Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:13](=[O:27])[C@@H:12]([CH2:28][C:29]([O:31]CC)=[O:30])[O:11]2)=[C:6]([O:34][CH3:35])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO.O1CCCC1>O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:13](=[O:27])[C@@H:12]([CH2:28][C:29]([OH:31])=[O:30])[O:11]2)=[C:6]([O:34][CH3:35])[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1O[C@H](c2ccc(OCC)cc2OC)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOc1ccc([C@H]2O[C@H](CC(=O)O)C(=O)N(CC(C)(C)C)c3ccc(Cl)cc32)c(OC)c1

Procedure:
A mixture of ethyl trans-5-(4-ethoxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (0.18 g), potassium carbonate (0.10 g), methanol (10 ml), tetrahydrofuran (10 ml) and water (5 ml) was refluxed for 1.5 h. The resulting mixture was concentrated in vacuo, acidified with 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo to give trans-5-(4-ethoxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid as colorless crystals (mp=230°-232° C.).
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
0.34 g. of 1-benzyloxy-2-[(2,6-dichlorophenyl)-imino]imidazolidine is hydrogenated under normal pressure in 5 ml. of ethanol and 2 ml. of 1N hydrochloric acid in the presence of 0.05 g. of palladium-on-charcoal (5%). After the uptake of hydrogen has ended, the catalyst is filtered off and the solution is evaporated. The residue is dissolved in water and the solution is adjusted to pH 10 with caustic soda solution and extracted, first with methylene chloride and then with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated to dryness in vacuo. The residue is recrystallized from acetonitrile, whereupon 2-[(2,6-dichlorophenyl)imino]-1-hydroxy-imidazolidine, m.p. 196°, is obtained. Recrystallization from methanol/acetonitrile raises the melting point to 215°.
Reaction SMILES: [C:1]([C:3]1([NH:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[OH-:15].[K+].[Cl-:17].[NH4+]>CO.O>[ClH:17].[CH2:10]([C:9]1[NH:2][C:1](=[O:15])[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[N:8]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(=O)NC1(C#N)CCCC1
Reactant: [OH-]
Reactant: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCCC1=NC2(CCCC2)C(=O)N1
Product: Cl
Temperature: 55 °C
Yield: 60.7 %

Procedure:
To 19.6 g (0.1 mol) of 1-cyano-1-n-pentanoylaminocyclopentane dissolved in 70 ml of methanol, 25 g (0,46 mol) of potassium hydroxide dissolved in 50 ml of water was added. The resulting solution was stirred and heated at 50-60° C., then under reflux conditions for 2,5 hours. The pH was decreased by the addition of 25 g of ammonium chlorid, then methanol was distilled off. The residue was extracted with 50 ml and 2×30 ml of toluene, the combined organic phases were evaporated to constant weight The residual 16 g of title compound was dissolved in 100 ml of acetone, the pH of the resulting solution was adjusted to 1-2 with hydrochloric acid solution, the mixture was crystallized, the crystals were collected by filtration to obtain 14 g of the title compound, yield 60.8%.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]([CH:15]2[C:24]3[C:23](=[O:25])[CH2:22][CH:21]([CH2:26][CH2:27][CH3:28])[CH2:20][C:19]=3[NH:18][C:17]([CH3:29])=[C:16]2[C:30]#[N:31])[CH:12]=[C:11]([O:32][CH2:33][CH3:34])[C:3]=1[O:4][CH2:5][CH:6]=[CH:7][C:8](O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:68][O:69][CH2:70][CH2:71][NH2:72]>ClCCl.O>[CH3:68][O:69][CH2:70][CH2:71][NH:72][C:8](=[O:9])[CH:7]=[CH:6][CH2:5][O:4][C:3]1[C:11]([O:32][CH2:33][CH3:34])=[CH:12][C:13]([CH:15]2[C:24]3[C:23](=[O:25])[CH2:22][CH:21]([CH2:26][CH2:27][CH3:28])[CH2:20][C:19]=3[NH:18][C:17]([CH3:29])=[C:16]2[C:30]#[N:31])=[CH:14][C:2]=1[Br:1]
Reactant: COCCN
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CC(=O)O)c(OCC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CC(=O)NCCOC)c(OCC)c1
Reaction time: 2 h

Procedure:
A mixture of 4-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxy-phenoxy]-but-2-enoic acid (0.1 g), HATU (0.108 g), DiPEA (165 μl) and 2-methoxyethylamine (25 μl) in dichloromethane was stirred for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 65.5 mg. MS-ESI: [M+H]+=586.4/588.4; HPLC: Rt=16.39 min. (method 1). Diast. ratio: 5:1
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCC[C@@H](C)CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC[C@H](C)CCCC(C)C)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
