Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:7]=[CH:8][CH:9]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH:11]([CH3:12])[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)=[O:13]
Reactant: BrBr
Reactant: CCC(=O)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)c1cccc(Cl)c1
Yield: 60 %

Procedure:
Bromine (6.07 ml, 0.12 mol) was added to a solution of 3′-chloropropiophenone (20 g, 0.12 mol) in chloroform (250 ml) at room temperature. The reaction was followed by TLC in DCM. When all of the starting material was consumed the mixture was washed with a saturated solution of sodium bicarbonate. The organic phase was dried over magnesium sulphate, filtered and evaporated. Recrystallisation from chloroform gives the desired compound in 60% yield as a pale yellow solid (18 g, 73 mmol).
Reaction SMILES: CC(O[C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[C:27](O)(=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]C.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1ccccn1
Product: CCCCCCCCCCN[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The acylated phenylalanine anilide imprint molecule was synthesized in three steps. (1) N-α-t-BOC-L-phenylalanine was coupled with 2-aminopyridine using DCC to give N-α-t-BOC-L-phenylalanine-2-aminopyridine. (2) The a-amine was then deprotected with TFA to give N-α-L-phenylalanine-2-aminopyridine.(3) To create a compound having the properties of a surfactant, the free amine was then acylated with decanoic acid using DCC to give N-α-decyl-L-phenylalanine-2-aminopyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:14]
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1-n1ccc2ccc([N+](=O)[O-])cc2c1=O
Yield: 23.9 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (I-24a: 400 mg, 2.0833 mmol) was reacted with 3-iodo-4-methyl-pyridine (456.2 mg, 2.08331 mmol), 1,4-dioxane (4.1 mL), copper iodide (39.6 mg, 0.2083 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (88.7 mg, 0.6249 mmol) and potassium phosphate (1.1 g, 5.2082 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 140 mg of the product (23.9% yield).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26]
Reactant: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 95 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
1.90 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.38 g of N-(6-chloroimidazo-[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 15 ml of 1-methyl-2-pyrrolidone; 0.841 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water and saline were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (95:5:1). The desired fraction was collected and recrystallized from ethyl acetate to yield 1.28 g of the title compound.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=NC2CCCCC2)CCCCC1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([OH:35])=O)=[CH:17]1.CNC>CN(C=O)C.C(#N)C>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([N:7]([CH3:8])[CH3:1])=[O:35])=[CH:17]1
Reactant: O=C(O)Cc1ccccc1Sc1c[nH]c2ccccc12
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1ccccc1Sc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (875 mg, 4.2 mmol) is added to [2-(1H-Indol-3-ylsulfanyl)-phenyl]-acetic acid (600 mg, 2.1 mmol) in 3 mL dry DMF and 7 mL acetonitril and stirred for 10 minutes at room temperature. 5.3 mL dimethyl amine (2M in THF, 10.6 mmol) is added and the reaction mixture is stirred 16 hours at room temperature. The reaction mixture is concentrated in vacuo. The residue is extracted with ethyl acetate (3 times). The combined orgnic phases are washed with brine, dried with MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/heptane) gives 116 mg (18%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>CN1C(=O)CCC1.ClCCl>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:13]=[CH:12][N:11]=2)[N:8]=1)[C:30](=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC(=O)Cl
Reactant: CNc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C=CC(=O)N(C)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N4-(6-(methylamino)pyridine-2-yl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (0.07 g, 0.18 mmol) in NMP (1 mL) was added acryloyl chloride (0.032 g, 0.36 mmol) at 0° C. and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane (2 mL), was washed with NaHCO3 (1 mL), water (1 mL), and brine (1 mL). The dichloromethane solution was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give N-methyl-N-(6-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyridin-2-yl)acrylamide (I-78) as a yellow solid. 1H NMR (DMSO-d6) δ ppm: 3.22 (s, 3H), 5.60 (dd, J=2.56 & 9.76 Hz, 1H), 6.12-6.16 (m, 2H), 6.79 (d, J=7.56 Hz, 1H), 6.96 (d, J=8.64 Hz, 5H), 7.09 (t, J=7.32 Hz, 1H), 7.23 (s, 1H), 7.33-7.37 (m, 4H), 7.45 (d, J=8.2 Hz, 2H), 7.32 (t, J=7.8 Hz, 1H), 8.24 (s, 1H); LCMS: m/e 439.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[N:14]4[C@@H:15]([CH3:19])[CH2:16][O:17][CH2:18][C:13]4=[N:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:31].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[N:14]4[C@@H:15]([CH3:19])[CH2:16][O:17][CH2:18][C:13]4=[N:12][C:7]=3[C:8]([NH2:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: C[C@H]1COCc2nc3cnc4cc(Br)ccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C[C@H]1COCc2nc3c(N)nc4cc(Br)ccc4c3n21
Temperature: 25 °C

