Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:27]B1OB(C)OB(C)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.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].O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[CH:6]=2)[C:2]([CH3:27])=[CH:3]1
Reactant: CB1OB(C)OB(C)O1
Reactant: COCCCn1cc(Cl)c2ccc(C(C)=O)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COCCCn1cc(C)c2ccc(C(C)=O)cc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
To a solution of 1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethanone (843 mg) in 1,4-dioxane (15 mL) were added potassium phosphate (1.35 g), trimethylboroxine (883 mg), tris(dibenzylideneacetone)dipalladium (290 mg) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-Phos) (605 mg) under argon, and the mixture was heated to stir at 110° C. for 4 hours. Thereto was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1→3/2) to give 1-[1-(3-methoxypropyl)-3-methyl-1H-indol-6-yl]ethanone [REx(9-1)] (663 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:30])[C:15](=[O:29])[CH2:16][NH:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21]([N+:25]([O-])=O)=[C:20]([CH3:28])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:25][C:21]1[C:22]([CH3:24])=[N:23][C:18]([NH:17][CH2:16][C:15]([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[CH3:30])=[O:29])=[N:19][C:20]=1[CH3:28]
Reactant: Cc1nc(NCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(NCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.5 %

Procedure:
Compound 62 (93 mg) and zinc (147 mg) were suspended in acetic acid (2 mL) and the suspension was stirred at room temperature (20 to 30° C.) for 3 hours. Subsequently, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane-5:1 to 3:1) to give 25.4 mg (29% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:19]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:18][CH:17]2[C:36](O)=[O:37])[CH:12]=[CH:13][C:14]=1[F:15].CC1(C)[O:44][C@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:36]([CH:17]1[CH:16]([C:11]2[CH:12]=[CH:13][C:14]([F:15])=[C:9]([Cl:8])[CH:10]=2)[C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:19]([CH2:31][C:32]([CH3:35])([CH3:33])[CH3:34])[NH:18]1)=[O:37]
Reactant: CC1(C)OC[C@@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)NCC[C@@H](O)CO)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 41.3 %

Procedure:
Step B In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 69c (0.2 g, 0.48 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1.0 mmol), HATU (0.23 g, 0.62 mmol) and iPr2NEt (0.3 mL, 1.72 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 74%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C1(C)C=CC=CC=1>[CH2:1]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOCCCCCCCC
Yield: 3.2 %

Procedure:
Control Reaction using NAFION 117: From the combination of 0.5 mL 1-octanol (3.17 mmol) and 0.314 g NAFION 117 (0.28 meq (0.89 meq/g)) in 3.0 mL toluene (1.1 M) as solvent was obtained 12.4 mg n-octyl ether (3% isolated yield) upon purification of the crude product (GC ratio of 90:10 (octanol:octyl ether)) by bulb-to-bulb distillation (bp 130° C./3 mm Hg (air bath temp)).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:22](/[CH3:27])=[C:23](/[F:26])\[CH2:24][OH:25])[CH3:2].C[N+]1([O-])CCOCC1>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:22](/[CH3:27])=[C:23](/[F:26])\[CH:24]=[O:25])[CH3:2]
Reactant: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(c1ccccc1)=CC(C)(C)O2
Agent: C[N+]1([O-])CCOCC1
Product: CCOc1cc2c(cc1/C(C)=C(/F)C=O)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure M, (2E)-3-(7-ethoxy-2,2-dimethyl-4 phenyl-2H-chromen-6-yl)-2-fluoro-but-2-en-1-ol (Compound 88, 137 mg, 0.37 mmol) and 4-methylmorpholine N-oxide (87 mg, 0.74 mmol) were reacted to give the title compound as a yellow oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2](C)=[CH2:3].[OH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10](C=C(C)C([O-])=O)([CH2:11]3)[CH2:9]1)[CH2:15]2.C1C2C(=CC3C(C=2COC(=O)C(C)=C)=CC=CC=3)C=CC=1.CC(C)C#N>O1CCCC1>[CH2:3]=[CH:2][C:1]([O:6][C:10]12[CH2:9][C:8]3([OH:7])[CH2:17][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:16]1)[CH2:11]2)=[O:5]
Reactant: CC(=CC12CC3CC(CC(O)(C3)C1)C2)C(=O)[O-]
Reactant: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OCc1c2ccccc2cc2ccccc12
Agent: CC(C)C#N
Solvent: C1CCOC1
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C

