Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Product: O=C(Cl)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6-benzyloxycarbonylamino-hexanoic acid(2.65 g, 10 mmol) in thionyl chloride (15 ml) was heated to reflux 1 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo to give (5-chlorocarbonyl-pentyl)-carbamic acid benzyl ester as tan oil. The oil was used without further purification. (5-Chlorocarbonyl-pentyl)-carbamic acid benzyl ester was dissolved in THF (50 ml). To this solution was added 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.37 g, 5 mmol). The resulting suspension was to reflux for 4 hours. The solvent was evaporated in vacuo and the resulting solid was partially purified by flash chromatography (60/40 ethyl acetate/hexane) to give a light yellow solid. The solid was recystallized from minimal ethyl acetate to give 1.24 g (48%) of product as an off-white solid: mp 122-125° C.; 1H NMR (DMSO-d6) 11.18 (s, 1H), 9.70 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.34-7.24 (m, 6H), 5.16 (dd, J=5.1 and 12.6 Hz, 1H), 5.00 (s, 2H), 3.02-2.84 (m, 3H), 2.65-2.43 (m, 4H), 2.12-2.05 (m, 1H), 1.65-1.15 (m, 6H; 13C NMR (DMSO-d6) 172.75, 171.95, 169.77, 167.72, 166.67, 156.08, 137.29, 136.57, 136.09, 131.43, 128.32, 127.70, 126.21, 118.25, 116.90, 65.08, 48.92, 36.47, 30.94, 30.67, 29.14, 25.77, 24.47, 21.99; Anal. Calcd. For C27H28N4O7: C, 62.30; H, 5.42; N, 10.76. Found: C, 62.40; H, 5.31; N, 10.48.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=O)[NH:10][C:9]([S:13][CH3:14])=[N:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])C.O=P(Cl)(Cl)Cl.[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C([O-])(=O)C>[OH:5][C:4]1[C:6]2[C:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=2[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1c(-c2ccccc2)nc(SC)[nH]c1=O
Agent: CC(=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1sc2nc(SC)nc(-c3ccccc3)c2c1O

Procedure:
Treatment of 5-ethyloxycarbonyl-2-methylthio-4-phenyl-6-oxopyrimidine (63 mg) with POCl3 (304 μl) and subsequent reaction of the product with ethyl 2-mercaptoacetate were performed according to the methods described in example 1. The pure title compound was obtained after chromatography on silicagel in heptanelethyl acetate 100/0→60/40 (v/v) as eluent.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.[SH:15][C:16]1[NH:17][C:18]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=2[N:20]=1>C(O)C.[OH-].[Na+]>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([S:15][CH2:2][C:3]3[N:8]=[C:7]([N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)[CH:6]=[CH:5][N:4]=3)=[N:17][C:18]=2[CH:24]=1
Reactant: ClCc1nccc(N2CCCCC2)n1
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3nccc(N4CCCCC4)n3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
A mixture of 2-chloromethyl-4-piperidino-pyrimidine (2.89 g) and 2-mercapto-5-methoxybenzimidazole (2.46 g) in ethanol (40 ml) and 1N sodium hydroxide (15 ml) was stirred at room temperature for 16 hours. After stripping the residue was washed with water and recrystallised from acetonitrile to give 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (3.5 g) m.p. 145°-147°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:15]=[N:16][C:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([CH3:21])[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([C:17]1[N:16]=[N:15][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[C:19]([CH3:20])[C:18]=1[CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(Cc2ccccc2)nnc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(C2=CCNCC2)c1C
Reaction time: 0.17 h
Yield: 125 %

