Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH3:36])[C:20]1=[O:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C:19]2([NH2:18])[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH3:36])[C:20]2=[O:37])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1C(=O)C(N)N=C(N2CCCCC2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(N2CCCCC2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1,3-dihydro-1-methyl-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2-one (Example 8-A), the title compound was prepared as a white solid having a melting point of 154-160° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([CH3:21])[C:17]=1S(C)=O)[CH3:2].CS(C)=[O:26].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([CH3:21])[C:17]=1[OH:26])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)=O)c(C)nn(C)c1=O
Reactant: CS(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a 50 ml volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfinyl-2,3-dihydro-3-pyridazinone ((2-19)-(1)-39) (0.60 g), DMSO (2.73 ml), and 10% of aqueous tetra-n-butylammonium hydroxide solution (9.4 g) were added under a nitrogen atmosphere, and stirred at 90° C. for 2 hours. The reaction mixture was added to water and hydrochloric acid was added to adjust pH to less than 2. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform) to give 0.33 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:19][C:18]([CH3:20])=[C:17]3[C:13]=2[CH2:14][C@H:15]2[C:21]([CH3:23])([CH3:22])[C@H:16]23)=[O:11])=[C:4]([O:24][CH3:25])[CH:3]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:25][O:24][C:4]1[CH:3]=[C:2]([O:1][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][C:10]([C:12]1[S:19][C:18]([CH3:20])=[C:17]2[C:13]=1[CH2:14][C@H:15]1[C:21]([CH3:22])([CH3:23])[C@H:16]12)=[O:11]
Reactant: ClCC1CO1
Reactant: COc1cc(O)ccc1CCC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc(OCC2CO2)ccc1CCC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 9 h
Yield: 66.2 %

Procedure:
A solution of 3-(4-hydroxy-2-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (600 mg, 1.68 mmol, Intermediate 20) in isopropanol (10 mL) and 3 N aq. NaOH (6 mL) is treated with epichlorohydrine (631 mg, 5.05 mmol). The reaction mixture is stirred at rt for 9 h before it is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(2-methoxy-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (459 mg) as an almost colourless oil; LC-MS: tR=1.13 min, [M+1]+=413.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([NH:8]C(=O)C)[CH:7]=1>O.CC(O)C>[NH2:8][C:6]1[C:5]([OH:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(=O)Nc1cc(Cl)cc([N+](=O)[O-])c1O
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 30 °C
Yield: 91 %

Procedure:
230.6 g (1 mole) of N-(5-chloro-2-hydroxy-3-nitrophenyl)acetamide prepared according to Example 1b was suspended in a mixture of 950 ml of water and 100 ml of 2-propanol under a mild nitrogen purge. 345 ml of 36% w/w hydrochloric acid was added followed by 25 ml of water. The mixture was heated to reflux in about 30° C., while vigorously stirring and refluxed for 2 hours. The mixture was cooled to 0-5° C. in about one hour and stirred for an additional hour at 0-5° C. The solid was filtered off, washed twice with 250 ml of water, and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 91%.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:20][CH2:21][CH2:22][NH2:23])[CH2:18][CH3:19]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:23][CH2:22][CH2:21][O:20][CH2:17][CH2:18][CH3:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCOCCN
Product: CCCOCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 77.8-78.9° C. and MS: m/e=297 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 2-propoxy-ethylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]2[C@@H:30]([CH3:31])[C@@H:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:38])[CH:7]=1)[CH3:2].IC.[CH3:42][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:39])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]2[C@@H:30]([CH3:31])[C@@H:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:28][C:27]2=[O:38])[CH:7]=1)[CH3:42])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To {4-methoxy-3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid ethyl ester (0.242 g, 0.45 mmol) and iodomethane (0.03 mL, 0.45 mmol) in THF (5 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1M in THF; 0.45 mL, 0.45 mmol). The reaction was stirred at −78° C. for 1 hour, and then at room temperature for 1 hour. The mixture was partitioned between H2O and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][N:3]=[CH:2]1.O.NN.Cl.N1(CCCCCCCCN2C(=O)C3C(=CC=CC=3)C2=O)C=CN=C1.N1(CCCCCCCCN)C=CN=C1>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1
Agent: Cl
Agent: NCCCCCCCCn1ccnc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCn1ccnc1

