Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([OH:23])=O)[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][NH2:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[NH:25][CH3:24])[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)O)ccc1Cl)C1CC1
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a sol. of {3-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-chloro-phenyl}-acetic acid (4.30 g, 12.6 mmol) in CH2Cl2 (130 mL) was added 1-chloro-N,N-2-trimethylpropenyl amine (1.87 mL, 15.2 mmol), and the mixture was stirred for 60 min. Methylamine (2M in THF, 25.0 mL, 50.0 mmol) was added, and the mixture was stirred overnight. More CH2Cl2 was added, and the mixture was washed with water and brine, was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 7:3) yielded the title compound (2.01 g, 45%). LC-MS: tR=0.95 min; ES+: 325.30.
Reaction SMILES: CS[C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]=1.[F:21][CH2:22][C:23]([NH:25][NH2:26])=O>CN(C)P(=O)(N(C)C)N(C)C>[F:21][CH2:22][C:23]1[N:4]2[C:5]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:6]=3[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][CH2:9][C:3]2=[N:26][N:25]=1
Reactant: NNC(=O)CF
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: FCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A solution of 8 g of 2-(methylthio)-5-phenyl-7-chloro-3H-1,4-benzodiazepine and 3.68 g of 2-fluoroacetic acid hydrazide [cp. M. A. Phillips, Agr.Vet.Chem. 2, 86-87 (1961), C. A. 57, 12314 (1962)] in 80 ml of hexamethylphosphoric acid triamide is heated for 8 hours at 140° The solvent is then distilled off in vacuo, and the residue distributed between methylene chloride and water. The organic phase is separated, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, and concentrated by evaporation. The residue is recrystallized from ethyl acetate/petroleum ether to obtain 1-(fluoromethyl)-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine, M.P. 153°-154°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO.O1CCCC1.[Br:29]N1C(=O)CCC1=O>>[Br:29][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[N:19]2[C:14]=1[CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
Into a 30 mL vial, 7-(4-Methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.205 g, 0.000642 mol), Methanol (4 mL, 0.1 mol) and Tetrahydrofuran (9 mL, 0.1 mol) were added. N-Bromosuccinimide (0.137 g, 0.000770 mol) was added portion wise over 5 minutes. The reaction was stirred at room temperature over night. The solvent was removed under vacuum. The solid was partitioned with water and filtered to give a yellow solid. The solid was washed with cold methanol to give 5-Bromo-7-(4-methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (140 mg, 55%). NMR 1H (DSMO-d6)-9.01 (s, 1H), 8.48 (d, 2H, J=8.48 Hz), 8.07 (d, 2H, J=8.53 Hz), 7.79 (s, 1H), 3.28 (s, 3H), 2.62 (s, 3H)
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@@H:33]([CH2:41][CH3:42])[C:34]([O:36]C(C)(C)C)=[O:35]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@@H:33]([CH2:41][CH3:42])[C:34]([OH:36])=[O:35])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](O)C(=O)OC(C)(C)C
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Product: CC[C@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and tert-butyl (S)-(−)-hydroxybutyrate, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 79-80° C.; MS m/e 617 (M−H)+;
Reaction SMILES: [OH:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:21]1([CH2:24][C:25]([NH2:33])([CH3:32])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C:25]([NH:33][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([OH:1])[CH2:3][O:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:32])[CH2:23][CH2:22]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(O)COC2)cn1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3(O)COC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-hydroxyoxetan-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 112d) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (37 mg, 47%); MS (ESI, m/z): 457.5 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].Br[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13]
Reactant: Sc1cccs1
Reactant: CC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)NCCCSc1cccs1
