Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].N1CCOCC1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[CH:23][C:24](Cl)=[O:25])[C:20](=[O:27])[O:19]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:24](=[O:25])[CH:23]=[C:21]1[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:22]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(Cl)c(Cl)c2)O1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred suspension of 3,4-dichlorobenzylamine (17.6 mg, 0.1 mmol) and resin bound morpholine (100 mg, 2.5–4.0 mmol/1 g) in CH2Cl2 (2 mL) was added (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (20 mg, 0.11 mmol) and the mixture stirred for 1 h. The mixture filtered and the filtrate concentrated to give the product as a white solid (33 mg, 100% yield). 1H NMR (500 MHz, CDCl3) δ: 7.39 (2H, m), 7.15 (1H, m), 6.60 (1H, s), 5.89 (1H, s), 4.50 (2H, d, J=6.0 Hz), 1.74 (6H, s). MS calcd for C14H14Cl2NO4 [M+H]+: 330.03. found: 330.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[CH3:17]O>>[CH:17]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CO
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: C(=Cc1ccccn1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To 67.5 parts of the quaternary salt of 2-picoline, also called 2-methylpyridine, (obtained as in Example 13) was added 100 parts methanol, one part piperidine, and 37 parts benzaldehyde. The solution was boiled at reflux for three hours, 175 parts 40% sodium hydroxide solution was added, and the heating continued 1.5 hour to give on workup, as in Example 13, 27 parts 2-styrylpyridine.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C.[CH3:10][C:11]1[C:16]2[CH2:17][CH2:18][CH2:19][C:15]=2[N:14]=[C:13]([NH:20][C:21]([NH:23][S:24]([C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29](OC)=[O:30])(=[O:26])=[O:25])=[O:22])[N:12]=1>CCCCCC.C(Cl)Cl.C1(C)C=CC=CC=1>[CH:5]([NH:8][C:29]([C:28]1[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=1[S:24]([NH:23][C:21]([NH:20][C:13]1[N:12]=[C:11]([CH3:10])[C:16]2[CH2:17][CH2:18][CH2:19][C:15]=2[N:14]=1)=[O:22])(=[O:26])=[O:25])=[O:30])([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2c(n1)CCC2
Reactant: CC(C)N
Agent: C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)NC(C)C)nc2c1CCC2
Reaction time: 2 h

Procedure:
To 21.2 ml of 25% trimethylaluminum in hexane (2.36 molar) under nitrogen is added 2.9 g of isopropyl amine in 100 ml of dried methylene chloride. The mixture is stirred at ambient temperature until evolution of methane gas ceases and then 19.5 g of methyl 2[[(6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-yl)aminocarbonyl]aminosulfonyl]benzoate and 200 ml of dry toluene is added. The resulting mixture is heated to distill off the methylene chloride and hexane, after which heating is continued at the reflux temperature of toluene. After 2 hours, the toluene is removed in vacuo, and 200 ml of methylene chloride and 100 ml of 10% hydrochloric acid are added. The phases are separated, and the methylene chloride phase is washed once with water, dried over magnesium sulfate, and filtered, and the methylene chloride distilled to yield the desired compound.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([I:10])[CH:8]=1)[C:3](=[O:14])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)[CH2:12]2
Reactant: COC(=O)c1c(I)cc(Cl)cc1CBr
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-iodo-benzoic acid methyl ester (0.389 g, 1.0 mmol), 4-fluoro-benzylamine (0.137 mL, 1.2 mmol), and K2CO3 (0.276 g, 2.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5-chloro-7-iodo-2-(4-fluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.149 g, 37%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.15 (s, 2H), 4.75 (s, 2H) 7.02 (t, 2H), 7.27 (t, 2H), 7.36 (s, 1H), 7.92 (s, 1H). GC-MS: m/z 401 (M)+.
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29])=[O:22].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1[C:10]2[C@@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH2:29])=[O:22])[CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Reactant: Nc1ccccc1C(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccccc1C(=O)CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCC3
Yield: 16.5 %

Procedure:
The title compound (0.031 g, 16%) was prepared by the general method of Example 402 from (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.11 g, 0.50 mmol), 4-chloro-2′-aminobutyrophenone (0.20 g, 1.0 mmol), KI (catalytic) and K2CO3(0.14 g, 1.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.80–2.20 (m, 7H), 2.20–2.60 (m, 3H), 2.82–2.95 (m, 1H), 2.98 (t, J=7.4 Hz, 2H), 3.05–3.20 (m, 2H), 3.20–3.38 (m, 2H), 3.64 (t, J=6.6 Hz, 1H), 3.68–3.80 (m, 1H), 3.81 (t, J=6.0 Hz, 1H), 6.26 (br, 2H), 6.58–6.68 (m, 2H), 6.80–6.92 (m, 2H), 7.10–7.30 (m, 2H), 7.52–7.72 (m, 1H), 7.77 (dd, J=1.3, 8.4 Hz, 1H), 8.09 (td, J=1.6, 8.4 Hz, 1H) ppm.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:5]=2[CH:6]=1.C([Li])CCC.CN(C)[CH:26]=[O:27].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[Si:12]([O:11][CH:7]1[C:5]2[CH:6]=[C:2]([CH:26]=[O:27])[S:3][C:4]=2[CH2:10][CH2:9][CH2:8]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2sc(Br)cc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCCc2sc(C=O)cc21
Yield: 92 %

