Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C[O:16][C:17]([C@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.Cl>>[CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH:9][C:17]([C@H:19]([NH2:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:16])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: COC(=O)[C@H](N)c1ccccc1
Agent: Cl
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Reaction time: 24 h

Procedure:
The wet mycelium so obtained is suspended in M/30-phosphate buffer (pH 6.0), containing 7-aminodeacetoxycephalosporanic acid and D-α-phenylglycine methyl ester hydrochloride (0.4 g), at 28° C for 24 hours. The amount of Cefalexin formed in the reaction mixture is 0.095 g when determined by microbiological assay.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].I[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[N:22]([CH3:23])[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:18]=2[N:31]=1>CN(C=O)C>[C:3]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[N:22]([CH3:23])[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:18]=2[N:31]=1)#[N:4]
Reactant: CN1CCN(C(=O)OC(C)(C)C)c2nc(CCI)ccc21
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)CCc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
NaH (620 mg, 24.55 mmol) was suspended in DMF (203 mL) at 0° C. under N2. Ethyl cyanoacetate (2.6 mL, 24.55 mmol) was added and the resulting mixture stirred for 30 min at 0° C. Tert-butyl 6-(2-iodoethyl)-1-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (6.6 g, 16.37 mmol) in DMF (10 mL) was introduced to the reaction mixture and stirred for 2 hours at room temperature. The mixture was cooled to 0 and quenched with water and extracted with EtOAc (3×). The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica, 90% EtOAC/Hex) to afford colorless oil (5.78 g, 91% yield). H NMR (CDCl3) δ 1.35 (q, 3H), 1.55 (s, 9H), 2.38 (m, 2H), 2.89 (t, 2H), 2.93 (s, 3H), 3.32 (t, 2H), 3.85 (t, 2H), 3.90(m, 1H), 4.30 (q, 2H), 6.85(d, 2H). LC-MS (M+H) 389.
Reaction SMILES: P(Cl)(OCC)(OCC)=O.[CH3:10][C@@H:11]([CH:31]([OH:33])[CH3:32])[CH:12]1[O:14][CH:13]1[CH2:15][C@H:16]1[C@H:21]([OH:22])[C@H:20]([OH:23])[C@H:19]([CH2:24]/[C:25](/[CH3:30])=[CH:26]/[C:27]([OH:29])=[O:28])[O:18][CH2:17]1.C(N(CC)CC)C.[Cl-].[CH3:42][O:43][C:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][NH3+:54])=[O:45]>O1CCCC1>[CH3:42][O:43][C:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][NH-:54])=[O:45].[CH3:10][C@@H:11]([CH:31]([OH:33])[CH3:32])[CH:12]1[O:14][CH:13]1[CH2:15][C@H:16]1[C@H:21]([OH:22])[C@H:20]([OH:23])[C@H:19]([CH2:24]/[C:25](/[CH3:30])=[CH:26]/[C:27]([OH:29])=[O:28])[O:18][CH2:17]1
Reactant: COC(=O)CCCCCCCC[NH3+]
Agent: C/C(=C\C(=O)O)C[C@@H]1OC[C@@H](CC2OC2[C@@H](C)C(C)O)[C@H](O)[C@@H]1O
Agent: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCC[NH-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diethyl chlorophosphate (0.507 g; 2.94 mM) was added to a solution of monic acid A (0.982 g; 2.94 mM) and triethylamine (0.412 ml; 2.94 mM) in dry tetrahydrofuran (50 ml). This solution was stirred at room temperature for three hours, under a nitrogen atmosphere. A solution of 8-methoxycarbonyloctylammonium chloride (0.65 g; 2.94 mM) and triethylamine (0.412 ml; 2.94 mM) in aqueous tetrahydrofuran (10 ml) was then added and the reaction mixture stirred for a further sixteen hours at room temperature. The solvent was then removed at reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulphate and the solvent removed to yield the crude amide as a yellow oil. The product was purified by preparative thin layer chromatography on four 20×20×20×0.2 cm silica plates, eluting with 12% methanol/chloroform. The major band afforded the pure 8-methoxycarbonyloctylamide of monic acid A as a colourless oil. (0.610 g; 40%), [α]D20 -0.74° (c, 1.0 CHCl3), λmax (EtOH) 223 nm (εm 14,130); νmax (CHBr3) 3350, 1780, 1660 and 1630 cm-1 ; δH (CDCl3) 5.93 (1H, broad t, (NH), 5.62 (1H, s, CH=C), 3.65 (3H, s, CO2CH3), 2.13 (3H, s, CH3 -15), 1.30 (s, methylene envelope), 1.20 (3H, d, J 6.0 Hz, CH3 -14), 0.92 (3H, d, J 7.0 Hz, CH3 -17); δC (CDCl3) 174.4, 167.6, 150.3, 120.4, 75.1, 70.8, 70.5, 68.9, 65.5, 61.0, 55.7, 51.5, 42.7, 39.8, 39.4, 34.1, 31.8, 29.6, 29.1, 27.0, 24.9, 20.8, 18.7, 12.6, m/e 513 (M+) 482, 366, 269, 227, 188, 172, 156, 11, 83.