Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([C:17]#[C:18][CH3:19])=[O:16].[C:20]([Mg]Br)#[C:21][CH3:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([C:20]#[C:21][CH3:22])([C:17]#[C:18][CH3:19])[OH:16]
Reactant: CC#CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: CC#C[Mg]Br
Product: CC#CC(O)(C#CC)c1cc(-c2cccc(Cl)c2)ccc1N

Procedure:
Following the procedure of Example 41, (4-amino-3′-chloro-biphenyl-3-yl)-propynyl-methanone (mp 112-114° C.; MS ((+) ESI) m/z 270/272 (M+H)+) was treated with propynylmagnesium bromide to give (4-amino-3′-chloro-biphenyl-3-yl)-dipropynyl-methanol which was reacted with 1,1′-carbonyldiimidazole to afford the title compound. Yellow solid: mp 151° C. (decomposed); 1H-NMR (DMSO-d6) δ 10.8 (s, 1H), 7.71 (dd, 1H, J=8.52, 1.94 Hz), 7.69 (m, 2H), 7.61 (d, 1H, J=7.64 Hz), 7.50 (t, 1H, J=7.85 Hz), 7.43 (d, 1H, J=7.99 Hz), 7.06 (d, 1H, J=8.23 Hz), 2.0 (s, 6H); MS (APCI) m/z 336 ([M+H]+, 20%).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([Br:15])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].NC1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][C@@H:25]([N:28]([CH3:30])[CH3:29])[CH2:24]2)=[CH:19][CH:18]=1>>[Br:15][C:7]1[S:6][C:5]2[C:3](=[O:4])[N:12]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C@@H:25]([N:28]([CH3:30])[CH3:29])[CH2:24]4)=[CH:19][CH:18]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Reactant: COC(=O)c1sc(Br)cc1N=CN(C)C
Product: CN(C)[C@@H]1CCN(c2ccc(-n3cnc4cc(Br)sc4c3=O)cc2)C1

Procedure:
5-Bromo-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with [(R)-1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method A1. The product with the molecular weight of 418.05 (C18H19BrN4OS) was obtained in this way; MS (ESI): 419 (M+H+).
Reaction SMILES: [CH:1]([CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4]1=[O:5])=C.[CH3:11][N:12](CCCC=C(C)C(N)=O)[CH3:13].[C:23]([O:28][CH2:29][CH2:30][OH:31])(=[O:27])[C:24]([CH3:26])=[CH2:25]>O>[CH3:1][C:3]([C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:12]([CH3:13])[CH3:11])=[O:5])=[CH2:10].[CH3:26][C:24]([C:23]([O:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH2:25]
Reactant: C=CC1CCCCNC1=O
Reactant: CC(=CCCCN(C)C)C(N)=O
Agent: C=C(C)C(=O)OCCO
Solvent: O
Product: C=C(C)C(=O)NCCCN(C)C
Temperature: 60 °C

Procedure:
Five hundred grams (500 g) of de-ionized water was added to 1000 g of a 30% aqueous solution of a terpolymer of vinyl caprolactam (VCap), dimethylamino propyl methacrylamide (DMAPMA), and 2-hydroxyethyl methacrylate (HEMA). GMA (12 g) was added drop-wise with continuous stirring. The obtained solution was heated at 60° C. for one hour. The resulting product was freeze dried to render a solid, white powder. A representative structure for the polymeric reaction is presented below, wherein x+y+z+a=100:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1([O:16][CH2:15][CH2:14][O:13]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:15]1[CH2:14][O:13][C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([CH2:5][CH2:4][CH2:3][OH:2])[O:16]1
Reactant: COC(=O)CCC1(c2ccccc2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCCC1(c2ccccc2)OCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 1.7 g of the ester compound obtained in 20 ml of dry diethyl ether was added 0.7 g of lithium aluminum hydride under ice-cooling, the mixture was stirred for 1 hour at 0° C., and then heated under reflux for 17 hours. After cooling, the reaction mixture was treated successively with an aqueous diethyl ether solution and water, and the precipitate was filtered off. The filtrate was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/ethyl acetate=10/1 by volume) to obtain 1.3 g of 4,4-ethylenedioxy-4-phenylbutyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[N+](C1C=CC=CC=1S([N:26]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)(=O)=O)([O-])=O.[BH3-]C#N.[Na+]>CO.C(OC)(OC)OC.C(O)(=O)C>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:35][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)=[CH:32][CH:33]=1
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(NCc1ccc(CNCc3ccccn3)cc1)CC2
Yield: 76.3 %

