Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[Cl:2][CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:24]=[O:26])=[CH:8][CH:7]=1)[CH2:13][CH2:14][Cl:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride 18 (1.22 g, 4 mmol) in dry chloroform (50 mL) was added triethylamine (0.72 mL) at room temperature. The clear solution obtained was then cooled to −10° C. and a solution of triphosgene (0.712 g, 2.4 mmole) in dry chloroform (10 mL) was added dropwise into a reaction mixture at 0° C. After being stirred for 30 min, the reaction mixture was evaporated to dryness under reduced pressure. The solid residue was triturated with dry THF (100 ml), filtered, and washed with small amount of THF. The combined filtrate and washings was evaporated to dryness to give the crude isocyanate 19, which was then dissolved in dry DMF (5 mL) and added dropwise to a solution of N1-(6-methoxy-2-methylquinolin-4-yl)benzene-1,3-diamine (0.56 g, 2 mmol) in dry DMF (10 mL) containing Et3N (1 mL). After being stirred for 5 h at room temperature, the solid separated was filtered and washed with dry DMF. The filtrate was evaporated to dryness in vacuo. The residue was purified by column chromatography using CHCl3/MeOH (100:3 v/v) as an eluent. The fractions containing the main product were combined and evaporated to dryness and the residue was recrystallized from CHCl3 to give BO-1547 (0.87 g, 81%); mp 225-227° C.; 1H NMR (DMSO-d6) δ 2.58 (3H, s, Me), 3.68-3.70 (8H, m, CH2), 3.97 (3H, s, OMe), 6.73-6.69 (3H, m, Ar—H), 7.03 (1H, d, J=7.6 Hz, Ar—H), 7.28 (2H, d, J=9.0 Hz, Ar—H), 7.35 (1H, d, J=7.7 Hz, Ar—H), 7.44 (1H, t, J=8.0 Hz, Ar—H), 7.64-7.62 (1H, m, Ar—H), 7.71 (1H, s, Ar—H), 7.93 (1H, d, J=9.1 Hz, Ar—H), 8.09 (1H, s, Ar—H), 8.84 (1H, s, NH, Exchangeable), 9.31 (1H, s, NH, Exchangeable), 10.49 (1H, s, NH, Exchangeable); ESI-HRMS calcd for C28H29Cl2N5O2 m/z 538.4682 (M+H). found 538.2451 (M+H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:44])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@@H:10]1[Cl:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 80.7 %

Procedure:
3.0 g (5.5 mmol) of 2,3,4,6-tetra-O-benzyl-D-glucopyranose were dissolved in 30 ml of anhydrous methylene chloride and the solution was stirred with 1.45 ml (2.11 g; 16.5 mmol) of oxalyl dichloride and 0.3 ml of dimethylformamide at room temperature. After one hour, the solution was concentrated under a high vacuum, the residue was taken up in 10 ml of methylene chloride and the mixture was filtered over about 10 g of silica gel. Renewed concentration gave 2.48 g (80%) of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride as a colorless syrup. The crude product was taken up in 20 ml of anhydrous acetonitrile and the mixture was heated under reflux with 3.0 g (38 mmol) of potassium hydrogen fluoride (24 hours at 100° C., dried over P2O5) for 8 hours. It was possible to purify the crude product by column chromatography on silica gel (methylene chloride/ether, 20:1). Yield: 1.1 g (47%) of 2,3,4,6 -tetra-O-benzyl-α-D-glucopyranosyl fluoride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:19][C:20]1[C:25]2[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[C:30]([NH:29][C:27]1[S:28][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:25]=2[N:26]=1)(=[O:32])[CH3:31]
Reactant: CCCCCCC(=O)N(CCCCCBr)C(C)C
Reactant: CC(=O)Nc1nc2c(O)cccc2s1
Product: CCCCCCC(=O)N(CCCCCOc1cccc2sc(NC(C)=O)nc12)C(C)C
Yield: 41.8 %

