Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])([CH3:5])[CH3:4])#[N:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([CH:37]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[CH:27]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]4[CH2:36][CH2:35]4)=[O:33])[N:30]=3)[CH:27]=2)[CH:37]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
3-(1-Cyano-1-methylethyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (2.0 mL) was added N-[6-(5-amino-2-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (75 mg, 0.233 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with ethyl acetate and diisopropyl ether to give the title compound (40.8 mg, 35%) as a colorless powder.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[N:6]([CH2:18][CH3:19])[C:7]2[C:12]([C:13]=1[C:14]#[N:15])=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[CH:8]=2.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:18]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[CH:8]=2)[C:13]([C:14]#[N:15])=[C:5]1[CH2:4][O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]
Reactant: Oc1ccccc1
Reactant: CCn1c(CBr)c(C#N)c2ccc(OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(COc2ccccc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of NaH (44 mg, 4 eq.) in DMF (0.5 mL) is added 2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (80 mg, 0.274 mmol) and phenol (2 eq.). After stirring for 20 h, the mixture is poured into ice water and extracted with CH2Cl2. The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile, compound 99.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3CC[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[CH:5]=1)([O-])=O.[C:17](O)(=O)[CH3:18]>CO.[Pd]>[CH:12]12[CH2:11][CH2:10][CH:9]([CH2:8][NH:7][CH2:6]1)[C:18]1[C:13]2=[CH:14][C:4]([NH2:1])=[CH:5][CH:17]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCCC2CC1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C1CCC2CNC1
Reaction time: 3 h
Yield: 89 %

Procedure:
4-Nitro-1-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene (250 mg, 1.15 mmol) was placed in methanol (10 mL) and acetic acid (0.2 mL). 10% Palladium on carbon (6.8 mg) was then added. The reaction was hydrogenated at 50 psi for 3 hours. The mixture was then filtered through celite and concentrated under reduced pressure. The residue was taken up in toluene (20 mL) and concentrated under reduced pressure to obtain 10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamine as a light brown oil (193 mg, 89%). LCMS (m/e) 189 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.89 (d, 1H, J=7.8 Hz), 6.53 (dd, 1H, J=2.4 and 7.8 Hz), 6.48 (d, 1H, J=2.3 Hz), 3.20-2.80 (m, 8H), 2.02 (d, 2H, J=8.7 Hz), 1.82 (d, 2H, J=10.7 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[C:11]([O:15][C:16](=[O:26])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:16](=[O:26])[O:15][C:11]([CH3:13])([CH3:14])[CH3:12])=[CH:20][CH:21]=1)=[O:10]
Reactant: Cc1ccccc1N=C=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
2-Methylphenylisocyanate (7.57 g, 59.83 mmol) was added dropwise at 0° C. to a solution of (4-amino-benzyl)-carbamic acid tert-butyl ester (13.30 g, 59.83 mmol, prepared analoguous to: Moloney, Gerard P.; Martin, Graeme R.; Mathews, Neil; Mine, Aynsley; Hobbs, Heather; et al. J. Med Chem. 1999, 42, 2504–2526) in 120 mL DCM. The reaction was heated under reflux for 16 h, cooled to r.t. and the precipitated product was collected by filtration and dried in vacuum (19.20 g, 54.00 mmol). M.p. 200–202° C.; TLC (PE/EtOAc 1/1) Rf 0.65; 1H NMR (400 MHz, D6-DMSO) δ 1.39 (s, 9H); 2.24 (s, 3H); 4.06 (d, J=6 Hz, 2H); 6.93 (mc, 1H); 7.12–7.17 (m, 4); 7.32 (mc, 1H); 7.40 (mc, 2H); 7.85 (mc, 1H); 7.90 (s, 1H); 8.98 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].C(O)(=O)C.O=[C:38]([CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1CCc2cc(OC)c(OC)cc21
Yield: 33.3 %

Procedure:
L-Alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester (4.0 g) is dissolved in 80 ml of ethanol, and 0.77 g of sodium acetate, 4.0 g of acetic acid, 4.0 g of ethyl 2-oxo-4-phenyl-butyrate, 12 g of molecular sieve 3A and 6.0 g of Raney nickel are added. Thereafter, the reaction and treatment are carried out as in Example 2 to give 2.0 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester as slightly yellow oil.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[CH:12][S:13][C:14]=1[CH3:15].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[CH:12][S:13][C:14]=1[CH2:15][Br:16]
Reactant: Cc1scnc1-c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2ncsc2CBr)c(Cl)c1

