Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>CO>[C:1]1([NH:7][C:8](=[S:11])[NH:9]/[N:10]=[CH:12]/[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccnc1
Reactant: NNC(=S)Nc1ccccc1
Solvent: CO
Product: S=C(N/N=C/c1cccnc1)Nc1ccccc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
4-Phenylthiosemicarbazide (890 mg, 5.3 mmol, 1.0 equiv) was added to a stirred solution of nicotinaldehyde (500 μL, 5.3 mmol, 1.0 equiv) in methanol (2.5 mL) at 23° C. The resulting pale yellow solution was heated to 65° C. and stirred for 3 h. The cooled reaction mixture was concentrated under vacuum. The residue was rinsed with cold ethyl acetate and vacuum-filtered to afford the title compound as off-white crystals (1.3 g, 93%): mp 208-210° C.; IR (KBr thin film) 3442 (w), 3298 (m), 3125 (w), 2940 (w), 2791 (w), 1594 (s), 1532 (s) cm−1; 1H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.22 (s, 1H), 9.03 (d, J=2 Hz, 1H), 8.59 (dd, J=5, 2 Hz, 1H), 8.38 (dt, J=8, 2 Hz, 1H), 8.18 (s, 1H), 7.55 (m, 2H), 7.45 (dd, J=8, 5 Hz, 1H), 7.21 (m, 1H); ESIMS m/z 257 ([M+H]+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH:32]6[CH2:34][CH:29]5[CH2:30][NH:31]6)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:35])[C:8]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][C:38]([CH3:40])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][C@@H:32]6[CH2:34][C@H:29]5[CH2:30][N:31]6[CH:38]([CH3:40])[CH3:37])=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:35])[C:8]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)=O
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CC2CC1CN2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
Treat a solution of chiral 1-cyclohexyl-3-[3,5-dichloro-4′-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.096 g, 0.18 mmol) in methanol (3 mL) and acetone (0.105 g, 1.81 mmol) with sodium cyanoborohydride (0.055 g, 0.88 mmol) and then acetic acid (0.057 g, 0.94 mmol). Stir the mixture for 3 hours at room temperature under a nitrogen atmosphere, dilute with ethyl acetate and wash with saturated sodium bicarbonate then water. Dry the organic layer with sodium sulfate and purify the crude product by silica gel chromatography using a gradient of 0 to 10% methanol in dichloromethane to afford 71 mg (68%) of the title compound: MS (m/z): 568 (M+).
Reaction SMILES: C(O)(=O)C(O)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[NH2:19])=[CH:10][CH:9]=1.C1CCN2C(=NCCC2)CC1.[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32]>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[NH:19][S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])=[CH:12][CH:13]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC1CCCC1c1ccc(Br)cc1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(4-bromo-phenyl)-cyclopentylamine oxalate salt (500 mg, 1.51 mmol), methylene chloride (5.0 mL) and the solution was cooled to 0° C. DBU (1.8 mL, 12.1 mmol) and isopropylsulfonyl chloride (1.02 mL, 9.06 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 233 mg (45%) of the purified title compound. The nmr was consistent with the assigned structure.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=1[CH:11]=O>C(O)(=O)C>[ClH:8].[C:2]([NH:6][N:7]=[CH:11][C:10]1[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:9]=1[Cl:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)NN=Cc1c(F)cccc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of t-butyl hydrazine hydrochloride (1.24 g, 10 mmol) and 2-chloro-6-fluorobenzaldehyde (1.1 mL, 10 mmol) dissolved in acetic acid (5 mL) was stirred at 50° C. for half hour. Hexanes (10 mL) was added, filtered and washed the white solid with hexanes (20 mL). Yield: 61%. ESMS: 229 (M+1).
