Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29](O)=[O:30])=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br.[S:34]1[C:38]2[CH2:39][CH:40]([NH2:43])[CH2:41][CH2:42][C:37]=2[N:36]=[C:35]1[NH2:44]>>[NH2:44][C:35]1[S:34][C:38]2[CH2:39][CH:40]([NH:43][C:29]([C@@H:25]3[CH2:26][CH2:27][CH2:28][N:24]3[C:22](=[O:23])[CH2:21][NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:30])[CH2:41][CH2:42][C:37]=2[N:36]=1
Reactant: Nc1nc2c(s1)CC(N)CC2
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Product: Nc1nc2c(s1)CC(NC(=O)[C@@H]1CCCN1C(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Yield: 36 %

Procedure:
The title compound was prepared from (2S)-1-[2-(Tritylamino)acetyl]-2-pyrrolidinecarboxylic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide according to the procedure described in EXAMPLE 25, and was obtained as a faint yellow crystalline solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][N:6]=1)[CH3:4].CS(O[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:17][CH:24]([CH3:23])[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=3)=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][N:6]=1)[CH3:4]
Reactant: COC(=O)Cc1ccc(CCCCOS(C)(=O)=O)cc1
Reactant: CCCc1c(O)ccc2c(CC)noc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OC(C)CCc2ccc(CC(=O)OC)cc2)ccc2c(CC)noc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
A suspension of sodium hydride (15 mg, 0.36 mmole) in DMF (1.5 mL) was treated with 3-ethyl-6-hydroxy-7-propylbenz-[4,5]-isoxazole (68 mg, 0.33 mmole) and the mixture stirred at room temperature for 10 minutes under a nitrogen atmosphere. A solution of methyl 4-(4-methansulfonyloxybutyl)phenylacetate (100 mg, 0.33 mmole) in DMF (0.5 mL) was added and the mixture stirred at 80° C. for 5 hours. The cooled reaction mix was dissolved in ethyl acetate and washed with water (twice), brine, dried over magnesium sulfate and concentrated in vacuo to an oil. The crude product was purified by thin layer chromatography on silica gel eluting with hexane:ethyl acetate (4:1) to give the title compound (80 mg) as an oil. NMR (CDCl3): δ 0.97 (t, 3H); 1.44 (t, 3H); 1.71 (m, 2H); 1.87 (m, 4H); 2.71 (t, 2H); 2.88 (t, 2H); 2.97 (q, 2H); 3.62 (s, 2H); 3.71 (s, 3H); 6.89 (d, 1H); 7.18 (d, 2H); 7.22 (d, 2H); 7.39 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH:12]2[CH2:18][C:19](Cl)=[O:20]>>[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH:12]2[CH2:18][C:19]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)CC1CC2CCC1C2
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(CC1CC2CCC1C2)Nc1ccc(C(=O)O)cc1

Procedure:
4-[Bicyclo-(2,2,1)hept-2-yl-acetamido]-benzoic acid was prepared as described in Example 3 from 9.63 g (0.07 mol) of p-aminobenzoic acid and 13.2 g (0.077 mol) of bicyclo(2,2,1)hept-2-yl-acetyl chloride.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C([O-])(O)=O.[Na+:20]>O1CCOCC1>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+:20]
Reactant: CCOC(=O)CCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C([O-])CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-chlorobutyrate (0.5 g, 3.32 mmol) in DMF (2 mL), piperidine (0.98 mL, 9.96 mmol), triethylamine (1.4 mL, 9.96 mmol) and a catalytic amount of KI were added and the resulting solution was refluxed overnight. After cooling at room temperature the solution was diluted with a saturated solution of NaHCO3 (10 mL) and extracts with Et2O (3×10 mL). The collected organic extracts were dried over Na2SO4, filtered and evaporated under vacuum to give the ethyl 4-piperidin-1-ylbutanoate as an oily residue (0.6 g, 3 mmol) pure enough for the next step. To a solution of the ester in dioxane (5 mL), few drops of 37% HCl were added and the solution was refluxed overnight. After cooling at room temperature the solvent was evaporated under vacuum and the residue was dried overnight in oven at 60° C. in vacuo. The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) and NaHCO3 (0.5 g, 6 mmol) was added. After stirring for 2 h, the precipitate was filtered off and the mother liquors concentrated to afford the intermediate sodium 4-piperidin-1-ylbutanoate (0.55 g, 2.84 mmol) as a colourless oil. 1H-NMR (DMSO-d6) δ 3.35 (m, 2H), 2.80 (m, 2H), 2.70 (m, 2H), 2.15 (t, 2H, J=3 Hz), 1.95 (m, 2H), 1.75 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[CH:8][C:7]=1[O:22][CH3:23])([CH3:5])[CH3:4].[OH-].[Na+]>C1COCC1>[OH:1][CH2:2][C:3]([C:6]1[CH:21]=[CH:20][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[O:22][CH3:23])([CH3:4])[CH3:5]
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1C(C)(C)CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1C(C)(C)CO
Reaction time: 3 h

