Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1>>[O:29]1[C:33]2([CH2:38][CH2:37][N:36]([C@H:2]3[CH2:19][C@@:18]4([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]5[C@@H:17]4[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@H:9]5[CH2:10][C@H:11]([N:22]5[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]5)[C@@H:12]4[OH:21])[CH2:4][C@@H:3]3[OH:1])[CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Product: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Yield: 85.9 %

Procedure:
2α,3α-Epoxy-16β-(4-hydroxy-1-piperidinyl)-5α-androstane-17β-ol is reacted with 1,4-dioxa-8-azaspiro[4.5]decane as described in Example 3 to obtain the title compound in a yield of 85.90%, m.p.: 253°-255° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:31]([OH:34])([CH3:33])[CH3:32])[N:23]=[C:22]2[CH2:35][O:36][CH2:37][CH3:38])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:31]([OH:34])([CH3:32])[CH3:33])[N:23]=[C:22]2[CH2:35][O:36][CH2:37][CH3:38])=[CH:16][CH:15]=1)([OH:7])=[O:5]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 96(b), but using 600 mg of ethyl 1-{4-[2-(t-butoxycarbonyl)phenyl]phenyl}methyl-2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [prepared as described in step (a) above], 585 mg of the hydrochloride of the title compound were obtained as a foam-like solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[C:4]([OH:28])[CH:3]=1.Br[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[C:4]([O:28][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:3]=1
Reactant: N#Cc1cccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)c1
Reactant: BrCC1CCCC1
Product: N#Cc1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 19, from 3-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-benzonitrile and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown solid (33%). MS (Turbo Spray): m/z=378.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:34])[C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:33])[CH2:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1)#[N:2].Cl.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(OCC)(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:34])[C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:33])[CH2:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1CCCC[C@@H]1CC(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCCC[C@@H]1CC(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)cc1
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of the compound (26.7 g, 57 mmol) obtained in the item (c) inchloroform (50 ml), a 4-N hydrochloride in ethyl acetate (30 ml) is added at 0° C. The mixture is stirred for 3 hours and then the solvent isevaporated. The resulting residue was dissolved in dichloromethane (250 ml)and triethylamine (19 ml) is added. Then, a solution of methanesulfonyl chloride (7.9 g, 68 mmol) in dichloromethane (50 ml) is added at 0°C. and the mixture is stirred for 3 hours. The organic layer is washed oncewith a saturated sodium bicarbonate solution, water and saturated brine, successively, and then dried over sodium sulfate. The resulting residue ispurified with silica gel chromatography (hexane-ethyl acetate) to give 18.6g of the titled compound (73%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:20][C:21]#[N:22]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[C:20](=[CH:6]/[C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3][CH2:1][CH3:2])/[C:21]#[N:22])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: CCOc1ccc([N+](=O)[O-])cc1C=O
Reactant: COc1ccc(CC#N)cc1OC
Product: CCOc1ccc([N+](=O)[O-])cc1/C=C(\C#N)c1ccc(OC)c(OC)c1
Yield: 45.1 %

Procedure:
2-Ethoxy-5-nitrobenzaldehyde (390 mg) and 3,4-dimethoxybenzyl cyanide (354 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (319 mg, yield: 45%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][CH:4]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)C>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[CH:10])=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)C#Cc1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOCC
Product: C#Cc1ccc(C(F)(F)F)cc1

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 19.0 grams (0.0784 mole) of 1-(4-trifluoromethylphenyl)-2-trimethylsilylethyne and 24.7 grams (0.0784 mole) of tetrabutylammonium fluoride trihydrate in 200 ml of diethyl ether. The reaction mixture was filtered through silica gel, and the silica gel was washed with diethylether. The wash and filtrate were combined and concentrated under reduced pressure yielding, 22.9 grams of ether concentrate which was predominantly 4-trifluoromethylphenylethyne.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]#[N:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)([CH3:21])([CH3:20])[CH3:19].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]#[N:17])[C:13]([O:15][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C#N)NC(=O)OCc1ccccc1
Yield: 67.4 %

