Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([O:25]C)=[O:24].[OH-].[Na+].O1CCOCC1.Cl>C(O)(=O)C.C(Cl)(Cl)Cl.O.CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1c(C)cc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A mixture of methyl 4-methyl-2-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (4.08 g), aqueous sodium hydroxide (0.94 g in 10 ml water), dioxane (20 ml) and methanol (80 ml) was refluxed for 14 hours. After allowing to cool to ambient temperature, the reaction mixture was poured into a mixture of water (150 ml) and chloroform (100 ml). The separated aqueous layer was adjusted to pH 2.9 with 10% aqueous hydrochloric acid. To this mixture was added acetic acid (15 ml) and stirred for 30 minutes under ice cooling. The resulting precipitates were collected by filtration, washed with water and dried in vacuo to give 4-methyl-2-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylic acid (2.80 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH:11](O)=O>>[CH3:9][C:6]1[C:7]2[N:8]=[CH:11][NH:1][C:2]=2[CH:3]=[C:4]([OH:10])[CH:5]=1
Reactant: O=CO
Reactant: Cc1cc(O)cc(N)c1N
Product: Cc1cc(O)cc2[nH]cnc12

Procedure:
276 mg (2.00 mmol) 3,4-diamino-5-methyl-phenol in 3.00 mL formic acid (98%) were refluxed for 1 h. The reaction mixture was then evaporated down and the residue was dried under HV.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25](OCC)=[O:26]>C1(C)C=CC=CC=1>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:10]=1[C:25]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:26]
Reactant: Cc1cc(N)no1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)C2=C(O)c3ccccc3N(c3ccccc3)C2)no1
Yield: 54.1 %

Procedure:
A solution of 2.0 g of 3-amino-5-methylisoxazole and 5.5 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 260 ml of toluene was refluxed for 10 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 3:1 ethyl acetate-hexane as the eluent) to yield 3.5 g (51%) of 1,2-dihydro-4-hydroxy-N-(5-methyl-3-isoxazolyl)-1-phenyl-3-quinolinecarboxamide. Recrystallization from dichloromethane afforded the analytical sample, m.p. 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=S)[NH:10][C:9]=2[CH:14]=1)=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:14][C:9]=2[N:10]=1
Reactant: COC(=O)c1ccc2oc(=S)[nH]c2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2oc(Cl)nc2c1
Temperature: 25 °C

Procedure:
In a round bottom flask equipped with a magnetic stirrer, nitrogen inlet, reflux condenser and drying tube were placed 5-methoxycarbonylbenzoxazolthione (5.2 g, 0.025 mole), phosphorus pentachloride (5.2 g, 0,025 mole), and phosphorus oxychloride (40 mL). The reaction mixture was heated by an oil bath at 95°-100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was distilled with a short path distillation apparatus and the product was collected at 160°-163° C. at 29 mm Hg. The product solidified on standing to give a pale yellow solid, m.p. 104°-106° C. Anal Calcd. for C9H6ClNO3: C, 51.1; H, 2.9; N, 6.6; Cl, 16.8. Found: C, 50.7; H, 2.9; N, 6.6; Cl, 16.3
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]\[C:5]([C:7]1[N:16]=[C:15]2[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:14]=32)[CH:8]=1)=O.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>C(O)(=O)C>[Br:21][C:19]1[CH:18]=[CH:17][C:14]2[C:15]3[N:9]([CH:8]=[C:7]([C:5]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:2]=[CH:3][N:4]=4)[N:16]=3)[CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1
Reactant: CN(C)/C=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Yield: 89.6 %

