Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([C:34](=[N:36]O)[NH2:35])[CH:30]=[CH:31][C:32]=1[F:33]>>[Cl:26][C:27]1[CH:28]=[C:29]([C:34]2[N:36]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH2:12]3)[O:24][N:35]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: NC(=NO)c1ccc(F)c(Cl)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)c(Cl)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 41 mg (0.22 mmol, 1.1 eq.) of 3-chloro-4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 51 mg (51% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[NH2:29][C@@H:30]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:31]([OH:42])[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([F:41])([F:40])[F:39].CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:29][C@@H:30]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:31]([OH:42])[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([F:41])([F:39])[F:40])=[O:16])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CN1CCC[C@H]1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1CCC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 731 mg (3.12 mmol) of N-(tert-butoxycarbonyl)-L-asparagine in 6 ml of anhydrous DMF was treated at 0° C. with 530 mg (3.44 mmol) of HOBT and 1.39 g (3.28 mmol) of CMTC. A solution of 1,114 mg (2.84 mmol) of the compound from Example 3 and 1.6 ml (14.20 retool) of N-methylmorpholine in 8 ml of DMF was then added. The cooling bath was removed and the mixture was stirred at room temperature for 3 h. It was then concentrated in vacuo and the residue was partitioned between 40 ml of ethyl acetate and 40 ml of water. The water phase was extracted with 10 ml of ethyl acetate, and the combined extracts were washed with 50 ml of water and dried over MgSO4. After evaporation of the solvent in vacuo and chromatography of the crude product on 200 g of silica gel (dichloromethane:methanol 9:1), 1.42 g (89% of theory) of the title compound were obtained as crystals. Melting points: 104° C. Rf =0.15, I(9:1) MS(FAB): m/e=517 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 4-methyl-aniline (Aldrich) according to the method described in Example 94. Melting Point: 125-126° C. (diethylether
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH2:19][NH:18][CH2:17][CH2:16]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH2:19][N:18]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1)[CH2:17][CH2:16]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Reactant: CCCN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCN1CCC(N2CCc3cc(OC)c([N+](=O)[O-])cc3C2)CC1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A mixture of 1-propyl-4-piperidinone (01.25 mL, 8.3 mmol), 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.0 g, 4.8 mmol), acetic acid (0.55 mL) and triethylamine (1.3 mL) in 1,2-dichloroethane (5 mL) was stirred for 30 minutes. Sodium triacetoxyborohydride (1.8 g, 2.8 mmol) was added. After stirring for 12 hours the reaction was quenched by the addition of saturated NaHCO3 (aq). The reaction was diluted with dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 6-(methyloxy)-7-nitro-2-(1-propyl-4-piperidinyl)-1,2,3,4-tetrahydroisoquinoline (1.43 g, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 7.60 (s, 1 H), 6.78 (s, 1 H), 3.91 (s, 3 H), 3.73 (s, 2 H), 3.07 (d, J=9.17 Hz, 2 H), 2.91 (t, J=5.87 Hz, 2 H), 2.83 (t, J=5.68 Hz 2 H), 2.47-2.60 (m, 1 H), 2.29-2.42 (m, 2 H), 2.04 (d, J=10.63 Hz, 2 H), 1.68-1.94 (m, 4 H), 1.49-1.66 (m, 2 H), 0.91 (t, J=7.33 Hz, 3 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[C:15]#[C:16][Si](C)(C)C>CO>[C:15]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:8]=1[F:7])[NH2:12])#[CH:16]
Reactant: C[Si](C)(C)C#Cc1cc(N)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(N)ccc1F
Temperature: 20 °C
Yield: 95.9 %

Procedure:
16 mg of potassium carbonate are added to a solution of 360 mg of 4-fluoro-3-[(trimethylsilyl)ethynyl]aniline in 5 ml of methanol. After stirring over night under argon and at a temperature in the region of 20° C., the medium is concentrated to dryness under reduced pressure, then taken up in 8 ml of water and neutralized with a few drops of hydrochloric acid (1 N), and then extracted three times with diethyl ether. The combined organic phases are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 225 mg of 3-ethynyl-4-fluoroaniline are obtained in the form of a brown oil, the characteristics of which are the following:
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[CH3:12][C:13]1[C:14](Cl)=[N:15][C:16]([Cl:20])=[N:17][C:18]=1[CH3:19]>>[CH3:12][C:13]1[C:14]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]2[CH3:1])=[N:15][C:16]([Cl:20])=[N:17][C:18]=1[CH3:19]
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: CC1NCCc2ccccc21
Product: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Yield: 60.4 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1-methyl-1,2,3,4-tetrahydroisoquinoline(3.9 g, 26.4 mmol) and 5,6-dimethyl-2,4-dichloropyrimidine(4.3 g, 24 mmol) prepared in the above Step 1 were used as starting materials, 4.17 g of the titled compound was prepared. (Yield: 60.4%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClC[C:20](OCC)=[O:21].CC(C)([O-])C.[K+].[Na]>O.C(O)C.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:20]=[O:21]
Reactant: CCCCCCC(=O)c1cc(C)ccc1OC
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCC(C=O)c1cc(C)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
1-(2-Methoxy-5-methylphenyl)heptan-1-one (81.6 g, 0.348 mol), ethyl chloroacetate (64 g, 0.522 mol) and benzene (100 ml) were mixed, and this solution was cooled to 0° C. Potassium t-butoxide (58.6 g, 0.522 mol) was added, and the mixture was stirred at room temperature for 0.5 hour. This solution was cooled again to 0° C. Then ethyl chloroacetate (32 g, 0.261 mol) and potassium t-butoxide (29.3 g, 0.261 mol) were added, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was poured onto ice (200 g) to stop the reaction and the aqueous layer was extracted 3 times with toluene (120 ml). The organic layer was washed successively with water, an aqueous acetic acid solution (water/acetic acid=50/1) and water (100 ml each), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue were added ethanol (90 ml) and sodium ethoxide previously prepared from sodium (13.1 g, 0.567 mol) and ethanol (260 ml), and the mixture was stirred at room temperature for 1.5 hours. Water (17 ml) was added to the reaction mixture, and the mixture was stirred for 0.5 hour. Ethanol was evaporated under reduced pressure. To this residue, water (350 ml) and conc. hydrochloric acid (63 ml) were added, and the mixture was refluxed under heating for 1.5 hours. The aqueous layer was extracted 3 times with ether (200 ml). The organic layers were combined, washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine (100 ml each), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was distilled under reduced pressure (450 pa, 155-160° C.) to give 2-(2-methoxy-5-methylphenyl)octanal (64.5 g, 74.6%/) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[C:10]([Cl:17])[CH:9]=2)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe]>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[C:10]([Cl:17])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(OCc2ccc(Br)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(Cl)cc(OCc2ccc(Br)cc2)c1

Procedure:
The product from Example 196a was reduced with Fe and NH4Cl following the procedure from Example 237E to give the title compound.
Reaction SMILES: [CH:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]1([CH2:7]/[CH:8]=[CH:9]/[CH:10]=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC/C=C/CC1CCCCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C/C=C/CC1CCCCC1
Temperature: 0 °C

Procedure:
To 10.2 g (65.93 mmol) of (E)-4-cyclohexyl-2-buten-1-ol dissolved in 700 mL of CH2Cl2 with 10 g crushed activated 4A molecular sieves was added 11.97 g (102.2 mmol) of N-methyl morpholine-N-oxide. This mixture was cooled to 0° C. and a catalytic amount 1.197 g (3.40 mmol) of tetrapropylammonium perruthenate was added slowly. After 18 hr the mixture was filtered through celite, concentrated in vacuo, and filtered through a plug of silica gel (6×6 cm 5% ether in hexanes) to provide the title compound as a colorless oil. Further purification by fractional distillation (bp 58°-60° C., 2 mm of Hg) afforded an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Si:21]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[N:36][CH:37]=1)[NH2:31])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>C(#N)C>[Si:21]([O:28][CH2:29][C@@H:30]([NH:31][C:17]1[C:12]2[CH2:11][N:10]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=3[C:7]#[N:8])[CH2:20][CH2:19][C:13]=2[N:14]=[CH:15][N:16]=1)[C:32]1[CH:37]=[N:36][C:35]([CH3:38])=[N:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Cc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (150 mg, 0.49 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethanamine (144 mg, 0.54 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.5 mL, 3 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC to yield the product as a yellow solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][OH:11])[CH2:5][CH2:4]1.F[C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C1COCC1.O>[I:19][C:16]1[CH:17]=[CH:18][C:13]([O:11][CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)=[N:14][CH:15]=1
Reactant: Fc1ccc(I)cn1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Ic1ccc(OCCN2CCOCC2)nc1
Temperature: 60 °C
Yield: 60 %

Procedure:
To a suspension of sodium hydride (2.15 g, 60% dispersion in mineral oil, 54.0 mmol) in THF (100 mL) at 0° C. was added 2-morpholinoethanol (5.43 mL, 44.8 mL). After 30 min 2-fluoro-5-iodopyridine (10.0 g, 44.8 mmol) was added and the reaction mixture was heated to 60° C. for 16 hr and was then cooled and diluted with water (75 mL). The resulting mixture was extracted with EtOAc (2×75 mL) and the combined organic extracts were dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 120 g, 20-60% EtOAc in isohexane, gradient elution) to afford 4-(2-(5-iodopyridin-2-yloxy)ethyl)morpholine as a yellow oil (9.35 g, 60%); Rt 0.94 min (Method 2, acidic); m/z 335 (M+H)+, (ES+).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(NC(=NC(C)C)O[C:21]([CH3:24])([CH3:23])[CH3:22])(C)C>C(Cl)Cl>[C:21]([O:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of N-BOC-D-serine (10 g, 48.7 mmol) in methylene chloride (50 ml) was added N,N′-diisopropyl-O-tert-butylisourea (35 ml, 3.5 M) via addition funnel, over 30 min. The reaction mixture was maintained at 0° C. for 2 hrs and then warmed to room temperature over night. The material was again cooled to 0° C. and a second portion of N,N′-diisopropyl-O-tert-butylisourea (28 ml, 3.5 M) was added. The material was stirred for 2 hrs at 0° C. and then warmed again to room temperature over night. Purification by flash silica gel chromatography using (20%) ethyl acetate/hexanes as eluant gave O-tert-butyl-N-BOC-D-serine (7.97 g) as a viscous oil which solidified on standing.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH2:15]([N:14]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1)[CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNCc1ccccc1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Solvent: CS(C)=O
Solvent: O
Product: CN(Cc1ccccc1)c1cnc2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-Dichloroquinoxaline (0.500 g, 2.5 mmol) was dissolved in DMSO (10 mL) at RT and N-methyl-1-phenylmethanamine (1.53 g, 12.56 mmol) was added to the reaction mixture. The reaction mixture was stirred at RT for 16 hrs. After completion of reaction (checked by TLC), water (100 mL) was added to the reaction mixture and it was extracted with ethyl acetate (50 mL×3). The organic layer was washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The organic layer was concentrated under vacuum to give the crude product.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:7])[CH2:2][CH2:3][CH3:4].CS(O)(=O)=[O:19].OO>>[CH2:1]([NH:5][C:6]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([O:15][OH:19])=[O:14])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)NC(=O)CCCC(=O)O
Reactant: CS(=O)(=O)O
Agent: OO
Product: CCCCNC(=O)NC(=O)CCCC(=O)OO

Procedure:
80.8 g (0.35 mol) of N-(N'-butylcarbamoyl)glutaramic acid, 123 g of methanesulfonic acid and 42 g (1.05 mol) of hydrogen peroxide (85% strength by weight) are reacted and worked up as described in Example 3.