Reaction SMILES: CC(C)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)=[C:9]([F:19])[CH:8]=1.[OH-].[K+]>C(O)CO.O.C(Cl)Cl>[F:19][C:9]1[CH:8]=[C:7]([NH2:6])[CH:12]=[CH:11][C:10]=1[CH:13]1[CH2:14][CH2:15][S:16][CH2:17][CH2:18]1
Reactant: CC(C)COC(=O)Nc1ccc(C2CCSCC2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: OCCO
Solvent: O
Product: Nc1ccc(C2CCSCC2)c(F)c1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 2-methylpropyl[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]carbamate (Step 1, 2.12 g, 6.81 mmol) in ethylene glycol (25 mL) is treated with aqueous potassium hydroxide (45%, 25.5 g, 204 mmol) with vigorous stirring, and the mixture is heated to 95° C. and stirred at this temperature for 18 h. The reaction is then cooled to ambient temperature and diluted with water (50 mL) and CH2Cl2 (100 mL), the layers are separated, and the organic phase is washed with water (50 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product is chromatographed on a Flash 40M 90 g silica gel cartridge with a gradient of EtOAc/heptane (15/85–25/75), and those fractions with an Rf=0.32 by TLC (EtOAc/hexanes, 25/75) are pooled and concentrated to give the title compound, mp 96–98° C.; MS (ESI+) for C11H14NFS m/z 212 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:10]([C:24]3[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(Cl)c23)cn1
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (4.1 g, 10 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.1 g, 10 mmol) and potassium carbonate (2.8 g, 20 mmol) in aqueous 1,4-dioxane was added dichlorobis(triphenylphosphine)palladium(II) (350 mg, 0.50 mmol). The reaction mixture was degassed and purged with nitrogen; this procedure was carried out a total of three times. After heating at reflux for 18 hours, the reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 2.0 g, 5.5 mmol, 55%. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.68 (d, J=0.5 Hz, 1H), 7.62 (br s, 1H), 7.36 (s, 1H), 5.68 (s, 2H), 3.99 (s, 3H), 3.54-3.59 (m, 2H), 0.91-0.97 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:32])=[C:6]([CH:31]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:21]=[N:22][N:23]([CH2:25][C:26]([O:28]CC)=[O:27])[N:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:32])=[C:6]([CH:31]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[N:21]=[N:22][N:23]([CH2:25][C:26]([OH:28])=[O:27])[N:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Br)ccc4Cl)CC3)nc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Br)ccc4Cl)CC3)nc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the ethyl (5-{2-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetate (50 mg, 0.096 mmol) in THF (319 μL) and MeOH (159 μL) was added 2 N NaOH (96 μL, 0.191 mmol) and the was mixture stirred at RT for 10 min. The THF and MeOH were evaporated and the aqueous layer was washed with Et2O (2×2 mL). The aqueous layer was acidified to pH 1 with 2 N HCl and stirred for 5 min. The mixture was filtered and washed with water followed by 1:1 Et2O/hexanes. The solid was dried under high vacuum to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.Cl[C:18]1[NH:22][C:21]2[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:26]([I:27])[C:20]=2[N:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:18]2[NH:19][C:20]3[C:26]([I:27])=[CH:25][C:24]([C:28]([F:31])([F:29])[F:30])=[CH:23][C:21]=3[N:22]=2)[C@H:10]([CH3:14])[CH2:9]1
Reactant: FC(F)(F)c1cc(I)c2nc(Cl)[nH]c2c1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(I)c2[nH]1

Procedure:
The piperazine from step (a) above (73 mg, 0.3 mmol) reacted with 2-chloro-4-iodo-6-(trifluoromethyl)-1H-benzoimidazole (69 mg, 0.2 mmol, Example 61c) under the conditions of Example 3c to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 552 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=1)[CH3:2].[CH2:16](OC(C1C=C(CCC)N=C(SC)N=1)=O)C>>[CH3:12][S:9]([C:7]1[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=[C:3]([CH2:1][CH2:2][CH3:16])[N:8]=1)(=[O:11])=[O:10]
Reactant: CCCc1cc(C(=O)OCC)nc(SC)n1
Reactant: CCc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Product: CCCc1cc(C(=O)O)nc(S(C)(=O)=O)n1

Procedure:
The title compound is obtained as a yellow solid (371 mg) in analogy to 6-ethyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid starting from 2-methylsulfanyl-6-propyl-pyrimidine-4-carboxylic acid ethyl ester; LC-MS: tR=0.65 min, [M+H]+=244.95.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]=[N:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[C:2]([O:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:7]=1
Reactant: CCCCCCCCBr
Reactant: N#Cc1ccc(N=Nc2ccc([N+](=O)[O-])cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCOc1cc(N)ccc1N=Nc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
10 g (37.3 mmol) of 4-((2-hydroxy-4-nitrophenyl)diazenyl)benzonitrile is dissolved in 200 mL of acetone, and 7.8 mL (44.9 mmol) of 1-bromooctane and 10.3 g (74.5 mmol) of potassium carbonate (K2CO3) are added thereto. Subsequently, the resultant reaction mixture is agitated at 60° C. for 24 hours while being refluxed, and then the temperature is lowered to room temperature. The reaction mixture is concentrated, dissolved in dichloromethane (CH2Cl2), passes through a silica gel pad, and the filtrated solution is recrystallized using dichloromethane (CH2Cl2) and n-hexane. The purified compound is dissolved in 150 mL of hot ethanol, and 12.5 g (74.4 mmol) of Na2S.5H2O dissolved in hot ethanol and water is added thereto. Subsequently the resultant reaction mixture is agitated at 80° C. for 5 hours, and then the temperature is lowered to room temperature. The resultant precipitated crystal is filtered, washed with water several times, and dried, thus obtaining 8.9 g (25.4 mmol) of 4-((4-amino-2-(octyloxy)phenyl)diazenyl)benzonitrile of the following Chemical Formula 1a-1. A yield is 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=[N:43][CH2:44][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48].Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C)CCCN>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:25](=[O:26])[NH:43][CH2:44][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])([CH3:28])[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)CCCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NCCCN(C)C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added N,N-dimethyl-propane-1,3-diamine (19 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (7 mg).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:23][CH2:22]3)=[N:13][N:12]2[CH:41]=1)=[O:8])C.[OH-].[Na+]>C(O)C>[C:35]1([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([CH:41]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:42])=[O:3])=[O:8])[N:10]=4)[N:13]=3)[CH2:22][CH2:23]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)CNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
0.810 g of N-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazine-2-carbonyl]glycine ethyl ester was dissolved in 4 ml of ethanol; 2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure; ice water and 2.1 ml of 1 N hydrochloric acid were added to the residue, followed by extraction with ethyl acetate-tetrahydrofuran (1:2); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was powdered by the addition of ethyl acetate, collected by filtration and washed with ethyl acetate to yield 0.183 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH:9]([OH:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:34])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH:9]([O:18][C:26]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)CCCC(O)C(=O)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(F)cc1
Yield: 92.6 %

Procedure:
To a mixture of ethyl 6-(4-fluorophenyl)-5-hydroxy-6-oxohexanoate (13.5 g), pyridine (4.40 g) and tetrahydrofuran (100 ml) was added dropwise phenyl chlorocarbonate (8.67 g) with stirring under ice-cooling. The mixture was stirred at room temperature for 16 hours. This reaction mixture was concentrated, diluted with ethyl acetate (400 ml) and washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluorophenyl)-6-oxo-5-phenoxycarbonyloxyhexanoate as a yellow oil (18.1 g, 93%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5](=O)[NH:4][C:3]1=[O:9].N1C=CN=C1.C(N(CC)CC)C.Cl[Si](C)(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)(Cl)Cl.O>[CH2:27]([NH:34][C:5]1[C:6](=[O:7])[N:2]([CH3:1])[C:3](=[O:9])[N:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN1C(=O)NC(=O)C1=O
Reactant: NCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1C(=O)N=C(NCc2ccccc2)C1=O