Procedure:
To a mixture of methacrylic acid (0.775 g, 9 mmol), 3-hydroxy-1 adamantylmethacrylate (1.42 g, 6 mmol), 9-anthrylmethylmethacrylate (1.38 g, 5 mmol) in 20 mL of tetrahydrofuran (THF) was added 2,2′-azobis(2-methylpropionitrile (0.24 g, 1.5 mmol). The resulting solution was purged by nitrogen for 30 minutes before it was heats to 72° C. for 18 hours under nitrogen. The solution was then cooled to room temperature and added drop-wise into 400 mL of de-ionized water. The solid was filtered with a frit funnel, washed with water (2×200 ml) and dried in a vacuum oven at 50° C. for 24 hours to afford 3.1 gram of P1 as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24]#[N:25])=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:24]([NH2:25])=[CH:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)=[N:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)Cc1ccc(NN)cc1
Product: CCOC(=O)Cc1ccc(-n2nc(-c3ccc(F)cc3)cc2N)cc1
Yield: 67.9 %

Procedure:
Using general method M, (4-hydrazinophenyl)acetic acid ethyl ester (36 g, 0.217 mol) and 3-(4-fluorophenyl)-3-oxopropionitrile (38 g, 0.26 mol) were combined to yield {4-[5-amino-3-(4-fluorophenyl)pyrazol-1-yl]phenyl}acetic acid ethyl ester (50 g, 68% yield). 1H NMR (300 MHz, CDCl3): δ 7.80 (s, 2H), 7.40 (m, 4H), 7.00 (m, 2H), 6.29 (s, 1H), 4.07 (q, J=3.9 Hz, 2H), 3.53 (s, 2H), 1.23 (t, J=3.9 Hz, 3H); MS (ESI) m/z: 340 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:7]=2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][N:29]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH3:38])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CNCCN(C)C)c2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN(C)CCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
The product of Example 67 (0.050 g) and formaldehyde (0.079 mL) were stirred in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.067 g) was then added and the mixture stirred at room temperature for 12 hours. The volatiles were removed under reduced pressure and the residue purified by HPLC to give the title compound as a solid (0.035 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccnc(Cl)n1
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccnc(Cl)n1
Temperature: 60 °C
Yield: 81.1 %

Procedure:
A stirred suspension of 1-t-butoxycarbonyl-4-[(methylamino)methyl]piperidine (3.50 g, 15.3 mmol), 2,4-dichloropyrimidine (2.74 g, 18.3 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in dimethylformamide (38 mL) is heated at 60° C. for 3 hours. Excess dimethylformamide is removed in vacuo and the residue is taken into water and chloroform. The phases are separated and the aqueous phase is extracted into chloroform (×2). The combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. Flash column chromatography eluting with a gradient of 30% ethyl acetate-hexane to 60% ethyl acetate-hexane provides 1-t-butoxycarbonyl-4-{[(2-chloropyrimidin-4-yl)(methyl)amino]methyl}piperidine (4.23 g, 80%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O>COCCOC>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OB(O)c1cccs1
Reactant: O=Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccccc1-c1cccs1

Procedure:
To a mixture of 2-bromobenzaldehyde (1.17 mL, 10.0 mmol) and 2.0 M aqueous sodium carbonate (75 mL) in DME (225 mL) were added thiophene-2-boronic acid (1.53 g, 12.0 mmol) and tetrakis(triphenylphosphine)palladium[0] (578 mg, 0.5 mmol). The mixture was heated to reflux under nitrogen for 16 hr. The resulting solution was cooled, and the crude product was extracted from aqueous solution with ethyl acetate. The organic layer was dried over MgSO4, and the solvents were removed under vacuum. The crude product was purified on flash column with 25% DCM in hexane to yield 2-(2-thienyl)benzaldehyde.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[O:8][C:7](C3C=CC=CC=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22]C1CC2N(C)C(CCC2)C1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:8]1[C:4]2=[CH:3][CH:2]=[CH:16][C:15]([C:17]([NH2:22])=[O:19])=[C:5]2[N:6]=[CH:7]1
Reactant: O=C(O)c1cc(F)cc2oc(-c3ccccc3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2ocnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 215.9 %

Procedure:
A mixture of 6-fluoro-2-phenylbenzo[d]oxazole-4-carboxylic acid (30 mg, 0.12 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (32 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (0.10 mL, 0.72 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-phenyl)benzoxazole-4-carboxamide (42 mg, 91%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.96 (d, J=7.5 Hz, 1H), 8.23-8.22 (m, 2H), 7.96 (d, J=10.5 Hz, 1H), 7.63-7.55 (m, 3H), 7.42 (d, J=7.0 Hz, 1H), 4.62-4.53 (m, 1H), 3.13-3.11 (m, 2H), 2.67-2.60 (m, 2H), 2.54 (s, 3H), 2.15-1.98 (m, 3H), 1.62-1.46 (m, 3H), 1.18-1.13 (m, 2H); 19F NMR (282 MHz, CDCl3) δ-113.93; MS (ESI+) m/z 394 (M+H); HPLC>99% (AUC), tR=12.78 min.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Br:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[N:10][C:11]=1[C:12]([F:15])([F:14])[F:13]>C(O)C>[Br:5][C:6]1[C:7]([O:1][CH2:2][CH3:3])=[N:8][CH:9]=[N:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: FC(F)(F)c1ncnc(Cl)c1Br
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncnc(C(F)(F)F)c1Br
Yield: 78.4 %

