Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]2[C@@H:6]([C@:7]([C:12]3[CH:13]=[C:14]([NH:20][C:21]([C:23]4[CH:32]=[CH:31][C:26]([C:27](=N)[O:28][CH3:29])=[CH:25][N:24]=4)=[O:22])[CH:15]=[C:16]([F:19])[C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2.Cl.C(=O)(O)[O-:35].[Na+]>[OH-].[Na+]>[NH2:1][C:2]1[O:3][C@@H:4]2[C@H:6]([C@@:7]([C:12]3[CH:13]=[C:14]([NH:20][C:21]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:28][CH3:29])=[O:35])=[CH:25][N:24]=4)=[O:22])[CH:15]=[C:16]([F:19])[C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2
Reactant: O=C([O-])O
Reactant: COC(=N)c1ccc(C(=O)Nc2cc(F)c(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(C(=O)Nc2cc(F)c(F)c([C@]3(C(F)F)N=C(N)O[C@H]4C[C@H]43)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
Methyl 6-((3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)carbamoyl)nicotinimidate (0.050 g, 0.111 mmol) was dissolved in hydrochloric acid (2N, 5 mL, 10.00 mmol) and stirred at room temperature. After 15 minutes, the reaction mixture was neutralized with 1 N sodium hydroxide (10 mL). A solution of aqueous saturated sodium bicarbonate (5 mL) was added and the mixture stirred for 10 minutes. The suspension was filtered and the solid was washed with water (10 mL). The solid was further purified by silica gel chromatography [10-90% (2% NH4OH in 3:1 ethyl acetate: ethanol) in hexane] to give the title compound (0.0298 g, 0.066 mmol, 59.5% yield). MS m/z=452.9 [M+H]+. 1H NMR (CHLOROFORM-d) Shift: 9.75 (s, 1H), 9.04 (dd, J=2.0, 0.7 Hz, 1H), 8.48 (dd, J=8.0, 2.0 Hz, 1H), 8.26 (dd, J=8.1, 0.7 Hz, 1H), 7.99 (ddd, J=11.7, 7.0, 2.8 Hz, 1H), 7.22-7.28 (m, 1H), 6.23 (td, J=55.8, 0.9 Hz, 1H), 5.17 (br. s., 2H), 4.01 (s, 3H), 3.92 (td, J=6.8, 2.6 Hz, 1H), 1.80-1.92 (m, 1H), 1.40-1.49 (m, 1H), 0.90-1.03 (m, 1H)
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH3:31][O:32][CH2:33][C:34]1([CH2:40]CO)[O:39][CH2:38][CH2:37][CH2:36][O:35]1>>[Na:1].[CH3:31][O:32][CH2:33][C:34]1([CH2:40][CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])[O:39][CH2:38][CH2:37][CH2:36][O:35]1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: COCC1(CCO)OCCCO1
Agent: [Na]
Product: COCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCCO1
Yield: 7 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 2-(2-(methoxymethyl)-1,3-dioxan-2-yl)ethanol obtained in the step (36a) to obtain the title compound (304 mg, total yield: 7.0%) as a light yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[S:16][CH:15]=[C:14]([C:17]([OH:22])([CH:19]([OH:21])[CH3:20])[CH3:18])[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Br:11][C:12]1[S:16][CH:15]=[C:14]([C:17]([OH:22])([CH3:18])[C:19](=[O:21])[CH3:20])[CH:13]=1
Reactant: CC(O)C(C)(O)c1csc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)C(C)(O)c1csc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.6 %

Procedure:
A solution of oxalyl chloride (19.12 mmol, 2.43 g) in anhydrous CH2C12 (100 mL) was cooled to −50° C. to −60° C. DMSO (39.83 mmol, 2.83 mL) is added dropwise at a rapid rate, with stirring. After 5 min, a solution of 2-(5-bromo-thiophen-3-yl)-butane-2,3-diol (15.93 mmol, 4.0 g) in anhydrous CH2Cl2 (25 mL) was added dropwise over 10 min, keeping the temperature at −50° C. to −60° C. After 15 min stirring, triethylamine (80 mmol, 11.15 mL) was added dropwise, keeping the temperature below −50° C. Stirring was then continued for 5 min. The reaction mixture was allowed to warm to room temperature and water (100 mL) was added. The separated aqueous layer was extracted with CH2Cl2 (70 mL×2). The combined organic layer was washed with brine (100 mL), dried (MgSO4), concentrated in vacuo. Chromatography on SiO2 (EtOAc/Hexanes, 1/2) gave 3.2 g (81%) of 3-(5-bromo-thiophen-3-yl)-3-hydroxy-butan-2-one as an oil; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=1.7 Hz, 1H), 6.98 (d, J=1.7 Hz, 1H), 4.48)s, 1OH), 2.16 (s, 3H), 1.72 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.CO>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[OH:8])=[CH:19][CH:20]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: NC1CCCCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(CCNC2CCCCC2O)cc1
Temperature: 100 °C

