Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([OH:14])=O)=[CH:8][NH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C)C=O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:14])=[CH:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2nc(Cl)ccc2c1=O
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1c[nH]c2nc(Cl)ccc2c1=O

Procedure:
7-Chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, (1 g) and N,N'-carbonyldiimidazole (1.1g) in dimethylformamide (12 ml) were heated at 100° for 1 hour. 5-Amino-1H-tetrazole (0.95 g) was added and the mixture was heated at 100° for 1 hour and cooled. The solid was filtered off and stirred with aqueous hydrochloric acid (10 ml, 2N) and the solid was collected and dried, m.p. above 350°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][OH:34]>>[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:34][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1
Reactant: OCc1cccc(F)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2cccc(F)c2)n1
Yield: 57 %

Procedure:
As described for Example 157, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 3-fluorobenzyl alcohol instead of 3-chlorobenzyl alcohol, was converted to the title compound (70 mg, 57%) which was obtained as a light yellow solid. MS: m/e=485.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:24]2[NH:25][C:4](=[CH:5][C:6]3[NH:10][C:9]([CH:11]=[C:12]4[N:16]=[C:15]([CH:17]=[C:18]5[N:22]=[C:21]([CH:23]=2)[C:20]([CH3:26])=[C:19]5[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:14]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:13]4[CH3:39])=[C:8]([CH:40]=[CH2:41])[C:7]=3[CH3:42])[C:3]=1[CH:43]=[CH2:44]>ClCCl.[Pd]>[CH3:41][CH2:40][C:8]1[C:9]2[NH:10][C:6](=[CH:5][C:4]3[NH:25][C:24]([CH:23]=[C:21]4[N:22]=[C:18]([CH:17]=[C:15]5[N:16]=[C:12]([CH:11]=2)[C:13]([CH3:39])=[C:14]5[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:19]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:20]4[CH3:26])=[C:2]([CH3:1])[C:3]=3[CH2:43][CH3:44])[C:7]=1[CH3:42]
Reactant: C=Cc1c(C)c2cc3[nH]c(cc4nc(cc5nc(cc1[nH]2)C(C)=C5CCC(=O)OC)C(CCC(=O)OC)=C4C)c(C)c3C=C
Agent: [Pd]
Solvent: ClCCl
Product: CCc1c(C)c2cc3[nH]c(cc4nc(cc5nc(cc1[nH]2)C(C)=C5CCC(=O)OC)C(CCC(=O)OC)=C4C)c(C)c3CC

Procedure:
In some aspects, a method of synthesizing a metal mesoporphyrin compound comprises forming a protoporphyrin methyl ester from hemin and converting the protoporphyrin methyl ester intermediate to a metal mesoporphyrin compound through metal insertion and hydrogenation. In some embodiments, metal insertion yields a metal protoporphyrin dimethyl ester intermediate. In further embodiments, the metal protoporphyrin dimethyl ester is hydrogenated in dichloromethane over palladium catalyst to form a metal mesoporphyrin dimethyl ester. In embodiments, the metal mesoporphyrin dimethyl ester is heated in dilute ammonium hydroxide to form the metal mesoporphyrin compound. In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like. In some embodiments, tin is the inserted metal. In embodiments, tin is inserted into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].Cl[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23]>CC(C)=O>[CH3:25][O:24][C:22](=[O:23])[CH:21]([O:9][C:8]1[CH:10]=[CH:11][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)[CH3:26]
Reactant: COC(=O)C(C)Cl
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(NC(C)=O)cc1
Yield: 27257.9 %

Procedure:
To a mixture of Paracetamol (150 grams, 992 mmol), anhydrous K2CO3 (540 Kg, 3.91 mol) and sodium iodide (18 g, 120 mmol) in anhydrous acetone (3 liters) was added methyl 2-chloropropionate (180 g, 1.469 mmol) and refluxed for 80 hours. Acetone was distilled off and water (3 liter) was added. Crude 16 was extracted into chloroform, dried over Na2SO4, distilled in hexane (750 ml), filtered and recrystallised in methanol to give pure 16 (95 g, 40.4%) as a white powder. The melting point was found to be 96.5-98.2° C. The product was tested by HPLC and found to be 99%+pure. The structure was confirmed with NMR.
Reaction SMILES: [OH-].[Li+].[CH3:3][C@H:4]1[C:12]2[C:11]([C:13]3[S:17][C:16]([C:18]([O-:20])=[O:19])=[CH:15][CH:14]=3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([O:21]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:5]1>C1COCC1.O>[OH:21][C@H:6]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:13]3[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=3)[C:12]=2[C@H:4]([CH3:3])[CH2:5]1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(-c3ccc(C(=O)[O-])s3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)O)s3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide (6 mg, 0.146 mmol) was added to a solution of 5-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylate (32 mg, 0.073 mmol) in THF (0.5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS of the reaction mixture showed no more starting material. THF was removed under reduced pressure, and 1N HCl (5 mL) was added. The reaction mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylic acid. The crude mixture was used directly in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][O:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].ClC1C=CC=C(C(O[O-])=[O:31])C=1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH2:11][CH2:12][O:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[O:31])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O[O-])c1cccc(Cl)c1
Reactant: O=C(OCCSc1ccc([N+](=O)[O-])cn1)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCCS(=O)c1ccc([N+](=O)[O-])cn1)c1cccc(Cl)c1