A solution of 6.5 g (41 mmol) of (R)-3,7-dimethyl-1-octanol and 7.8 g (41 mmol) of p-toluenesulphonyl chloride in 50 ml of absolute chloroform is treated at 0° with 7.9 g (0.1 mol) of absolute pyridine. The mixture is subsequently stirred at 4° for 20 hours. For the working-up the mixture is poured on to 500 g of ice and extracted three times with chloroform. The combined organic phases are washed first with cold 1-N hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and subsequently with saturated aqueous common salt solution. After drying over potassium carbonate and removal of the solvent under reduced pressure, the crude product is chromatographed on 300 g of silicagel with benzene. There are obtained 11.4 g (89%) of (R)-3,7-dimethyl-1-octanol p-toluenesulphonate; [α]D20 = +2.0 (c = 4.0, benzene).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: COCCN
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Product: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
The compound from Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of 2-methoxyethanamine (722 mg, 9.61 mmol) in CH2Cl2. Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc/hexane giving the title compound as a yellow oil (1.1 g, 100%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.CO.CC(O)=O>[CH2:29]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(CCNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium triacetoxyborohydride (5.46 g, 26 mmol) is added in small portions to a stirred solution of aniline (2.0 g, 21.5 mmol) and phenylacetaldehyde (2.83 g, 24 mmol) in dry DMF/MeOH/AcOH (87:10:3, 120 ml). After stirring at rt for 90 min, the volatiles are removed under reduced pressure. The residue is dissolved in dichloromethane (200 ml) and extracted twice with 1 N HCl. The combined aqueous layers are washed with EtOAc, then ammonium hydroxide solution is added to pH 9, and the mixture is extracted with dichloromethane. The solvent is evaporated, and the crude product is purified by silica gel chromatography (hexane/EtOAc, 5:1) affording pure title compound as a yellow oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:20].[CH3:21][CH2:22][O:23][C:24]([CH3:26])=O>CN(C=O)C>[NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:20].[CH3:2][N:1]1[CH2:26][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CN1CCOCC1
Product: NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Two minutes later, a solution of PheNH2HCl (1.2 g, 0.6 mmol), obtained by cleavage of the t-butoxycarbonyl group from BocPheNH2 with 4.5N HCl in EtOAc, and NMM (0.6 g, 6 mmoles) in DMF is added thereto.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.C(OCC)(=O)C>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 3.3 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 5.0 ml of triethylamine followed by ice bath cooling. A solution of 4.0 g of 4-nitrobenzoyl chloride in 20 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, brine, dried with Na2SO4 and filtered. The filtrate is concentrated in vacuo to a solid which is dissolved in methylene chloride, passed through silica gel and the pad washed with ethyl acetate. The combined filtrate is concentrated in vacuo to give 5.3 g of the desired product as a yellow solid, m.p. 188°-190° C.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.C(C([NH:13][C:14]1[N:22]=[C:21]([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]([NH:31][C@@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[O:30])[CH2:24]2)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C@@H:37]1[CH2:41][C@H:40]([NH:42][C:43](=[O:46])[CH2:44][CH3:45])[C@@H:39]([OH:47])[C@H:38]1[OH:48])CC)C.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(C3CCC3)=O)[C@@H](O)[C@H]2O)=C(N[CH2:74][CH:75]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)N=1>>[C:76]1([CH:75]([C:82]2[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=2)[CH2:74][NH:13][C:14]2[N:22]=[C:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]([NH:31][C@@H:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)=[O:30])[CH2:24]3)[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[C@@H:37]2[CH2:41][C@H:40]([NH:42][C:43]([CH:44]3[CH2:3][CH2:2][CH2:45]3)=[O:46])[C@@H:39]([OH:47])[C@H:38]2[OH:48])[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Product: O=C(N[C@@H]1CCNC1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)C5CCC5)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
This compound is prepared analogously to N-((1S,2R,3S,4R)-4-{6-(1-ethyl-propylamino)-2-[(R)-3-((R)-3-pyrrolidin-3-ylureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate (Example 54) by replacing N-{(1S,2R,3S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 14) with cyclobutanecarboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide (an intermediate used to prepare Example 23).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].CC1C=CC=CC=1.[F:22][C:23]([F:28])([F:27])[CH:24]([OH:26])[CH3:25].[H-].[Na+]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([O:26][CH:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])(=[O:12])=[O:13]
