Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH2:37][C:38](O)=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH2:37][C:38]([N:21]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10]2)=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccc([C@@H](CN2CC[C@H](OC3CCCCO3)C2)NOC2CCCCO2)cc1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N(OC1CCCCO1)[C@H](CN1CC[C@H](OC2CCCCO2)C1)c1ccccc1
Yield: 69.8 %

Procedure:
This was prepared from 1-(S)-Phenyl-N-tetrahydropyranyloxy-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethylamine and 3,4-dichlorophenylacetic acid in 69.8% yield as a clear brown viscous oil according to a procedure similar to that described in Example 1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.I[CH3:20].[Cl-].[NH4+]>CN(C)C=O.O1CCCC1>[CH3:20][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
Into 3 ml of tetrahydrofuran was suspended 0.06 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at 0° C. The mixture was stirred at room temperature for 10 minutes, 0.22 g of iodomethane and 1 ml of dimethylformamide were added, and the mixture was stirred at 40° C. for 3 hours. Thereafter, the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.26 g of 4-methyl-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (3)).
Reaction SMILES: [NH2:1][C:2](=[O:15])/[C:3](/[C:13]#[N:14])=[N:4]/[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:20]C1C=CC=CC=1>Cl>[ClH:20].[NH2:14][C:13]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:2]([NH2:1])=[O:15]
Reactant: Clc1ccccc1
Reactant: N#C/C(=N\Nc1ccccc1Br)C(N)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: NC(=O)c1nnc2c(Br)cccc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
(E)-2-Amino-N′-(2-bromophenyl)-2-oxoacetohydrazonoyl cyanide (50.1 g, 187.5 mmol), AlCl3 (100 g, 750 mmol), and chlorobenzene (419 mL, 412 mol) were stirred at 115° C. overnight under N2. The reaction mixture was subsequently cooled to RT and 2M HCl (820 mL) was slowly added. The reaction mixture was stirred at 100° C. for 1 hour and then cooled. The product was collected by vacuum filtration, rinsed with EtOH (200 mL) and Et2O (100 mL), and dried under high vacuum to give an HCl salt of the title compound as a yellow solid (31.25 g, 62.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (1H, s), 9.43 (1H, s), 8.61-8.59 (1H, d, J=8.4 Hz), 8.43 (1H, s), 8.32-8.30 (1H, d, J=7.6 Hz), 7.94 (1H, s), 7.69-7.65 (1H, m); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 2.659 minutes) ESI+APCI m/z [M+H]+ 267.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:32][O:33][NH2:34])[N:26]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>CN(C=O)C>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:32][O:33][NH:34][S:9]([CH3:8])(=[O:11])=[O:10])[N:26]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1c(CONS(C)(=O)=O)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 4.6 %

Procedure:
Triethylamine (0.634 mL, 4.55 mmol) and methanesulfonyl chloride (0.211 mL, 2.73 mmol) were added to a solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL). A solid formed immediately. The mixture was stirred for 3.5 hours at room temperature, then additional triethylamine (0.634 mL) and methanesulfonyl chloride (0.211 mL) were added. The reaction mixture was stirred for an additional 1.5 hours, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration to provide 40 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}methanesulfonamide. Additional crystals were isolated from the mother liquor after a seed crystal was added. The two crops were combined and dried in a vacuum oven to provide 160 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}methanesulfonamide as pale yellow crystals, mp 232-234° C.
Reaction SMILES: [ClH:1].Cl.[C@H]1(CN2CCC([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])CC2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.N[CH:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)[CH2:51][CH2:50]1>>[ClH:1].[ClH:1].[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][N:52]2[CH2:53][CH2:54][CH:49]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:50][CH2:51]2)[CH2:58][CH2:59]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (115, see example 66)) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [Li+].[Cl-].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[I:13]I>C1COCC1>[I:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: II
Reactant: c1ccc2cnccc2c1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Ic1nccc2ccccc12
Reaction time: 2 h
Yield: 96 %

