Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C(C([Sn])=[C:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31]CCC)CCC.BrC1C=C(C2NN=C(NC(C3CC4C(=CC=CC=4)C3)=O)C=2)C=CC=1.C([Sn](CCCC)(CCCC)C1C=CC=CC=1)CCC>>[C:7]1([C:31]2[CH:30]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][CH:4]=[C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[CH:9]=2)[CH:6]=1
Reactant: O=C(Nc1cc(-c2ccc(Br)cc2)[nH]n1)C1Cc2ccccc2C1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: O=C(Nc1cc(-c2cccc(Br)c2)[nH]n1)C1Cc2ccccc2C1
Product: O=C(Nc1cc(-c2cccc(-c3ccccc3)c2)[nH]n1)C1Cc2ccccc2C1

Procedure:
The title compound was prepared in the same manner as that described in Example 33 except that 5-(4-bromophenyl)-3-(2-indanyl)carbonylaminopyrazole and tributylvinyltin used in Example 33 were replaced with 5-(3-bromophenyl)-3-(2-indanyl)carbonylaminopyrazole and tributylphenyltin, respectively.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][NH:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[C:22]([Cl:27])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1B(O)O>>[CH3:18][CH:16]([CH3:17])[CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:29])=[O:28])=[CH:9][CH:10]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][C:35]=2[Cl:37])=[C:22]([Cl:27])[CH:21]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(Br)c(Cl)c2)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC(C)CC(Oc1ccc(-c2ccc(Cl)cc2Cl)c(Cl)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 24 starting from 3-{4-[1-(4-bromo-3-chloro-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 2,4-dichlorophenyl boronic acid. The isomers are resolved by methods described herein or known to one skilled in the art. Isomer 1 MS: 533.2 [M−H]−; Isomer 2 MS: 533.2 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:16]1([CH2:21][C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)O)[CH:20]=[CH:19][N:18]=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CO.C(Cl)Cl>[N+:13]([C:3]1[C:2]([O:1][C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:12])([O-:15])=[O:14]
Reactant: O=C1CCCc2c1ccc(O)c2[N+](=O)[O-]
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
To a solution of 6-hydroxy-5-nitro-1-tetralone (2.09 g, 10.1 mmol) in dry THF (50 mL) was added (R)-2-imidazol-1-yl-1-phenyl-ethanol (2.28 g, 12.1 mmol) followed by triphenylphosphine (3.18 g, 12.1 mmol). After approximately 10 min, diethylazodicarboxylate (1.9 mL, 12.1 mmol) was added slowly. The reaction became homogenous within 2 min. The reaction was allowed to stir at RT overnight. The reaction mixture was concentrated under reduced pressure and the residue was triturated with Et2O to remove some of the phospine by-products. The residue was dissolved in EtOAc and washed with H2O, saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated to give a foam/oil. Purification by chromatography (SiO2, 10 to 20% acetone/Cl2Cl2 then 5% MeOH/CH2Cl2) afforded the title compound as a light brown foam (3.06 g, 8.1 mmol, 80%). The structure was confirmed by NMR and mass spectrometry. MS m/z 378 (M++H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].O.Cl[CH2:20][C:21]([NH2:23])=[O:22]>CC(C)=O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a stirred solution containing 5 g (0.022 mole) of 3,5-ditrifluoromethylphenol, 1.6 g (0.024 mole) of 85% potassium hydroxide, 10 ml of water and 200 ml of acetone, 0.024 mole of chloroacetamide was added in one portion. The stirred reaction mixture was heated at 56°-60° C. for 22 hours. After cooling to 0° C., 600 g of ice water was added and stirring continued at 0°-10° C. for 30 minutes. The resulting solid was collected by filtration, washed with water until neutral to litmus and air dried at 25°-30° C. A product with a melting point of 139°-141° C. (determined after recrystallization from 6:1 mixture of heptane and isopropyl alcohol) was obtained with a 32% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)([OH:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1>>[NH2:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[N:3]=[C:4]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][C:15]([C:19]5[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=5)([OH:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:35][N:34]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: OC1(c2ccc(Cl)cc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(O)(c5ccc(Cl)cc5)CC4)cc3n2)cn1
Yield: 46.7 %

