Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:14]NOC.C[Mg]Br>>[Br:1][C:2]1[CH:10]=[C:6]([C:7](=[O:9])[CH3:14])[CH:5]=[N:4][C:3]=1[O:11][CH3:12]
Reactant: CNOC
Reactant: COc1ncc(C(=O)O)cc1Br
Agent: C[Mg]Br
Agent: Cl
Product: COc1ncc(C(C)=O)cc1Br

Procedure:
5-Bromo-6-methoxynicotinic acid and N,O-dimethylhydroxylamine hydrochloride were treated in the similar manner to Reference Example 7(5), and then the resulting compound and methylmagnesium bromide were treated in the similar manner to Reference Example 7(6) to give 1-(5-bromo-6-methoxypyridin-3-yl)ethanone [Ex(296-1)] as a colorless powder.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(F)cc1F
Yield: 49.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (1.0 g), triethylamine (0.54 mL), 2,4-difluorocinnamic acid (0.72 g), WSC.HCl (0.75 g), and methylene chloride (40 mL), to give the captioned compound (0.73 g, 49%) as an oily product.
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15](=[O:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:21][CH2:16][C:15]([C:11]1[C:12]([CH3:14])=[CH:13][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:9][C:10]=1[CH3:18])=[O:17]
Reactant: CCc1ccc(Oc2cc(C)c(C(C)=O)c(C)c2)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CCc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
To a solution of 1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (6.00 g, 22.4 mmol) in acetonitrile (44.7 mL) was added tetrabutylammoniumtribromide (TBABr3, 10.8 g, 22.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (8.2 g), which was used directly for the next step without further purification.
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=4)=[N:12][O:13][C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](C(C)(C)C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3]C1.[CH3:40][OH:41]>>[O:41]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=4)=[N:12][O:13][C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:10]([CH3:11])([CH3:8])[CH2:14][OH:13])(=[O:17])=[O:18])=[CH:9][C:4]=2[O:3][CH2:40]1
Reactant: CO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2onc(OCCOc3ncc(Br)cn3)c2-c2ccc3c(c2)OCO3)cc1
Product: CC(C)(CO)c1ccccc1S(=O)(=O)Nc1onc(OCCOc2ncc(Br)cn2)c1-c1ccc2c(c1)OCO2
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flasks each containing 50 ml of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1 ″ throw. Two mLs of this inoculum was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-5-isoxazolyl)-4-(tert-butyl)benzene-sulfonamide (Example 2) dissolved in 0.5 mL of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 144 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][C:37]([NH:40][CH2:41][CH2:42][CH2:43][NH2:44])([CH3:39])[CH3:38]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][CH2:42][CH2:41][NH:40][C:37]([CH3:39])([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CC(C)(C)NCCCN
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCCNC(C)(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 75.1 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) were added N-(1,1dimethylethyl)-1,3-propanediamine (0.028 mL, 0.177 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (17 mg, 75%). LC-MS m/z 566 (M+H)+; 1H-NMR (MeOD) δ 1.11 (s, 9H), 1.27 (d, 6H), 1.60 (m, 2H), 2.31 (s, 3H), 2.45 (m, 2H), 3.15 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]=[C:12]([CH:14]3[CH2:17][C:16](=O)[CH2:15]3)[S:13][C:9]=2[CH:8]=1.C([BH3-])#N.[Na+]>CO>[Br:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]=[C:12]([C@H:14]3[CH2:15][C@@H:16]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:17]3)[S:13][C:9]=2[CH:8]=1
Reactant: C1CCNC1
Reactant: O=C1CC(c2nc3ccc(Br)cc3s2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Brc1ccc2nc([C@H]3C[C@@H](N4CCCC4)C3)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (295 μl, 3.54 mmol) was added to a solution of the product of Example 1C (100 mg, 0.354 mmole) in 2 ml methanol and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (56 mg, 0.891 mmole) was added and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product which was purified by column chromatography (0.5% ammonium hydroxide and 5% methanol in dichloromethane) to give 65 mg (55%) of the title compound. 1H NMR (400 MHz, CDCl3) for the cis isomer δ ppm 7.97 (d, J=1.84 Hz, 1H) 7.80 (d, J=8.90 Hz, 1H) 7.54 (dd, J=8.75, 1.99 Hz, 1H) 3.56-3.66 (m, 1H) 3.05-3.19 (m, 1H) 2.55-2.75 (m, 6H) 2.41-2.53 (m, 2H) 1.75-1.92 (m, 4H). MS: (M+H)+=337/339.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1)C1C=CC=CC=1.C(N(CC)CC)C.C(OC([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=O)(C)(C)C.[Na]>C(Cl)Cl>[N:30]1([CH:11]2[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C1CNCC(N2CCNCC2)C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
