Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:32]([O:34][C:35](=[O:40])[CH2:36][C:37]([O-:39])=O)[CH3:33].FC(F)(F)C(O)=O.[CH3:48][O:49][C:50]1[CH:70]=[CH:69][C:53]([O:54][C:55]2[CH:68]=[CH:67][C:58]([CH2:59][NH:60][C:61]([C:63]3([NH2:66])[CH2:65][CH2:64]3)=[O:62])=[CH:57][CH:56]=2)=[C:52]([C:71]([F:74])([F:73])[F:72])[CH:51]=1>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:40])[CH2:36][C:37]([NH:66][C:63]1([C:61](=[O:62])[NH:60][CH2:59][C:58]2[CH:57]=[CH:56][C:55]([O:54][C:53]3[CH:69]=[CH:70][C:50]([O:49][CH3:48])=[CH:51][C:52]=3[C:71]([F:73])([F:74])[F:72])=[CH:68][CH:67]=2)[CH2:65][CH2:64]1)=[O:39])[CH3:33]
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)NC1(C(=O)NCc2ccc(Oc3ccc(OC)cc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
87 μL (0.50 mmol) of DIPEA and 80.9 mg (0.25 mmol) of TBTU were added to a solution of 33.27 mg (0.25 mmol) of monoethylmalonate in 100 μL DMF and the mixture was stirred for 5 min at RT. Then 83 mg (0.17 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 85a) was added and the mixture was stirred for 1.5 h at ambient temperature. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27]>>[OH:39][C:31]1[CH:30]=[CH:29][C:28]([CH:26]([OH:27])[CH2:25][NH:24][CH:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:12]=[CH:11][C:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:23])=[CH:2][CH:3]=4)(=[O:8])=[O:9])=[CH:15][CH:14]=3)[CH2:17][CH2:18]2)=[CH:33][C:32]=1[NH:34][S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: Cc1ccc(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: Cc1ccc(S(=O)(=O)c2ccc(N3CCC(NCC(O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 from 0.13 g (0.4 mmol) of Reference Example 25, 1-[4-(Toluene-4-sulfonyl)-phenyl]-piperidin-4-one, and 0.12 g (0.5 mmol) of (R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide, yielding 0.18 g of a white solid; m.p. 115-118° C.; MS (ES) m/z 560.0 (MH+); HRMS (FAB) Calcd. for C27H34N3O6S2 (MH+): 560.1889, Found: 560.1886.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[N:16]([CH3:21])[N:17]=[C:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH3:21][N:16]1[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])=[CH:19][C:18]([CH3:20])=[N:17]1
Reactant: Cc1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)n(C)n1
Reactant: OB(O)c1cccnc1F
Product: Cc1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cccnc5F)cc4c32)n(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate C, 50 mg, 0.135 mmol) and 2-fluoropyridine-3-boronic acid (Aldrich, Buchs, Switzerland, 25 mg, 0.179 mmol) to give the title compound as a red solid. (HPLC: tR 2.57 min (Method A); M+H=389 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.07 (s, 1H), 8.27-8.22 (m, 1H), 8.18-8.13 (m, 1H), 8.06-7.99 (m, 1H), 7.89-7.83 (m, 1H), 7.51-7.45 (m, 1H), 7.24-7.20 (m, 1H), 6.45 (s, 1H), 3.60 (s, 3H), 3.55 (s, 3H), 2.24 (s, 3H))
Reaction SMILES: C([O:8][CH:9]1[CH2:12][C:11]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]3[N:23]=[C:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=4)[C:25]([C:26]([NH2:28])=[O:27])=[C:19]3[CH2:18]2)=[O:16])([CH3:13])[CH2:10]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:36][C:31]1[CH:30]=[C:29]([C:24]2[C:25]([C:26]([NH2:28])=[O:27])=[C:19]3[CH2:18][N:17]([C:15]([NH:14][C:11]4([CH3:13])[CH2:10][CH:9]([OH:8])[CH2:12]4)=[O:16])[CH2:22][CH2:21][N:20]3[N:23]=2)[CH:34]=[CH:33][C:32]=1[F:35]
Reactant: CC1(NC(=O)N2CCn3nc(-c4ccc(F)c(Cl)c4)c(C(N)=O)c3C2)CC(OCc2ccccc2)C1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC1(NC(=O)N2CCn3nc(-c4ccc(F)c(Cl)c4)c(C(N)=O)c3C2)CC(O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
