Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22]>C(Cl)Cl>[C:21](=[O:22])([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[O:11][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)OC(=O)CNC(=O)OC(C)(C)C

Procedure:
One millimole of t-butoxycarbonyl-glycine in 10 ml methylene chloride at 0° is treated successively with one millimole each of triethylamine and isobutyl chloroformate, forming N-(t-butoxycarbonyl)glycyl i-butyl carbonate. To this solution at -78° is added p-nitrobenzyl 5-methoxymethyl 6H-1,3-thiazine-4-carboxylate and then a second millimole of triethylamine. The reaction mixture is allowed to warm to room temperature over one hour, and kept at 25° one hour. The mixture is then washed successively with aqueous pH 2 buffer, water, and aqueous bicarbonate, dried with MgSO4, filtered and evaporated, affording p-nitrobenzyl 7-t-butoxycarbonylamino-3-methoxymethyl decephalosporanate, which may be purified if desired by chromatography on silica gel, eluting with 4:1 chloroform-ethyl acetate.
Reaction SMILES: CN(C(ON1N=NC2C=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]2[CH:38]=[C:39]([C:54]([OH:56])=O)[CH:40]=[C:41]3[C:46]=2[O:45][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:43][C:42]3=[O:53])[CH:29]=[CH:30][CH:31]=1.CCN(C(C)C)C(C)C.Cl.N1CCC1>C(Cl)Cl>[N:15]1([C:54]([C:39]2[CH:40]=[C:41]3[C:46](=[C:37]([C@H:33]4[CH2:34][CH2:35][CH2:36][N:32]4[C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[CH:38]=2)[O:45][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:43][C:42]3=[O:53])=[O:56])[CH2:14][CH2:13][CH2:10]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
HATU (368 mg, 0.97 mmol) was added to a stirred solution of 8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (212 mg, 0.48 mmol >98% enantiomeric purity, see Example 1.06 for details of preparation) and DIPEA (0.674 mL, 3.87 mmol) dissolved in DCM (1 mL) under nitrogen. The resulting solution was stirred at room temperature for 1 h. Azetidine hydrochloride (271 mg, 2.90 mmol) was added and the mixture was stirred at room temperature for 15 h. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness to afford 6-(azetidine-1-carbonyl)-8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4H-chromen-4-one (28 mg, 12%) as a pale yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)=[N:30]\[OH:31])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C(C)C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C(C)C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-isopropyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=453.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17](O)=O)[N:9]([C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH3:10])=[CH:4][CH:3]=1.ClC(=C)[C:22]#[N:23].[C:25](OC(=O)C)(=O)C.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:10])[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:25][C:17]=2[C:22]#[N:23])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)C(F)(F)F)C(C(=O)O)c1ccc(Cl)cc1
Reactant: C=C(Cl)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 2-(p-chlorophenyl)-N-(trifluoroacetyl)sarcosine (147.7 g, 0.50 mol) in acetonitrile is treated dropwise with α-chloroacrylonitrile (54.7 g, 0.62 mol) and acetic anhydride (153 g, 1.5 mol), stirred vigorously, treated dropwise with triethylamine (58.1 g, 0.57 mol) at 56°-60° C. over a 11/4 hour period, heated at 60° C. for 16 hours and concentrated in vacuo to give a residue. The residue is partitioned between ethyl acetate and water. The organic phase is concentrated in vacuo to afford an amber solid residue. Said solid is purified by flash chromatography (silica; ethyl acetate/hexanes) and recrystallized from methanol to give the title product as a pale yellow solid, mp 129.5°-130.5° C.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(C)C)C(C)C.C1C(=O)N([Br:23])C(=O)C1.S(=O)(=O)(O)O>C(Cl)Cl.O>[Br:23][C:5]1[CH:4]=[CH:3][CH:2]=[C:1]([CH3:8])[C:6]=1[OH:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: O
Product: Cc1cccc(Br)c1O
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a solution of o-cresol (20.0 g, 0.19 mol) and iPr2NH (2.63 mL, 18.5 mmol) in CH2Cl2 (500 mL), a solution of NBS (32.9 g, 0.19 mol) in CH2Cl2 (500 mL) was added dropwise over 7 h and the mixture was stirred over night at room temperature. The reaction mixture was acidified to pH=1 with conc. sulfuric acid and water (400 mL). The organic layer was separated, dried with Na2SO4, and concentrated under reduced pressure. 34.6 g of the crude product was obtained (yield: 97%). 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 5.54 (s, 2H), 6.71 (t, J=7.6 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=2)[CH:20]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C:12]1[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:23]=[CH:22]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
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: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: Brc1ccc2cc(-c3cc4ccccc4c4ccccc34)ccc2c1
Temperature: 85 °C
Reaction time: 7 h
Yield: 43.5 %

