Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH:11]1([C:14]#N)C[CH2:12]1.[CH2:16]([O:18]CC)C>>[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:16]([CH:11]1[CH2:14][CH2:12]1)=[O:18]
Reactant: Fc1ccccc1CBr
Reactant: CCOCC
Reactant: N#CC1CC1
Agent: [Mg]
Product: O=C(Cc1ccccc1F)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium powder (7.2 g) in anhydrous diethyl ether (60 ml) was added a solution of 2-fluorobenzylbromide (30 ml) in diethyl ether (30 ml), then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a solution of cyclopropyl cyanide (18.2 ml) in diethyl ether (120 ml) over 100 minutes. After stirring for 30 minutes at room temperature the stirred mixture was heated under reflux for 1 hour. After the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed successively with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene as the eluant to afford the desired product (23 g containing solvent) as a yellow liquid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])=[CH:11][CH:10]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH2:1]([C:3]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])=[CH:13][CH:14]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(O[C@@H]3CCCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCCCC3=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of 2-ethyl-3-(4-{[(1R,2R)-2-hydroxycyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.2 g) in dichloromethane (5 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.21 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.13 g, 65%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=[S:20])[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[N:10][CH:9]=[CH:8]3)[O:5]1.[CH3:21][NH:22][CH3:23]>>[ClH:1].[CH3:21][N:22]([CH3:23])[CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=[S:20])[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[N:10][CH:9]=[CH:8]3)[O:5]1
Reactant: CN1CC(CCCl)Oc2c(ccc3cnccc23)C1=S
Reactant: CNC
Product: CN(C)CCC1CN(C)C(=S)c2ccc3cnccc3c2O1
Product: Cl

Procedure:
Following the procedure of Example 31, 2-(2-chloroethyl)-2,3-dihydo-4-methyl-1,4-oxazepino[7,6-f]isoquinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:26])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccnc1-c1ccc(F)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-(4-fluorophenyl)pyridin-3-carboxylate (10.5 g.) and MCPBA (12.33 g., 65%) in dichloromethane was stirred at 0° C. for 1 hour and then at ambient temperature for 2 hours. It was then washed with saturated sodium bicarbonate solution (300 ml.), dried and applied directly to a silica flash column which was eluted firstly with ethyl acetate/iso-hexane (1:1), ethyl acetate and ethyl acetate/methanol (9:1) to give 2-(4-fluorophenyl)-3-(methoxycarbonyl)pyridine-1-oxide as a white solid (10.5 g.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[N+]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[N:18]([CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:17]2=[O:31])([O-])=O.O>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:22]2[CH:21]=[C:20]3[C:16](=[CH:15][CH:14]=2)[C:17](=[O:31])[N:18]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:19]3=[O:23])=[CH:6][CH:5]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Sc3ccc(Cl)cc3)cc2C(=O)N1Cc1cccnc1
Temperature: 120 °C
Yield: 50.9 %

Procedure:
To a suspension of 42 mg of sodium hydride (about 60%) in 10 ml of dimethylformamide was added 150 mg of 4-chlorothiophenol, and the resultant mixture was stirred at 60° C. for 30 minutes and mixed with 300 mg of 5-nitro-2-(3-pyridylmethyl)-1H-isoindole-1,3 (2H)-dione. The mixture was heated at 120° C. for 8 hours under stirring, mixed with water and shaken with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resultant, residue was chromatographed on a column of silica gel, eluting with chloroform to give 201 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>C(O)C.C(Cl)Cl>[Cl:11][C:12]1[N:17]=[C:16]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[CH3:10])[CH:15]=[CH:14][N:13]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1cccc(N)c1C
Solvent: ClCCl
Solvent: CCO
Product: COc1cccc(Nc2ccnc(Cl)n2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.8 %

