Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][O:22][C:23]2[C:24]([CH3:32])=[CH:25][C:26]([CH:29]([NH2:31])[CH3:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:26]3[CH:25]=[C:24]([CH3:32])[C:23]([O:22][CH2:21][C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:34][CH:33]=4)=[CH:28][N:27]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ncc1OCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCc1ccc(F)cc1
Yield: 69 %

Procedure:
The title compound is prepared in 69% yield (527 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (516 mg, 1.85 mmol, Step-1 of Intermediate-1) and 1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (550 mg, 1.85 mmol, Amine-79, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [OH:1][C@H:2]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:29]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([O:25]CC)=[O:24])[N:20]=[N:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[OH:1][C@H:2]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[CH:29]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:21]([CH2:22][C:23]([OH:25])=[O:24])[N:20]=[N:19][N:18]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1nnnc1-c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(-c4nnnn4CC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from ethyl [5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1H-tetraazol-1-yl]acetate (which was obtained in Example 98) by NaOH hydrolysis as an off-white solid; mp>210° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.30–1.50 (m, 2 H), 1.80–2.00 (m, 2 H), 2.60–3.50 (m, 5 H), 2.92 (s, 3 H), 3.70–3.85 (m, 2 H), 4.50–4.60 (m, 1 H), 4.70–4.80 (m, 2 H), 6.84 (d, J=8.2 Hz, 1 H), 6.95–7.05 (m, 3 H), 7.20 (d, J=1.6 Hz, 1 H), 7.66 (d, J=8.7 Hz, 2 H); MS (ES) m/z: 530.2 (M−H)−; HRMS Calcd. for C21H28N7O4S (M−H)−: 530.1827. Found: 530.1827.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([CH:8]([CH3:10])[CH3:9])=[N:5][CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]2)[C:20]1=[O:39]>>[CH:8]([C:6]1[O:7][C:3]([CH2:2][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:31]4=[CH:32][C:33]5[O:37][CH2:36][O:35][C:34]=5[CH:38]=[C:30]4[O:29][CH2:28]3)[C:20]2=[O:39])=[CH:4][N:5]=1)([CH3:10])[CH3:9]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CC(C)c1ncc(CCl)o1
Agent: BrCC1CCCCO1
Product: CC(C)c1ncc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)o1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-chloromethyl-2-isopropyloxazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(2-isopropyl-1,3-oxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (11%) as a colorless solid: mp 75-77° C.; 1H NMR (300 MHz, CDCl3) δ7.42 (s, 1H), 7.26 (dd, J=7.4, 7.4 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.07-7.00 (m, 2H), 6.48 (s, 1H), 6.15 (s, 1H), 5.83 (d, J=4.2 Hz, 2H), 4.83 (ABq, 2H), 4.78 (ABq, 2H), 3.10-2.95 (m, 1H), 1.30 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ177.3, 169.4, 155.8, 148.9, 142.3, 141.8, 135.3, 135.1, 132.2, 128.9, 123.8, 123.5, 119.5, 109.6, 103.1, 101.5, 93.6, 80.3, 58.2, 36.6, 28.5, 20.4, 20.3; MS (ES+) m/z 405.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.C(O)C>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5ccccc5)nc43)cc2)CCC1
Temperature: 100 °C