Procedure:
A 2-L, three-necked, Morton flask, equipped with mechanical stirrer, was charged with (11S)-3-bromo-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (9.12 g, 28.7 mmol) and CH2Cl2 (500 mL). The mixture was stirred at ambient temperature and MCPBA (10.35 g, 50% purity) was then added slowly in portions. The reaction was stirred at ambient temperature for 2 hours. Concentrated aqueous NH4OH solution (200 mL) was then slowly added to the reaction mixture followed by careful addition of p-toluenesulfonyl chloride (6.29 g, 33.0 mmol) in small portions. The reaction was stirred rapidly at ambient temperature overnight. The reaction was then treated with H2O (500 mL) and vigorous stirring was maintained for 2 hours. The layers were allowed to separate and a tan precipitate formed. The aqueous layer was removed and the organic layer, containing the precipitate, was filtered to give 6.0 g of (11S)-3-bromo-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a tan solid. The product was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][C:2]12[O:10][B:9]([C@@H:11]([NH:28][C:29]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][NH:35][CH2:34]4)=[O:30])[CH2:12][C:13]3[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[O:8][CH:7]1[CH2:6][CH:5]1[CH2:40][CH:3]2[C:4]1([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+].Br[CH2:50][CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56].O>CN(C=O)C>[C:55]([O:54][C:53]([NH:52][CH2:51][CH2:50][N:35]1[CH2:34][C:33]2[C:37](=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C@H:11]([B:9]3[O:8][CH:7]4[C:2]([CH3:1])([CH:3]5[CH2:40][CH:5]([CH2:6]4)[C:4]5([CH3:42])[CH3:41])[O:10]3)[CH2:12][C:13]3[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:30])[CH:32]=2)[CH2:36]1)=[O:59])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CN(CCNC(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoate from Example 9 step 2 (263 mg, 0.46 mmol) in DMF (5 mL) was added K2CO3 (252 mg, 1.84 mmol) and tert-butyl 2-bromoethylcarbamate (122 mg, 0.54 mmol). The resulting reaction was stirred at room temperature overnight. Water (15 mL) was added and the aqueous phase was extracted with EtOAc. The organic phase was washed with IN HCl, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to 1:2). ESI-MS m/z 718.1 (MH)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[C:3](=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[O:2]1.C(OCC)(OCC)O[CH2:18][CH3:19]>>[CH2:1]1[O:12][C:11]2[C:3](=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[C:5]([O:7][CH2:18][CH3:19])=[O:6])[O:2]1
Reactant: CCOC(OCC)OCC
Reactant: O=C(O)c1c([N+](=O)[O-])ccc2c1OCO2
Product: CCOC(=O)c1c([N+](=O)[O-])ccc2c1OCO2
Yield: 67 %

Procedure:
Following the procedure employed in Example 15, condensation of 2,3-methylenedioxy 6-nitrobenzoic acid (10 g) with 40 ml of triethyl orthoformate gives the title compound in 67% yield after ethanol crystallization.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[S:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[S:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2N)cs1
Yield: 100.7 %

Procedure:
Following General Procedure A, the title compound (588 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (376 mg, 2.36 mmol), tert-butyl [4-(chloromethyl)-1,3-thiazol-2-yl]carbamate (391 mg, 1.57 mmol) and K2CO3 (1.08 g, 3.45 mmol) in DMF (10 ml).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][N:8]([CH2:26][C:27]([O:29]CC)=O)[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[O:17])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][OH:33]>O1CCOCC1>[OH:33][NH:32][C:27](=[O:29])[CH2:26][N:8]([CH2:7][CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)=[O:17])=[O:10]
Reactant: CCOC(=O)CN(CCC1CCCC1)C(=O)N1CCCC1C(=O)Nc1cccc(O)c1
Reactant: NO
Solvent: C1COCCO1
Product: O=C(CN(CCC1CCCC1)C(=O)N1CCCC1C(=O)Nc1cccc(O)c1)NO
Reaction time: 36 h