Procedure:
Mix (±)-2-aminocyclohexanol (1.5227 g, 13.2 mmol), K2CO3 (4.56 g, 33.0 mmol), and 1-(2-chloroethyl)-4-methoxybenzene (2.0 mL, 13.2 mmol) in DMF (30 mL). Heat at 100° C. for 24 hours. Cool down to room temperature and filtrate with MeOH wash. Concentrate and remove DMF azeotropically with xylenes. Take up the residue in CH2Cl2 and H2O (100 mL each). Separate the layers and extract the aqueous layer with CH2Cl2 (2×100 mL). Wash the organic layers with H2O and brine (100 mL each). Dry the combined organic layers over MgSO4, concentrate and purify by flash chromatography, eluting with 50:45:5 EtOAc/CH2Cl2/2.0 M NH3 in MeOH to afford 2-(4-methoxyphenethylamino)cyclohexanol. (1.38 g, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[C:11]3[C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][S:8][C:7]=2[CH:21]=1>O.C(O)C.[Fe](Cl)(Cl)Cl>[NH2:18][C:14]1[C:11]2[C:12](=[O:13])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][C:7]=3[S:8][CH2:9][C:10]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)SCc1cccc([N+](=O)[O-])c1C2=O
Agent: Cl[Fe](Cl)Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)SCc1cccc(N)c1C2=O

Procedure:
In a mixture of water and ethanol (20 ml), 3-methoxy-10-nitro-6,11-dihydrodibenzo[b,e]thiepin-11-one obtained in Reference Example 18 (0.36 g, 1.2 mmol) was heated under reflux in the presence of reduced iron (0.36 g) and iron (III) chloride (40 mg) for 2 hours. After the reaction was completed, the reaction mixture was filtered while hot and the filtrate was evaporated under reduced pressure to give crude 10-amino-3-methoxy-6,11-dihydrodibenzo[b,e]thiepin-11-one (1.2 mmol). This crude product was added without purification to an acid chloride prepared from 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.38 g, 2.39 mmol) and thionyl chloride (0.36 ml, 2.39 mmol) in dimethylacetamide (10 ml) in the same manner as in Example 1-48, followed by stirring at room temperature for 6 hours. After the reaction, purification of the reaction product was carried out according to the procedure of Example 1-48 to give Compound 1-49 (0.32 g, yield: 65%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:38])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccccc5Cl)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccccc5Cl)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of (4-{3-[6-(2-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (227 mg, 0.41 mmol) in ethanol (4 mL) and concentrated HCl (4 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative-HPLC to give N-{3-[6-(2-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 60 mg). 1HNMR (300 MHz, CD3OD): δ 8.25 (d, 1H, J=5.7 Hz), 8.19 (s, 1H), 7.88 (t, 1H, J=8.7 Hz), 7.53-7.50 (m, 2H), 7.35-7.22 (m, 3H), 7.10 (d, 1H, J=5.7 Hz), 7.02 (d, 1H, J=8.7 Hz), 4.77 (s, 2H), 4.05 (brs, 1H), 3.32 (brs, 1H), 2.23 (brs, 4H), 1.81-1.74 (m, 4H). LC-MS: [M+H]+ 448.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](=[S:9])[NH2:8])=[CH:5][CH:4]=1.CO[CH:16](OC)[CH2:17]Br>Cl.C(O)C>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:9][CH:16]=[CH:17][N:8]=2)=[CH:5][CH:4]=1
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: COC(CBr)OC
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2nccs2)cc1
Yield: 60 %

