Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:2]3[N:3]=[CH:4][C:5]4[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[C:6]=4[N:7]=3)=[CH:36][CH:37]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)nc2)CC1
Reactant: N#Cc1cc2cnc(Cl)nc2n1C1CCCC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Nc3ncc4cc(C#N)n(C5CCCC5)c4n3)nc2)CC1
Yield: 49.6 %

Procedure:
Following Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (95 mg, 0.385 mmol) and 4-(6-amino-pyridin-3-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (124 mg, 0.424 mmol) gave 4-[6-(6-cyano-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (96 mg) [following SiO2 chromatography, eluting with a 1-3% MeOH/dichloromethane and subsequent trituration with a diethyl ether]. The material is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])=[O:26])=[CH:21][CH:20]=3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH:28]O>CO.C(OCC)(=O)C.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])(=[O:28])=[O:26])=[CH:21][CH:20]=3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: OO
Reactant: CS(=O)c1ccc(-c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)cc1
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)cc1
Temperature: 25 °C

Procedure:
0.5 g (1.4 mmol) of the product of Example 44 was dissolved in a mixture of 4 mL of methanol and 16 mL of ethyl acetate. The solution was treated 0.045 g sodium tungstate dihydrate and 0.63 mL (5.6 mmol) of 30% hydrogen peroxide solution while heating at reflux over a period of 4 hours. A further 0.3 mL (2.8 mmol) hydrogen peroxide was added. The mixture was refluxed overnight and then cooled to room temperature. A white solid was recovered by filtration and was washed with water to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25][N:14]1[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:15]1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)c(F)c2)c1=O
Yield: 92.1 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3, 4-difluorobenzyl bromide were reacted to yield the title compound as a yellow crystalline powder (yield: 92.1%).
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:39])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:38])[C@H:16]([CH2:34][CH2:35][S:36][CH3:37])[NH:17][P:18]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].[OH-].[Na+].O>CC(C)=O>[CH2:20]([P:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:40])=[O:2])=[O:39])=[O:38])[CH2:34][CH2:35][S:36][CH3:37])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)NP(=O)(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CSCC[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h
Yield: 99.2 %

