Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:16])[C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][NH2:6].[N:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2)=[C:18]=[O:19]>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:16])[C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][NH:6][C:18]([NH:17][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2)=[O:19]
Reactant: NCc1cc(F)c(N2CCOCC2)c(F)c1
Reactant: O=C=Nc1cccc2cnccc12
Solvent: CCOCC
Product: O=C(NCc1cc(F)c(N2CCOCC2)c(F)c1)Nc1cccc2cnccc12

Procedure:
The product from Example 177A (500 mg, 2.19 mmol) in diethyl ether (5 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The resulting waxy precipitate was collected by filtration and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.79 (s, 1H), 8.54 (d, 1H, J=6.1 Hz), 8.26 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.94 (d, 1H, 6.1 Hz), 7.76 (d, 1H, 8.2 Hz), 7.60 (t, 3H, J=7.6 Hz), 7.10 (t, 1H, J=6.0 Hz), 7.03 (m, 2H), 4.31 (d, 2H), 3.68 (m, 4H), 3.07 (m, 4H); MS (ESI+) m/z 399 (M+H).
Reaction SMILES: [N:1]([CH:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:7]1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([CH:4]([NH2:1])[CH3:5])[CH2:7]2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CC(N=[N+]=[N-])C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Temperature: 50 °C
Yield: 67.3 %

Procedure:
A mixture of 3-(1-azido-ethyl)-1-(4-chloro-2-nitro-phenyl)-pyrrolidine (214 mg, 0.7 mmol), triphenylphosphine (500 mg) and water (0.171 mL) in tetrahydrofuran (20 mL) was heated at 50° C. overnight. The resulting mixture was evaporated under reduced pressure; the residue was diluted with ethyl acetate, washed twice with water and once with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH) to give 127 mg (65% yield) of 1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethylamine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C@@H:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:18].Cl.[CH2:20](O)[CH3:21]>>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH2:12][C@@H:13]([OH:17])[C:14]([O:16][CH2:20][CH3:21])=[O:15])=[CH:4][C:3]=1[Cl:18]
Reactant: Nc1c(Cl)cc(C[C@@H](O)C(=O)O)cc1C(F)(F)F
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](O)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A mixture of 14.3 g (50.0 mmol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-propionic acid and 100 ml of ethanol was combined with 100 ml of an approx. 12-molar ethanolic hydrochloric acid solution and stirred overnight. The reaction mixture was evaporated down under reduced pressure.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:13]=1[NH2:14]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:14][C:13]1[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:12]=1[F:11]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(F)c(F)c1F
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)c(F)c1F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2,3,4-trifluoroaniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (white solid, mp 182-183° C.). MS(ES+) m/z 264 ([M+1]+, 100).
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:18](=[O:20])[CH3:19]>C(Cl)Cl>[F:10][C:11]1[C:16]([N+:6]([O-:9])=[O:7])=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:18](=[O:20])[CH3:19]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1c(F)cccc1F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a −40° C. mixture of concentrated H2SO4 (100 mL) and fuming HNO3 (100 mL) was added 1-(2,6-difluorophenyl)ethanone (20 g, 128 mmol) dropwise. The resulting mixture was stirred at −40° C. for 2 h then poured slowly onto ice. That mixture was diluted with DCM and the phases were separated. The aqueous layer was neutralized with sat. aq. NaHCO3 and then extracted with DCM. All organic portions were combined, dried over MgSO4, filtered, and concentrated to give 1-(2,6-difluoro-3-nitrophenyl)ethanone (26.3 g, 131 mmol, >theoretical) that was used without further purification.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2]C.[C:6](=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:8])[CH3:7].Cl.[CH2:21]1COCC1>>[CH2:13]([O:12][C:10]([CH:9]([C:6]([CH3:21])([CH3:7])[CH2:8][CH2:1][CH3:2])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])[CH3:14]
Reactant: CCC[Mg]Br
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: Cl
Product: CCCC(C)(C)C(C(=O)OCC)C(=O)OCC
Temperature: -50 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of n-propylmagnesium bromide in THF (1.62N, 149 ml, 242 mmol), anhydrous THF (200 ml) was added and the mixture was cooled to -50° C. After adding hydrated copper acetate (2.42 g, 12.1 mmol), a solution of diethyl isopropylidenemalonate (22 g, 110 mmol) in anhydrous THF (100 ml) was slowly added to the solution at -50° C., and the mixture was stirred at -50° C. for 2 hours. Aqueous hydrogen chloride (1N, 260 ml) was added at room temperature and the mixture was extracted with ethyl acetate (500 ml, 100 ml×3). Aqueous saturated solution of sodium hydrogencarbonate (100 ml) was added to the combined organic layers and filtered. The aqueous layer was separated from the organic layer of the filtrate. The organic layer was washed with brine (300 ml), dried over magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to give ethyl 2-ethoxycarbonyl-3,3-dimethylhexanoate (24.92 g, 102 mmol, 92.7%, b.p.: 85°-87° C./1 mmHg). The structure was identified by the following data.
Reaction SMILES: [C:1]1([CH:7]([C:40]([O:42]C(C)(C)C)=[O:41])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)=O.C(C(CCCC)C([O-])=O)C.[Na+:60].[Na][Na]>C(OCC)(=O)C.C(O)C>[Na+:60].[Na+:60].[C:1]1([CH:7]([C:40]([OH:42])=[O:41])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH:7]([C:40]([OH:42])=[O:41])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(C(=O)OC(C)(C)C)c3ccccc3)[C@H]2SC1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Agent: [Na][Na]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COC(=O)C1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(C(=O)O)c3ccccc3)[C@H]2SC1