Procedure:
To ethyl 2-[N-(2-(cyclopentyl)ethyl)-N-[2-(3-hydroxyphenyl)aminocarbonyl-pyrrolidin-1-carbonyl)amino]acetate (200 μmol) in dioxane (2 mL) was added 50% aqueous hydroxylamine (1 mL), and the reaction stirred for 36 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-{N-[2-(cyclopentyl)ethyl]-N-[2-(3-hydroxyphenyl)aminocarbonylpyrrolidin-1-ylcarbonyl]-amino}acetamide. 1H NMR (DMSO-d6): δ9.33 (br s, 1H), 7.25-7.24 (m, 1H), 7.07-6.99 (m, 2H), 6.45-6.41 (m, 1H), 4.38 (dd, J=8.4, 8.4, 1H), 3.88 (d, J=16.5, 1H), 3.66 (d, J=16.5, 1H), 3.48-3.46 (m, 2H), 3.27-3.22 (m, 1H), 3.20-3.01 (m, 1H), 2.19 (br s, 1H), 1.91 (br s, 1H), 1.73-1.68 (m, 5H), 1.63-1.41 (m, 6H), 1.08-1.05 (m, 2H). ES−MS: calcd. for C21H30N4O5 (418.2); found: 417.7 [M−1].
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52](O)=[O:53])=[CH:40][CH:41]=2)[N:36]=1.Cl.[NH2:56][CH:57]1[C:66]2[CH:65]=[C:64]([O:67][CH2:68][C:69]3[CH:70]=[C:71]([CH:74]=[CH:75][CH:76]=3)[C:72]#[N:73])[CH:63]=[CH:62][C:61]=2[CH2:60][CH2:59][CH2:58]1>CN(C)C=O>[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([NH:56][CH:57]3[C:66]4[C:61](=[CH:62][CH:63]=[C:64]([O:67][CH2:68][C:69]5[CH:76]=[CH:75][CH:74]=[C:71]([C:72]#[N:73])[CH:70]=5)[CH:65]=4)[CH2:60][CH2:59][CH2:58]3)=[O:53])=[CH:40][CH:41]=2)[N:36]=1
Reactant: N#Cc1cccc(COc2ccc3c(c2)C(N)CCC3)c1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC4CCCc5ccc(OCc6cccc(C#N)c6)cc54)ccc23)CC1
Reaction time: 2 h
Yield: 79.1 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 uL, 0.07 mmol) were added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) and 3-{[(8-amino-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]methyl}benzonitrile HCl salt (30 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) at r.t. The reaction was stirred for 2 h. and the product was purified without workup by RP-HPLC (pH=10) to afford the desired compound (0.013 g, 30%) as an amorphous white solid. 1H NMR (400 MHz, DMSO): δ8.84 (d, 1H), 7.77-7.6 (m, 5H), 7.46 (dd, 1H), 7.42 (m, 1H), 6.99 (d, 1H), 6.80 (dd, 1H), 6.74 (m, 1H), 6.36 (bs, 2H), 5.12 (m, 1H), 5.02 (s, 2H), 3.51 (bs, 4H), 3.27 (s, 4H), 2.62 (m, 2H), 2.17 (s, 3H), 1.88 (m, 2H), 1.70 (m, 2H). Analytical LCMS (M+H)+: m/z=548.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][C:21]2([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][C:21]2([OH:27])[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)=[O:6])[CH2:25][CH2:26]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Reactant: OC1(Cc2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)CCCN2CCC(O)(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 105 °C
Yield: 54.4 %