Procedure:
In argon atmosphere, a mixture of 15.53 g (69.6 mmol) of 9-phenanthreneboronic acid, 20.00 g (69.9 mmol) of 2,6-dibromonaphthalene, 1.62 g (1.40 mmol) of tetrakis(triphenylphosphine)palladium (0), 150 ml of dimethoxyethane, 150 ml of toluene, and 106 g of a 2 M sodium carbonate aqueous solution was stirred at a bath temperature of 85° C. for 7 h. The reaction mixture was added with water and extracted with toluene. After washing with water, the organic phase was dried over magnesium sulfate. Then the toluene was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 11.6 g (yield: 43%) of 6-bromo-2-(9-phenanthrenyl)naphthalene.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:6](OCC)=[O:7])C.[NH2:21][C:22]([NH2:24])=[S:23].[CH3:25][O-].[Na+].Cl>CO>[OH:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[C:6]([OH:7])[N:24]=[C:22]([S:23][CH3:25])[N:21]=1
Reactant: CCOC(=O)C(Oc1ccccc1OC)C(=O)OCC
Reactant: NC(N)=S
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(SC)nc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2-methoxyphenoxy)malonic acid diethyl ester (10.0 g) and thiourea (4.04 g) in methanol (100 ml) is added dropwise with stirring a 28% solution of sodium methoxide in methanol (17.07 g) over a period of 30 minutes under ice-cooling. The mixture is stirred at room temperature overnight. After the reaction is completed, the mixture is evaporated under reduced pressure to remove the solvent, and water (200 ml) is added to the residue. To the mixture is further added methyl iodide (3.30 ml), and the mixture is reacted at room temperature for three hours. The reaction solution is acidified with 10% aqueous hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water, and dried to give 4,6-dihydroxy-5-(2-methoxyphenoxy)-2-methylthiopyrimidine (8.90 g).
Reaction SMILES: [NH2:1][CH:2]=[CH:3][CH2:4][CH2:5][NH2:6].[N:7]1([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([S:23](Cl)(=[O:25])=[O:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][N:14]=[C:13]2[N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccc2ncnc(N3CCCCC3)c2c1
Reactant: NC=CCCN
Solvent: ClC(Cl)Cl
Product: NCCCCNS(=O)(=O)c1ccc2ncnc(N3CCCCC3)c2c1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
In 100 ml of chloroform was dissolved 4.4 g of 1,4-diaminobutene, and to the solution was added dropwise 50 ml of a chloroform solution containing 3.1 g of 4-piperidino-6-quinazolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and the reaction solution was extracted with a 10% aqueous hydrochloric acid solution. The chloroform layer was washed with water and dried with anhydrous potassium carbonate. Then chloroform was distilled from the chloroform layer, and the residue was separated by Prep LC/System 500 (Waters Associates, U.S.A.) [column: Prepack 500/C18 ; solvent: H2O/CH3CN=85/15 (volume ratio); flow rate: 100 ml/minute] to give 2.8 g of N-(4-aminobutyl)-4-piperidino-6-quinazolinesulfonamide [i.e. Compound(31)] as an oily substance in a yield of 77%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.C1(C)C=CC=CC=1.[CH2:17]([O:21][C:22]([C:24]1[N:25]=[C:26](Br)[C:27]2[C:32]([C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[CH2:17]([O:21][C:22]([C:24]1[N:25]=[C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:27]2[C:32]([C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: OB(O)c1ccccn1
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
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: CCO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(-c2ccccn2)c2ccccc2c1OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of Pyridin-2-ylboronic acid (323 mg, 2.5 mmol) in EtOH (2.5 ml) was added subsequently toluene (15 ml), 4-Benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (1.035 mg, 2.5 mmol, see example D-86a), Pd(PPh3)4 (292 mg, 0.25 mmol), and aq. 2 M Na2CO3 solution (2.5 ml, 5 mmol). The mixture was then refluxed with stirring under N2 protection for 24 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (15 ml) and the mixture was extracted with EtOAc (30 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using CH2Cl2 MeOH=982 as the eluent gave a dark oil that was further purified by flash column chromatography on silica gel using CH2Cl2 MeOH=991 as the eluent and subsequently by preparative TLC using CH2Cl2 MeOH=982 as the eluent (had to be repeated several times) to give the title compound as a yellow oil (19 mg); MS-(+)-ion M+1=413.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CS([O-])(=O)=O.[CH2:17]([N:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22]O)[CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH3:25])[CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCN(CC)CCCO
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1