Procedure:
To 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (170 mg, 0.358 mmol) is added 50% TFA in DCM. The reaction mixture is stirred for 10 min and concentrated to afford 3-benzyl-4,5-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazine as a yellow sticky solid (125 mg, 100%). To a solution of 3-benzyl-4,5-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazine (180 mg, 0.644 mmol) in dioxane is added methyl-5-chloropyrazine-2-carboxylate (222 mg, 1.29 mmol) and TEA (0.45 mL, 3.22 mmol) in a microwave tube. The reaction mixture is heated at 160° C. for 40 min in a microwave reactor. The mixture is concentrated to afford a brown oil and purified by prep HPLC, eluting with 10%-100% acetonitrile:water (both mobile phases modified by 3% n-PrOH). Fractions containing the desired product are combined and freeze-dried to afford a white solid (80 mg, 30%).
Reaction SMILES: CI.[C:3]([C@@H:6]1[CH2:10][C@H:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][NH:7]1)(=[O:5])[NH2:4].[C:21](=O)(O)[O-].[Na+]>CN(C)C=O>[C:3]([C@@H:6]1[CH2:10][C@H:9]([S:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:8][N:7]1[CH3:21])(=[O:5])[NH2:4]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.07 ml of methyl iodide was added, whilst ice-cooling, to a solution of 0.6 g of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (5) above] dissolved in 4.5 ml of dry dimethylformamide. The mixture was then stirred at 0° to 5° C. for 5 minutes and at room temperature for 20 minutes. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then the residue was subjected to column chromatography using a Lobar column (Merck, LiChroprep Si 60, size B), and 252 mg of the title compound, melting at 113°-114° C., were obtained as crystals from the fractions eluted with a 9:1 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:4]=2[N:3]=1.[C:22](OC)(=[O:25])[C:23]#[CH:24]>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[N:3]3[CH:24]=[CH:23][C:22](=[O:25])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=3[F:16])[C:5]=2[CH:17]=1
Reactant: C#CC(=O)OC
Reactant: NC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Solvent: CO
Product: O=c1ccn2c(n1)CN=C(c1c(F)cccc1F)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 2, 2-amino-7-chloro-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 9-chloro-7-(2,6-difluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](O)=[O:34]>>[OH:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH2:19][CH:10]([N:9]([CH2:21][CH2:22][CH3:23])[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:33]([C:25]3[NH:24][C:32]4[C:27]([CH:26]=3)=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:34])[CH2:3][CH2:2]1)[CH2:11]2
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Product: CCCN(CCN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1)C1CCc2c(O)cccc2C1
Yield: 49.6 %

Procedure:
Compound 40e was prepared following Procedure G using 39b (43 mg, 0.14 mmol) and indole-2-carboxylic acid (30 mg, 0.19 mmol) to give 40e (32 mg, 62%) after column chromatography. 1H NMR (400 MHz, CD3OD) δ 1.02-1.06 (t, 3H, J=7.2 Hz), 1.77-1.79 (m, 3H), 2.27 (m, 1H), 2.63-2.66 (bs, 4H), 3.03-3.16 (m, 5H), 3.30-3.41 (m, 3H), 3.89 (bs, 4H), 6.59-6.61 (d, 1H, J=7.6 Hz), 6.63-6.65 (d, 1H, J=8 Hz), 6.84 (s, 1H), 6.94-6.98 (t, 1H, J=7.2 Hz), 7.04-7.08 (t, 1H, J=7.2 Hz), 7.19-7.23 (t, 1H, J=7.2 Hz), 7.41-7.61 (d, 1H, J=8 Hz), 7.59-7.61 (d, 1H, J=8 Hz). The free base of 40e was then converted into its HCl salt. m.p. 166-165° C. Anal. [C28H36N4O2.3HCl] C, H, N.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][N:6]2[N:5]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+].CCOC(C)=O>C1COCC1>[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH:15][C:33](=[O:35])[CH3:34])[CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: Cc1nn2ccc(OCCN)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)NCCOc1ccn2nc(C)c(-c3nc(-c4ccccc4)c(-c4nc[nH]n4)s3)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a suspension of 2-({2-methyl-3-[4-phenyl-5-(1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridin-5-yl}oxy)ethanamine di-hydrochloride (100 mg, 0.20 mmol) obtained in Example 73-B(i) and TEA (0.75 mL) in THF (10 mL), was added acetic anhydride (0.5 mL, 5.3 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (50 mL) and EtOAc (50 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc and diisopropyl ether, and dried to give the title compound (33 mg, 35%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][CH:20]([CH3:22])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]#[N:25])=[CH:3][C:4]=3[CH3:23])[N:12]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(Br)ccc1-c1noc(-c2ccc(CC(C)C)cc2)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)ccc1-c1noc(-c2ccc(CC(C)C)cc2)n1

