Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([NH2:23])[NH:11][C:10](=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[N:8]=2)[NH:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(O)(=O)C>[C:24]([NH:23][C:2]1([NH2:1])[NH:11][C:10](=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[N:8]=2)[NH:3]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2cnc3c(n2)C(=O)NC(N)(N)N3)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(-c2cnc3c(n2)C(=O)NC(N)(NC(C)=O)N3)cc1OC
Yield: 77 %

Procedure:
A suspension of the compound of example 101 (10.46 g, 35 mmoles) in acetic anhydride (600 ml) and acetic acid (200 ml) was refluxed for 1 hour until a clear solution was formed. By cooling down the reaction mixture in the refrigerator, the precipitate formed was filtered off, washed with ethyl acetate and diethyl ether, and then dried over P2O5 under vacuum, providing the title compound as a yellow powder (9.19 g, yield: 77%). This compound was further characterized by the following spectra:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18].[CH2:20](C1C2C(=CC=C(OC)C=2)CCC1=O)C>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:19][CH3:20])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18]
Reactant: CCC1C(=O)CCc2ccc(OC)cc21
Reactant: COc1ccc2c(c1)C(C)(CCCCCl)C(=O)CC2
Product: CCC1(CCCCCl)C(=O)CCc2ccc(OC)cc21

Procedure:
Using a procedure analogous to that described in Example I for the preparation of 1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone there is obtained from 35 g. of 1-ethyl-7-methoxy-2-tetralone; 37.4 g. of the title product b.p, 160°-173° C. (0.4 mm.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[CH:14]OC)[C:8]2=O.S(O)(O)(=O)=O.[CH3:22][S:23][C:24](=[NH:26])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:14]=[N:25][C:24]([S:23][CH3:22])=[N:26][C:8]=3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CSC(=N)N
Reactant: COC=C1CCc2c(OC)cccc2C1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccc2c1CCc1cnc(SC)nc1-2
Yield: 72.5 %

Procedure:
To a solution of 5-methoxy-2-methoxymethylene-1-tetralone (9.78 g) in tetrahydrofuran (200 ml) was added 2-methyl-2-thiopseudourea sulfate (8.34 g), followed by potassium carbonate (9.7 g), and the mixture was refluxed overnight. Solvent was then removed under reduced pressure, the residue stirred with diethyl ether, and filtered. Concentration of the filtrate gave a brown solid, which upon crystallization from ethanol gave 7-methoxy-2-methylthio-5,6-dihydrobenzo[h]quinazoline (8.3 g) as a light brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:11][N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CNCCC(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCN(C)c1ccc([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitropyridine (158 mg, 1 mmol), N-methylisoamylamine (101 mg, 1 mmol), and finely ground potassium carbonate (419 mg, 3 mmol) were heated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness to yield 220 mg. ES-MS calcd for C11H17N3O2 (m/e) 223.28, obsd 224.1 (M+H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:12]1[C:13]([Cl:28])=[C:14]([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:18][N:19]=1)[C:15]#[N:16].[Cl:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32]>C1COCC1>[Cl:28][C:13]1[C:12]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[Cl:29])=[N:19][CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[C:14]=1[C:15]#[N:16]
Reactant: Nc1ccccc1Cl
Reactant: COc1cccc(-c2cnc(Cl)c(Cl)c2C#N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(-c2cnc(Nc3ccccc3Cl)c(Cl)c2C#N)c1
Reaction time: 1 h
Yield: 20.8 %

Procedure:
A 1 M solution of lithium bis(trimethylsilyl)amide (0.573 mL, 0.573 mmol) was added to a solution of 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (40 mg, 0.143 mmol, from Step 3 of Example 128) and 2-chloroaniline (36.6 mg, 0.287 mmol) in THF (2 mL) at room temperature. After 1 h at room temperature, LCMS and HPLC analysis indicated that a 1:2 mixture of two products were formed. The reaction mixture was quenched with saturated sodium bicarbonate (5 mL) and diluted with ethyl acetate (60 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5-20% ethyl acetate in hexanes, gave 3-chloro-2-(2-chlorophenylamino)-5-(3-methoxyphenyl)isonicotinonitrile as yellow solid (11 mg, 21% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.51-8.63 (1H, m), 8.35 (1H, s), 7.87 (1H, s), 7.38-7.51 (2H, m), 7.29-7.37 (1H, m), 6.97-7.16 (4H, m), 3.88 (3H, s); MS (ES+) m/z: 370 (M+H); LC retention time: 4.28 min (analytical HPLC Method A). The minor product was found to be 2-chloro-3-(2-chlorophenylamino)-5-(3-methoxyphenyl)isonicotinonitrile.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:14][C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:17])[CH2:14][C:13]2=[CH:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(C1Cc2ccc(OCCCBr)cc21)N1CCCCC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCCCOc1ccc2c(c1)C(C(=O)N1CCCCC1)C2

