Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(Cl)Cl.C(N(CC)CC)C.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>O>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
A 1 L round-bottomed flask was charged with tert-butyl piperazine-1-carboxylate (20.70 g, 111 mmol, Sigma-Aldrich, St. Louis, Mo.), 300 mL of CH2Cl2, and triethylamine (17.81 mL, 128 mmol). After cooling to 0° C., 2-thiophenesulfonyl chloride (21.31 g, 117 mmol, Sigma-Aldrich, St. Louis, Mo.) was added and the reaction was stirred at 0° C. for 30 min. The mixture was diluted with water (200 mL) and the layers were separated, dried (MgSO4) and concentrated to give tert-butyl 4-(thiophen-2-ylsulfonyl)piperazine-1-carboxylate (37.0 g) as a white solid. To this solid was added 300 mL of EtOAc, and 4 N HCl in dioxane (100 mL). The mixture was heated to 65° C. to give a clear solution. Over the course of 2 h, a white precipitate formed. The white precipitate was collected by filtration and dried under reduced pressure to give 4-(thiophen-2-ylsulfonyl)piperazine hydrochloride (26.0 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]C1.IC1C=CC(OCCCN2CCC[C@H]2C)=CC=1.CN1C=CC(C(O)=O)=C1.[N:45]1([C:50]([C:52]2[CH:56]=[CH:55][NH:54][CH:53]=2)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH3:9][C@@H:10]1[CH2:3][CH2:4][CH2:1][N:5]1[CH2:6][CH2:7][CH2:8][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:54]2[CH:55]=[CH:56][C:52]([C:50]([N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:51])=[CH:53]2)=[CH:16][CH:17]=1
Reactant: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: O=C(c1cc[nH]c1)N1CCCC1
Agent: C[C@@H]1CCCN1CCCOc1ccc(I)cc1
Agent: Cn1ccc(C(=O)O)c1
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2ccc(C(=O)N3CCCC3)c2)cc1

Procedure:
The titled compound was prepared as a colorless amorphous substance by repeating the procedure of Example 1, except that the 1-cyclobutyl-4-(4-iodophenoxy)piperidine was replaced by (2R)-1-[3-(4-iodophenoxy)propyl]-2-methylpyrrolidine (which can be synthesized in accordance with the method described in WO2009063953) and the methyl 1H-pyrrole-3-carboxylic acid by 3-(pyrrolidin-1-ylcarbonyl)-1H-pyrrole.
Reaction SMILES: [C:1]1([Si:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@H:21]1([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[CH2:22]1.CO>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]1([Si:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:27][CH2:26][C@H:25]2[O:28][C@@H:21]([N:29]3[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:22][C@@H:23]2[OH:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A solution of triphenylsilyl chloride (0.437 g, 1.48 mmol) in dry pyridine (4 mL) was added drop-wise to a solution of 2′-deoxyuridine (0.278 g, 1.22 mmol) in dry pyridine (4 mL) previously cooled in an ice-salt bath. The reaction mixture was kept at 0° C. for 1 h. The reaction was monitored by TLC (10% CH3OH in CHCl3) and quenched with CH3OH (50 L). The solvent was removed under reduced pressure to give a crude yellow liquid which was further purified by silica gel column chromatography (Isolute SI column) using a gradient elution of 0→10% CH3OH in CHCl3. The fractions with Rf=0.30 (10% CH3OH/CHCl3) were combined and concentrated to yield the title compound as a white crystalline solid (0.506 g, 85%).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:26][C:25](OS(C(F)(F)F)(=O)=O)=[C:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1.[Cl-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:26][C:25]([C:48]4[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=4)=[C:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: C[C@]12CC(OS(=O)(=O)C(F)(F)F)=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]1CC13OCCOC12OCCO3
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C2=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)C2)cc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
21.6 g (42.6 mmol) of 3,3; 17,17-bis- (ethylenedioxy) -11-trifluoromethylsulfonyloxy-5,9(11)-estradiene is disson, red in a mixture of 360 ml of toluene and 170 ml of ethanol and mixed in succession with 2.5 g of palladiumtetrakistriphenylphosphine, 3.6 g of lithium chloride, 55 ml of 2 m sodium carbonate solution and 7.2 g (46.8 mmol) of 4-methoxyphenyl boronic acid. The reaction mixture is then stirred for 2 hours at 95° C. cooled to room temperature and mixed with saturated sodium chloride solution. The organic phase is separated, washed in succession with 5% sodium hydroxide solution and water, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane. 19.2 g of 3,3;17,17-bis-(ethylenedioxy)11-(4-methoxyphenyl)-5,9(11)-estradiene is obtained as white foam.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][NH:5][CH:6]=1.[Br:12]N1C(=O)CCC1=O>>[Br:12][C:6]1[NH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[CH3:1]
