Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]3[C:13]([CH:19]=[O:20])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=3)[C:5]=12.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]3[C:13]([CH:19]=[O:20])=[CH:14][C:15]([O:18][CH2:28][CH2:29][O:30][CH3:31])=[N:16][CH:17]=3)[C:5]=12
Reactant: COCCBr
Reactant: O=Cc1cc(=O)[nH]cc1OCc1cccn2ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C=O)c(OCc2cccn3ccnc23)cn1
Temperature: 25 °C
Yield: 5 %

Procedure:
To a mixture of 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (100 mg, 0.37 mmol, 1 equiv) and K2CO3 (153.2 mg, 1.11, 3.0 eq.) in DMF (5 mL) was added 1-bromo-2-methoxyethane (154.3 mg, 1.11 mmol, 3.0 eq.). The mixture was stirred at rt O/N, filtered, concentrated, and purified on silica gel using 10% MeOH/DCM as eluent to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)isonicotinaldehyde (6.0 mg, 5%) as an yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.08 (d, J=6.8 Hz, 1H), 8.06 (s, 1H), 7.60 (dd, J=6.8, 1.2 Hz, 2H), 7.27 (dd, J=6.9, 1.0 Hz, 1H), 7.09 (s, 1H), 6.78 (t, J=6.9 Hz, 1H), 5.58 (s, 2H), 4.35 (dd, J=5.4, 3.9 Hz, 2H), 3.66 (dd, J=5.4, 3.9 Hz, 2H), 3.36 (s, 3H). LRMS (M+H+) m/z 328.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>CC(C)=O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[C:2]([NH2:1])[CH:7]=1
Reactant: CN(C)CCCl
Reactant: Nc1cc(Cl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)CCOc1ccc(Cl)cc1N
Yield: 74.5 %

Procedure:
To a suspension of 2-Amino-4-chloro-phenol (1.43 g, 10 mmoles, 1 eq) and potassium carbonate (6.9 g, 50 mmoles, 5 eq) in acetone (25 ml) was added in one portion (2-Chloro-ethyl)-dimethyl-amine hydrochloride (2.16 g, 15 mmoles, 1.5 eq). The reaction mixture was refluxed under Nitrogen for 6 hours at which time the suspension was filtered and the solid washed with acetone. The combined filtrate was concentrated under vacuum and purified by flash chromatography (EtOAc/MeOH/NEt3: 87/9/3) to afford a beige solid (1.6 g, yield=72%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.C(N(CC)CC)C>ClCCl.O>[O:11]=[C:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: -78 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
A solution of oxalyl chloride (545 μL, 6.36 mmol) in dichloromethane (25 mL) was cooled to −78° C. While maintaining an internal temperature of −78° C., the dropwise addition of DMSO (903 μL, 12.7 mmol) followed by 1,1-dimethylethyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.78 mmol in 30 mL of dichloromethane) and finally triethylamine (3.25 mL, 23.1 mmol in 20 mL of dichloromethane) was performed. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The reaction mixture was diluted with water and partitioned and the organic portion was washed twice with water. The combined aqueous portion was extracted once with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 893 mg, 5.20 mmol (90%) of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate as a colorless oil, which solidified upon standing. 1H NMR (400 MHz, DMSO): 4.67 (s, 4H), 1.42 (s, 9H). GC/MS for C8H13NO3: 171.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]([CH3:24])[CH:26]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cn1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c2ccccc21