Reaction SMILES: [C:1]1([N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:24]=3[N:25]=[C:26]([NH:28][C:29](=[S:32])[NH:30][CH3:31])[N:27]=2)[C@@H:16]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[CH2:17]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][O:40][C:41]1[CH:62]=[CH:61][C:44]([C:45](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)=[CH:43][CH:42]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:45]([O:22][CH2:21][C@H:20]2[O:23][C@@H:16]([N:15]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[S:32])[NH:30][CH3:31])[N:27]=[C:11]([O:10][C:8](=[O:9])[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:12]=4[N:13]=[CH:14]3)[CH2:17][C@@H:18]2[OH:19])([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:44]2[CH:61]=[CH:62][C:41]([O:40][CH3:39])=[CH:42][CH:43]=2)=[CH:51][CH:50]=1
Reactant: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)O3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
The above-obtained 6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (400 mg, 0.744 mmol) was azeotroped with anhydrous pyridine three times and dissolved in anhydrous pyridine (8.0 mL), and 4,4′-dimethoxytrityl chloride (278 mg, 0.818 mmol) was added thereto. The mixture was stirred at room temperature for 3 hours, and then sodium bicarbonate water (3 mL) was added thereto to terminate the reaction. The reaction solution was extracted with ethyl acetate (150 mL)/sodium bicarbonate water (120 mL) once and with ethyl acetate (150 mL)/brine (100 mL) twice. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (N60: spherical neutral silica gel) with methanol/3% to 4% chloroform containing 1% triethylamine to give 5′-O-(4,4′-dimethoxytrityl)-6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (570 mg, 78%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:13]([C:14]#[N:15])[C:12]=2[Cl:20])[C:4]=1[F:21])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1Cl
Yield: 77.9 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.062 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. for 6 h with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 16 h. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from boiling EtOH, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(2,5-dichloro-3-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.067 g, 0.141 mmol, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 8.27 (s, 1H), 8.02 (d, J=2.06 Hz, 1H), 7.78 (s, 1H), 7.53 (d, J=8.38 Hz, 1H), 7.40 (t, J=7.69 Hz, 1H), 7.25 (d, J=1.65 Hz, 1H), 4.53 (d, 2H). LC-MS (ES−) m/z 471.01, 473.00, 474.99 [M−1]. LC-MS (ES+) m/z 472.91, 474.92, 476.90 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH2:10]([O:12][CH2:13][CH2:14]O)[CH3:11].[H-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[Cl:9][C:5]1[C:4]([CH2:11][CH2:10][O:12][CH2:13][CH3:14])=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CCOCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOCCc1nc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,3,5-Trichloropyridine (9.12 g, 0.050 mol) and 2-ethoxyethanol (5.40 g, 0.060 mol) were dissolved in 50 mL DMSO, followed by portionwise addition of NaH (2.4 g, 60% dispersion in oil, 0.060 mol). The mixture was heated to 80° C. for 3 hours, stirred at room temperature overnight, then heated to 120° C. for 5 hours. The reaction mixture was then diluted to 900 mL with brine, and extracted three times with 100 mL ether. The ether extracts were combined, washed twice with 100 mL water, diluted with 300 mL hexane, filtered through phase-separating paper, and concentrated in vacuo. The residue was purified via silica gel chromatography (first column with 10-50% EtOAc in hexane; second column with 0-10% EtOAc in hexane). Concentration of pure fractions gave 3,6-dichloro-2-(2-ethoxyethyl)pyridine as the major isomer (5.78 g white solid, M.P. 33-34° C.) and 2,3-dichloro-6-(2-ethoxyethyl)pyridine as the minor isomer (1.43 g white solid, M.P. 47-48° C.).
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[O:19]=[C:20]1[N:24]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:23][CH2:22][N:21]1[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][N:41]=1)[C:35](OC)=[O:36]>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][N:41]=[C:32]([N:21]2[CH2:22][CH2:23][N:24]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:20]2=[O:19])[CH:33]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3cccnc3)C2=O)c1
Reactant: NCc1ccc(F)c(F)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccnc(N2CCN(Cc3cccnc3)C2=O)c1
Yield: 59 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 3,4-difluorobenzylamine to react with methyl 2-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)isonicotinate, N-(3,4-difluorobenzyl)-2-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 59% yield: mp 178-180° C.; 1H NMR (300 MHz, CDCl3) δ 8.63-8.53 (m, 3H), 8.36 (dd, J=5.4, 0.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.39 (dd, J=5.1, 1.5 Hz, 1H), 7.31-7.26 (m, 1H), 7.17-7.03 (m, 4H), 4.61 (d, J=6.6 Hz, 2H), 4.46 (s, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.39 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.8, 157.0, 152.9, 149.5, 149.4, 148.5, 142.6, 135.8, 134.9, 131.9, 123.9, 123.8, 117.6, 117.4, 117.0, 116.8, 116.1, 108.9, 45.5, 43.1, 41.3, 41.2; MS (ES+) m/z 423.9 (M+1).