1-Benzyl-3-piperidone hydrochloride (700 mg, 2.7 mmol), triethylamine (270 mg, 2.7 mmol) and 1-(tert-butoxycarbonyl)-piperizine (500 mg, 2.7 mmol) in DCM, was stirred at rt for 1 h, then heated to 50° C. for 40 min. Sodium triacetoxyborahydride (1.12 g, 5.3 mmol) was added and the reaction mixture allowed to cool, with stirring, over 12 h then concentrated to dryness in vacuo. The residue was partioned between DCM/water, the organics dried (MgSO4) and concentrated to dryness in vacuo. The resulting residue in EtOH (10 ml) was hydrogenated with 10% w/w palladium on carbon (200 mg) under hydrogen at rt for 18 h. The reaction was filtered through celite and concentrated to dryness in vacuo to give 3-piperazine-1-yl-piperidine as a pale yellow gum (700 mg, 2.6 mmol, 97%). 8H (CDCl3, 300K) 3.43-3.37 (4H, m br), 3.21 (1H, d br, J=11.6 Hz), 3.01 (1H, d br, J=12.2 Hz), 2.59-2.47 (6H, m br), 2.45-2.38 (1H, m), 1.99-1.92 (1H, m br), 1.82-1.75 (1H, m), 1.58-1.48 (1H, m), 1.45 (9H, s), 1.42-1.33 (1H, m). m/z (ES+, 70V) 270.3 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:36][CH2:37][CH3:38])=[C:28]([CH:35]=1)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:36][CH2:37][CH3:38])=[C:28]([CH:35]=2)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:4][CH:5]=1
Reactant: CCCc1ccc(O)cc1OCC(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC(=O)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.79 g), methyl 2-(5-hydroxy-2-propylphenoxy)acetate (1.17 g), anhydrous potassium carbonate (0.72 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.60 g, 61%) of methyl 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: Br.C([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[C:16](=O)[CH3:17])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[CH3:17][C:16]1[N:15]([CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]=1
Reactant: [H][H]
Reactant: CC(=O)N(c1ccccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Br
Solvent: CO
Product: Cc1nc2ccccc2n1C1CCNCC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
In this reference example, 14.8 g of 1-benzyl-4-[N-(2-nitrophenyl)-N-acetylamino]-piperidine hydrobromide obtained in the same manner as that of Refernce Example 4, 250 ml of methanol and 1.0 g of 5% palladium carbon are mixed and stirred at room temperature under the atmospheric pressure in the current of hydrogen for 12 hours. The resultant reaction mixture is filtered. The filtrate is mixed with 29 ml of concentrated hydrochloric acid and stirred overnight. The reaction solution is concentrated and the residue is dissolved in 50 ml of water. The solution is adjusted to pH 11.0 with 1 N aqueous sodium hydroxide. The solution is extracted with 50 ml of chloroform three times, and the extract is washed with 20 ml of a saturated aqueous sodium chloride and dried. The extract is freed from the solvent by distillation. The residue is mixed with n-hexane and stirred for crysallization. The crystals are separated by filtration, recrystallized from a mixed solvent of n-hexane and ethanol to obtain 6.7 g of 4-(2-methyl-benzimidazol-3-yl)-piperidine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.CC1(C)[O:20][C:19](=O)[C:16]2([CH2:18][CH2:17]2)[C:15](=[O:22])[O:14]1>ClCCl>[O:20]=[C:19]1[CH:16]([C:15]([OH:22])=[O:14])[CH2:17][CH2:18][N:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: ClCCl
Product: O=C(O)C1CCN(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
A mixture of 3-trifluoromethyl-phenylamine (2.8 g, 17.5 mmol) and 6,6-dimethyl-5,7-dioxa-spiro[2.5]octane-4,8-dione (1.0 g, 5.8 mmol) was stirred at 20-25° C. for 18 hrs. The reaction mixture was diluted with dichloromethane and washed with 10% NaOH solution (3×10 ml). The aqueous layer was cooled and acidified with dil HCl. The aqueous layer was extracted with dichloromethane, washed with saturated brine solution. The organic layer was dried over Na2SO4 and evaporated to obtain 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid (1.1 g, 69%) as an off white solid.