Procedure:
Alternatively, to a suspension of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-meth-(Z)-ylideneamide (8.52 g, 23.5 mmol) in acetic acid (50 mL) was added isopropylhydrazine hydrochloride (3.37 g, 30.5 mmol) and the reaction mixture heated at 100° C. for 1 h. The reaction mixture was allowed to cool to RT and was poured onto water (500 mL) causing the product to precipitate as an off-white solid. The product was collected by filtration, washed with water (−200 mL) and dried in vacuo at 45° C. for 16 h to yield 194 as an off-white solid (7.88 g, 86%). 1H NMR (400 MHz, d6-DMSO) 8.43 (1H, d, J=8.6 Hz), 7.97 (1H, s), 7.92 (1H, d, J=0.6 Hz), 7.36 (1H, dd, J=8.6, 2.0 Hz), 7.30 (1H, d, J=2.0 Hz), 5.86 (1H, sept, J=6.6 Hz), 4.56-4.52 (4H, m), 1.48 (6H, d, J=6.6 Hz). LCMS: RT=4.69 min, M+H+=374/376. 1H NMR showed product to contain ˜5% 8-iodo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1>O>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: Clc1ccnc2ccccc12
Reactant: C1CNCCN1
Solvent: O
Product: c1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
Piperazine (13.2 g) was melted by heating at 140° C., and 4-chloroquinoline (2.5 g) was added thereto. The mixture was stirred at 140° C. for 30 min. The reaction mixture was added to iced water, and the mixture was extracted with chloroform to give 1-(4-quinolyl)piperazine (3.45 g) as a pale-yellow oil.
Reaction SMILES: O.Cl.Cl.NCC1(CC2C=CC=CC=2)CCN(CCCC2(C3C=CC([Cl:35])=C(Cl)C=3)CCCN([C:21](=[O:28])[C:22]3C=CC=C[CH:23]=3)C2)CC1.[NH2:44][CH2:45][C:46]1([CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH2:54][C:55]2([C:69]3[CH:74]=[CH:73][C:72]([Cl:75])=[C:71]([Cl:76])[CH:70]=3)[CH2:60][CH2:59][CH2:58][N:57]([C:61](=[O:68])[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:56]2)[CH2:48][CH2:47]1.Cl.Cl.C(N(CC)CC)C.C(Cl)(=O)CC.Cl>C(Cl)Cl>[ClH:35].[C:61]([N:57]1[CH2:58][CH2:59][CH2:60][C:55]([CH2:54][CH2:53][CH2:52][N:49]2[CH2:50][CH2:51][C:46]([CH2:77][C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)([CH2:45][NH:44][C:21](=[O:28])[CH2:22][CH3:23])[CH2:47][CH2:48]2)([C:69]2[CH:74]=[CH:73][C:72]([Cl:75])=[C:71]([Cl:76])[CH:70]=2)[CH2:56]1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: NCC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Agent: CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Reaction time: 0.08 h
Yield: 121.4 %

Procedure:
A solution of 0.6 g of the compound obtained in EXAMPLE 9 and 0.18 ml of triethylamine in 10 ml of DCM is cooled to 0° C., 0.1 ml of propionyl chloride is added dropwise and the mixture is stirred for 5 minutes. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed twice with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (95/5; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.37 g of the expected product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[SH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([S:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:3][N:4]=2)=[CH:14][CH:15]=1
Reactant: Sc1ccncc1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Solvent: CCOC(C)=O
Product: Clc1ccc(Nc2nnc(Sc3ccncc3)c3ccccc23)cc1

Procedure:
1-Chloro-4-(4-chlorophenylamino)-phthalazine (R. D. Haworth and S. Robinson, J. Chem. Soc. 1948, pp.777-782) (2.00 g; ˜6.12 mmol) can be melted together with one equivalent of 4-mercaptopyridine at about 140° C. for about 10-30 min. to yield a residue which is dissolved in ethyl acetate, washed with aqueous sodium carbonate and then evaporated in vacuo. The residue can be purified by chromatography on silica gel using a gradient of pure methylene chloride to 50% acetone in methylene chloride to yield pure 1-(4-chlorophenylamino)-4-(4-pyridylthio)phthalazine. The intermediate thioether can be stirred as a solution in acetic acid as 30% aqueous hydrogen peroxide is added in small portions until TLC analysis indicates that all starting material has been consumed. The crude product is isolated by dilution with ethyl acetate, washing with aqueous carbonate solution to remove acetic acid and evaporation in vacuo. Pure invention compound can be obtained by chromatography on the residue on silica gel using methylene chloride/acetone gradients.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=O)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].C1(CNC2N=CC(C(C3C4C(=NC=CC=4)NC=3)=O)=CC=2)CC1>>[CH:2]1([CH2:1][NH:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)=[CH:10][N:11]=2)[CH2:4][CH2:3]1
Reactant: CC(C)CNc1ccc(C(=O)c2c[nH]c3ncccc23)cn1
Agent: O=C(c1ccc(NCC2CC2)nc1)c1c[nH]c2ncccc12
Product: c1cnc2[nH]cc(Cc3ccc(NCC4CC4)nc3)c2c1

Procedure:
was prepared following the protocol of Scheme 8, substituting (6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0025 with [6-(Cyclopropylmethyl-amino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0030 (prepared as described in Example 5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:36][C:37](OC)=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1CO>[Cl:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])[C:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]([CH2:36][CH2:37][OH:38])[CH2:10]1)(=[O:15])=[O:16])=[CH:25]2
Reactant: COC(=O)CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: OCC1CCCO1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC1CCO
Reaction time: 48 h

