Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([CH2:45][CH3:46])[CH2:10][O:11][C:12]1[CH:44]=[CH:43][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:18]2=[O:42])=[CH:14][CH:13]=1>C(Cl)Cl>[O:8]=[C:9]([CH2:45][CH3:46])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:42])=[CH:43][CH:44]=1
Reactant: CCC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
50 ml of trifluoroacetic acid were added to a solution of 19.3 g of 5-[4-(2-oxobutoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 94) in 100 ml of methylene chloride, and the mixture was stirred at room temperature for 1.5 hours. At the end of this time, it was concentrated by evaporation under reduced pressure. Water was added to the residue, and the mixture was neutralized with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed by evaporation under reduced pressure, and the resulting residue was applied to a silica gel chromatography column, and eluted, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent. It was then recrystallized from a mixture of ethyl acetate and diisopropyl ether, to give 9.55 g of the title compound, melting at 141.5° to 145.7° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]([C:21](O)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:16]1[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccccc1
Yield: 68.6 %

Procedure:
N-(2-(5-chloro-1H-Indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared following Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), biphenyl-2-carboxylic acid (0.0943 g; 0.466 mmol), HATU (0.193 g; 0.508 mmol) and N,N-diisopropylethylamine (0.179 mL; 1.06 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.109 g (68%) of N-(2-(5-chloro-1H-Indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Cl:1][CH:2]([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=1.[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C1(C)C=CC=CC=1>[Cl:13][C:7]1[CH:6]=[C:5]([O:4][C:3]([F:15])([F:14])[CH:2]([Cl:1])[F:16])[C:10]([Cl:11])=[CH:9][C:8]=1[NH:12][C:23]([NH:22][C:20](=[O:21])[C:19]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:18]=1[F:17])=[O:24]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)Cl)cc1Cl

Procedure:
A solution of 5.9 g (0.02 mole) of the above prepared 4-(2-chloro-1,1,2-trifluoroethoxy)-2,5-dichlorobenzeneamine in 100 ml toluene was placed in a 500 ml 3-necked round bottom flask fitted with a mechanical stirrer, thermometer and reflux condenser and 5.5 g (0.03 mole) of 2,6-difluorobenzoyl isocyanate was added while stirring. The temperature rose from 23° to 34° C. in a few minutes. The mixture was heated under reflux while stirring for one hour giving a clear solution which was cooled in an ice water bath. The toluene was removed by evaporation in a rotary evaporator and 25 ml acetic acid and 5 ml water were added to the residue. The resulting mixture was heated to boiling, giving a clear solution, cooled in an ice water bath and suction filtered. The filter cake obtained was washed with a little cold aqueous acetic acid and dried at room temperature. Weight, 8.5 g of white solid. m.p. 177°-179° C. The structure was verified by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([OH:16])=O)[NH:12][N:13]=1.O.[NH2:18][NH2:19]>CO.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([NH:18][NH2:19])=[O:16])[NH:12][N:13]=1
Reactant: NN
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: NNC(=O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Yield: 86.5 %