Procedure:
A mixture of 2.11 g of 4-chloro-1-(4-methoxy-phenyl)-butan-1-one (1), 1.60 g of 4-(4-chloro-benzyl)-piperidin-4-ol (5), 1.96 g of K2CO3, and 0.45 g of KI in acetonitrile (50 mL) was stirred and refluxed at 100 to 110° C. for 19 hours under nitrogen atmosphere. After the solvent was removed, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine and dried over MgSO4. After the solvent was removed, the obtained oily residue was purified by silica gel chromatography (chloroform:methanol=20/1 to 10/1) and the purified product was recrystallized from AcOEt/Et2O to afford 1.55 g of compound (6).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 10 g of ethyl 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate and 50 ml of phosphorus oxychloride was heated at 60°C with stirring for 1 hour. The excess phosphorus oxychloride was removed under reduced pressure and the product was poured into ice-water. The insoluble matter was filtered off, the filtrate was adjusted to pH 8 by the addition of aqueous ammonia under cooling and extracted with ether. The extracts were dried over anhydrous magnesium sulfate. Then 0.5 g of activated carbon was added to the ether extracts for decoloration. The ether extracts were filtered, concentrated to a small volume and cooled. The precipitate was filtered to provide 8.6 g of ethyl 4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate as yellow needles, m.p. 99°-100°C (decomp.).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=O)=[CH:4][CH:3]=1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)=[N:16]3)=[C:10]([CH3:11])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(Br)s3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc(Br)s4)n3n2)cc(OC)c1OC
Yield: 7.8 %

Procedure:
In a similar manner as described for Example 9, 5-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)thiophene-2-carboxamide (Intermediate 22) (0.35 g, 0.70 mmol) and 1,2,4-triazole (290 mg, 4.2 mmol) in pyridine (5 mL) and phosphorus oxychloride (0.200 mL, 2.1 mmol) gave 7-(5-bromothien-2-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.026 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.70 (s, 1H), 9.24 (s, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.38 (d, J=4.0 Hz, 1H), 7.10 (s, 2H), 3.81 (s, 6H), 3.66 (s, 3H), 2.51 (s, 3H). MS m/z 476, 478 (M+1, M+3).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]=2C)[N:6]=1)(=O)=O.[C-:26]#[N:27].[Na+].C(OCC)(=O)C>CS(C)=O>[C:21]([C:17]1[CH:16]=[C:15]([C:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[N:10]=[C:5]([C:26]#[N:27])[N:6]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: [C-]#N
Reactant: Cc1c(-c2cc(CCCO)nc(S(C)(=O)=O)n2)cccc1C(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)c1cccc(-c2cc(CCCO)nc(C#N)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
To a stirring solution of 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3-tert-butyl-methyl-phenyl)-pyrimidine (4.6 g) in DMSO (120 ml) at room temperature was added sodium cyanide (647 mg). The resulting suspension was stirred at room temperature for 3 hours. After adding ethyl acetate (200 ml), the mixture was then washed with water (100 ml×3). Organic layer was dried over MgSO4 and concentrated in vacuo, the residue was columned on silica gel using Petrol and EtOAc as eluent to give 4-(3-tert-butyl-phenyl)-6-(3-hydroxy-propyl)-pyrimidine-2-carbonitrile (4.0 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH:10]([OH:13])CO)=[CH:8][O:9][C:5]=2[CH:4]=1>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH:10]=[O:13])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(C(O)CO)coc2c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(C=O)coc2c1
Yield: 52.2 %

Procedure:
NaIO4 (0.204 g, 1.12 mmol) was added to 1-(6-methoxy-benzofuran-3-yl)-ethane-1,2-diol (0.180 g, 1.196 mmol) in THF (50 mL) and water (1 mL) with stirring. The mixture was stirred overnight at room temperature under N2. Water (10 mL) was added, and the mixture was concentrated to half its volume and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhyd. MgSO4, and evaporated to give a residue, which was purified on a silica gel column eluting with EtOAc/hexane (1:10) to give 6-methoxybenzofuran-3-carbaldehyde (0.110 g, 73%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:14]2[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][NH:15]2)[CH:6]=[C:7]([F:13])[C:8]=1[C:9]([F:12])([F:11])[F:10].CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:36])[O:34][CH3:35]>C(Cl)Cl>[F:13][C:7]1[CH:6]=[C:5]([CH:14]2[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][N:15]2[C:33]([O:34][CH3:35])=[O:36])[CH:4]=[C:3]([F:2])[C:8]=1[C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2cc(F)c(C(F)(F)F)c(F)c2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (3.118 g, 8.67 mmol) and DIPEA (3.02 mL, 17.34 mmol) were dissolved in DCM (30 mL). Methyl carbonochloridate (1.024 mL, 13.00 mmol) was added and the reaction stirred at room temperature for 1.5 h. Additional methyl carbonochloridate (0.341 mL, 4.33 mmol) was added and stirring continued for 0.5 h. DCM (170 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo to yield dimethyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-piperidine-1,4-dicarboxylate (2.85 g, 86%) as a colorless oil. MS m/z 382 (M+H)+