Temperature: 23 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of thiophene-2-thiol (1.8 g, 15.9 mmol, 1.0 eq), N-(3-bromopropyl) acetamide (4.3 g, 23.9 mmol, 1.5 eq) and K2CO3 (4.4 g, 31.8 mmol, 2.0 eq) in CH2Cl2 (50 mL) was stirred at 23° C. for 1 hour. Then the mixture was extracted with CH2Cl2. (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated to give white solid N-(3-(thiophen-2-ylthio)propyl)acetamide (2.5 g, 72.8%); LC-MS (m/z)=215.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][OH:16]>>[Cl:1][C:2]1[C:3]([O:16][CH2:15][CH2:14][C:13]([F:18])([F:17])[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OCCC(F)(F)F
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Product: O=C(O)c1cnc(OCCC(F)(F)F)c(Cl)c1
Yield: 66 %

Procedure:
The title compound is prepared in 66% yield (6.48 g, white solid) from 5,6-dichloronicotinic acid (7.00 g, 36.5 mmol) and 3,3,3-trifluoropropan-1-ol (8.32 g, 72.9 mmol) in a similar manner to Step-1 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6](O)[CH2:7][CH2:8][C:9]=2[CH:10]=1.[C:12]1(=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[CH2:8][CH2:7][CH:6]([N:13]3[C:14](=[O:21])[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]3=[O:22])[C:5]2=[N:4][CH:3]=1
Reactant: OC1CCc2cc(Br)cnc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(rac)-3-Bromo-6,7-dihydro-5H-[1]pyrindin-7-ol (4.84 g, 22.6 mmol) and isoindoline-1,3-dione (3.66 g, 24.9 mmol) were dissolved in THF (130 ml); then, triphenylphosphine (7.41 g, 28.3 mmol) was added, followed by a solution of di-tert-butyl azodicarboxylate (6.25 g, 27.1 mmol) in THF (3.0 ml) below 5° C.; stirring at RT was then continued for 20 hours. The reaction mixture was concentrated in vacuo to give a crude product (23.507 g), which was purified by flash chromatography (silica gel, 100 g, 10% to 50% EtOAc in heptane) to give 2-((rac)-3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)isoindoline-1,3-dione (11.114 g, not pure). This intermediate was dissolved in ethanol (140 ml), then, while stirring, hydrazine hydrate (3.01 g, 2.95 ml, 75.1 mmol) was added and the reaction mixture was heated up to reflux. After 2 hours, it was poured into NaOH 1N (150 ml) and extracted with CH2Cl2 (2×100 ml). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (8.845 g) which was purified by flash chromatography (silica gel, 100 g, 0% to 20% MeOH in CH2Cl2) to yield the title compound (1.80 g, 37%) as purple oil. MS: 213.0 (MH+, 1Br).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:21]=1[C:22]([NH2:24])=[O:23].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:24][C:22](=[O:23])[C:21]4[C:20](=[CH:28][C:27]([O:29][CH3:30])=[CH:26][C:25]=4[O:31][CH3:32])[N:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1C
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(C)=O)C(C)C4)cc3)nc2c1
Temperature: 155 °C
Yield: 21.9 %

Procedure:
To a solution of 4-(4-acetyl-3-methylpiperazin-1-yl)benzaldehyde (0.400 g, 1.62 mmol) in DMA (15 mL) was added 2-amino-4,6-dimethoxybenzamide (0.349 g, 1.78 mmol), NaHSO3 (0.201 g, 1.94 mmol) and p-TsOH (0.030 g, 0.16 mmol). The resulting solution was heated to 155° C. for 5 hours. The mixture was cooled to room temperature, diluted with water, extracted with CH2Cl2, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.150 g, 21%). 1H NMR (300 MHz, DMSO-d6): mixture of rotamers δ 11.57 (s, 1H), 8.10 (d, J=8.9 Hz, 2H), 6.90-7.14 (m, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 4.42-4.75 (m, 0.5H), 4.03-4.42 (m, 1H), 3.61-4.02 (m, 8H), 3.41-3.60 (m, 1H), 2.85-3.13 (m, 2H), 2.63-2.85 (m, 0.5H), 1.88-2.13 (m, 3H), 1.04-1.31 (m, 3H). ESI MS m/z 423 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[S:11])[CH:6]=[CH:7][CH:8]=1.Br.Br[CH2:16][CH2:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>O>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:18]2[CH2:17][CH2:16][S:11][C:10]2=[N:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)=[S:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCCBr
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(N=C2SCCN2C(=S)Nc2cccc(C(F)(F)F)c2)c1

Procedure:
A mixture of 6.1 g. of m-trifluoromethylphenyl isothiocyanate, 6.8 g. of 2-bromoethylamine hydrobromide, 3.5 g. of sodium carbonate, and about 100 ml. of chloroform was stirred at ambient temperature for about 14 hours. To the reaction mixture was added about 50 ml. of water. The aqueous phase was washed with chloroform which was added to the organic phase. The organic phase then was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtering, the solvent was removed under reduced pressure. The residue was recrystallized from petroleum ether to give N-(3-trifluoromethylphenyl)-2-(3-trifluoromethylphenylimino)-3-thiazolidinecarbothioamide, m.p. 116°-7°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].[OH-].[Na+]>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:35][CH:36]=3)[CH2:28][CH2:29]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(N)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(NS(C)(=O)=O)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
1-Acetyl-N-{3-[4-(4-aminobenzyl)-1-piperidinyl]propyl}-N-(3,4-dichlorophenyl)-4-piperidinecarboxamide (Example 303) (18 mg, 0.033 mmol) was dissolved in tetrahydrofuran (0.3 mL). To the solution were added triethylamine (5.0 mg, 0.050 mmol) and methanesulfonyl chloride (4.9 mg, 0.043 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added aqueous solution of 1N-sodium hydroxide (5 mL), and the mixture was extracted with ethyl acetate (5 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to alumina column chromatography (alumina 2 g, ethyl acetate), and the desired fraction was concentrated under reduced pressure to give the titled compound (16 mg, 0.026 mmol, Yield 78%) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][N:16]([CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>>[CH3:15][N:16]([CH3:24])[C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[NH:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(N(C)C)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and N,N-dimethyl-m-phenylenediamine (51 mg, 0.243 mmol) similar to Example 13 and isolated as a dark green oil (49 mg, 66%). 1H NMR (CDCl3): 8.82-8.79 (m, 1H), 8.47 (d, J=7.8 Hz, 1H), 7.84-7.78 (m, 1H), 7.37-7.21 (m, 3H), 6.68-6.66 (m, 3H), 6.58-6.54 (m, 1H), 2.96 (s, 6H), 2.46 (s, 3H).
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](O)=[O:8])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.CN(C)C1C=CN=CC=1.O>[C:1]1(=[O:21])[N:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([NH2:24])=[O:8])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a stirred mixture of α-phthalimidophenylacetic acid (2.50 g, 8.89 mmoL) in tetrahydrofuran (50 mL) is added carbonyldiimidazole (1.50 g, 9.25 mmoL) and a few crystals of 4-dimethylaminopyridine. The reaction is then heated to 50° C. for 45 minutes. After the reaction mixture cools to room temperature, 1 mL of concentrated ammonium hydroxide is added via syringe. The reaction is stirred for 1 hour, then diluted with 50 mL of water and partially concentrated to remove the majority of the tetrahydrofuran. The resulting slurry is filtered and the solid washed with copious amounts of water. The solid is dried in vacuo (60° C.,<1 mm) to afford 1.9 g (76%) of α-phthalimidophenylacetamide, which may be alternatively named as N-phthaloylphenylglycinamide, as an off-white powder: mp 218-220° C.; 1H NMR (DMSO-d6)δ 9.00-7.75 (m, 4 H, Ar), 7.61 (br s, 1H, CONH2), 7.55-7.20 (m, 6H, Ar, CONH2), 5.82 (s, 1H, CHCO2); 13(1NMR (DMSO-d6)δ 168.2, 167.1, 135.6, 134.5, 131.4, 129.4, 127.9, 127.7, 123.1, 56.3. Anal (C16H12N2O3), C, H, N.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:43]12[CH2:52][CH:47]3[CH2:48][CH:49]([CH2:51][CH:45]([CH2:46]3)[CH:44]1[NH2:53])[CH2:50]2>C(#N)C>[CH:43]12[CH2:52][CH:47]3[CH2:48][CH:49]([CH2:51][CH:45]([CH2:46]3)[CH:44]1[NH:53][C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])=[O:3])[CH2:50]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)NC1C2CC3CC(C2)CC1C3
Yield: 6.6 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (113 mg, 0.30 mmol), triethylamine (168 uL, 1.20 mmol, 4 eq) in acetonitrile (1.5 mL, was cooled to 0° C. and treated with isobutyl chloroformate (43 uL, 0.33 mmol, 1.1 eq) followed by the hydrochloride salt of 2-adamantylamine (113.2 mg, 0.60 mmol, 2 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 10 mg (6.5%) of L-isoleucine, N-[1-(adamantan-2-ylcarbamoylmethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:27][S-:28].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][S:28][CH3:27])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: C[S-]