Procedure:
A solution of 3-fluoro-4-nitrophenol (2 mmol) and methanesulfonate of 3-diethylamino-1-propanol (2.5 mmol) in DMF (4 mL) is added with K2CO3 (4 mmol) and heated following the general procedure III (Step A). The product, 2-fluoro-4-(3-diethylamino-1-propoxy)nitrobenzene is obtained (470 mg) after purification using silica gel column chromatography.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>C(O)C.O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 58.6 %

Procedure:
A stiffed mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-ethanone (5.3 g, 22 mmol), and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. RecrystaIlization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=118°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH2:20]([N:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1)[C:21]#[CH:22]>>[O:30]=[S:26]1(=[O:29])[CH2:27][CH2:28][N:23]([CH2:20][C:21]#[C:22][C:17]2[S:18][C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]3[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=3[F:1])[CH:16]=2)[CH2:24][CH2:25]1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCS(=O)(=O)CC1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCS(=O)(=O)CC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 80.2 %

Procedure:
Prepared from 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) and commercially available N-propargyl-S,S-dioxo-4-thiapiperidine (34 mg, 0.19 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 5 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a white powder (45 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6 Hz, 1H), 7.61 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.55 (m, 2H), 6.49 (m, 1H), 3.86 (br s, 2H), 3.72 (s, 2H), 3.17 (m, 8H).
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2C2C=CC(C([O-])=O)=CC=2)=[CH:12][C:11]=1[N+:31]([O-:33])=[O:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[C@H]([O:42]C1C=CC(OC(=O)C2C=CC=CC=2)=CC=1[N+]([O-])=O)CCCCCC>>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:42])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[N+:31]([O-:33])=[O:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(-c2ccccc2-c2ccc(C(=O)[O-])cc2)cc1[N+](=O)[O-]
Reactant: CCCCCC[C@H](C)Oc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1[N+](=O)[O-]

Procedure:
The benzoyl ester of (S)-4'-(1-methylheptyloxy)-3'-nitro-4-biphenylylbenzoate was saponified using the same procedure as that used for saponification of (S)-[4-(1-methylheptyloxy)-3-nitrophenyl]-benzoate except that the reaction was carried out at 60° C. to give (S)-4'-(1-methylheptyloxy)-3'-nitro-4-hydroxybiphenyl (Compound 17, Scheme II, R2 =(S)-OCH(CH3)C6H13) as a very viscous orange liquid after flash chromatography with hexanes/ethyl acetate [88/12]; Rf [hexanes/ethyl acetate 85/15]: 0.17; 1H NMR (300 MHz, CDCl3): δ 0.86(t, 3H, J=6.6 Hz), 1.18-1.52(m, 8H), 1.35(d, 3H, J=6.1 Hz), 1.62(m, 1H), 1.78(m, 1H), 4.50(m, 1H), 5.22(broad s, 1H), 6.89(d, 2H, J=8.5 Hz), 7.07(d, 1H, J=8.8 Hz), 7.39(d, 2H, J=8.5 Hz), 7.62(dd, 1H, J=2.4 Hz, J=8.8 Hz), 7.92(d, 1H, J=2.4 Hz); 13C NMR (300 MHz, CDCl3): δ 13.99, 19.49, 22.50, 25.19, 29.10, 31.65, 36.17, 76.57, 115.94, 116.17, 123.30, 127.99, 131.21, 131.64, 133.09, 141.00, 15.42, 155.52; IR (CHCl2); 350, 3300(broad), 3020, 2920, 2840, 1610, 1540, 1510, 1485, 1350, 1260, 1220, 1160, 1110, 1040, 925, 825 cm-1 ; Mass spectrum, m/z(rel.intensity): 343(M+ 5), 231(100), 185(6), 57(6), 43(12).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C(O)(=O)C>O1CCCC1>[C:1]1([N:7]2[C:11]([B:17]([OH:22])[OH:18])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OB(O)c1ccnn1-c1ccccc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a solution of 1-phenyl-1H-pyrazole (20.0 g) in tetrahydrofuran (700 mL) was added dropwise n-butyllithium (2.5M hexane solution, 58.3 mL) under a nitrogen atmosphere at −78° C., and the mixture was stirred at the same temperature for min. To the reaction mixture was added triisopropyl borate (52.2 g) at −78° C., and the mixture was stirred at the same temperature for 1 hr. The mixture was gradually warmed to room temperature, and stirred at room temperature for 20 hr. To the reaction mixture was added acetic acid (20 mL) to adjust to pH 5, and the mixture was concentrated to give the title compound (25.0 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:8]1([C:6]2[CH:7]=[C:2]([C:16]3[C:15]([CH3:14])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:21])[N:3]=[CH:4][N:5]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: Cc1cccc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1-c1cc(-c2ccccc2)ncn1
Yield: 23 %