Reaction SMILES: [C:1]([O:14][CH:15]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][CH:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:16]1[CH3:33])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC1(C)O[O:36]1>>[C:1]([O:14][CH:15]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]([OH:36])[CH:17]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:16]1[CH3:33])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)NC(c2ccccc2)C1C
Reactant: CC1(C)OO1
Product: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)N(O)C(c2ccccc2)C1C
Yield: 99.4 %

Procedure:
The general procedure of Example 2 is repeated using 11.5 g (25.5 mmol) of 2,6-diphenyl-3-methylpiperidin-4-yl laurate and 570 mL (25.5 mmol) of dimethyldioxirane (0.045M in acetone). 11.8 g (99% yield) of the title compound is isolated: mp 84°-91° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[O:19])[CH:7]=[CH:8][C:9]=1[C:10](=[O:16])[C:11]([CH2:13][CH2:14][OH:15])=[CH2:12].C(=O)(O)[O-].[Na+]>CO>[OH:16][CH:10]([C:9]1[CH:8]=[CH:7][C:6]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[O:19])=[CH:5][C:4]=1[F:3])[CH:11]([CH3:12])[CH2:13][CH2:14][OH:15]
Reactant: C=C(CCO)C(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(CCO)C(O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg of sodium borohydride was added to a methanol (8 ml) solution of 320 mg of N-(3-fluoro-4-(2-(2-hydroxyethyl)acryloyl)phenyl)pyridine-2-carboxamide, and the reaction liquid was stirred at room temperature for 1 hour. Aqueous saturated sodium bicarbonate was added to the reaction liquid, extracted with chloroform, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=100/1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+].Cl>CC(C)=O>[C:2]1([NH:1][C:8](=[O:18])[C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)c1ccc(C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
N,N'-diphenylterephthalamide (Structure I) is synthesized from aniline and terephthaloyl chloride using acetone as a reaction media and an aqueous solution of NaOH to neutralize the HCl generated. Terephthaloyl chloride (87.2 grams, 0.43 moles) is first added to a stirred, 2-liter reaction flask containing one liter of acetone. After the terephthaloyl chloride has dissolved, aniline (80.0 grams, 0.86 moles) is added dropwise using an addition funnel over a 30 minute period. During the course of this addition, a white precipitate is formed. A 200 ml aqueous solution of NaOH (34.3 grams, 0.86 moles) is then added, also using an addition funnel, over a 30 minute period. The reaction temperature during both the aniline and NaOH addition is maintained below 35° C. by blowing air onto the outside of the reaction flask. After the NaOH addition, the reaction mixture is stirred for three hours and then vacuum filtered (filtrate pH=7). The filter cake obtained is washed with 400 ml of acetone and then added to one liter of deionized water, stirred for 15 minutes and filtered. This filter cake is washed with 500 ml of acetone and then dried in a 105° C. vacuum oven to a constant weight. This final product (114.4 grams, yield=84.2%) exhibited a sharp melting endotherm by differential scanning calorimetry (DSC) at 346° C. Also Fourier transform infrared (FTIR) analysis showed the following absorbances which are indicative of the structure for the final product: 3329 cm-1 (N--H stretch), 1528 cm-1 (Amide II band) and 1650 cm-1 (Amide I band). ##STR9##
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)/[C:4]([O:6]CC)=O)#[N:2].[C:23]([NH2:31])(=[NH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>CO>[O:6]=[C:4]1[NH:31][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:30][C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)=[C:3]1[C:1]#[N:2]
Reactant: CCOC(=O)/C(C#N)=C/c1ccc(Oc2ccccc2)cc1
Reactant: N=C(N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nc(-c2ccccc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (E)-ethyl 2-cyano-3-(4-phenoxyphenyl)acrylate (100 mg, 0.341 mmol) and benzamidine (45.1 mg, 0.375 mmol) in methanol (1 mL) was stirred at room temperature for 15 h while opening to the air. The mixture was treated with ethyl acetate (30 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4) and concentrated to give crude 6-oxo-4-(4-phenoxyphenyl)-2-phenyl-1,6-dihydropyrimidine-5-carbonitrile as tan solid. The crude material was taken to next reaction without purification. MS (ES+) m/z: 366 (M+H); LC retention time: 4.525 min (analytical HPLC Method B).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([N:29]1CCN(CCCCl)CC1)=[O:28])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:24]([O:26][C:27]([N:29]1[CH2:4][CH2:5][N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:2][CH2:3]1)=[O:28])[CH3:25]