Procedure:
The product was neutralised and the free thiazole was treated with N-bromosuccinimide in refluxing carbon tetrachloride for 16 hours with irradiation by a lamp to give 4-(2',4'-dichlorophenyl)-5-bromomethyl thiazole The crude product was dissolved in dry acetonitrile, sodium triazole (0.91 g; 0.01 mole) was added and the mixture stirred for 16 hours at 20° C. to give, after chromatography using silica gel/chloroform: 2% ethanol, the title compound (0.71 g; 23%). m.p. 120°-123° C.
Reaction SMILES: S([O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(C1C=CC(C)=CC=1)(=O)=O.C1(O)C=CC=CC=1.[OH:32][C@@H:33]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46](O)[CH:45]=1)[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].C([O-])(C)(C)C.[K+]>CN(C=O)C>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][C@H:33]([C:44]1[CH:49]=[C:48]([CH:47]=[CH:46][CH:45]=1)[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[OH:32])=[O:43])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1

Procedure:
A mixture of (S)-tert-butyl 2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.6 g, 5.4 mmol), phenol (7, Intermediate I) (0.8 g, 2.9 mmol), t-BuO−K+ (0.5 g, 4.5 mmol) in anhydrous DMF (5 mL) was heated at +45° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, partitioned between EtOAc and 5% NaOH, organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure. Purification by column chromatography gave (S)-tert-butyl 2-((3-((R)-3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pyrrolidine-1-carboxylate as a light yellow oil. Yield (0.8 g, 59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:24])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CN(C)S(=O)(=O)c1ccc(Br)s1)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
To a solution of 5-bromothiophene-2-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 71) (210 mg) in N,N-dimethylformamide (2 mL) was added 60% sodium hydride (32 mg). After stirring for 45 minutes, methyl iodide (100 μL) was added. Water was added, the solution was extracted with ethyl acetate. After washing the organic layer with saturated sodium chloride water, and then was dried with anhydrous sodium sulfate, the residue that was obtained upon removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (110 mg) was obtained as a colorless oily matter.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[N:12]=[C:13]([CH3:27])[C:14]2[CH:20]=[C:19](Br)[C:18](=[O:22])[N:17]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:15]=2[N:16]=1.[Si:28]([C:32]#[CH:33])([CH3:31])([CH3:30])[CH3:29]>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.[Cu](I)I.O1CCOCC1>[NH2:10][C:11]1[N:12]=[C:13]([CH3:27])[C:14]2[CH:20]=[C:19]([C:33]#[C:32][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18](=[O:22])[N:17]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:15]=2[N:16]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc2c1cc(C#C[Si](C)(C)C)c(=O)n2C1CCC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A flask was charged with Pd(PPh3)2Cl2 (84.2 mg, 0.120 mmol) and copper iodide (34.3 mg, 0.180 mmol). To this were added 1,4-dioxane (12 mL) and diisopropylethylamine (0.84 mL, 4.8 mmol) via syringe. 2-Amino-6-bromo-8-cyclobutyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (371 mg, 1.20 mmol) was introduced, and the resulting yellow solution was carefully sparged with nitrogen for 10 min. TMS-acetylene (0.50 mL, 3.6 mmol) was then added via syringe, and the resulting black solution was stirred at 70° C. for 1 h. Solvent was removed under reduced pressure. The crude solid was purified by flash chromatography on silica gel eluting with CHCl3 then 3% MeOH in CHCl3 to afford the title product (322 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[N:4][CH:3]=1.[CH2:14](B(O)O)[CH2:15][CH3:16]>>[CH3:13][C:5]1[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:7][C:2]([CH2:14][CH2:15][CH3:16])=[CH:3][N:4]=1
Reactant: CCCB(O)O
Reactant: CCOC(=O)c1nc(Cl)cnc1C
Product: CCCc1cnc(C)c(C(=O)OCC)n1

