Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].CN(C)[CH:20]=[O:21]>>[C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][O:21][C:20]2[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=2)[CH:12]=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: BrCCCCc1ccccc1
Reactant: CN(C)C=O
Agent: [K+]
Product: O=Cc1cccc(OCCCCc2ccccc2)c1

Procedure:
A solution of 380 mg of m-hydroxybenzaldehyde, 600 mg of 1-bromo-4-phenylbutane and 580 mg of potassium carbonate in 3 ml of N,N-dimethylformamide was stirred overnight at room temperature. After dilution with ethyl acetate, the reaction mixture was washed with water, 1N sodium hydroxide, water and saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure to give 660 mg of m-(4-phenylbutoxy)benzaldehyde.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[C:57]([CH:60]([NH-:64])[C:61](=[O:63])[NH2:62])(=[O:59])[NH2:58].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:57]([CH:60]([NH-:64])[C:61](=[O:63])[NH2:62])(=[O:59])[NH2:58]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]C(C(N)=O)C(N)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 82 mg of Z-Phe-His-OH, 64 mg of H-Leu-Val-Ile-dicarbamoylmethyl amide, 29 mg of HOBt and 45 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B9). Rf (B9)=0.37, Rf (B11)=0.46.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[C:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.C([O-])(=O)C.[Na+].[I:22]Cl>C(Cl)(Cl)Cl.CO.O=[Pt]=O>[I:22][C:5]1[CH:6]=[C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:15]=[CH:16][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(C=C2CCOCC2)cc1
Reactant: ClI
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ccc(CC2CCOCC2)cc1I
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 34 %

Procedure:
A mixture of 4-(4-nitrobenzylidene)tetrahydro-2H-pyran (2.0 g) and PtO2 (0.2 g) is hydrogenated at 40 p.s.i. H2 for 3.5 h. The mixture is filtered through celite and the filtrate condensed. The crude residue is dissolved in a mixture of 40 mL CHCl3 and 4 mL MeOH. To this is added sodium acetate (2.24 g), followed by the dropwise addition of a solution of ICl (0.69 mL) in MeOH (10 mL). The reaction is stirred at room temperature for 1 h then quenched by pouring into an iced saturated solution of aqueous sodium bisulfite (200 mL). The mixture is stirred for 30 minutes then concentrated until all of the organics are gone. The aqueous solution is extracted with CH2Cl2 (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed (Biotage flash 40M, eluent CH2Cl2) to yield 1.0 g (34%) of the desired product as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Cl:17][C:18]1[N:19]=[C:20]([C:24](O)=[O:25])[NH:21][C:22]=1[CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:17][C:18]1[N:19]=[C:20]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])[NH:21][C:22]=1[CH3:23]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: Cc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(C)[nH]1
Yield: 84 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (1 g, 4.34 mmol), 4-chloro-5-methyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (5c) (0.35 g, 2.17 mmol), WSC hydrochloride (1.25 g, 6.52 mmol) and HOBT (0.30 g, 2.22 mmol), to obtain 0.68 g of the title compound as a white solid (84%).
