Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:17]([O:16][C@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1csc(N2CC[C@H](O)C2)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CC[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of (3S)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (4.1 g, 16.9 mmol) (obtained as described in Reference Example 20(3)) in dimethylformamide (120 ml) were added t-butyldiphenylsilyl chloride (8.8 ml, 33.8 mmol) and imidazole (2.3 g, 33.8 mmol) in an ice bath, and then the reaction mixture was brought to room temperature in 10 minutes, and stirred for overnight. After checking the completion of the reaction, ethanol (1.18 ml) was added thereto in an ice bath, and then the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→1:1) as the eluant to afford (3S)-3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (7.60 g, yield 94%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 11 h
Yield: 3.6 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (80 ml). To the suspension were added potassium carbonate (300 mg, 2.2 mmol) and 2-dimethylaminoethylchloride (160 mg, 1.1 mmol) in order. The mixture was stirred at room temperature for 11 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (10% methanol/chloroform) to give the subject compound (9 mg, yield 4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2C=CC(Br)=CC=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Br:29][C:30]1C=CC2N=C(C3CCCN3)N[C:34]=2[CH:43]=1>>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]2[CH:21]=[C:30]([Br:29])[CH:43]=[CH:34][C:19]=2[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: Brc1ccc2nc(C3CCCN3)[nH]c2c1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1)C(C)C

Procedure:
Prepared by the same method as (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester but using 6-bromo-2-pyrrolidin-2-yl-1H-benzoimidazole as the substrate. 193 mg crude solid were used for the next step.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[NH:41][C:40]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[CH:39][C:38]2=[O:49]>O1CCOCC1.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>[N:43]1([C:40]2[NH:41][C:42]3[C:37]([C:38](=[O:49])[CH:39]=2)=[CH:36][CH:35]=[CH:34][C:33]=3[C:7]2[C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[C:12]=3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:44][CH2:45][O:46][CH2:47][CH2:48]1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c3c2oc2ccccc23)OC1(C)C
Reactant: O=c1cc(N2CCOCC2)[nH]c2c(Br)cccc12
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: [K+]
Solvent: C1COCCO1
Product: O=c1cc(N2CCOCC2)[nH]c2c(-c3ccc([N+](=O)[O-])c4c3oc3ccccc34)cccc12
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
In a Schlenk tube, 1-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) dibenzofuran (12) (500 mg, 1.47 mmol) and potassium carbonate (480 mg, 3.69 mmol) were solubilised in dioxane (10 mL) and degassed. Concurrently, 8-bromo-2-morpholin-4-yl-1H-quinolin-4-one (21) (380 mg, 1.23 mmol) and Pd(PPh3)4 (71 mg, 0.06 mmol) were solubilised in dioxane (10 mL) and degassed. The solutions were mixed together in a microwave vessel, which was placed into the microwave reactor at 180° C. for 30 min. Upon cooling, DCM (20 mL) was added. The solution was washed with water (20 mL), then dried on magnesium sulfate and evaporated. The residue was purified by flash chromatography using AcOEt/EP (8:2) as eluant to furnish the title compound (303 mg, 0.74 mmol, 60%) as a yellow solid: Rf=0.67 (AcOEt); mp: 247° C.; λmax (EtOH)/nm 251; IR (cm−1) 3421, 2852, 2360, 2333, 1614, 1573, 1500, 1435, 1429, 1348, 1309, 1233, 1199, 1152, 1124, 1039, 991, 917, 866, 823; 1H NMR, (300 MHz, CDCl3) δ 3.04 (4H, m, 2×CH2—N-morpholine), 3.54 (4H, m, 2×CH2—O-morpholine), 5.92 (1H, s, H-3), 7.19-7.45 (2H, m), 7.51-7.58 (2H, m), 7.65-7.70 (2H, m), 8.31 (2H, m), 8.67 (1H, d, J=7 Hz); MS (EI) m/z 442.29 M+; HRMS calcd for C25H20N3O5 [M+H]+ 442.1397, found 442.1398.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[N:24]=[C:25]=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:25]([NH:24][C:18]3[C:17]([CH3:16])=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:23])=[O:26])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1N=C=O
Reactant: Nc1cc(Nc2cccc(Cl)c2)ncn1
Product: Cc1cccc(C)c1NC(=O)Nc1cc(Nc2cccc(Cl)c2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 2,6-dimethylphenyl isocyanate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:31]
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cccc(Cl)c4)cc23)CC1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-l-piperazinyl)-naphthalene (0.24 g, 0.995 mmol) and triethylamine (0.146 mL, 1.09 mmol) and 3-chlorobenzoyl chloride (0.138 mL, 1.09 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was isolated using flash chromatography and trituration from hexane and recrystallization from ethyl acetate (with a seed crystal) to yield 0.076g (20%) of the title compound: mp 147°-148° C. HRMS m/e calculated for C22H22ClN3O; 379.1448. Observed m/e: 379.14473. Analysis calculated for C22H22ClN3O: C, 69.56; H, 5.84; N, 11.06. Found: C, 68.95; H, 5.81; N, 10.96.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Br:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Br:11][CH2:12][CH2:13][C:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:15]
Reactant: O=C(Cl)CCBr
Reactant: c1ccc2c(c1)CCNC2
Product: O=C(CCBr)N1CCc2ccccc2C1

