Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25]([C:28](=O)[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1>>[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25](/[C:28](=[N:6]/[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])/[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: CS(=O)(=O)NN
Product: C/C(=N\NS(C)(=O)=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 60 %

Procedure:
The title compound was prepared from methanesulfonohydrazide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 60% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.63 (s, 1H), 8.85 (dd, 1H), 8.30 (d, 1H), 8.09 (d, 1H), 7.94 (d, 1H), 7.75 (m, 3H), 7.47 (q, 1H), 4.58 (s, 2H), 3.10 (s, 3H), 2.26 (s, 3H). LCMS (method A): [MH]+=413, tR=4.57 min.
Reaction SMILES: O[N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1.N.[H][H]>C(O)C.[Ni].O>[NH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)Cc1ccc(CC2CCCC2=NO)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(CC2CCCC2N)cc1
Yield: 98.2 %

Procedure:
In an autoclave, a solution of 75.1 g (0.27 mole) of ethyl 4-[(2-hydroxyiminocyclopentyl)methyl]benzeneacetate in 800 ml of anhydrous ethanol saturated with NH3 is combined with about 37.5 g of Raney Nickel in water. The mixture is stirred under 80 atmospheres of hydrogen, at 80° C. during 4 hours. After cooling, the catalyst is filtered and rinsed with ethanol. The concentrated filtrate under reduced pressure, gives 69.3 g (yield=98.3%) of an orange oil which crystallizes but which is used without any other purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]([CH3:40])[C:37]([NH2:39])=[O:38].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>O1CCOCC1.C(Cl)Cl>[CH3:35][N:36]([CH3:40])[C:37](=[O:38])[NH:39][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccnc(Br)c1
Reactant: CN(C)C(N)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cc(CNc2ccccc2C(=O)Nc2cc3ccccc3cn2)ccn1
Yield: 23.7 %

Procedure:
100 mg (0.23 mmol) of 2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide is heated in 2 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 61 mg (0.69 mmol) of N,N-dimethylurea, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a cover gas and in a moisture-free environment for 9 hours to a bath temperature of 100° C. It is then mixed with 20 ml of methylene chloride, suctioned off and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate as an eluant. 24 mg (24% of theory) of 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-yl-methyl]-amino}-N-(3-isoquinolinyl)-benzamide is obtained. (MS (CI): 441 (M++H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][NH2:27]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:27][CH3:26])=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: CN
Reactant: Cc1nccc(-c2ccc(Cl)cc2F)c1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2F)ccnc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)-2-methylnicotinic acid (180 mg, 0.678 mmol) in DCM (5 mL) and DMF (0.2 mL) at 0° C., was added oxalyl chloride (0.178 mL, 2.033 mmol). The reaction mixture was stirred for 3 h at RT then diluted with DCM (5 mL) and treated with a solution of methylamine hydrochloride (457 mg, 6.78 mmol) in DCM (5 mL) cooled to 0° C. The mixture was stirred for another 1 h at RT. The solution was extracted with DCM (20 mL), washed with saturated NaHCO3 (2×10 mL) and water (20 mL); dried over Na2SO4 and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N,2-dimethylnicotinamide (50 mg, 0.179 mmol, 27% yield) as a brown gum. LC/MS, (ESI) m/z 279.2 [(M+H)+, calcd for C14H13ClFN2O 279.1]; LC/MS retention time (method D): tR=0.62 min.
Reaction SMILES: CN1CCOCC1.[OH:8][C@H:9]1[C@@H:21]2[C@@H:17]([C@@H:18]([O:23][CH3:24])[O:19][C@H:20]2[CH3:22])[CH2:16][C@@H:15]2[C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2>C(Cl)Cl>[CH3:24][O:23][C@@H:18]1[C@H:17]2[CH2:16][C@@H:15]3[C@@H:10]([C:9](=[O:8])[C@H:21]2[C@H:20]([CH3:22])[O:19]1)[CH2:11][CH2:12][CH2:13][CH2:14]3
Reactant: CO[C@H]1O[C@@H](C)[C@@H]2[C@H](O)[C@H]3CCCC[C@@H]3C[C@H]12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CO[C@H]1O[C@@H](C)[C@@H]2C(=O)[C@H]3CCCC[C@@H]3C[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
Also, the synthesis was possible separately through following process. Namely, 0.77 g(1.50 equivalents) of N-methylmorpholine and 2.50 g of molecular sieve 4A(MS4A) were added to 1.05 g(4.37 mmol) of (1S,3S,3aS,4R,4aS,8aR,9aS)-4-hydroxy-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan in 10 ml of methylene chloride solution, then 76.8 mg(0.05 equivalents) of tetrapropylammonium perruthenate(TPAP) were added, and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was filtered through celite and the residue was washed with ether(100 ml). The filtrate was washed with 10% aqueous solution of Na2S2O3 and then with brine (each 20 ml×1). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off to obtain 0.99 g of (1S,3S,3aR,4aS,8aR,9aS)-1-methoxy-3-methyl-4-oxo-dodecahydronaphtho[2,3-c]furan (yield 95%).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11](OC)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[K+]>C1COCC1>[C:2]1([CH:1]([OH:8])[CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCC(O)c1ccccc1
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
Methyl 3-benzoylpropionate (50 g, 0.25 mol) in 300 ml of anhydrous THF was added under nitrogen dropwise over one hour to a suspension of LAH in 500 ml of anhydrous THF. After the addition the mixture was refluxed for 20 hours. After cooling to room temperature 14.3 ml of water was added dropwise followed by the addition of 14.3 ml of 15% KOH and then 42.9 ml of water. The mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure to remove the THF. The residue was partitioned between methylene chloride and 1 N HCl. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give 4-phenyl-4-hydroxybutanol (37.90 g, 91%) as a white solid, mp 63-68° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>>[C:7]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)(=[O:9])[CH3:8]
Reactant: C1CSCCN1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCSCC1

