Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]>C(O)C>[C:9]([C:8]1[CH:17]=[CH:18][C:5]([NH:2][NH2:3])=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: NNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 75 %

Procedure:
20 ml of hydrazine hydrate were added to the suspension of 52.33 g of 4-chloro-3-nitrobenzophenone in 200 ml of abs. ethanol under stirring. The reaction mixture was stirred at room temperature for 75 minutes, then slowly heated to the boiling point. After completion of the violent reaction, the mixture was refluxed for an additional 1 hour. After cooling down, the crystals were filtered by suction, thoroughly washed with water and dried at 80° C. Thus, 38.62 g (75%) of 4-benzoyl-2-nitrophenylhydrazine were obtained as orange-red crystals, m.p.: 163°-164° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=34)=[C:12]([F:27])[CH:11]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:27][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:3]=[CH:2][N:7]=[C:6]([NH2:8])[N:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=12
Reactant: Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2nccc(Oc3ccc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
50 mg (0.13 mmol) of 6-chloro-N4-{3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine are dissolved in 10 ml of ethanol. 36 μl (0.26 mmol) of triethylamine and 28 mg (0.03 mmol) of 10% palladium-on-carbon are added, and the mixture is hydrogenated under atmospheric pressure in a hydrogen atmosphere overnight. The mixture is then filtered through Celite®, and the celite is washed with methanol. The solvent is removed under reduced pressure and the crude product is purified by preparative HPLC.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([F:47])[CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][C:42]=1[F:47])=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 90%).
Reaction SMILES: [C:1]([CH2:9][C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[O:15])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.O[N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47]>CN(C)C=O>[C:1]([CH2:9][C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([O:24][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47])=[O:23])=[O:19])=[O:15])=[S:11])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=S)CC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CNC(=O)CNC(=S)CC(=O)c1ccccc1)NCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of (2-benzoylthioacetyl)glycylglycylglycine (2.72 mmol) in 10 mL of dimethylforamide was added 0.56 g of dicyclohexylcarbodiimide (2.72 mmol) and 0.31 g of N-hydroxysuccinimide (2.72 mmol). The solution was stirred at room temperature for 24 hours. The resultant white solid was filtered off. The solvent was removed from the filtrate by rotary evaporator (vacuum pump, 35.) to give the product as a yellow semisolid. This solid was dried under vacuum overnight. The product was then recrystallized from 100 mL of hot 2-propanol to give 0.27 g of a white powder after filtration and drying under vacuum (21%). NMR (DMSO-d6)δ 2.81 (s, 4H), 3.79 (m, integral obscured by water), 3.89 (s, integral obscured by water), 4.28 (d, 2H), 7.58 (d, 2H), 7.71 (t, 1H), 7.93 (d,2H), 8.29 (br t, 1H), 8.54 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[O:24])[CH:20]=[CH:21][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[2-methyl-5-(thiophen-3-ylcarbonylamino)-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.07 min, MH− 392. NMR: δH [2H6]-DMSO 10.11, (1H, s), 9.11, (1H, s), 8.83, (1H, t), 8.35, (1H, s), 8.30, (1H, dd), 7.85, (1H, s), 7.78, (1H, d), 7.67-7.63, (3H, m), 7.31, (1H, d), 3.20, (2H, t), 2.31, (3H, s), 1.06, (1H, m), 0.46, (1H, m), 0.27, (1H, m).
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][C:45]1[N:46]=[C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)[O:48][CH:49]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][CH2:44][C:45]1[N:46]=[C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:53]=[N:52]2)[O:48][CH:49]=1
Reactant: COCc1coc(Cn2ncc(N)n2)n1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COCc1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (1.14 g, 5.26 mmol) in CH2Cl2 (30 mL) was treated at rt with DMAP (160 mg, 1.31 mmol), HOBt (854 mg, 6.32 mmol), EDC (2.52 g, 13.15 mmol) and DIPEA (3.60 mL, 21.03 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(methoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (1.10 g, 5.26 mmol) in CH2Cl2 (22 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (45 mL), the layers were separated and the org. phase was washed with water (45 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil: TLC: rf (4:6 hept-EA)=0.20. LC-MS-conditions 07: tR=0.88 min, [M+H]+=409.11.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2ccc(O)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl[benzoate (Compound I) 75.0 mg (0.143 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.01 (2H, d, J=8.3 Hz), 7.59 (2H, d, J=8.4 Hz), 7.45 (2H, s), 7.20-7.17 (3H, m), 6.92-6.89 (2H, m), 5.97 (1H, t, J=4.7 Hz), 2.35 (2H, d, J=4.7 Hz), 1.34 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18]([OH:20])[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([OH:28])=[O:27])[C:10]=23)=[CH:4][CH:3]=1.[CH3:29]COCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18]([OH:20])[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:10]=23)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Product: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)O)cc(F)cc12