Procedure:
Sodium azide (2.4 g) is added to a stirred solution of 5-(3-bromopropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene (12.8 g) in ethanol/water (13 ml/130 ml). The reaction mixture is refluxed overnight, poured into water, washed with methylene chloride and the organic extract washed, dried, filtered and evaporated in vacuo affording the desired azide product as an oil, which is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[B:16](F)([F:18])[F:17].CCOCC.[N:25](OC(C)(C)C)=O>COCCOC>[CH3:15][O:14][C:12]([C:4]1[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=[C:2]([N:1]=[N-:25])[CH:3]=1)=[O:13].[F:17][B+:16][F:18]
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)c1cc(N)cc2c1OCCO2
Reactant: FB(F)F
Solvent: CCOCC
Solvent: COCCOC
Product: COC(=O)c1cc(N=[N-])cc2c1OCCO2
Product: F[B+]F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A solution of methyl 7-amino-2,3-dihydro-1,4-benzodioxine-5-carboxylate (4.89 g, 23.3 mmol) in ethylene glycol dimethyl ether (15 mL) was cooled to −5° C. and then slowly added boron trifluoride diethyl etherate (3.85 mL, 30.3 mmol) followed by tert-butyl nitrite (3.05 mL, 25.6 mmol). The resulting gray suspension was allowed to warm to 0° C. and stirred for 1 h, at which time it was filtered and rinsed with ethyl acetate to give 6.24 g (93%) of difluoroboranylium {8-[(methyloxy)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}diazenide as a gray powder: 1H NMR (400 MHz, d6-DMSO): 8.73 (br s, 1H), 8.32 (br s, 1H), 4.64 (br m, 2H), 4.47 (br m, 2H), 3.88 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]4[CH2:20][CH2:19]4)[CH:13]=[CH:12][C:11]=3[CH3:22])=[O:8])[S:5][CH:6]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2ccc(Cl)cc2)c1C

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-methylthiophene-2-carboxamide a with commercially available 4-chlorophenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 197). HPLC Ret time=3.67 min. LCMS [M+H]+ 425.17.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=2)[C:9]#[N:10])[CH2:3][CH2:2]1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=2)[C:9](=[NH:10])[O:12][CH2:13][CH3:14])[CH2:2][CH2:3]1
Reactant: N#Cc1cncc(C2CC2)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1cncc(C2CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.3 %

Procedure:
To a solution of 5-cyclopropylnicotinonitrile (0.45 g, 3.1 mmol) in ethanol was added sodium ethoxide (0.212 g, 3.1 mmol). The reaction mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure to afford the title compound (0.45 g) which was used without further purification. MS (ES+APCI) (M+H) 191.2; LCMS retention time 1.149 min (Method L1).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]3)=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[CH2:28](O)[CH:29]([CH3:31])[CH3:30]>>[ClH:1].[ClH:1].[ClH:1].[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:20][CH2:19]3)=[O:16])[CH2:13][CH2:14]2)[CH2:5][CH2:4]1
Reactant: O=C(O)CN1CCC(NC(=O)N2CCN(C3CCNCC3)CC2)CC1
Reactant: CC(C)CO
Agent: Cl
Product: CC(C)COC(=O)CN1CCC(NC(=O)N2CCN(C3CCNCC3)CC2)CC1

Procedure:
Prepared from 4-[[4-(4-piperidinyl)-piperazin-1-yl]carbonylamino]piperidinoacetic acid dihydrochloride and isobutanol.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.[SH:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:9][C:8]1[C:3]([CH2:2][S:27][C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: Sc1ncccn1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CSc1ncccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine (1.23 g, 3.0 mmol), 2-mercaptopyrimidine (330 mg, 2.9 mmol) and triethylamine (335 mg, 3.3 mmol) in isopropanol (100 ml) is heated under reflux for 4.5 h. After cooling, the suspension is stirred at room temperature for a further 18 h and then at 0° C. for 0.5 h. The precipitate is filtered off, washed with isopropanol and dried at 40° C. in vacuo. The crystalline solid is then suspended in water (50 ml) and sodium carbonate solution (10 ml). After filtration and drying in vacuo at 40° C., the title compound is isolated as a pale beige solid. Yield 1.40 g (93%), m.p. 143-147° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[F:17][C:18]([F:26])([F:25])[C:19]([F:24])([F:23])[C:20](O)=O>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:20]([C:19]([F:24])([F:23])[C:18]([F:26])([F:25])[F:17])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Product: N#Cc1ccccc1-c1ccc2[nH]c(C(F)(F)C(F)(F)F)nc2c1
Temperature: 115 °C

