Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:32]1[O:40][C:39]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=2[O:33]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:33]1[C:34]2[CH:35]=[CH:36][C:37]([N:18]3[C:19]4[C:15](=[CH:14][C:13]([C:11]([N:8]5[CH2:7][CH2:6][N:5]([CH:1]6[CH2:2][CH2:3][CH2:4]6)[CH2:10][CH2:9]5)=[O:12])=[CH:21][CH:20]=4)[CH:16]=[C:17]3[C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:38][C:39]=2[O:40][CH2:32]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc2c(c1)OCO2)N1CCN(C2CCC2)CC1
Yield: 24 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3,4-methylenedioxybenzeneboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (24%).
Reaction SMILES: [F-].[K+].[C:3]1(B(O)O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15](=[O:27])[NH:16][C:17]([C:23]([F:26])([F:25])[F:24])=[N:18]2>C1COCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[C:3]1([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[C:15](=[O:27])[NH:16][C:17]([C:23]([F:24])([F:25])[F:26])=[N:18]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1[nH]c(C(F)(F)F)nc2cccc(Cl)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c(C(F)(F)F)nc2cccc(-c3ccccc3)c12
Temperature: 100 °C
Yield: 116.6 %

Procedure:
Palladium (II) acetate (19 mg, 0.085 mmol), potassium fluoride (498 mg, 8.57 mmol), 2-(di-tert-butylphosphino)biphenyl (51.1 mg, 0.171 mmol), and phenylboronic acid (522 mg, 4.27 mmol) were combined in a microwave vial under an argon atmosphere. A solution of 5-chloro-2-(trifluoromethyl)quinazolin-4(3H)-one (710 mg, 2.86 mmol) in dry THF (9 mL) was added and the mixture was heated in the microwave at 100° C. for 30 min. After this time, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1N NaOH (25 mL) and saturated NaCl (25 mL). The organic layer was separated, dried over sodium sulfate and then concentrated under reduced pressure to give the crude product (968 mg), which was used in the next step without further purification.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:2]([NH:6][NH:7][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)NNC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of t-butylhydrazine hydrochloride (1.24 g, 10 mmol) in toluene (30 ml) at room temperature was added dropwise a 50% aqueous solution of sodium hydroxide (0.8 g, 10 mmole). After 15 min., the reaction mixture was cooled to 5° C. and a solution of benzoyl chloride (1.42 g, 10 mmol) in toluene (5 ml) and a solution of 50% aqueous sodium hydroxide (0.8 g, 10 mmol) were added dropwise simultaneously from separate addition funnels while maintaining the temperature at or below 10°. Following the addition, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was diluted with toluene washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent removed under vacuum to afford a yellow oil which slowly solidified on standing. The product was recrystallized from ethyl ether:hexane to afford white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([C:12]2[NH:13][C:14](=[O:22])[NH:15][C:16](=[O:21])[C:17]=2[CH:18]([CH3:20])[CH3:19])=[O:11])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+].Cl[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([N:39]2[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[CH:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([C:12]2[N:13]([CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([N:39]4[C:40](=[O:49])[C:41]5[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=5)[C:47]4=[O:48])[CH:34]=3)[C:14](=[O:22])[NH:15][C:16](=[O:21])[C:17]=2[CH:18]([CH3:20])[CH3:19])=[O:11])[CH:9]=1)[C:5]#[N:6]
Reactant: O=C1c2ccccc2C(=O)N1c1cc(CCl)ccn1