Procedure:
A solution of 2-(5-nitro-2-pyridinylthio)ethyl-3-chlorobenzoate, (5) [20 mg, 0.059 mmol; prepared according to the method outlined in Scheme 2; 1H NMR (CDCl3): δ 9.22 (d, J=1.8 Hz, 1H), 8.24 (dd, J=2.4 and 9.0 Hz, 1H), 7.95-7.91 (m, 1H), 7.90 (t, J=0.9 Hz, 1H), 7.56-7.51 (m, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 4.61 (t, J=6.6 Hz, 2H), 3.68 (t, J=6.6 Hz, 2H)] and m-chloroperbenzoate (m-CPBA) 50%, 21 mg, 0.060 mmol) was stirred at room temperature for 1.25 h. The reaction mixture was then diluted with dichloromethane and washed with saturated aqueous solution of NaHCO3 and then dried over anhydrous MgSO4. The crude product was purified by silica gel chromatography to give 2-[(5-nitro-2-pyridinyl)sulfinyl]ethyl-3-chlorobenzoate (6). LCMS: purity: 99%; MS (m/e): 355 (MH+).
Reaction SMILES: OC1C=CC(CNC(=O)C2C=CC(NC3C4N(C=CN=4)C(C4C=NNC=4)=CN=3)=CC=2)=CC=1.[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37](Br)=[N:36][CH:35]=1.[CH3:44][N:45]([CH2:47][C:48]1[N:49]=[N:50][N:51]([C:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=2)[CH:52]=1)[CH3:46].CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37]([NH:59][C:56]2[CH:55]=[CH:54][C:53]([N:51]3[CH:52]=[C:48]([CH2:47][N:45]([CH3:46])[CH3:44])[N:49]=[N:50]3)=[CH:58][CH:57]=2)=[N:36][CH:35]=1
Reactant: CN(C)Cc1cn(-c2ccc(N)cc2)nn1
Reactant: Brc1ncc(Br)n2ccnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CN(C)Cc1cn(-c2ccc(Nc3ncc(Br)n4ccnc34)cc2)nn1
Yield: 36.1 %

Procedure:
In the same way as described for Compound 90, step 1, using 5,8-dibromoimidazo[1,2-a]pyrazine (116.9 mg, 0.422 mmol), 4-(4-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenylamine (91.7 g, 0.422 mmol), NaOtBu (56.8 mg, 0.591 mmol), Pd2(dba)3 (15.5 mg, 0.0169 mmol), Xantphos (19.5 mg, 0.0337 mmol) and toluene (5 mL). The crude product is purified by Isolute FlashSilicaII cartridge chromatography eluting with 99:1 DCM/NH3 (7M in MeOH), followed by 97:3 DCM:NH3 (7M in MeOH). The title compound (63 mg, 36%) is isolated after a second column chromatography purification eluting with 97:3 DCM:NH3 (7M in MeOH).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:21])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].Cl.[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([O:21][C:10]1[C:11]2[O:12][C@H:13]3[C:14](=[O:15])[CH2:16][CH2:17][C@@H:18]4[C@@:5]53[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]4[CH2:20][C:7]([C:6]=25)=[CH:8][CH:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC[C@]23c4c5ccc(OCc6ccccc6)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.1 %

