Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:21])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.IC1C2C(=O)C3C=CC=CC=3CCC=2C(C(OC)=O)=CC=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[I:1][C:2]1[C:7]2[C:8](=[O:21])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1CCc1cccc(I)c1C2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: COC(=O)c1ccc(I)c2c1CCc1ccccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c(=O)c3c(I)cccc3ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 260 mg of the mixture of methyl 6-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-1-carboxylate and its 4-iodo form prepared in Example 6-c in 10 ml carbon tetrachloride were added 130 mg of N-bromosuccinimide and 5 mg of azobisisobutyronitrile, followed by heating under reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with diethyl ether, and the solvent was removed. To the residue was added 10 ml of dimethylformamide, and further added 0.15 ml of 1,8-diazabicyclo[5.4.0]undecene at room temperature, followed by stirring at room temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:4), to give 200 mg of a mixture of the title compound with its 4-iodo form as a colorless powder.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[S:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:23]>CO>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O-:19])=[O:18])[C:12]2=[CH:11][C:10]=1[S:20][CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:23]
Reactant: CSc1cc2n(c1C(=O)c1ccccc1)CCC2C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1cc2n(c1C(=O)c1ccccc1)CCC2C(=O)[O-]

Procedure:
To a solution of 300 mg of 5-benzoyl-6-methylthio-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of sodium hydroxide, in the form of a 0.1N solution. The solvent is evaporated in vacuo and the residue is taken up in 2 ml of methanol, followed by precipitation with ether, to yield crude sodium 5-benzoyl-6-methylthio-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1.[NH:17]1[CH:24]=[CH:23][C:21]([NH2:22])=[N:20][C:18]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:22][C:21]1[CH:23]=[CH:24][N:17]([CH2:2][C:3]2[O:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=2)[C:18](=[O:19])[N:20]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)o1
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2ccc(-c3ccccc3[N+](=O)[O-])o2)c(=O)n1
Reaction time: 12 h
Yield: 66.8 %

Procedure:
To a solution of 2-(bromomethyl)-5-(2-nitrophenyl)furan 11a (230 mg, 0.815 mmol) and cytosine 14a (181 mg, 1.63 mmol) in anhydrous DMF (4 mL) was added cesium carbonate (398 mg, 1.22 mmol) at 25° C. The resulting solution was stirred for 12 h at the same temperature. After removal of the DMF under reduced pressure, the residue was diluted with CHCl3 and washed three times with water. The organic layer was dried over anhydrous MgSO4 and concentrated in a vacuum. The residue was purified by column chromatography eluting with ethyl acetate/methanol (20:1) to afford 170 mg (67%) of the cytosine 15a as a white solid. 1H NMR (DMSO) δ: 7.87 (1H, d, J=8.0 Hz), 7.82 (1H, d, J=7.5 Hz), 7.73 (1H, t, J=7.5 Hz), 7.58 (1H, d, J=7.0 Hz), 7.56 (1H, t, J=8.5 Hz), 7.16 (1H, s), 7.09 (1H, s), 6.86 (1H, d, J=3.5 Hz), 6.48 (1H, d, J=3.0 Hz), 5.72 (1H, d, J=7.5 Hz), 4.89 (2H, s); 13C NMR δ: 166.33, 155.63, 152.62, 147.82, 147.11, 145.59, 132.72, 129.41, 128.80, 124.16, 122.73, 110.07, 110.92, 94.21, 44.57.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[C:18]1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][CH3:14])=[CH2:18])=[CH:4][CH:3]=1
Reactant: CCCC(C)(C)C(=O)CCc1ccc(Cl)cc1
Reactant: Cc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C(CCc1ccc(Cl)cc1)C(C)(C)CCC
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A suspension of 47.4 g (0.133 mol) of methyl-triphenylphosphonium bromide and 15.3 g (0.137 mol) of potassium tert.-butylate in 250 ml of absolute toluene is heated under reflux for 30 minutes under dry nitrogen. 25.3 g (0.1 mol) of 1-(4-chlorophenyl)-4,4-dimethyl-3-heptanone, dissolved in 10 ml of absolute toluene, are then added dropwise during the course of 5 minutes. The reaction mixture is heated under reflux for a further 15 hours, then cooled to room temperature, washed twice with water and concentrated under reduced pressure. The residue is taken up in ethyl acetate, cooled to 5° C. and the crop of crystals formed is filtered off by suction. The filtrate is concentrated and distilled under reduced pressure. 23 g (91.8% of theory) of 2-(4-chlorophenylethyl)-3,3-dimethyl-1-hexene are obtained in the form of a yellow oil of boiling point 85°-87° C./0.1 mbar. ##STR30##
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]([C:19]1[CH:20]=[C:21]([CH:25]2[C:29]3[C:30]([CH3:44])=[C:31]([NH:36][C:37](=[O:43])[CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:32]([CH3:35])=[C:33]([CH3:34])[C:28]=3[O:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)=O.O>CN(C=O)C>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][C:37]([NH:36][C:31]1[C:32]([CH3:35])=[C:33]([CH3:34])[C:28]2[O:27][CH2:26][CH:25]([C:21]3[CH:20]=[C:19](/[CH:17]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:24]=[CH:23][CH:22]=3)[C:29]=2[C:30]=1[CH3:44])=[O:43]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1cccc(C=O)c1)CO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a solution of sodium hydride (a 60% dispersion in liquid paraffin, 79 mg, 1.98 mmol) in DMF (10 mL) was added dropwise at 0° C. under an argon atmosphere ethyl diethylphosphonoacetate (444 mg, 1.98 mmol) and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise at 0° C. a solution of N-(3-(3-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (684 mg, 1.80 mmol) obtained in Example 173 in DMF (5 mL) and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, was added to water and the product was extracted with ethyl acetate-THF. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 750 mg (yield: 93%) of the title compound. Melting point: 199-200° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14]>C(NCCCC)CCC.C(O)(=O)CCCCC.C(O)(=O)C>[CH3:14][C:13](=[CH:10][CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])[CH:12]=[O:15]
Reactant: CC1=CCC(CC=O)C1(C)C
Reactant: CCC=O
Solvent: CC(=O)O
Solvent: CCCCNCCCC
Solvent: CCCCCC(=O)O
Product: CC(C=O)=CCC1CC=C(C)C1(C)C
Temperature: 100 °C
Yield: 93.9 %