Procedure:
To a suspension of tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate (20 g) in toluene (200 mL) and ethanol (200 mL) was added saturated aqueous sodium bicarbonate (150 mL) and phenyl boronic acid (9.9 g). The reaction was degassed for 5 minutes and the Pd (PPh3)4 (1.0 g) was added. The reaction was again degassed for 5 minutes and then heated to 100° C. for 2 days or until reaction is complete by LCMS. The reaction mixture was cooled to room temperature, and dichloromethane (250 ml×3) and water (100 mL) were added to the reaction. The organics were washed with saturated sodium bicarbonate (1×250 mL) and water (1×250 mL), dried over sodium sulfate and concentrated. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product with some impurities. The solid was re-crystallized with ethyl acetate affording an off-white solid (7.2 g). 400 M Hz 1H NMR (DMSO-d6) δ: 8.23 (d, J=8.0 Hz, 1H), 8.04-7.98 (m, 3H), 7.94 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.46-7.35 (m, 6H), 7.18-7.14 (m, 1H), 6.90 (bs, 1H), 6.33 (dd, J=7.6 Hz and 4.4 Hz, 1H), 2.48-2.40 (m, 4H), 2.09-2.00 (m, 1H), 1.89-1.79 (m, 1H), 1.30 (m, 9H); LCMS: 533 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:26]1[C:33]2[CH2:32][CH2:31][CH2:30][N+:29]=2[CH2:28][CH2:27]1>CCOCC.CCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:33]23[CH2:32][CH2:31][CH2:30][N:29]2[CH2:28][CH2:27][CH2:26]3)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: C1CC2=[N+](C1)CCC2
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: c1ccc(COc2cncc(C34CCCN3CCC4)c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
3-Benzyloxy-5-bromopyridine (1.18 g, 4.47 mmol) was dissolved in Et2O and cooled to -78° C. A solution of 2.5M t-BuLi (5.8 mL, 9.83 mmol) in pentane was added, and the reaction was stirred for 10 minutes. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (1.4 g, 6.70 mmol) was added, and the reaction mixture was allowed to stir for 3 hours at -78° C. then allowed to warm to -20° C. and stir for 2 hours. The cold bath was removed, 2N HCl was added, and the mixture was extracted with Et2O. The phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (286 mg, 22%): mp 45°-49° C. 1H NMR (CDCl3, 300 MHz) δ1.58-1.69 (m, 2H), 1.78-1.83 (m, 2H), 1.89-2.03 (m, 4H), 2.63-2.72 (m, 2H), 3.05-3.18 (m, 2H), 5.12 (s, 2H), 7.31-7.54 (m, 6H), 8.17 (d, J=3.0 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H); MS (CI/NH3) m/z: 295 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].Br[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:36][CH:35]([CH3:37])[CH2:34][N:12]([C:10]([C:2]1[N:3]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)=[O:11])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (147 mg) was dissolved in dimethylformamide (12 ml), (2-bromoethyl)benzene (58 μl) and cesium carbonate (200 mg) were added and the mixture was stirred at 65° C. for 3 hr. (2-Bromoethyl)benzene (58 μl) was added, and the mixture was further stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (164 mg). MS (ESI+, m/e) 618 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].O>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:12]([CH3:13])=[N:18][NH:19][C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(=O)C(SCc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(C)c1SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
To a solution of crude 3-(4-chloro-benzylsulfanyl)-pentane-2,4-dione [prepared as described above from 3-chloro-pentan-2,3-dione (1.03 g, 7.63 mmol) and 4-chlorobenzyl mercaptan (1.21 g, 7.63 mmol)] in ethanol (60 mL) was added hydrazine hydrate (0.713 mL, 22.9 mmol) and p-toluenesulfonic acid monohydrate (ca. 25 mg). The solution was heated to reflux and stirred for 15 hours. The reaction mixture was allowed to cool to room temperature, and water (300 mL) was added. The precipitate that formed was removed by filtration, washed with water, and dried to provide 1.38 g (72%) of the product as a white solid: 1H NMR (CDCl3) δ 7.17 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 3.57 (s, 2H), and 2.02 (s, 6H) ppm. 13C NMR (CDCl3) δ 137.2, 132.7, 130.3, 128.3, 105.2, 39.9, 10.7 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][NH:28][CH2:27][CH2:26]2.C(N(CC)CC)C>CC(N(C)C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH:7]=[N:8]2)=[C:4]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:29]2)[N:3]=1
Reactant: CC(c1ccccc1)n1cnc2nc(Cl)nc(Cl)c21
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CN(c1nc(Cl)nc3ncn(C(C)c4ccccc4)c13)CC2
Yield: 38.4 %