Procedure:
The product of Example 30 was followed using thiomorpholine and acetic anhydride giving the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[C:22]([CH:28]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([O:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[C:22]([CH:28]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:8]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)c1cc(N)ccc1OCCN(CC)CC
Product: CCOC(=O)c1cc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN(CC)CC

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and ethyl 5-amino-2-(2-diethylamino-ethoxy)-benzoate. The reaction mixture was evaporated down i. vac. and the residue was dissolved in dichloromethane. The org. phase was washed with water, dried over sodium sulphate and evaporated down i. vac. Purification by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether/EtOAc 70:30→50:50) yielded the product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([CH2:16][CH:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH:14]=3)[N:9](COCC[Si](C)(C)C)[CH:8]=2)=[CH:4][NH:3]1.Cl>CCO>[CH3:1][N:2]1[CH2:6][C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([CH2:16][CH:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH:14]=3)[NH:9][CH:8]=2)=[CH:4][NH:3]1
Reactant: CN1CC(c2cn(COCC[Si](C)(C)C)c3ncc(CC4CCC(=O)CC4)cc23)=CN1
Agent: Cl
Solvent: CCO
Product: CN1CC(c2c[nH]c3ncc(CC4CCC(=O)CC4)cc23)=CN1
Temperature: 90 °C
Yield: 61.9 %

Procedure:
To a solution of 88 (19 mg, 42 μmol) in EtOH (1 mL) was added 10% aq. HCl (1 mL) and the reaction mixture heated to reflux (bath temperature 90° C.) for 18 h. The solution was then concentrated and the residue purified by preparative LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 91 (8 mg, 26 μmol, 62%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 1.49-1.63 (m, 2H), 2.04-2.19 (m, 3H), 2.31-2.50 (m, 4H), 2.92 (d, J=6.9 Hz, 2H), 4.06 (s, 3H), 7.67 (s, 1H), 7.68 (s, 1H), 7.85 (s, 1H), 8.24 (s, 1H), 8.38 (s, 1H), 12.35 (br s, 1H). MS (CI) m/z 309 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:9][C:10]1[CH:15]=[C:14]([C:2]2[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Nc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1ccnc(-c2cccc(Cl)c2)c1
Temperature: 120 °C
Yield: 47.1 %