Reactant: CCOC(=O)c1c[nH]cc1C
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1c[nH]c(Br)c1C
Yield: 76.7 %

Procedure:
Using ethyl 4-methyl-1H-pyrrole-3-carboxylate (4.50 g) and N-bromosuccinimide (5.2 g), a procedure as in Reference Example 40 was performed to give the title compound as a pale-yellow solid (yield 5.20 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([OH:18])=[CH:7][C:6]=1[N:5]2[CH3:19].Cl[C:21]1C=C2C(=CC=1)C(=O)C1C(O)=CC(O)=CC=1N2.C(=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([O:18][CH3:21])=[CH:7][C:6]=1[N:5]2[CH3:19]
Reactant: O=c1c2ccc(Cl)cc2[nH]c2cc(O)cc(O)c12
Reactant: Cn1c2cc(Cl)ccc2c(=O)c2c(O)cc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(O)c2c(=O)c3ccc(Cl)cc3n(C)c2c1
Yield: 65 %

Procedure:
A method analogous to Method E-6, applied to 6-chloro-1,3-dihydroxy-10-methyl-10H-acridin-9-one, 18 (52 g, 0.2 mol), dry acetone (1.75 L), potassium carbonate (80 g, 0.58 mol) and iodomethane (175 ml, 0.74 mol) added for 3 hrs reflux gave complete reaction, work-up and recrystallisation gave the title compound (37 g, 0.13 moles, 65%).
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20](Cl)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[F:32])[C:14]2=[O:33])[CH2:9][CH2:8]1)(C)(C)C.[NH2:36][C:37]1[CH:38]=[C:39]([O:45][CH3:46])[C:40]([O:43][CH3:44])=[CH:41][CH:42]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[N:15]1[CH2:16][C:17]2[C:18](=[N:19][C:20]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=3)=[N:21][CH:22]=2)[N:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]2)[C:14]1=[O:33]
Reactant: COc1ccc(N)cc1OC
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(N2Cc3cnc(Nc4ccc(OC)c(OC)c4)nc3N([C@H]3CC[C@H](O)CC3)C2=O)c(F)c1
Temperature: 160 °C

Procedure:
A mixture of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(2-fluoro-4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g, 0.38 mmol) (from Example 17c supra), 4-amino-veratrole (76.6 mg, 0.50 mmol) (Aldrich) and p-toluenesulfonic acid monohydrate (95.1 mg, 0.50 mmol) (Aldrich) in 2-propanol (4 mL) was placed in a microwave reactor (SmithSynthesizer™). The reaction mixture was heated at 160° C. for 15 minutes. After cooling, it was concentrated under reduced pressure and purified by RP-HPLC (C-18, eluted with acetonitrile-water) to give 3-(2-fluoro-4-methoxy-phenyl)-1-(trans-4-hydroxy-cyclohexyl)-7-(3,4-dimethoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.13 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:13][Mg+].[Br-]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]([OH:12])[CH3:13])[C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=Cc1cc(Cl)cc2c1OCO2
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)c1cc(Cl)cc2c1OCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Chlorobenzo[d][1,3]dioxole-4-carbaldehyde (147.0 mg, 0.79 mmol) was dissolved in 6 mL of diethyl ether and cooled to 0° C. MeMgBr (0.60 mL, 1.99 mmol) was added to the solution and the ice bath was removed. The reaction was allowed to stir at rt for 10 min and at reflux for 30 min. The reaction was cooled to 0° C. and 10 mL of sat NH4Cl were added to quench the reaction. The diethyl ether layer was separated and washed with water (10 mL×2). The organic layer was dried over Na2SO4 and the solvent was removed by rotary evaporation to collect the desired product (155.0 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 6.90 (d, 1H), 6.75 (d, 1H), 6.01 (d, 2H), 4.96 (m, 1H), 1.50 (d, 3H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[C:8](=[C:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:9]3[C:14]([CH2:15][O:16][C:6]=2[CH:5]=1)=[CH:13][CH:12]=[CH:11][N:10]=3.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:29]1[C:4]([Cl:3])=[CH:5][C:6]2[O:16][CH2:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[C:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:7]=2[CH:28]=1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3OCc3cccnc32)CC1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=C2c3cc(Br)c(Cl)cc3OCc3cccnc32)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