Procedure:
In methanol (20 ml), 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acid (1.00 g) was dissolved, and 6 drops of concentrated sulfuric acid was added thereto. The mixture was heated under reflux for 19 hours. After the mixture was allowed to cool, hydrazine monohydrate (0.97 g) was added to the mixture, and the resulting mixture was heated under reflux for 16 hours. The mixture was concentrated under a reduced pressure, and water was added thereto. The precipitated crystal was separated by filtration, washed with water, and dried to give the title compound (912 mg, 87%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][N:17]([CH3:30])[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[NH2:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18][N:17]([CH3:16])[CH3:30])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1ccc(N)c(OCCN(C)C)c1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OC)cc2OCCN(C)C)c1C(=O)OC
Yield: 20 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 2-(2-dimethylaminoethoxy)-4-methoxyphenylamine (0.65 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.82 g of the product at 95:5 methylene chloride-methanol. This material was dissolved in methylene chloride (100 mL) and extracted with dilute aqueous HCl (3×75 mL). The combined aqueous extracts were washed with methylene chloride (3×75 mL), made basic (Na2CO3), and extracted into methylene chloride (3×75 mL). The organic phases were dried (MgSO4) and evaporated, providing 0.25 g, in 20% yield: 1H NMR (CDCl3) δ 2.28 (s, 6H), 2.70 (t, J=5.8 Hz, 2H), 3.80 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 4.06 (t, J=5.8 Hz, 2H), 6.46 (dd, J=8.6 Hz, J=2.5 Hz, 1H), 6.54 (d, J=2.7 Hz, 1H), 7.00 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.09-7.23 (m, 3H), 7.87 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([C:22]4[C:23]([O:29][CH3:30])=[N:24][CH:25]=[C:26]([F:28])[CH:27]=4)[OH:21])=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:31]=1.C[O-].[Na+].C([NH2:38])=O>>[Br:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([C:22]4[C:23]([O:29][CH3:30])=[N:24][CH:25]=[C:26]([F:28])[CH:27]=4)[OH:21])=[C:14]([C:16]([NH2:38])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:31]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1cc(F)cnc1OC)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: COc1ncc(F)cc1C(O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)(hydroxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)(hydroxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford the crude title compound which was carried forward without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C@@H:4]([CH:5]=[CH:6][C:7](=[O:13])[S:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C@H:3]1[C:14]([O:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)[CH3:18])=[O:15].C(S)(C)(C)C>>[CH3:32][C:2]1([CH3:1])[C@@H:4]([CH:5]=[CH:6][C:7](=[O:13])[S:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C@H:3]1[C:14]([O:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)[CH3:18])=[O:15]
Reactant: CC(OC(=O)[C@@H]1[C@H](C=CC(=O)SC(C)(C)C)C1(C)C)c1cccc(Oc2ccccc2)c1
Solvent: CC(C)(C)S
Product: C[C@@H](OC(=O)[C@@H]1[C@H](C=CC(=O)SC(C)(C)C)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Example 19, 3 g of (R) α-(3-phenoxyphenyl)-ethyl (1R,cis) 2,2-dimethyl-3-[(ΔZ)carboxyethenyl]cyclopropane-carboxylate and tert.-butylmercaptan were reacted to obtain after chromatography over silica gel and elution with a 95-5 hexane-ethyl acetate mixture 0.97 g of the Z isomer of (R) α-(3-phenoxyphenyl)ethyl (1R,cis) 2,2-dimethyl-3-[3-oxo-3-tert.-butylthio-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+134°±3.5° (c=0.65% in chloroform) and 1.10 g of the corresponding E isomer with a specific rotation of [α]D20 =+44.5°±1.5° (c=0.85% in chloroform).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:44]([O:46]C)=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:22][C:23](=[O:25])[OH:24])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[OH-].[Na+]>CO>[NH2:1][CH2:2][C:3]([NH:5][C@@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:44]([OH:46])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:22][C:23](=[O:24])[OH:25])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)CNC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)CN)C(=O)O
Reaction time: 3 h

Procedure:
Two grams (g) of BOC-Gly-D-Arg-Gly-Asp-Phe-Val-OMe (SEQ ID NO 1) were first dissolved in 60 milliliters (ml) of methanol to which was added 1.5 ml of 2N sodium hydroxide solution to form an admixture. The admixture was then stirred for 3 hours at 20 degress C. (20 C.). After evaporation, the residue was taken up in water, acidified to pH 3 with diluted HCl and extracted with ethyl acetate. The extract was dried over Na2 So4, evaporated again and the resultant BOC-Gly-D-Arg-Gly-Asp-Phe-Val-OH (SEQ ID NO 2) was stirred at 20 C. for 2 hours with 20 ml of 2 N HCl in dioxane. The resultant admixture was evaporated to obtain H-Gly-D-Arg-Gly-Asp-Phe-Val-OH (SEQ ID NO 3) that was subsequently dissolved in a mixture of 1800 ml of dichloromethane and 200 ml of dimethylformamide (DMF) followed by cooling to 0 C. Thereafter, 0.5 g of dicyclohexylcarbodiimide (DCCI), 0.3 g of 1-hydroxybenzotriazole (HOBt) and 0.23 ml of N-methylmorpholine were added successively with stirring.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:27])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:9]([Cl:26])[CH:8]=1)=[O:5].[C:28](OCC)(OCC)(OCC)[CH3:29]>>[Cl:26][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:27])[N:1]=[C:28]2[CH3:29])[CH:12]=[CH:11][C:10]=1[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1Cl
Reactant: CCOC(C)(OCC)OCC
Product: CCCCCCN(CCCCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1Cl
Temperature: 150 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of (Z)-3-amino-N-(3-chloro-4-(dihexylamino)phenyl)but-2-enamide (3.94 g, 10 mmol) and triethyl orthoacetate (80 mL) was stirred at 150° C. overnight. The mixture was then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as pale yellow oil (1.36 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[CH2:5].Br[CH:20]([C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[N:12]1([C:9]2[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][CH:20]([C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)[C:21]([F:24])([F:23])[F:22])=[CH:7][CH:8]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Reactant: C=C(O[Si](C)(C)C)c1ccc(-n2cncn2)cc1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C(CC(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Temperature: 180 °C
Yield: 31.5 %