Procedure:
To a solution of [(2-bromo-4,5,6,7-tetrahydro-1-benzothiophen-4-yl)oxy](t-butyl)dimethylsilane (5.6 g, 16 mmol) that was obtained in Example 8 (8b) in tetrahydrofuran (30 ml) was slowly added dropwise n-butyllithium (a 1.6 M solution in hexane, 11 ml, 18 mmol) at −78° C. with stirring, and the resulting mixture was stirred for 5 minutes. Subsequently, to the resulting mixture was added N,N-dimethylformamide (2.5 ml, 32 mmol) at the same temperature with stirring, and the resulting mixture was stirred for 30 minutes. After stirring, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (50 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (4.4 g) in a yield of 92% as a colourless oily product.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16]>C(OCC)C>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:16][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: OCc1ccccc1Cl
Agent: Cl
Solvent: CCOCC
Product: O=C1CCC(CCC(=O)OCc2ccccc2Cl)N1
Temperature: 100 °C

Procedure:
Five grams of dihydro 1H-pyrrolizine-3,5(2H, 6H) dione is dissolved in 31 g of o-chlorobenzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 100° C. for 71 hours. The mixture is cooled and dissolved in 150 ml of anhydrous diethylether. The solution is cooled to induce crystallization and the resulting crystals are isolated by filtration. Recrystallization from toluene-diethyl ether yields 5-oxo-2-pyrrolidinepropanoic acid o-chlorobenzyl ester with a melting point of 99°-100° C.
Reaction SMILES: [C:1]([C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:16][CH:17]=C)[CH2:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:6])#[N:2].CSC>C(Cl)Cl>[C:1]([C:3]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[C:5](=[O:6])[CH2:4]1)#[N:2]
Reactant: C=CCC(C#N)(CC(=O)NCc1ccc(F)cc1)c1ccccc1
Solvent: CSC
Solvent: ClCCl
Product: N#CC1(c2ccccc2)C=CN(Cc2ccc(F)cc2)C(=O)C1
Reaction time: 0.17 h

Procedure:
Into a cooled (−78° C.) solution of 3-cyano-N-(4-fluorobenzyl)-3-phenylhex-5-enamide (8.00 g, 24.8 mmol) in CH2Cl2 (500 mL) was bubbled ozone until a blue color persisted. The mixture was stirred for 10 min, then dimethyl sulfide (84.6 g, 1.36 mol) was added. After stirring for 48 hours at room temperature, the mixture was concentrated under vacuum. The residue was partitioned between EtOAc and water. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum. The residual material was purified using silica gel column chromatography eluting with 0-40% EtOAc in hexanes. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.45 (m, 5H), 7.29 (m, 2H), 7.15 (t, J=8.9 Hz, 2H), 6.78 (d, J=7.7 Hz, 1H), 5.50 (d, J=7.7 Hz, 1H), 4.72 (s, 2H), 3.17 (q, J=16 Hz, 2H) ppm. ES MS M+1=307.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]2)[N:16]=1)[CH3:10].[CH3:40]NC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:10]([N:9]([CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]2)[N:16]=1)[CH3:8])[CH3:40]
Reactant: CNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C)n4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)Cc1nc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 60.4 %