Reactant: CC(C)c1c(C(=O)c2cc(Cl)cc(C#N)c2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)c2cc(Cl)cc(C#N)c2)n(Cc2ccnc(N3C(=O)c4ccccc4C3=O)c2)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To a stirred solution of 3-Chloro-5-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-benzonitrile (317 mgmg, 1 mmol), anhydrous powdered potassium carbonate (134 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol) in DMF (5 ml) at room temperature, was added 2-(4-Chloromethyl-pyridin-2-yl)-isoindole-1,3-dione (272 mg, 1 mmol). After stirring for overnight, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:1); Rf˜0.3 fraction was collected.) to afford 160 mg (29%) of a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([CH2:21][C:22]([CH3:24])=[CH2:23])=[C:9]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:8]=[C:9]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:10]([CH2:21][C:22]2([CH3:24])[CH2:23][O:42]2)=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cc1c(OCc2ccccc2)cc(C(=O)OC(C)(C)C)cc1OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2(C)CO2)c(OCc2ccccc2)c1
Yield: 48.3 %

Procedure:
To a solution of 3,5-bis-benzyloxy-4-(2-methyl-allyl)-benzoic acid tert-butyl ester (227a) (80 g, 0.18 mol) in CH2Cl2 (500 mL) was added m-CPBA (62 g, 0.36 mol) portion-wise. The mixture was refluxed overnight. The solid was filtered and washed with CH2Cl2. The filtrate was washed with saturated aqueous Na2S2O4 (250 mL) and brine (250 mL). The organic layer was separated, dried over Na2SO4 and concentrated to give a brown oil. The crude oil was quickly purified by column chromatography (EtOAc/petroleum ether=1/10) to give the title compound (40 g, 48.2% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:7][N+:8]([CH3:23])([CH3:22])[CH2:9][CH2:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.[H][H]>O.[Pd]>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]([CH3:21])[CH2:10][CH2:9][N+:8]([CH3:23])([CH3:22])[CH3:7])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CN(CC[N+](C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: COS(=O)(=O)[O-]
Solvent: O
Product: CN(CC[N+](C)(C)C)c1ccc(N)cc1
Reaction time: 2 h

Procedure:
10 g (28.6 mmol) of the compound from Step 9.2 was dissolved in 80 mL of water and hydrogenated in the presence of 1 g of Pd/C (10%) under 9 bar of hydrogen pressure. After 2 hours, the catalyst was filtered off and the filtrate was evaporated to dryness. This gave 9.3 g (99.6% of the theoretical) of a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:10]1=2.CN(CCN1C2C(=CC=C([NH:44][C:45]([C:47]3[S:48][CH:49]=[CH:50][CH:51]=3)=N)C=2)CCC1)C(=O)OC1C=CC=CC=1>C(O)C.C([O-])(O)=O.[Na+]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2[CH:16]=[C:17]([NH:20][C:45]([C:47]3[S:48][CH:49]=[CH:50][CH:51]=3)=[NH:44])[CH:18]=[CH:19][C:10]1=2
Reactant: CN1CCCC1CCN1CCCCc2cc(N)ccc21
Reactant: CN(CCN1CCCc2ccc(NC(=N)c3cccs3)cc21)C(=O)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN1CCCC1CCN1CCCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
A solution of 4 (170 mg, 0.62 mmol) in dry ethanol (15 mL) was treated with 5 (0.355 g, 1.24 mmol) and stirred for overnight (17 h) at room temperature. The reaction mixture was diluted with saturated NaHCO3 solution (100 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic fractions were washed with brine (50 mL), dried (Na2SO4) and concentrated. The crude product was purified by dry column chromatography (MeOH:CH2Cl2, 2:98 followed by 2 N NH3 in MeOH:CH2Cl2 3:97) to give compound 45 (177 mg, 74%) as a yellow solid. 1H-NMR (DMSO-d6) δ: 1.38-1.69 (m, 8H), 1.83-1.89 (m, 2H), 2.02-2.12 (m, 2H), 2.19 (s, 3H), 2.65-2.68 (m, 2H), 2.80-3.12 (m, 5H), 6.32 (brs, 2H), 6.62-6.64 (m, 2H), 6.85-6.88 (d, 1H, J=8.9 Hz), 7.06-7.09 (t, 1H, J=3.8 Hz), 7.56-7.58 (d, 1H, J=5.0 Hz), 7.69-7.71 (d, 1H, J=3.6 Hz); ESI-MS (m/z, %): 383 (MH+, 33), 192 (100), 142 (51). ESI-HRMS calculated for C22H30N4S (MH+), calculated: 383.2253; observed: 383.2263; HPLC-purity: 93.49% by area.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.N1CCCCC1.[NH:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31]>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:35]4[NH:29][C:30](=[O:31])[NH:32][C:33]4=[O:34])=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3cccc(O)c3)nc12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(-c4cccc(O)c4)nc23)N1