Procedure:
A mixture of 3-methoxy-2-methyl-phenylamine (0.68 g, 5 mmol) and 2,4-dichloro-pyrimidine (0.74 g, 5 mmol) were suspended in ethyl alcohol (10 mL) and stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.085 g, 7%) as yellow solids.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[N:16]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=2)=[CH:8][N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:6]1=[O:35])[CH3:4].F[C:37](F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(CC)C(C)C)(C)C.CO>ClCCl>[CH3:37][O:1][CH2:2][C@H:3]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)[N:15]=[CH:14][CH:13]=2)=[CH:8][N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:6]1=[O:35])[CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H](CO)n1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)cn(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC[C@@H](C)n1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)cn(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To a solution of (R)-4-(5-(3-(1-hydroxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 111) (95.1 mg) in dichloromethane (1.0 ml) were added under ice-cooling trifluoromethanesulfonic anhydride (50.2 μl) and N,N-diisopropylethylamine (70.2 μl) and the resulting mixture was stirred under ice-cooling for one hour. To the reaction mixture was added methanol (5 ml) and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(3-(1-methoxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (51.0 mg) as pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.[OH:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:37][CH2:36][O:35][C:2]2[N:7]=[CH:6][C:5]([C:8]([C:10]3[C:11]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:12]=4[S:13][C:14]=3[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: OCCN1CCCC1
Reactant: COc1ccc2c(C(=O)c3ccc(Cl)nc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCC4)nc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 84 %

Procedure:
The title compound was prepared in 84% yield from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 6-chloropyrid-3-yl ketone (Part A) and 1-(2-hydroxyethyl)pyrrolidine by essentially following the procedures described in Example 9, Part B.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2ccc(C)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 4-methylbenzylbromide (204 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.131 g (36.9%); MS m/z: 356.5 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.25 (s, 3H); 2.55 (q, 2H, 3J=7.6 Hz); 4.60 (s, 4H); 6.68 (br s, 1H); 6.72 (dd, 1H, 4J=1.8 Hz, 3J=8.9 Hz); 7.09-7.19 (m, 8H); 7.32 (d, 1H, 3J=8.9 Hz); 7.89 (s, 1H); 11.88 (br s, 1H); HPLC (METHOD [A]): rt 18.62 min (100%)
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6](F)[NH:5][C:4]=2[CH:3]=1.Cl.[CH3:15][C:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.C>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:22][C:16]3([CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:5][C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Reactant: CC1(N)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CCCCC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 7.9 %