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (9.6 mmoles, 2.0 g) was dissolved in 40 ml of pentafluoropropionic acid and heated at 115° C. for 20 hours. After cooling, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The ethyl acetate solution was added slowly to saturated sodium bicarbonate. The intermediate was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographed over silica gel eluded with 25% ethyl acetate in hexane to yield 1.1 g of 5-(2-cyanophenyl)-2-pentafluoroethyl-1H-benzimidazole. (MS).
Reaction SMILES: [S:1]1[C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]2[S:9][CH:10]=[CH:11][CH:2]12.O=P(Cl)(Cl)Cl>ClCCl>[S:1]1[C:5]([C:6]#[N:8])=[CH:4][CH:3]2[S:9][CH:10]=[CH:11][CH:2]12
Reactant: NC(=O)C1=CC2SC=CC2S1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CC1=CC2SC=CC2S1
Yield: 67 %

Procedure:
3a,6a-Dihydro-thieno[3,2-b]thiophene-2-carboxylic acid amide 2 (4.0 g, 21.6 mmol) was mixed with 50 mL of POCl3 and the mixture was heated to reflux for 2 hours before POCl3 was removed with a rotary evaporator. Dichloromethane (100 mL) was added and then 100 mL of ice water was added dropwise. The organic layer was further washed with water (30 mL) twice before the solvent was removed. The brown oil obtained was passed through a short column of silica gel with dichloromethane as eluent. After removal of the solvent, a yellow oil was obtained (2.4 g, yield 67%). 1H NMR (CDCl3, 500 MHz): δ 7.80 (s, 1H), 7.72 (d, 1H, J=5.0), 7.30 (d, 1H, J=5.0); 13C NMR (CDCl3, 500 MHz): δ 143.39, 138.27, 133.52, 129.72, 119.38, 114.60, 110.27.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:6]2.[C:19](#[N:23])[CH2:20][C:21]#[N:22].C([O-])(=O)C.[K+].II>CO>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[C:20]([C:19]#[N:23])[C:21]#[N:22])[CH:10]=[CH:11]1)[S:6]2
Reactant: N#CCC#N
Reactant: FC(F)(F)c1ccc2c(c1)Sc1ccccc1N2
Agent: CC(=O)[O-]
Agent: II
Agent: [K+]
Solvent: CO
Product: N#CC(C#N)=c1ccc2c(c1)Sc1cc(C(F)(F)F)ccc1N=2

Procedure:
To a stirred solution of 2.6 g 7-trifluoromethylphenothiazine, 1 g malononitrile and 4 g potassium acetate in 70 ml methanol was added a solution of 4 g iodine in 50 ml methanol. The precipitated dye was filtered, washed repeatedly with methanol and recrystallised in chloroform-methanol. Yield 0.6 g (18%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:11][C:3]=12.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30](B(O)O)[CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O>[F:8][C:7]1[C:2]([C:28]2[CH:27]=[C:26]([F:25])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])=[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[NH:9][C:4]2=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)c(F)cnc3[nH]2)CC1
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 120 °C