Procedure:
(+/−)-[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 14, 100 mg) was esterified in Et2O by addition of an excess of CH2N2. After removal of the solvents, the title ester was obtained quantitatively as a pale yellow solid and used as such.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]3[CH:38]=[CH:37][C:26]([C:27]([O:29]CC4C=CC=CC=4)=[O:28])=[CH:25][CH:24]=3)[CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[H][H]>CO.[Pd]>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]3[CH:38]=[CH:37][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH2:19]2)[CH2:14]1)=[O:11])=[O:7]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)OCc4ccccc4)cc3)C2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)O)cc3)C2)C1
Yield: 90.8 %

Procedure:
In a round-bottom flask, a solution of benzyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoate (258 mg, 0.43 mmol) in methanol (400 μL) and Palladium (10%) on Carbon (50 mg) was purged with hydrogen gas for two minutes; the reaction was then subjected to 1 atmosphere of hydrogen gas for two hours. The flask was purged with Argon, then the mixture was filtered and concentrated to afford 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoic acid (197 mg, 91%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]([NH:15][NH2:16])=[O:14].N1C=CC=CC=1.[C:23](Cl)(Cl)=[O:24]>C(COC)OC>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]1[O:14][C:23](=[O:24])[NH:16][N:15]=1
Reactant: NNC(=O)c1c(Cl)ccc2cc(Cl)cnc12
Reactant: O=C(Cl)Cl
Solvent: COCCOC
Solvent: c1ccncc1
Product: O=c1[nH]nc(-c2c(Cl)ccc3cc(Cl)cnc23)o1
Yield: 62 %

Procedure:
12.8 g (50 millimoles) of 3,7-dichloroquinoline- 8-carboxylic hydrazide (compound No. 1) were suspended in 100 ml of dimethoxyethane, 7.9 g (100 millimoles) of pyridine were added and phosgene was then passed in over a period of 4 hours at 25° C. Excess phosgene and the solvent were removed, the residue was stirred into water and the mixture was filtered under suction to give 8.7 g (62%) of a product of melting point of 87° C. (compound No. 33).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:29][CH:28]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(C)(C)C)cc4)cc3=O)cn12
Reaction time: 17 h
Yield: 47 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (200 mg) in DMF (3 ml) were added 1-(bromomethyl)-4-(tert-butyl)benzene (178 mg) and potassium carbonate (197 mg) at room temperature, and the mixture was stirred for 17 h. The mixture was poured into water, and the resultant solid was collected by filtration. The solid was recrystallized from acetone to give the title compound (143 mg) as white crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:28])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)=[O:12])=[CH:23][CH:22]=2)[O:17]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C(O)c1cc2ccccc2o1
Product: CC1(C)OB(c2ccc(NC(=O)c3cc4ccccc4o3)cc2)OC1(C)C
Yield: 83 %