Procedure:
A stirred solution of 5.0 grams (0.024 mole) of 4-trifluoromethylbenzthioamide, 4.4 grams (0.026 mole) of bromoacetaldehyde dimethyl acetal, and 4 drops of concentrated hydrochloric acid in 50 ml of ethanol was heated at reflux for 18 hours. After this time the reaction mixture was subjected to column chromatography on silica gel. Elution was accomplished using 20% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 3.3 grams of 2-(4-trifluoromethylphenyl)thiazole. The nmr spectrum was consistent with the proposed structure. The reaction was repeated several times.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:16]([OH:17])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:25].[OH:17][C@@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C(N[C@@H]1CNC[C@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl (3R,4R)-3-benzyloxycarbonylamino-4-hydroxypyrrolidine-1-carboxylate (16 g) was dissolved in chloroform (143 mL), followed by addition of a solution (72 mL) of 4 M HCl in 1,4-dioxane, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to obtain benzyl ((3R,4R)-4-hydroxypyrrolidin-3-yl)carbamate mono hydrochloride. This compound was used in the subsequent step without purification.
Reaction SMILES: [S:1](=[O:33])(=[O:32])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]3)[N:19]=[CH:18][N:17]=2)[CH2:6]1)[NH2:2].FC(F)(F)C(O)=O.O>>[S:1](=[O:33])(=[O:32])([O:3][CH2:4][C@H:5]1[CH2:6][C@@H:7]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]3)[N:19]=[CH:18][N:17]=2)[C@H:8]([OH:9])[C@@H:12]1[OH:11])[NH2:2]
Reactant: CC1(C)O[C@@H]2[C@@H](COS(N)(=O)=O)C[C@@H](Nc3cc(N[C@H]4CCc5ccccc54)ncn3)[C@@H]2O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)[C@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
A solution of [(3aR,4R,6R,6aS)-6-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-methyl sulfamate (60.0 mg, 0.126 mmol) was treated with a 9:1 mixture of trifluoroacetic acid in H2O (5.00 mL, 58.4 mmol) and the mixture was stirred for 10 min before being concentrated in vacuo. The crude material was purified via reverse phase C18 preparative HPLC eluting with a gradient of 5 to 70% of 0.1% FA/95% ACN/5% H2O in 0.1% FA/99% H2O/1% ACN over 16 min to afford the title compound (27.0 mg, 49%). 1H NMR (400 MHz, DMSO-d6, δ): 8.13 (s, 1H), 7.98 (s, 1H), 7.44 (s, 2H), 7.28-7.02 (m, 5H), 6.72 (bs, 1H), 5.53 (s, 1H), 5.41 (s, 1H), 4.63 (d, J=5.3 Hz, 1H), 4.09 (dd, J=5.1, 9.5 Hz, 1H), 3.97 (dd, J=7.0, 9.5 Hz, 1H), 3.81 (bs, 1H), 3.71-3.60 (m, 2H), 3.01-2.87 (m, 1H), 2.87-2.70 (m, 1H), 2.47-2.37 (m, 1H), 2.30-2.09 (m, 2H), 1.89-1.72 (m, 1H), 1.19-1.05 (m, 1H) ppm. LC/MS: Rt=1.13 min, ES+ 436 (AA standard).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:3]([OH:5])=[O:4].O.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].Cl>C1COCC1.CCOC(C)=O>[CH2:20]([O:19][C:17]([NH:1][C@H:2]([CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:3]([OH:5])=[O:4])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
(R)-2-amino-5-(tert-butoxy)-5-oxopentanoic acid (1.00 g, 4.92 mmol) was suspended in THF (18.45 ml)/Water (6.15 ml) and cooled to 0° C. using an ice bath. To the cold slurry was slowly added benzyl chloroformate (0.773 mL, 5.41 mmol) and the reaction mixture was allowed to stir for 2.5 h. The slurry was diluted with 50 mL of EtOAc before being acidified to pH 3 using an aqueous 1N HCl solution. The crude product was extracted three times with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was obtained as a clear oil and was subjected to silica gel chromatography using 100% Hexanes to 100% ethyl acetate as eluant. The product, (R)-2-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid, was obtained as a colorless oil (1.41 g, 71%). 1H NMR (400 MHz, chloroform-d) δ 7.44-7.29 (m, 5H), 5.53 (d, J=7.5 Hz, 1H), 5.13 (s, 2H), 4.41 (d, J=5.1 Hz, 1H), 2.56-2.30 (m, 2H), 2.21 (dd, J=13.5, 6.5 Hz, 1H), 2.06-1.88 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:9](O)=[N:8][C:7]([CH:11]3[CH2:13][CH2:12]3)=[N:6][C:5]=2[N:14]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)([Cl:26])=O>>[Cl:1][C:2]1[S:3][C:4]2[C:9]([Cl:26])=[N:8][C:7]([CH:11]3[CH2:13][CH2:12]3)=[N:6][C:5]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C2CC2)nc2nc(Cl)sc12
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2nc(C3CC3)nc(Cl)c2s1