Procedure:
Using General Procedure G: 7-methoxy-2-tetralone (60 mg, 0.34 mmol), N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (100 mg, 0.24 mmol) and NaBH3CN (59 mg, 0.94 mmol) in MeOH (3 mL), trimethyl orthoformate (1.7 mL) and acetic acid (3 drops) were reacted for 3.5 hours. Following work-up, the crude material was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) to give the desired product (71 mg, 52%) as a yellow foam.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([CH3:10])=[N:3]1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=4)=[O:9])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1cc(C(=O)O)n(C)n1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Temperature: 79 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A dry 250 mL flask was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (0.989 g, 7.057 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (40 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.26 g, 4.994 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a tan solid (1.4 g, 3.74 mmol, 75%).
Reaction SMILES: [CH2:1]([CH:5]([C:9](O)=O)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4].N1CCCCC1.C=O>C(O)C>[CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C(=O)O)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C(CCCC)C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of n-butylmalonic acid (17.2 g, 107 mmol) in ethanol (200 ml) was added piperidine (12.76 ml, 129 mmol) and 37% aq. formaldehyde (40.3 ml, 538 mmol). The solution was heated to 80° C. during which time a precipitate appeared and then gradually redissolved over 1 hour. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate (200 ml), washed successively with 1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a clear oil (13.37 g, 97%). 1H-NMR; δ (CDCl3), 6.29 (1H, s), 5.65 (1H, s), 2.34-2.28 (2H, m), 1.54-1.26 (4H, m) and 0.94 (3H, t, J=7.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([NH:16][NH2:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[C:18]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)(=O)[CH3:19].C(O)C>C(O)(=O)C.O1CCCC1>[N:24]1[CH:25]=[CH:26][C:21]([C:18](=[N:17][NH:16][C:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:15])[CH3:19])=[CH:22][CH:23]=1
Reactant: CC(=O)c1ccncc1
Reactant: NNC(=O)c1cc([N+](=O)[O-])cc2ccccc12
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NNC(=O)c1cc([N+](=O)[O-])cc2ccccc12)c1ccncc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A mixture of 5.0 gm of (0.0216 mole) of 3-nitro-1-naphthalenecarboxylic acid hydrazide, 2.62 gm (0.0216 mole) of 4-acetylpyridine, 400 ml of ethanol, 100 ml of tetrahydrofuran, and 20 drops of glacial acetic acid was refluxed 10 hr. The hot solution was filtered. The filtrate was cooled to room temperature and then chilled. The product was collected, washed with Skellysolve B and dried to furnish 6.31 gm (87%) of the title compound having a melting point of 228.5° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(O)[CH2:11][CH2:10]1)=O)(C)(C)C.[OH-].[Na+]>C(O)(=O)C>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH:11]=2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(Sc2ccccc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc(Sc2ccccc2C2=CCNCC2)cc1
Temperature: 25 °C

Procedure:
Concentrated aq hydrochloric acid (10 ml) was added to a stirred solution of 1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol (0.84 g, 2.1 mmol) in acetic acid (30 mL). The solution was boiled under reflux overnight, cooled to room temperature and then stirred in an ice bath. An aqueous solution of NaOH (9.1 M, 40 mL) was slowly added and the unclear solution was extracted with ethyl acetate (2×40 ml). The combined organic phases were dried (MgSO4) and the solvents evaporated in vacuo. The crude material (0.48 g) was dissolved in ethyl acetate (3.2 mL) at 50° C. and a solution of oxalic acid (0.11 g) in EtOH (3.2 mL) was slowly added. The target compound was collected as a white oxalic salt. 1H (DMSO-d6) δ 7.3-7.2 (m, 7H); 7.15 (m, 1H); 7.00 (m, 1H); 5.6 (d, 1H); 3.7 (d, 2H); 3.25 (t, 2H); 2.6 (m, 2H); 2.3 (s, 3H). LC/MS (m/z) 282.2 (MH+); RT=2.24; purity (UV, ELSD): 99%, 100%; yield: 0.31 g (40%).
Reaction SMILES: C([OH:4])(C)C.[CH2:5]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10])[CH:6]=[CH2:7].C1CCN2C(=NCCC2)CC1.[CH:31]1([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH:45](Br)[CH3:46])[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CO.C(Cl)(Cl)Cl>[CH2:5]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:46][CH2:45][CH2:44][C:43]([N:40]3[CH2:41][CH2:42][N:37]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:38][CH2:39]3)=[O:4])=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10])[CH:6]=[CH2:7]
Reactant: CC(Br)CCN1CCN(C2CCCCC2)CC1
Reactant: CC(C)O
Reactant: C=CCN1C(=O)CCc2cc(O)ccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCN1C(=O)CCc2cc(OCCCC(=O)N3CCN(C4CCCCC4)CC3)ccc21