Procedure:
To Hydromorphone HCl (50.0 g, 155.3 mmol) in dimethylformamide (500 mL) was added sodium hydride (14.30 g, 357.4 mmol) portionwise with cooling. The addition was conducted over 25 minutes. The reaction was stirred at room temperature for 1.5 hours before the addition of benzyl chloride (17.88 mL, 357.4 mmol) over 10 minutes with cooling. The reaction was allowed to warm to room temperature and stirred for 40 hours. The reaction was incomplete so additional benzyl chloride (1.79 mL, 15.5 mmol) was added. After 4 hours, the reaction was quenched with water (60 mL), acidified with aqueous HCl (2M, 800 mL) and washed with ethyl acetate/diethyl ether (3:1) (2×800 mL). The aqueous phase was basified with aqueous NaOH (2M, 800 mL) and extracted with ethyl acetate (2×1 L). The organic phases were combined, washed with water/brine (1:1) (2×800 mL) and dried over MgSO4 before concentration under reduced pressure. The residue was taken up in ethyl acetate and washed with water/brine (2×500 mL), dried over MgSO4 before concentration under reduced pressure to give (4R,4aR,7aR,12bS)-9-(benzyloxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (47.9 g, 95% pure by NMR, 82% yield); [M+H]+ 376.2. This was taken onto the next step without purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[C:13](C(O)=O)=[N:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10])([OH:3])=[O:2]>SCC(O)=O>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2]
Reactant: O=C(O)c1cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)ccc1Cl
Agent: O=C(O)CS
Product: O=C(O)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Temperature: 175 °C
Yield: 71.9 %

Procedure:
A suspension of 2-(3-carboxy-4-chloro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (3.4 g) in mercaptoacetic acid (2 ml) was stirred at 175° C. After 20 h the resulting solution was cooled to room temperature during which time a precipitate formed. The mixture was dumped into ice-water, stirred for 30 minutes and filtered to give a yellow solid. The solid was dried under vacuum for 24 hours to give 2.1 g of the title intermediate. Mass spectrum [M−1] 3:1 ratio of 266.1 and 268.1; 1H nmr (500 MHz, CD3OD) δ 7.58 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.72 (dd, J=2.6 and 8.8 Hz), 8.09 (d, J=2.6 Hz).
Reaction SMILES: I[C:2]1[C:7]([C:8]([NH:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([O:18][CH3:19])[N:5]=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:19][O:18][C:6]1[C:7]2[C:8](=[O:9])[NH:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:2]=2[CH:3]=[CH:4][N:5]=1
Reactant: COc1nccc(I)c1C(=O)NNc1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1nccc2c1c(=O)[nH]n2-c1ccccc1
Yield: 63.6 %

Procedure:
A solution of 4-iodo-2-methoxy-N′-phenylnicotinohydrazide (640 mg), L-proline (39.9 mg), potassium carbonate (479 mg) and copper(I) iodide (33.0 mg) in DMSO (25 mL) was stirred overnight at 60° C. under nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (266 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:15])=[O:12])[CH:8]=[C:7]([Cl:26])[C:3]=1[C:4](O)=[O:5].Cl.[CH3:28][O:29][C:30](=[O:42])[C@H:31]([CH2:33][NH:34][C:35]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)=[O:36])[NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:15])=[O:12])[CH:8]=[C:7]([Cl:26])[C:3]=1[C:4]([NH:32][C@H:31]([C:30]([O:29][CH3:28])=[O:42])[CH2:33][NH:34][C:35]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)=[O:36])=[O:5]
Reactant: C[C@@H](NC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1)c1cccc2ccccc12
Reactant: COC(=O)[C@@H](N)CNC(=O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Yield: 16.7 %

Procedure:
A solution of 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid (Example 38; 1.00 g, 2.6 mmol), 3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester hydrochloride (Example 301; 680 mg, 2.6 mmol), HBTU (1.27 g, 3.35 mmol), HOBT (450 mg, 3.3 mmol), and diisopropylethylamine (1.33 g, 10.3 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature over the weekend. The solvent was evaporated and ethyl acetate (200 mL) was added. The solution was washed with 1 M HCl (100 mL), saturated aqueous sodium hydrogen carbonate (Note: some material was lost due to effervescence at this stage) and brine (200 mL each), then dried (MgSO4), filtered, evaporated and chromatographed (70% ethyl acetate/hexanes) to give N-[2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (260 mg, 17%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:18]=[C:17]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:16]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C(O)C>[CH2:34]([O:33][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:18]=1)[CH2:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[C:8]([CH3:38])[CH:9]=1)[CH:35]([CH3:36])[CH3:37]
Reactant: CCOC(=O)COc1ccc(SCc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester (130 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 230 mg (%). HPLC-MS: m/z: 539.5 (M+H)+; Rt: 2.49 min.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([C:23]3[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(-c2ccc(Cl)nn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)nn2)cc1
Yield: 55.6 %