Procedure:
A solution of 2.3 g (6.2 mmol) of 3-(4-bromo-2-methylphenyl)-5-(4-(2-methylpropyl)phenyl)-1,2,4-oxadiazole (from Step A), 1.46 g (12.4 mmol) of zinc cyanide and 2.15 g (1.86 mmol) of Pd(PPh3)4 in 20 mL of DMF was stirred at 100° C. for 20 h. The reaction was cooled and quenched with 10 mL of sat'd NaHCO3. The quenched mixture was extracted with 100 mL of dichloromethane. The extract was dried and concentrated to afford 1.40 g of the title compound which was used without further purification: ESI-MS 318 (M+H); LC-1: 4.8 min.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2ncccc2C)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ncccc2C)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(3-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 70) (161 mg, 0.310 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1.5 h then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined and concentrated in vacuo to give a residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.22 mL, 0.220 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-(3-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (103.3 mg, 0.214 mmol, 68.9% yield) as a light brown solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].N1(CC2C=CC(O)=CC=2)CCCC1.[CH2:20]([N:27]([CH3:35])[C:28]([CH:30]1[CH2:33][C:32](=[O:34])[CH2:31]1)=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>C1COCC1.O>[CH2:20]([N:27]([CH2:28][C@@H:30]1[CH2:31][C@H:32]([OH:34])[CH2:33]1)[CH3:35])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CC(=O)C1
Agent: Oc1ccc(CN2CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C[C@H]1C[C@@H](O)C1

Procedure:
LiAlH4 (5.4 g, 0.14 mol) was added to a solution of intermediate 2, N-Benzyl-N-methyl-3-oxocyclobutanecarboxamide (15.5 g, 0.07 mol) in absolute THF (100 mL) under stirring in argon. The mixture was refluxed under stirring for 2 h and cooled. Then 10 N NaOH (14 mL) and water (5 mL) were added. The organic layer was decanted, and the aqueous one was extracted with THF (2×50 mL). The organic layers were evaporated to afford the title compound (8.6 g, 59%) as a colorless oil. 1H NMR-data (DMSO-d6): 7.19-7.33 (m, 5H, Ph); 4.85 (d, 1H, OH, J=6.6); 3.83-3.94 (m, 1H); 3.40 (s, 2H, CH2); 2.24-2.34 (m, 4H); 2.07 (s, 3H, NCH3); 1.81-1.92 (m, 1H); 1.34-1.44 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])=[N:3][CH:2]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl.O>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccncn1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccncn3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of 4-(1-(pyrimidin-4-yloxy)ethyl)benzoic acid (0.1 g, 0.4 mmol) in anhydrous dichloromethane (20 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (85 mg, 0.6 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120 mg, 0.6 mmol) and triethylamine (0.2 mL, 1.2 mmol), and stirred at room temperature for 0.5 hour, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (90 mg, 0.6 mmol) was added and stirred for 3 hours. To the reaction mixture was added water (20 mL), extracted with dichloromethane (20 mL) two times, combined and concentrated the organic layers, the residue was purified by column chromatography with dichloromethane/methanol=15:1 to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyrimidin-4-yloxy)ethyl)benzamide (60 mg, 40% yield). LRMS (M+H+) m/z: calcd for 378.17. found 378. HPLC purity (214 nm): 98%. 1H NMR (CD3OD, 300 MHz) δ 8.67 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 6.98 (dd, J=6.0 and 1.2 Hz, 1H), 6.36 (q, J=6.6 Hz, 1H), 6.15 (s, 1H), 4.52 (s, 2H), 2.39 (s, 3H), 2.28 (s, 3H), 1.69 (d, J=8.7 Hz, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:15]=[O:16])=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Br)c(C(F)(F)F)c1
Reaction time: 18 h
Yield: 86 %

Procedure:
A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CH2Cl2 (500 mL), then concentrated under reduced pressure. The CH2Cl2 treatment/concentration protocol was repeated and resulting amber oil was stored at −20° C. for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+).
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=C[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CNOC.[O:39]1[CH2:44][CH2:43][CH2:42][O:41][CH:40]1[C:45]1[CH:50]=[CH:49][C:48]([C:51]2[S:52][C:53]3[CH:59]=[C:58]([C:60]([OH:62])=O)[CH:57]=[CH:56][C:54]=3[N:55]=2)=[C:47]([F:63])[CH:46]=1>CN(C=O)C.O>[O:39]1[CH2:44][CH2:43][CH2:42][O:41][CH:40]1[C:45]1[CH:50]=[CH:49][C:48]([C:51]2[S:52][C:53]3[CH:59]=[C:58]([C:60]([N:9]([O:8][CH3:4])[CH3:10])=[O:62])[CH:57]=[CH:56][C:54]=3[N:55]=2)=[C:47]([F:63])[CH:46]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Reaction time: 0.5 h