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1c(C)n(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and 0.21 g of sodium methanethiolate in 5 ml of dimethylformamide are stirred at room temperature for 16 hours. The reaction mixture is poured into 100 ml of water and the aqueous mixture is extracted with 50 ml of ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using diethyl ether/n-hexane (7:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-methylthiomethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 3.67 ppm (d, 1H), 3.62 ppm (d, 1H), 3.50 ppm (s, 3H), 2.43 ppm (s, 3H), 2.17 ppm (s, 3H), 1.36 ppm (2xd, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CC1C=CC(CN)=CC=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ncccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 151.9 %

Procedure:
Using General Procedure B: To a stirred solution of 2-methyl-pyridine-3-carbaldehyde (75 mg, 0.62 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (246 mg, 0.62 mmol) and AcOH (40 μL, 0.62 mmol) in THF (6.2 mL) was added NaBH(OAc)3 (394 mg, 1.86 mmol) and the mixture was stirred at room temperature overnight. Purification of the crude white foam (280 mg) by column chromatography on silica gel (200:3:1—CH2Cl2:MeOH:NH4OH) afforded the desired product (116 mg, 37%) as a colorless syrup.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N2CCN(CC2)C1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][S:30]([C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)(=[O:31])=[O:32])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCOS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a stirred solution of 4-nitrobenzeneethanol (3.34 g, 20.0 mmol) and triethylenediamine (3.36 g, 30.0 mmol) in DCM (62.7 mL) at 0° C. was added 4-nitrobenzenesulfonyl chloride (4.97 g, 22.43 mmol) in portions over a 5 min period. The reaction mixture was then stirred at room temperature for 2 h. Water (50 mL) was added and the resulting mixture was stirred for 10 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (5.8 g, 82% yield) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[C:6]2[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:7]2=[N:8][CH:9]=1.C([O-])=O.[NH4+].C(Cl)Cl.CO>CO.[Pd]>[CH3:19][Si:17]([CH3:18])([CH3:20])[CH2:16][CH2:15][O:14][CH2:13][N:10]1[C:7]2=[N:8][CH:9]=[C:4]([CH2:2][CH2:3][OH:1])[CH:5]=[C:6]2[N:12]=[CH:11]1
Reactant: C[Si](C)(C)CCOCn1cnc2cc(C3CO3)cnc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cnc2cc(CCO)cnc21
Temperature: 70 °C
Yield: 51.9 %

Procedure:
6-Oxiranyl-3-(2-trimethylsilylethoxymethyl)-3H-imidazo-[4,5-b]pyridine (918 mg, 3.15 mmol) was combined with 10% Pd/C (400 mg) and ammonium formate (993 mg, 15.75 mmol) and the mixture was suspended in methanol (25 mL). The reaction mixture was heated to 70° C. for 2.5 h. After cooling to ambient temperature, the mixture was filtered through celite®, eluted with methanol, concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel using 75% ethyl acetate/hexanes then 95.5 CH2Cl2 /MeOH as the eluents, which provided 480 mg of the title compound (43% yield for 3 steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([N:13]=[C:14]=[O:15])=[O:12].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:10][C:11](=[O:12])[NH:13][C:14]2=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=NC(=O)CCl
Reactant: Nc1cccc(Br)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: O=C1CN(c2cccc(Br)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromoaniline (1.0 mL, 9.18 mmol) and chloroacetyl isocyanate (0.780 mL, 9.18 mmol) in dioxane (100 mL) was stirred at room temperature for 2 hr. Dioxane (50 mL) and DBU (3.40 mL, 23.0 mmol) were added and the solution stirred at room temperature for 16 hr. The solution was concentrated in vacuo and the residue taken up in EtOAc and H2O. The mixture was then acidified with 1N HCl, then the aqueous phase extracted with EtOAc. The combined organics were then washed with H2O and brine and dried over Na2SO4. The solution was concentrated in vacuo and the residue recrystallized from EtOAc/hexanes to give 1-(3-bromophenyl)-2,4-imidazolidinedione as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.42 (s, 2H), 7.24-7.30 (m, 2H), 7.50-7.52 (m, 1H), 7.87 (s, 1H), 11.27 (s, 1H).