Procedure:
from 3,4-dihydro-1H-isoquinoline and 3-bromopropanoyl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.C(O)(=O)C.C(N)=N.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: N=CN
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Cl)c(N)c1

Procedure:
40.8 g of 1-chloro-2,4-dinitrobenzene, 2 g of Raney nickel (60%, aqueous), 1.5 g of formamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 11/4 hours. 1-Chloro-2,4-diaminobenzene, 99% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>C(OC)(C)(C)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: COC(=O)[C@H](Cc1ccccc1)N=Cc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
L-phenylalanine methyl ester hydrochloride (120.00 g), benzaldehyde (56.5 ml), anhydrous sodium sulfate (158.07 g) and triethylamine (77.5 ml) were added to tert-butylmethyl ether (480 ml), and the mixture was stirred overnight at 5° C. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, n-hexane was added, and the solvent was distilled off again under reduced pressure. To the concentrate was added n-hexane, and the crystallization was conducted by cooling with ice to obtain desired N-(phenylmethylene)-L-phenylalanine methyl ester (126.01 g) in a yield of 85.0%. Further, the mother liquor was concentrated under reduced pressure, and the concentrate was crystallized by cooling with ice to obtain N-(phenylmethylene)-L-phenylalanine methyl ester (13.86 g) in a yield of 9%. Thus, the crystals of N-(phenylmethylene)-L-phenylalanine methyl ester were obtained in a total yield of 94%. A part of the resulting crystals were converted into a phenylalanine methyl ester. It was analyzed by HPLC using an optically active column, and identified to have the optical purity of >99.5%e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][S:10]([C:13]1[N:14]=[C:15]2[S:20][CH:19]=[C:18]([CH3:21])[N:16]2[N:17]=1)(=[O:12])=[O:11].[CH3:22]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH3:22])[S:10]([C:13]1[N:14]=[C:15]2[S:20][CH:19]=[C:18]([CH3:21])[N:16]2[N:17]=1)(=[O:11])=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cccc(Cl)c1NS(=O)(=O)c1nc2scc(C)n2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: Cc1cccc(Cl)c1N(C)S(=O)(=O)c1nc2scc(C)n2n1
Yield: 60.8 %

Procedure:
To a solution of the product of Example 1 (3 g) in dimethylformamide (20 ml) was added potassium t-butoxide (1.1 g) with cooling and stirring. Dimethyl sulphate (0.92 ml) was added dropwise, and the reaction mixture was stirred overnight. Addition to ice/water/ether and filtration, followed by recrystallisation from ethyl acetate gave 1.9 g of the desired product, mp 178°-180° C.
Reaction SMILES: O=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[C:24]1([C@@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[B-](F)(F)(F)[O+](C)C>C1(C)C=CC=CC=1>[C:24]1([C@@H:30]([N:32]=[C:2]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:4][CH2:3]2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)c3ccccc32)CC1
Agent: C[O+](C)[B-](F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](N=C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21)c1ccccc1

