Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55](C(C)(C)C)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:56]([NH2:55])=[O:57])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: CC(C)(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedures of Example D41, using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-isocyanato-2-methylpropane as the starting materials, and Example D87 in 60% yield (2 steps). LCMS for C24H26ClN8O3 (M+H)+: m/z=509.0.
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[C:17]2[O:16][C:15](=[O:18])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)C.[CH3:21][C:22]1[O:26][C:25]([CH:27]([NH2:33])[C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)=[CH:24][CH:23]=1>CO>[CH3:21][C:22]1[O:26][C:25]([CH:27]([NH:33][C:4]2[C:5](=[O:20])[C:6](=[O:19])[C:7]=2[NH:8][C:9]2[C:17]3[O:16][C:15](=[O:18])[NH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[C:28]2([CH3:32])[CH2:29][O:30][CH2:31]2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc3[nH]c(=O)oc23)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc4[nH]c(=O)oc34)c(=O)c2=O)C2(C)COC2)o1
Temperature: 65 °C
Yield: 45.8 %

Procedure:
A mixture of 0.35 g (1.28 mmol, 1 eq) of 3-ethoxy-4-(2-oxo-2,3-dihydrobenzooxazol-7-ylamino)cyclobut-3-ene-1,2-dione and 0.278 g (1.53 mmol, 1.2 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 6 ml of methanol was heated at 65° C. for 5 hours. The methanol was evaporated off and the residue was chromatographed on silica gel, eluted with 95/5 dichloromethane/methanol. The paste obtained was crystallized from ethyl ether, filtered and dried under vacuum at 40° C. 0.24 g of product was obtained in the form of a beige solid. Yield=46%. HPLC 96.4%, ES+ [410].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OCc2ccccc2)c1
Reaction time: 6 h

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (300 mg, 1.7 mmol) was dissolved in DMF (8.5 ml) and treated with benzyl bromide (200 μl, 1.7 mmol). Cs2CO3 (610 mg, 1.87 mmol) was then added and the reaction mixture stirred at room temp. for 6 hours. The mixture was filtered and washed with DMF (3×10 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:12]=3[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C(C)=CC(C)=CC=1C.[C:38]1([O:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[O:44]([C:45]([NH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:12]=3[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1nn(-c2cccc(N)c2)c2c1CS(=O)(=O)c1ccccc1-2
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1nn(-c2cccc(NC(=O)Oc3ccccc3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 1-(3-aminophenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide hydrochloride (100 mg, 0.243 mmol) in THF (10 mL) are added 2,4,6 collidine (0.06 mL, 0.487 mmol), phenylchloroformate (0.04 mL, 0.365 mmol) then stirred at RT for 18 h. After this time, reaction mixture is concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 100 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)NCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (444.5 mg, 1.349 mmol) in a mixture of dichloromethane (20.0 mL) and triethylamine (470 μL, 3.37 mmol) was cooled to 0° C. Myristoyl chloride (367 μL, 1.35 mmol) was slowly added over a period of 10 minutes. The reaction mixture was allowed to stir at 0° C. for 1 hour at which time analysis by thin layer chromatography indicated that there was no starting material left. The reaction mixture was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate solution (2×15 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography (20 g of silica gel eluted with 2% methanol in dichloromethane) followed by recrystallization from ethyl acetate (1.2 mL) and then further purified by column chromatography (25 g of silica gel eluted sequentially with 300 mL of 1% CMA in chloroform, 500 mL of 2% CMA in chloroform, 500 mL of 3% CMA in chloroform, 500 mL of 4% CMA in chloroform, 750 mL of 5% CMA in chloroform, and 600 mL of 6% CMA in chloroform) to provide 9.5 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)tetradecanamide as a white waxy solid, m.p. 85-87° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:23])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(=O)CC>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:23])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Cc1ccc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2C)c1F
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[5-(3-fluorophenyl)-2-methyl-phenyl]methyl amino]phenol (124 mg, 0.361 mmol, 1.0 eq) and Cs2CO3 (176.5 mg, 0.542 mmol, 1.5 eq) in 2-Butanone (10 mL) was added ethyl bromoacetate (72.4 mg, 0.433 mmol, 1.2 eq) and the reaction stirred 30 min. The reaction was filtered and the filtrate evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as an oil/gum (100 mg, 65%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:21][CH:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Nc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 13 h
Yield: 88.3 %

Procedure:
To a stirred mixture of 2,4-difluoro-1-nitrobenzene (4.77 g, 30 mmol) and K2CO3 (4.14 g, 30 mmol) in THF (30 mL) was added isopropyl amine (1.77 g, 30 mmol) in THF (10 mL) at 0° C. After being stirred for 13 h, the insoluble materials were removed by pad of Celite and the filtrate was consentrated under reduced pressure to give title compound (5.25 g, 88%) as a pale yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1>C(O)=O>[CH:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:37][CH:38]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: O=CO
Product: O=CNCCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 0 °C