Procedure:
To a solution of the compound (0.82 g) obtained in Step 4 in phosphorus oxychloride (2.5 ml) was added N,N-diisopropylethylamine (0.25 ml) under ice-cooling, and the mixture was heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained residue was dissolved in ethyl acetate, poured into ice water and partitioned. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:8) to give the title compound (0.79 g).
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[CH:21](=[O:28])C1C=CC=CC=1.C(C1C2=C3C(C4C5C(=CC=CC2=5)C=CC=4)=CC=CC3=CC=1)#C.BrC1C=C(C=C(Br)C=1)C=O>[Cu]I>[C:16]1([CH:21]=[O:28])[C:17]2=[C:20]3[C:9]([C:8]4[C:19]5[C:4](=[CH:3][CH:2]=[CH:1][C:18]2=5)[CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=[CH:12][C:13]3=[CH:14][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Agent: [Cu]I
Agent: C#Cc1ccc2cccc3c4cccc5cccc(c1c23)c54
Agent: O=Cc1cc(Br)cc(Br)c1
Product: O=Cc1ccc2cccc3c4cccc5cccc(c1c23)c54
Yield: 31 %

Procedure:
The first route employs bromoperylene PMI-12 and 3,5-diethynylbenzaldehyde (16) as the starting materials. The reaction under copper-free conditions, similar to those employed for the Sonogashira coupling of two porphyrins (Wagner, R. W. et al., Chem. Mater. 1999, 11, 2974-2983) afforded only a small amount (8.9%) of perylene-aldehyde 18 (entry 1, Table 1). The same reaction in the presence of CuI failed to produce perylene-aldehyde 18 (entry 2). We next examined the reaction with the reverse ethyne/bromo substitution pattern on the perylene and benzaldehyde. The reaction of ethynylperylene PMI-12′ and 3,5-dibromobenzaldehyde (14) (2:1 ratio) with CuI cocatalysis afforded 18 in 31% yield (entry 3). A further increase in the amount of perylene PMI-12′ (2.4:1 ratio) gave 18 in 66% yield (entry 4). Repetition of this reaction furnished 18 in 83% yield. While of limited scope, the survey of the Sonogashira reaction of perylene PMI-12 or PMI-12′ with aldehyde 14 or 16 revealed important reactivity differences between a bromoperylene and an ethynylperylene. Unlike perylene-aldehyde 15, compound 18 proved to be very soluble, thereby enabling subsequent porphyrin-forming reactions.
Reaction SMILES: C([O:5][C:6](=[O:47])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][NH:37][C:38]([C:40]1[CH:44]=[C:43]([Cl:45])[S:42][C:41]=1[Cl:46])=[O:39])(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:29][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:47])=[O:5])=[C:10]([CH2:36][NH:37][C:38]([C:40]4[CH:44]=[C:43]([Cl:45])[S:42][C:41]=4[Cl:46])=[O:39])[CH:11]=3)[N:19]=2)=[CH:25][CH:26]=1
Reactant: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)c2cc(Cl)sc2Cl)c1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CCC(=O)O)c(CNC(=O)c2cc(Cl)sc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of the 3-(4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-2-{[(2,5-dichloro-thiophene-3-carbonyl)-amino]-methyl}-phenyl)-propionic acid tert-butyl ester (367 mg, 0.531 mmol) in CH2Cl2 (20 mL) was treated with anisole (2.0 mL) then TFA (6.0 mL). The mixture was stirred at room temperature for 2 h and concentrated. The residue was co-evaporated with CCl4 three times, dried under vacuum, triturated with ether, and filtered to obtain the title compound as a white solid (301 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 2.38 (t, 2H, J=8.3 Hz), 2.71 (t, 2H, J=7.3 Hz), 2.82 (t, 2H, J=6.3 Hz), 4.07 (t, 2H, J=6.6 Hz), 4.28 (d, 2H, J=4.9 Hz), 6.68 (d, 1H, J=9.3 Hz), 6.77 (s, 1H), 7.00 (d, 1H, J=8.3 Hz), 7.24 (s, 1H), 7.29 (t, 1H, J=5.9 Hz), 7.39 (t, 2H, J=7.8 Hz), 7.63 (t, 2H, J=7.8 Hz), 7.71 (d, 2H, J=8.3 Hz), 7.88 (d, 2H, J=8.3 Hz), 8.69 (t, 2H, J=5.9 Hz). MS (ES) m/e 635.1 [M+1].
Reaction SMILES: [N+](C1C([N+]([O-])=O)=C(C)C=C[C:5]=1[O:14]CC1OC1)([O-])=O.C(NCC(OC1C=CC=CC=1OC)C)C1C=CC=CC=1.[ClH:39].Cl.Cl.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([CH3:50])[CH:46]=[CH:45][C:44]=1[O:51][CH2:52][CH:53]([OH:68])[CH2:54][NH:55][CH2:56][CH:57]([O:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[O:66][CH3:67])[CH3:58]>C(O)C.[Pd]>[ClH:39].[OH:68][CH:53]([CH2:54][NH:55][CH2:56][CH:57]([O:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[O:66][CH3:67])[CH3:58])[CH2:52][O:51][C:44]1[C:43]2[NH:42][C:5](=[O:14])[NH:49][C:48]=2[C:47]([CH3:50])=[CH:46][CH:45]=1
Reactant: COc1ccccc1OC(C)CNCC(O)COc1ccc(C)c(N)c1N
Reactant: Cc1ccc(OCC2CO2)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Agent: COc1ccccc1OC(C)CNCc1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccccc1OC(C)CNCC(O)COc1ccc(C)c2[nH]c(=O)[nH]c12