Procedure:
To a mixture of 2-benzyloxycarbonylamino-2-cyanoacetic acid (2.00 g, 8.54 mmol), toluene (20 ml) and t-butyl alcohol (6.33 g, 85.4 mmol), was added trifluoroacetic acid anhydride (7.17 g, 34.2 mmol) dropwise and the solution was stirred for half an hour. The reaction solution was neutralized by adding 10% NaOH aqueous solution (18 g), the organic layer was separated and washed with water three times, dried over sodium sulfate, insoluble materials were filtered and the filtrate was condensed to give t-butyl 2-benzyloxycarbonylamino-2-cyanoacetate (1.67 g, yield 67.4%) as a pale yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27]C1CNCCN1>>[CH3:27][CH:23]1[NH:22][CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:24]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: CC1CNCCN1
Product: CC1CN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3n2)CCN1

Procedure:
The title compound was prepared following the procedure described for 6a using 2-methylpiperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.00 (3H, s), 2.78 (4H, brm), 3.05 (1H, m), 4.30 (2H, m), 7.07 (2H, m), 7.39 (2H, dd, J=8.24, 7.97 Hz), 7.75 (1H, d, J=9.34 Hz), 8.27 (2H, dd, J=7.42, 1.10 Hz), 8.37 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH2:12][OH:13])([CH2:10][OH:11])[CH2:8][OH:9])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>C1COCC1>[OH:11][CH2:10][C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)([CH2:12][OH:13])[CH2:8][OH:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(CO)(CO)CO)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(CO)(CO)CO)on1)Oc1ccccc1

Procedure:
To a stirred mixture of 2-(3-aminoisoxazol-5-yl)-2-(hydroxymethyl)propane-1,3-diol (1 equivalent) and potassium carbonate (2-5 equivalents) in anhydrous THF at rt is added phenyl chloroformate (1-2 equivalents), then stirring is continued at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between water and dichloromethane. The organic layer is separated and the aqueous layer is further extracted with dichloromethane. The combined extracts are washed with water or brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford phenyl 5-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)isoxazol-3-ylcarbamate.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:28][NH:29][CH3:30].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.ClCCl.O>[F:23][C:24]([F:38])([F:39])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:28][N:29]([CH3:30])[C:11](=[O:13])[C:10]1[C:14]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:8][CH:9]=1
Reactant: O=C(O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Yield: 84 %

Procedure:
A mixture of 46 mg (0.15 mmol) 6-morpholin-4-yl-4-phenoxy-nicotinic acid, 43 mg (0.17 mmol) (3,5-bis-trifluoromethyl-benzyl)-methylamine, 32 mg (0.17 mmol) 1-(3-diaminopropyl)-3-ethyl-carbodiimide hydrochloride and a catalytic amount of 4-(N,N-dimethylamino)-pyridine in 3 ml dichloromethane was stirred at room temperature over night. The reaction mixture was diluted with water, adjusted to pH 6 with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. Flash column chromatography afforded 68 mg (83%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=2)[C:8]#[N:9])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: N#Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Yield: 77 %