Temperature: 50 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To 7-(cyclopropylamino)-5-(3hydroxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (100 mg, 0.340 mmol) in EtOH (2 mL) was added piperidine (67 μL, 0.680 mmol), and hydantoin (34 mg, 0.34 mmol). The reaction was stirred at 50° C. overnight. The solid formed was isolated by filtration to provide 70 mg of 5-((7-(cyclopropylamino)-5-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. (55%). LCMS (M+1=377)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]([CH:29]([OH:35])[CH2:30][O:31][CH2:32][O:33][CH3:34])=[CH:21][C:22]3[NH:26][CH:25]=[N:24][C:23]=3[C:27]=2[F:28])=[C:14]([Cl:36])[CH:13]=1>C(Cl)Cl.O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]([C:29](=[O:35])[CH2:30][O:31][CH2:32][O:33][CH3:34])=[CH:21][C:22]3[NH:26][CH:25]=[N:24][C:23]=3[C:27]=2[F:28])=[C:14]([Cl:36])[CH:13]=1
Reactant: COCOCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCOCC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of oxalyl chloride (0.11 mL, 0.22 mmol) in CH2Cl2 (1 mL) at −78° C. is added DMSO (0.016 mL, 0.22 mmol). After stirring for 3 minutes, a solution of 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanol 101 (25 mg, 0.056 mmol) in methylene chloride (1 mL) is added. The resulting solution is stirred for 30 minutes at −78° C. TEA (0.1 mL, 0.71 mmol) is added. The reaction mixture is slowly warmed to room temperature, stirred for 5 minutes at room temperature, and diluted with water and CH2Cl2. The organic layer is separated, dried over MgSO4, filtered, and concentrated to give the crude product which is directly used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=O)C.C[Al](C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:11][C:10]1[C:6]2[C:4](=[O:3])[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:13][CH2:12][C:7]=2[NH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)c[nH]c1CCNCCN1CCOCC1
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A stirred solution of 4-methyl-2-[2-(2-morpholin-4-yl-ethylamino)-ethyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.08 g, 10 mmol) in 50 ml of toluene was added dropwise slowly with 2M trimethyl aluminum in toluene (10 ml, 20 mmol) under an argon atmosphere. The mixture was stirred for 1 hour at room temperature and heated to reflux for another 4 hours. The reaction mixture was cooled down to, 0° C. in ice/water bath, added with 1N hydrochloric acid (30 ml) and cold water (50 ml), and stirred for 5 minutes. The mixture was adjusted to pH12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (40 ml×3). The combined organic extracts were washed with brine (15 ml), filtered through a pad of Celite. The filtrate was dried with anhydrous sodium sulfate, filtered and concentrated, under reduced pressure to give 3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-Pyrrolo[3,2-c]pyridin-4-one (2.31 g) as a red oil which was used as such.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:8]1[N:7]([CH2:17][CH2:18][O:19][CH3:20])[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:9]=1)[CH3:15]
Reactant: COCCBr
Reactant: CCOC(=O)Cc1nc(C(C)(C)C)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(C(C)(C)C)nn1CCOC
Temperature: 55 °C
Reaction time: 6 h
Yield: 66.1 %

Procedure:
Ethyl (3-tert-Butyl-1H-1,2,4-triazol-5-yl)acetate (Preparation 116, 27.4 g, 0.13 mol) and 1-bromo-2-methoxyethane (13.7 mL, 0.143 mol) was dissolved in DMF (400 mL). K2CO3 (90.0 g, 0.65 mol) was added and the reaction mixture was stirred for 6 hours at 50-60° C. The reaction was cooled to room temperature, diluted with water (400 mL), and extracted with Et2O (3×100 mL). The combined organic extracts were washed with brine (3×200 mL), dried with Na2SO4, and evaporated to afford a mixture of alkylated triazole residues. The mixture was separated using HPLC (Luna 10 u 018(2), 100 A, 21.2×250 mm, H2O/acetonitrile 30-40%) to afford ethyl[3-tert-Butyl-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl]acetate (23.14 g, 66%).