Procedure:
To a solution containing 3-chloro-6-(4-trifluoromethoxyphenyl)-pyridazine (157 mg, 0.57 mmol), 4-aminophenylboronic acid (118 mg, 0.86 mmol) and 2 M K2CO3 (0.57 mL, 1.14 mmol) dissolved in 3.5 mL of dry 1,4-dioxane was added dichlorobis(triphenylphosphine)palladium(II) (4 mg, 0.006 mmol). The mixture was irradiated using a CEM Discover microwave at 190° C. for 30 min. The mixture was diluted with 100 mL of ether and washed with brine (30 mL). The organic phase was then dried over MgSO4, filtered and concentrated. The residue was purified via radial chromatography using a 97:3 CHCl3/CH3OH solution as the eluent (Rf=0.26) to afford the title compound (105 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.6 Hz, 2H), 8.01 (d, J=8.6 Hz, 2H), 7.30-7.45 (m, 4H), 6.82 (d, J=8.6 Hz, 2H), 3.96 (bs, 2H); EIMS 331 (M+).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].CN(C)C=O.[N-:26]=[N+:27]=[N-:28].[Na+]>C1(C)C=CC=CC=1>[N:26]([C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20])=[N+:27]=[N-:28]
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCN1CC(C)=C(N=[N+]=[N-])C2=C1N1CN(OC)C=C1C=N2
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1.5 g of intermediate A1 are stirred into 10 ml N,N-dimethylformamide. 1 g NaN3 is added at room temperature. The mixture is heated up to 60° C. and stirred for 5 hours. 100 ml toluol are added. The organic layer is separated and washed with 3×30 ml water. 90 ml of the solvent are removed. The reaction product precipitates. The crude product is purified by crystallisation from toluol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[CH:14]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][O:49][C:50](=[O:68])[CH2:51][C:52]1[C:53]([CH3:67])=[N:54][N:55]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][C:60]=2[F:66])[C:56]=1[CH3:57]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:48][O:49][C:50](=[O:68])[CH2:51][C:52]1[C:53]([CH3:67])=[N:54][N:55]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:14][C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:61][C:60]=2[F:66])[C:56]=1[CH3:57]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2F)c1C
Reactant: Cc1c(C(=O)O)oc2ccc(F)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(C)nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2F)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.7 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran-2-carboxylic acid (194 mg, 1 mmol) in 5 mL dimethylformamide is added diisopropylethylamine (0.516 mL, 3 mmol) and HATU (399 mg, 1.05 mmol) is added. After stirring at room temperature for 25 minutes dimethylformamide (1 mL) and then intermediate [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (291 mg, 1 mmol) is added. Subsequently diisopropylethylamine (0.344 mL, 2 mmol) and dimethylformamide (2 mL) is added, and the mixture is stirred at room temperature for 48 hours. Then ethyl acetate and water are added and the precipitate is filtered off. The organic layer is extracted twice with acetic acid (1 N), once with an aqueous solution of NaHCO3 (5% by weight) and twice with water, dried over MgSO4. The solvent is removed by evaporation in vacuo. The residue is purified by MPLC (dichloromethane/methanol 96:4) to yield 120 mg of (1-(2-fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=468; TLC: Rf=0.72 (dichloromethane/methanol 9:1, silicagel 60 F254)). b) To a solution of (1-(2-fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)-amino]-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (119 mg, 0.26 mmol) in dioxane/water (7 mL/7 mL) is added an aqueous solution of NaOH (1 M, 2.3 mL) and the mixture is stirred at room temperature for 12 hours and at 60° C. for 2 hours. The mixture is diluted with water, acidified with hydrochloric acid (1 M, 1 mL) and extracted with ethyl acetate. The organic layer is dried over MgSO4, the solvent evaporated in vacuo, the residue is crystallized with diisopropyl ether and the precipitate is isolated by filtration to yield 69 mg of the title compound (ESI mass spectrum: [M+H]+=454; Retention time HPLC: 0.90 min (method D)).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([S:15]([NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.COC(=O)[C@@H](C(C)C)N.COC(=O)[C@@H](C)N>O1CCOCC1.C(Cl)Cl>[N:12]1([S:15]([NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: COC(=O)[C@@H](C)N
Agent: COC(=O)[C@H](N)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Hydrogen chloride gas was bubbled through a solution of methyl 2-(R)-[(4-tert-butoxycarbonylpiperazine-1-sulfonyl)amino]propionate (3.6 g, 10.7 mmol) [prepared by proceeding as described in Example 2, but substituting 4-(5-chloropyridin-2-yloxy)piperidine and D-valine methyl ester with 1-tert-butoxycarbonyl-1,4-piperazine and D-alanine methyl ester, respectively] in 10% dioxane/methylene chloride (100 ml) for 10 min. The reaction was stirred at RT for 4 h and concentrated in vacuo to give methyl 2-(R)-[(piperazine-1-sulfonyl)amino]propionate (91%) as a white solid that was used without further purification.