Procedure:
A mixture of formic acid (0.19 ml) and acetic anhydride (0.4 ml) is stirred with heating at 50°-60° C. for 1.5 hour. Thereto is added 1-{1-[4-(4-aminobutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.6 g) at room temperature and the mixture is stirred at room temperature for 13 hours. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate, water and saline solution and dried with sodium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol=50:1→25:1) to give 1-{1-[4-(4-formylaminobutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.49 g).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=1.Cl>N1C=CC=CC=1>[F:29][C:27]1[CH:26]=[C:25]([S:30]([NH:21][C:20]2[C:14]3[CH2:13][O:12][C:11]([NH:10][C@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)=[N:16][C:15]=3[CH:17]=[CH:18][CH:19]=2)(=[O:31])=[O:32])[CH:24]=[C:23]([F:22])[CH:28]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
(R)—N2-Indan-1-yl-4H-benzo[d][1,3]oxazine-2,5-diamine (example 2) (150 mg, 0.54 mmol) was dissolved in 5 mL pyridine and 3,5-difluoro-benzenesulfonyl chloride (112 mg, 0.53 mmol) was added. The reaction mixture was stirred at room temperature overnight. 1N HCl was added until pH5. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The crude product was purified by a silica gel column chromatography with heptane/ethyl acetate 1:1 to give a white solid (24 mg, 9%), MS: m/e=456.0 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[N+:17]([O-])=O.CN(C=O)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCCC>[NH2:17][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[Cl:7])[C:12]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:14]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)Nc2ccccc2)ccc1Cl
Yield: 68.9 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (2.5 mL, 28.66 mmol), 4-chloro-3-nitrobenzoic acid (4.02 g, 19.94 mmol), DMF (1.0 mL, 12.92 mmol), and aniline (3.6 mL, 39.51 mmol) to afford the product (3.39 g) after trituration in hexane; m.p. 194-197° C. after recrystallization from ethyl acetate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=2)[O:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH2:14][OH:15])=[CH:2]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:22][S:23]([O:15][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([CH2:10][O:9][C:8]2[CH:19]=[CH:20][CH:21]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)[CH:12]=1)(=[O:25])=[O:24]
Reactant: OCc1cccc(COc2cccc(-c3ccsc3)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1cccc(COc2cccc(-c3ccsc3)c2)c1

Procedure:
104 mg of 3-[3-(3-thienyl)phenoxymethyl]benzyl alcohol was dissolved in 1 ml of ethyl acetate, and 45 microliters of methanesulfonyl chloride and 88 microliters of triethylamine were added with ice cooling and stirring. The reaction mixture was stirred for 1 hour. The precipitate was removed by filtration, and the organic layer was separated, then dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated to give 3-[3-(3-thienyl)phenoxymethyl)benzyl methanesulfonate as a pale yellow oil.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][C:18]([O:20][C@H:21]3[CH2:25][CH2:24][O:23][CH2:22]3)=[O:19])[CH:11]=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH2:40])[CH:32]=[CH:33][C:34]=1[C:35]1[O:39][CH:38]=[N:37][CH:36]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:40][C:8](=[O:26])[NH:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][NH:17][C:18](=[O:19])[O:20][C@H:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH:32]=[CH:33][C:34]=1[C:35]1[O:39][CH:38]=[N:37][CH:36]=1
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: O=C(Nc1cccc(CNC(=O)O[C@H]2CCOC2)c1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)Nc2cccc(CNC(=O)O[C@H]3CCOC3)c2)ccc1-c1cnco1
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Added 2e (15 g, 1.0 eq) and 2g (8.58 g, 1.07 eq) into a jacketed reactor of suitable size before adding ethyl acetate (225 ml, 15 vol) and diisopropylethylamine (5.43 g, 1.0 eq), then heated the mixture to reflux (75-85° C.) for 24 hours. Once the reaction was complete, the mixture was cooled to room temperature and stirred for an additional 1 hour. Precipitated solid was filtered, washed with EtOAc 2 times (45 ml, 3 vol each wash), then dried at 58° C. for 18 hours (until a LOD is achieved of less than 1%) to give 17.46 g of crude 2h (90.4% yield, 98.46% a/a) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH3:14])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:15]([Cu])#[N:16]>CN(C=O)C.N1C=CC=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:5]([CH3:14])[CH:4]=[N:3][C:2]=2[C:15]#[N:16])=[CH:8][CH:9]=1
Reactant: N#C[Cu]
Reactant: Cn1cnc(Br)c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1cnc(C#N)c1-c1ccc(Cl)cc1
Temperature: 200 °C