Procedure:
The preparation was performed in a similar manner as Reference Example 1.13 (d) from ethyl 6-chloro-3-methylpyrazine-2-carboxylate (Reference Example 1.13 (c)) (1.50 g, 7.48 mmol) and n-propylboronic acid (1.32 g, 15.0 mmol) to give ethyl 3-methyl-6-propylpyrazine-2-carboxylate. MS (APCI): m/z 209 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[C:18]([CH:19]=[O:20])=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[N:22]=3)[CH:16]=[CH:15][N:14]=1)[CH:8]=[CH:7]2.C(Cl)Cl.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[C:18]([CH2:19][OH:20])=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[N:22]=3)[CH:16]=[CH:15][N:14]=1)[CH:8]=[CH:7]2
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ccc6cc(C(C)(C)C#N)cc(F)c6c5=O)c4C=O)nn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ccc6cc(C(C)(C)C#N)cc(F)c6c5=O)c4CO)nn(C)c3=O)cc2C1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
In a 25 mL round-bottomed flask, 2-(8-fluoro-2-{3-formyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl -propionitrile (800 mg, 1.35 mmol, 1.0 equiv.) was combined with dry DCM (25 ml) and dry methanol (5 mL) to give a light yellow solution. The reaction mixture was cooled to 0° C. and sodium borohydride (91.8 mg, 2.43 mmol, Eq: 1.8) was added. The reaction mixture was stirred at 0° C. for 40 min. and then was quenched with 2 mL saturated NH4Cl with stirring for 5 min. The reaction mixture was poured into 100 mL H2O and extracted with DCM (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude foam was taken up in 20 mL DCM and 15 mL methanol. To this mixture was added 200 mg of 10% Pd/C (Degussa brand). The reaction mixture was stirred at room temperature for 2 h. The solid was removed by filtration and washed several times with 10% methanol in DCM. The combined filtrate and washes were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 4% MeOH holding gradient as each peak came off). Center cut fractions were concentrated to give a glass, which was triturated with ether to afford 2-(8-fluoro-2-{3-hydroxymethyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-proprionitrile as an off-white solid. (M+H)+=596 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6 H) 2.52 (s, 3 H) 2.94 (t, J=5.67 Hz, 2 H) 3.65 (d, J=2.27 Hz, 2 H) 3.90 (s, 3 H) 4.05-4.22 (m, 3 H) 4.42-4.60 (m, 2 H) 5.85 (s, 1 H) 6.66 (dd, J=7.55, 1.89 Hz, 1 H) 7.22 (dd, J=12.46, 1.89 Hz, 1 H) 7.35 (d, J=7.55 Hz, 1 H) 7.53 (d, J=1.89 Hz, 1 H) 7.62 (d, J=4.91 Hz, 1 H) 7.92 (s, 1 H) 7.99 (s, 1 H) 8.68 (d, J=4.91 Hz, 1 H).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[C:18]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:16][C:15]=2[F:26])=[N:11][C:10]=1[C:27]([OH:29])=O)=O)(C)(C)C.[NH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][CH2:40][C@H:39]([NH:43]C(=O)OC(C)(C)C)[CH2:38]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[C:18]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:16][C:15]=2[F:26])=[N:11][C:10]=1[C:27]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][CH2:40][C@@H:39]([NH2:43])[CH2:38]1)=[O:29]
Reactant: CC(C)NC(=O)c1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Product: CC(C)NC(=O)c1ccc(F)c(-c2nc(C(=O)Nc3cnccc3N3CCC[C@@H](N)C3)c(N)s2)c1
Yield: 8 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(2-fluoro-5-(isopropylcarbamoyl)phenyl)thiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (5 mg, 8%). 1H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 8.61 (dd, J=7.4, 2.2 Hz, 1H), 8.46 (d, J=7.6 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J=5.3 Hz, 1H), 7.98-7.86 (m, 1H), 7.69 (s, 2H), 7.48 (dd, J=11.3, 8.7 Hz, 1H), 7.14 (d, J=5.3 Hz, 1H), 4.13 (td, J=13.5, 6.8 Hz, 1H), 3.20 (d, J=8.8 Hz, 9H), 3.01 (d, J=12.1 Hz, 2H), 2.70 (d, J=18.9 Hz, 1H), 1.89 (d, J=9.6 Hz, 1H), 1.78 (d, J=22.6 Hz, 2H), 1.40-1.23 (m, 1H), 1.19 (d, J=6.6 Hz, 6H). ESIMS m/z=498.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: COc1ccc(CC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)Cc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[C:3]=1[CH3:11]
Reactant: Cc1c(I)cccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(I)c1C
Reaction time: 40 h