Procedure:
The title compound was prepared according to the general procedure of 5-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting ethyl(methyl)amine (73 mg, 0.3 mmol) for dimethylamine to afford 25 mg of the title compound (60.4%).
Reaction SMILES: O=C(C)CC[S:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:7])=[O:6].C[O-:16].[Na+:17]>C1COCC1.CO>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][S:5]([O-:16])(=[O:7])=[O:6].[Na+:17]
Reactant: COC(=O)CCS(=O)(=O)CCC(C)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a suspension of 12 (141 g, 636 mmol) in THF (1.2 L) and MeOH (700 ml) in an ice bath was added slowly sodium methoxide (144 ml of a 25% solution in MeOH, 1.05 equiv). At the end of the addition, the bath was removed and the mixture stirred at r.t. for 1 h. The solvents were than evaporated and the remaining solid was triturated in ether containing a small amount of EtOAc. The slightly hygroscopic white solid was filtered and dried under high vacuum o.n. to yield 108.7 g (98%) of 13.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:13]([OH:15])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:22][O:23][C:24](=[O:42])[CH2:25][C:26]1[C:27]([CH3:41])=[N:28][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][C:34]=2[F:40])[C:30]=1[CH3:31].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:22][O:23][C:24](=[O:42])[CH2:25][C:26]1[C:27]([CH3:41])=[N:28][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:13]([C:4]3[N:3]([CH2:1][CH3:2])[C:11]4[C:6]([CH:5]=3)=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)=[O:15])=[CH:35][C:34]=2[F:40])[C:30]=1[CH3:31]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2F)c1C
Reactant: CCn1c(C(=O)O)cc2cc(F)ccc21
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(=O)Nc2ccc(Cn3nc(C)c(CC(=O)OC)c3C)c(F)c2)cc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To a solution of 1-ethyl-5-fluoro-1H-indole-2-carboxylic acid (140 mg, 0.68 mmol) in 6 mL dichloromethane is added oxalyl chloride (0.094 mL, 0.68 mmol) and a drop dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a solution of [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (177 mg, 0.61 mmol) and diisopropylethylamine (0.23 mL, 1.35 mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (8.255 mg, 0.069 mmol) the solution is stirred at room temperature for 12 hours. The solution is extracted twice with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated in vacuo. The residue is purified by MPLC (dichloromethane/methanol 95:5) to yield 160 mg of (1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=481; Retention time HPLC: 0.93 min (method D)). b) To a solution of (1-(4-[(1-ethyl-5-fluoro-1H-indole-2-carbonyl)amino]-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (160 mg, 0.33 mmol) in dioxane (2 mL) is added an aqueous solution of NaOH (1 M, 0.66 mL) and the mixture is stirred at 60° C. for 1 hour. The solvent is evaporated in vacuo, and the residue is suspended in water and treated with acetic acid (2 M). The precipitate is freeze dried, dissolved in methanol and a little dimethylformamide, and the product is precipitated with a little water, filtered and dried to yield 137 mg of the title compound (ESI mass spectrum: [M+H]+=467; Retention time HPLC: 0.89 min (method D)).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].N1[CH:19]=[CH:18][CH:17]=[CH:16]1.CO.[C:22]12[CH:45]=[C:43]3[N:44]=[C:40]([CH:41]=[CH:42]3)[CH:39]=[C:37]3[NH:38][C:34]([CH:35]=[CH:36]3)=[CH:33][C:31]3=[N:32][C:28]([CH:29]=[CH:30]3)=[CH:27][C:25]([NH:26]1)=[CH:24][CH:23]=2>C(O)(=O)CC>[CH3:1][Si:2]([C:16]#[C:17][C:18]1[CH:19]=[CH:8][C:7]([C:27]2[C:25]3[NH:26][C:22](=[CH:23][CH:24]=3)[C:45]([C:10]3[CH:13]=[CH:14][C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])=[CH:8][CH:9]=3)=[C:43]3[N:44]=[C:40]([CH:41]=[CH:42]3)[C:39]([C:10]3[CH:13]=[CH:14][C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])=[CH:8][CH:9]=3)=[C:37]3[NH:38][C:34]([CH:35]=[CH:36]3)=[C:33]([C:10]3[CH:9]=[CH:8][C:7]([C:6]#[C:5][Si:2]([CH3:1])([CH3:3])[CH3:4])=[CH:14][CH:13]=3)[C:31]3=[N:32][C:28]=2[CH:29]=[CH:30]3)=[CH:6][CH:5]=1)([CH3:4])[CH3:3]
Reactant: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Reactant: c1cc[nH]c1
Reactant: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Solvent: CO
Solvent: CCC(=O)O
Product: 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
Temperature: 80 °C
Yield: 12 %

Procedure:
5.02 g of 4-trimethylsilylethynylbenzaldehyde (25 mmol) were dissolved in 210 ml of propionic acid and then heated to 80° C. 1.72 ml of pyrrole (25 mmol) were subsequently added portionwise over a period of one hour. The temperature was subsequently increased and the mixture was kept at reflux for 4 hours. After a return to ambient temperature, 75 ml of methanol were added to the reaction medium, which was then left to stand for 14 hours in order for the porphyrin to crystallize. The medium was filtered over sintered glass and the product was rinsed with methanol. 2.87 g (3 mmol; yield 12%) of the expected porphyrin (1) were obtained in the form of a purple powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12](Cl)(=[O:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=O.C([N:18]([CH2:21][CH3:22])CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][NH:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH:31]=2)=[CH:26][CH:25]=1>ClCCl>[CH2:21]([NH:18][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:12](=[O:14])(=[O:13])[N:37]([CH2:36][C:32]2[CH:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH:35]=[CH:34][CH:33]=2)[CH2:38][C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[C:10]([OH:11])=[C:2]([Cl:1])[CH:3]=1)[C:22]1[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Cl)c(O)c(S(=O)(=O)Cl)c1
Reactant: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cc(Cl)c(O)c(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cccc(-c3ccc(Cl)cc3)c2)c1
Reaction time: 3.5 h
Yield: 43.4 %