Bromine (0.5 ml, 9.7 mmol) was added to a solution of ethyl 4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-1-piperidine-carboxylate (1.0 g., 2.6 mmol) in methylene chloride (15 ml) at 20° C. The solution was stirred for 2 hours at 20° C. The reaction mixture was poured onto ice (50 g), basified with 10% NaOH, and extracted with methylene chloride (100 ml). The organic layer was separated, washed with water (20 ml), dried (MgSO4), filtered and evaporated, yielding an oil which was chromatographed on silica gel and eluted with 1:1 ethylacetate/hexanes. The product, ethyl 4-(9-bromo-8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-1-piperidine-carboxylate (0.8 g., 66% yield) was obtained as a white solid; MS (CI, M+H)=465.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[C:15]1([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[CH:21]([NH:28][C:11](=[O:12])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:14])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CC#N
Product: O=C(NC(c1ccccc1)c1ccccc1)C(=O)c1c[nH]c2ccccc12

Procedure:
N-Benzhydryl-2-(1H-indol-3-yl)-2-oxo-acetamide was synthesized following scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and C,C-diphenyl-methylamine. Yield (52%). HPLC ret. time 3.59 min, 1099% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.56 (d, J=9.1 Hz, 1H), 8.56 (d, J=3.2 Hz, 1H), 8.22 (m, 1H), 7.54 (m, 1H), 7.43-7.26 (m, 12H), 6.32 (d, J=9.1 Hz, 1H); ESI-MS 355.5 m/z (MH+).
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BrH:12].N([O-])=O.[Na+].[Br-]>O.C(#N)C>[Br:12][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In a 1 L, three necked flask fitted with a dropping funnel and thermometer, were charged 2-amino-3-fluorobenzoic acid (20.0 g, 0.13 mol) and acetonitrile (160 mL). After cooling to 0° C., HBr (47%, 160 mL) was added drop wise over 10 min. To the resulting solution a solution of NaNO2 (10.0 g, 0.14 mol) in water (20.0 mL) was added drop wise over 1 h. After addition, the reaction mixture was stirred at 0° C. for 5 min, and cupper(I) bromide (22.0 g, 0.15 mol) was added portionwise over 30 min. Stirring was continued at 70° C. in a an oil bath for 1 h. After cooling to 0° C., 700 mL of water was added and the precipitate was filtered, washed with cold water and dried under vacuum to give 28.23 g (100%) of the title compound as a white solid. The crude product was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH2:21][C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O.C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:22])/[C:21](=[CH:39]/[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=5)/[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2C1
Reactant: O=Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2/C1=C\c1ccccn1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
1-(4-Fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6 (1H)-one (114, R1=4-Fluorophenyl) (15.0 g, 50.8 mmol) and THF (430 mL) were stirred until a solution formed. The mixture was cooled to about −70° C. then LiHMDS (1M in THF, 53 mL, 53.0 mmol) was added keeping the internal temperature between about −65 and −70° C. After about 45 min picolinaldehyde (16.32 g, 152 mmol) was added. After about 5 min the mixture was allowed to warm to about −10° C. over about 90 min. Acetic acid (5.8 mL, 102 mmol) was added to the mixture then the slurry was concentrated under reduced pressure. The material was partitioned between water (500 mL), sat. aq. NaHCO3 (˜75 mL) and DCM (200 mL). The aqueous layer was extracted with DCM (60 mL) then the combined organics were dried over MgSO4, filtered and concentrated on the rotovap to yield (E)-1-(4-fluorophenyl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6(1H)-one which was used directly in the next step without further manipulation; LC/MS, method 3, Rt=2.46 min, MS m/z 385 (M+H)+.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[C:21]=1[OH:38])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:39]N1C(C)(C)C(=O)N(Cl)C1=O.C(OCC)(=O)C>CC(C)=O>[CH2:1]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:29]=[C:28]([Cl:39])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[C:21]=1[OH:38])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCCCNC(=O)c1ccc2c(NC(=O)OCC(C)C)cccc2c1O
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOCCCNC(=O)c1cc(Cl)c2c(NC(=O)OCC(C)C)cccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