Procedure:
To the crude benzyl 4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzoate (from step 3) was added THF (2 mL) followed by aqueous NaOH (1.7 mL of 3.0 M, 5.0 mmol). The reaction mixture was stirred for 3 h. The reaction mixture was acidified to pH 3 and was extracted with EtOAc 3 times. The organic layers were dried over sodium sulfate and the solvent was evaporated to give 4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzoic acid. ESI-MS m/z calc. 224.1, found 224.2 (M+1)+; Retention time: 2.46 minutes (4 min run).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3N(C)C(C)=NC=3)O)[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.[CH3:39][C:40]1[C:45]([C:46]([C:48]2[N:52]([CH3:53])[N:51]=[N:50][CH:49]=2)=[O:47])=[CH:44][CH:43]=[C:42]([CH3:54])[N:41]=1>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:46]([C:45]3[C:40]([CH3:39])=[N:41][C:42]([CH3:54])=[CH:43][CH:44]=3)([C:48]3[N:52]([CH3:53])[N:51]=[N:50][CH:49]=3)[OH:47])[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.68 mL, 1.7 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (0.404 g, 0.936 mmol, Intermediate 45: step d) in dry THF (17 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (0.346 g, 1.601 mmol, Intermediate 19: step b) in dry THF (8 mL) was added dropwise. The reaction was stirred for 10 minutes, then was moved into an ice bath and allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-4% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=1.7 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.76 (dd, J=8.1, 1.6 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.40 (dd, J=8.8, 2.2 Hz, 1H), 6.96-6.90 (m, 2H), 6.83 (s, 1H), 5.01 (s, 1H), 4.33 (s, 2H), 4.09 (s, 3H), 3.91 (s, 3H), 2.51 (s, 3H), 2.32 (s, 3H); MS m/e 569.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:33]=[C:34]([SH:39])[CH:35]=[C:36]([Cl:38])[CH:37]=1>CN(C)C=O>[Cl:31][C:32]1[CH:33]=[C:34]([S:39][C:2]2[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[N:5]=[C:4]([CH3:16])[C:3]=2[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:35]=[C:36]([Cl:38])[CH:37]=1
Reactant: COc1ccc(Cn2nc(C)c(C(=O)c3ccccc3)c2Cl)cc1
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c(C(=O)c3ccccc3)c2Sc2cc(Cl)cc(Cl)c2)cc1
Temperature: 100 °C
Yield: 58.1 %

Procedure:
A solution containing 170 mg of [5-chloro-1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone in 10 ml of N,N-dimethylformamide was treated with 83 mg of potassium carbonate and 107 mg of 3,5-dichlorothiophenol. The mixture was heated at 100° C. for 4 h. The mixture was treated with a further 83 mg of potassium carbonate and 107 mg of 3,5-dichlorothiophenol. The mixture was then heated at 50° C. for 64 h. The mixture was treated with a further 83 mg of potassium carbonate and 107 mg of 3,5-dichlorothiophenol. The mixture was then heated at 100° C. for 2 h. The solvent was removed under reduced pressure and residue partitioned between dichloromethane/water, washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified via flash chromatography on silica gel using diethyl ether/petroleum ether (1:4 to 1:3) to give 140 mg of [5-(3,5-dichlorophenylthio)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone as a colourless oil. Mass spectrum (ES) m/z 483[M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[C:14]2[C:10]=1[CH2:11][CH:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](OCC)=[O:32])[CH2:13]2.Cl>C(OCC)C>[CH3:23][O:22][C:15]1[C:16]([O:20][CH3:21])=[C:17]([O:18][CH3:19])[C:9]([O:8][CH3:7])=[C:10]2[C:14]=1[CH2:13][CH:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH2:11]2
Reactant: CCOC(=O)CCCCCCCC1Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Lithium aluminium hydride (41.8 mg, 1.10 mmols) was added to a diethyl ether (3.0 ml) solution of ethyl 8-(4,5,6,7-tetramethoxyindan-2-yl)octanoate (150 mg, 367 mmols), with cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 4:1) to obtain the entitled compound (138 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:17][NH2:18].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[N:18][CH3:17])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN=Cc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
In 30 ml of toluene, 0.8 g (5.7×10−3 moles) of 6-chloropyridine-3-aldehyde and 10 g of Na2SO4 were mixed and while the mixtures was stirred, a 40% aqueous solution of methylamine (1.4 g, 1.1×10−2 mole) was added dropwise over 30 minutes, followed by addition of 10 g of MgSO4. The mixture was allowed to stand at room temperature overnight, after which it was filtered. The filtrate was concentrated to give 0.6 g (yield 68%) of N-(6-chloro-3-pyridylmethylidene)methylamine as crystals.