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a solution of 1-methyl-imidazolidine-2,4,5-trione (Example 1.3, Part A) (800 mg, 6.25 mmol), imidazole (467 mg, 6.87 mmol), N,N-dimethylaminopyridine (cat.) and triethylamine (1.82 mL, 13.1 mmol) in chloroform (13 mL) was added chlorotrimethylsilane (1.67 mL, 13.1 mmol) dropwise at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred for 2 h. Benzylamine (0.75 mL, 6.87 mmol) was added and the reaction mixture was stirred for a further 22.5 h. The reaction mixture was diluted with chloroform and water and the chloroform extracts were dried and evaporated. The crude product was purified by column chromatography (PS with gradient elution to DCM:EtOAc 3:1) to give the product as a colourless solid (838 mg, 62%), mp 152-154° C. δH (300 MHz, CD3CN) 7.95 (v br s, 1H, NH), 7.41-7.27 (m, 5H, PhH), 4.64 (s, 2H, CH2), 2.95 (s, 3M, CH3). Mass spectrum (ESI) m/z 218 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=O)[CH:8]=2)[N:3]=1.[Cl-].[OH:34][NH3+:35]>CO.N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:35][OH:34])[CH:8]=2)[N:3]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cccc(C(=NO)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C

Procedure:
To a solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.090 g, 0.213 mmol, prepared as Example 15, Step 1) in MeOH (4.0 mL) was added hydroxyammonium chloride (0.044 mL, 1.063 mmol) followed by 3 drops of pyridine. The reaction mixture was brought up to reflux for 41 h until the conversion was completed, determined by LCMS. The reaction mixture was cooled to RT and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA) to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone oxime as a off-white solid. MS (ESI, pos. ion) m/z: 439 (M+1).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Si:27]([O:34][CH:35]([C:41]1([CH2:45][CH2:46][CH3:47])[CH2:44][CH2:43][CH2:42]1)[CH2:36][CH:37]=[CH:38][CH2:39]O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl.CCCCCC>[Br:1][CH2:39][CH:38]=[CH:37][CH2:36][CH:35]([C:41]1([CH2:45][CH2:46][CH3:47])[CH2:44][CH2:43][CH2:42]1)[O:34][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: BrBr
Reactant: CCCC1(C(CC=CCO)O[Si](C)(C)C(C)(C)C)CCC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCC1(C(CC=CCBr)O[Si](C)(C)C(C)(C)C)CCC1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Bromine (0.17 mL, 3.22 mmol) was added to a solution of triphenylphosphine (844 mg, 3.22 mmol) and imidazole (219 mg, 3.22 mmol) in CH2Cl2 (11.0 mL) at 23° C. After 0.5 h a solution of the alcohol 7 (838 mg, 2.68 mmol) in CH2Cl2 (2.7 mL) was added. The reaction was stirred for 1 h, diluted with hexane and then filtered through celite. The filtrate was concentrated in vacuo and purified by FCC (silica gel, 100% hex) to give 870 mg (86%) of the bromide 8 as a clear, light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[C:17]1([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][C:25]([CH:34]=O)=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][C:25]([CH2:34][NH:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH2:13][CH2:12]3)=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Product: Fc1ccccc1N1CCN(CCNCc2cc(-c3ccccc3)n(-c3ccccc3)n2)CC1
Yield: 74.5 %

Procedure:
Compound 68 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([CH:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)[CH2:6]1)[CH2:3][NH:2]2.[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1>[CH3:18][C:17]([CH3:19])([CH3:20])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([CH:5]3[CH2:6][CH:1]4[CH2:24][CH2:23][CH:4]3[CH2:3][N:2]4[C:30]([C:27]3[CH:28]=[CH:29][O:25][N:26]=3)=[O:31])=[CH:8][CH:9]=2)[N:13]([CH3:22])[C:14]1=[O:21]
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CCC3CN4)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CCC3CN4C(=O)c3ccon3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5-1, 30.2 mg, 0.09 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 15.6 mg, 0.14 mmol, 1.5 equiv), DIPEA (48 μL, 0.28 mmol, 3.0 equiv) and HATU (52.4 mg, 0.14 mmol, 1.5 equiv) were added to anhydrous 1,4-dioxane (0.92 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 5-2 as a white solid. MS m/z (M+H): calculated=424.2343; observed=424.2345.