Procedure:
In tetrahydrofuran - methanol (10/1, 55 mL) was dissolved 4-(tert-butoxycarbonyl)-1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[(methoxycarbonyl)methyl]piperazine (2.5 g), followed by the addition of lithium borohydride (135 mg). The resulting mixture was stirred for 48 hours. The solvent was distilled off under reduced pressure. Water and chloroform were then added to the reaction mixture and the mixture was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (ethyl acetate:hexane=2:3), whereby the title compound (1.84 g) was obtained as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24]C(=O)OC(C)(C)C)[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[N:13][C:8]=2[O:7][CH2:6][S:5]1(=[O:39])=[O:38])#[N:2]>C(O)(C(F)(F)F)=O>[NH2:24][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:12]3[C:11]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:10][C:9]4[N:4]([CH2:3][C:1]#[N:2])[S:5](=[O:39])(=[O:38])[CH2:6][O:7][C:8]=4[N:13]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC#N)S(=O)(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: N#CCN1c2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2OCS1(=O)=O
Reaction time: 0.01 h
Yield: 60.7 %

Procedure:
tert-Butyl (1-(4-(1-(cyanomethyl)-2,2-dioxido-7-phenyl-1H-pyrido[3,2-e][1,3,4]oxathiazin-6-yl)phenyl)cyclobutyl)carbamate (32 mg, 0.059 mmol) was dissolved in TFA (3 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜3 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (3 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (16 mg, 49% yield). 1H-NMR (500 MHz, MeOD) δ 7.83 (1H, s), 7.44 (2H, d), 7.39 (2H, d), 7.26-7.35 (3H, m), 7.20-7.26 (2H, m), 5.53 (2H, s), 5.01 (2H, s), 2.68-2.78 (2H, m), 2.50-2.60 (2H, m), 2.14-2.27 (1H, m), 1.87-1.99 (1H, m). LCMS (Method A) RT=4.00 min, M+2H+=448.12.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=2)[CH:4]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl.Cl>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:4]2[C:3]([OH:2])=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9]3)=[O:23])=[CH:20][CH:19]=1
Reactant: COc1ccc2cc(S(C)(=O)=O)ccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a solution of 2-methoxy-6-methylsulfonylnaphthalene (0.93 g, 3.93 mmol), [prepared as described in step 2 above], in 1,2-dichloroethane (40 ml) was added 4-fluorobenzoyl chloride (0.93 ml, 7.87 mmol) and aluminum chloride (1.05 g, 7.87 mmol) and the reaction mixture was heated at reflux. After 16 h, the reaction mixture was poured in 2N HCl and extracted into methylene chloride. The organic layer was separated and washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by flash chromatography (gradient elution 10-60% ethyl acetate/hexanes) to give 1.2 g of 5-(4-fluorobenzoyl)-6-hydroxy-2-methylsulfonyl-naphthalene as a tan solid (89% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[S:7]([O-:10])([O-:9])=[O:8].[Na+:11].[Na+].O>COC(C)(C)C>[CH2:2]([S:7]([O-:10])(=[O:9])=[O:8])[CH2:3][CH2:4][CH:5]=[CH2:6].[Na+:11]
Reactant: C=CCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: C=CCCCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-Bromo-1-pentene (199.74 g), sodium sulfite (202.67 g), and water (650 ml) were mixed at room temperature. Under reflux, the solution was stirred for 19 hours. After cooling to room temperature, t-butyl methyl ether was added thereto. The aqueous layer separated was concentrated and dehydrated azeotropically with toluene. Thus, sodium 4-pentene-1-sulfonate (1) containing inorganic substances (387.51 g) was obtained as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>CO.O>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:11][NH:14][CH2:13][CH2:12][NH2:15]
Reactant: NCCN
Reactant: COc1ccc(C2CO2)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(C(O)CNCCN)cc1