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1-methyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=489.9.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([C:22]([NH:24][NH2:25])=O)[CH2:21][CH2:20][CH2:19]1>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([C:22]2[N:10]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[N:25][N:24]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: COC1=NCCCCCC1
Reactant: NNC(=O)C1(c2ccccc2F)CCC1
Product: Fc1ccccc1C1(c2nnc3n2CCCCCC3)CCC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
8-Methoxy-2,3,4,5,6,7-hexahydroazocine (47 μl, 0.412 mmol) was added to the solution of 1-(2-fluorophenyl)cyclobutanecarbohydrazide, and the reaction was stirred at 120° C. overnight. After cooling, the solution was concentrated, and the product was purified by preparative HPLC as the trifluoroacetate salt. The salt was added to a saturated sodium bicarbonate solution and extracted with ethyl acetate to give the freebase. The extract was dried over magnesium sulfate, filtered and evaporated to give the purified triazole (2-34) as a solid (12.5 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][CH2:14]Cl)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:11][O:13][CH3:14])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 31.4 g (183.3 mmol) of 3-Bromo-phenol in 450 mL of dried acetonitrile a dispersion of 12 g (274.9 mmol) of sodium hydride (55% in oil) was added portionwise at 0° C. The mixture was then allowed to agitate at 0° C. for 3 hours. A solution of 25 g (210.8 mmol) of chloromethyl ethyl ether in 30 mL of acetonitrile was added dropwise, and the mixture was allowed to agitate overnight at room temperature (20-30° C.). The reaction mixture was then filtered and the filter cake was washed with a small amount of acetone. The combined filtrates were evaporated. This gave 32.3 g of 1-Bromo-3-methoxymethoxy-benzene. The resulting crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:17]([OH:19])=[O:18])=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:1][C:2]1[O:3][C:4]([C:17]([O:19][CH3:25])=[O:18])=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc3c(c2)CCCC3)c(C(=O)O)o1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1oc(C)nc1-c1ccc2c(c1)CCCC2
Yield: 76 %

Procedure:
To a solution of [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]carboxylic acid (6.0 g) in methanol (120 mL) was added conc. sulfuric acid (6.0 mL) and the mixture was stirred with heating under reflux for 18 hrs. The reaction mixture was concentrated and the residue was diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give methyl [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]carboxylate (4.75 g, yield 76%) as crystals. Recrystallization from ethanol gave colorless crystals. melting point: 96–97° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([F:15])[C:12]=2[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:16][C:10]1[C:9]([CH3:17])=[C:8]2[C:13](=[C:12]([F:14])[C:11]=1[F:15])[N:4]([CH:3]=[CH2:2])[CH:5]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:7]2=[O:18]
Reactant: CCOC(=O)c1cn(CCBr)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cn1cc(C(=O)OCC)c(=O)c2c(C)c(F)c(F)c(F)c21
Temperature: 80 °C
Yield: 96.1 %

Procedure:
A rapidly stirred suspension of 1.98 g (5.08 mmol) of ethyl 1-(2-bromoethyl)-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate, 3.50 g (25.3 mmol) of ground potassium carbonate, and 40 ml of DMF was heated at 80° C. under argon for four hours. The suspension was concentrated and the residue was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate and concentrated to give 1.52 g of the title compound as a DMF complex, mp 150°-152° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]2[N:28]([CH3:36])[C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[CH:38]=[CH:37][C:27]3[N:28]([CH3:36])[C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)C(C)(C)CCC(=O)N4C)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (60%); 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.48 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 8.04 (d, J=9.26 Hz, 1H), 7.84 (s, 1H), 7.65 (d, J=8.20 Hz, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 7.13 (d, J=8.65 Hz, 1H), 7.00 (m, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.17 (s, 3H), 2.12 (m, 2H), 1.90 (m, 2H), 1.16 (s, 6H); MS (m/e)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:30])([CH3:29])[CH2:11][C:12](=[O:28])[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]4[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=4[CH:27]=3)=[O:14])[C:4]=2[O:3][CH2:2]1.[F:31][C:32]([Si](C)(C)C)([F:34])[F:33].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:30])([CH3:29])[CH2:11][C:12]([OH:28])([C:32]([F:34])([F:33])[F:31])[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]4[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=4[CH:27]=3)=[O:14])[C:4]=2[O:3][CH2:2]1
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC(C)(C)c3cccc4c3OCO4)cc12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cccc4c3OCO4)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.67 g of 6-[4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxo-valeroyl-amino]-4-methyl-2,3-benzoxazin-1-one is dissolved under argon in 35 ml of dimethylformamide and mixed with 4.66 ml of trifluoromethyl-trimethylsilane and 2.6 g of cesium carbonate while being cooled with ice. After 18 hours of stirring at room temperature, a spatula tip full of tetrabutylammonium fluoride is added, and it is stirred for one hour at room temperature. After 300 ml of water is added, it is extracted with ethyl acetate, the organic phase is dried (Na2SO4) and concentrated by evaporation. The crude product is chromatographed on silica gel. With hexane/ethyl acetate (80:20), 1.33 g of the title compound is obtained in a pure state.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC(C)C)[nH]n1
Yield: 29 %