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Br:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[I:39]NC(=O)CCC(N)=O>C1COCC1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Br:26])[C:9]=1[I:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)CCC(=O)NI
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2c(Br)cccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2c(Br)cccc2c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Carbamate 10 (1.20 g, 2.80 mmol) was dissolved in freshly distilled THF (0.17 M) under Ar and in the absence of light, and TsOH□H2O (53 mg, 0.28 mmol) and N-iodosuccinamide (753 mg, 3.30 mmol) were added. The reaction mixture was allowed to stir at 25° C. for 2 h. After 2 h, the reaction was quenched with the addition saturated aqueous NaHCO3 and diluted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography (SiO2, 5×16 cm, 5% EtOAc/hexanes elution) provided 11 (1.47 g, 94%) as an orange solid. 1H NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.62 (d, J=7.0 Hz, 2H), 7.39 (t, J=7.2 Hz, 2H), 7.34 (d, J=7.0 Hz, 1H), 7.32 (s, 1H), 7.25-7.22 (m, 2H), 5.28 (s, 2H), 1.58 (s, 9H). 13C NMR (CDCl3, 125 MHz) δ 155.8, 152.4, 139.0, 136.7, 135.9, 132.2, 131.9, 130.0, 128.5, 128.3, 128.0, 127.9, 121.4, 120.2, 120.1, 117.0, 101.9, 81.3, 71.3, 28.3. IR (film) νmax 3378, 2978, 1730, 1225, 1145 cm−1. ESI-TOF HRMS m/z 553.9820 (M+H+, C22H21BrINO3 requires 553.9822).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([OH:11])=O>>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:4][CH2:2][CH3:3])=[O:11]
Reactant: CCN
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: Cl
Product: CCNC(=O)c1ccc(F)c(F)c1
Yield: 56 %

Procedure:
Using ethanamine hydrochloride and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (56% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 3.28 (qd, J=7.24, 5.56 Hz, 2 H) 7.55 (dt, J=10.48, 8.40 Hz, 1 H) 7.73 (m, J=7.33, 4.74, 2.08, 1.14, 1.14 Hz, 1 H) 7.88 (ddd, J=11.75, 7.83, 2.15 Hz, 1 H) 8.58 (t, J=4.93 Hz, 1 H). ESI-MS: m/z 186.1 (M+H)+. mp=94.1-96.2° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[C@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@H:26]([OH:25])[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: O[C@H]1CCNC1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidin-3-ol and isolated as colorless gum (12.5 mg, 69%). MS(m/e): 387.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[N:7]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6][CH2:5]2.[Cl-].[NH4+].O>C(O)(C)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[N:7]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6][CH2:5]2
Reactant: COc1ccc(S(=O)(=O)N2CCc3cc(Br)cc([N+](=O)[O-])c32)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(S(=O)(=O)N2CCc3cc(Br)cc(N)c32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A mixture of 17 (9 g, 0.021 mol), iron (3.65 g, 0.065 mol), and ammonium chloride (2.33 g, 0.043 mol) in isopropanol (200 ml)-water (50 ml) was stirred at 100° C. for 4 h. After cooling, the reaction mixture was filtrated and extracted with CH2Cl2. The combined organic layer was dried by MgSO4 and evaporated to give a residue that was purified by silica gel flash column chromatography (EtOAc:n-hexane=2:3) to afford compound 18, yield 89%.