Procedure:
30.5 g. 2,3-Dinitro-1-(2,3-epoxypropoxy)-4-methylbenzene and 32.6 g. N-benzyl-2-(2-methoxyphenoxy)-propylamine are boiled under reflux for 3 hours in 500 ml. ethanol. The reaction mixture is then hydrogenated in the presence of 10 g. 10% palladium-charcoal in 1 liter ethanol at 50° C. and 30 bar. The catalyst is filtered off and the filtrate is acidified with 2 N hydrochloric acid, clarified with active charcoal and evaporated to dryness. There are obtained 59 g. 2,3-diamino-1-{2-hydroxy-3-[2-(2-methoxyphenoxy)-propylamino]-propoxy}-4-methylbenzene trihydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[CH:11]=2)O)[CH:7]=1.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[CH:11]=2)[CH:7]=1
Reactant: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1F
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1F
Reaction time: 3 h
Yield: 82.4 %

Procedure:
(5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanol 4d (12.7 g, 35.3 mmol) was dissolved in 100 mL dichloromethane, followed by addition of triethyl silicane (16.9 mL, 106 mmol) and dropwise addition of boron trifluoride etherate (8.95 mL, 70.6 mmol). The reaction mixture was stirred for 3 hours. Thereafter, the reaction mixture was partitioned after 50 mL saturated sodium bicarbonate solution were added. The aqueous phase was extracted with ethyl acetate (100 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound 4-[(5-bromo-2-chloro-phenyl)methyl]-1-ethoxy-2-fluoro-benzene 4e (10 g, pale yellow grease), yield: 82.4%. 1H NMR (400 MHz, CDCl3): δ 7.33-7.27 (m, 3H), 6.95-6.90 (m, 3H), 4.14 (q, 2H), 4.01 (s, 2H), 1.49 (t, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:6]([CH2:11][CH3:12])[N:7]=[C:8]([CH3:10])[CH:9]=1.CO.[NH3:16]>>[CH2:11]([N:6]1[C:5]([CH2:4][C:3]([NH2:16])=[O:2])=[CH:9][C:8]([CH3:10])=[N:7]1)[CH3:12]
Reactant: N
Reactant: CCn1nc(C)cc1CC(=O)OC
Solvent: CO
Product: CCn1nc(C)cc1CC(N)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(2-Ethyl-5-methyl-2H-pyrazol-3-yl)-acetic acid methyl ester (4.64 g, 25.46 mmol) was dissolved in 7N ammonia in methanol (100 ml, 700 mmol NH3). The reaction mixture was stirred at rt for 20 h. The solvent was removed under reduced pressure to give 4.25 g (quant. yield) of 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-acetamide. LC-MS: tR=0.33 min; [M+H]+=no ionisation.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]C)=[O:26])[CH:19]=3)[NH:14]2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1>[CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=3)[NH:14]2)=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NC(=O)C1CC1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NC(=O)C1CC1
Yield: 86 %

Procedure:
A mixture of methyl 2-(2-(cyclopropanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (57 mg, 0.15 mmol, 1.0 eq.) and 1.8 mL aqueous solution of sodium hydroxide (2 M, 3.76 mmol, 25 eq.) in tetrahydrofuran (3 mL) was stirred at reflux for 3 h. Thin layer chromatography indicated that the starting material was consumed completely. The tetrahydrofuran was removed under reduced pressure and the residue was acidified to pH 5-6 with 1 M hydrochloric acid. Then a lot of white precipitates were formed and collected by filtration to afford 47 mg of 2-(2-(cyclopropanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; yield: 86%. MS (ESI+APCI) M+1=365.