Procedure:
A mixture of Example 255B (600 mg, 1.696 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (403 mg, 2.374 mmol), phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (110 mg, 0.170 mmol), and potassium phosphate (1080 mg, 5.09 mmol) in 12 mL tetrahydrofuran and 3 mL water was degassed with nitrogen and heated in a Biotage microwave for 40 minutes at 120° C. The mixture was extracted with ethyl acetate and purified by silica gel column chromatography eluting with 0-5% methanol in dichloromethane to afford the title compound. MS (ESI(+)) m/e 444 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[CH3:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Cl[C:18]([O:20][CH2:21][CH2:22][Cl:23])=[O:19].C(=O)=O>O1CCOCC1.O>[CH3:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][C:18](=[O:19])[O:20][CH2:21][CH2:22][Cl:23]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(NC(=O)OCCCl)cccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
91 g of 2-nitro-6-aminotoluene and 31 g of calcium carbonate are initially introduced into the reaction vessel in 750 ml of dioxane, and are heated up to 70° C. 87 g of β-chloroethyl chloroformate are added dropwise to this mixture in the course of two hours such that the reaction mixture refluxes gently, carbon dioxide being evolved. The mixture is subsequently stirred under reflux for a further two hours and then cooled to 35° C., and water and ice are added. The product which has precipitated is filtered off with suction, washed with water, and dried.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].Br[CH:13]([CH3:17])[C:14](Br)=[O:15]>>[CH3:17][CH:13]1[C:14](=[O:15])[O:3][CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:11])[O:10]1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CC(Br)C(=O)Br
Product: CC1OC(=O)C(c2ccccc2)OC1=O
Yield: 33 %

Procedure:
3-methyl-6-phenyl-2,5-dioxane-1,4-dione (9) was synthesized by using mandelic acid and 2-bromopropionyl bromide. Recrystallization from toluene gave white crystals. Mp 153-156° C. Yield: 33%. 1H NMR (CDCl3) δ7.43 (m, 5H), 5.92 (s, 1H) 5.17 (q, 1H), 1.63 (d, 3H). 13C NMR (CDCl3 δ166.90, 165.55, 131.24, 129.95, 128.92, 127.44, 77.74, 72.77, 16.42 MS (m/q) 207.4 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:7][C:3]([CH2:2][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:4][N:5]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2ncc(CBr)o2)cc1
Reactant: C1CCNCC1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ncc(CN3CCCCC3)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
5-(Bromomethyl)-2-(4-nitrophenyl)oxazole (800 mg, 2.82 mmol) was heated with piperidine (10 mL) in a sealed tube at 100-110° C. for 12 h. The resulting mixture was allowed to cool ambient temperature and then poured into water (30 0 mL) and stirred for 30 min. The resultant solid was filtered and washed with water to remove excess piperidine. The residue was dried to give 2-(4-nitrophenyl)-5-(1-piperidylmethyl)oxazole (700 mg, 86%) as light orange colour solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([O:30]C)=[CH:10][C:11]([O:28]C)=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[CH:14][C:13]3=[O:27])[CH2:6][CH2:5][N:4]1[CH3:32].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[OH:28][C:11]1[CH:10]=[C:9]([OH:30])[C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([CH3:32])[C@H:3]2[CH2:2][OH:1])=[C:17]2[C:12]=1[C:13](=[O:27])[CH:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[O:16]2
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc([N+](=O)[O-])c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc([N+](=O)[O-])c4)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 24 (0.5 g, 1.13 mmol) and pyridine hydrochloride (1.2 g, 10.38 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(SC)C=CC=CC=1.[OH:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:28][CH2:27][N:26]([S:29]([NH:32][C:33]([N:35]3[CH2:38][C@H:37]([NH:39]C(=O)OCC4C=CC=CC=4)[C:36]3=[O:50])=[O:34])(=[O:31])=[O:30])[C:25]2=[O:51])[CH:20]=[CH:21][C:22]=1[OH:23]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:39][C@H:37]1[CH2:38][N:35]([C:33]([NH:32][S:29]([N:26]2[CH2:27][CH2:28][N:24]([C:19]3[CH:20]=[CH:21][C:22]([OH:23])=[C:17]([OH:16])[CH:18]=3)[C:25]2=[O:51])(=[O:30])=[O:31])=[O:34])[C:36]1=[O:50]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(c3ccc(O)c(O)c3)C2=O)C1=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(c3ccc(O)c(O)c3)C2=O)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 16 ml of trifluoroacetic acid and 4 ml of thioanisole was cooled to 0° C., and 4 g (7.7 mmol) of (S)-[1-[[[[3-(3,4-dihydroxyphenyl)-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was added. The mixture was stirred overnight at room temperature, evaporated in vacuo, and the residue triturated with ether. The precipitate was filtered off by suction, washed with ether, dichlormethane and isopropanol and dried in vacuo; yield: 3.19 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In THF (250 ml) was dissolved 3-nitrobenzyl chloride (25.0 g), and to the mixture was added piperidine (36 ml). The reaction mixture was stirred at room temperature for 20 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1-(3-nitrobenzyl)piperidine (32.2 g) as pale yellow oil.