Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:9][C:8]=1[N+:25]([O-])=O.CCN(C(C)C)C(C)C>C1COCC1.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]1[C:8]([NH2:25])=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1cccc(Br)c1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1cccc(Br)c1
Reaction time: 23 h
Yield: 58.4 %

Procedure:
To a solution of N-(3-bromobenzyl)-2-nitro-4-(quinolin-2-ylmethoxy)aniline (5.9 g, 13 mmol) in THF (200 mL) was added DIPEA (1.1 mL, 6.4 mmol) followed by 5% platinum on carbon (0.4 g, 1.9 mmol). The reaction vessel was evacuated and placed under 1 atmosphere of H2 atmosphere for 23 h. The mixture was then flushed with N2 and filtered through a pad of Celite. The Celite was then rinsed with additional THF and the filtrate was concentrated to dryness. The resulting residue was purified using FCC to provide 3.3 g of the title compound as a tan solid. MS (ESI): mass calcd. for C23H20BrN3O, 434.33; m/z found 435.0 [M+H]+.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.C#C.CC[N:19](CC)[CH2:20][CH3:21].C[N:25](C=O)C>[Cu]I.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>[NH:25]1[CH:21]=[CH:20][N:19]=[C:1]1[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CCN(CC)CC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 4 (0.78 g, 1.7 mmol), acetylene intermediate A5 (0.56 g, 1.7 mmol, synthesized as described in Scheme 1-1), CuI (63 mg, 0.33 mmol), and Et3N (0.67 mL, 5.0 mmol) in DMF (20 mL) was added Pd(PPh3)4 (0.19 g, 0.165 mmol). The resulting mixture was degassed with N2, and then stirred at 100° C. overnight in a sealed tube. The reaction mixture was slowly dropped into H2O (100 mL). The precipitate was collected and then dissolved in EtOAc. The organic phase was dried, filtered, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (EtOAc) to afford 5 (420 mg, 34% yield). LC-MS (ESI): m/z 746.4 (M+H)+
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:15])[CH:9]=[CH:10][C:11]=1[Cl:12].Cl>>[ClH:5].[CH2:1]([N:19]1[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=2)[C@H:17]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:18]1)[CH:2]=[CH2:3]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC[C@@H]1CN1CCCC1
Reactant: C=CCBr
Agent: Cl
Product: C=CCN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)[C@H](CN2CCCC2)C1
Yield: 81 %

Procedure:
The compound was prepared by coupling of allyl bromide with 1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine in 81% yield; mp: (HCl salt)157-160° C.; 1H NMR (free base, 200 MHz, CDCl3) δ1.4-2.0 (6H, m), 2.3-3.0 (6H, m), 3.1-3.8 (4H, m), 4.3-4.8 (1H, m), 4.9-5.1 (2H, m), 5.7-5.9 (1H, m), 7.0-7.3 (3H, m); MS (FAB) 396 (M+H)+; Anal. Calcd for C20H27Cl2N3O.2HCl: C, 51.19; H, 6.23; N, 8.95. Found: C, 50.89; H, 6.42; N, 8.65.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:4]=1.[CH:25]1([C:28](Cl)=O)[CH2:27][CH2:26]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:4]=[C:3]([C:2]3[N:1]=[C:28]([CH:25]4[CH2:27][CH2:26]4)[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CCC(=O)N1CCN(c2cc(-c3noc(C4CC4)n3)ccn2)CC1