Reactant: CC(O)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(OS(=O)(=O)c1ccc2ccccc2c1)C(F)(F)F
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a cooled (ice-bath) suspension of 41.7 parts of 2-naphthalenesulfonyl chloride in 174 parts of methylbenzene were added dropwise 20.0 parts of 1,1,1-trifluoro-2-propanol. After stirring for 1 hour, there was added dropwise a mixture of 9.6 parts of a dispersion of sodium hydride in mineral oil (50%) and some methylbenzene while cooling on ice. Subsequently, the whole was diluted dropwise with water. The organic layer was separated, dried, filtered and evaporated, yielding 53.2 parts (99.9%) of (2,2,2-trifluoro-1-methylethyl) 2-naphthalenesulfonate (interm. 28).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.[CH:12]1[C:15]2[CH:16]=[CH:17][C:18]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][C:27]([N+]([O-])=O)=[CH:28][CH:29]=[C:22]4[C:21]3=[O:33])=[CH:19][C:14]=2[CH:13]=1>O>[CH:12]1[C:15]2[CH:16]=[CH:17][C:18]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][C:27]([O:7][C:1]5[CH:6]=[CH:5][CH:4]=[C:3]([C:12]#[C:13][C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[CH:2]=5)=[CH:28][CH:29]=[C:22]4[C:21]3=[O:33])=[CH:19][C:14]=2[CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccc2c(c1)C=C2
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccc(Oc3cccc(C#Cc4ccccc4)c3)cc2C(=O)N1c1ccc2c(c1)C=C2
Temperature: 35 °C
Reaction time: 2 h

Procedure:
The dark phenolate/DMSO solution was allowed to cool to about 35° C. in an oil bath. N-4-benzocyclobutenyl 4-nitrophthalimide (1.00g, 3.40 mmol) was added next. The resultant reaction mixture was stirred under N2 at 30°-35° C. for another 21/2 hours. Then, the reaction mixture was poured into a separatory funnel containing about 300 ml of H2O and extracted with ethyl acetate (100 ml, 3×50 ml). The organic extract was then washed with saturated NaCl solution (2×150 ml) and dried over MgSO4. The volume of the dried extract was concentrated on a rotary evaporator to about 10 ml and passed through a chromatographic column containing about 100 g of silica gel saturated with petroleum ether. Elution was carried out with 100 ml petroleum ether, followed by 1:2 CH2Cl2 / petroleum ether. 4 bands were developed in the column. The desired product which was contained in the first band, was isolated as light yellow microcrystals. Yield: 0.45 g (30%). Calc. for C30H19NO3 : 81.62% C; 4.34% H; 3.17% N. Found: 81.05% C; 4.31% H; 3.09% N. Mass Spectroscopy: 441 (M+, 100%). Proton NMR (CDCl3): 3.20 (singlet, alicyclic protons); 7.00-7.93, (complex, aromatic protons). IR(KBr): 2700 m (alicyclic C--H stretches); 1706 m, 1778 vs (symmetric and asymmetric stretches of imide group): 1238 ms (Ar--O--Ar stretch).
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:17]N(C=O)C>>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C@H:2]([C:4]([O:6][CH3:17])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
CBZ-Ala (10, 0.165 g, 0.74 mmol) was added to 6 mL of dry DMF containing 1.1 g (500 mol % ) of 2 (R=Me) and the reaction mixture was stirred at 16 h a t room temperature. Following the general procedure gave 0.163 g of 19, 93%, as an oil: [α]25D -32.7° (c 1.3, MeOH) [Lit14 [α]25D -33.0° (c 1.0, MeOH )]; IR 3340, 3060, 3030, 1720; 1H NMR δ 7.34-7.26 (m, 5H), 5.53 (d, 1H, J=5.9), 5.10 (s, 2H), 4.39 (t, 1H, J=7.3), 3.73 (s, 3H), 1.40 (d, 3H, J=7.2).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#N)=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:5]=1.[CH3:17]I.C[N:20]([CH:22]=O)C>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:17])([CH3:11])[C:22]#[N:20])=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:5]=1
Reactant: CN(C)C=O
Reactant: N#CCc1ccc(Br)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Br)cc1C(F)(F)F
Reaction time: 0.33 h
Yield: 75 %

Procedure:
NaH 95% (2.28 g, 94.7 mmol) was suspended in DMF (25mL) and cooled to 0° C. (4-Bromo-2-trifluoromethyl-phenyl)-acetonitrile (5 g, 18.94 mmol) from step 2 above, was dissolved in THF (35 mL) and slowly added via cannula to the NaH suspension. The reaction mixture was stirred for 20 min. Methyl iodide (11.79 mL, 189.36 mmol) was added and the resulting mixture was stirred overnight at room temperature. Reaction was quenched with H2O (100 mL). Solvents were removed in vacuo and residue partitioned between EtOAc and 1 N HCl (100 mL). The organic phase was dried over Na2SO4 and evaporated. The crude organic product was purified by flash column chromatography (5% EtOAc in hexanes) to give the product (4.14 g, 75%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.6 (s, 6H), 7.46 (d, J=5.3 Hz, 1 H), 7.67 (d, J=8.3 Hz, 1 H), 7.78 (s, 1H).