Procedure:
N-(5-Bromopentyl)-N-isopropylheptanamide (75 mg, 0.23 mmol) was alkylated with commercial N-(4-hydroxybenzo[d]thiazol-2-yl)acetamide (54 mg, 0.26 mmol) as described above to give analog 30 (43 mg, 42%) as a sticky solid. TLC:EtOAc/hexanes (1:4), Rf˜0.30; 1H NMR (300 MHz, 45/55 mixture of rotamers) δ 11.50 (br s, —NH, 1H), 7.37-7.42 (m, 1H), 7.18-7.26 (m, 1H), 6.84-6.88 (m, 1H), 4.58-4.78 and 4.00-4.10 (m, 1H for two rotamers), 4.02 (t, J=6.3 Hz, 2H), 3.12 (t, J=7.3 Hz, 2H), 2.22-2.45 (m, 5H), 1.82-1.92 (m, 2H), 1.44-1.70 (m, 4H), 1.20-1.40 (m, 8H), 1.11-1.19 (m, 6H), 0.82-0.95 (m, 3H); 13C NMR (75 MHz) δ 173.94, 172.78, 169.40, 169.36, 157.89, 151.62, 138.43, 138.32, 133.91, 133.87, 124.92, 124.85, 114.02, 113.87, 109.66, 108.35, 69.46, 69.08, 48.53, 48.33, 45.94, 43.61, 41.20, 34.26, 34.09, 31.91, 31.88, 31.39, 29.55, 29.45, 29.37, 29.30, 25.88, 25.77, 25.71, 24.43, 24.16, 23.55, 22.77, 21.59, 20.80, 14.28. HRMS (ESI-neg) calcd for C24H36N3O3S [M−1]− 446.2477, found 446.2434.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])(C)C)[CH3:12])(C)(C)C.C1(N)CCC1.[F:36][C:37]1[C:60]([N:61]2[CH2:65][CH2:64][CH2:63][C:62]2=[O:66])=[CH:59][C:58]([N:67]2[CH2:71][CH2:70][CH2:69][C:68]2=[O:72])=[CH:57][C:38]=1C(N[C@H]([C@@H]1C[C@@H](C)C(=O)O1)CC1C=CC=CC=1)=O>>[CH2:23]([C@H:8]([NH:7][C:6](=[O:30])[C:38]1[CH:57]=[C:58]([N:67]2[CH2:71][CH2:70][CH2:69][C:68]2=[O:72])[CH:59]=[C:60]([N:61]2[CH2:65][CH2:64][CH2:63][C:62]2=[O:66])[C:37]=1[F:36])[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH:15]1[CH2:16][CH2:17][CH2:20]1)[CH3:12])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cc(N3CCCC3=O)cc(N3CCCC3=O)c2F)OC1=O
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Agent: NC1CCC1
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F)C(=O)NC1CCC1

Procedure:
Prepared in an analogous manner to D1 from cyclobutylamine and 2-fluoro-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-3,5-bis-(2-oxopyrrolidin-1-yl)benzamide (D50).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[F:13][C:14]([F:22])([F:21])[C:15]#[C:16][C:17]([O:19][CH3:20])=[O:18]>CO>[CH3:1][O:2][C:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:15]([C:14]([F:22])([F:21])[F:13])=[CH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:6]=1)=[O:12]
Reactant: COC(=O)C#CC(F)(F)F
Reactant: COC(=O)Cc1ccc(N)cc1
Solvent: CO
Product: COC(=O)C=C(Nc1ccc(CC(=O)OC)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Into 30 ml of methanol were dissolved 2.17 g (13.2 mmol) of methyl-p-aminophenylacetate, and, under stirring and cooling with ice, a solution of 2.00 g (13.2 mmol) of methyl 3- trifluoromethylpropiolate in 10 ml of methanol was added dropwise. After 30 minutes, solvent was distilled off to obtain methyl 3-(4-methoxycarbonylmethylphenylamino)-3-trifluoromethylacrylate (4.17 g) as a yellow oily substance.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([C:13]([OH:15])=[O:14])[O:11][C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:33]([N:35]([CH2:38][CH2:39][O:40][CH:41](O)[CH3:42])[CH2:36][CH3:37])[CH3:34]>C(Cl)(Cl)Cl.O>[C:1]1([CH:7]2[CH:12]([C:13]([O:15][CH2:42][CH2:41][O:40][CH2:39][CH2:38][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])=[O:14])[O:11][C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1Oc2ccccc2OC1c1ccccc1
Reactant: CCN(CC)CCOC(C)O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)CCOCCOC(=O)C1Oc2ccccc2OC1c1ccccc1
Reaction time: 0.25 h