Procedure:
Dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester (1.87 g, 3.0 m mole) was dissolved in acetone (18 ml), and 1N sodium hydroxide (4.5 ml) was added thereto under cooling and the mixture was stirred for 4 hours. To the solution, water (100 ml) was added, and the solution was washed with diethyl ether. Ethyl acetate (200 ml) was added thereto and the mixture was adjusted to pH 2 with 1N hydrochloric acid while stirring strongly. The ethyl acetate phase was separated and this phase was dried over anhydrous sodium sulfate. The solvent was evaporated to obtain an oily dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline (1.81 g, yield: 99.1%). All of thus obtained product (3.0 m mole) was dissolved in ethanol (15 ml) and L-arginine (0.58 g, 3.0 m mole) water (5 ml) solution was added thereto. The solvent was evaporated and water was added thereto, and thus obtained solution was freeze-dried to obtain dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline L-arginine salt (2.27 g, yield: 98.7% from dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester). This product gave a single spots respectively in Rf =0.8 for peptides in the free form and Rf =0.25 for arginine by a thin layer chromatography (developing solvent, n-butanol:acetic acid:water=2:1:1, Colour forming method, spraying of 25% hydrobromic acid and 0.1% ninhydrin, and heating). After a hydrolysis of the product with 6N hydrochloric acid, and amino acids were analyzed. Methionine:Proline:Arginine=1.00:2.03:0.95.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[C:11]=2[N:10]([CH3:33])[C:9]1=[O:34])(=O)C.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]2[C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[C:9](=[O:34])[N:10]([CH3:33])[C:11]=3[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:16]2)=[CH:31][CH:30]=1
Reactant: CC(=O)OCCCn1c(=O)c2c(c(-c3cccc(Cl)c3)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1c(-c1cccc(Cl)c1)cn2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-7-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (50 mg, 0.1 mmol) in THF (0.5 mL) and water (0.5 mL) was added LiOH.H2O (8.4 mg, 0.2 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-7-(3-chlorophenyl)-3-(3-hydroxypropyl)-1-methyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (20 mg, 41% yield). 1H NMR (CDCl3) δ: 7.39-7.29 (m, 5H), 7.25-7.17 (m, 3H), 6.91 (s, 1H), 5.56 (s, 2H), 4.28-4.15 (m, 2H), 3.62 (s, 1H), 3.52 (d, J=4.8 Hz, 2H), 3.21 (s, 3H), 1.96-1.82 (m, 2H). LCMS: MH+ 458 and TR=2.953 min.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[CH2:30]([OH:35])[CH2:31][CH2:32][C:33]#[CH:34]>N1CCCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:3][Si:2]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][OH:35])=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:11][CH:12]=1)([CH3:4])[CH3:1]
Reactant: C#CCCCO
Reactant: C[Si](C)(C)C#Cc1ccc(-n2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc32)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(-n2ccc3cc(C#CCCCO)ccc32)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To 1.62 g (3.7 mmol) Trifluoro-methanesulfonic acid 1-(4-trimethylsilanylethynyl-phenyl)-1H-indol-5-yl ester in 5 ml piperidine, 230 mg (0.2 mmol) tetrakis-(triphenylphosphine)-palladium and 40 mg (0.2 mmol) CuI were added. The solution was evaporated and purged with argon three times, before 0.56 ml (6 mmol) 4-pentyn-1-ol were added. The solution was stirred at 80° C. for 2 h. The solution was concentrated and the residue dissolved in 0.5M HCl and ether. The inorganic phase was extracted with ether, the organic phases were washed with water and dried over Na2SO4. Purification on silica gel with CH2Cl2 yielded 980 mg (71%) 5-[1-(4-Trimethylsilanylethynyl-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol as orange viscous oil, MS: 371 (M).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)=[CH:19][CH:18]=1.[C:33](O)(=[O:39])/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH3:38]>CN(C)C1C=CN=CC=1.ClCCl>[C:33]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)=[CH:19][CH:18]=1)(=[O:39])/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH3:38]
Reactant: CCC/C=C/C(=O)O
Reactant: CCCCCc1ccc(-c2ccc(O)cc2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1ccc(-c2ccc(CCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
Dicyclohexylcarbodiimide (0.2 g) was added to a solution of 2-(4-hydroxyphenyl)-5-pentylthiophene (0.25 g), (E)-hex-2-enoic acid, (0.1 g) 4-(dimethyiamino)pyridine (0.05 g) and dichloromethane (20 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down. The residue was purified by column chromatography on silica gel using hexane/ethyl acetate (9/1 v/v) as eluent and recrystallisation from hexane to yield 0.17 g of 2-(4-[(E)-hex-2-enoyloxy]phenyl)-5-pentylthiophene, K 47° C., [N 46° C.], I.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>O1CCOCC1>[N:1]([C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[C:13]=[O:14]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(N=C=O)c1

Procedure:
To a vigorously stirred solution of 3-aminobenzenesulphonamide (1 g, 5.8 mmol) in dry 1,4-dioxane (25 mL) is added trichloromethyl chloroformate (1.72 g, 8.7 mmol) and the reaction mixture is heated to reflux for 3 hours. The solvent is removed in vacuo to yield the title compound which is used without further purification.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:13]=2[C:12](B(O)O)=[CH:11][CH:10]=1>>[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:13]=2[C:12]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: O=C1C=C(Br)CCC1
Product: O=C1C=C(c2cccc3c2oc2ccccc23)CCC1
Yield: 83 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and dibenzofuran-4-boronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 20% ethyl acetate/hexanes) yielded the product (141 mg, 83%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.91 (d, J=6.9 Hz, 2H), 7.30-7.58 (m, 5H), 6.90 (s, 1H), 2.97 (t, J=4.7 Hz, 2H), 2.56 (t, J=6.1 Hz, 2H), 2.21 (quintet, J=5.8 Hz, 2H). 13C (75 MHz, CDCl3): 200.1, 156.2, 155.9, 153.3, 128.6, 127.7, 125.6, 125.3, 124.0, 123.5, 123.2, 123.0, 122.0, 120.7, 111.9, 37.7, 29.0, 23.2. HRMS (LCT Electrospray): mass calcd for (C18H14O2+Na) m/z 285.0891; measured [M+Na]+: m/z 285.0895.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[CH3:14][S:15]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=3)[S:24][C:23]=2[CH:38]=1)(=[O:17])=[O:16].ClCCl.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl>[CH3:14][S:15]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:26]([C:9](=[O:11])[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][Br:1])=[CH:13][CH:12]=3)=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=3)[S:24][C:23]=2[CH:38]=1)(=[O:16])=[O:17]
Reactant: O=C(O)c1ccc(OCCBr)cc1
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCBr)cc2)cc1
Temperature: 0 °C