Procedure:
Into 100 ml isopropanol were added 2.0 g of 1-allyl-6-hydroxy-3,4-dihydrocarbostyril and 1.8 ml of DBU. The mixture was refluxed under stirring and 4.2 g of 4-cyclohexyl-1-γ-bromobutylpiperazine was added thereto. After the addition operation, the reaction mixture was further refluxed under stirring for 8 hours, then concentrated. The residue thus obtained was extracted with chloroform and the chloroform layer was washed with 1N-NaOH aqueous solution and water, then dried with anhydrous sodium sulfate. The drying agent was removed by filtration and the mother liquor was concentrated. The residue thus obtained was treated by a silica-gel column chromatography [the solvent used was a mixture of chloroform:methanol=20:1 (vol/vol)]. 3.5 Grams of 1-allyl-6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]-3,4-dihydrocarbostyril was obtained as in the form of a colorless syrupy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:30][CH:31]1[CH2:36][NH:35][CH2:34][CH:33]([CH3:37])[NH:32]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:35]4[CH2:34][C@@H:33]([CH3:37])[NH:32][C@@H:31]([CH3:30])[CH2:36]4)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Reactant: CC1CNCC(C)N1
Product: C[C@@H]1CN(C(=O)c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(Cl)cc4Cl)cc2CCO3)C[C@H](C)N1

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and 2,6-dimethylpiperazine were reacted by General Procedure B to give 360. NMR: (CDCl3): 1.01-1.20 (6 H, br m, Me), 2.40-2.62 (2 H, br, m), 2.73 (2 H, s), 2.82-2.87 (1 H, br, m), 2.98-3.00 (2 H, m), 3.29 (3 H, s, Me), 3.52-3.60 (1 H, br m), 4.18-4.21 (2 H, m), 4.45-4.55 (1 H, br, s, NH), 6.76 (1 H, s, Ar), 6.94 (1 H, d, J 8.3, Ar), 7.15 (1 H, dd, J 8.3 and 1.9, Ar), 7.23 (1 H, d, J 8.4, Ar), 7.28 (1 H, dd, J 8.5 and 2.2, Ar) and 7.44-7.48 (2 H, m, Ar). MS: (ESI+) MH+=544.11
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(C(N)C(=O)O[C@H]2CN3CCC2CC3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(NC(=O)c2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-p-tolylacetate dihydrochloride (I109) (116 mg, 0.33 mmol) in DCM (5 ml), were added triethylamine (139 μl, 1.00 mmol) and benzoyl chloride (46.5 μl, 0.40 mmol). The reaction was stirred at RT for 3 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-p-tolylacetate (70.0 mg; 55% yield). The product was used in the next step without any further purification.
Reaction SMILES: FC1C=CC(CC(=O)[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:29][N:17]3[C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=CC=1.CN1CC[O:44][CH2:43]C1.ClC(OCC)=O.CN(C)O>C1COCC1.C(Cl)Cl>[CH3:43][O:44][N:11]([CH3:10])[C:12]([C:14]1[N:15]=[C:16]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][N:17]2[C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:13]
Reactant: CN1CCOCC1
Reactant: O=C(CNC(=O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1)Cc1ccc(F)cc1
Agent: CCOC(=O)Cl
Agent: CN(C)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: -12 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
3-Benzyloxy-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (product of example 5, 100 mg, 0.263 mmol) was dissolved in THF (1 mL) and DCM (11 mL) and cooled to −20° C. N-Methylmorpholine (30 μL, 0.265 mmol) was added and the temperature was raised to −12° C. Ethyl chloroformate was added and after 2 minutes, the solution of dimethylhydroxylamine. The reaction was warmed to room temperature and stirred for one hour. After this time, the mixture was quenched by addition of 0.2 M HCl. The layers were separated and the organic layer was washed sequentially with 0.2 M HCl, 0.5 M NaOH (2×) and brine. Then dried and concentrated. The product was isolated as a yellow solid (112 mg, 100% yield) and was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl.CS(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH:16]=[C:17]([CH:19]=[O:20])[N:18]=2)=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CO)nc2-c2ccc(Cl)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-n2cc(C=O)nc2-c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
To 8 ml of a 1:1 mixture of dimethyl sulfoxide and dichloromethane stirring in a dry ice/isopropanol bath under nitrogen was added dropwise oxalyl chloride (321 μl, 3.69 mmol) After stirring for 10 minutes, a solution of 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-methanol (Example 158) (670 mg, 1.85 mmol) in 25 ml of a 1:1 mixture of dimethyl sulfoxide and dichloromethane. Stirring was continued while warming to 0° C., where it was maintained for 15 minutes. Triethylamine (1.87 g, 18.5 mmol) was added, and the mixture was stirred overnight while warming to room temperature. The mixture was partitioned between dichloromethane and water, the organic layer was washed with water and then brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane gave the title compound as an off-white solid (330 mg): mp (DSC) 203° C. Anal. Calc'd. for C17H13ClN2O3S (MW 360.82): C, 56.59; H, 3.63; N, 7.76. Found: C, 56.24; H, 3.62; N, 7.50.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1>>[C:41]([C:40]1[CH:43]=[C:36]([C:2]2[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:37]=[N:38][CH:39]=1)#[N:42]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 156.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a white solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=472.2 [M+H]+, m/z=470.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=6.97 Hz, 3H) 3.14 (q, J=7.01 Hz, 2H) 3.32-3.41 (m, 2H) 3.49 (q, J=5.71 Hz, 2H) 4.62 (t, J=5.26 Hz, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.77-7.92 (m, 2H) 8.10 (d, J=2.20 Hz, 1H) 8.54 (t, J=1.96 Hz, 1H) 8.78 (d, J=2.20 Hz, 1H) 9.04 (dd, J=5.50, 2.08 Hz, 2H) 10.25 (s, 1H).
Reaction SMILES: [C:1]1([C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Mg+].[Br-].[C:25]1(C(O)=O)C2C(=CC=CC=2)C=CC=1>C(OCC)C.S(Cl)(Cl)=O>[CH3:25][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[C:11]([C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)=[O:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=C(c1cccc2ccccc12)c1c[nH]c2ccccc12
Reactant: O=C(O)c1cccc2ccccc12
Agent: C[Mg+]
Agent: [Br-]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1[nH]c2ccccc2c1C(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 1133.2 %