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyridin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (235 mg) obtained in Example 56-1) was dissolved in pyridine (1 mL), then cyclopropanecarbonyl chloride (0.065 mL) was added thereto and heated under reflux for 90 minutes. The reaction liquid was diluted with ethyl acetate, washed with water, aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 187 mg of the entitled compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=4)[C:11]=3[CH:23]=2)=[N:4][N:3]=1.O1CCC[CH2:25]1.[H-].[Na+].IC>C(OCC)(=O)C.CN(C)C=O>[CH3:25][O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[C:11]3[CH:23]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(CO)cc4)c3c2)o1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COCc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a mixture of [4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenyl]methanol (193 mg, 0.630 mmol), tetrahydrofuran (3 mL) and N,N-dimethylformamide (3 mL) was added sodium hydride (60% in oil, 37.8 mg, 0.945 mmol) at room temperature, and the resulting mixture was stirred for 10 min. Iodomethane (0.0588 mL, 0.945 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/tetrahydrofuran=2/1), and crystallized from hexane/tetrahydrofuran to give the title compound (146 mg, yield 73%) as colorless crystals.
Reaction SMILES: Cl.C(OCC)C.[NH2:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.Cl[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O>C(O)C.[Cl-].[Cl-].[Zn+2]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:11]2[CH:21]=[C:22]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:24][CH:25]=[C:26]3[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)c1ccc2nccc(-c3ccccc3)c2c1
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
HCl/diethyl ether (30.8 ml) was added to a solution of 4-amino-4'-chlorobenzophenone (35 g) in ethanol (250 ml) at room temperature and the mixture was stirred for 15 minutes. FeCl3.6H2O (69.4 g) and then ZnCl2 (2.05 g) were added portionwise and the mixture was stirred at 65° C. for 30 minutes. 3-Chloro-1-phenyl-1-propanone (25.46 g) was added and the mixture was stirred and refluxed for one night. The mixture was poured into ice and extracted with DCM. The organic layer was washed with K2CO3 10%, dried (MgSO4), filtered off and evaporated. The residue was crystallized from ACN. The mother layers were purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 99/1). The pure fractions were collected and evaporated, yielding 19.4 g (37%) of (4-chlorophenyl)(4-phenyl-6-quinolinyl)methanone (interm. 8-a).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH3:24][C:25]1[CH:29]=[CH:28][S:27][C:26]=1[CH:30]=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:30]([C:26]3[S:27][CH:28]=[CH:29][C:25]=3[CH3:24])[N:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: Cc1ccsc1C=O
Product: Cc1ccsc1-c1nc2cc(Br)cc(N)n2n1

Procedure:
The title compound, MS m/e (%): 309 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 3-methylthiophene-2-carboxaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[CH:11](=O)[CH3:12].[O-:14][C:15]#[N:16].[Na+]>C(O)(C)(C)C.O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[O:14])[NH:16][C:11]([CH3:12])=[N:9]2)=[C:4]([F:10])[CH:3]=1
Reactant: CC=O
Reactant: N#C[O-]
Reactant: NNc1ccc(Cl)cc1F
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nn(-c2ccc(Cl)cc2F)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A stirring solution of 80.3 grams (0.500 mole) of 4-chloro-2-fluorophenylhydrazine in 180 ml of tert-butanol/water (88/12) is cooled to 0° to 5° C., and a solution of 23.4 grams (0.525 mole) of acetaldehyde in 50 grams of tert-butanol/water (88/12) is added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture is stirred for five minutes, and a slurry of 39.8 grams (91.5% pure-0.560 mole-12% molar excess) of sodium cyanate in 90 grams of water is added in one portion. Additional water is used to wash any of the remaining slurry of sodium cyanate from its container into the reaction mixture. The reaction mixture is cooled to 0° to 5° C. and 39 3 grams (0.655 mole-5% equivalent excess, based on equivalents of sodium cyanate and its sodium carbonate impurity) of acetic acid is added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred for about two hours during which time it is allowed to warm to about 20° C. Upon completion of the two hour stirring time, the reaction mixture is cooled to 10° C. and 321 grams (0.537 mole) of a 12.4% aqueous solution of sodium hypochlorite is added dropwise during a 40 minute period. Upon completion of addition, the reaction mixture is stirred for an additional 40 minutes. The tert-butanol/water medium is then distilled from the reaction mixture by slowly heating the reaction mixture to about 100° C. Upon completion of the distillation, the pot residue is filtered, washed with water and dried, yielding 1-(4-chloro-2-fluorophenyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CC(C)=O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: ClCC1CO1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC2CO2)cc1
Yield: 67.2 %