Procedure:
2-Chloropyridin-4-amine (200 mg, 1.556 mmol), 3-chlorophenylboronic acid (243 mg, 1.556 mmol) and Pd(PPh3)4 (450 mg, 0.389 mmol) were combined in dioxane (4 mL) and saturated K2CO3 solution (2 mL). The mixture was heated at 120° C. for 30 minutes in a microwave. The solvent was removed to give a residue which was purified by silica column chromatography eluting with a gradient of 0-5% methanol in dichloromethane to give the title compound as light yellow oil (150 mg, 47.1% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:66]/[O:67]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:12]([NH:14][C@@H:15]2[C:64](=[O:65])[N:17]3[C:18]([C:48]([O:50]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:49])=[C:19]([S:22][CH2:23][C:24]4[CH:25]=[N:26][N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:28]=4)[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:66]/[OH:67])/[C:12]([NH:14][C@@H:15]2[C:64](=[O:65])[N:17]3[C:18]([C:48]([OH:50])=[O:49])=[C:19]([S:22][CH2:23][C:24]4[CH:25]=[N:26][NH:27][CH:28]=4)[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)CS[C@H]23)cs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Reaction time: 1 h

Procedure:
Under nitrogen atomosphere, a solution of aluminium chloride (2.65 g) in anisole (5.7 ml) was added dropwise to a solution of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(1-tritylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (3.32 g) in a mixture of anisole (5.7 ml) and nitromethane (22.5 ml) at −24° C. After stirring for 1 hour at the same temperature, the reaction was quenched with 1N hydrochloric acid (22.5 ml). The mixture was poured into a mixture of water and ethyl acetone. The aqueous layer was separated and the organic layer was reextracted with water. The combined aqueous layer was concentrated in vacuo, chromatographed on a HP-20 column (eluent: water-methanol). After the concentration, the resulting precipitate was collected by filtration to afford 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:25](=O)[CH3:26])[C:11]([O:13][C@@H:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12].[NH2:28][C:29]([CH2:35][F:36])=[CH:30][C:31]([O:33][CH3:34])=[O:32]>C(O)(C)(C)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][C@@H:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])=[C:25]([CH3:26])[NH:28][C:29]([CH2:35][F:36])=[C:30]1[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)C=C(N)CF
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)O[C@@H](c1ccccc1)C(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)O[C@@H](c2ccccc2)C(Cl)(Cl)Cl)C1c1cccc(Cl)c1Cl

Procedure:
(S)-2,2,2-Trichloro-1-phenylethyl 2-(2,3-dichlorophenylmethylene)-3-oxobutanoate (10.8 g, 23 mmoles) and methyl 3-amino-4-fluoro-2-butenoate (3.7 g, 28 mmoles) were heated at 55° in dry tert-butanol (50 ml) for 68 hours. The solvent was removed and the residue purified and separated into single diastereomers by HPLC eluting with methylene chloride/petroleum ether (60°-80° ) mixtures.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[O:12]CCO2)=[CH:4][C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)O.[SH:29][CH2:30][C:31]([OH:33])=[O:32]>Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[S:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Cl)c1
Reactant: O=C(O)CS
Agent: Cl
Product: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1C(SCC(=O)O)c1cccc(Cl)c1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
A mixture of intermediate (9) (0.088 mol) and mercapto-acetic acid (0.0836 mol) in HCl 6N (500 ml) was stirred and refluxed for 1 hour, then cooled and poured out into ice water. The precipitate was filtered off, washed with water and taken up in DCM. The organic solution was dried (MgSO4), filtered and the solvent was evaporated till dryness. The product was used without further purification, yielding 35.5 g (90.5%) of [[[2-amino-5-(4-chlorobenzoyl)phenyl](3-chlorophenyl)methyl]thio]-acetic acid (intermediate 19).
Reaction SMILES: Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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.O.CCOCC>[F:33][C:34]1[CH:39]=[C:38]([C:2]2[C:3]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[C:4]3[CH:10]=[N:9][N:8]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[C:5]3=[N:6][CH:7]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4cccc(F)c4)cnc32)cc1
Yield: 80.9 %