Reaction SMILES: [CH:1]1([CH2:7][N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:28])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1>[CH:1]1([CH2:7][N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:28])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCCCCN(CC1CCCCC1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCN(CC1CCCCC1)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(cyclohexylmethyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxy-propanoate (0.031 g, 0.057 mmol) in THF (2.0 mL) were added water (2.0 mL) and lithium hydroxide (0.006 g, 0.26 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was acidified with 2M HCI and extracted with ethyl acetate (4×25 mL). The combined organic phase was washed with brine (25 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.027 g (93%) of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]([I:15])=[C:12](I)[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].S([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C(O)C.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][CH:12]=[C:11]([I:15])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2nc(I)c(I)[nH]2)cc1Cl
Agent: O=S([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2nc(I)c[nH]2)cc1Cl
Yield: 84.1 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-4,5-diiodo-lH-imidazole (0.93 g, 2.0 mmol) and sodium sulfite (1.01 g, 8.0 mmol) in ethanol (33 ml) and water (8 ml) was refluxed for 24 h. After addition of EtOAc (200 ml) and brine (20 ml) the organic layer was separated, then dried with Na2SO4, evaporated and chromatographed over SiO2 with EtOAc-hexane (6:1) to obtain 2-(3,4-dichloro-phenyl)-4-iodo-1H-imidazole (0.57 g, 84%) as a solid mass. Mp. 206-207° C. (EtOAc/hexane), MS: m/e=338 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([N:28]2[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]2)[N:10]=1.Br[CH2:36][C:37]([NH2:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([N:28]2[CH2:33][CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[C@H:30]([CH3:34])[CH2:29]2)[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:13]([CH3:15])[N:14]=1
Reactant: NC(=O)CBr
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1N1CCN[C@H](C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1N1CCN(CC(N)=O)[C@H](C)C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methyl-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine (32 mg, 0.07 mmol), 2-bromoacetamide (29 mg, 0.21 mmol), sodium carbonate (44 mg) and DMA (1 mL) is heated at 60° C. under nitrogen with magnetic stirring for 18 h. The reaction mixture is allowed to cool and partitioned between EtOAc (8 mL) and water (2 mL). The organic layer is separated, washed with water (2 mL), brine (2 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a colorless oil. Purification by chromatography on silica gel (2% MeOH/DCM/0.1% Ammonium hydroxide) provides the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.06-7.26 (m, 5H), 6.81-6.83 (m, 2H), 5.58 (br d, J=6.3 Hz, 1H), 4.97 (dd, 2H), 3.77-3.86 (m, 2H), 3.25-3.33 (m, 2H), 2.80-3.00 (m, 4H), 2.45-2.62 (m, 5H), 2.22 (s, 3H), 2.16 (s, 6H), 1.27 (d, J=6.8 Hz, 6H), 0.93 (d, J=6.6 Hz, 3H).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Br:14])[CH:8]=1)(=O)=O.[C-:15]#[N:16].[Na+]>CN(C=O)C>[Br:14][C:9]1[CH:8]=[C:7]([CH2:6][C:15]#[N:16])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CS(=O)(=O)OCc1ccc(F)c(Br)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a stirred solution of 3-bromo-4-fluorobenzyl methanesulfonate (60 g, 0.212 mol) in DMF (300 mL) at 0° C. was added NaCN (31.1 g, 0.635 mol, 3 eq) portionwise. After stirring at room temperature 4 h, the reaction mixture was partitioned in EtOAc and water. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=4:1) to give 2-(3-bromo-4-fluorophenyl)acetonitrile (30 g, 3 step overall yield: 55%). 1H NMR (400 MHz, CDCl3) δ 7.56-7.54 (m, 1H), 7.28-7.24 (m, 1H), 7.14 (t, J=4.4 Hz, 1H), 3.73 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]4[CH2:32][CH2:31]4)[OH:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.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]>[CH:30]1([C@H:28]([OH:29])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]5([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]5)=[CH:3][CH:4]=4)[N:9]=3)[CH3:13])=[O:16])[NH:18]2)=[O:34])=[O:33])[CH2:32][CH2:31]1