Procedure:
As described for example 17e, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (31 mg, 29%) which was obtained as a white solid. MS: m/e=360.2 [M+H]+.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([O:17][S:40]([CH3:39])(=[O:42])=[O:41])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)O)[C@H]2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1
Yield: 91.1 %

Procedure:
p-Nitrobenzyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e4) (100 mg) was suspended in dichloromethane (6 ml) containing triethylamine (45 mg). The mixture was cooled to 0° and methanesulphonyl chloride (38.4 mg in 1.3 ml dichloromethane) was added dropwise over 5 minutes. After 25 minutes at 0° further quantities of triethylamine (15 mg) and methanesulphonyl chloride (13 mg) were added to the solution. After a further 10 minutes the solution was diluted with dichloromethane (10 ml) and was washed with cold water (20 ml), phosphate buffer (pH 3.1) (20 ml) and 5% NaHCO3 solution (20 ml). The organic layer was dried (MgSO4) and evaporated in vacuo to afford p-nitrobenzyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (e5) as a yellow foam (107 mg); νmax (CH2Cl2) 1780, 1700, 1625, 1525, 1350, 1330 and 1175 cm-1.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[CH:15]1([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:28]([C@H:30]([CH3:39])[C@H:31]([OH:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH2:17][CH2:16]1.C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:62][CH:63]3[CH2:67][CH2:66][CH2:65][CH2:64]3)=N2)C=1)(C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:63]1([CH2:62][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([S:18][CH:15]3[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[C:26]([N:28]([C@H:30]([CH3:39])[C@H:31]([OH:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:29])=[O:27])[CH2:67][CH2:66][CH2:65][CH2:64]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)Cc1ccc(SC2CC2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
A round bottom flask with a stir bar and argon inlet was charged with tetrahydrofuran (10 mL) and cooled to −78° C. 1,1,1,3,3,3-hexamethyldisilazane (1.2 mL, 5.69 mmol) was then added followed by the dropwise addition of a solution of n-butyl lithium (2.5M solution in hexanes, 2.12 mL, 5.32 mmol) and it was stirred at −78° C. for 15 min. After this time, a solution of 2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-acetamide (900 mg, 2.53 mmol) in tetrahydrofuran (6 mL) was added dropwise over 10 min keeping the reaction below −60° C. It was then stirred for 15 min, warmed to 0° C. and stirred for 20 min and then recooled to −78° C. It was then treated with a solution of iodomethylcyclopentane (prepared in PCT WO 2004/052869 A1 Example 1, 798 mg, 3.79 mmol) in 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (643 μL, 5.32 mmol) dropwise. The reaction was then stirred at −78° C. for 30 min and then warmed to 0° C. and stirred for 3 h. The reaction was then diluted with ethyl acetate (30 mL) and washed with a saturated aqueous ammonium chloride solution (3×10 mL). The aqueous layers were then combined and extracted with ethyl acetate (2×10 mL). The organics were then washed with a saturated aqueous brine solution (15 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 25% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (719 mg, 65%) as a clear colorless oil: [α]25589=−52.6° (c=0.19, methanol); ES-HRMS m/e calcd for C27H35NO2S (M+H)+ 438.2462, observed 438.2461.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]1.CO>CN1C(=O)CCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]4)[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(Br)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(N[C@H]4CC[C@H](O)CC4)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 160 °C