Procedure:
One g. of 4-(2-bromoethoxy)benzoic acid was converted to the acid chloride, and was combined with 1.2 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene, 20 ml. of dichloromethane and 0.5 ml. of trifluoromethanesulfonic acid. The mixture was stirred under reflux overnight, and was then poured into ice-water. The organic layer was separated, washed with sodium carbonate solution, dried and evaporated under vacuum to obtain 2.1 g. of brown oil. The oil was chromatographed over a 4×8 cm. silica gel column with 9/1 toluene/ethyl acetate and the product-containing fractions were combined and evaporated under vacuum to obtain 1.8 g. of purified product as an oil. The product was identified by its MH+ molecular ion, m/e 626, in the field desorption mass spectrum and by an absorption maximum in the infrared spectrum, in chloroform, at 1645 cm.-1 attributable to the CO function. A small sample was recrystallized from methanol to obtain white crystals, m.p. 105°-107° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][N:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:18]=[CH:17][N:16]=1
Reactant: COc1cc(C=O)ccn1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C2N=C(c3cccs3)OC2=O)ccn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A mixture of N-(2-thienylcarbonyl)glycine (454 mg, 2.45 mmol), 2-methoxy-4-pyridinecarboxaldehyde (370 mg, 2.7 mmol), sodium acetate (201 mg, 2.45 mmol) and acetic anhydride (3.0 mL) was stirred at 90° C. for 3 hours in a sealed tube. Thereafter, the temperature of the reaction solution was returned to room temperature, and water (15 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1 hour. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (50 mL) and was then dried under reduced pressure, so as to obtain 572 mg of the above-captioned compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]([Cl:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CS(C)=O>[ClH:20].[NH2:1][C@H:2]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CS(C)=O
Product: Cl
Product: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A mixture of 1.65 g. (10 mmole) of racemic phenylalanine and 1.27 g. (10 mmole) of benzyl chloride in 10 ml. dimethylsulfoxide is stirred at 60° C. for 7 hours and then allowed to cool. Dimethylsulfoxide is removed by stirring four times with 25 ml. ethyl ether and then decanting off the ethyl ether. The residue is stirred with 25 ml. hot ethanol, filtered from some insoluble solid and the filtrate diluted with 100 ml. ethyl ether to precipitate the ester hydrochloride. After filtering and drying, essentially pure benzyl phenylalaninate hydrochloride is obtained. Recrystallization from a warm mixture of 8 ml. water and 1 ml. 0.1 N hydrochloric acid gives an analytical sample, m.p. 190.5-192.5° C.
Reaction SMILES: Cl.[O:2]1[C:6]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1.[NH:14]=[C:15]=[NH:16].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[O:2]1[C:6]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:15]([NH2:16])=[NH:14])=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1
Reactant: Nc1ccc(-c2cnco2)cc1
Reactant: N=C=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1ccc(-c2cnco2)cc1
Yield: 110.9 %

Procedure:
Hydrochloric acid (4.04 mL, 24.35 mmol) was added to a solution of 4-(oxazol-5-yl)aniline (5 g, 31.22 mmol) and carbodiimide (1.444 g, 34.34 mmol) in ethanol (50 mL). The resulting mixture was heated to reflux for 5 h. The reaction mixture was concentrated under reduced pressure and potassium carbonate (2.59 g, 18.73 mmol) in water (50.00 mL) was added. The formed crystals were filtered off, washed with several portions of potassium carbonate (aq) and dried over night under reduced pressure. The crude solid was slurried in DCM and filtered to give 1-(4-(oxazol-5-yl)phenyl)guanidine (7.00 g, 86%). No further purification. MS (ESI+)/(ESI−) m/z 203/201
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.[C:38](OC(=O)CN)(C)(C)C.Cl.C(OC(=O)[C@@H](C)N)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C@H:23]([CH3:38])[C:24]([OH:26])=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)N[C@H](C)C(=O)O