Procedure:
A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with TMPMgCl LiCl (5 mL, 1.2 M in THF, 6.0 mmol). Isoquinoline (703 mg, 5.45 mmol) in THF (5 ml) was added dropwise at room temperature. During addition, the reaction mixture became red and the metalation was complete after 2 h (as checked by GC analysis of reaction aliquots quenched with a solution of I2 in THF, the conversion was more than 98%). A solution of I2 in THF (6 ml, 1 M in THF, 6.0 mmol) was slowly added at −20° C. The reaction mixture was quenched with sat. aqueous NH4Cl solution (10 mL). The aqueous phase was extracted with ether (4×10 mL), dried with Na2SO4 and concentrated in vacuo. The crude residue was purified by filter column chromatography (CH2Cl2/pentane) yielding 1-iodoisoquinoline (7a; 1.33 mg, 96%) as slightly yellow crystals (mp=74-76° C.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](N=O)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=[O:25])=CC=1.C(N(CC)CC)C.O>CC(N(C)C)=O>[C:1]([C:5]1[C:6](=[O:17])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9](=[O:25])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 117.6 %

Procedure:
270 g (1.15 mols) of 2,6-ditert.butyl-4-nitrosophenol are dissolved in 2.5 liters of dimethylacetamide. A solution of 256 g (1.35 mols) of p-toluenesulphonic acid chloride in 1.1 liters of dimethylacetamide is added dropwise at room temperature. 112 g (1.10 mols) of triethylamine are then added rapidly and the mixture is stirred for 2 hours at 80° C. After cooling, it is poured into 15 liters of water and the precipitated product is filtered off. After drying it is recrystallised from hexane. 298 g of 2,6-ditert.butyl-benzoquinone monoxime p-toluenesulphonate of melting point 110° C are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1S.COC1C=C(S)C=CC=1.COC1C=CC=CC=1[S:27][Cl:28].COC1C=C(SCl)C=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:27][Cl:28])=[CH:5][CH:4]=1
Reactant: COc1ccccc1SCl
Reactant: COc1ccccc1S
Agent: COc1cccc(S)c1
Agent: COc1cccc(SCl)c1
Product: COc1ccc(SCl)cc1

Procedure:
By the same procedure or by the procedure of Preparation 7, o-methoxythiophenol and m-methoxythiophenol are converted, respectively, to o-methoxybenzenesulfenyl chloride and m-methoxybenzenesulfenyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.6 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-Chloro-phenyl)-3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (60.1 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:32]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:32])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
To a solution of intermediate 49 (Example 99) (4.0 g, 19 mmol) in THF (30 mL) at 0° C. under the argon atmosphere was added PPh3 (6.3 g, 24 mmol) followed by CBr4 (8.0 g, 24 mmol). The mixture was stirred at the same temperature for 15 min and then stirred at room temperature for additional 15 h. Most of the solvent was removed and the residue purified by flash chromatography on silica gel (hexane) to afford the title compound (3.5 g, 66%) as a colorless oil.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Sn](CCCC)(CCCC)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)CCC>COCCOC.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>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cc2nc(-c3ccccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C
Yield: 106.4 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26; 50 mg, 0.08 mmol) in 1,2 dimethoxyethane (1 mL) was added 2-(tributylstannyl)pyridine (0.040 mL, 0.125 mmol) and Pd(PPh3)4 and the reaction mixture was degassed with argon for 5 minutes. The reaction was heated to 110° C. in a microwave reactor for 20 minutes. The crude reaction mixture was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a clear oil (45.2 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36ClN2O3: 531.23. found: 531.68.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:16])[CH3:15].CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:19]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15]
Reactant: CC(O)CCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)CCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The above alcohol (16.17 mmol) was oxidised using methods described in EP-A-164 187 (Swern oxidation, DMSO, oxalyl chloride, triethylamine) to give 8-(3',5'-bistrifluoromethylbenzyloxy)-octan-2-one. The ketone was reacted with triethyl-4-phosphonocrotonate/lithium diisopropylamide to give ethyl 11-(3',5'-bistrifluoromethyl)benzyloxy- 5-methylundeca-2,4-dienoate. The ester was converted into the amide as in Example 5.
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:9]3[N:31]=[C:12]([CH:13]=[C:14]4[NH:30][C:17](=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.Cl.[CH3:39][O:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(Cl)Cl>[CH3:39][O:40][C:41](=[O:51])[CH:42]([NH:43][C:2]1[C:3]2[NH:7][C:6]([C:8]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:9]3[N:31]=[C:12]([CH:13]=[C:14]4[NH:30][C:17](=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2)[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: Brc1c2nc(c(-c3ccccc3)c3ccc(cc4nc(c(-c5ccccc5)c5ccc1[nH]5)C=C4)[nH]3)C=C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)Nc1c2nc(c(-c3ccccc3)c3ccc(cc4nc(c(-c5ccccc5)c5ccc1[nH]5)C=C4)[nH]3)C=C2