To a stirred solution of Intermediate 260A (70 mg, 0.137 mmol) in DCM (10 mL), cooled to −78° C., was added BCl3 (0.547 ml, 0.547 mmol, 1.0 M in DCM) and the resulting mixture was allowed to warm to RT and stir for 16 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with DCM (3×25 mL). The combined organic layers were dried over Na2SO4 and evaporated. The crude compound was purified by preparative HPLC to afford Compound 260 as an off-white solid (9.0 mg, 16% yield). HPLC Ret. Times 6.51 min. and 6.54 min. (HPLC Methods A and B). MS(ES): m/z=422 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (dd, J=7.31, 2.16 Hz, 1H), 7.69 (dt, J=6.24, 2.49 Hz, 1H), 7.43-7.48 (t, 1H), 7.11-7.41 (m, 2H), 6.96 (s, 1H), 6.68 (s, 1H), 4.90 (dd, J=10.42, 6.15 Hz, 1H), 4.70 (s, 2H), 4.08-4.18 (m, 2H), 3.97 (m, 1H), 3.82 (s, 2H), 2.45-2.56 (m, 1H), 2.26-2.38 (m, 1H), 1.95-1.98 (m, 1H), 1.70-1.75 (m, 1H), 1.74 (s, 1.5H), 1.24-1.40 (s, 1.5H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9](=[S:10])[NH:8][N:7]=[N:6]1.CN(C)C=O.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CC(C)=O>[NH2:2][CH2:3][CH2:4][N:5]1[C:9]([S:10][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:8][N:7]=[N:6]1
Reactant: COc1ccc(CCl)cc1
Reactant: NCCn1nn[nH]c1=S
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CSc2nnnn2CCN)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 22.8 g. (12.5 mmol) of 1-(2-aminoethyl)-1,4-dihydro-5H-tetrazole-5-thione, hydrochloride in 100 ml. of N,N-dimethylformamide and 100 ml. of acetone was added 34.3 ml. (25 mmol) of triethylamine. To the resulting suspension was added slowly a solution of 19.5 g. (12.5 mmol) of p-methoxybenzyl chloride in 30 ml. of acetone. After stirring at room temperature for 15 hours, the mixture was filtered. The filtrate was evaporated to dryness. The residue was taken up in 350 ml. of 5% NaHCO3, and extracted with ethyl acetate. The combined extract was dried (MgSO4) and evaporated to dryness to give an oil which was chromatographed on a silica gel column, eluting with a gradient of 5-10% ethanol in chloroform. Fractions containing product by thin layer chromatography were pooled, and evaporated to dryness to give 1-(2-aminoethyl)-5-(4-methoxybenzylthio)-1H-tetrazole as a brown oil (26 g., 80%). An analytical sample of the crystalline amine hydrochloride (mp 148°-150°) was obtained by treating the product with an ethereal HCl solution.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[NH:8][C:9](=[O:19])[C:10]([OH:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CCOCC>[CH2:26]([O:18][C:10]1[C:9](=[O:19])[N:8]2[C:7]([CH2:6][S:5][CH2:4][CH2:3][CH2:2]2)=[N:12][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc(CSCCCCl)[nH]c(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCSC2
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 2-((3-chloropropylthio)methyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (5 g, 16 mmol) and K2CO3 (4.5 g, 32.5 mmol) in DMF (150 mL) was placed in preheated oil bath and stirred for 1.5 h. After this, benzylbromide (2.4 mL, 20 mmol) was added and continued stirring for additional 3 h. Then, the reaction mixture was cooled, diluted with ether (250 mL0, washed with water (3×50 mL). The combine aq. layers extracted with ether (4×100 mL) and combined with previous organic phase, and washed with brine (50 mL). The organic layer was dried (Na2SO4/activated carbon), filtered and concentrated to give viscous paste. Crystalization of this paste from CH2Cl2/hexanes provided the product as a white solid (4.4 g, 75%). 1H NMR (500 MHz, CDCl3) δ: 7.48-7.46 (2H, m), 7.37-7.30 (3H, m), 5.25 (2H, s), 4.36-4.31 (4H, m), 3.89 (2H, s), 2.94 (2H, t, J=5.6 Hz), 2.16-2.12 (2H, m), 1.30 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C18H21N2O4S: 361.1222; found: 361.1221.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:27]2[CH:28]=[N:29][CH:30]=[C:25]([F:24])[CH:26]=2)[CH:16]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)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: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cncc(F)c2)c1
Yield: 3.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-((5-fluoropyridin-3-yl)methyl)benzamide was prepared according to method B N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.156 g; 0.449 mmol), 5-fluoropyridin-3-ylboronic acid (0.071 g; 0.494 mmol), tetrakis(triphenylphosphine)palladium(0) (0.026 g; 0.022 mmol), sodium carbonate (0.095 g; 0.898 mmol), sodium iodide (0.204 g; 1.35 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Purification by preparative TLC on silica gel (eluent 50% ethyl acetate in heptane) furnished 0.006 g (3%) of the title compound as a white solid.