Procedure:
A mixture of 46A (25 mg, 0.046 mmol) and (trans)-4-aminocyclohexanol (100 mg, 0.868 mmol) in NMP (0.4 mL) was heated at 160° C. in a microwave for 1.5 h (300 W), and then cooled to room temperature. The mixture was diluted by MeOH, and purified by preparative reversed-phase HPLC to give 6-((trans-4-aminocyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-((6-((trans-4-hydroxycyclohexyl)amino)-2-pyridinyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (12 mg, 28%) as a yellow solid. HPLC Rt=2.517 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=575.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:14])[C:11]=1[S:12][CH3:13])[CH:7]=[O:8]>CO.C(Cl)Cl>[F:14][C:10]1[CH:9]=[C:6]([CH2:7][OH:8])[CH:5]=[C:4]([F:3])[C:11]=1[S:12][CH3:13]
Reactant: CSc1c(F)cc(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CSc1c(F)cc(CO)cc1F
Temperature: 25 °C

Procedure:
Sodium borohydride (25 mg, 0.66 mmol) was added to a 0° C. slurry of the product of step A (124 mg, 0.659 mmol) in methanol (4.39 mL). After 30 min the reaction mixture was warmed to room temperature, and at 1.5 h the reaction was diluted with DCM and quenched with 0.1 N HCl. The aqueous was extracted with DCM (2×) and then washed with saturated aqueous NaCl (1×). The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 6.81 (d, J 7.5 Hz, 2H), 4.55 (s, 2H), 3.23 (s, 1H), 2.37 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([F:27])[CH:33]=4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(I)cc3)nc2)CC1
Reactant: OB(O)c1ccnc(F)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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(F)c4)cc3)nc2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a sealed tube was added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-iodophenyl)acetamide 177-2 (520 mg, 1.1 mmol), 2-fluoropyridin-4-ylboronic acid 178-1 (237 mg, 1.6 mmol), Pd(PPh3)4 (65 mg, 0.055 mmol), saturated Na2CO3 (5 mL), ethanol (5 mL) and toluene (15 mL). The reaction was heated to 110° C. and stirred for 16 hours. The reaction was cooled down to room temperature, then extracted with ethyl acetate. The crude product was purified by silica-gel flash chromatography, eluted with ethyl acetate to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-fluoropyridin-4-yl)phenyl)acetamide 178 as off-white solid. MS m/z 434.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.58 (s, 1H), 8.30 (d, 1H, J=5.6 Hz), 8.04 (d, 1H, J=2.8 Hz), 7.94 (d, 1H, J=9.2 Hz), 7.84-7.82 (m, 2H), 7.71-7.69 (m, 1H), 7.53-7.49 (m, 3H), 7.44 (dd, 1H, J1=9.2 Hz, J2=2.8 Hz), 3.76 (s, 2H), 3.59 (b, 4H), 3.16 (t, 2H, J=2.8 Hz), 3.09 (t, 2H, J=2.8 Hz), 2.04 (s, 3H).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].Br[CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:4]([O:3][C:1]([N:11]1[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[C:13](=[O:17])[CH2:12]1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OCCBr
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCN1CCN(C(=O)OCc2ccccc2)CC1=O
Reaction time: 1 h

Procedure:
Amine preparation: to 4-CBZ-piperazin-2-one (1.95 g) in DMF (5 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 660 mg) in several aliquots. After stirring for 1 h, 2-bromoethylacetate (1.38 ml) was added. The reaction mixture was stirred at room temperature overnight; it was then diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The resulting residue was purified using flash chromatography to yield 4-(2-acetoxy-ethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (925 mg).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc4ccccc43)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate B instead of Intermediate C and with indole instead of 2-phenyl-1H-imidazole. LCMS: 376.2 m/z (M+H)+; ret. Time: 9.10 min (Analytical Method A).