Procedure:
A mixture of 15.2 gm (0.1 mole) of methyl 4-hydroxybenzoate, 27.6 gm (0.2 mole) potassium carbonate and 31 mL (0.4 mole) epichlorohydrin in 250 mL acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated. The residue was taken up in 100 mL toluene and washed with 100 mL 1.0 N NaOH and 2×100 mL water. The toluene phase was then dried over magnesium sulfate and evaporated to provide the crude product as an oil. Purification was effected by vacuum distillation (66°-67°; 75 u pressure) and provided 14 gm (67%) of a clear oil when gradually crystallized at room temperature: mp 54°-55° C. The NMR and IR spectra and elemental analysis data were consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:17][CH2:18][C:19]#[CH:20]>CN(C=O)C.CCOCC>[CH2:20]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:19][C:18]#[CH:17]
Reactant: C#CCCI
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCCC(C(=O)OCC)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A suspension of NaH (60%, 8.50 g, 213 mmol) in 200 mL of DMF was added tert-butyl ethyl malonate (36.3 g, 193 mmol) drop-wise at 25° C. The mixture was stirred for 1 hour and 4-iodobut-1-yne (38.2 g, 212.2 g) was added drop-wise. The resulting suspension was stirred overnight and diluted with 1 L of ether, and washed with water (3×200 mL), brine, dried over anhydrous Na2SO4 and concentrated to afford tert-butyl ethyl but-3-yn-1-ylpropanedioate, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21].CS(C1C2C(=CC=CC=2)NC=1)(=O)=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH2:9][N:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[N:24]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)CCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Agent: CS(=O)(=O)c1c[nH]c2ccccc12
Product: CS(=O)(=O)CCn1c(Cn2nc(S(C)(=O)=O)c3ccccc32)nc2cc(Cl)ccc21

Procedure:
Example 1-12 was prepared in analogy to Example 1-2 by using 5-chloro-2-(chloromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-benzo[d]-imidazole and 3-(methylsulfonyl)-1H-indazole instead of 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole and 3-(methylsulfonyl)-1H-indole.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:28]3[CH2:29][CH2:30][CH2:31][C@@H:27]3[CH2:26][O:25][CH3:24])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: COC[C@H]1CCCN1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CS(C)=O
Product: COC[C@H]1CCCN1c1cc(NC(=O)c2ccc(C(C)(C)O)cc2)nc2ccnn12
Temperature: 25 °C
Yield: 71.2 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and (R)-2-(methoxymethyl)pyrrolidine (35 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 20-45% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a orange solid (44 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 1.90-2.18 (m, 4 H) 3.24 (s, 3 H) 3.37 (dd, J=9.47, 7.20 Hz, 1 H) 3.54 (dd, J=9.73, 3.66 Hz, 1 H) 3.68-3.79 (m, 1 H) 3.83-3.98 (m, 1 H) 5.25 (br. s., 1 H) 6.28 (d, J=2.27 Hz, 1 H) 7.06 (s, 1 H) 7.61 (d, J=8.59 Hz, 2 H) 7.98 (d, J=8.59 Hz, 2 H) 8.04 (d, J=2.02 Hz, 1 H) 10.81 (s, 1 H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:7][CH3:8])=[N:5][CH3:6].Cl.[C:10](Cl)(=O)[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:8][NH:7][C:4]1[N:5]([CH3:6])[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:2][N:3]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CN=C(NC)NN
Agent: Cl
Agent: I
Solvent: c1ccncc1
Product: CNc1nnc(-c2ccncc2)n1C
Temperature: 160 °C
Yield: 26.2 %

Procedure:
A mixture of 1000 mg (4.35 mmol) N-amino-N′, N″-dimethyl-guanidine hydriodide (Henry; Smith; J. Amer. Chem. Soc.; 73; 1951; 1858) and 774 mg (4.35 mmol) isonicotinoyl chloride hydrochloride in 3 ml of pyridine was heated with microwaves for 5 min at 160° C. K2CO3(sat) was added and the mixture was extracted 4 times with CHCl3. The organic phase was dried and concentrated. Recrystallization from ethanol, water and EtOAc gave 216 mg (26%) of a yellow white solid. 1H NMR (DMSO), d (ppm): 2.85 (d, 3 H) 3.45 (s, 3 H) 6.25 (d, 1 H) 7.65 (m, 2 H) 8.67 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[CH3:19][CH:20]1[C:25](=[O:26])[CH2:24][C:23](=O)[CH2:22][O:21]1>>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:3]3[C:4](=[O:8])[NH:5][N:6]([CH3:7])[C:2]=3[NH:1][C:23]3[CH2:22][O:21][CH:20]([CH3:19])[C:25](=[O:26])[C:24]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC1OCC(=O)CC1=O
Product: CC1OCC2=C(C1=O)C(c1ccc(F)c(Br)c1)c1c(n(C)[nH]c1=O)N2