Procedure:
To a suspension of 2-chloro-4-pyridinecarbonitrile (0.50 g, 3.61 mmol), Cs2CO3 (1.70 g, 7.22 mmol) and 4-(trifluoromethyl)phenylboronic acid (0.82 g, 3.61 mmol) in dioxane (18 mL) was added palladium acetate (0.02 g, 0.07 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.07 g, 0.14 mmol). The reaction vessel was sealed and heated to 100° C. for 4 hours and cooled to rt. The reaction mixture was filtered through a pad of celite, concentrated and purified by FCC (0%-100% EtOAc in hexane) to provide the desired product (0.69 g, 78%). MS (ESI): mass calcd. for C13H7F3N2, 248.2; m/z found 249.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.00-8.92 (m, 1H), 8.63-8.57 (m, 1H), 8.38 (d, J=8.1, 2H), 7.94-7.85 (m, 3H).
Reaction SMILES: [ClH:1].Cl.[C:3]1([CH:9]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:10]2[N:15]3[CH2:16][CH2:17][C@@H:12]([C@@H:13]([C:18](N)=[O:19])[CH2:14]3)[C@@H:11]2[NH:21][CH2:22][C:23]2[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(C1C=C(C=O)C(OC)=CC=1)(=O)=[O:43]>Cl>[ClH:1].[ClH:1].[C:35]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:10]2[N:15]3[CH2:16][CH2:17][C@@H:12]([C@@H:13]([C:18]([OH:43])=[O:19])[CH2:14]3)[C@@H:11]2[NH:21][CH2:22][C:23]2[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccc(S(C)(=O)=O)cc1C=O
Reactant: COc1ccc(S(C)(=O)=O)cc1CN[C@H]1[C@H]2CCN(C[C@@H]2C(N)=O)[C@H]1C(c1ccccc1)c1ccccc1
Agent: Cl
Product: COc1ccc(S(C)(=O)=O)cc1CN[C@H]1[C@H]2CCN(C[C@@H]2C(=O)O)[C@H]1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.6 %

Procedure:
A solution of (3R,4S,5S,6S)-6-Diphenylmethyl-5-(-2-methoxy-5-methylsulfonyl-benzylamino)-1-azabicyclo[2.2.2]octane-3-carboxamidedihydrochloride (the compound of Example 1, 400 mg) in conc. HCl (10 ml) was warmed up to 90° C. and stirred for 15 hr. After cooling down to room temperature, the mixture was evaporated in vacuo. The residue was recrystallized from EtOAc-MeOH to give a titled compound (268.2 mg, 55.6%) as a white crystalline.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[C:9]1([C:2]2[CH:7]=[C:6]([C:17]3[C:18]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:14]=[CH:15][CH:16]=3)[N:5]=[CH:4][N:3]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: c1ccc2c(-c3cc(-c4cccc5ccccc45)ncn3)cccc2c1
Yield: 41 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 5.00 g of 4,6-dichloropyrimidine, 11.56 g of 1-naphthaleneboronic acid, 7.12 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 2.91 g of 1-naphthaleneboronic acid, 1.82 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and was dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 2:1, so that a pyrimidine derivative Hd1npm, which was the objective substance, was obtained (yellow white powder, yield of 41%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (i-1) of Step 1 is shown below.
Reaction SMILES: [CH2:1]([N:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:36])(=[O:35])[NH2:34])=[CH:23][CH:22]=1)[C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41]>>[CH2:1]([N:5]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:35])(=[O:36])[NH:34][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=2[Cl:37])=[CH:25][CH:26]=1)[C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:16])[F:17])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Product: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Yield: 29 %

Procedure:
Following the procedure of Example 1, Step I, 1-butyl-3-methyl-1-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3-[2-(trifluoromethyl)phenyl]urea was acylated with 2-chlorobenzoic acid. After work-up, the crude product was purified initially by flash chromatography on silica gel (elution with 2% and then 5% MeOH in CH2Cl2). Further purification by HPLC on a Zorbax C8 Semiprep reversed phase column (70:30 MeCN--H2O, containing 0.1% TFA) provided a 29% yield of the title compound as a stiff, white foam, mp>60° C. (gradual); homogeneous by TLC (95:5 CH2Cl2 --MeOH); FAB-MS m/e 658 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([O:13]P(O)(O)=O)=[CH:12][C:7]=2[O:6][C:4](=[O:5])[CH:3]=1.[Mg]>>[CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][C:4](=[O:5])[CH:3]=1
Reactant: Cc1cc(=O)oc2cc(OP(=O)(O)O)ccc12
Agent: [Mg]
Product: Cc1cc(=O)oc2cc(O)ccc12