Procedure:
To a suspension of 12.8 g of (3-phenyl-1,4-benzodioxan-2-yl)-carboxylic acid in 100 cc of CHCl3, 5.1 g of triethylamine are added. The mixture is chilled and 5.4 g of ethyl chlorocarbonate are added dropwise. After stirring for 15 minutes, 8.8 g of N,N-diethylaminoethoxyethanol are added. After 2 hours the mixture is treated with water, the organic phase is separated and dried over Na2SO4. The solvent is removed under vacuum and the residue is transformed in the corresponding citrate (m.p. 73°-74°, from isopropanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 104.5 %

Procedure:
To a suspension of 5-chloro-2-nitrobenzoic acid (21 g, 100 mmol) in dry methylene chloride (200 mL) at 0° C. were added several drops of DMF, followed by oxalyl chloride (13 mL, 150 mmol). The reaction was warmed to ambient temperature. After 16 hours the solvents were removed and the viscous oil dried in vacuo to afford 23 g (quantitative yield) of 5-chloro-2-nitrobenzoyl chloride; NMR (CDCl3) 8.1 (d, 1), 7.7 (m, 2) ppm.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:3][CH2:2][CH2:1][NH:4][CH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)#[N:13]
Reactant: CN=C(NC#N)SC
Reactant: NCCN
Reactant: ClCc1nccs1
Product: CNC(=NCCNCc1nccs1)NC#N

Procedure:
Reacting ethylendiamine with 2-chloromethylthiazole by the procedure of Example 34, then reacting the resulting N-(2-thiazolymethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a), gives N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2-(2-thiazolylmethylamino)ethyl]guanidine trihydrochloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]34[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]5)[CH2:16]3)[CH2:22]4)=[O:14])[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[CH3:29][O:30][CH2:31][CH2:32]Br>>[CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH2:32][CH2:31][O:30][CH3:29])[C:10](=[N:12][C:13]([C:15]34[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]5)[CH2:16]3)[CH2:24]4)=[O:14])[S:11][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: COCCBr
Reactant: CS(=O)(=O)c1ccc2nc(NC(=O)C34CC5CC(CC(C5)C3)C4)sc2c1
Agent: [H-]
Agent: [Na+]
Product: COCCn1c(=NC(=O)C23CC4CC(CC(C4)C2)C3)sc2cc(S(C)(=O)=O)ccc21

Procedure:
The product from Example 62A, sodium hydride (60% solution in mineral oil) and 2-bromoethyl methyl ether were processed as described for Example 17B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61-1.80 (m, 6H), 1.87-1.94 (m, 6H), 1.99-2.07 (m, 3H), 3.24 (s, 3H), 3.26 (s, 3H), 3.78 (t, J=5.4 Hz, 2H), 4.63 (t, J=5.3 Hz, 2H), 7.82-7.91 (m, 1H), 7.93-8.03 (m, 1H), 8.46 (d, J=1.7 Hz, 1H); MS (ESI+) m/z 449 (M+H)+; Anal. Calculated for C22H28N2O4S2: C, 58.90; H, 6.29; N, 6.24. Found: C, 58.86; H, 6.30; N, 6.25.
Reaction SMILES: C([O:4][CH:5]1[CH2:13][C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]2[CH:7]([CH2:8][N:9]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10]2)[C:6]1=[O:33])(=O)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:26]([N:9]1[CH2:8][CH:7]2[CH:11]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13][CH:5]([OH:4])[C:6]2([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH3:34])[OH:33])[CH2:10]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(=O)OC1CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Temperature: 0 °C
Yield: 64.8 %