Procedure:
A mixture of 3-iodo-2-methyl-benzoic acid (90 mmol, 23.6 g), methanol (250 mL), and concentrated sulfuric acid (13 mL) was refluxed with stirring for 40 h before it was concentrated in vacuo. The residue was dissolved in ethyl acetate and the mixture was neutralized by adding small portions of a saturated aqueous NaHCO3 solution with stirring. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellowish oil (24.3 g); 1H NMR (CDCl3, 200 MHz): δ=7.96 (d, 1H), 7.71 (d, 1H), 6.91 (t, 1H), 3.89 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:10]=[CH:9]2.[C:20]1([O:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(Cl)Cl.O>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([C:23]1[CH:24]=[CH:25][C:20]([O:26][CH3:27])=[CH:21][CH:22]=1)(=[O:18])=[O:17])[CH:10]=[CH:9]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)c2ccc3cc(Br)ccc3c2)cc1
Temperature: 4 °C
Yield: 23.1 %

Procedure:
Aluminium chloride (3.33 g) was added portionwise over 30 minutes to a stirred mixture of 6-bromonaphth-2-ylsulphonyl chloride (6.11 g) and anisole (3.33 g) in dry methylene chloride (35 ml). The resultant mixture was stirred for 24 hours. Methylene chloride (75 ml) was added. the mixture cooled to 4° C. and water (100 ml) added cautiously. The mixture was acidified with 2M hydrochloric acid, separated and the aqueous phase extracted with methylene chloride (30 ml). The combined organic phases were washed with water, dried (MgSO4) and evaporated. Recrystallisation of the residue from an ethyl acetate/ethanol mixture gave 4-(6-bromonaphth-2-ylsulphonyl)anisole (1.74 g), m.p. 180-181° C.;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][C:13]([C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:22]=[CH:21][CH:20]=1)([OH:18])[CH2:14]2>C(Cl)Cl>[NH2:28][CH2:27][CH2:26][NH:25][C:23]1[N:24]=[C:19]([C:13]2([OH:18])[CH2:14][CH:15]3[N:10]([CH:9]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:42])[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[Cl:2])[CH:11]([CH2:17][CH2:16]3)[CH2:12]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCCNc1cccc(C2(O)CC3CCC(C2)N3C(c2ccccc2Cl)c2ccccc2Cl)n1
Agent: Cl
Solvent: ClCCl
Product: NCCNc1cccc(C2(O)CC3CCC(C2)N3C(c2ccccc2Cl)c2ccccc2Cl)n1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Add HCl (1N in ether, 0.36 ml) to a solution of the product from Step 2 (11 mg, 0.018 mmol) in CH2Cl2 at RT for 24 h. Add HCl (1N in ether, 0.36 ml) and stir at RT for 24 h. Add another 0.36 ml of HCl (1N in ether ) and stir at 30° C. for 24 h. Concentrate, treat with ether and filter to give the title compound as white solid. ESI-MS 497.1 (100, M+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(CC)CC>CS(C)=O>[NH2:24][C:18]1[C:17]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[N:22][C:21]([Br:23])=[CH:20][N:19]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CNc2nc(Br)cnc2N)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (4.97 g, 22.40 mmol) was dissolved in DMSO (80 ml), and then 3,5-dibromopyrazine-2-amine (8.5 g, 33.60 mmol) and Et3N (6.3 ml) were added, followed by stirring at 130° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give tert-butyl 3-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)piperidine-1-carboxylate (2.19 g, two steps: 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)ccc1C(=O)OC
Yield: 84.7 %

Procedure:
To a solution of methyl 4-chloro-2-hydroxybenzoate (21 g, 112.55 mmol) in acetone (200 mL) was added ethyl 2-bromoacetate (28.3 g, 169.46 mmol) and potassium carbonate (23.4 g, 169.31 mmol). After refluxing for 3 h, the solids were collected by filtration. The resulting mixture was concentrated under vacuum, dissolved in petroleum ether (300 mL) and filtered to give methyl 4-chloro-2-(2-ethoxy-2-oxoethoxy)benzoate as a red solid (26 g, 85%).