Procedure:
A 500 mL four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel was charged with 171 g (0.98 mol) of campholenic aldehyde (purity: 88%), 5.8 g (0.045 mol) of dibutyl amine and 5.3 g (0.046 mol) of hexanoic acid, and the contents in the flask were stirred while heating at 100° C. Then, 91 g (1.6 mol) of propionaldehyde was gradually dropped into the flask for 6 h, and the resultant mixture was aged for 1 h and then cooled. Thereafter, 3.2 g (0.053 mol) of acetic acid was added to the mixture to remove amines therefrom, thereby separating the mixture into two layers. The thus separated organic layer was washed with water and further separated into two layers, thereby obtaining 280 g (0.92 mol) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-but-2-en-1-al (purity as measured by gas chromatography: 63.4%) (yield based on theoretical amount: 94%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([OH:26])=O.[NH3:27]>>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([NH2:27])=[O:26]
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CCOC3)c12
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@@H]3CCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 5-methyl-4-{2-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamino}-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:18](N)=[NH:19]>CCO>[OH:5][C:4]1[C:3]2[C:2](=[CH:11][CH:10]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:8]=2)[N:1]=[CH:18][N:19]=1
Reactant: N=CN
Reactant: COCCOc1ccc(N)c(C(=O)OC)c1
Agent: Cl
Solvent: CCO
Product: COCCOc1ccc2ncnc(O)c2c1
Temperature: 130 °C
Yield: 95.2 %

Procedure:
To methyl 2-amino-5-(2-methoxyethoxy)benzoate (964 mg, 4.2 mmol) in absolute EtOH (25 mL) was added formamidine hydrochloride (1.4 g, 17.2 mmol) and the mixture heated in a sealed tube at 130° C. overnight. The mixture was cooled to room temperature and filtered to give 4-hydroxy-6-(2-methoxyethoxy)quinazoline (871 mg, 4.0 mmol, 95%). 1H NMR (300 MHz, DMSO-d6) δ 8.42 (br s, 1H), 7.99 (s, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.43 (dd, 1H), 4.21 (dd, 2H), 3.70 (dd, 2H), 3.32 (s, 3H); LC-MS (ESI) m/z 221 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([C:9]1[O:13][N:12]=[C:11]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:20][C:21]1[CH:33]=[CH:32][C:24]2[NH:25][C:26]([S:28](Cl)(=[O:30])=[O:29])=[N:27][C:23]=2[CH:22]=1>>[CH2:2]([C:9]1[O:13][N:12]=[C:11]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[S:28]([C:26]2[NH:25][C:24]3[CH:32]=[CH:33][C:21]([Br:20])=[CH:22][C:23]=3[N:27]=2)(=[O:30])=[O:29])[N:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1nc2cc(Br)ccc2[nH]1
Reactant: c1ccc(Cc2nc([C@@H]3CCCCN3)no2)cc1
Agent: Cl
Product: O=S(=O)(c1nc2cc(Br)ccc2[nH]1)N1CCCC[C@H]1c1noc(Cc2ccccc2)n1