Procedure:
A solution of 22 g of (3aRS,5RS,7aRS)-5-acetoxy-2-benzyl-7,7-diphenylperhydroisoindol-4-one in 220 cm3 of tetrahydrofuran is added dropwise to a suspension of 84.4 g of 2-methoxyphenylmagnesium bromide in 1000 cm3 of tetrahydrofuran at room temperature, while stirring. The reaction mixture is stirred at room temperature for 18 hours, treated with 200 cm3 of an aqueous saturated solution of ammonium chloride and taken up in 200 cm3 of ethyl ether and 200 g of ice. The organic phase is separated by settling, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 250 cm3 of petroleum ether and then recrystallized from 200 cm3 of methanol; the crystals are washed with 200 cm3 of isopropyl ether. 16.4 g of (3aRS,4RS,5RS,7aRS)-2-benzyl- 7,7-diphenyl-4- (2-methoxyphenyl)perhydroisoindole-4,5-diol which melts at 236° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[N:3]=1>C(O)(=O)C.C(Cl)(Cl)Cl.[Zn]>[O:1]=[C:2]1[NH:3][C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:6]([C:8]([O:10][CH3:11])=[O:9])[NH:7]1
Reactant: COC(=O)c1cc(C(=O)OC)nc(O)n1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=CC(C(=O)OC)NC(=O)N1
Reaction time: 0.5 h

Procedure:
Dimethyl 2-hydroxypyrimidine-4,6-dicarboxylate (1.0 g. 4.7 mmol) was dissolved in warm acetic acid (17M. 70 ml) and heated to 70°. Zinc dust (1.5 g. 22.9 mmol) was added to this stirred solution portionwise over a period of 1 h. Each addition of a zinc portion was accompanied by a purple colour change of the reaction mixture. This colour slowly dissipated, then further zinc was added in similar fashion until completion. The resulting mixture was stirred at 70° for 30 min. The reaction mixture was filtered and washed with acetic acid (17M, 2×10 ml). The filtrate was evaporated to dryness under reduced pressure to give a colourless oil. The residual oil was dissolved in chloroform (100 ml), filtered and the solvent removed to give colourless crystals. The crude product was recrystallized from methanol to give dimethyl 2-oxo-1,2,3,6-tetrahydropyrimidine-4,6-dicarboxylate as colourless prisms, (283 mg. 28%) m.p. 177°-179°
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)C(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)c1cccnc1
Agent: [Li]CCCC
Product: COc1ccc(-c2cccnc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methylnicotinamide. After precipitation in aqueous phase at pH 4, followed by filtration and drying, a beige-coloured powder is obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:13]1[C:14]2[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: Fc1ccccc1Br
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccccc1-n1ccc2ccccc21
Temperature: 75 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.431 g, 10.0 mmol), and 2-bromofluorobenzene (1.75 g, 10.1 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (0.347 g, 0.30 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30.0 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.35 g (64%) of the product 4-(2-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5](OCC)=[O:6].C(O)C>C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH:3]2[CH2:2][NH:1][C:5](=[O:6])[CH:4]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(c1ccccc1)C(CN)c1ccc(Cl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1NCC(c2ccc(Cl)cc2)C1c1ccccc1

Procedure:
30 g. of ethyl 4-amino-3-p-chlorophenyl-2-phenyl-butyrate are heated for 15 minutes at 150°C. Liberation of ethanol is observed. The reaction medium is taken up in 120 ml. of toluene and the resulting solution is filered. After cooling the solution, the crystals formed are separated and recrystallized several times from toluene. 12 g. of 4-p-chlorophenyl-3-phenyl-2-pyrrolidinone are obtained; m.p. 148°-151°C. Nuclear magnetic resonance analysis shows that it is the cis-isomer.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[N:7][N:6]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[C:5]1=[O:23])[CH:2]=[CH2:3].[CH:24]([C:27]1[CH:34]=CC(CBr)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.O>[CH:24]([C:27]1[CH:28]=[CH:29][C:2]([CH2:1][N:4]2[C:9](=[O:10])[C:8]([O:11][CH3:12])=[N:7][N:6]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:5]2=[O:23])=[CH:3][CH:34]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1ccc(CBr)cc1
Reactant: C=CCn1c(=O)c(OC)nn(-c2cccc(NC(C)=O)c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(C(C)C)cc2)c1=O
Yield: 11.1 %