Procedure:
To 4-bromo-5-(4-chlorophenyl)-1-methyl-1H-imidazole (1.3 g, 4.79 mmol) in DMF (8.4 mL) and pyridine (1.6 mL) was added CuCN (1.3 g, 14.4 mmol). The reaction was heated in a microwave reactor at 200° C. for 35 min. After cooling to ambient temperature, the reaction was quenched by addition of a 3:1 solution of NH4OH/saturated aqueous NH4Cl (60 mL). The reaction was extracted with EtOAc, organics separated, washed with saturated aqueous NaHCO3, and dried with saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide desired product and recovered starting material. The recovered starting material was resubjected to the reaction conditions and purified as above to provide additional desired product. MS (m/z) 218.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].C(=O)(O)[O-].[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOC(C)=O.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]([OH:9])[CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(Cl)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
2-Amino-5-chlorophenol (1.45 g, 10 mmol) was dissolved in EtOAc (30 ml) and water (20 ml). Sodium bicarbonate (1.25 g, 15 mmol) then benzoyl chloride (1.42 g, 10 mmol) were added and the mixture was stirred at room temperature for 1 h. The layers were partitioned and the organic layer was washed with brine, dried and concentrated in vacuo. The residue was triturated with di-ethyl ether to yield the title compound (2.05 g, 82%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[CH:5]([C:11]([OH:13])=[O:12])[C@:6]([CH:9]=[CH2:10])([CH3:8])[S:7][C@H:3]12.[O:16]([CH2:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[O:16]([CH2:23][C:24]([NH:1][C@@H:2]1[C:14](=[O:15])[N:4]2[CH:5]([C:11]([OH:13])=[O:12])[C@:6]([CH:9]=[CH2:10])([CH3:8])[S:7][C@H:3]12)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: C=C[C@@]1(C)S[C@@H]2[C@H](N)C(=O)N2C1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C[C@@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O

Procedure:
6β-Amino-2α-vinyl-2β-methylpenam-3-carboxylic acid is acylated in acetone-water with phenoxyacetyl chloride in the presence of sodium carbonate to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>O1CCCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[C:42]([NH:41][C:25](=[O:26])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:43]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: Nc1cccnc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1cccnc1
Reaction time: 0.25 h
Yield: 22.6 %

Procedure:
N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine (I) (3.71 g) was dissolved in dry tetrahydrofuran (100 ml) and, under ice cooling, triethylamine (1.5 ml) was added thereto. After stirring for 15 minutes, ethyl chlorocarbonate (1.10 g) was added, followed by stirring for 30 minutes. To this solution was added 3-aminopyridine (0.94 g) and the reaction was carried out at room temperature for 7 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate. After a conventional post-treatment, N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine 3-pyridylamide (II) (1.01 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][O:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][NH:11][C:12](=O)[O:13]C1C=CC=CC=1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1.C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]([F:34])([F:35])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=1)[CH2:6][O:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][NH:11][C:12](=[O:13])[NH:36][CH:37]1[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Yield: 72.1 %

Procedure:
Compound 84 produced in Example 77 (0.85 g, 1.7 mmol), tert-butyl 4-aminopiperidin-1-carboxylate (0.34 g, 1.7 mmol) and triethylamine (0.28 mL, 2.0 mmol) were dissolved in isopropyl alcohol and heated to reflux for 20 hours. After the solvent was evaporated therefrom in vacuo, the residue was purified by a column chromatography (toluene:acetone=4:1) to give Compound 85 (0.74 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:11]
Reactant: C1COCCN1
Reactant: Cc1c[nH]c(C)c1CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c[nH]c(C)c1CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a suspension of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (10 g, 60.8 mmol) in 60 ml of dichloromethane was added 1,1′-carbonyldiimidazole (11.6 g, 71.8 mmol) followed morpholine (5.5 ml, 60.8 mmol) and N,N-diisopropylethylamine (Hunig's base, 10 ml, 60.8 mmol). The dark red reaction mixture was stirred at room temperature overnight and poured into ice water. The organic layer was washed with brine until the wash had a pH of about 6, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column eluting with dichloromethane-methanol (98:2) to give 13.84 g (96%) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-1-morpholin-4-yl-propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCc1ccc(-c2ccc(OC)c(Cl)c2F)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc(O)c(Cl)c2F)cc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
22.0 g of the compound (b66) was dissolved in 200 mL of methylene chloride. 23.7 g of boron tribromide was added dropwise to the resulting solution in a temperature range of −27 to −20° C., and the temperature of the solution was gradually increased to room temperature, followed by stirring over night. The resulting reaction mixture was poured slowly to 300 mL of iced water, and the mixture was left at rest to separate into an organic layer and an aqueous layer, followed by extracting to the organic layer. The resulting organic layer was washed with a sodium chloride aqueous solution in three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was a yellowish solid. 19.7 g of the residue was purified by recrystallization from a mixed solvent of heptane and toluene (heptane/toluene=2/1 by volume) to obtain 18.0 g of 3-chloro-2-fluoro-4′-propylbiphenyl-4-ol (b67). The resulting compound (b67) was a white solid.