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][C:13]1([O:19][CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1.[Li+].[OH-]>C1COCC1.O>[C:24]([O:23][C:21]([N:11]([CH2:12][C:13]1([O:19][CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][C:9]([OH:28])=[O:8])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC1(CN(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC1(CN(CC(=O)O)C(=O)OC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.2 %

Procedure:
The latter ester (1.25 g) was dissolved in THF/H2O (3:2,25 mL). After LiOH (0.30 g, 12.9 mol) was added, the mixture was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure. H2O (13 mL) was added to the residue. The resulting solution was washed with EtOAc, rendered acidic by the addition of aqueous 1M HCl and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated to dryness to give the acetic acid derivative, 2-{tert-butyloxycarbonyl[(1-methoxycyclohexyl)methyl]amino}acetic acid (0.56 g, 72% yield from 1-methoxycyclohexanemethanamine); 1H NMR(CDCl3) δ4.04 (s,0.6H), 3.94 (s,1.4H), 3.41 (s,1.4H), 3.35 (s,0.6H), 3.23 (s,1.9H), 3.18 (s,1.1H), 1.78-1.22 (m,20H); FAB mass spectrum, m/z: 302 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)C2C(=C(C)C(OC)=CC=2)N=1)[CH3:12]>>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:14]([O:13][CH2:11][CH3:12])[CH:23]=[C:22]2[O:24][CH:25]1[CH2:42][CH:41]2[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]3[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]2=[O:43])[CH2:37]3)[CH2:26]1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Reactant: COc1cccc(N)c1Br
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(Br)c2n1

Procedure:
The title compound (6) was prepared from 2-bromo-3-methoxyaniline following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=631 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CCOCC>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([N:20]=[CH:23][N:24]([CH3:26])[CH3:25])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N=CN(C)C)nc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.1 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine in 10 ml of dimethylformamide dimethyl acetal is warmed on a steam bath. Solution occurs followed by an exothermic reaction and precipitation of a solid. This mixture is stirred at room temperature for 16 hours and then diluted with ether and filtered to obtain the crude product as a yellow solid. Recrystallization of this from acetonitrile gives pure N'-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-yl]-N,N-dimethylmethanimidamide, mp 236°-238° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([C:17]([O:19]CC)=O)=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[O-]CC.[Na+].Cl>CN(C=O)C.O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(-c3ccc(Br)o3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CNC(=O)c1ncc2c(-c3ccc(Br)o3)noc2c1O
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate (62 mg, 0.176 mmol) was dissolved in 10 mL of DMF. Glycine (0.264 g, 3.51 mmol) and sodium ethoxide (0.179 g, 2.63 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 62 mg of the title compound. MS: (+) m/z 382, 384 (M+1, 79Br/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3=[N:8][C:9](C#N)=[C:10]([C:12]#[N:13])[N:11]=[C:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1.[OH:20]O.ClCCl>CS(C)=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3=[N:8][C:9]([OH:20])=[C:10]([C:12]#[N:13])[N:11]=[C:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: N#Cc1nc2c(nc1C#N)-c1ccc(Cl)cc1C2=O
Reactant: OO