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[N:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCOCC>C1COCC1.C(Cl)Cl>[NH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: N#CCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a stirred solution of (4,4-diphenylpiperidin-1-yl)acetonitrile (3.90 g, 14.1 mmol, 1.0 equiv) in anhydrous THF (10 mL) under argon was added a solution of BH3 in THF (1.0 M, 50 mL, 50 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature and concentrated to a volume of about 30 mL. Aqueous HCl (6 N, 50 mL) was added cautiously and stirring was continued for 2 hours at 50° C. The mixture was cooled to room temperature, basified to pH 10 by addition of 6 N aq. NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2Cl2 (30 mL) was added HCl in ether (1.0 M, 16 mL, 1.1 equiv). After removal of the solvents, the residue was dissolved in CH2Cl2 (10 mL) and this solution was added dropwise into ether (100 mL) with swirling. The resulting solid was filtered and washed with ether (3×50 mL). This solid was taken up in water (20 mL), which was basified to pH 10 by addition of 1 M aqueous NaOH, and extracted with CH2Cl2 (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 3.70 g (94%) of white solid, which was characterized spectroscopically.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:15]=[C:14]([C:16]3[S:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[O:13][N:12]=2)[CH:7]=[N:8][CH:9]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:21][C:18]1[S:17][C:16]([C:14]2[O:13][N:12]=[C:11]([CH2:10][N:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:9][N:8]=[CH:7]3)[CH:15]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cncn1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cncn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 720 mg 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazole-4-carboxylic acid methyl ester in 10 ml THF and 3 ml water, 57.0 mg lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid and the precipitate collected by filtration and washed with 3 ml water. The product was obtained as a white solid which was dried under reduced pressure. Yield: 650 mg
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][NH:13][CH3:14].[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C=O)C>[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([N:13]([CH2:12][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([C:4]=2[CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:14])=[O:26])=[CH:18][CH:17]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1c(C)c2ccccc2n1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
To a stirred solution of 1,3-dimethyl-2-(methylaminomethyl)-1H-indole (0.6 g, 3.2 mmole) in 1:1 DMF(CH2Cl2 (25 mL) was added (E)-3-(6aminopyridin-3-yl)acrylicacid (0.50 g, 3 mmole), HOBt H2O (0.43 g, 3.2 mmole), and DCC (0.66 g, 3.2 mmole). After stirring at RT for 16 hr the reaction was concentrated under vacuum. Purification by flash chromatography on silica gel (3% methanoUCHCl3) gave the title compound (0.83 g, 83%) as an off-white solid: LCMS (ES) n/e 335.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].CC1C=CC(S(O[CH2:23][C@@H:24]2[CH2:26][O:25]2)(=O)=O)=CC=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:23][C@@H:24]1[CH2:26][O:25]1
Reactant: Oc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OC[C@@H]2CO2)cc1F
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 13.0 g of 3,4-difluorophenol and 200 ml of N,N-dimethylformamide, there were added 4.8 g of a dispersion of sodium hydride in mineral oil (50%) and, after stirring for 1 hour, a solution of 22.8 g of (S)-(oxiranylmethyl) 4-methylbenzenesulfonate (ester) in some N,N-dimethylformamide. Stirring at room temperature was continued overnight. The reaction mixture was poured into icewater and the product was extracted with methylbenzene. The extract was washed with NaCl(dil.) and water and was then dried, filtered and evaporated. The residue was distilled (13.3 Pa, 55° C.), yielding 9.5 g (51.0%)of (S)-[(3,4-difluorophenoxy)methyl]-oxirane (interm. 1).
Reaction SMILES: [OH-].[K+].[CH3:3]S(C)=O.[OH:7][C:8]1[C:18]([OH:19])=[CH:17][C:11]2[S:12][C:13]([C:15]#[N:16])=[CH:14][C:10]=2[CH:9]=1.ICI>ClCCl.O>[O:7]1[C:8]2[CH:9]=[C:10]3[CH:14]=[C:13]([C:15]#[N:16])[S:12][C:11]3=[CH:17][C:18]=2[O:19][CH2:3]1
Reactant: N#Cc1cc2cc(O)c(O)cc2s1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: ICI