Procedure:
A mixture of 0.2 mole of 2-[4-(1H-imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-dione, 0.22 mole of hydrazine hydrate and 400 ml of ethanol was heated on a steam bath for 3 hours and then treated with 400 ml of 3N hydrochloric acid and heated at reflux for an additional 2 hours. The insoluble material was filtered off and the mother liquor was concentrated to a low volume and again filtered. The remainder of the volatile material was distilled off and the residue was treated with saturated potassium carbonate solution. The 1H-imidazole-1-butanamine was extracted into methylene chloride and further purified by distillation on a Kugelrohr apparatus. In a like manner from 2-[5-(1H-imidazol-1-yl)pentyl]-1H-isoindole-1,3(2H)-dione was prepared 1H-imidazole-1-pentanamine and from 2-[8-(1H-imidazol-1-yl)octyl]-1H-isoindole-1,3(2H)-dione was prepared 1H-imidazole-1-octanamine.
Reaction SMILES: [CH:1]1([N:4]([CH3:18])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][Si](C)(C)C)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=2)[CH3:18])[CH2:3][CH2:2]1
Reactant: CN(Cc1cccc(C#C[Si](C)(C)C)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(CN(C)C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution cyclopropyl-methyl-(3-trimethylsilanylethynyl-benzyl)-amine (Intermediate 90, 0.355 g, 1.38 mmol) in methanol (10 mL) was treated with potassium carbonate (0.13 g, 0.95 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (0.22 g, 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:2]=1.[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NCCN2CCOCC2)CCCCC1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[NH2:20][C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[NH:15][C:12]([C:10]1[N:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[S:8][CH:9]=1)=[O:14])=[O:19]
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: NC(=O)c1ccccc1N
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccccc1NC(=O)c1csc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-(3-Pyridyl)thiazole-4-carboxylic acid (206 mg, 1 mmol) and 2-amino-benzamide (163 mg, 1.2 mmol) are mixed, and chloroform (10 ml) and pyridine (1.2 ml) are added. Then 1-hydroxybenzotriazole hydrate (230 mg) and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-P-toluene-sulphonate CAS[2491-17-0] (635 mg) are added, and the mixture is stirred at room temperature for 20 h. The solid is filtered off with suction and washed with ethyl acetate, water and again with ethyl acetate. Purification of the solid by preparative HPLC results in Example 1.1 as a white foam (58 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Product: CC(=O)N1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(1-Acetyl-4-piperidinyl)propionic acid (10.0 g) was added by portions to thionyl chloride (30 ml) at room temperature. After stirring at room temperature for 30 minutes, thionyl chloride was evaporated under reduced pressure to give the crude product of 3-(1-acetyl-4-piperidinyl)propionyl chloride. Aluminum chloride (20 g) was added by portions to a suspension of the crude product and 2,2,2-trifluoro-N-(2-methoxyphenyl)acetamide (10.0 g) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was poured into ice (200 g), extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate), and the solvent was evaporated to give the title compound as colorless crystals (8.83 g) having a melting point of 77 to 79° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].N1C=CC=CC=1.[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>CN(C)C1C=CN=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCCCl
Yield: 73 %

Procedure:
A mixture comprising 4-chlorobutyryl chloride (12.6 g, 89.2 mmol), tert-butanol (25 mL), pyridine (6.9 g, 86.5 mmol) and 4-dimethylaminopyridine (1.0 g, 8.2 mmol) was heated at 50° C. under an atmosphere of dry nitrogen for 12 hours to give a white suspension. The suspension was partitioned between ethyl ether (250 mL) and water and the organic layer was separated and washed repeatedly with water then 0.1M aqueous hydrochloric acid, saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a colorless oil. The oil was distilled at 0.5 mmHg (51° C.) to provide tert-butyl 4-chlorobutyrate as a colorless liquid (11.27 g, 73% yield); 1H NMR (300 MHz, CDCl3): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]3)=[C:20]3[CH2:26][CH2:25][CH:24]([OH:27])[C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:42].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:29]3)=[C:20]3[CH2:26][CH2:25][C:24](=[O:27])[C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:42]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3=O)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.5 %

Procedure:
To a solution of tert-butyl {(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (100 mg, 0.17 mmol) in DCM (0.8 mL), Dess-Martin periodinane (95 mg, 0.22 mmol) was slowly added. The reaction mixture was stirred at room temperature for 40 min. The reaction mixture was neutralized with 1 M NaOH, diluted with MeOH, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography using CombiFlash® (0 to 100% EtOAc in hexanes) to give light brown powder as the sub-title compound (41 mg, 41%). LCMS calc. for C30H31F3N5O4 (M+H)+: m/z=582.2. Found: 582.2.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1ccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-n2nccn2)c1
Product: Cc1ccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)c(-n2nccn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A89 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 426 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.45-6.45 (m, 8H), 4.90-2.70 (m, 5H), 2.35-0.65 (m, 11H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C:6]=2[CH:21]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH3:13])[C:6]=3[CH:21]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(N)ccc21
Product: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(Nc3ccc(Br)cc3)ccc21

