Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+:2].[C:3]1([C:9](=[O:14])[CH2:10][C:11](=O)[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH3:12][C:11]([NH2:2])=[CH:10][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:14]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(N)=CC(=O)c1ccccc1

Procedure:
A mixture containing 200 ml of methanol, 50 ml of concentrated aqueous ammonium hydroxide and 50 g of 1-phenyl-1,3-butanedione (same as benzoylacetone) was stirred at ambient temperature for 22 hours after which time a tlc analysis (ether/silica gel) indicated very little remaining starting material. Some white solid 1-methyl-3-phenyl-3-oxo-1-propenamine had crystallized from the pale yellow solution. The mixture was concentrated on a rotary evaporator to dryness to yield 1-methyl-3-phenyl-3-oxo-1-propenamine as a yellow solid. To the yellow solid was added 75 ml of dimethylformamide and 25 g of methyl propiolate (same as methyl 2-propynoate) and the resulting mixture was refluxed for 10 hours, and concentrated on a rotary evaporator. The remaining solid was recrystallized from isopropyl alcohol and dried at 90°-95° C. to yield 29.6 g of 5-benzoyl-6-methyl-2(1H)-pyridinone, m.p. 185°-187° C. The mother liquor from the above recrystallization was concentrated on a rotary evaporator to yield another 6 g of the product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4](Cl)[CH:3]=1.[C:12]1([NH2:19])[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>ClC1C=CC=CC=1.[Cu]>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[NH:19][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: Nc1ccccc1N
Agent: [Cu]
Solvent: Clc1ccccc1
Product: O=C1Nc2ccccc2Nc2cc(Br)ccc21
Yield: 41.5 %

Procedure:
A mixture of 4-bromo-2-chlorobenzoic acid (2.35 g, 10 mmol), 1,2-benzenediamine (1.08 g, 10 mmol) and copper (0.63 g, 10 mmol) in chlorobenzene (150 mL) was heated to reflux for 48 hours and filtered. The filter cake was washed with ethyl acetate several times. The combined filtrates were concentrated under vacuum and the residue was purified by flash column chromatography on silica gel with 8:2 hexanes/ethyl acetate to provide 1.20 g (22%) of the desired product. MS (DCI) m/e 289 (M+H)+, 307 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.02 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.06 (dd, J=8.4, 1.8 Hz, 1H), 6.92-6.95 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:25]=[C:24]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[C:40]1([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:47]1([N:46]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:9]4[C:14]([C:15]([C:22]5[CH:27]=[C:26]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH:25]=[C:24]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[CH:23]=5)=[C:16]5[C:21]=3[CH:20]=[CH:19][CH:18]=[CH:17]5)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:4][CH:3]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Clc1ccc(-c2c3ccccc3c(-c3cc(-c4ccccc4)cc(-c4ccccc4)c3)c3ccccc23)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(-c3ccccc3)cc(-c3c4ccccc4c(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4ccccc34)c2)cc1
Yield: 86 %

Procedure:
Under an atmosphere of argon, 9-(4-chlorophenyl)-10-(3,5-diphenylphenyl)anthracene (2.3 g, 4.4 mmole), diphenylamine (0.9 g, 5.3 mmole, 1.2 eq), tris(dibenzylideneacetone)dipalladium(0) (0.1 g, 0.11 mmole, 5% Pd), a toluene solution of tri-t-butylphosphine (66% by weight, 0.05 ml, 0.16 mmole, 0.7 eq to Pd) and sodium t-butoxide (0.6 g, 6.3 mmole, 1.4 eq) were suspended in anhydrous toluene (20 ml). The resultant mixture was refluxed for 8 hours. The reaction mixture was filtered and washed with toluene, water and methanol, and a light yellow solid substance was obtained. The obtained solid substance was suspended in boiling toluene (40 ml). After the suspension was cooled while being left standing, the suspension was filtered, and a light yellow solid substance (2.5 g, the yield: 86%) was obtained. It was confirmed in accordance with 1H-NMR and FDMS that the obtained product was Compound (A14).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:19]([CH3:21])[CH3:20])=[C:7]([Cl:18])[N:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:18][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:19]([CH3:21])[CH3:20])[N:3]=[C:2]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: CN(C)c1nc2nc(Cl)nc(N3CCSCC3)c2nc1Cl
Reactant: C1CNCCN1
Product: CN(C)c1nc2nc(N3CCNCC3)nc(N3CCSCC3)c2nc1Cl