Reaction SMILES: C[C:2]12[CH:8]3[C:9]([O:11][C:12](=O)[CH:7]3[CH:4]([CH:5]=[CH:6]1)C2)=O>CC(OOC(=O)C1C=CC=CC=1)(CCC(C)(OOC(=O)C1C=CC=CC=1)C)C>[O:11]1[C:12]([C:7]2[CH:4]=[CH:5][CH:6]=[CH:2][CH:8]=2)=[CH:9]1
Reactant: CC12C=CC(C1)C1C(=O)OC(=O)C12
Agent: CC(C)(CCC(C)(C)OOC(=O)c1ccccc1)OOC(=O)c1ccccc1
Product: C1=C(c2ccccc2)O1

Procedure:
To this inhibited epoxy diester-styrene mixture about 5.49 parts of NADIC methyl anhydride and about 0.048 part of 2,5-dimethyl-2,5 bis(benzoyl peroxy) hexane catalyst (sold by Wallace & Tiernan Inc. under the Tradename of Luperox 118) were added, as a final step, at 25° C, to provide the solventless epoxy-styrene impregnating resin. The viscosity of the epoxy-styrene impregnating resin was measured to be about 200 cps at 25° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([CH2:12][C:13]#[N:14])=[CH:3]1.[O:15]([C:17]#[N:18])[K]>>[C:13]([CH2:12][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:17]([NH2:18])=[O:15])[CH:6]=2)[N:2]([CH3:1])[CH:3]=1)#[N:14]
Reactant: N#CO[K]
Reactant: Cn1cc(CC#N)c2cc(N)ccc21
Product: Cn1cc(CC#N)c2cc(NC(N)=O)ccc21
Yield: 80 %

Procedure:
A solution of 7.0 g (0.038 mole) of 1-methyl-5-aminoindole-3-acetonitrile was treated with KOCN as in Example 1 to give a beige solid which was filtered off, washed with cold water and triturated with 50% aq. EtOH to give 6.95 g (80%) of a beige solid: m.p. 250° (dec); nmr (d6 -DMSO) δ(TMS) 8.41 (1, s), 7.65 (1, s), 7.42-7.08 (3, m), 5.73 (2, s, --NH2 --), 4.00 (2, s, --CH2 --) and 3.73 ppm (3H, S, N--CH3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:32]=[N:33][C:34](I)=[N:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:30][C:31]1[CH:32]=[N:33][C:34]([N:1]2[CH2:6][CH2:5][CH:4]([O:7][C:8]3[S:9][C:10]4[CH:16]=[C:15]([CH:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH2:3][CH2:2]2)=[N:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Reactant: Clc1cnc(I)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCN(c5ncc(Cl)cn5)CC4)sc3c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (337 mg, 0.807 mmol) and 5-chloro-2-iodopyrimidine (213 mg, 0.888 mmol) in DMF (10 mL) was added potassium carbonate (335 mg, 2.421 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to rt, diluted with water (30 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from EtOAc to afford tert-butyl 4-(2-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (133 mg, 0.251 mmol, 31% yield) as an off white solid. LCMS (m/z)=531 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.[OH-].[K+].Cl>CO.C(#N)C1C=CC=CC=1>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: N#Cc1ccccc1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a mixture of 306 mg (purity: 99.0%; 1.84 mmol) of 4-hydroxy-3,6-dichloropyridazine and 826 mg (5.48 mmol) of 2-cyclopropyl-6-methylphenol were added benzonitrile (2.76 g) and 323 mg (5.48 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 271 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 53%) was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[N:11][NH:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+].ClCCl>C(#N)C>[Cl:20][C:9]1[N:10]=[N:11][C:12]([C:13]([F:16])([F:15])[F:14])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=c1cc(-c2ccccc2)c(C(F)(F)F)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: FC(F)(F)c1nnc(Cl)cc1-c1ccccc1
Yield: 12768.7 %

Procedure:
To a stirred solution of 5-phenyl-6-trifluoromethyl-2H-pyridazine-3-one (D2) (20.66 g, 0.086 mol) in acetonitrile (150 ml) was added phosphorous oxychloride (20 ml, 0.215 mmol) and the reaction heated at reflux for 1 h. After this period, the reaction mixture was poured into a saturated solution of sodium hydrogen carbonate, ice and dichloromethane. Further solid sodium hydrogen carbonate was then added until gas evolution had ceased. The organic layer was then separated, dried (Na2SO4) and the solvents evaporated in vacuo. The crude residue was then filtered through silica gel, eluting with dichloromethane, in order to remove the minor isomer. After evaporation of the solvent, the crude product was then re-purified by column chromatography (silica; 0-25% ethyl acetate/heptane) to yield D3 (7.1 g, 32%). C11H6ClF3N2 requires 258; Found 259 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([OH:21])=[O:20])[CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)c1
Yield: 73.9 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and m-aminobenzoic acid (0.18 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.30 g (74%) 146 as a very pale dull yellow powder: mp=368-370° C.; Rf0.83 (A): Rf0.93 (C): Rf0.53 (D): IR (cm−1): 2700-3280 (OH), 3122 (C═CH), 2687 (C—H), 1781 (C═O), 1727 (bs, C═O), 1622 (C═C), 1588 (C═C), 1546 (N═O), 1461 (C═C), 1420 (C═C), 1386 (C—O), 1350 (N═O), 1113 (C—O), 727 (C═CH); MS m/z (rel intensity) 311 (68), 285 (46), 267 (46), 191 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=2[NH:9][C:8](=O)[CH2:7]1.CN(C)C1C=CC(C)=CC=1.[Cl-:37].[P+]=O>C1(C)C=CC=CC=1>[Cl:37][C:8]1[CH2:7][N:6]([CH2:5][C:4]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:3]=2[O:2][CH3:1])[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=2[N:9]=1
Reactant: [Cl-]
Reactant: COc1ccc(CN2CC(=O)Nc3ccc(OC)cc3C2=O)c(OC)c1
Agent: O=[P+]
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CC(Cl)=Nc3ccc(OC)cc3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4-(2,4-Dimethoxy-benzyl)-7-methoxy-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (23.7 g, 67 mmol) and N,N-dimethyl-p-toluidine (19.2 mL, 133 mmol) were mixed in toluene (200 mL) and heated to 100° C. Then phosphorous oxide chloride (6.7 mL, 73 mmol) was added dropwise and heating at 100° C. was continued for 2.5 h. The resulting dark red solution was evaporated to dryness and the residue redissolved in THF (150 mL) and used directly in the subsequent step.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][N:15]([CH3:32])[S:16](=[O:31])(=[O:30])[O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH:28]=O.C(=O)([O-])O.[Na+]>C1COCC1.O>[CH3:14][N:15]([CH3:32])[S:16](=[O:31])(=[O:30])[O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH:28]=[CH:5][C:3]#[N:4]
Reactant: COc1cc(C=O)c(OS(=O)(=O)N(C)C)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=CC#N)c(OS(=O)(=O)N(C)C)cc1OC
Temperature: -10 °C
Yield: 80 %

Procedure:
Add 3.1 g (0.0773 mol) of sodium hydride in portions to a solution at 0° C. of 11.9 ml (0.0736 mol) of diethyl cyanomethylphosphonate in 400 ml of THF. Cool the mixture to −10° C. and add dropwise a suspension of 21.3 g (0.0736 mol) of 2-formyl-4,5-dimethoxyphenyl dimethylsulphamate in 200 ml of THF. Stir for 30 minutes and hydrolyse with 600 ml of a solution of sodium hydrogen carbonate and water (50/50) and then extract the solution twice with 300 ml of toluene each time. The organic phase is washed with 100 ml of water and 100 ml of saturated aqueous NaCl solution and then dried over MgSO4, filtered and evaporated to dryness. The residue obtained is crystallised in 80 ml of diisopropyl ether at ambient temperature and then filtered and washed with 20 ml of diisopropyl ether and dried in vacuo. 18.4 g of title product are obtained.