Procedure:
A solution of tert-butyl 4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (A4) (5.0 g, 15.8 mmol), (S)-1-phenylethanamine (3.0 ml, 23.8 mmol) and boron trifluoride dimethyl etherate (0.5 ml, 5 mmol) in dry toluene (150 ml) was heated at 140° C. under a Dean-Stark trap for 24 hours. The solvent was distilled and the residue was cooled with an ice bath, dissolved in ethyl acetate, washed with saturated NaHCO3, and water. The organic phase was dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 4-(1-phenylethylimino)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B1) as a gum. LC-MS analysis of the crude indicated that there is trace of starting material (A4). LC-MS: m/e=419.37 (M+H). Rt=2.24 min.
Reaction SMILES: [CH3:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]2[N:6]([CH2:10][C:11]3[C:12]4[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:30]([O:32][CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:31].CO>C(OCC)(=O)C>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][CH:33]([N:8]1[C:4]2[CH:3]=[C:2]([CH3:1])[C:22]([CH3:23])=[CH:21][C:5]=2[N:6]([CH2:10][C:11]2[C:12]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=3[S:14][CH:15]=2)[C:7]1=[O:9])[O:32][CH2:30][CH3:31])[CH3:39]
Reactant: Cc1cc2[nH]c(=O)n(Cc3csc4cccc(C)c34)c2cc1C
Reactant: CCOC=CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 130 °C
Yield: 31.1 %

Procedure:
To a mixture of 5,6-Dimethyl-1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.31 mmol) and K2CO3 (86 mg, 0.62 mmol) in a microwave vial was added Ethyl 3-ethoxyacrylate (0.45 g, 3.1 mmol). The reaction mixture was heated to 130° C. for 20 min in a microwave. The reaction mixture was then diluted with ethyl acetate (since there was some insoluble material left, MeOH was added to the solution mixture to solubilize the material). This organic phase was washed with water (×2). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexane:ethyl acetate as an eluent to afford 45 mg of the desired product as an oily foam. LCMS (ESMS): m/z 467.32 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)C>[C:32]([C:31]1[CH:30]=[N:29][CH:28]=[CH:27][C:26]=1[N:21]1[CH2:20][CH2:19][CH:18]([CH2:17][NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:24])[CH2:23][CH2:22]1)([OH:34])=[O:33]
Reactant: O=C(O)c1cnccc1Cl
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCN(c2ccncc2C(=O)O)CC1

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloronicotinic acid (91 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (5 mL) yielded, after RPHPLC purification, 45 mg (33%) of the title compound as a trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([O:33]CC)=O)[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:37][NH2:38]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:38][CH3:37])=[O:33])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-methylamine in ethanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (d, J=4.42 Hz, 4 H), 1.61-1.77 (m, 4 H), 2.35-2.44 (m, 2 H), 2.91 (d, J=4.84 Hz, 3 H), 3.34-3.42 (m, 4 H), 4.14-4.23 (m, 4 H), 7.14 (t, J=8.95 Hz, 2 H), 7.40 (dd, J=8.84, 5.48 Hz, 2 H), 7.99 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.14 (d, J=4.63 Hz, 1 H), 17.22 (s, 1 H); ES+ MS: 481 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:24])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17]C)[C:12]=2[CH:19]2OCC[O:20]2)[CH:5]=[CH:6][CH:7]=1.O.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:24])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[CH:19]=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1nccc(NC[C@@H](O)c2cccc(Cl)c2)c1C1OCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c(NC[C@@H](O)c2cccc(Cl)c2)cc[nH]c1=O
Temperature: 70 °C
Yield: 10.7 %