Procedure:
A solution of tert-butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.30 g, 0.597 mmol, see Example 1), 3-fluorophenylboronic acid (0.125 g, 0.896 mmol), Pd(PPh3)4 (0.0690 g, 0.0597 mmol) and Cs2CO3 (0.778 g, 2.39 mmol) in dioxane:H2O (8 mL, 3:1) was heated at 80° C. for 6 hours. Ether (50 mL) and H2O (20 mL) were then added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of solvent, the resulting residue was purified by column chromatography (DCM:ethyl acetate, 5:1) to give tert-butyl 4-(5-(3-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.25 g, 81%) as a solid. MS ESI (+) m/z 518.4 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.31 (s, 1H), 8.16 (s, 1H), 7.51 (m, 1H), 7.39 (m, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.18 (m,l H), 6.86 (d, J=8.8 Hz, 2H), 5.53 (s, 2H), 3.70 (s, 3H), 3.29 (m, 4H), 3.25 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][NH2:25])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][NH:25][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-yl}oxy)ethanamine (0.40 g, 0.90 mmol) was dissolved in dichloromethane (8 mL) and propane-1-sulfonyl chloride (0.169 g, 1.18 mmol) and N,N-dimethylpyridin-4-amine (0.152 g, 1.24 mmol) were added. The reaction mixture was stirred at room temperature over night. Water was added and the aqueous phase was extracted several time with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane:methanol=99:1). Yield: 0.35 g (0.68 mmol, 76%, colorless oil).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]3([C:44]#[N:45])[CH2:43][CH2:42]3)[CH:39]=2)O1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][N:38]([CH2:40][C:41]5([C:44]#[N:45])[CH2:43][CH2:42]5)[CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CC3(C#N)CC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3cnn(CC4(C#N)CC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}cyclopropanecarbonitrile (7.2 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol) and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling, it was diluted with methanol. The solid was filtered off. The filtrate was purified with RP-HPLC (pH=10) to afford 5.3 mg of the desired product. LCMS (M+H)+: m/z=484.2.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:31]([OH:33])=[O:32])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[CH3:34]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CO>[CH3:34][O:32][C:31](=[O:33])[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[NH:18][C:1]([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Product: COC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 102.8 %

Procedure:
Commercially available Nα-Fmoc-Nδ-Boc-L-ornithine (1.00 g), WSCI hydrochloride (0.633 g), and HOBt (0.446 g) were reacted in methanol (20 ml) for 23 hours at room temperature. After the reaction, methanol was removed and the residue was extracted with chloroform. The extract was washed with water, saturated aqueous solution of sodium hydrogencarbonate, and saturated brine, and dried over anhydrous sodium sulfate to remove water. Syrup obtained by removing the solvent was purified by silica gel column chromatography (50 g, chloroform/ethyl acetate=5/1) to obtain the title compound (1.06 g) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]=[O:15])[CH:13]=1)[N:10]([CH2:16][CH2:17][CH3:18])[CH2:9][CH2:8][C:7]2([CH3:20])[CH3:19])([CH3:3])[CH3:2].[CH3:21][Mg]Br>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]([OH:15])[CH3:21])[CH:13]=1)[N:10]([CH2:16][CH2:17][CH3:18])[CH2:9][CH2:8][C:7]2([CH3:20])[CH3:19])([CH3:2])[CH3:3]
Reactant: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C=O)c21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)O)c21

Procedure:
Following General Procedure C, 6-isopropyl-4,4-dimethyl-1-n-propyl-1,2,3,4-tetrahydro-quinoline-8-carbaldehyde (Intermediate 8, 4.54 g, 19.2 mmol) and a solution of methyl magnesium bromide (3M, 16 ml, 47.9 mmol) in THF were reacted to give the title compound as a light yellow oil after purification by column chromatography using 5% ethyl acetate in hexane.