Procedure:
Prepared from 6-amino-4-(4-chlorophenyl)-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+(457/459/461); MS (ESI) m/z [M−H]−(455/457/459); Anal. calcd for C22H18BrClN2O2: C, 57.73; H, 3.96; N, 6.12. Found: C, 56.88; H, 3.90; N, 5.70.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[SH:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].N12CCCN=C1CCCCC2>CN(C=O)C.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:3][CH:4]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCSc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Chloro-5-cyanopyridine (500 mg, 3.6 mmol), tert-butyl (2-mercaptoethyl)carbamate (426 mg, 2.4 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (549 mg, 3.6 mmol) are dissolved in DMF (5 ml) and stirred at RT under argon for 12 h. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (3×75 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. After removal of the solvent, the residue is purified by preparative RP-HPLC (gradient of eluent: water/acetonitrile 90:10 to 10:90). 612 mg (91% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([C:5]1[N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[C:9](=[O:11])[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 28.8 %

Procedure:
To a solution of 2-butyl-6-methylpyrimidin-4(3H)-one (3.38 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (6.64 g) in acetonitrile (50 mL) was added cesium carbonate (8.61 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (2.09 g, 29%) as a colorless viscous substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11](S(C)(=O)=O)[C:10]([CH3:17])([CH3:16])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[OH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:16][C:10]1([CH3:17])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=[C:2]([O:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[CH:3]=[C:4]2[NH:11]1
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1S(C)(=O)=O
Reactant: N#Cc1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Cn2c(cc(OCc3cccc(C#N)c3)nc2=O)N1

Procedure:
To a solution of 7-chloro-2,2-dimethyl-1-(methylsulfonyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (200 mg, 0.720 mmol) and 3-(hydroxymethyl)benzonitrile (288 mg, 2.16 mmol) in N,N-dimethylformamide (DMF) (3.5 mL) was added K2CO3 (299 mg, 2.16 mmol). The reaction mixture was sealed in a microwave vial and irradiated with a microwave using initial normal to 100° C. for 1 h. Purification via mass-directed auto-preparation afforded the title product as a white solid.
Reaction SMILES: [N:1]1([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5]1)(=[O:32])=[O:31]
Reactant: CCOC(=O)C1(N2CCNCC2)CCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)CCC1

Procedure:
Ethyl 1-(piperazin-1-yl)cyclobutanecarboxylate (0.71 mmol) was dissolved in CH2Cl2 (5 ml). Triethylamine (0.30 ml, 2.1 mmol), followed by 2-chlorobenzenesulfonyl chloride (0.11 ml, 0.79 mmol), was added at room temperature. The orange-colored solution was stirred at room temperature for 6 h before saturated NaHCO3 solution was added. The mixture was extracted twice with EtOAc. Combined organic layers were washed once with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, gradient 5-10% Et2O/CH2Cl2) to give ethyl 1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)cyclobutanecarboxylate as a colorless oil.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])(C)(C)C.C(OC([NH:21][C@H:22](C(O)=O)[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.C(OC(N[C@H](C(O)=O)COCC1C=CC=CC=1)=O)(C)(C)C.C(OC(N[C@H](C(O)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1)=O)(C)(C)C.C(N[C@H](C(O)=O)CC1N=CNC=1)C1C=CC=CC=1.[N+](C1C=CC(OC(=O)[C@H](CCC(=O)N)NC(OCC2C=CC=CC=2)=O)=CC=1)([O-])=O>CN(C)C=O>[NH2:21][C@H:22]([C:6]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Nα -Benzyloxycarbonyl-L-glutaminyl-L-prolyl-Nim -benzyl-L-histidyl-Nim -benzyl-L-histidyl-O-benzyl-L-tyrosyl-O-benzyl-L-seryl=l-tryptophyl-D-alanine resin is prepared by the General Procedure, given below, by successive coupling of 30 g. (0.0198 mol) of Nα -t-butoxycarbonyl-D-alanine resin with 1.) 9.1 g (0.03 mol) of Nα -t-butoxycarbonyl-L-tryptophan and 6.8 g. (0.03 mol) of dicyclohexylcarbodiimide, 2.) 9.0 g. (0.03 mol) of Nα -t-butoxycarbonyl-O-benzyl-L-serine and 6.8 g. (0.033 mol) of dicyclohexylcarbodiimide, 3.) 11.1 g. (0.03 mol) of Nα -t-butoxycarbonyl-O-benzyl-L-tyrosine and 6.8 g. (0.033 mol) of dicyclohexylcarbodiimide, 4.) 10.5 g. (0.03 mol) of Nα -t-butoxycarbonyl-Nim -benzyl-L-histidine and 6.8 g. (0.033 mol) of dicyclohexylcarbodiimide, 5.) 10.5 g. (0.03 mol) of Nα -t-butoxycarbonyl-Nim -benzyl-L-histidine and 6.8 g. (0.033 mol) of dicyclohexylcarbodiimide, 6.) using 2/3 of the resin obtained in Step 5 with 4.4 g. (0.02 mol) of Nα -t-butoxycarbonyl-L-proline and 4.6 g. (0.022 mol) of dicyclohexylcarbodiimide and 7.) using 1/2 of the resin obtained in Step 6 with 8 g. (0.02 mol) of Nα -benzyloxycarbonyl-L-glutamine p-nitrophenyl ester in dimethylformamide solution and the excess removed by drainage.