Procedure:
0.94 g (13.77 mmoles) of sodium ethoxide was added, at room temperature, to a solution of 3.00 g (11.48 mmoles) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine dissolved in 50 ml of ethanol. The mixture was stirred to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 2.44 g (yield: 82.9%) of 5-bromo-4-ethoxy-6-trifluoromethylpyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:19][CH:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[CH2:13][CH:12]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>N1C=CC=CC=1>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:10]2[C:5]3[C:6](=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=3)[C:8]([C:11]3[CH2:19][CH:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[CH2:13][CH:12]=3)=[CH:9]2)=[O:26])=[CH:23][CH:22]=1
Reactant: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2n1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Nc1ccc2c(n1)c(C1=CCN3CCCC3C1)cn2C(=O)c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A mixture of 0.10 gm (0.39 mMol) 5-amino-3-(1,2,3,4,5,8-hexahydroindolizin-7-yl)pyrrolo[3,2-b]pyridine and 0.56 μL (0.47 mMol) 4-fluorobenzoyl chloride in 10 mL pyridine was stirred at 55° C. for 18 hours. The reaction mixture was then partitioned between 1N sodium hydroxide and 3:1 chloroform:isopropanol. The phases were separated and the organic phase washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to radial chromatography (2 mm silica plate) eluting with dichloromethane containing 10% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.077 gm (57%) of the title compound. The title compound was recrystallized twice from ethanol:water and dried under reduced pressure to provide a sample for analysis.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=O)(O)=[O:28]>C(O)CO>[C:38]1([C:36]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27](=[O:28])[N:1]([C:3]3[CH:8]=[C:7]([C:9]4[C:18]5[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=5)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=4)[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CCOc1cc2cc(CO)cc(-c3ccnc(NN)c3)c2cc1OCC
Solvent: OCCO
Product: CCOc1cc2cc(CO)cc(-c3ccnc(-n4nc(-c5ccccc5)c5ccccc5c4=O)c3)c2cc1OCC
Yield: 75.7 %

Procedure:
1-(2-Hydrazino-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (177 mg), 1-carboxy-2-phenylcarbonylbenzene (191 mg) and ethylene glycol (1 ml) are treated in the same manner as in Example 104-(3) to give 1-{2-(4-phenyl-1(2H)-phthalazinon-2-yl)-4-pyridyl}-3-hydroxymethyl-6,7-diethoxynaphthalene (206 mg), which is listed in Table 14.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:25]=[C:24]3[C:19]([C:20](=[O:34])[C:21]([C:29]([O:31]CC)=[O:30])=[CH:22][N:23]3[CH2:26][CH2:27]Cl)=[CH:18][C:17]=2[Cl:35])[CH2:12][CH2:11]1)(=O)C>C(O)C.Cl.O.N>[Cl:35][C:17]1[CH:18]=[C:19]2[C:24](=[N:25][C:16]=1[N:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1)[N:23]([CH:26]=[CH2:27])[CH:22]=[C:21]([C:29]([OH:31])=[O:30])[C:20]2=[O:34]
Reactant: CCOC(=O)c1cn(CCCl)c2nc(N3CCN(C(C)=O)CC3)c(Cl)cc2c1=O
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)nc21
Yield: 51.4 %