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, D-alanine tert-butyl ester hydrochloride was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[CH:2].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30]C(OC(C)(C)C)=O)[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=1)=[N+:17]=[N-:18].Cl>O.O1CCOCC1.CO>[NH2:30][C@@H:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH:2]=[C:1]([C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:5][CH:4]=3)[N:18]=[N:17]2)=[CH:20][CH:21]=1)[C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N=[N+]=[N-])cc1)C(=O)O
Reactant: C#Cc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(-n2cc(-c3ccc(Oc4ccccc4)cc3)nn2)cc1)C(=O)O
Temperature: 100 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
A mixture of 1-ethynyl-4-phenoxy-benzene (126 mg, 0.65 mmol) and (S)-3-(4-azido-phenyl)-2-tert-butoxycarbonylamino-propionic acid (200 mg, 0.65 mg) in H2O:dioxane (5:1) was heated at 100° C. in a sealed tube for overnight. After completion of reaction, 3N HCl (5 ml) was added and the mixture was stirred for 2 hr at 50° C. Removal of solvent gave crude product which was dissolved in MeOH and purified by preparative HPLC to give 45 mg of desired product (yield: 29%). 1H-NMR (400 MHz, CD3OD): δ (ppm) 3.2 (m, 1H), 3.4 (m, 1H), 4.3(m, 1H), 6.9(d, 2H), 7.0(d, 2H), 7.2(m, 1H), 7.3(d, 2H), 7.4-7.55 (m, 6H), 8.0(s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-])=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>[H][H].[Pd].CC(O)C.C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:8]2[C:7]3[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][C:6]=3[N:10]=[CH:9]2)=[CH:17][CH:16]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:10]2[C:6]3[CH:5]=[C:4]([NH2:1])[CH:12]=[CH:11][C:7]=3[N:8]=[CH:9]2)=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: COc1ccc(CCl)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(Cn2cnc3cc(N)ccc32)cc1
Product: COc1ccc(Cn2cnc3ccc(N)cc32)cc1
Yield: 43 %
Yield: 48 %

Procedure:
A reaction of 5-nitrobenzimidazole (4.3 g, 27 mmol) and 4-methoxybenzyl chloride (4.3 ml, 30 mmol) in a procedure described in Example 9 produces 5.6 g .(19 mmol, 73%) of a mixture of 1- and 3-(4-methoxybenzyl) -5-nitrobenzimidazole, which was converted to the corresponding amines in hydrogenation (H2/Pd-C). The amine mixture was subjected to column chromatography (10%-30% i-PrOH/CH2Cl2) to provide 2.1 g (8.2 mmol, 43%) of 1-(4-methoxybenzyl)-5-aminobenzimidazole and 2.4 g (9.2 mmol, 48%) of 3-(4-methoxybenzyl)-5-aminobenzimidazole.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.C(O)(=O)C.[C:16]([CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])[NH2:23])#[N:17]>O>[C:16]([CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([N:23]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])[CH:24]=[CH:25][C:26]=1[Cl:27])#[N:17]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: N#CCCc1cc(N)ccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: N#CCCc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirred slurry of 5.0 g of 3,4,5,6-tetrahydrophthalic anhydride in 5 ml. of glacial acetic acid under N2 is added 7.5 g of 3-(2-cyanoethyl)-4-chloroaniline and the mixture heated to reflux for 2 hours. The reaction mixture is cooled to room temperature, water is added together with several mls. of conc. HCl and the mixture extracted with ether. The combined ether extracts are washed with saturated brine and then dried over MgSO4. Filtration and removal of the solvent yielded 8.9 g of a brown oil. The oil is dissolved in CH2Cl2, passed through a plug of alumina, the solvent removed, and then further purified by MPLC eluting with 25% EtOAc/hexanes to yield the product as a yellow solid, m.p. 87°-97° C.