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one, 3-bromo-4-fluorobenzaldehyde, and the product from Example 44C could be processed as described in Example 22 to provide the title compound.
Reaction SMILES: C([Li])CCC.[C:6]([Si](C)(C)C)#[CH:7].[O:12]1[CH:16]=[C:15]([C:17](=[O:19])[CH3:18])[N:14]=[CH:13]1>C1COCC1.O>[O:12]1[CH:16]=[C:15]([C:17]([OH:19])([C:6]#[CH:7])[CH3:18])[N:14]=[CH:13]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)c1cocn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C#CC(C)(O)c1cocn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5M in hexane, 1.03 mL, 2.57 mmol) in THF (3 mL) at −78° C. was added dropwise ethynyl(trimethyl)silane (0.34 mL, 2.38 mmol). The reaction was stirred at −78° C. for 10 minutes and then 1-(1,3-oxazol-4-yl)ethanone (220 mg, 1.98 mmol) was added in more THF (2 mL). The reaction was stirred at −78° C. to RT for 1 hr. The mixture was then diluted with water and the volatiles removed. The product was then extracted with EtOAc (2×15 mL) and the combined organics washed with water (2×5 mL) and dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography (eluted with 2-13% methanol) to give the title compound; 1H NMR (500 MHz, CDCl3) delta 1.85 (3H, s), 2.61 (1H, s), 2.92 (1H, s), 7.71 (1H, s), 7.87 (1H, s).
Reaction SMILES: [F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].[C:23](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[N:11]([CH3:23])[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: CCOC(=O)c1c[nH]c2cnc3c(F)c(F)ccc3c2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3c(F)c(F)ccc3c2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A suspension of 35 g of ethyl 7,8-difluoro-1-oxo-1,4-dihydrobenzo[f][1,7]-naphthyridine-2-carboxylate and 31.8 g of potassium carbonate in 350 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature of 90° C. for 3 hours. After cooling to 50° C., 65 g of methyl iodide were added; the mixture was heated at 90° C. for 3 hours. After cooling to 20° C., the insoluble material was dewatered, washed 4 times with 100 cm3 of water, 3 times with 100 cm3 of ethanol, and twice with 100 cm3 of diethyl ether. 25.5 g of ethyl 7,8-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of white crystals, which melted at 320° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CN1CCOCC1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.[NH2:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>CN1CCCC1=O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([NH:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[O:25])=[CH:22][CH:23]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(O)c2cc(C=C(C)c3ccc(C(=O)O)cc3)cnc2n1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(C)=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g of 2-acetamido-4-hydroxy-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine in 50 mL of N-methylpyrrolidinone containing 0.18 g of N-methylmorpholine was added 0.22 g of phenyl N-phenylphosphoramidochloridate in a single portion. After stirring the mixture at room temperature for 1 hour, 0.20 g of diethyl L-glutamate was added. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure and the residue was triturated with chloroform. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to preparative thin layer chromatography on silica gel using a 5% methanol in chloroform mixture as the eluent. This gave 74.6 mg (25%) of the title compound as a pale yellowish solid; NMR (CDCl3, 250 MHz) d 1.22 (t, 3H, J=7.1 Hz), 1.30 (t, 3H J=7.1 Hz), 2.11-2.57 (m, 10H), 4.14 (q, 2H, J=7.1 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.75-4.83 (m, 1H), 6.86 (brs, 1H), 7.18 (brs, 1 H), 7.57 (d, 2H, J=8.42 Hz), 7.84 (d, 2H, J=8.42 Hz), 8.50 (d, 1H, J=2.01 Hz), 8.96 (brs, 1H), 10.34 (brs, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: c1ccsc1
Reactant: Fc1ccc(CBr)cc1
Agent: [Pd]
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: Fc1ccc(Cc2cccs2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
A solution of thiophene (12.6 g, 0.15 mol) in a mixture of anhydrous ether (230 mL) and anhydrous THF (70 mL) was treated dropwise at 0° C. with a 2.5M solution of n-butyllithium in hexane (54.0 mL, 0.134 mol). The mixture was stirred at 0° C. for 1.5 hours and then transferred by cannula into a -78° C. solution of 4-fluorobenzylbromide (23.6 g, 0.125 mol) containing tetrakis(triphenylphosphine) palladium (0) (1.25 g) in anhydrous THF (200 mL). The reaction mixture was stirred at ambient temperature under nitrogen overnight and then quenched with saturated NH4Cl solution (100 mL) and partitioned between ether and additional NH4Cl solution. The ether layer was dried over MgSO4, concentrated in vacuo and the residue subjected to vacuum distillation to give 19.4 g (81%) of 2-(4-fluorophenylmethyl)thiophene. b.p. 74°-83° C. at 0.6-0.7 mm of Hg.