Procedure:
The title compound was prepared by a similar method to Example 1 from 5-benzyl-3-[(2S)-2-piperidyl]-1,2,4-oxadiazole hydrochloride [see-Preparation 7] and 5-bromo-1H-benzo[d]imidazole-2-sulfonyl chloride [see Preparation 88]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 70:30, by volume, hexane:ethyl acetate, in 10% increments, to afford 2-[(2S)-2-(5-benzyl-1,2,4-oxadiazol-3-yl)-1-piperidyl]sulfonyl-5-bromo-1H-benzo[d]imidazole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[CH3:11][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[NH2:1]
Reactant: Nc1ncccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccnc1N
Yield: 78 %

Procedure:
A stirred suspension of 2-amino-nicotinic acid (12.15 g, 87.95 mmol) in a mixture of MeOH (175 mL) and THF (500 mL), under nitrogen at room temperature, was added a solution of trimethylsilyldiazomethane (2M in hexane, 50 mL, 99.5 mmol)) dropwise. After completion of the reaction the volatiles were removed in vacuo and the crude product triturated with disisopropyl ether, filtered and dried to give 2-amino-nicotinic acid methyl ester (10.44 g) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13]C)=[CH:11][CH:10]=[C:9]([S:15](=[O:22])(=[O:21])[NH:16][CH2:17][C:18]([OH:20])=[O:19])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:1]([C:4]1[O:5][C:6]2[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([S:15](=[O:21])(=[O:22])[NH:16][CH2:17][C:18]([OH:20])=[O:19])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)NCC(=O)O)c2cc(C(C)=O)oc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CC(=O)c1cc2c(S(=O)(=O)NCC(=O)O)ccc(O)c2o1
Temperature: 130 °C

Procedure:
A mixture of 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-methoxybenzofuran and AlCl3 in chlorobenzene was heated at 130° C. to give 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-hydroxybenzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])=[CH:4][CH:3]=1.BrC1C=CC(N)=CC=1.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc(Br)cc1
Agent: Nc1ccc(Br)cc1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc(Br)cc1
Yield: 78 %

Procedure:
This compound was prepared using 125 mg (0.5 mmol) of 2-[(4-bromophenyl)-hydrazono]malononitrile, which was derived from 4-bromoaniline (172 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 109 mg (78%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 6.15 (br s, 4H), 7.52 (d, 2H), 7.61 (d, 2H), 10.71 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1.Cl.ClC1C=CN=CC=1>O1CCOCC1>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([N:1]2[CH:13]=[CH:17][CH:16]=[CH:15]2)[CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1c(N)cccc1Cl
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: N#Cc1c(Cl)cccc1-n1cccc1
Yield: 87.8 %

Procedure:
A solution of 2-amino-6-chloro-benzonitrile (30 g), 2,5-dimethoxytetrahydrofuran (30 g) and 4-chloropyridine hydrochloride (17 g) in dioxane was heated to 70° C. for 2.5 h. The solvent was evaporated in vacuo. Dichloromethane was then added to the residue and the spent 4-chloropyridine hydrochloride filtered off. The dichloromethane was evaporated in vacuo to give 1-(3′chloro-2′-cyanophenyl)pyrrole (35 g)
Reaction SMILES: [C:1]([C:3]1[C:8]([Cl:9])=[CH:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[CH3:11][O-:12].[Na+]>C1COCC1>[Cl:9][C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[C:6]([O:12][CH3:11])[CH:7]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc(C#N)c(Cl)c1
Reaction time: 3 h

Procedure:
The product from Example 27A (0.865 g, 5.0 mmol) was dissolved in THF (10 mL) and 0.27 g NaOMe was added. After 3 h and 25° C., the reaction was quenched in 5% aq. NaHCO3 solution and extracted with diethyl ether. The organic phase was dried, evaporated, and the residue purified by column chromatography, eluting with 70:30 hexanes:ethyl acetate to yield 0.27 g (32%, second eluting component) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 3H), 7.29 (d, 1H), 8.28 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][C:32]1=[O:42])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>O1CCCC1>[C:1]([O:5][C:6](=[O:43])[N:7]([CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][C:32]1=[O:42])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:27])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCBr
Reactant: CC(C)(C)OC(=O)N(CCCCNCCCn1c(=O)[nH]c2ccccc2c1=O)CCCn1c(=O)[nH]c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCN(CCCCN(CCCn1c(=O)[nH]c2ccccc2c1=O)C(=O)OC(C)(C)C)CCCn1c(=O)[nH]c2ccccc2c1=O