Procedure:
Benzhydryl 7-(2-phenyl-2-tert-butoxycarbonylacetamido)-3-methoxycarbonyl-3-cephem-4-carboxylate (0.257 g., 0.399 mmol.) was dissolved in 40 ml. 97-100% formic acid and allowed to react for 1 hour at room temperature. The reaction mixture was evaporated to dryness to give a residue which was dissolved in ethyl acetate and extracted with sodium bicarbonate solution. The aqueous extracts were combined, layered with cold ethyl acetate, and acidified with cold 1N.HCl. The organic layer was separated, washed with brine and dried (Na2SO4). Evaporation to dryness gave 0.209 g. of acid which was dissolved in 40 ml. ethanol and treated with 2 equivalents of sodium 2-ethylhexanoate. The solution was evaporated in vacuo until a precipitate was noted. The solution was placed in the refrigerator overnight and filtered to give 27 mg. of the disodium salt: nmr (acetone-d6) 3.75 (m, 5, CO2CH3, C2 --H), 4.85 (2-s, 1, side chain CH), 5.17, 5.28 (2-d, 1, J = 5.0 Hz, C6 --H), and 5.92 ppm (q, 1, J = 5.0 Hz and 9.0 Hz, C7 --H).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[F:21])[C:13]2=[O:22])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[F:21])[C:13]2=[O:22])[C:9]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][CH2:31][O:30][CH3:29])[N:34]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3c(F)cccc3C2=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A solution of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (230 mg, 0.75 mmol) in methylene chloride (10 mL) was treated with N,N-dimethylformamide (1 drop) and cooled to 0° C. It was then treated with a solution of oxalyl chloride (2.0 M in methylene chloride, 452 μL, 0.91 mmol) and stirred for 15 min at 0° C. and then warmed to room temperature and stirred for 30 min. After this time, the reaction mixture was concentrated in vacuo to about 1 mL and then methylene chloride was added (5 mL). One third of the resulting volume (˜2 mL, ˜0.25 mmol of the in situ generated acid chloride) was added to a flask containing 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US20080021032, Example 72, 53 mg, 0.38 mmol) and 2,6-lutidine (55 μL, 0.50 mmol) in methylene chloride (5 mL) at 0° C. The reaction mixture was then allowed to warm up to room temperature and stirred overnight for 16 h. After this time, the reaction mixture was quenched with an aqueous saturated sodium bicarbonate solution (10 mL) and extracted with methylene chloride (3×10 mL). The organic layers were then combined and washed with a 1N aqueous hydrochloric acid solution, dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (4 g silica gel column, 40-60% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (70 mg, 65%) as a white foam: [α]28D=−63.0° (c=0.10, methylene chloride); HR-ES(+) m/e calcd for C23H29N4O3F [M+H]+ 429.2297, observed 429.2297; 1H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.41-7.62 (m, 4H), 6.39 (d, J=2.11 Hz, 1H), 5.11 (dd, J=4.68, 10.72 Hz, 1H), 4.91 (d, J=17.81 Hz, 1H), 4.61 (d, J=17.81 Hz, 1H), 4.14 (t, J=4.98 Hz, 2H), 3.63 (t, J=4.98 Hz, 2H), 3.20 (s, 3H), 1.46-2.02 (m, 7H), 0.83-1.24 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[C:13]([Cu])#[N:14].[C-]#N.[Na+]>CN(C=O)C>[C:13]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 105 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
28 g (0.1 mol) of methyl 4-hydroxy-3-iodobenzoate 2 dissolved in 100 mL of DMF was treated with 9.92 g (0.11 mol) of CuCN and 0.49 g (0.11 mol) of NaCN. The system was flushed with nitrogen after which the mixture warmed to 105° C. and stirred to 18 h. The mixture was allowed to cool to room temperature, and any precipitates were removed via filtration and washed with EtOAc. The combined organics were diluted with 200 mL of water and then extracted with EtOAc (2×200 mL). The combined layers were dried over sodium sulfate, filtered and evaporated to dryness. After drying under vacuum, the resulting 18 g (100% yield) of 3 was characterized by LCMS and HNMR.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].O>O1CCCC1>[CH2:21]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCCCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Sodium hydride (60%, 5.78 g, 144.59 mmol) was added to anhydrous tetrahydrofuran (250 ml) and cooled to 0° C. To this mixture, diethyl malonate (25.09 g, 156.64 mmol) was slowly added dropwise, followed by stirring for 1 hour at room temperature. 7-Iodo-1-heptene (27 g, 120.49 mmol) dissolved in anhydrous tetrahydrofuran (50 ml) was then slowly added dropwise to the mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40) to give diethyl 2-(6-heptenyl)malonate (25.8 g, Yield 84%).
Reaction SMILES: [Cl:1][C:2]([Cl:16])([Cl:15])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1)=[O:6].OP([O-])(O)=O.[K+].O.[C-:24]#[N:25].[K+]>CN(C)C=O>[OH:14][CH:13]([C:11]1[N:12]=[C:8]([NH:7][C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:15])[Cl:16])=[O:6])[S:9][CH:10]=1)[C:24]#[N:25]
Reactant: [C-]#N
Reactant: O=Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1