Procedure:
Employing the procedure of Preparation B, 730 mg of 2,6-dichloro-7-(1-phenylethyl)purine, 573 mg of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride and 505 mg of triethylamine in 25 ml of dimethylacetamide gave 430 mg of the desired intermediate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: COc1ccc2c(-c3ccc(F)c(F)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3,4-difluoro-phenylboronic acid to give [1-(3,4-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][NH:6][C:7](=[O:15])[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])C.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][C:4](=[O:16])[CH2:5][NH:6][C:7](=[O:15])[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: CCOC(=O)CNC(=O)CN1CCCC1=O
Product: CCCCNC(=O)CNC(=O)CN1CCCC1=O
Yield: 96.9 %

Procedure:
9.12 g (0.04 mole) of N-(2-oxo-1-pyrrolidineacetyl)-glycine ethyl ester are heated for 12 hours under reflux with 7.7 g (0.1 mole) of n-butylamine. The reaction mixture is evaporated to dryness and the crystallized residue is washed with diethyl ether. The residual product is dried after filtration and washing with diethyl ether. 9.9 g of N-n-butyl-2-(2-oxo-1-pyrrolidineacetamido)-acetamide are thus obtained (yield: 97% of theory); M.P. 105°-106° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH3:13])[CH:12]=2)[CH:6]=1.[H][H]>[Pd].CO>[NH2:14][C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[CH:12][C:11]=1[CH3:13]
Reactant: [H][H]
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])c(C)c2)cn1
Agent: [Pd]
Solvent: CO
Product: Cc1cn(-c2ccc(N)c(C)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A mixture of 5-(4-methylimidazol-1-yl)-2-nitrotoluene (198 mg), 10% Pd/C (58 mg) and methanol (3.0 ml) was hydrogenated with hydrogen of 1 atmosphere. The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was distilled under reduce pressure to give 149 mg (87.6%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:23][C:24]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([Cl:33])=[CH:26][N:25]=1.C(N(CC)CC)C>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][C:27]([Cl:33])=[CH:28][C:29]=1[C:30]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:31]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc(Cl)cnc4Cl)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol), 2,5-dichloropyridine-3-carbonyl chloride (0.42 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) in THF (30 mL) was stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting with 95:5 methylene chloride-methanol, providing 0.50 g of the product (54% yield): mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.53-2.58 (m, 2H), 2.83-2.97 (m, 1H), 4.93 (d, J=5.7 Hz, 2H), 5.17 (dd, J=12.5 Hz, d=5.3 Hz, 1H), 7.82-7.91 (m, 3H), 8.28 (d, J=2.5 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 9.35 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.3, 48.9, 122.1, 127.3, 130.3, 131.6, 133.4, 134.9, 137.8, 138.0, 145.0, 148.8, 164.1, 166.9, 167.5, 169.8, 172.8; Anal. calcd for C20H14Cl2N4O5.0.2H2O: C, 51.68; H, 3.12; N, 12.05. Found: C, 51.64; H, 3.05; N, 11.98.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12]CC)=[O:11])=[C:6]([O:15][CH3:16])[C:5]([O:17][CH:18]([F:20])[F:19])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.O>[Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([O:15][CH3:16])[C:5]([O:17][CH:18]([F:19])[F:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1c(Br)ccc(OC(F)F)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(OC(F)F)ccc(Br)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a stirring solution of ethyl 2-(6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)acetate (300 mg, 0.845 mmol) in tetrahydrofuran was added lithium hydroxide in water and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was acidified to pH 2 and then extracted with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulphate and concentrated under reduced pressure to afford 2-(6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)acetic acid as a solid (180 mg, 66%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Br:31])[CH:30]=1)[CH2:26]Br>>[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Br:31])[CH:30]=1)[CH2:26][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCc1cc(Br)cc(Br)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Br)cc(Br)c2)c1
Yield: 75.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (402 mg, yield: 75.2%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:31]([CH:32]([F:43])[C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)=[C:30]([CH:44]4[CH2:49][CH2:48][C:47]([F:51])([F:50])[CH2:46][CH2:45]4)[C:29]4[CH:28]([O:52]CC5C=CC(OC)=CC=5)[CH2:27][C:26]([CH3:63])([CH3:62])[CH2:25][C:24]=4[N:23]=3)[CH2:18][CH2:17]2)=[N:14][CH:15]=1)(O)=[O:8]>>[F:51][C:47]1([F:50])[CH2:46][CH2:45][CH:44]([C:30]2[C:29]3[CH:28]([OH:52])[CH2:27][C:26]([CH3:62])([CH3:63])[CH2:25][C:24]=3[N:23]=[C:22]([CH:19]3[CH2:18][CH2:17][N:16]([C:13]4[N:14]=[CH:15][C:10]([C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[O:8])=[CH:11][N:12]=4)[CH2:21][CH2:20]3)[C:31]=2[CH:32]([F:43])[C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:37][CH:38]=2)[CH2:49][CH2:48]1
Reactant: C1COCCN1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(=O)O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(C(=O)N5CCOCC5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of the second step of Reference Example 25 and Example 38 were performed except for using morpholine instead of methylamine aqueous solution, and from 70 mg of the crude product of 2-[1-(5-Carboxypyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared in the first step of Reference Example 25, 27 mg of the title compound was obtained as a white solid (yield: 49%).
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9])[CH2:2][CH3:3].[F:10][C:11]1[C:12](=[O:18])[NH:13][C:14](=[O:17])[NH:15][CH:16]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:1]([S:4][CH2:5][CH2:6][NH:7][C:8]([N:15]1[CH:16]=[C:11]([F:10])[C:12](=[O:18])[NH:13][C:14]1=[O:17])=[O:9])[CH2:2][CH3:3]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CCCSCCN=C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCSCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 8 h