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4-thiomorpholino-7-dimethylamino-pteridine and piperazine.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:49][NH:50][CH:51]1[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]1>CN(C)C=O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:38]([C:35]2([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][C:23]4[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:50]([CH3:49])[CH:51]5[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]5)=[O:12])[CH:24]=4)=[CH:27][CH:28]=3)=[O:34])[CH2:36][CH2:37]2)=[O:47])=[CH:45][CH:44]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: CNC1CCN(C)CC1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccn2)CC1
Reaction time: 62 h
Yield: 86.8 %

Procedure:
[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and methyl(1-methylpiperidin-4-yl)amine (0.045 ml) was added thereto, followed by stirring for 62 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (37.6 mg, 86.8%).
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.ClC1C=C([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:37])=[N:34][CH:35]=2)C=CC=1Cl.[Cl:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][C:52]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[Cl:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][C:52]=1[C:30]1[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]2[CH2:39][CH2:40][CH:41]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH2:42][CH2:43]2)=[O:37])=[N:34][CH:35]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(C(F)(F)F)ccc2Cl)cnc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, (5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (see example 28) was reacted with 2-chloro-5-trifluoromethyl-phenyl-boronic acid, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water to give the title compound as light brown amorphous solid. MS: 452.2 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][NH2:19]>C(O)C.CO>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,6-Dichloro-3-Nitropyridine (2.0 g, 10 mmol) and sodium carbonate (2.8 g, 26 mmol) were added to a round bottom flask under nitrogen, and suspended in ethanol (100 mL). 2M methylamine in methanol (7.8 mL) was then added and stirred at room temperature for 3 hours. The yellow solution was concentrated, and then redissolved in ethyl acetate followed by washing with sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The yellow solid was then redissolved in ethanol and recrystallized to give 6-chloro-N-methyl-3-nitropyridin-2-amine (1-1) as a yellow solid. MS (M+H)+: observed=188.0, calculated=188.6.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH2:16]([O:18][C:19](=[O:28])[CH:20]=[C:21](OCC)OCC)[CH3:17].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:18][C:19](=[O:28])[CH2:20][C:21]1[NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=2[S:7](=[O:8])(=[O:9])[N:10]=1)[CH3:17]
Reactant: CCOC(=O)C=C(OCC)OCC
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC1=NS(=O)(=O)c2c(COCOC)csc2N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 2-amino-4-methoxymethoxymethyl-thiophene-3-sulfonic acid amide (0.76 g, 3.01 mmol) in N,N-dimethylformamide (10 mL) at 25° C. was added 3,3-diethoxy-acrylic acid ethyl ester (0.68 g, 3.61 mmol). The reaction was stirred at 70° C. for 5 h before triethylamine (1.68 mL, 12.04 mmol) was added to the mixture. The reaction was stirred at 70° C. overnight. It was then cooled to 25° C., diluted with ethyl acetate (10 mL) and washed with 1.0 M aqueous hydrochloric acid solution (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford the desired product, (7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid ethyl ester (0.55 g, 1.57 mmol, 52%), as a brown oil. 1H NMR (400 MHz, CDCl3) δ: 1.32 (3H, t, J=7.2 Hz), 3.42 (3H, s), 3.68 (2H, s), 4.26 (2H, q, J=7.2 Hz), 4.76 (2H, s), 4.80 (2H, s), 7.00 (1H, s), 8.00 (1H, s).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7].[OH-].[K+].CN(C)[CH:26]=[O:27]>>[CH2:6]([N:8]1[C:9]2[CH:10]=[CH:11][C:12]([CH:26]=[O:27])=[CH:13][C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:7]
Reactant: CN(C)C=O
Reactant: CCN1c2ccccc2Sc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1c2ccccc2Sc2cc(C=O)ccc21
Temperature: 25 °C