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1nc2c(nc1O)-c1ccc(Cl)cc1C2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a suspension of 50 mg (0.19 mmol) 17g and 2.2 mg (5 Mol-%) Na2MoO4 in 2 ml DMSO was added dropwise 82 μl (0.95 mmol) of an aqueous solution of H2O2 (35%). The colour turned to red, and the mixture was stirred for 48 h at room temperature. After addition of 20 mL Dichloromethane, the resulting solution was washed with water and sat. brine (3×5 ml). After drying, filtration and evaporation, the crude product was purified by chromatography (DCM/MeOH 8/2) to yield 35 mg (70%) compound 42 as yellow-orange powder. 1H-NMR (d6-DMSO, 300 MHz): δ (ppm)=7.55 (s, 1H); 7.64 (m, 2H). ESI−MS: calcd for C12H4ClN3O2: 257.64; found: 255.9 (M-H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[C:17]3[N:18]([CH:32]=[CH:33][N:34]=3)[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=[O:26])[CH:21]=2)[CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[C:17]3[N:18]([CH:32]=[CH:33][N:34]=3)[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([OH:27])=[O:26])[CH:21]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COCC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)OC)c3)nn3ccnc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Yield: 24.5 %

Procedure:
To a stirred solution of methyl 3-(8-(6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (0.155 g, 0.34 mmol) in dioxane (10 mL) and H2O (4 mL) was added NaOH (135 mg, 3.4 mmol) at 40° C. After 4 h the mixture was washed with ether (10 mL), the aqueous layer adjusted to pH=4 with concentrated HCl, then was concentrated and filtered. The collected solid was washed with ether and dried to afford 3-(8-(6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.037 g, 28% over two steps) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.80 (s, 1H), 8.54 (s, 1H), 8.20-8.08 (m, 3H), 7.72 (d, 1H, J=1.5 Hz), 7.59 (t, 1H, J=7.8 Hz), 7.45 (t, 1H, J=7.8 Hz), 6.31 (d, 1H, J=7.5 Hz), 6.17 (d, 1H, J=8.4 Hz), 4.21 (brs, 1H), 3.62-3.58 (m, 1H), 3.51-3.42 (m, 2H), 3.34-3.32 (m, 1H), 3.11 (s, 3H), 2.10-2.00 (m, 4 h). LC-MS: [M+H]+, 445, tR=1.714 min, HPLC: 95.14% at 214 nm, 95.00% at 254 nm, tR=5.9 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].Cl.[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl>C(OCCOCCO)C.CO>[ClH:13].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2ccccc2c1
Agent: Cl
Solvent: CCOCCOCCO
Solvent: CO
Product: c1ccc2cc(N3CCNCC3)ccc2c1
Yield: 57.4 %

Procedure:
A solution of naphthalen-2-amine (2 g, 14 mmol) and bis(2-chloroethyl)amine hydrochloride (2.51 g, 14.1 mmol, 1 eq) in diethylene glycol monoethyl ether (3 mL) was stirred overnight at 149° C. (oil bath). The resulting solution was diluted with methanol (2 ml). The crude product was re-crystallized from diethyl ether to afford 1-(naphthalen-2-yl)piperazine hydrochloride as a yellow solid (2 g, 58%). (ES, m/z): [M+H]+ 213.0
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.CS(O[CH2:34][CH:35]1[CH2:39][CH2:38][O:37][CH2:36]1)(=O)=O>>[O:37]1[CH2:38][CH2:39][CH:35]([CH2:34][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([CH:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:2])=[O:28])[CH2:14][CH2:15]3)=[CH:20]2)[CH2:36]1
Reactant: CS(=O)(=O)OCC1CCOC1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CC3CCOC3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.1 g (0.26 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester and 0.067 g (0.37 mmol) of freshly prepared tetrahydro-furan-3-ylmethyl methanesulfonate. After standard purification, 0.045 g (39% of yield) of the expected acid were obtained.