CH:11]=[C:12]([CH3:13])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([O:14][C:10]2[CH:11]=[C:12]([CH3:13])[C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[NH:8][C:7]=3[CH:9]=2)[CH:21]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc2[nH]c(C3CC3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CC3)nc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
90 mg (0.48 mmol) 2-cyclopropyl-4-methyl-1H-benzo[d]imidazol-6-ol and 77 mg (0.50 mmol) 4,6-dichloropyrimidine in 2.0 mL DMF were combined with 70 mg (0.50 mmol) potassium carbonate and stirred for 8 h at 50° C. Then ice water was added and the substance was extracted with ethyl acetate and concentrated by rotary evaporation i.vac.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3](=O)[CH2:4][C:5](OC)=[O:6].[CH3:11][NH:12][NH2:13]>CO>[F:1][CH:2]([F:10])[C:3]1[CH:4]=[C:5]([OH:6])[N:12]([CH3:11])[N:13]=1
Reactant: CNN
Reactant: COC(=O)CC(=O)C(F)F
Solvent: CO
Product: Cn1nc(C(F)F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of methyl 4,4-difluoro-3-oxobutanoate (64 g, 0.38 mol) in methanol (500 mL) was added methylhydrazine (20.5 mL, 0.38 mol). The reaction mixture was left to stir overnight at room temperature. The volatiles were removed in vacuo, toluene was added (400 mL), the mixture was evaporated again, and this procedure was repeated. The resulting solid residue was purified chromatographically on silica gel using ethyl acetate/dichloromethane mixture (1:2, Rf=0.35). The resulting oil was crystallized from ether (200 mL) and dried under the vacuum of a membrane pump (10 mm Hg) for 3 h to give 28 g (49.8%) of the title product.
Reaction SMILES: [CH3:1][C@@:2]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:8][CH2:9][N:10]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[N:11]1)[C:3]([O:5]CC)=[O:4].C[C@@](S(C)(=O)=O)(CCN1C(C2C=CC=CC=2)=C(C)N=N1)C(OCC)=O.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C@@:2]([S:22]([CH3:25])(=[O:23])=[O:24])([CH2:8][CH2:9][N:10]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[N:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@](C)(CCn1nnc(-c2ccccc2)c1C)S(C)(=O)=O
Agent: CCOC(=O)[C@@](C)(CCn1nnc(C)c1-c1ccccc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccccc2)nnn1CC[C@](C)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the mixture of ethyl (2R)-2-methyl-4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanoate and ethyl (2R)-2-methyl-4-(4-methyl-5-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanoate (150 mg, 0.41 mmol, 1 eq) in THF (5 mL) and water (1 mL) was added LiOH (0.41 mmol, 1 eq) and the reaction mixture was allowed to stir at RT overnight. The reaction mixture was acidified with 1M HCl and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered and concentrated and the crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:24])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([NH:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])=[O:35])[CH:6]=[C:7]([Cl:24])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2nccc(Oc3c(Cl)cc(N)cc3Cl)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3c(Cl)cc(NC(=O)Nc4ccc(F)cc4F)cc3Cl)c2cc1OC
Yield: 74 %

Procedure:
3,5-Dichloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]-aniline (53 mg) was dissolved in chloroform (5 ml), and 2,4-difluorophenyl isocyanate (34 μl) was added to the solution. The mixture was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 56 mg (yield 74%) of the title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH2:44][C@H:45]1[O:49][C@@H:48]([N:50]2[CH:57]=[C:56]([F:58])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[C@H:47]([OH:59])[C@@H:46]1[OH:60])=[O:42])[C@H:37]([CH2:39][CH3:40])[CH3:38])=[O:34])[CH3:32])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[ClH:61].C(O)C.[H][H]>C(O)C.CO.[C].[Pd]>[ClH:61].[ClH:61].[NH2:11][C@H:12]([C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH2:44][C@H:45]1[O:49][C@@H:48]([N:50]2[CH:57]=[C:56]([F:58])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[C@H:47]([OH:59])[C@@H:46]1[OH:60])=[O:42])[C@H:37]([CH2:39][CH3:40])[CH3:38])=[O:34])[CH3:32])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Yield: 98.8 %

Procedure:
0.94 Gram (1.11 mmol) of the ester obtained as described above was dissolved in ethanol (100 ml) and methanol (20 ml), and 0.40 g of 10% palladium-carbon and 0.50 g (4.93 mmol) of 36% hydrogen chloride-ethanol were added. The mixture was stirred in a stream of hydrogen under normal pressure for 2 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with ether (20 ml) to obtain 0.71 g (99%) of the desired 5'-O-{N-(N-lysylalanyl)isoleucyl}-5-fluorouridine dihydrochloride as a colorless powdery solid.