Procedure:
A 3.7 ml (0.04 mol) quantity of phosphorus oxychloride (from Aldrich) was added dropwise to 4.4 ml (0.06 mol) of dry dimethylformamide (DMF) at 0° C. under a nitrogen atmosphere. This solution was warmed up slowly to room temperature. Then 5 g (0.02 mol) of 10-ethylphenothiazine in dry DMF was added dropwise to the solution. The reaction mixture was heated at 80° C. for 24 hours and poured into ice water. The obtained solution was neutralized with potassium hydroxide until the pH reached 6–8. The product was extracted with chloroform. The chloroform extract was dried with anhydrous sodium sulfate, filtered and distilled. The product was recrystallized from methanol. The yield of 10-ethylphenothiazine-3-carbaldehyde was 3.7 g (66%). The product had a melting point of 94–95° C. (recrystallized from methanol). A 1H NMR spectrum yielded the following results: (100 MHz, CDCl3, δ, ppm): 1.50 (t, J=7.0 Hz, 3H, CH3); 4.02 (q, J=7.0 Hz, 2H, CH2); 6.95–6.39 (m, 5H, Ar), 7.52–7.70 (m, 2H, Ar), 9.83 (s, 1H, CHO).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]([Cl:38])=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]([Cl:38])=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1cc(Cl)c2ccccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To 2 mL of a chloroform solution containing 149 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. After the solvent was removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform], to give 71 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-chloroquinolin-2(1H)-one as a pale yellow solid.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]4[C:30]5[N:37]([CH2:38][CH3:39])[C:36]([C:40]6[C:44]([NH2:45])=[N:43][O:42][N:41]=6)=[N:35][C:31]=5[CH:32]=[N:33][CH:34]=4)[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>ClCCl>[CH2:38]([N:37]1[C:30]2[C:29]([CH2:28][NH:27][CH2:26][CH2:25][CH2:24][N:21]3[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]3)=[CH:34][N:33]=[CH:32][C:31]=2[N:35]=[C:36]1[C:40]1[C:44]([NH2:45])=[N:43][O:42][N:41]=1)[CH3:39]
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNCCCN3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)c21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCn1c(-c2nonc2N)nc2cncc(CNCCCN3CCNCC3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
The product from step 4 (0.17 g, 0.28 mmole) was dissolved in dichloromethane (3 ml) and treated with piperidine (0.3 ml, 2.8 mmole). The mixture was stirred at room temperature under argon for 4 hours. The solvent was removed in vacuo and the residue purified by column chromatography on silica gel eluting with ammonia/methanol/dichloromethane (1:9:90) to afford the title compound (0.063 g). MS (ES+) m/e 386 [M+H]+.
Reaction SMILES: F[C:2]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5].[O:20]1C2C=CC=C(C(O)=O)C=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:16]2[CH:17]=[CH:18][CH:2]=[C:3]([C:4]([NH:6][C:7]3[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=3)=[O:5])[C:15]=2[O:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: O=C(O)c1cccc2c1OCCO2
Product: O=C(Nc1c[nH]nc1C(=O)O)c1cccc2c1OCCO2

Procedure:
The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D), but using 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid as the starting acid to give 4-[(2,3-dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-1H-pyrazole-3-carboxylic acid (340 mg) as a white solid. (1H NMR (300 MHz, DMSO-d6) δ 13.5 (s, 2H), 11.2 (s, 1H), 8.4 (s, 1H), 7.7 (d, 1H), 7.1 (d, 1H), 7.0 (t, 1H), 4.5 (s, 2H), 4.4 (s, 2H)).
Reaction SMILES: [CH2:1]([C:8]1([OH:27])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)C2CCCC1CCC2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>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.C(COC)OC>[CH2:1]([C:8]1([OH:27])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:21]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCN1CCC(O)(Cc2ccccc2)CC1)Nc1ccnc(Cl)c1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
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: [K+]
Solvent: COCCOC
Product: O=C(NCCN1CCC(O)(Cc2ccccc2)CC1)Nc1ccnc(Cc2ccccc2)c1
Temperature: 90 °C

Procedure:
A mixture of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-chloro-pyridin-4-yl)-urea (98 mg, 0.3 mmol), B-benzyl-9-BBN (0.5 M in THF, 4 mL, 2 mmol), triphenylphosphine (29 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol), 2 M aq. K2CO3 (0.5 mL) and dimethoxyethane (1 mL) is degassed and heated under argon at 90° C. for 7 days. The mixture is evaporated and the residue purified by preparative HPLC to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C>O1CCCC1.CCCCCC>[CH:9]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([B:17]([OH:20])[OH:18])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccc(CC2CC2)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(CC2CC2)cc1
Temperature: -70 °C