Procedure:
N-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-ethylenediamine is prepared by reacting 2-(4-methoxyphenyl)oxirane (37.5 g.) dissolved in methanol (52 cc.) with ethylenediamine (30 cc.) dissolved in a mixture of methanol (52 cc.) and water (20 cc.). On distillation under reduced pressure, a product (22.3 g.), b.p. 165°-169° C./0.2 mm.Hg, is obtained, which crystallises on cooling and melts at 68° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.[C:19]1(OB(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C.O1CCCC1.O1CCCC1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[NH:10][C:4]3[C:5]([N:8]=2)=[N:6][CH:7]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=3)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2nc3ncc(Br)cc3[nH]2)c1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3[nH]2)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
Under an argon stream, a mixture of 6-bromo-2-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine (Compound of Reference Example 2) (21.3 g), phenylboric acid (22.2 g), tetrakis(triphenylphosphine)palladium(0) (7.60 g), 2 M sodium carbonate (175 ml), toluene (525 ml) and tetrahydrofuran (175 ml) was stirred at 90° C. for 24 hours. The reaction mixture was distributed into ethyl acetate-tetrahydrofuran (3:1, v/v) and water. The organic layer was washed with water, dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain 2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (14.0 g, 66%). The crystals were recrystallized from chloroform-methanol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CCN(C(C)C)C(C)C>C(#N)C>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([N:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CNc1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N(C)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
4-Fluoro-N-methylaniline (0.33 g, 2.67 mmol) is added to a solution of ethyl 2-bromo-2-phenylacetate (0.36 mL, 2.06 mmol) in acetonitrile (6.86 mL) and DIPEA (0.47 ml, 2.67 mmol). The dark solution is stirred at 100° C. under microwave irradiation for 1 hour. Then solvent is evaporated and the crude is purified by flash chromatography (Petroleum ether/EtOAc=97/3) to obtain intermediate I118 as a yellow solid (0.59 g, 100% yield).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:32]3[NH:33][C:29](=[CH:30][CH:31]=3)[C:28]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[C:41][Si](C)(C)C)=[CH:36][CH:35]=3)=[C:27]3[N:46]=[C:24]([CH:25]=[CH:26]3)[C:23]([C:47]3[CH:52]=[CH:51][C:50]([C:53]#[C:54][Si](C)(C)C)=[CH:49][CH:48]=3)=[C:22]3[NH:59][C:19]([CH:20]=[CH:21]3)=[C:18]([C:60]3[CH:65]=[CH:64][C:63]([C:66]#[C:67][Si](C)(C)C)=[CH:62][CH:61]=3)[C:17]3=[N:72][C:14]=2[CH:15]=[CH:16]3)=[CH:9][CH:8]=1)(C)C.CC(C)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C(Cl)(Cl)Cl.O1CCCC1>[C:53]([C:50]1[CH:49]=[CH:48][C:47]([C:23]2[C:22]3[NH:59][C:19](=[CH:20][CH:21]=3)[C:18]([C:60]3[CH:65]=[CH:64][C:63]([C:66]#[CH:67])=[CH:62][CH:61]=3)=[C:17]3[N:72]=[C:14]([CH:15]=[CH:16]3)[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]#[CH:5])=[CH:8][CH:9]=3)=[C:32]3[NH:33][C:29]([CH:30]=[CH:31]3)=[C:28]([C:34]3[CH:35]=[CH:36][C:37]([C:40]#[CH:41])=[CH:38][CH:39]=3)[C:27]3=[N:46][C:24]=2[CH:25]=[CH:26]3)=[CH:52][CH:51]=1)#[CH:54]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2c3nc(c(-c4ccc(C#C[Si](C)(C)C)cc4)c4ccc([nH]4)c(-c4ccc(C#C[Si](C)(C)C)cc4)c4nc(c(-c5ccc(C#C[Si](C)(C)C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C#Cc1ccc(-c2c3nc(c(-c4ccc(C#C)cc4)c4ccc([nH]4)c(-c4ccc(C#C)cc4)c4nc(c(-c5ccc(C#C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reaction time: 20 h

Procedure:
A solution of 700 mg (0.7 mmol) of protected TEPP (1) obtained above in 500 ml of a chloroform/tetrahydrofuran (THF) mixture (1/1 v/v) was cooled in a bath of liquid nitrogen and acetone to a temperature of between −30 and −50° C., and then a 1 mol/l solution of tetrabutylammonium fluoride (TBAF) in THF (259 mg, 0.99 mmol in 1 ml) was added to the reaction mixture, which was subsequently stirred for 20 hours. The rise in temperature was not controlled. The solvent was subsequently evaporated off and the deprotected porphyrin (2) was obtained in the form of a purple powder (747 mg, 1.05 mmol).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].OO.NC(N)=[O:21].[OH-].[Na+]>CO.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][CH:4]=1)(=[O:21])[NH2:2]
Reactant: NC(N)=O
Reactant: CCOC(=O)c1ccc2[nH]cc(C#N)c2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1c[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A solution of ethyl 3-cyano-1H-indole-5-carboxylate (1.05 g, 4.89 mmol) in methanol (12 mL) was added to a 0° C. solution of urea hydrogen peroxide (4.74 g, 48.9 mmol) and sodium hydroxide (11.7 mL of a 2.5 M solution in water, 29.3 mmol). The mixture was allowed to warm to room temperature and stir overnight. An additional 2 mL of a 2.5 M solution of sodium hydroxide was added and the reaction was left stirring 4 hours. The mixture was concentrated and acidified to pH 2 using 6 M hydrochloric acid. The resulting precipitate was filtered off and dried under vacuum at 60° C. to give the title compound (915 mg, 92%). 1H NMR (400 MHz, DMSO-d6, δ): 12.46 (br. s., 1 H), 11.84 (s, 1 H), 8.85 (s, 1 H), 8.12 (d, J=2.5 Hz, 1 H), 7.75 (dd, J=8.6, 1.6 Hz, 1 H), 7.50-7.63 (m, 1 H), 7.47 (d, J=8.6 Hz, 1 H), 6.88 (br. s., 1 H).