Procedure:
The procedures used in FIG. 5 could not be applied to 4-MUP for two reasons. First, the background reading obtained from a 1 mM solution was off scale on the Turner model 111. If the concentration was reduced to 0.030 mM then the background reading was comparable to a 1 mM solution of BBTP or ABTP. Since the Km for 4-MUP in this buffer is approximately 30 micromolar then the turnover of 4-MUP is reduced thus lowering the sensitivity of the substrate for AP. It was found that with freshly prepared 30 micromolar solutions of 4-MUP that it gave approximately one half to one third the signal obtained with a 1.0 mM solution of BBTP. Secondly, it was found that basic aqueous solutions of 4-MUP containing magnesium cause the 4-MUP to hydrolyze and form 4-methyl umbelliferone. This results in a significant background increase. This limits the test to having the 4-MUP being reconstituted with buffer usually within 8 hours of use even when this solution is stored at 4° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[N:35]1([CH2:41][CH2:42][C:43](O)=[O:44])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CO>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[C:43](=[O:44])[CH2:42][CH2:41][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C(=O)CCN1CCCCC1
Reaction time: 2 h
Yield: 11.5 %

Procedure:
To the product from step (v) of example 29 (480 mg, 1.04 mmol) in DMF (5 mL), 3-(piperidin-1-yl)propanoic acid (196 mg, 1.25 mmol) and HATU (475 mg, 1.25 mmol) were added at rt and stirred for 2 hours. After adding 1 mL of methanol, the crude product was purified by RPHPLC and the resulting residue was triturated with diethyl ether: EtOAc (5:1). The suspension was filtered to afford the title compound as a white solid (72 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2N)[CH2:4][CH2:3]1.F[B-](F)(F)F.[H+].N([O-])=O.[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:29]=[CH:30][C:31]=1[Cl:32]>O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([NH:33][C:34](=[O:37])[CH:35]=[CH:36][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CN1CCN(c2ccccc2N)CC1
Reactant: C=CC(=O)Nc1ccc(Cl)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Product: CN1CCN(c2ccccc2C=CC(=O)Nc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.5 h

Procedure:
In a flame-dried 3-neck round bottom flask containing a magnetic stir bar, water condensor and dry nitrogen (N2) inlet were placed 2-(4-methylpiperazin-1-yl)-aniline (0.200 g, 1.05 mmol) and 50% aqueous tetrafluoroboric acid (HBF4)(0.33 ml, 2.63 mmol). To the stirred mixture, sodium nitrite (0.076 g, 1.10 mmol) in 2 mL of water was added and stirring was continued at 0° C. for 30 minutes. A solution of N-(3,4-dichlorophenyl)-acrylamide (0.454 g, 2.1 mmol) in 4 mL of methanol, followed by palladium (II) acetate (5 mg) were then added and the reaction was refluxed for 30 minutes. After allowing the reaction to cool, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was washed with saturated brine and dried with CaSO4, filtered and concentrated in vacuo to a crude dark solid. Chromatography on silica gel, eluting with 75% ethyl acetate:hexanes, 100% ethyl acetate and finally 0.5% methanol: ethyl acetate provided a yellow solid, 0.221 g which was recrystallized from ethyl acetate to give the title product, 0.120 g.
Reaction SMILES: O[C:2]12[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH:7]1[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[C:5]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([CH3:26])[NH:3]2>C1(C)C=CC=CC=1>[CH3:26][C:4]1[NH:3][C:2]2[CH2:10][CH2:9][S:8](=[O:11])(=[O:12])[C:7]=2[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:5]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(C)NC2(O)CCS(=O)(=O)C2C1c1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC2=C(C1c1ccccc1[N+](=O)[O-])S(=O)(=O)CC2

Procedure:
A mixture of methyl 2,3,3a,4,7,7a-hexahydro-3a-hydroxy-5-methyl-7-(2-nitrophenyl)-1,1-dioxothieno [3,2-b]pyridine-6-carboxylate (2.5 g, 0.0065 moles) and toluene (60 mL) was refluxed for 24 hours. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol. The crystals were washed with diethyl ether 2x and dried at 65° C. under high vacuum for 48 hours. This gave 1.78 g product; mp 215°-217° C.