Procedure:
A mixture of 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g, 2.08 mmol), 1-methylcyclohexylamine hydrochloride (373 mg, 2.49 mmol) and triethylamine (0.58 ml, 4.16 mmol) in ethanol (3 ml) was stirred for 20 h at 50° C. and then for 22 h at 100° C. in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was triturated with water followed by adjustment to pH <2 with 4M hydrochloric acid. The crude product was isolated by filtration and dissolved in 1 N sodium hydroxide followed by treatment with decolourising charcoal. After filtration, the solution was acidified to pH <2 with 4M hydrochloric acid and the precipitate was filtered off and purified by chromatography (dichloromethane/methanol (19:1)). Recrystallisation from ethanol afforded 55 mg (8%) of the pure title compound; mp 218-219° C.; 1H-NMR (DMSO-d6): δ1.18-1.54 (m, 11H), 1.97-2.12 (m, 2H), 6.55 (br s, 1H), 7.12 (s, 1H), 10.60 (br s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:10]([F:13])([F:12])[F:11])[C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5].[C:14]1([S+:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl[CH:34]([CH2:38][CH3:39])[C:35](Cl)=[O:36].N1C=CC=CC=1.[ClH:46]>C(#N)C>[Cl:46][CH2:39][CH2:38][CH2:34][C:35]([O:1][CH:2]([C:10]([F:13])([F:11])[F:12])[C:3]([F:8])([F:9])[S:4]([O-:7])(=[O:6])=[O:5])=[O:36].[C:27]1([S+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: Cl
Reactant: CCC(Cl)C(=O)Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(CCCCl)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a mixture of 7.39 g (0.015 mole) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate, 2.33 g (0.017 mole) of chlorobutyric chloride, and 37 g of acetonitrile, 1.42 g (0.018 mole) of pyridine was added dropwise, followed by stirring at room temperature for 3 hours. Then 18 g of 5% dilute hydrochloric acid was added to the reaction solution whereupon acetonitrile was distilled off under vacuum. The residue was combined with 40 g of dichloromethane whereupon the organic layer was separated. The organic layer was washed with 30 g of water, from which dichloromethane was distilled off under vacuum. To the residue was added 40 g of methyl isobutyl ketone. This was washed with 30 g of water, with 30 g of dilute aqueous ammonia, and three times with 30 g of water whereupon methyl isobutyl ketone was distilled off under vacuum. Ether was added to the residue, followed by decantation and vacuum drying. The target compound was obtained as brown oil (7.94 g, yield 87%).
Reaction SMILES: C(OC(=O)C)(=O)C.[F:8][C:9]1[CH:10]=[C:11]([CH:16](O)[CH2:17][N+:18]([O-:20])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1.C(O)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][N+:18]([O-:20])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: O=[N+]([O-])CC(O)c1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])C=Cc1cc(F)cc(F)c1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Add acetic anhydride (160 mL) to a solution of 1-(3,5-difluorophenyl)-2-nitroethanol (330 g) and 4-dimethylaminopyridine (18 g) in dichloromethane (1000 mL), at room temperature using a water bath to keep the temperature below 35° C. Add acetic acid over 30 min and stir the reaction mixture overnight. Dilute with dichloromethane (660 mL) and wash with 2% aqueous HCl, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, dry (magnesium sulfate) and concentrate. Wash the crude with hexanes to give the title compound (220 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:12]([O:14]C)=O)=[C:5]([N:9]=[C:10]=[S:11])[S:6][C:7]=1[CH3:8])[CH3:2].[CH3:16][C:17]1[N:21]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:20]=[N:19][CH:18]=1>>[CH2:1]([C:3]1[C:4]2[C:12](=[O:14])[N:25]([CH2:24][CH2:23][CH2:22][N:21]3[C:17]([CH3:16])=[CH:18][N:19]=[CH:20]3)[C:10](=[S:11])[NH:9][C:5]=2[S:6][C:7]=1[CH3:8])[CH3:2]
Reactant: Cc1cncn1CCCN
Reactant: CCc1c(C)sc(N=C=S)c1C(=O)OC
Product: CCc1c(C)sc2[nH]c(=S)n(CCCn3cncc3C)c(=O)c12

Procedure:
The compound was synthesized starting from methyl 4-ethyl-2-isothiocyanato-5-methylthiophene-3-carboxylate (0.10 g, 0.41 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.058 g, 0.41 mmol) as described above.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:14]([Br:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:4]=1[CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[ClH:1].[NH:2]([C:3]1[C:14]([Br:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:4]=1[CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[C:17]([CH3:18])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)Cc1cc(C)cc(Br)c1N
Agent: Cl
Product: CCN(CC)Cc1cc(C)cc(Br)c1NC(C)=O

Procedure:
1.53 gm of 2-amino-3-bromo-N,N-diethyl-5-methyl-benzylamine hydrochloride were dissolved in 50 ml of acetic acid anhydride at 75°C. The solution was evaporated to dryness in vacuo, and the residue was recrystallized from ethanol, yielding 2-acetamino-3-bromo-N,N-diethyl-5-methyl-benzylamine hydrochloride, m.p. 170°-172°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][CH:14]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Product: FC(F)(F)c1cnc(Cl)nc1-c1c[nH]c2ccccc12

Procedure:
Starting materials: 2,4-dichloro-5-(trifluoromethyl)pyrimidine and 1H-indole. m/z 298.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH3:9][CH:10]([CH2:12][C@@H:13]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14](ON1C(=O)CCC1=O)=[O:15])[CH3:11].N(CC)(CC)CC>Cl.CN(C=O)C>[NH:24]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@@H:13]([C:14]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:15])[CH2:12][CH:10]([CH3:11])[CH3:9]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 58.3 %