Procedure:
2-Methylindole 1 (10 g, 76 3 mmol) was dissolved in diethylether (100 ml) under nitrogen atmosphere and cooled to 0° C. MeMgBr (3M) solution (26.7 ml, 80.15 mmol) was added dropwise and allowed to stir at room temperature for 3 hours. In the meantime, 1-naphthoic acid (13.13 g, 76 3 mmol) was dissolved in thionyl chloride (50 ml) and refluxed for 90 min, then the solvent was removed under vacuo and the residue was dissolved in diethylether (50 ml). The resulting solution was added dropwise to the indole reaction mixture at 0° C. and then allowed to stir at room temperature for 2 hours. A solution of ammonium chloride (200 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature overnight. The solid that was formed was collected by filtration, washed with water and hexane then dried in a dessicator over phosphorous pentoxide to give 9.7 g (45%) (2-methyl-1H-indol-3-yl)(naphthalen-1-yl) methanone 2 as a cream solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:32])[NH:28][CH:29]3[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:33]1([NH2:40])[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1.C(O)(C(F)(F)F)=O>>[NH2:39][C@H:36]1[CH2:37][CH2:38][C@H:33]([NH:40][C:2]2[CH:3]=[C:4]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:32])[NH:28][CH:29]4[CH2:31][CH2:30]4)=[CH:23][CH:22]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:34][CH2:35]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(NC1CC1)c1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccc(C(=O)NC4CC4)cc3)c3ncc(C(=O)Nc4ccncc4)n3n2)CC1
Temperature: 160 °C

Procedure:
To a 1 dram vial was added 6-chloro-8-(4-(cyclopropylcarbamoyl)phenylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (39 mg, 0.087 mmol) and (trans)-cyclohexane-1,4-diamine (99 mg, 0.871 mmol). The reaction solution was heated neat at 160° C. for 1 hour. The solution was cooled and purified by preparative HPLC to yield 6-((trans-4-aminocyclohexyl)amino)-8-((4-(cyclopropylcarbamoyl)phenyl)amino)-N-4-pyridinylimidazo[1,2-b]pyridazine-3-carboxamide (11.90 mg, 0.023 mmol, 26.0% yield) as a TFA salt. 1H NMR (500 MHz, CD3OD) δ ppm 8.73-8.76 (2H, m), 8.28-8.32 (2H, m), 8.19 (1H, s), 7.86-7.90 (2H, m), 7.41-7.45 (2H, m), 6.48-6.50 (1H, m), 3.78-3.85 (1H, m), 3.14-3.21 (1H, m), 2.83-2.88 (1H, m), 2.32-2.38 (2H, m), 2.12-2.18 (3H, m), 1.55-1.64 (3H, m), 1.42-1.51 (3H, m), 0.78-0.84 (2H, m), 0.62-0.69 (2H, m) LC/MS, m/z 526.17 (M+1). HPLC Rt, 2.21 min. Waters Sunfire C18 column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.