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-(4-chloro-phenyl)-piperidin-4-ol (146 mg, 0.30 mmol) was reacted with 2-amino-pyrimidine-5-boronic acid pinacol ester (94 mg, 0.45 mmol) in General Procedure A. After extraction into 2M HCl, the mixture was washed with EtOAc then made basic and the precipitate collected by filtration. Purification on silica gave 421 as a pale yellow solid (75 mg, 0.14 mmol). NMR (CD3OD, 400 MHz), 9.19 (s, 2H); 7.52 (m, 2H); 7.39 (s, 1H), 7.35 (m, 2H); 4.08 (t, 4H, J=4.1 Hz); 3.97 (s, 2H); 3.89 (t, 4H, J=4.8 Hz); 2.87 (d, 2H); 2.70 (t, 2H, J=11.2 Hz); 2.18 (m, 2H); 1.77 (d, 2H, J=13.2 Hz)_MS: (ESI+): MH+=538.27
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[C@@H:24]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[ClH:26].[C@H:15]1([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[C@@H:24]2[N:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The ester 62 (3.8 g, 10.8 mmol) is dissolved in 15 ml of dioxane and after addition of 70 ml of a 4M solution of HCl in do of HCl in dioxan the mixture is stirred for 4 hours at RT. The product is filtered off and is used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7](=[NH:11])OCC.[NH3:17]>C(O)C>[ClH:2].[Cl:2][C:3]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([NH2:11])=[NH:17]
Reactant: CCOC(=N)COc1cccc(Cl)c1Cl
Reactant: N
Agent: Cl
Solvent: CCO
Product: N=C(N)COc1cccc(Cl)c1Cl
Reaction time: 72 h

Procedure:
11.8 g (0.041 mole) of ethyl 2-(2,3-dichlorophenoxy)acetimidate hydrochloride are added rapidly to a solution, cooled to 10° C., of 3.5 g (0.21 mole) of ammonia in 100 ml of absolute ethanol. The reaction mixture is left for 3 days at room temperature. After removal of a few suspended particles by filtration, the reaction mixture is concentrated to dryness under reduced pressure. The solid residue obtained is purified by washing with ether and recrystallization from isopropanol. Yld: 8.0 g (75%), m.p. 204.5°-206.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26]O.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCCc1cccs1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCc1cccs1)c1cc(F)ccc1F
Yield: 66.1 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330 mmol) obtained in Example 5 and 2-(2-thienyl)ethanol (144 mg, 1.32 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (159 mg, 0.660 mmol). The resulting mixture was heated under reflux for 15 hours under a nitrogen atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=12:1 eluate was concentrated, whereby the title compound (90.0 mg, 0.218 mmol, 53%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14](=O)[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1C>O>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[N:13]=[C:14]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[CH3:2]
Reactant: CCOCCNc1cnccc1NC(=O)CN1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOCCn1c(CN2CCN(Cc3ccccc3)CC2)nc2ccncc21
Reaction time: 16 h
Yield: 56.1 %

Procedure:
A mixture of 37.8 parts of N-[3-[(2-ethoxyethyl)amino]-4-pyridinyl]-4-(phenylmethyl)-1-piperazineacetamide, 0.1 parts of 4-methylbenzenesulfonic acid and 450 parts of dimethylbenzene was stirred for 16 hours at reflux temperature using a water separator. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (93:7 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 20.2 parts (56.1%) of 3-(2-ethoxyethyl)-2-[[4-(phenylmethyl)-1-piperazinyl]methyl]-3H-imidazo[4,5-c]pyridine as a residue (compound 11).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH:28]2[CH2:33][CH:30]([CH2:31][CH:32]=1)[C:29]2([CH3:35])[CH3:34])(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:27]2[CH:28]3[CH2:33][CH:30]([CH2:31][CH:32]=2)[C:29]3([CH3:35])[CH3:34])=[C:6]([CH3:19])[CH:5]=1
Reactant: CC1(C)C2CC=C(OS(=O)(=O)C(F)(F)F)C1C2
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: COC(=O)c1ccc(C2=CCC3CC2C3(C)C)c(C)c1