Procedure:
To a stirred solution of 1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (6 g, 23 mmol) and 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichlorobenzene (7.1 g, 34.7 mmol) in 1,2-dichlorobenzene (30 mL) was degassed with argon. To this CuCl (0.23 g, 2.31 mmol) and 2,2-bipyridyl (0.73 g, 4.63 mmol) was added to the above reaction mixture and the resultant reaction mixture was heated to 180° C. for 18 h. After completion of the reaction (by TLC), the reaction mixture was absorbed onto silica gel and purified by column chromatography (SiO2; 10% EtOAc in petroleum ether) to afford title compound as a solid (3 g, 31%): 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.33 (m, 1H), 7.30 (m, 2H), 4.20 (m, 1H), 3.63 (m, 2H); ESIMS m/z 412.14 ([M−H]−).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][SH:13]>>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][S:13][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: SCc1cccs1
Product: COC(=O)CCSCc1cccs1

Procedure:
Methyl 3-[(2-thienylmethyl)thio]propanoate (55) was prepared in the manner described above in Example 52 using methyl acrylate and 2-thienylmethyl mercaptan.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37](O)=[O:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37](=[O:38])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Yield: 85.1 %

Procedure:
Preparation of example 88 from the title compound of Example 7 (hydrochloride) (44 mg, 0.141 mmol), 4-(2-carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (43 mg, 0.169 mmol), triethylamine (0.059 mL, 0.423 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (64 mg, 0.169 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 8:5:2 CH2Cl2:hexane:methanol), also in an analogous manner, afforded the title compound (62 mg, 0.120 mmol) as a yellow powder in 85% yield.
Reaction SMILES: [CH2:1]([C:3]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:34]#[C:35][CH2:36][O:37]S(C)(=O)=O)[C:18]4[S:22][C:21]([N:23]5[CH2:28][N:27]([CH3:29])[CH2:26][N:25]([CH2:30][CH3:31])[C:24]5=[O:32])=[N:20][C:19]=4[CH:33]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].O[N:48]1[C:52](=[O:53])[C:51]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:50]2[C:49]1=[O:58].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:58]=[C:49]1[C:50]2[C:51](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52](=[O:53])[N:48]1[O:37][CH2:36][C:35]#[C:34][C:17]1[C:18]2[S:22][C:21]([N:23]3[CH2:28][N:27]([CH3:29])[CH2:26][N:25]([CH2:30][CH3:31])[C:24]3=[O:32])=[N:20][C:19]=2[CH:33]=[C:15]([C:12]2[CH:11]=[N:10][C:9]([N:6]3[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:8][CH2:7]3)=[N:14][CH:13]=2)[CH:16]=1
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCOS(C)(=O)=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCON4C(=O)c5ccccc5C4=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 60 °C