Procedure:
Next, 1.6 g of 4-chloro-6-phenylpyrimidine synthesized in Step 1, 1.5 g of 2,6-dimethylphenylboronic acid, 1.8 g of sodium carbonate, 59 mg of PdCl2(PPh3)2, 20 mL of N,N-dimethylformamide (abbreviation: DMF), and 20 mL of water were put into a 100-mL round-bottom flask, and the air in the flask was replaced with argon. Then, heating was performed by irradiation with microwaves (2.45 GHz, 100 W) for 2 hours. An organic layer was extracted from the obtained mixture with the use of dichloromethane, and was washed with water and saturated brine. Magnesium sulfate was added and gravity filtration was performed. A solvent in the obtained filtrate was distilled off, and the given residue was purified by flash column chromatography using a mixed solvent of ethyl acetate and hexane (ethyl acetate: hexane=1:5) as a developing solvent, whereby 0.50 g of the objective substance, Hppm-dmp (abbreviation) was obtained (yield: 23%, a pale yellow oily substance). A synthesis scheme of Step 2 is shown in (a-2) below.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[N:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:39][C:35]4[CH:36]=[CH:37][N:38]=[C:33]([CH3:32])[CH:34]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: Cc1cc(C=O)ccn1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4ccnc(C)c4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 6-methyl-4-pyridinecarboxaldehyde (10 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:45][CH2:46][C:47]1[N:48]=[CH:49][NH:50][CH:51]=1>CN(C=O)C>[NH:50]1[CH:51]=[C:47]([CH2:46][NH:45][C:8]([C:4]2[N:5]([CH3:7])[CH:6]=[C:2]([Cl:1])[CH:3]=2)=[O:10])[N:48]=[CH:49]1
Reactant: NCc1c[nH]cn1
Reactant: Cn1cc(Cl)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(Cl)cc1C(=O)NCc1c[nH]cn1
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of 4-chloro-1-methyl-1H-pyrrole-2-carboxylic acid (55 mg, 0.34 mmol) and triethylamine (0.100 mL, 0.72 mmol) in DMF (2 mL), BOP (217 mg, 0.49 mmol) was added. After 5 min of stirring, a solution of 4-aminomethylimidazole 11-2 (100 mg, 1.03 mmol) in DMF (2 mL) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to give N-((1H-imidazol-4-yl)methyl)-4-chloro-1-methyl-1H-pyrrole-2-carboxamide (81 mg).
Reaction SMILES: [C:1]1(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[O:9])O1.[NH2:11][C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:20][C:12]1([N:11]2[C:3](=[O:9])[C:4]3=[CH:8][S:7][CH:6]=[C:5]3[C:1]2=[O:10])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CC1(N)CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2cscc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(N2C(=O)c3cscc3C2=O)CCC(=O)NC1=O
Yield: 79.1 %

Procedure:
1.54 g of thieno(3,4-c)furan-1,3-dione was dissolved in 20 mL of anhydrous THF, and 1.42 g of 3-amino-3-methylpiperidin-2,6-dione was added. The reaction mixture was allowed to react at room temperature for 4 h, and 2 g of CDI and a catalytic quantity of DMAP were added. The reaction mixture was allowed to reflux for 6 h during which time a solid precipitated. The reaction solution was cooled and filtered to obtain a white solid (2.2 g). MS (m/z): 278 (M)+.