Yield: 69.5 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (1.00 g, 3.62 mmol) and 6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl trifluoromethanesulfonate (1.17 g, 4.34 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 5% ethyl acetate in hexane, afforded the title compound (0.680 g) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH:26]3[CH2:28][CH2:27]3)[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:29](Cl)(=[O:31])[CH3:30].O>N1C=CC=CC=1>[C:21]([O:20][C:19](=[O:25])[NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:29](=[O:31])[CH3:30])[S:3][C:4]=3[N:5]=2)[CH:26]2[CH2:28][CH2:27]2)[CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N(c2ncc3nc(N)sc3n2)C2CC2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2cnc(N(c3cccc(NC(=O)OC(C)(C)C)c3)C3CC3)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(cyclopropyl)amino]phenyl}carbamate (1.20 g, 3.01 mmol) in pyridine (20 mL) was added acetyl chloride (859 μL, 12.1 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (60 mL), and the mixture was extracted with ethyl acetate (60 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and filtered through a basic silica gel pad. The filtrate was concentrated under reduced pressure to give tert-butyl(3-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl](cyclopropyl)amino}phenyl)carbamate as a dark-purple solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[CH2:9](C(CC)(CC)C([O-])([O-])[O-])[CH3:10]>C1(C)C=CC=CC=1>[CH2:9]([O:7][C:6]([CH:4]1[CH2:5][C:2](=[O:1])[CH2:3]1)=[O:8])[CH3:10]
Reactant: O=C1CC(C(=O)O)C1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(=O)C1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCl (120 mL). The organic phase was separated, washed with a saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (6.5 g, 80% yield) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].O.[NH2:11][NH2:12]>CCO>[Cl:9][C:5]1[N:4]=[N:3][C:2]([NH:11][NH2:12])=[C:7]([NH2:8])[CH:6]=1
Reactant: Nc1cc(Cl)nnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1nnc(Cl)cc1N
Temperature: 100 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred suspension of 3,6-dichloropyridazin-4-amine (Step 112.1) (1.49 g, 9.09 mmol) in EtOH (15 mL) was added hydrazine hydrate (11.04 mL, 227 mmol) and the resulting mixture was heated up and stirred at 100° C. for 3 hr. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was triturated with water (25 mL) to afford the title product (478 mg, 3 mmol, 33% yield) as yellow solid. tR: 0.24 min (LC-MS 2); ESI-MS: 160 [M+H]+ (LC-MS 2); ESI-MS: 158 [M−H]− (LC-MS 2).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)[N:5]=[N:6][C:7]=1[Cl:8].[NH3:26]>C1COCC1.C(O)C>[Cl:8][C:7]1[N:6]=[N:5][C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:3][C:2]=1[NH2:26]
Reactant: N
Reactant: Fc1ccccc1Cn1nc(-c2nnc(Cl)c(Cl)n2)c2cccnc21
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7.000 g (purity 38%, 7.090 mmol) of 3-(5,6-dichloro-1,2,4-triazin-3-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine in 200 ml of absolute THF were initially introduced. With ice-cooling, 4.254 ml (8.508 mmol) of 2N ammonia solution in ethanol were added and the mixture was stirred for 1 h at 0° C. Again with ice-cooling, 4.254 ml (8.508 mmol) of 2N ammonia solution in ethanol were added and the mixture was stirred for 1.5 h at RT. 30 ml (60.000 mmol) of 2N ammonia solution in ethanol was added and the mixture was stirred for 15 min at RT. The reaction mixture was concentrated on a rotary evaporator, suspended in 100 ml of dichloromethane, admixed with 50 ml (100.00 mmol) of 2N ammonia solution in ethanol and stirred for 2 h at RT. The mixture was concentrated on a rotary evaporator and purified by chromatography on silica gel (mobile phase: dichloromethane/methanol, gradient 20:1→10:1). The product-containing fractions were concentrated and stirred with DMSO. The solid was filtered off with suction, after-washed with acetonitrile and dried under high vacuum. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). This gave 1.68 g of the target compound (purity 65%; 43% of theory).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH2:16]([Cl:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl-:23].[C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[N+:9]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)c1nc(-c2cccnc2)[nH]c1C
Reactant: ClCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)c1nc(-c2ccc[n+](Cc3ccccc3)c2)[nH]c1C
Product: [Cl-]

Procedure:
A mixture of 10.0 g (0.05 mole) of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone, 13 ml (0.1+ mole) of benzyl chloride, 10 ml (0.05+ mole) of N,N-diisopropylethylamine and 250 ml of dioxane was stirred at reflux for 18 hours. The resulting precipitate was collected by filtration of the hot mixture, washed free of color with tetrahydrofuran, then dried in vacuo at 100° C. and gave 12.2 g of the desired product as a yellow solid, mp 230°-232° C.