Procedure:
The general procedure was used to couple 5-bromo-10,20-diphenylporphin (27.1 mg, 0.05 mmol) with (L)-phenylalanine methyl ester hydrochloride (43 mg, 0.2 mmol), using Pd (OAc)2 (1.12 mg, 0.005 mmol) and DPEphos (5.38 mg, 0.01 mmol) in the presence of Cs2CO3 (65.2 mg, 0.2 mmol). The reaction was conducted in THF at 100° C. for 24 h. The title compound was isolated by flash chromatography (silica gel, methylene chloride: hexanes (v/v)=8:2) as a purple-red solid (12 mg, 36%). 1H NMR (300 MHz, CDCl3) δ 9.79 (s, 1H), 9.14 (d, J=4.8 Hz, 1H), 9.09 (d, J=4.8 Hz, 1H), 8.84 (d, J=4.8 Hz, 1H), 9.28 (d, J=4.8 Hz, 1H), 9.01-9.06 (m, 3H), 8.98 (d, J=4.8 Hz, 1H), 8.67 (d, J=4.8 Hz, 2H), 8.18 (m,4H), 7.77 (m, 6H), 7.49 (dd, J=1.5, 8.4 Hz, 2H), 7.34-7.43 (m, 3H), 6.60 (d, bro., 1H), 5.52 (d, bro, 1H), 3.63 (t, J=6.9 Hz, 1H), 3.32 (s, 3H), 2.16 (s, 2H), −2.32 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ 174.2, 141.7, 136.8, 134.5, 131.8, 130.8, 129.8, 128.8, 128.5, 127.6, 127.2, 126.8, 126.1, 119.4, 102.2, 72.1, 51.7, 40.8. UV-vis (CH2Cl2, λmax, nm): 420, 521, 562, 660. HRMS-MALDI ([M+H]+): calcd for C42H34N5O2, 640.2707; found: 640.2714.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[C:9]([C:13]1[S:17][C:16]([CH:18]=[CH2:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[C:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:19][CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(C(C)(C)C)s1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(C(C)(C)C)s1
Yield: 60.3 %