Procedure:
To a solution of potassium carbonate (1.52 g) in ethanol (40 ml) which was kept at 90°-95° C., was added ethyl 7-(4-acetyl-1-piperazinyl)-6-chloro-1-(2-chloroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (4.0 g) and the mixture was heated to reflux for 1.5 hours. After the mixture was cooled, the resulting potassium 7-(4-acetyl-1-piperazinyl)-6-chloro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylate was collected, and dissolved in 30 ml of water and 20 ml of 1 N sodium hydroxide. The mixture was heated to reflux for 2 hours and acidified with acetic acid, and then adjusted to pH 8 with ammonia solution to give a precipitate. The precipitate was dissolved in diluted hydrochloric acid and adjusted again to pH 8 with ammonia water to give 1.56 g of 6-chloro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid, m.p. 272°-274° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:71])[C@@H:66]1[CH2:70][CH2:69][NH:68][CH2:67]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28]([N:68]5[CH2:69][CH2:70][C@@H:66]([N:65]([CH3:71])[CH3:64])[CH2:67]5)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: CN(C)[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(C(=O)c2ccc3c(c2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a stirred solution of 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid (82 mg; 0.19 mmol) in DMF (5 ml) was added HATU (103 mg; 0.27 mmol), DIPEA (50 μl; 0.27 mmol) and (R)-(+)-3-(dimethylamino)pyrrolidine (501; 0.38 mmol). The reaction mixture was stirred at room temperature for 4 h upon which time it was diluted with EtOAc (20 ml) and washed successively with satd. NaHCO3 (20 ml) and brine (2 20 ml). The organic layer was dried (Na2SO4), concentrated and purified by prep. LCMS to give 418 as an off-white solid (53 mg; 53%). δH (400 MHz, CDCl3) 1.80-1.95 (m, 1H), 2.03-2.15 (br m, 1H), 2.24 (br s, 3H), 2.35 (br s, 3H), 2.62-2.85 (br m, 1H), 3.16 (br s, 2H), 3.30-4.00 (m, 4H), 4.33 (br s, 2H), 6.92-7.20 (m, 4H), 7.40 (br s, 1H), 7.51-7.61 (m, 1H), 7.77 (s, 1H), 8.11 (s, 1H). [M+H]+: 522
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]([Cl:27])([Cl:26])[CH2:11][O:12][C:13]([C:15]1[N:20]2[C:21](=[O:24])[CH:22]([NH2:23])[C@H:19]2[S:18][CH2:17][C:16]=1[CH3:25])=[O:14].Cl[C:29]1[C:34]([O:35][C:36](=[O:53])[CH:37]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:38](OC2C=CC=CC=2)=[O:39])=[C:33](Cl)[C:32](Cl)=[C:31](Cl)[C:30]=1Cl>C(Cl)Cl>[Cl:27][C:10]([Cl:9])([Cl:26])[CH2:11][O:12][C:13]([C:15]1[N:20]2[C:21](=[O:24])[CH:22]([NH:23][C:38](=[O:39])[CH:37]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:36]([O:35][C:34]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:53])[C@H:19]2[S:18][CH2:17][C:16]=1[CH3:25])=[O:14]
Reactant: O=C(Oc1ccccc1)C(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
2.8 ml. (0.02 moles) of triethylamine are added to a suspension of 3.8 g. (0.01 mole) of 7-amino-3-methyl-ceph-3-em-4-carboxylic acid trichloroethyl ester hydrochloride in 30 ml. of methylene chloride. The separated triethylamine hydrochloride is filtered off, the filtrate is cooled to 0° C., and 5.02 g (0.01 mole) of phenylmalonic acid phenylester pentachlorophenyl ester are added. The obtained clear solution is stirred at the same temperature for 30 minutes, thereafter it is washed with 2 n aqueous hydrochloride acid and the solvent is evaporated. The residue is treated with absolute ethanol. 4.7 g. (80%) of 7-(α-phenoxycarbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid trichloroethyl ester are obtained. The white, crystalline substance melts at 120°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[CH:4]=1.CCC(C(C(O)=O)(C)C)C1C=CC2C=C(OC)C=CC=2C=1.OC1C=CC2C(=CC=CC=2)C=1C(O)=O.[N+](=C)=[N-].[CH3:52][O:53][C:54](C1C2C(=CC=CC=2)C=CC=1OC)=[O:55].BrBr>C(O)(=O)C>[CH3:52][O:53][C:54]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([Br:13])=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[O:55]
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: BrBr
Agent: C=[N+]=[N-]
Agent: CCC(c1ccc2cc(OC)ccc2c1)C(C)(C)C(=O)O
Solvent: CC(=O)O
Product: COC(=O)c1c(OC)ccc2cc(Br)ccc12

Procedure:
2-Alkoxy-6-bromo-naphthalenes, especially 2-methoxy-6-bromo-naphthalene, are important starting compounds for the production of pharmaceutical products, especially synthetic estrogens, such as methallenestril (see The Merck Index, 8th Edition, (1968), page 669). For the production of 2-methoxy-6-bromo-naphthalene, 2-hydroxy-naphthalene-1-carboxylic acid was converted with diazomethane into 2-methoxy-naphthalene-1-carboxylic acid methyl ester, the latter was brominated with bromine in acetic acid to form 6-bromo-2-methoxy-naphthalene-1-carboxylic acid methyl ester, then the carboxylic acid methyl ester group was hydrolyzed, and the resulting 6-bromo-2-methoxy-naphthalene-1-carboxylic acid was decarboxylated to form 2-methoxy-6-bromo-naphthalene (see J. Chem. Soc. 1941, 687 + 688).