Reaction SMILES: [N+](C)([O-])=O.C[C:6]([O:8][CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl-].[Zn+2].[Cl-].O.CO>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][O:8][CH3:6])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 10 ml of nitromethane were added 2.72 g of 7-ACA, 3.0 g of methanol, 10.0 g of zinc chloride and 3.1 g of antimony pentachloride. The mixture was heated at 50° C. for 25 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 150 ml of water. Then, the mixture was adjusted to pH 7.5 with sodium bicarbonate at a temperature of from 0° C. to 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. To the resulting mixture was added 0.3 g of activated charcoal, and the mixture was stirred, followed by filtration. The resulting filtrate was adjusted to pH 3.5 with 36 % hydrochloric acid, and then concentrated by evaporation under reduced pressure so that a precipitate was formed. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.64 g. The yield of the desired product was 67 %.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([NH2:14])=[CH:12][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][N:30](C(OC(C)(C)C)=O)[CH:31]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[NH:29]1[CH:28]=[C:27]([C:3]2[CH:4]=[C:5]([N:9]3[C:13]([NH2:14])=[CH:12][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:10]3)[CH:6]=[CH:7][CH:8]=2)[CH:31]=[N:30]1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cccc(-c3cn[nH]c3)c2)n1
Temperature: 80 °C
Yield: 76 %

Procedure:
A solution of 1-(3-bromophenyl)-3-t-butyl-1H-pyrazol-5-amine hydrochloride (0.253 g, 0.77 mmol, available from Example 54), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.28 g, 0.95 mmol, commercially available) and Cs2CO3 (1.0 g, 3.1 mmol) in DMF (5 mL) and H2O (2 mL) was placed under Ar for 15 min. Palladium tetrakis(triphenylphosphine) was added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (2×30 mL). The extracts were washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4) concentrated and purified via column chromatography to yield 1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-amine (163 mg, 76% yield). MS (ESI) m/z: 282.3 (M+H+).
Reaction SMILES: C(OC(N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[N:45]=[CH:44][C:43](Br)=[CH:42][N:41]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[Cl:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][C:53]=1[Cl:54]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[N:45]=[CH:44][C:43]([C:51]3[CH:50]=[CH:49][C:48]([Cl:47])=[C:53]([Cl:54])[CH:52]=3)=[CH:42][N:41]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1
Yield: 78 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.00 g) and 3,4-dichlorobenzeneboronic acid (0.61 g), to yield the title compound as a white solid (0.93 g, 78%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[C:9](I)[CH:8]=[C:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]2=[O:23])[CH2:3][CH2:2]1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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>[CH:1]1([CH2:4][N:5]2[CH:10]=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:8]=[C:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]2=[O:23])[CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1cc(I)cn(CC2CC2)c1=O)OCc1ccccc1
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: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cc(-c2ccccc2)cn(CC2CC2)c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.132 mg, 0.11 mmol) and benzyl 1-(cyclopropylmethyl)-5-iodo-2-oxo-1,2-dihydropyridin-3-ylcarbamate (0.097 mg, 0.229 mmol) in tetrahydrofuran (1 mL) were stirred at room temperature for 30 minutes. A solution of phenylboronic acid in ethanol (1 mL) was then added to the reaction mixture. After 1 h, a 2 M solution of sodium carbonate (1 mL) was added and the reaction was heated to reflux. After 3 h, the mixture was allowed to cool to ambient temperature and extracted with ethyl acetate and water. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 5% to 30% ethyl acetate in hexanes gradient elution) gave the title compound (0.061 g). MS 375 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[OH-].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:8]=2)[CH:3]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc2cc(Br)ccc2c1

Procedure:
22.29 g (0.1 mol) of 2-bromo-6-naphthol, 11.22 g (0.2 mol) of potassium hydroxide, and 32.36 g (0.13 mol) of 1-bromododecane were dissolved in ethanol (300 ml), and the solution was refluxed for 8 hr. Thereafter, water was added thereto, the mixture was cooled, and the resultant precipitate was collected by filtration and washed with a sodium hydroxide solution and then with water. The crude product thus obtained was recrystallized from ethyl acetate to give 2-bromo-6-dodecyloxynaphthalene.