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[CH:3][C:4]([O:6][CH3:7])=[O:5].N1CCCCC1.[SH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].CCOCC>CO>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C:2]([S:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:8])[CH3:1]
Reactant: COC(=O)CCS
Reactant: COC(=O)C=C(C)C
Solvent: CO
Solvent: CCOCC
Solvent: C1CCNCC1
Product: COC(=O)CCSC(C)(C)CC(=O)OC
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.1 %

Procedure:
To a well-stirred mixture of methyl 3-methylbut-2-enoate (50.0 g, 438 mmol), 40% Triton B in MeOH (5 mL) and piperidine (4 mL) were added dropwise at 0° C., then methyl 3-mercaptopropanoate (50 g, 396 mmol) was added. After stirring for 24 h at 60° C., Et2O (500 mL) was added, and the organic phase washed thoroughly with 10% H2SO4 (150 mL), sat. NaHCO3 (150 mL), and brine (200 mL) successively, dried over Na2SO4 and evaporated under vacuum to give the title compound as a colorless oil (90.1 g, 97.23%).
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[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=2)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=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: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 120 °C
Yield: 59.6 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.350 g, 0.839 mmol) (Peak 1, Example 49, Step 7), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.311 g, 1.01 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (41.1 mg, 0.0503 mmol), potassium carbonate (0.464 g, 3.35 mmol) in 1,4-dioxane (5.0 mL) and water (2.5 mL) was degassed and recharged with nitrogen three times, and heated at 120° C. for 2 h. The reaction was diluted with ethyl acetate and then washed with water and brine, dried over NaSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with methanol in DCM (0-10%) to afford the desired product (260 mg, 59.7%). LCMS (M+H)+: m/z=520.4.
Reaction SMILES: OC1C=C([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])C=CC=1C1C=CC=CC=1.IC1C=C2C(=CC=1)C(=O)[NH:36][C:35](=O)C2=COC.NC[C:48]1[CH:49]=[CH:50][C:51]([C:55]2[CH:60]=[CH:59][CH:58]=CN=2)=[C:52]([OH:54])[CH:53]=1>>[OH:54][C:52]1[CH:53]=[C:48]([CH:49]=[CH:50][C:51]=1[C:55]1[CH:35]=[N:36][CH:58]=[CH:59][CH:60]=1)[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Reactant: NCc1ccc(-c2ccccn2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2cccnc2)c(O)c1
Yield: 76 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (50 mg, 0.15 mmol) and 5-Aminomethyl-2-pyridin-2-yl-phenol (53 mg, 0.27 mmol) in 76% yield: MS (ESI): 498.0 (M+1)+1.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]([C:9](=[O:24])[CH2:10][CH2:11][CH2:12][C:13]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][CH2:16][CH2:15][O:14]2)C(=O)O1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1>[O:24]=[C:9]([CH2:10][CH2:11][CH2:12][C:13]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:14][CH2:15][CH2:16][O:17]1)[CH2:5][C:6]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8]
Reactant: Nc1ccccc1
Reactant: CC1(C)OC(=O)C(C(=O)CCCC2(c3ccccc3)OCCO2)C(=O)O1
Solvent: Cc1ccccc1C
Product: O=C(CCCC1(c2ccccc2)OCCO1)CC(=O)Nc1ccccc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
Step AAH (4): To a solution of 2,2-dimethyl-5-(4-(2-phenyl-1,3-dioxolan-2-yl)butanoyl)-1,3-dioxane-4,6-dione (4.0 g, 11.04 mmol) in xylene (30 mL) was added aniline (1.21 mL, 13.3 mmol). The r×n was stirred at 140° C. for 2 h. The crude reaction contents were directly loaded onto silica gel and purified by silica gel column chromatography (60% EtOAc/hexanes) to afford 3-oxo-N-phenyl-6-(2-phenyl-1,3-dioxolan-2-yl)hexanamide (3.0 g, 77% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 9.16 (br. s., 1 H) 7.54 (d, J=7.63 Hz, 2 H) 7.44 (d, J=7.02 Hz, 2 H) 7.28-7.39 (m, 5 H) 7.12 (t, J=7.48 Hz, 1 H) 3.97-4.07 (m, 2 H) 3.72-3.82 (m, 2 H) 3.53 (s, 2 H) 2.60 (t, J=7.32 Hz, 2 H) 1.89-1.97 (m, 2 H) 1.67-1.79 (m, 2 H).