Reactant: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)COCCOC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCCOC4)cc3n2)N1
Temperature: 50 °C

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (244 mg, 0.459 mmol), 6-vinyl-[1,4]dioxepane-6-carboxylic acid 57d (79 mg, 0.459 mmol), triethylamine (140 mg, 192 μL, 1.38 mmol) and tri(o-tolyl)phosphine (28 mg, 0.092 mmol) in 1,4-dioxane (9 mL) was degassed with nitrogen for 5 min and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.046 mmol) was added and the mixture was heated to 80° C. for 45 min and then allowed to cool. The suspension was filtered and evaporated to give crude title compound which was used in the next stage without further purification. LCMS (m/z) 624.2 [M+H], Tr=1.58 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]=[CH:12][CH:13]=[CH2:14])[CH3:2].[CH2:16]([O:18][C:19]([N:21]=[N:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]1[CH:12]=[CH:13][CH2:14][N:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]1[C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH3:2]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: C=CC=Cc1ncccc1C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1C1C=CCN(C(=O)OCC)N1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9.8 g of 2-(1,3-butadienyl)nicotinic acid ethyl ester and 9.2 g of diethyl-azodicarboxylate are mixed with 30 ml of toluene and heated to 80° under nitrogen. After 1 hr a further 3 g of diethyl-azodicarboxlate are added and after 3 hrs a further 5 g. After a further 4 hrs the reaction mixture is allowed to cool to RT and stirred overnight. The solvent is removed by evaporation under vacuum and the resulting oil chromatographed on silica gel and eluted with ethylacetate/hexane to give the title compound as black oil.
Reaction SMILES: [CH2:1]([C@H:6]([N:10]([CH2:15][C:16]([O-:18])=[O:17])[CH2:11][C:12]([O-:14])=[O:13])[C:7]([O-:9])=[O:8])[CH2:2]C([O-])=O.[Na+].[Na+].[Na+].[Na+].[OH2:23]>>[C:12]([OH:14])(=[O:13])[CH2:11][N:10]([CH2:15][C:16]([OH:18])=[O:17])[C@H:6]([C:7]([OH:9])=[O:8])[C@@H:1]([CH3:2])[OH:23]
Reactant: O
Reactant: O=C([O-])CC[C@@H](C(=O)[O-])N(CC(=O)[O-])CC(=O)[O-]
Agent: [Na+]
Product: C[C@@H](O)[C@@H](C(=O)O)N(CC(=O)O)CC(=O)O
Yield: 85 %

Procedure:
The solution obtained in example 1 was acidified using an ion exchange resin. Acidification took place using Amberlite IR-120, a strong acid ion exchange resin: 55 g of GLDA solution, 110 g of Amberlite IR-120 as such, and ca 100 g of water were stirred in a 500 ml round-bottomed flask for at least 48 h. After filtering off the resin the solution was dried by evaporation of water at reduced pressure at 70° C. The light-coloured crispy foam obtained was further dried in a vacuum oven at 65° C. This resulted in a solid product in a yield of circa 85%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:20]([O-])=O)=[CH:4][C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C)C=O>[NH2:20][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cccc(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(Cl)c(N)cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 5-chloro-2-(2-fluoro-6-methoxybenzyloxy)-4-nitrophenol (5 g) and potassium carbonate (3.16 g) in N,N-dimethylformamide (15 mL) was added ethyl bromoacetate (2.2 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (75 mL). To the solution were added methanol (75 mL) and nickel(II) bromide (0.17 g). To the mixture was added sodium borohydride (1.73 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−2/1) to give the title compound (4.11 g).