Procedure:
HBTU (0.80 g, 2.11 mmol) was added to a solution of di-isopropylethylamine (0.61 mL, 3.52 mmol), N,O-dimethylhydroxylamine hydrochloride (0.21 g, 2.11 mmol), and 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)benzo[d]thiazole-6-carboxylic acid (0.51 g, 1.41 mmol) in DMF (7 mL). The reaction mixture was stirred for 30 min, diluted with water, and extracted with EtOAc three times. The combined extracts were dried (MgSO4), concentrated under vacuum, and purified by silica gel chromatography to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-N-methoxy-N-methylbenzo[d]thiazole-6-carboxamide as an oil. MS (ESI) m/z: Calculated: 402.1; Observed: 403.1 (M++1).
Reaction SMILES: C[Si]([N:5]([Si](C)(C)C)[C:6]1[NH:7][C:8]([C:19]#[N:20])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])(C)C.Cl>CO>[NH2:5][C:6]1[NH:7][C:8]([C:19]#[N:20])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18]
Reactant: C[Si](C)(C)N(c1[nH]c(C#N)cc1-c1ccc(Cl)cc1Cl)[Si](C)(C)C
Agent: Cl
Solvent: CO
Product: N#Cc1cc(-c2ccc(Cl)cc2Cl)c(N)[nH]1

Procedure:
A solution of 2-(di(trimethylsilyl)amino-3-(2,4-dichlorophenyl)-5-cyanopyrrole (4, 11.8 g, 30 mmol) in methanol (50 ml) is treated with 2N aqueous hydrochloric acid (30 ml). The mixture is heated to reflux for 1 hour and concentrated in vacuo. The aqueous phase then is basified with solid sodium carbonate and the product is extracted with ethyl acetate. The extract is washed with brine, dried over MgSO4 and concentrated in vacuo to give the product.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[S:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16]([C:18]1[CH:22]=[C:21]([NH2:23])[N:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=1)=[O:17])[CH3:14].IN1C(=O)CCC1=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[C:22]2[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=3)=[N:23][C:21]=2[N:20]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:19]=1)=[O:17])[CH3:14]
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: CCOC(=O)c1cc(N)n(C(C)(C)C)c1
Agent: O=C1CCC(=O)N1I
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(NC(=O)c3ccc(C)cc3)sc12
Temperature: 0 °C
Yield: 41 %

Procedure:
4-Methyl-benzoyl isothiocyanate (4.5 ml, 29.5 mmol) was added neat, via syringe under N2 blanket, to a stirred solution of 5-amino-1-tert-butyl-1H-pyrrole-3-carboxylic acid ethyl ester (5.6 g, 26.6 mmol) in anhydrous THF (270 ml), and brought to reflux for 1.5 hours. The solution was chilled to 0° C., then neat N-iodosuccinimide (6.6 g, 29.3 mmol) was added, and the solution was allowed to stir and warm to ambient temperature overnight for 16 hours. Reaction was slowly poured into a stirred 10% (w/v) sodium metabisulfite aqueous solution (200 ml), then extracted with ethyl acetate, dried (MgSO4), and flash chromatographed (silica gel, 25% (v/v) EtOAc/hexanes). Isolated product was crystallized from ethyl acetate/hexanes to afford 4.2 g (41%) of white powder, mp. 200-201° C. MS:M+H=386.
Reaction SMILES: O.[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].[NH:14]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:15]([C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1>CN(C=O)C>[NH:14]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:15]([C:26]([NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:10])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
2.00 equivalents water and 1 equivalent Arg (Mw=174.2) were mixed with DMF and stirred at room temperature until a solution was obtained. 1.03 equivalents of Z-Trp-OSu (Mw=435.45; purity=98%) were dissolved in DMF and poured in the arginine solution. Stirring was then continued at room temperature for at least 5 hours. After checking the termination of the reaction by HPLC, the reaction mixture was precipitated by adding slowly cold acetonitrile (0±5° C.) and kept at this temperature for at least 30 minutes before filtration. The precipitate was washed 3 times with a mixture of CH3CN/IPE(Isopropylether) (1/1) and then 2 times with IPE. The solid was then dried in vacuo at 45° C. A white solid was finally obtained.