Reaction SMILES: [O-]CC.[Na+].[Na].[Br-].[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=O.[CH2:21]([O:28][C:29]([C:31]([C:36]#[N:37])=[CH:32]OCC)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(I)C>C(O)C.CN(C)C=O>[CH2:21]([O:28][C:29]([C:31]([C:36]#[N:37])=[CH:32][C:15]1[N:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]2=[N:7][C:16]=1[O:18][CH2:19][CH3:20])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC=C(C#N)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C[n+]1cccc(C)c1N
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1nc2c(C)cccn2c1C=C(C#N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a stirred sodium ethoxide solution, freshly prepared with 140 mg of sodium in 30 ml of absolute ethanol, was added 850 mg (3 mmol) of 2-amino-1-(ethoxycarbonylmethyl)-3-methylpyridinium bromide, then the mixture was stirred for 30 min at room temperature. The reaction mixture was treated with 1-(benzyloxycarbonyl)-1-cyano-2-ethoxyethylene (710 mg; 3 mmol) followed by stirred for 30 min at room temperature. The resultant precipitates were collected by filtration, dried, then dissolved in 8 ml of N,N-dimethylformamide (DMF). Ethyl iodide (0.32 ml; 4 mmol) was added to the DMF solution and the mixture was stirred for 2 hours at 60° C. The reaction mixture was cooled at room temperature, extracted with ethyl acetate, the solution was washed with water, dried over anhydrous magnesium sulfate, successively. After removal of the solvent, the residue was chromatographed over silica-gel [eluant: n-hexane-ethyl acetate (1:1)] to give 470 mg (yield: 43%) of the titled compound as yellow needles.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].CC(=CC)C.C1C[O:21]CC1.P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C)(C)C.O.CCOC(C)=O>[Cl:1][C:2]1[C:6]([C:7]([OH:21])=[O:8])=[CH:5][NH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1[nH]cc(C=O)c1Cl
Reactant: C1CCOC1
Agent: CC=C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
To a solution of methyl 3-chloro-4-formyl-1H-pyrrole-2-carboxylate (0.5 g, 2.67 mmol) dissolved in tert-butanol (25 mL) was added 2-methyl-2-butene/2M in THF (20.26 mL, 40.5 mmol). A solution of sodium dihydrogen phosphate monoH2O (2.57 g, 18.66 mmol) and sodium chlorite (2.170 g, 23.99 mmol) in water (25.00 mL) was added dropwise over a period of 15 min. The solution was stirred at RT for 2.5 h. Aqueous citric acid (10 w/w %) was added until a pH of 4-5 was observed. EtOAc (50 mL) was added, the layers separated and the aqueous layer extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate filtered and evaporated. The crude material was triturated with a minimal amount of EtOAc to afford 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.5 g, 92% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 14.4 (br. s., 1H), 12.4 (br. s., 1H) 7.51 (d, 1H) 3.78 (s, 3H). MS: m/z 202.0 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:13][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 6-nitroindole (4.05 g 25 mmol) in DMF (50 mL) was added K2CO3 (8.63 g, 62.5 mmol) and MeI (5.33 g, 37.5 mmol). After stirring at room temperature overnight, the mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the product 1-methyl-6-nitro-1H-indole (4.3 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]([CH3:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]([CH3:16])([CH3:17])[C:12]([F:14])([F:15])[F:13]
Reactant: COc1cc(F)c(C(C)(C)C(F)(F)F)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(c1c(F)cc(O)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1,3-difluoro-5-methoxy-2-(2,2,2-trifluoro-1,1-dimethylethyl)benzene (7.93 g, 31.2 mmol) and 1 M dichloromethane solution of boron tribromide (150 ml, 150 mmol) was stirred at room temperature for 16 hours. Then, the reaction was quenched with water and the product was extracted with ethyl acetate which was dried over sodium sulfate. Then, filtration, evaporation, purification by silica gel column chromatography, eluting with hexane/ethy lacetate (10:1), furnished 7.79 g (quant.) of the title compound as a brown solid.