Procedure:
Ethyl 4-ethyl-1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-(3-methylsulfonyloxyprop-1-ynyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (368 mg, 0.55 mmol), N-hydroxyphthalimide (134 mg, 0.82 mmol), potassium iodide (9 mg, 0.05 mmol) and potassium carbonate (152 mg, 1.10 mmol) were dissolved in anhydrous DMF (5 mL) under argon and heated to 60° C. for 3 h. The cooled mixture was diluted with water, extracted into EtOAc (4×30 mL) and the organic phase washed with water then brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. A yellow solid was obtained and the mixture was purified by chromatography, Biotage SP4, 40 g Si cartridge, 50-80% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as a pale yellow oil, 233 mg (58%). MS: 737.13 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13]2)[CH3:8].I[C:24]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:44])[CH:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:36][CH3:37])=[CH:29][C:25]=1[C:26]([NH2:28])=[O:27].C(OCC)(=O)C>O1CCOCC1.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>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:24]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:44])[CH:35]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:36][CH3:37])=[CH:29][C:25]=1[C:26]([NH2:28])=[O:27])[CH:14]=[CH:13]2)[CH3:8]
Reactant: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Reactant: CCOc1ccc2cc(B(O)O)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOc1ccc2cc(-c3ccc(NC(=O)C(CC)c4ccccc4)cc3C(N)=O)ccc2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.5 ml of saturated aqueous sodium carbonate solution, 40 mg (0.18 mmol) of 6-ethoxy-2-naphthaleneboronic acid and 14 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 50 mg (0.12 mmol) of the compound of Example 5A in 3 ml of dioxane. The mixture is stirred at 80° C. overnight and, after addition of 50 ml of ethyl acetate, extracted three times with 50 ml of water. The organic phase is dried over magnesium sulfate and freed of solvent under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 10:90→95:5). 26 mg (44% of theory) of product are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH2:10]([NH2:13])[C:11]#[CH:12].C(=O)([O-])[O-].[K+].[K+].C1COCC1>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH2:10][C:11]#[CH:12])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: C#CCN
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
2,4,5-Trichloropyrimidine (500 mg, 2.7 mmol), propargyl amine (149 mg, 2.7 mmol), and potassium carbonate (373 mg, 2.7 mmol) were combined in a 30 ml reaction vial with 5 ml THF and stirred at room temperature overnight. The reaction was poured into 50 ml water and extracted with EtOAc (3×20 ml). The combined organic was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield (2,5-dichloro-pyrimidin-4-yl)-prop-2-ynyl-amine (488 mg, 90%) as a yellow oil that crystallizes upon standing. This was used crude in the next reaction.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]12[NH:24][CH:20]([CH2:21][CH2:22][CH2:23]1)[C:19](=O)[NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][C:8]2=O.O.[OH-].[Na+]>O1CCCC1>[CH:20]12[NH:24][CH:7]([CH2:23][CH2:22][CH2:21]1)[CH2:8][NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH:18][CH2:19]2
Reactant: O=C1NCCNCCNCCNC(=O)C2CCCC1N2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C1CC2CNCCNCCNCCNCC(C1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
Lithium aluminum hydride in tetrahydrofuran (thf, 1.0M, 25 ml, 25.0 mmol) was added to anhydrous thf (25 ml) in a 250 ml flask under argon containing a stir bar. A slurry of 3,6,9,12,18pentaazabicyclo[12.3.1]octadecan-2,13-dione prepared as in Example 38B (1.196 g, 4.326 mmol) in thf (50 ml) was added to the stirred lithium aluminum hydride solution (over about 10 min), and about 35 ml more thf was added to this to aid the addition. Gas evolved as the slurry went in; the color was beige and the reaction mixture was heterogeneous. After about 10 min of stirring, a reflux condenser was connected to the flask, and the reaction mixture was heated to reflux. The reaction mixture became yellow. Heating was stopped after 16 h, and the reaction mixture was cooled to room temperature. Water (0.95 ml) was added slowly with water bath cooling. Gas evolution occurred, and the reaction was exothermic. Next, 15% aqueous sodium hydroxide (0.95 ml) was added, and then 2.85 ml more water. After stirring for about an hour, thf (60 ml) was added and the stirring was continued. The mixture Was filtered 1 h later under a strong flow of nitrogen from an inverted funnel, and the filtrate was stripped and placed on the vacuum line. The solid was recrystallized from hot acetonitrile under argon to give 631 mg (58% yield) of long white needles: mp 90°-90.5° C. (under nitrogen); 1H NMR (CDCl3) δ 1.05 (m, 2 H), 1.26 and 1.36 (br s and quart. t, J=13.0, 4.0 Hz, 3 H), 1.50 (m, 2 H), 1.80 (br m, 3 H), 2.40-3.05 (several m, 19 H): Exact mass (M+H)+ : calcd, 256.2501; found, 256.2513 (C13H30N5).