Procedure:
To the above solution of 2-propylthioethyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (20 ml.) at 80° C. and stirred for further 8 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(2-propylthioethyl)carbamoyl]-5-fluorouracil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23]C(=O)C(F)(F)F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]([CH2:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37])[CH3:32].Cl>O1CCOCC1.CC(O)C>[NH2:23][C:19]1[CH:18]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]4[CH:38]=[CH:39][CH:40]=[C:34]([CH2:33][N:31]([CH3:30])[CH3:32])[CH:35]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)Cc1cccc(N)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Temperature: 90 °C
Yield: 41 %

Procedure:
To a solution of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (3.0 g, 0.007 mols) (see Example 1, Step C) in 1,4-dioxane (60 mL) and i-PrOH (60 mL) was added 3-[(dimethylamino)methyl]aniline (1.61 g, 0.011 mol) followed by catalytic 12M HCl. After heating four days at 90° C., reaction was quenched with saturated NaHCO3 (100 mL), solvent removed by rotary evaporation, aqueous layer extracted with DCM (3×200 mL), organic layers concentrated, and purified by column chromatography (0-100% 9:1:0.1 DCM:MeOH:NH4OH) to provide the product (1.25 g, 40%) as tan foam. ES-LC/MS m/z=436 [M+H]+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]2[N:22]([CH2:26][C:27](O)=[O:28])[C:23](=[O:25])[O:24][C:20]=2[CH:19]=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>CN1C(=O)CCC1>[Cl:17][C:18]1[CH:31]=[CH:30][C:21]2[N:22]([CH2:26][C:27]([N:12]3[CH2:13][CH2:14][N:9]([CH2:8][C:7]4[CH:15]=[CH:16][C:4]([F:3])=[CH:5][CH:6]=4)[CH2:10][CH2:11]3)=[O:28])[C:23](=[O:25])[O:24][C:20]=2[CH:19]=1
Reactant: O=C(O)Cn1c(=O)oc2cc(Cl)ccc21
Reactant: Fc1ccc(CN2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Cn1c(=O)oc2cc(Cl)ccc21)N1CCN(Cc2ccc(F)cc2)CC1

Procedure:
In a 4 mL vial was added 1-(4-fluoro-benzyl)-piperazine dihydrochloride (13) (51 mg, 0.22 mmol, 1.0 equiv), (6-chloro-2-oxo-benzooxazol-3-yl)-acetic acid (50 mg, 0.22 mmol, 1.00 equiv), DIEA (153 μL, 0.88 mmol, 4.0 equiv), HATU (100 mg, 0.26 mmol, 1.20 equiv) and 1.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at room temperature overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-chloro-3-{2-[4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (14): HPLC retention time, 1.05 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 403.8, found, 404.5.