Reaction SMILES: NC1C=CC(N2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]1.F[C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1>>[N+:43]([C:40]1[CH:41]=[CH:42][C:37]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:26][CH2:27]2)=[CH:38][CH:39]=1)([O-:45])=[O:44]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2)CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
tert-Butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate (G29) can be prepared by nucleophilic aromatic substitution of commercially available tert-butyl piperidin-4-ylcarbamate (G26) and 1-fluoro-4-nitrobenzene (G27) under thermal conditions to give tert-butyl (1-(4-nitrophenyl)piperidin-4-yl)carbamate (G28). Reduction of G28 with hydrogen in the presence of a catalyst, for example 10% palladium on charcoal gives tert-butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate (G29).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Cl[C:34]([O:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]([O:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:35])[CH2:17][CH2:18]1)=[N:7]2
Reactant: CC(C)(C)COC(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)OCC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure N using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and neopentyl chloroformate to give neopentyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (DMSO-d6) δ ppm 0.93 (br s, 9H), 2.09 (br s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.29-3.33 (m, 4H), 3.58 (br s, 4H), 3.69 (t, J=4.4 Hz, 4H), 3.74 (s, 2H), 6.50 (s, 1H), 7.14-7.19 (m, 1H), 7.30-7.28 (m, 1H), 7.51 (d, J=2 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=555.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:33](Cl)(Cl)([Cl:35])[Cl:34]>C(#N)C>[Cl:34][C:33]([Cl:35])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)C(=O)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)C(=C(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
A solution of 29.9 g (0.15 mol) of the keto ester of Example 2 in 300 ml of acetonitrile were treated with 117.9 g of PPh3 (0.45 mol), and 69.3 g (0.45 mol) of carbon tetrachloride were then added dropwise. After the reaction solution had remained at approximately 56° C. for 4 hours, it was concentrated; the residue obtained was chromatographed over silica gel with cyclohexane/MtBE (3:1). This gave 39.2 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].[H-].[Na+].Cl>CN(C)C=O>[CH2:13]([O:12][C:10]([CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:15]([O:16][CH2:17][CH3:18])=[O:19])=[O:11])[CH3:14]
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OC)cc1
Temperature: 0 °C

Procedure:
27.7 g of ethyl 4-methoxyphenylacetate and 34 ml of diethyl carbonate were dissolved in 150 ml of N,N-dimethylformamide, and the solution was subjected to reflux under heating, while gradually adding 6.5 g of sodium hydride for 1 hour. After further refluxing under heating for 2 hours, the resulting reaction solution was poured into a mixture of ice water and hydrochloric acid, followed by extraction with ethyl acetate. The resulting organic layer was washed with water, and then dried to distill off the solvent. The residue thus obtained was purified by silica gel column chromatography using toluene as an eluant, thereby obtaining 26.7 g of ethyl 2-ethoxycarbonyl-2-(4-methoxyphenyl)acetate in the form of light yellow oil.
Reaction SMILES: [CH3:1][Mg]I.[C:4]([CH:6]([OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)#[CH:5].S(=O)(=O)(O)O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.O1CCCC1>[C:4]([CH:6]([OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:1])[CH:8]=1)#[CH:5]
Reactant: C#CC(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: C[Mg]I
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(C(=C)c2ccccc2)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To methyl magnesium iodide (1.4 g) in ether (25 cm3) was added a solution of α-ethynyl-3-benzoylbenzyl alcohol (0.5 g) in ether (10 cm3) with stirring during 10 minutes at 20° C., then the mixture refluxed for 5 minutes and poured onto a mixture of 40% sulphuric acid (40 cm3), sodium thiosulphate (3 g) and tetrahydrofuran (20 cm3). After 16 hours at 20° C., this mixture was extracted with ether (3×150 cm3), washed with sodium thiosulphate solution (2M), saturated sodium chloride, dried and finally evaporated to give the title product, yield 0.48 g (96%) nD20 1.5942.