Procedure:
Amide coupling of benzofuran-2-carboxylic acid with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine was done according to Example 20, Step 4 to give benzofuran-2-carboxylic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide in 83% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (s, 12 H) 7.4 (m, 1 H) 7.5 (m, 1 H) 7.7 (d, J=8.3 Hz, 2 H) 7.7 (dd, J=8.5, 0.9 Hz, 1 H) 7.8 (m, 4 H) 10.6 (s, 1 H)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.CO>[NH2:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][CH:38]3[CH2:39][CH2:40]3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Temperature: 100 °C

Procedure:
To 23C (0.464 mmol, 260 mg) in NMP (2 mL) was added TFA (0.2 mL). The resulting reaction mixture was heated at 100° C. for 24 hrs. The reaction mixture was diluted with MeOH and purified by HPLC Phenomenex Axia Luna 5 micron 30×100 mm) with 20% to 100% MeOH (0.1% TFA) in water (0.1% TFA) to isolate 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (107 mg, 0.243 mmol, 52.3% yield) as white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.500 minutes. [M+H]=441.12. 1H NMR (400 MHz, MeOD) δ ppm 8.21-8.35 (1H, m), 8.01 (1H, s), 7.96 (1H, d, J=1.76 Hz), 7.33-7.51 (1H, m), 6.07 (1H, s), 3.60-3.85 (1H, m), 3.08-3.27 (1H, m), 2.49-2.66 (1H, m), 2.25-2.45 (2H, m), 2.06-2.28 (2H, m), 1.35-1.69 (4H, m), 0.77-0.97 (2H, m), 0.50-0.73 (2H, m).
Reaction SMILES: C([O:4]C1C=C(C=CC=1Cl)N)C=C.C1(=O)OC(=O)C2=CC=CC=C12.[CH2:24]([C:27]1[C:32]([OH:33])=[C:31]([Cl:34])[CH:30]=[CH:29][C:28]=1[N:35]1[C:39](=[O:40])[C:38]2[CH2:41][CH2:42][CH2:43][CH2:44][C:37]=2[C:36]1=[O:45])[CH:25]=[CH2:26]>>[Cl:34][C:31]1[C:32]2[O:33][CH:25]([CH2:26][OH:4])[CH2:24][C:27]=2[C:28]([N:35]2[C:39](=[O:40])[C:38]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]3[C:36]2=[O:45])=[CH:29][CH:30]=1
Reactant: C=CCc1c(N2C(=O)C3=C(CCCC3)C2=O)ccc(Cl)c1O
Reactant: C=CCOc1cc(N)ccc1Cl
Agent: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1c1ccc(Cl)c2c1CC(CO)O2

Procedure:
The title compound was prepared, as a white solid, m.p.: 181°-183° C., from 3B and phthalic anhydride in three steps, according to the procedures described for preparing Example 4 from 3D.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]([OH:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[CH:15]([O:18][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:17])[CH3:16]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 120 °C

Procedure:
A mixture of 2.13 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I) Br in 5 ml triethylamine and 25 ml isopropanol was heated to 120° C. for 16 h in a sealed tube. The volatiles were removed in vacuo and the residue was taken up in 70 ml 1 N HCl. Extraction with ethyl acetate, drying of the combined organic fractions and evaporation yielded a residue which was purified by reversed phase preparative HPLC eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded the title compound. MS (m/e): 257.0 ([M−H]−, 100%)
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1O.[C:18](=[O:21])([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:21][CH2:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[I:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(O)c1I
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1c(OCc2ccccc2)cccc1OCc1ccccc1
Reaction time: 18 h
Yield: 71.4 %