Procedure:
To a heterogeneous mixture of 3-chloro-5-(chlorosulfonyl)-4-hydroxybenzoic acid (0.47 g, 1.8 mmol) in anhydrous dichloromethane (20 mL), at room temperature under nitrogen, was added triethylamine (0.49 mL, 3.5 mmol). To the resulting homogeneous mixture was added a solution of 1-(4′-chlorobiphenyl-3-yl)-N-(4-fluoro-benzyl)methanamine (1.1 g, 3.5 mmol) in anhydrous DCM (5 mL). The resulting mixture was stirred for 15 h before 3-chloro-5-(chlorosulfonyl)-4-hydroxybenzoic acid (0.47 g, 1.8 mmol) was added. After 3.5 h, triethylamine (0.49 mL, 3.5 mmol) was added and the reaction mixture was war wed to 40° C. After 6 h, the reaction mixture was concentrated in vacuo to remove volatiles and treated with saturated aqueous NaHCO3 solution. The resulting mixture was washed twice with Et2O and the organic washings were discarded. The aqueous layer was acidified with 1 N HCl until pH 1-2 (EMD color PHast pH 0-14 pH strips) and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford an off-white solid. The crude product was purified by preparative HPLC (YMC-Pack, ODS-A, 50×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA) to afford the desired compound (254 mg, 26%) as a white solid. 1H NMR (DMSO-d6) δ 13.25 (bs, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.57-7.46 (m, 5H), 7.38-7.05 (m, 7H), 4.54 (s, 2H), 4.50 (s, 2H). MS (ESI): 558.2 (M−H)−.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.O1CCOCC1.B([C:38]1[CH:39]=[CH:40][C:41]([Cl:47])=[C:42]([CH:46]=1)[C:43]([OH:45])=[O:44])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O>[Cl:47][C:41]1[CH:40]=[CH:39][C:38]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=3[CH:26]=2)=[CH:46][C:42]=1[C:43]([OH:45])=[O:44]
Reactant: O=C(O)c1cc(B(O)O)ccc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(Cl)c(C(=O)O)c3)cc12
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 31.4 %

Procedure:
Alternative Procedure: To a 150 mL sealed tube was added 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.0 g, 2.4 mmol), dioxane (14.4 mL), water (2.9 mL), tetrakis(triphenyl phosphine)palladium(0) (0.055 g, 0.048 mmol), 5-borono-2-chlorobenzoic acid (0.720 g, 3.59 mmol), and cesium carbonate (1.171 g, 3.59 mmol). The tube was sealed and heated in an oil bath overnight at 85° C. The reaction mixture was cooled, diluted with 150 mL of ethyl acetate, washed sequentially with 20 mL of 0.5M HCl then brine. The product solution was filtered through a plug of CELITE® then evaporated to dryness. The resulting solid was taken up in 10 mL of 1:1 DMF and acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/trifluoroacetic acid where solvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 3.5 μm C18 4.6×150 mm column at a gradient of 50-100% B and a flow rate of 40 mL/min. over 20 minutes with a 5 minute hold. Solvent was evaporated giving 319.5 mgs (32% yield) of 2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid as a white powder. The LC/MS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using the following set of conditions: PHENOMENEX® Luna 10 μm C18, 3.0×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 4 minutes with a 1 minute hold at a rate of 5 mL/minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83-2.91 (m, 3H), 7.35-7.45 (m, 2H), 7.65 (d, J=8.53 Hz, 1H), 7.69-7.75 (m, 1H), 7.76-7.82 (m, 1H), 7.85-7.93 (m, 2H), 7.98-8.05 (m, 2H), 8.08 (d, J=2.26 Hz, 1H), 8.43-8.53 (m, 1H), 13.50 (br. s., 1H). LCMS m/z 424.0 (M+H), Rt=3.105 min., 100% purity.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)O
Yield: 76.3 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (10.8 g) prepared by the method described in Preparation A-2 (5) and β-alanine (5.36 g), N-[3-hexadecanoyloxyoctadecanoyl]-β-alanine (9.33 g) was obtained as crystals according to a similar manner to that of Preparation B-1.