In 30 ml of acetone, 5.28 g (0.01 mol) of 2-(3-dodecoxypropylcarbamoyl)-5-isobutoxycarbonylamino-1-naphthol synthesized in accordance with the method described in JP-A No. 123158/1987 was dissolved and 2.00 g (0.01 mol) of 1,3-dichloro-5,5-dimethylhydantoin was added to the solution, followed by stirring for 2 hours at room temperature. Then 50 ml of ethyl acetate was added to the reaction mixture, followed by washing with a 5% aqueous sodium hydroxide solution and then washing with water. The solvent was distilled off and crystallization from acetonitrile was carried out, to give 5.17 g (yield: 92%) of 2-(3-dodecoxypropylcarbamoyl)-4-chloro-5-isobutoxycarbonylamino-1-naphthol
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.CCN(CC)CC.[O:26](S(C(F)(F)F)(=O)=O)[S:27]([C:30]([F:33])([F:32])[F:31])(=O)=[O:28]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[S:27]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2)(=[O:28])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 1,1-dimethylethyl 6-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate (0.146 g; 0.586 mmol) and Et3N (0.17 mL; 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added Tf2O (0.11 mL; 0.67 mmol(, dropwise over 2 min. The mixture was stirred overnight, gradually warming to room temperature, diluted with CH2Cl2, washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum which slowly solidified. 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.87 (t, J=5.7 Hz, 2H), 3.66 (br. t, J=5.5 Hz, 2H), 4.59 (s, 2H), 7.04-7.12 (m, 2H), 7.18 (d, J=8.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23].N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2](/[N:1]=[C:18]2\[C:17]([CH3:23])=[CH:16][C:21](=[O:22])[CH:20]=[CH:19]\2)[C:3](=[O:15])[N:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(O)c1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC1=CC(=O)C=C/C1=N/c1c(C)n(C)n(-c2ccccc2)c1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of meta-cresol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C1(CNCC2CCCCC2)CCCCC1.Br[C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1.N(C)(C1CCCCC1)C1CCCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[F:29][C:24]1[C:23](/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C=CC(=O)OC
Reactant: Fc1ncccc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cccnc1F
Temperature: 110 °C

Procedure:
To Pd[P(t-Bu)3]2 (0.210 g, 0.411 mmol) was added dioxane (6 mL), methyl acrylate (2.00 mL, 22.2 mmol), N,N-dicyclohexylmethylamine (3.60 mL, 17.0 mmol), and 3-bromo-2-fluoropyridine (1.02 g, 5.80 mmol). The reaction mixture was degassed and heated to 110° C. for 5 min. The reaction was cooled to room temperature and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% to 50% EtOAc in hexanes) gave the product which contained Cy2NMe. The Cy2NMe was removed by dissolving the mixture in DCM (5 mL) and diluting with hexanes (10 mL). The solution was concentrated to a volume of 5 mL and the solid precipitate was collected by filtration and dried under high vacuum to give (E)-methyl 3-(2-fluoropyridin-3-yl)acrylate as a white solid. MS (ESI, pos. ion) m/z: 182.1 (M+1).
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[N:11]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:18][C:17](=[O:29])[C:13]([C:14]([OH:16])=[O:15])=[CH:12]1.[OH-].[Na+]>O>[F:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[N:11]1[C:19]([C:20]2[CH:21]=[CH:22][C:23]([N:26]([CH3:27])[CH3:28])=[CH:24][CH:25]=2)=[CH:18][C:17](=[O:29])[C:13]([C:14]([OH:16])=[O:15])=[CH:12]1
Reactant: COc1ccc(-n2cc(C(=O)O)c(=O)cc2-c2ccc(N(C)C)cc2)c(F)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(O)cc2F)cc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
In 10 ml of 47% by weight hydrobromic acid was suspended 0.3 g of 1-(2-fluoro-4-methoxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid, and the suspension was refluxed for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with 10 ml of water. The resulting solution was then adjusted to a pH of 12 with 20% by weight aqueous sodium hydroxide solution and washed with 20 ml of chloroform. The aqueous layer was adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals were collected by filtration, washed with 10 ml of water, and dried to obtain 0.17 g of 1-(2-fluoro-4-hydroxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 250° C. or more.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[N-]=C=O.[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12>>[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12
Reactant: CCCCN=C=O
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Agent: [N-]=C=O
Product: CCCCNC(=O)Nc1cccc(N2CN=c3occc3=C2N)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using butyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 326 [M+H]+.