Procedure:
[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}carbamic acid tert-butyl ester (2 g, 3.4 mmol) was dissolved in 40 mL tetrahydrofuran. Sodium hydride (0.16 g, 6.7 mmol) and 1-bromohexane (0.67 g, 4.0 mmol) were added thereto and stirred under reflux. The solvent was concentrated under reduced pressure, and silica gel column-chromatography of the remaining residue was performed to give the title compound of white solid (0.52 g, 23%).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:33][C:34]#[CH:35])[C:10]([NH:12][C@@H:13]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.[O:43]1[CH2:48][CH2:47][N:46]([CH2:49]C(O)=O)[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>ClCCl.O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[CH2:49][N:46]2[CH2:47][CH2:48][O:43][CH2:44][CH2:45]2)[CH2:33][C:34]#[CH:35])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:26][CH:27]=1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OCc1ccccc1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C#CC[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
(S)-Benzyl 2-((S)-2-(tert-butoxycarbonylamino)pent-4-ynamido)-3-(4-methoxy phenyl)propanoate (1.1 g, 2.3 mmol) was dissolved in dichloromethane (10 mL) and treated with TFA (1.5 mL) for 1 h at ambient temperature. The solvent was removed and the residue was added to a solution of 2-morpholinoacetic acid (0.33 g, 2.3 mmol) and HATU (1.0 g, 2.6 mmol) in dichloromethane (20 mL). N-Methylmorpholine (0.63 mL, 5.7 mmol) was added at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (20 mL) was added and the resulting mixture was extracted with dichloromethane (20 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=200:1 to 100:1) to afford (S)-Benzyl 3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)pent-4-ynamido)propanoate (0.8 g, 69% yield) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([Cl:20])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
2′,4′-Dichloro-biphenyl-4-carboxylic acid (2 g) was suspended in toluene (30 mL) and thionyl chloride (5 mL) added. The mixture was heated to reflux for 4 hours and then evaporated to dryness and the procedure repeated. Evaporation gave the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(O)=O.[Na+].[CH3:25][O:26][C:27](Cl)=[O:28].Cl>O1CCOCC1>[CH3:25][O:26][C:27]([NH:16][CH:15]([CH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:17]([OH:19])=[O:18])=[O:28]
Reactant: COC(=O)Cl
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)NC(Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)O
Reaction time: 3 h

Procedure:
A mixture of 3-(4-nitro-1-naphthyl)alanine (0.65 g, 2.5 mmol), aqueous NaHCO3 (5 mL) and methylchloroformate (230 uL, 3 mmol, 1.2 eq) in dioxane (10 mL) was stirred for 3 hours, acidified to a ph <3 with aqueous 2N HCl and extracted with ethyl acetate. The combined organic layers was washed with water (1×25 mL), brine(1×25 mL), dried (MgSO4), filtered and concentrated under reduce pressure to provide the titled compound. MS (APCI(+)) m/e 319 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:32]([F:35])([F:34])[F:33])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30][CH3:31])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].ClC1C=C(C2(C(F)(F)F)ON=C(C3C4C(=CC=CC=4)C(C(NCCS(C)(=[N:66][C:67](=[O:72])[C:68]([F:71])([F:70])[F:69])=O)=O)=CC=3)C2)C=C(Cl)C=1.FC(F)(F)C(N)=O.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:32]([F:33])([F:34])[F:35])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][S:30]([CH3:31])=[N:66][C:67](=[O:72])[C:68]([F:71])([F:70])[F:69])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: CS(=O)(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: NC(=O)C(F)(F)F
Solvent: ClCCl
Product: CS(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a stirred suspension of 4-[4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylthio)ethyl]-1-naphthalenecarboxamide (prepared analogously as described for the compound of Example 3, Step A) (200 mg), 2,2,2-trifluoroacetamide (80 mg), MgO (57 mg), and Rh2(OAc)4 (4 mg) in dichloromethane (4 mL) was added PhI(OAc)2 (172 mg) at room temperature. The resulting mixture was stirred overnight at room temperature, then filtered through a short pad of Celite® diatomaceous filter aid, and rinsed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetates (1:1 to 1:4) as eluent to afford the title compound as a semisolid (70 mg, 30% yield).