Procedure:
To a mixture of (S)-1-(3-chloro-phenyl)-2-(3-[1,3]dioxolan-2-yl-2-methoxy-pyridin-4-ylamino)-ethanol (223 mg, 0.64 mmol) and H2O (0.75 mL) was added HCl solution in dioxane (4 M, 10 mL). After it was heated at 70° C. for 4 h, the reaction mixture was evaporated to dryness. HPLC purification of the residue afforded the title compound (20.1 mg, 11%). 1H NMR (DMSO-d6) δ 3.37 (m, 1H) 3.58 (m, 1H), 4.58 (m, 1H), 5.95 (d, J=6 Hz, 1H), 7.30-7.40 (3H), 7.49 (s, 1H), 9.94 (s, 1H, CHO), 10.30 (m, 1H, NH), 10.95 (m, 1H, 1H). ESI-MS m/z 293.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[CH3:16][S:17]SC>C1COCC1>[F:10][C:4]1[CH:3]=[C:2]([S:17][CH3:16])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(Br)cc1F
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(SC)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-bromo-2-fluoroanisole (5.0 g, 24.4 mmol) in THF (100 mL) was added n-butyllithium (23 mL, 1.6M in hexanes, 36.8 mmol) at −78° C. After stirring at −78° C. for 1 h, dimethyl disulfide (11 mL, 12.2 mmol) was added and the reaction was then allowed to warm to room temperature slowly. After stirring at room temperature for 12 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. The residue was used directly in next step.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>O1CCOCC1.O.[Pd]>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:29]=[CH:28][N:27]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CCOC(=O)Cc1nc2ccc(Br)cc2s1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1nc2ccc(-c3ccnc(F)c3)cc2s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
SiliaCat DPP-Pd (0.26 mmol/g loading, from Silicycle, 100 mg, 0.67 mmol), ethyl 2-(6-bromobenzo[d]thiazol-2-yl)acetate (described in WO2011/074560, 200 mg, 0.67 mmol), potassium phosphate (348 mg, 2.00 mmol) and (2-fluoropyridin-4-yl)boronic acid (141 mg, 1.00 mmol) in dioxane (5 mL)/water (0.2 mL) were purged with argon for 5 minutes and then heated at 90° C. After 4 hours, the reaction mixture was diluted with water (50 mL), extracted with DCM (3×50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes over 15 minutes) to give Compound B23a (120 mg, 57% yield) as a brown solid. HPLC: RT=0.95 min (LCMS Method M). MS (ES): m/z=316.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, J=1.7 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.12 (d, J=8.5 Hz, 1H), 8.02 (dd, J=8.5, 1.9 Hz, 1H), 7.81 (d, J=5.2 Hz, 1H), 7.64 (s, 1H), 4.38 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[Cl-].[NH4+]>C1COCC1>[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:13]=1[CH:14]([C:7]1[O:6][CH:10]=[CH:9][N:8]=1)[OH:15]
Reactant: c1cocn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C(O)c2ncco2)c(Cl)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (1.6M in hexane, 7.4 ml) was added to a solution of oxazole (0.78 ml) in THF (100 ml) which had been cooled to -70° C. The mixture was stirred at that temperature for 1 hour. A solution of 2-chloro-4-nitrobenzaldehyde (2 g) in THF (5 ml) was added and the mixture was stirred at -70° C. for 3 hours. A saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give 1-(2-chloro-4-nitrophenyl)-1-(2-oxazolyl)methanol (1.45 g), m.p. 158°-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C>CO>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
To a suspension of 3-bromo-4-chloro-benzoic acid (10 g, 42.6 mmol) in MeOH (100 mL) cooled with ice bath, was added acetyl chloride (30.4 mL, 0.43 mol) dropwise. The mixture was then stirred at room temperature for 12 hrs and concentrated to yield 3-bromo-4-chloro-benzoic acid methyl ester as a yellow solid (10.6 g). NMR (CDCl3), 6, 8.28 (1H, s), 7.91 (1H, brs), 7.52 (1H, brs), 3.92 (3H, s).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6]CC)=O.[CH2:13]([NH:16][C:17]([NH2:19])=[O:18])[CH2:14][CH3:15].Cl>O.C(O)C>[CH2:13]([N:16]1[C:2](=[O:10])[CH2:3][C:4](=[O:6])[NH:19][C:17]1=[O:18])[CH2:14][CH3:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCNC(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCCN1C(=O)CC(=O)NC1=O

Procedure:
Metallic sodium (2.6 g, 113 mmol) is added to ethanol (60 ml). The mixture is stirred until the sodium has completely finished reacting. Diethyl malonate (116 ml, 105 mmol) and n-propylurea (10 g, 98 mmol) are then added and the mixture is stirred under reflux for 5 h. After conc. HCl (5 ml) and hot water (45 ml) have been added, the mixture is filtered and the filtrate is concentrated in vacuo. Ethanol is added to the residue and the mixture is stirred. The solid is filtered off with suction and dried.