Procedure:
Add benzyl bromide (7.97 g, 46.6 mmol) to a solution of 2-iodo-benzene-1,3-diol (5.00 g, 21.2 mmol) and cesium carbonate (15.2 g, 46.6 mmol) in dimethylformamide (200 mL) and stir. After 18 hours, concentrate under reduced pressure. Add water (500 mL) and stir. After 1 hour, filter the resulting precipitate washing with water and hexanes to yield the title compound as an off-white solid (6.30 g, 71%): 1H NMR (CDCl3) δ 5.18 (s, 4H), 6.55 (d, 2H), 7.19 (t, 1H), 7.29-7.53 (m, 10H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.Cl.C[N:17](C)CCCN=C=NCC.O[N:28]1C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C)C=O>[NH3:17].[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH2:28])=[O:14])[CH:6]=[CH:5]2
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N
Product: NC(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.8 %

Procedure:
A solution of 6-hydroxy-2-napthoic acid (1.88 g, 9.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.11 g, 10.98 mmol), 1-hydroxybenzotriazole (1.48 g, 10.98 mmol) and ammonium carbonate (4.80 g, 49.95 mmol) in N,N-dimethylformamide (70 ml) was left to stir at room temperature under a nitrogen atmosphere for 3 days. The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (6×50 ml). The combined organic extracts were washed with water (25 ml), saturated aqueous sodium chloride (25 ml), dried (sodium sulfate) and the solvent removed in vacuo. The solid was absorbed onto silica gel and purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.880 ammonia (95:5:0.5 changing to 90:10:1) to give the title compound as a pale yellow solid (1.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N:12]1[CH:17]=[CH:16][C:15]([C:18]([Cl:20])=O)=[CH:14][CH:13]=1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[ClH:20].[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][O:8][C:5]2[CH:6]=[CH:7][C:2]3[O:1][C:18]([C:15]4[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=4)=[CH:10][C:9](=[O:11])[C:3]=3[CH:4]=2)[CH2:24][CH2:23]1
Reactant: O=C(Cl)c1ccncc1
Reactant: OC1CCNCC1
Reactant: CC(=O)c1cc(O)ccc1O
Product: Cl
Product: O=c1cc(-c2ccncc2)oc2ccc(OCCCCCCN3CCC(O)CC3)cc12

Procedure:
The compound was prepared by the method of Example 11 from 2',5'-dihydroxyacetophenone, 4-pyridylcarbonyl chloride, and 4-hydroxypiperidine: mp 165°-166° C.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:18][CH3:19])[C:16]=1[OH:17])[CH:12]=O.S([O-])([O-])(=O)=O.O[NH3+:26].O[NH3+].ClC1C2C(=CC=CC=2)C=CC=1>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:18][CH3:19])[C:16]=1[OH:17])[C:12]#[N:26]
Reactant: [NH3+]O
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Clc1cccc2ccccc12
Solvent: ClCCl
Product: COc1cc(C#N)cc(Br)c1O
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 1280 parts by weight of anhydrous sodium sulfate, 462 parts by weight of 3-bromo-4-hydroxy-5-methoxybenzaldehyde, 172 parts by weight of hydroxylammonium sulfate and 298 parts by weight of 1-chloronaphthalin. Following evacuation to 70 mbar, the mixture is heated to 130° C. and kept at this temperature for 31/2 hours. The reaction mixture is then cooled to 30° C. and nitrogen is introduced until atmospheric pressure is reached. After 2650 parts by weight of dichloromethane are added, the suspension is kept for 20 min at room temperature while further stirred and then filtered. The filter cake is extracted three times each with 2000 parts by weight of dichloromethane. The solvent extracts are combined with the first filtrate and evaporated to 1/3 of their volume. The solution of the raw product in dichloromethane is subjected to column chromatography using 1400 parts by weight of silica gel 60 [70-230 mesh (Merck)] and 26500 parts by weight of dichloromethane as eluent. After a portion corresponding to the dead volume of the column is first discarded, the next 17000 parts by weight are collected in one fraction and evaporated to dryness. The residue is freed from traces of adsorbed 1-chloronaphthalin at 80° C. in the vacuum. 334.5 parts by weight of 3-bromo-4-hydroxy-5-methoxybenzonitrile are obtained with a purity of over 98% (TLC) and a melting point of 144°-145° C.