Procedure:
Sodium hydride (6.05 g-50% suspension in oil, 0.126 mol) was washed with petroleum ether, suspended in dry DMSO (90 ml) and heated with stirring at 60°-70° C. for 2 hours. The reaction mixture was then cooled to 15° C. and methyltriphenylphosphonium bromide (44.5 g, 0.125 mmol) was added portionwise with rapid stirring over a 1/2 hour period. The reaction mixture was stirred at room temperature for a further 1 hour after the addition and 5-t-butyl-2-thiophenecarboxaldehyde (21.01 g, 0.125 mol) was added dropwise over a period of 1 hour. The resultant reaction mixture was stirred at room temperature for 12 hours, poured into water (300 ml) and extracted with ether (4×150 ml). The ethereal extracts were washed with water (4×100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by column chromatography (silica eluted with hexane) to give (5-t-butylthiophen-2-yl)-ethylene (5.25 g, 25%). Ethyl diazoacetate (4.69 g, 0.041 mol) in dry dichloromethane (80 ml) was added dropwise to a solution of (5-t-butylthiophen-2-yl)-ethylene (5.1 g, 0.031 mol) and anhydrous copper (II) sulphate (0.3 g) in dry dichloromethane (20 ml) at 90° C. by means of a syringe pump over a period of 5 hours. The dichloromethane was distilled over during the addition. After complete addition the remaining dichloromethane was removed in vacuo and the resulting brown oil purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 19:1) to give ethyl 2-(5-t-butylthiophen-2-yl)-cyclopropanecarboxylate (4.72 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:12]([CH3:36])([CH3:35])[C:13]([NH:15][C:16]1[O:20][N:19]=[C:18]([C:21]([CH3:34])([CH3:33])[CH2:22][O:23]CC2C=CC(OC)=CC=2)[CH:17]=1)=[O:14])(=[O:11])=[O:10]>ClCCCl.Cl.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:12]([CH3:36])([CH3:35])[C:13]([NH:15][C:16]1[O:20][N:19]=[C:18]([C:21]([CH3:34])([CH3:33])[CH2:22][OH:23])[CH:17]=1)=[O:14])(=[O:11])=[O:10]
Reactant: COc1ccc(COCC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)c3ccc(F)cc3F)on2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Product: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(F)cc2F)on1
Reaction time: 18 h
Yield: 109.1 %

Procedure:
To a solution of 21 mg (0.041 mmol) of 2-(2,4-Difluoro-benzenesulfonyl)-N-{3-[2-(4-methoxy-benzyloxy)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-methyl-propionamide in DCE (1 ml) and 4M HCl solution (0.5 mL), a few drops of water are added and the reaction mixture stirred over night for 18 h. The solvents are removed to yield 18 mg of 2-(2,4-difluoro-benzenesulfonyl)-N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-propionamide. Yield 100%, ES-MS: m/z 403 [M+H].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]2)O1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44](Cl)[N:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:20]2)[N:43]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Clc1nccc(OCc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(B4OC(C)(C)C(C)(C)O4)cc23)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(-c4nccc(OCc5ccccc5)n4)cc23)C1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a mixture of (S)-tert-butyl 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.), 4-(benzyloxy)-2-chloropyrimidine (2.0 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv) in a 20 ml microwave vial, DME and 2M Na2CO3 were added (1.0 M). The vial was submitted to 125° C. for 20 min in microwave. The resulting mixture was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed with NaCl(sat.), dried over Na2SO4, concentrated and purified by reverse-phase HPLC to yield (S)-tert-butyl 1-(6-(4-(benzyloxy)pyrimidin-2-yl)quinolin-4-yl)piperidin-3-ylcarbamate (88%). LC/MS=512.1 (M+H), LC=3.40 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:25]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([I:25])=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3cccc(OCc4ccccc4)c3n2)cc1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3c(OCc4ccccc4)cccn3c2I)cc1
Reaction time: 2.5 h

Procedure:
To a 0° C. solution of 8-(benzyloxy)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (0.25 g, 0.79 mmol) in N,N-dimethylformamide (8.0 mL) was added dropwise a solution of N-iodosuccinimide (0.17 g, 0.79 mmol) in N,N-dimethylformamide (4 mL). The reaction was stirred for 2.5 hours and concentrated to a volume of 2 mL The mixture was diluted with ethyl acetate, washed twice with 1M aqueous sodium hydroxide, and concentrated. The residue was purified by silica gel chromatography, eluting with 5% acetone in dichloromethane to yield 0.23 (67%) of 8-(benzyloxy)-2-(4-fluorophenyl)-3-iodoimidazo[1,2-a]pyridine. 1H NMR (CDCl3): δ 8.10 (dd, 2H), 7.90 (d, 1H), 7.53 (d, 2H), 7.40 (m, 3H), 7.19 (t, 2H), 6.81 (t, 1H), 6.61 (d, 1H), 5.46 (s, 2H); MS m/z 445 (M+1).