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].Cl.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([SH:20])[N:15]=1.C(N(CC)CC)C>CCO>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[CH2:3][S:20][C:16]1[N:15]=[C:14]([CH3:13])[CH:19]=[CH:18][N:17]=1
Reactant: Clc1cncc(Cl)c1CBr
Reactant: Cc1ccnc(S)n1
Agent: Br
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccnc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine hydrobromide (1.3 g, 5.0 mmol), 4-methylpyrimidine-2-thiol hydrochloride (543 mg, 3.3 mmol), and triethylamine (1.8 mL, 12.9 mmol) in absolute EtOH (35 mL) was stirred at room temperature overnight. The mixture was evaporated, co-evaporated with EtOAc (10 mL), and dried in vacuo. The solid residue was treated with water (75 mL). The mixture was extracted with 50% ethyl acetate/Et2O (75 mL). The organic extract was extracted with brine (2×75 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-4% MeOH/CH2Cl2), affording the title compound (800 mg, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.45 (s, 3H), 4.70 (s, 2H), 7.17 (d, 1H, J=5.1 Hz), 8.54 (d, 1H, J=5.1 Hz), 8.67 (s, 2H); M+287.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:13]=[O:14].CC(=CC)C.[O-:20]Cl=O.[Na+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([OH:20])=[O:14]
Reactant: Cc1cc(-c2ccccc2)sc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccccc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a stirred solution of 3-methyl-5-phenyl-thiophene-2-carbaldehyde (0.200 g, 0.99 mmol) and 2-methyl-2-butene (2.77 g, 0.040 mol) in dimethylformamide (4 ml) at 0° C. was added NaClO2 (0.894 g, 9.89 mmol) and NaH2PO4 (1.09 g, 7.91 mmol) in water (5 ml). The solution was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed at reduced pressure and the residue partitioned between dichloromethane (10 ml) and 1N HCl solution (10 ml). The organic was separated, the aqueous layer extracted with dichloromethane (2×5 ml). The combined organic layers were dried (MgSO4) and the solvent removed at reduced pressure to give a yellow oil. Purification by flash column chromatography 50% ethyl acetate/petrol 40-60° C.) gave the sub-title compound as a white solid (0.14 g, 69% yield): 1H NMR (400 MHz, CDCl3) δH 2.65 (3H, s), 7.25 (1H, s) 7.35-7.80 (5H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24](=[O:73])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]([CH2:44][C:45]5[C:54]6[C:49](=[CH:50][C:51]([Br:55])=[CH:52][CH:53]=6)[CH:48]=[CH:47][C:46]=5[O:56][CH3:57])[C:36](=[O:58])[C@@H:35]([NH:59][C:60](=[O:72])[C@@H:61]([N:63](C(OC(C)(C)C)=O)[CH3:64])[CH3:62])[CH2:34]4)=[O:32])=[CH:27][CH:26]=3)[CH2:16][C@H:15]([NH:74][C:75](=[O:87])[C@@H:76]([N:78](C)[C:79](=O)OC(C)(C)C)[CH3:77])[C:14]1=[O:88])=[C:7]([O:89][CH3:90])[CH:6]=[CH:5]2.C([Cl:94])(=O)C>CO>[ClH:94].[ClH:94].[Br:55][C:51]1[CH:50]=[C:49]2[C:54](=[CH:53][CH:52]=1)[C:45]([CH2:44][N:37]1[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N:33]([C:31](=[O:32])[C:28]3[CH:27]=[CH:26][C:25]([C:24]([N:17]4[C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:13]([CH2:12][C:8]5[C:9]6[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=6)[CH:5]=[CH:6][C:7]=5[O:89][CH3:90])[C:14](=[O:88])[C@@H:15]([NH:74][C:75](=[O:87])[C@@H:76]([NH:78][CH3:79])[CH3:77])[CH2:16]4)=[O:73])=[CH:30][CH:29]=3)[CH2:34][C@H:35]([NH:59][C:60](=[O:72])[C@@H:61]([NH:63][CH3:64])[CH3:62])[C:36]1=[O:58])=[C:46]([O:56][CH3:57])[CH:47]=[CH:48]2
Reactant: CC(=O)Cl
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)cc2)c2ccccc21
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@H]1CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)NC)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)cc2)c2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
tert-Butyl N-[(1S)-2-[[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-1-[4-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]benzoyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (24 mg, 0.018 mmol) and acetyl chloride (6.3 μL, 0.089 mmol) were combined in MeOH (2 mL) and stirred at room temperature overnight. The mixture was concentrated and the residue triturated with acetonitrile to give the title compound (18.3 mg, 84%) as a solid. LC-MS: 1149 [M−H].