Procedure:
1-Bromo-4-(cyclopropylmethyl)benzene (2.11 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to −70° C. under an argon atmosphere. A 1.25M solution of n-butyl lithium in hexane (8.8 ml) was added at such a rate that the temperature did not exceed −65° C. with stirring, which was maintained for a further 30 minutes. Trimethyl borate was added slowly keeping the temperature below −60° C. and the reaction mixture was stirred for a further 1.5 hours at −70° C. After warming to −5° C., the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (50 ml) and the organic phase was separated. The aqueous layer was extacted with ethyl acetate (2×30 ml) and combined organic phases were dried (MgSO4) and evaporated to give 4-(cyclopropylmethyl)phenylboronic acid (1.52 g); 1H NMR (d6-DMSO): 0.2 (d, 2H), 0.5 (d, 2H), 0.9-1.07 (m, 1H), 2.5 (partly obscured by DMSO), 7.2 (d, 2H), 7.7 (d, 2H); mass spectrum (−ve ESP) 175 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[OH:30][C:24]1[CH:29]=[CH:28][C:27]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccccc1
Reactant: OC(c1ccc(I)cc1)(c1ccc(I)cc1)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(C(c2ccc(I)cc2)(c2ccc(I)cc2)c2ccc(I)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
10 parts by weight of tris(4-iodophenyl)methanol, 4.4 parts by weight of phenol, and 2 parts by weight of conc. sulfuric acid were put into a reaction vessel and stirred for 4 hours while heating at 80° C. After cooling, a 10% sodium hydroxide solution was added to the reaction solution, and stirring was carried out for 2 hours. A deposited precipitate was collected by filtration, thus giving 8.5 parts by weight of 4-hydroxyphenyl[tris(4-iodophenyl)]methane (yield: 76%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[C:23](=[CH:24][OH:25])[C:22]([CH:26]([CH3:28])[CH3:27])=[N:21][C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:19]2)=[CH:14][CH:13]=1.C(Cl)Cl.C1COCC1>C(Cl)Cl.CCOCC.C(N(CC)CC)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([CH:24]=[O:25])=[C:22]([CH:26]([CH3:28])[CH3:27])[N:21]=[C:20]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C1=NC(c2ccccc2)=NC(c2ccc(F)cc2)C1=CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Dimethylsulfoxide (DMSO) (3.10 gm, 39.7 mmol) was added to a solution of oxalyl chloride (2.520 gm, 19.8 mmol) in methylene chloride (100 ml) which was cooled to -78° C. under argon. The solution was allowed to stir 15 minutes. Then, 4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-5-hydroxymethylene-pyrimidine obtained in step (iii) above (4.942 gm, 15.3 mmol) was added to the flask as a methylene chloride/THF (25 ml/10 ml) solution. The solution was stirred for 20 minutes and then triethylamine (10.6 ml) was added. The solution was stirred for an additional 10 minutes, then was warmed to room temperature. The solution was diluted with ether, washed with water and brine, then dried over Na2SO4, filtered and concentrated to afford a yellow solid. The solid was recrystallized from EtOAc/hexane to give the title compound as fine yellow needles (4.064 gm, 83%) (mp: 127-129° C.).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].S(C1C=CC(C)=CC=1)(O[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])(=O)=O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCN(OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 72 °C
Yield: 77.3 %

Procedure:
N-(tert-Butoxycarbonyl)-N-(3,6,9-trioxadecyl)-O-benzylhydroxylamine (14) was synthesized by adding sodium hydride (80% oil dispersion, 0.488 g, 16.3 mmol) to N-(tert-butoxycarbonyl)-O-benzylhydroxylamine [Ramasamy, supra] (2.66 g, 11.9 mmol) in dry DMF (20 mL), and stirring was continued for several minutes. 3,6,9-Trioxadecyl tosylate [Schultz et al, supra] (4.93 g, 15.5 mmol) in DMF (3 mL) was added by syringe, and the suspension was heated at 72° C. for 18 hours under nitrogen. After cooling, the reaction was quenched with water (100 mL) and then extracted with other (4×50 mL). The combined organic layers were washed with brine (100 mL) and the solvent was removed in vacuo. Column chromatography with 4% EtOH/CHCl3 produced 3.40 g (77%) of (14) as a liquid: NMR δ 1.50 (s, 9 H), 3.31 (s, 3 H), 3.5-3.7 (m, 12 H), 4.82 (s, 2 H), 7.25-7.41 (m, 5 H). Analysis: (C19H31NO6) C, H, N.