Procedure:
According to Scheme 3 Step 5: A suspension of compound 6(D) (60 mg, 0.22 mmol), 4-isopropylbenzyl bromide (41 μL, 0.24 mmol) and potassium carbonate (90 mg, 0.65 mmol) was stirred at 60° C. for 15 h in acetonitrile (2 mL). The mixture was diluted with AcOEt and water. The organic layer was washed twice with water and once with brine. The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (Merck Flashmart prepacked column 10 g SiO2) using CH2Cl2/MeOH 98/2 as eluent to afford N-(3-(4-(4-isopropylbenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 6(E) (10 mg, 11%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:29][C@H:30]3[CH2:34][CH2:33][C:32](=[O:35])[CH2:31]3)[C:17]([NH:19][C:20]3[N:21]=[CH:22][C:23]([C:26](O)=O)=[N:24][CH:25]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[OH:36]N1C2C=CC=CC=2N=N1.Cl.[CH3:47][N:48]([CH3:57])[CH2:49]CCN=C=NCC.Cl.CNC>CN(C=O)C.O.C(N(CC)CC)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:29][C@H:30]3[CH2:34][CH2:33][C:32](=[O:35])[CH2:31]3)[C:17]([NH:19][C:20]3[N:21]=[CH:22][C:23]([CH2:26][C:49]([N:48]([CH3:57])[CH3:47])=[O:36])=[N:24][CH:25]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C1CC[C@H](C[C@@H](C(=O)Nc2cnc(C(=O)O)cn2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cc1cnc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 5-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyrazine-2-carboxylic acid (102 mg), 1-hydroxybenzotriazole (44 mg), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide monohydrochloride (59 mg) in DMF (5 mL) were added dimethylamine monohydrochloride (22 mg) and triethylamine (0.09 mL) at room temperature. The reaction mixture was stirred at room temperature overnight, and water was then added thereto for liquid separation. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (wetting with hexane:ethyl acetate=1:1, chloroform:methanol=1:0-10:1) to obtain 5-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)-N,N-dimethylpyrazine-2-carboxyamide (64 mg) as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.CO[N:11](C)[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+:22]>O1CCCC1.C([N-]C(C)C)(C)C.[Li+]>[Cl:1][C:2]1[N:3]=[C:4]2[NH:22][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Fc1cccc(Cl)n1
Reactant: [NH4+]
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc2c(-c3ccccc3)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-6-fluoropyridine (1.0 g, manufactured by Matrix Chemical LLC) in tetrahydrofuran (40 mL, manufactured by Kanto Chemical Co., Inc.), lithium diisopropylamide (23% solution in tetrahydrofuran/ethylbenzene/heptane, 5.07 mL, manufactured by Sigma-Aldrich Corp.) was added dropwise at −78° C., and the mixture was stirred for 30 minutes. Subsequently, N-methoxy-N-methylbenzamide (1.27 mL, manufactured by Sigma-Aldrich Corp.) was added thereto at the same temperature, and while the temperature was gradually raised to room temperature, the mixture was stirred overnight. A saturated aqueous solution of ammonium chloride (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×30 mL), washed with brine (30 mL), and dried (MgSO4). The solvent was then evaporated, and isopropanol (20 mL, manufactured by Kanto Chemical Co., Inc.) and hydrazine hydrate (1.22 mL, manufactured by Tokyo Chemical Industry Co., Ltd.) were added to the obtained residue. The mixture was heated and stirred for 12 hours at 80° C. The mixture was cooled to room temperature, and then hexane (10 mL) was added to the reaction solution. The solvent was evaporated, to give 180 mg of the title compound. LC-MS: HPLC retention time 1.53 minutes, m/z (M+H) 230, condition C-1.