Procedure:
To a mixture of 1.0 g. of 2-(β,β,β-trichloroethoxycarbonyl)amino-4-formylthiazole, 0.87 g. of KH2PO4, 6 ml. of water and 4 ml. of dimethylformamide is added 0.33 g. of KCN at room temperature and the mixture is stirred for 30 minutes. The reaction mixture is extracted with ethyl acetate and the ethyl acetate layer is washed with water and dried. Evaporation of ethyl acetate gives α-hydroxy-[2-(β,β,β-trichloroethoxycarbonyl)aminothiazol-4-yl]-acetonitrile 1.127 g.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](N)[C:5]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])=[N:6][C:7]=1[NH:8][C:9]1[CH:13]=[C:12]([CH:14]2CC2)[NH:11][N:10]=1.CC[N:30]([CH:34](C)C)C(C)C.[F:37]C1C=CC([C@@H](N)C)=CC=1>CCCCO.O>[F:37][C:2]1[C:7]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:6][C:5]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])=[C:4]([CH:3]=1)[C:34]#[N:30]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(Cl)cc1N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: O
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Temperature: 130 °C
Yield: 89.6 %

Procedure:
A suspension of 2,5-difluoro-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile (Method 41, 0.20 g, 0.85 mmol), DIEA (0.14 g, 1.1 mmol), and (S)-1-(4-fluorophenyl)ethanamine (0.23 g, 1.7 mmol) in n-BuOH (2 ml) was heated to 130° C. for 18 hours. The reaction was then cooled to room temperature, diluted with water (20 ml), and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.27 g, 91%). 1H NMR (400 MHz, CD3OD) δ 7.38-7.32 (m, 3H), 7.03-6.99 (m, 2H), 5.99 (br s, 1H), 5.15-5.14 (m, 1H), 2.24 (s, 3H), 1.53 (d, J=6.8 Hz, 3H). MS: Calcd.: 354. Found: [M+H]+ 355.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][NH:16][C:15](=[N:19]N)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1>C(N)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=4)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN=c1cc(-c2c[nH]nc2-c2cccc(Cl)c2)cc[nH]1
Solvent: NCc1ccccc1
Product: Clc1cccc(-c2n[nH]cc2-c2ccnc(NCc3ccccc3)c2)c1
Yield: 121.9 %

Procedure:
A solution of the bromopyridine compound prepared in step 3 of Example A-219 (150 mg, 0.5 mmol) in benzylamine (5 ml) was heated at 175° C. for six hours. After cooling, excess benzylamine was removed by high vacuum distillation and ethyl acetate added to the residue. After washing the organic phase with water and drying over magnesium sulfate, the solvent was removed in vacuo and the residue chromatographed on silica gel using mixtures of ethyl acetate and toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyridinamine (110 mg, 61%) as a solid, m.p. 179-180 ° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.C(Cl)Cl.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:29](=[O:32])[CH2:30][CH3:31])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)CC)n2oc(=O)nc2n1
Reaction time: 1.5 h