Procedure:
Proline (0.842 g, 7.31 mmoles), in its HCl salt form, is dissolved in DMF and stirred with Boc-D-Leu-OSU (2.4 g, 7.31 mmoles) and (C2H5)3N (1.02 ml, 7.31 mmoles), prepared in Step C above, at room temperature overnight. The reaction mixture is filtered and the filtrate is concentrated under vacuum to dryness. The residue is dissolved in ethyl acetate washed with 0.1 N HCl, and then washed twice with H2O. The organic layer is dried over anhydrous Na2SO4 and the solvent removed by evaporation. The crude product is purified by silica gel column, yielding 1.4 g of pure Boc-D-Leu-Pro-OH.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([O:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[Cl:21])=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[Cl:21][C:13]1[CH:14]=[C:15]([C:16](=[O:17])[N:3]([CH3:4])[CH3:2])[CH:19]=[CH:20][C:12]=1[C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1

Procedure:
290 mg of dimethylamine hydrochloride was coupled to 1 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N HCl, 0.1 N NaOH and brine, dried (MgSO4) and evaporated to afford tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate. 1.1 g of tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate was treated with TFA (4 mL) containing trace amounts of H2O for 2 h. The reaction mixture was evaporated, and then added 0.1 N HCl. The resulting solid was filtered and washed with H2O to yield 2-chloro-4-(dimethylcarbamoyl)benzoic acid. 100 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(dimethylcarbamoyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4-dimethylterephthalamide. MS (Q1) 414.1 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C:8](=O)[CH3:9].CC([O-])=O.[Na+].Cl.[NH2:30][OH:31]>CCO>[F:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C:8](=[N:30][OH:31])[CH3:9]
Reactant: CC(=O)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1F
Temperature: 60 °C
Yield: 0.1 %

Procedure:
A mixture of 1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (0.7 g, 2.118 mmol), NaOAc (1.73 g, 21.1 mmol), and hydroxylamine hydrochloride (0.735 g, 10.55 mmol) in EtOH (20 mL) was heated at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure, water (200 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). The combined extracts were concentrated under reduced pressure to afford 0.66 mg (90%) of 1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone oxime as a white solid. MS (ESI): m/z=348.2 [M+1]+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:25][S:26]([O:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][CH:11]=2)=[CH:21][CH:20]=1)(=[O:28])=[O:27]
Reactant: OCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 82 %

Procedure:
In substantially the same manner as in Reference Example 12, 2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethanol was allowed to react with methanesulfonyl chloride to give 2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethyl methanesulfonate. The yield was 82%. Recrystallization from acetone-isopropyl ether gave colorless prisms, mp 121-122° C.
Reaction SMILES: C(OC([NH:11][C@H:12]([B:20]([OH:22])[OH:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.[C:23]([OH:28])(=[O:27])[C@H:24]([CH3:26])[OH:25]>C1C=CC=CC=1>[C:23]([O-:28])(=[O:27])[C@H:24]([CH3:26])[OH:25].[NH2:11][C@H:12]([B:20]([O-:22])[O-:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)B(O)O)OCc1ccccc1
Reactant: C[C@H](O)C(=O)O
Solvent: c1ccccc1
Product: C[C@H](O)C(=O)[O-]
Product: N[C@@H](Cc1ccccc1)B([O-])[O-]
Reaction time: 2 h

Procedure:
1.42 (5 mmol) of (R)-1-benzyloxycarbonylamino-2-phenylethane boronic acid (V) is refluxed with 80 ml of benzene and 0.45 g (5 mmol) of (S)-(+)-lactic acid (VI) in a Dean Stark apparatus for 5 hrs. After cooling the mixture is concentrated, redissolved in 75 ml of methanol and then transferred to a two-necked flask. The mixture is flushed with nitrogen, 1 gram of 10% palladium on activated carbon is added and hydrogen gas is passed through the stirred mixture for 2 hrs. 75 ml of methanol-water (1:1 v /v) is added and the mixture filtered slowly through celite (30 g). The filtrate is collected and concentrated to give (S)-lactate-1-(R)-amino-2-phenylethane boronate (VIII).