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc2cc3c(cc2s1)OCO3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of powdered potassium hydroxide (12.36 g) and dimethylsulphoxide (100 ml) was stirred at room temperature for 5 min. then treated with 5,6 -dihydroxy-benzo[b]thiophene-2-carbonitrile (5.26 g). After 1 minute di-iodomethane (4.4 ml) was added and the suspension was stirred at room temperature for 75 minutes, then more di-iodomethane (2.2 ml) was added. After a further 30 minutes the reaction was poured into water (500 ml) and extracted with ethyl acetate (2×100 ml). The organic extracts were combined, washed with 2MHCl and saturated brine, then dried and evaporated to give a brown crystalline residue. The crude product was suspended in hot dichloromethane (200 ml), filtered, and the filtrate was passed through a column of silica gel (0.2-0.5 mm, Merck, 25 g). The appropriate fractions were combined and evaporated to dryness to give a white solid (3.4 g). Crystallisation from acetone/ether afforded pure thieno[2,3-f]-1,3-benzodioxole-6-carbonitrile, m.p. 179°-180° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:13]=[C:12]([C:24](OCC)=[O:25])[C:11]3=[O:29])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:24]([C:12]2[C:11](=[O:29])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:9]=3)[N:14]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:13]=2)=[O:25])=[CH:33][CH:32]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 190 °C

Procedure:
A flask containing ethyl 6-(4-morpholinylmethyl)-4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-quinolinecarboxylate (0.21 g) is treated with 4-chlorobenzylamine (2.0 mL). The reaction is tightly capped and heated to 190° C. for 1 hour. The reaction is cooled to room temperature, adsorbed onto silica and chromatographed on silica eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from ethyl acetate to afford 0.14 g of the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].C1(C)C=CC=CC=1.[CH3:11][O:12][C:13]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:14]=1[C:15]([C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[CH:19][C:18]=1Cl)=[O:16].CN(C)P(=O)(N(C)C)N(C)C>O>[CH3:11][O:12][C:13]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:14]=1[C:15]([C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[CH:19][C:18]=1[O:2][CH3:1])=[O:16]
Reactant: C[O-]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(OC)cncc2C(F)(F)F)c(OC)c1OC
Yield: 63.9 %

Procedure:
16.4 g (304 mmol) of sodium methoxide was added to a toluene 150 ml solution of 18.5 g (47.5 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-trifluoromethylpyridine obtained in step (c) and 16.6 ml (95.4 mmol) of hexamethylphosphoric triamide, followed by stirring under reflux by heating for 30 minutes. Water was added thereto to terminate the reaction, the aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 11.7 g (yield 64%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine (compound No. 122; m.p. 103-106° C.).
Reaction SMILES: [F:1][C:2]([F:7])=[C:3]([F:6])[CH:4]=[CH2:5].[C:8]1([S:14]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:16]CCl>C(=O)([O-])[O-].[Ca+2]>[Cl:16][CH:4]([CH2:5][S:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([F:6])=[C:2]([F:7])[F:1]
Reactant: ClSc1ccccc1
Reactant: C=CC(F)=C(F)F
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: FC(F)=C(F)C(Cl)CSc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 1,1,2-trifluoro-1,3-butadiene (8.0 g. 74 mmol) and calcium carbonate (50 mg) in 85 mL of dichloromethane at -40° C. in a round-bottom 250 mL flask was added a solution of phenylsulfenyl chloride (7.1 g, 49 mmol) in 20 mL of dichloromethane over 2 hours. The reaction mixture was left to stand overnight at room temperature and poured into ice water. The organic layer was washed with aqueous 5% sodium metabisulfite solution and brine, then dried over anhydrous magnesium sulfate. Evaporation of solvent followed by distillation gave 12.1 g (97.5%) of 3-chloro-4-phenylthio-1,1,2-trifluoro-1-butene as a light yellow oil, bp 84°-86° C. (1.0 mm Hg). 1H-NMR (300 MHz, CDCl3): δ 3.39(2H, d, J=8 Hz), 4.58(1H, ttd, J=1.5, 8, 33 Hz), 7.2-7.4(5H, phenyl protons). Mass spectrum: m/e=252,254 (M+). 19F-NMR (300 MHz, CDCl3): φ F3 =-11.8, F2 =116.7, F1 =99.3. J(F12 =64.5, J(F23)=111.2, J(F13)=33.0, J(F3H)=26.4.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]=[O:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1.O>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([CH2:15][OH:16])=[N:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ncc(-c2ccc(F)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ncc(-c2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
NaBH4 (138 mg, 3.6 mmol) was added to a solution of 5-(4-fluorophenyl)-1,3-oxazole-2-carbaldehyde (0.58 g, 3.03 mmol) in methanol (10 ml). The mixture was stirred at room temperature for 2 hours, then poured into water (50 ml), extracted with DCM (30 ml), washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo to afford 460 mg (79%) of the title compound: δH (360 MHz, CDCl3) 2.57 (1H, m), 4.79 (2H, d, J 5.5) 7.12 (2H, t, J 8.5), 7.24 (1H, s), 7.60-7.64 (2H, m); m/z (ES+) 194 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33]([N:36]=[N+:37]=[N-:38])[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(Cl)ncn5)ccc43)cc2)CC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(N=[N+]=[N-])ncn5)ccc43)cc2)CC1
Reaction time: 2.5 h

Procedure:
To a solution of 218 mg (0.44 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amide in 2.5 ml DMF, 57 mg (0.88 mMol) NaN3 are added at rt. After 2.5 h at 68° C., the resulting red solution is poured into water and extracted three times with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: MS: [M+1]+=500; HPLC: AtRet=10.5.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.O.Cl>[C:18]([NH:10][C:8]([C:3]1[C:2]([OH:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1nccnc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC(=O)c1nccnc1O)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
In 50 mL of tetrahydrofuran is suspended 1.00 g of 3-hydroxy-2-pyrazinecarboxamide. Then, 3.5 mL of triethylamine and 1.67 mL of benzoyl chloride are successively added thereto. The resulting solution is stirred at 60° C. for 5 hours and cooled. The deposited crystals are collected by filtration. The crystals thus obtained are suspended in a mixture of 8 mL of water and 1 mL of 1 mol/mL hydrochloric acid, stirred at ambient temperature for 30 minutes, and collected by filtration to obtain 0.41 g of N2-benzoyl-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][C:6]1[C:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[C:8]([CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1>CO>[ClH:4].[CH3:5][C:6]1[C:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[C:8]([CH2:15][NH2:16])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])cc(CNC(=O)OC(C)(C)C)c1N1CCOCC1
Reactant: CC(=O)Cl
Solvent: CO
Product: Cc1cc([N+](=O)[O-])cc(CN)c1N1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
0.81 mL of acetyl chloride was slowly added to 5 mL of MeOH at 0° C. The solution was stirred for 30 min at room temperature and then tert-butyl N-{[3-methyl-2-(morpholin-4-yl)-5-nitrophenyl]methyl}carbamate (200 mg, 0.57 mmol) dissolved in 5 mL of MeOH was added. The reaction mixture was stirred for 3 h and then evaporated to yield expected compound as an orange solid (162 mg, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>>[F:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(Cl)cn1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(Cl)cn1

Procedure:
An 0.5 g. portion of 5-chloro-2-aminopyridine was reacted with 0.6 g. of 2,6-difluorobenzoyl isocyanate as described in Example 1. The isolated product was 0.8 g. of the product named in the heading above, m.p. 226°-229° C. Its elemental analysis showed the following results:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[C:10]([O:16][CH3:17])(=[O:15])[C:11](OC)=[O:12].Cl>CCOCC.CCCCCC.C(OCC)(=O)C>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:11]([C:10]([O:16][CH3:17])=[O:15])=[O:12]
Reactant: COC(=O)C(=O)OC
Reactant: Cc1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1ccccc1C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
5.1 g (0.21 mol) of magnesium was placed in 300 ml of dry ether and 34.18 g (0.2 mol) of 2-bromotoluene was added dropwise thereto under a nitrogen atmosphere to prepare a Grignard reagent. The Grignard reagent solution was cooled to −78° C. and 23.6 g (0.2 mol) of dimethyl oxalate was added dropwise thereto. The resulting solution was stirred for 30 minutes, mixed with crushed ice, acidified with 20% hydrochloric acid and then extracted with ether. The organic layer was washed three times with water, dried over magnesium sulfate, and the solvent was removed under a reduced pressure to obtain a residue. The residue was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (9:1) as an eluent to obtain 24.2 g (yield 68%) of the title compound as a colorless liquid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.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.[CH3:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][C:49]=1[N+:55]([O-:57])=[O:56]>CN(C=O)C>[CH3:47][C:48]1[CH:54]=[CH:53][C:51]([NH:52][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)=[CH:50][C:49]=1[N+:55]([O-:57])=[O:56]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of 3-(trifluoromethyl)benzoic acid (8 g, 42.1 mmol), HATU (19.20 g, 50.5 mmol) and DIPEA (13.91 mL, 84 mmol) in DMF (350 mL) was stirred for 15 min at rt. 4-methyl-3-nitroaniline (6.40 g, 42.1 mmol) was added and stirred overnight at 60° C. After cooling to room temperature the reaction was quenched with H2O. After stirring for 10 minutes the resulting precipitate was collected and washed with water to give compound N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide 66 (12 g, 88%). (m/z)=325 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9]1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>O1CCCC1>[CH3:23][N:24](/[CH:26]=[C:11]1\[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[C:10]\1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:25]
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CN(C)/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,5-Bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one [(Example 107, Step 1), 0.20 g, 0.73 mmol] and N,N-dimethylformamide dimethylacetal (0.12 mL, 0.88 mmol, 1.2 equiv) were combined in tetrahydrofuran (5 mL) and placed into a preheated oil bath at 65° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.