Procedure:
5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 80 ml. of methylene chloride and 5 ml. of triethylamine. 2.2 ml. of propionyl chloride in 20 ml. of methylene chloride are added dropwise at 0° C. The mixture is stirred for 90 minutes, then diluted with water, adjusted to pH 4 and extracted with methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed over silica gel using chloroform for the elution. Recrystallization from methylene chloride and diethyl ether yields pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}propionamide having a melting point of 157°-159° C.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]=2[CH:21]=1)[C:4]([O:6]CC)=O)#[N:2].CCCCCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:6]=[C:4]1[C:21]2[C:11](=[CH:12][CH:13]=[C:14]3[S:18](=[O:19])(=[O:20])[CH2:17][CH2:16][C:15]3=2)[NH:10][CH:9]=[C:3]1[C:1]#[N:2]
Reactant: CCOC(=O)C(C#N)=CNc1ccc2c(c1)CCS2(=O)=O
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: N#Cc1c[nH]c2ccc3c(c2c1=O)CCS3(=O)=O
Temperature: 290 °C
Reaction time: 0.5 h
Yield: 377.9 %

Procedure:
1.5 g (0.85 mmol) of ethyl 2-cyano-3-[(1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)amino]acrylate were suspended in 15 ml of Dowtherm A and heated in a metal bath at 290° C. for about 1 h. The reaction mixture was then cooled to RT. The mixture was subsequently mixed with hexane and stirred at RT for 30 min; the precipitate produced thereby was filtered off with suction and washed with hexane. 836 mg (65%) of the desired product were obtained in the form of brownish crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:8]([Cl:11])(Cl)[Cl:9].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13]>>[C:2]1([P:8]([Cl:11])([Cl:9])=[S:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: ClP(Cl)Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: S=P(Cl)(Cl)c1ccccc1
Temperature: 300 °C

Procedure:
The procedure of Example 10 was repeated using 33.6 grams (0.3 moles) of chlorobenzene, 41.1 grams (0.3 moles) of phosphorus trichloride and 22.2 grams (0.05 moles) of phosphorus pentasulfide. The reaction mixture was heated at 300° C. for 7 hours. The product, phenylphosphonothioic dichloride, in a yield of 18.3 grams, was isolated by distillation and redistillation, and had a boiling point of 58° C. and 62° C. (0.02 millimeters of mercury) and an nD25 of 1.6235 as against the reported nD25 of 1.6220 for phenylphosphonothioic dichloride.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][N:14]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1)[CH3:15].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:15][N:14]([CH2:16][C:17]1[CH:18]=[CH:19][C:20](/[CH:21]=[CH:22]/[C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:23][CH:24]=1)[CH3:13]
Reactant: C=Cc1ccc(CN(C)C)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1/C=C/c1ccc(CN(C)C)cc1
Temperature: 140 °C
Reaction time: 13 h
Yield: 33.9 %

Procedure:
6.7 g (39 mmol) of ethyl 2-chloronicotinate, 8.2 g (51 mmol) of 4-(N,N-dimethylaminomethyl)styrene, 9.9 g (98 mmol) of triethylamine, 0.36 g of palladium(II) acetate and 0.96 [lacuna] of tri(o-tolyl)phosphine were mixed in 150 ml of dimethylformamide and, after addition of 1 ml of water, stirred at 140° C. for 13 h. The reaction mixture was then concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate and water. The organic phase was separated off, washed with water, dried and concentrated in vacuo. The residue was then crystallized as oxalate from isopropanol after addition of an equivalent amount of oxalic acid. 4.1 g (27%) of the product were obtained as monooxalate.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].O>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Yield: 91.9 %

Procedure:
Under a dry argon atmosphere, a borane-tetrahydrofuran complex (39.7 g, 0.463 mole) as a 1M solution in tetrahydrofuran was added slowly to a stirred solution of 2,6-dimethyl-3-nitrobenzoic acid (60.2 g, 0.308 mole) in 350 ml of anhydrous tetahydrofuran. The reaction mixture was heated at 60° for approximately 18 hours. Water (20 ml) was slowly added to the reaction mixture, and the resultant mixture was concentrated under reduced pressure to give a residue. The residue was washed with three 100 ml portions of methylene chloride, then three 100 ml portions of a 2N aqueous sodium hydroxide. The washes were combined and the organic phase separated. The aqueous phase was washed with four 250 ml portions of methylene chloride, and the organic phases were combined, dried with anhydrous magnesium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give 2,6-dimethyl-3-nitrobenzene-1-methanol (51.3 g, mp 86.5°-88.5°).