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CCOC(=O)N1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(CCCOc2ccc(C3(C#N)CCOCC3)cc2)CC1
Yield: 28.7 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (500 mg, 2.46 mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid ethyl ester (570 mg, 2.43 mmol), DMF (10 ml) and K2CO3 (1.36 g, 9.84 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. The crude product was subjected to chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to provide the title compound (280 mg, 28%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.14 (q, 2H), 4.11-4.05 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.55-3.42 (m, 4H), 2.53 (t, 2H), 2.47-2.36 (m, 4H), 2.15-1.92 (m, 6H), 1.26 (t, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.N1C=CC=CC=1.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCCC1.CN(C1C=CN=CC=1)C>[O:21]1[CH2:22][CH2:23][N:18]([C:24]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:2]2)=[O:25])[CH2:19][CH2:20]1
Reactant: c1cncc(-c2cc[nH]n2)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(N1CCOCC1)n1ccc(-c2cccnc2)n1
Temperature: 80 °C

Procedure:
To a stirred solution of 3-(1H-pyrazol-3-yl)pyridine (0.435 g, 3 mmol) in tetrahydrofuran (15 ml) was added pyridine (0.367 ml, 4.50 mmol), DMAP (18.33 mg, 0.150 mmol). The solution was treated with 4-morpholinecarbonyl chloride (0.368 ml, 3.15 mmol). The reaction was heated to 80° C. for 20 hours. THF was removed by vacuum, the residue was partitioned between DCM and water. The organic phase was dried over MgSO4 and filtered. After evaporation the crude product was chromatographed in petroleumether:EtOAc=2:1. (Yield: 174 mg, 21%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[OH:15].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1nc(Br)cc(Br)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Br)cc(Br)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a stirred mixture of sodium hydride (0.6 g) in DMF (50 mL) was slowly added 14 (7.1 g). After the addition was complete, the mixture was stirred at room temperature for 15 minutes, then benzyl chloride (3.05 g) was added all at once. The mixture was then heated at 90° C. for six hours, cooled, poured into water (500 mL) and extracted with ether (2×200 mL). The ether extracts were combined, washed with 2N NaOH (50 mL), dried (MgSO4) and the solvent was evaporated to give 15 as a light yellow solid (8.3 g). Recrystallization from a small volume of methanol gave an analytical sample, m.p. 75-76° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:18]=[C:17]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[O:20])[C:16]([OH:36])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[CH3:47][C:37]1[CH:42]=[CH:41][C:40]([S:43]([O:36][C:16]2[C:17]([C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[S:30]([N:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[O:20])=[N:18][C:9]([Br:8])=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Oc2c(C(=O)NCc3ccc(F)cc3S(=O)(=O)N(C)C)nc(Br)c3cccnc23)cc1
Reaction time: 5 h

Procedure:
Triethylamine (0.65 mL, 4.66 mmol) was added slowly to a suspension of 5-bromo-N-{2-[(dimethylamino)sulfonyl]-4-fluorobenzyl}-8-hydroxy-1,6-naphthyridine-7-carboxamide (1.50 g, 3.10 mmol) in chloroform (15 mL) to give a yellow cloudy solution. p-Toluenesulfonyl chloride (0.71 g, 3.73 mmol) was then added slowly and the mixture was aged at 40° C. for five hours. The mixture was quenched with 10% KHSO4 solution and the layers were separated. The aqueous layer was extracted twice more with CHCl3. The combined organic extracts were washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a crude yellow oil. The oil was dissolved in a minimal amount of CHCl3 and purified on an Isco column (110 g silica) running a 0 to 2.5% MeOH/CHCl3 gradient over 30 minutes. The collected fractions were concentrated in vacuo to afford the desired material as a white solid foam.