Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[F:23][CH:24]([F:41])[C:25]1[N:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])=[CH:30][C:26]=1[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:41][CH:24]([F:23])[C:25]1[N:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])=[CH:30][C:26]=1[C:27]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[O:28]
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)c1
Yield: 9.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 50 mg, 0.18 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 56 mg, 0.18 mmol), oxalyl chloride (23 mg, 0.18 mmol), DMF (1 drop) and DIPEA (48 mg, 0.37 mmol) in CH2Cl2 (1.5 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.67 (s, 1H), 8.84-8.82 (d, J=7.8 Hz, 1H), 8.79 (s, 1H), 8.71 (d, J=1.8 Hz, 1H), 8.48 (t, 1H), 8.21-8.19 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.89-7.86 (m, 2H), 7.76 (s, 3H), 7.42-7.06 (t, J=54.6 Hz, 1H), 4.44-4.42 (d, J=5.4 Hz, 2H), 2.44 (m, 1H), 1.05 (d, J=6.6 Hz, 6H); MS [M+H]+: 560.45.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=CC=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)CCC.C1(=O)CCCCC1.C([O:43][C:44](=[O:47])CC)C>>[CH2:21]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][CH2:17][C:44]([OH:47])=[O:43])=[CH:13][N:14]=1)[CH2:22][CH2:23][CH3:28]
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCOC(=O)CC
Solvent: O=C1CCCCC1
Solvent: CCCCN
Product: CCCCN(C(=O)Nc1ncc(SCCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from n-butylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)propionic acid ethyl ester.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (example E.26) (0.150 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.092 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 51%). MS (ISP) 407.3 [(M+H)+]; mp 208-211° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].CS(O[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][CH:28]=2)=[CH:18][CH:17]=1)(=O)=O>CN(C)C=O.O>[N:1]1([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:27][CH:28]=3)=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C(=C/c1nc(COc2ccc(CCCn3ccnc3)cc2)co1)\c1ccccc1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of imidazole (70 mg) in N,N-dimethylformamide (5 ml) was added, at 0° C., sodium hydride (60%, in oil, 50 mg). The mixture was stirred for one hour. To the reaction mixture was added 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate (350 mg). The mixture was stirred for 1.5 hour at 70° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The resulting crystalline product was recrystallized from ethyl acetate-hexane to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole (200 mg, 61%) as colorless prisms, mp 127-128° C.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([O:21]C)=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O.CCOC(C)=O>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([OH:21])[CH:13]=3)[C:18]=2[CH:19]=[CH:20][C:3]=1[OH:2]
Reactant: COc1ccc2c3ccc(OC)cc3c3ccccc3c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2c3ccc(O)cc3c3ccccc3c2c1
Temperature: 25 °C

Procedure:
2,7-dimethoxytriphenylene (358 mg, 1.24 mmol) and pyridine hydrochloride (1.72 g, 14.9 mmol) were heated in a flask to 185° C. for 5 h. After cooling to rt, the remaining solid was diluted with H2O and EtOAc, separated, dried, and concentrated. Taken on crude.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[C:16](=[O:27])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: OCc1cccc(Br)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a solution of (3-bromophenyl)methanol (10 g, 53.5 mmol) and pyridine (8.65 mL, 107 mmol) in DCM (80 mL) at 0° C. was added a solution of 4-nitrophenyl carbonochloridate (12.93 g, 64.2 mmol) in DCM (20 mL) dropwise. Upon the completion of addition, the reaction mixture was stirred at 0° C. for 2 h. After this time, the reaction was quenched with water. The organic layer was separated and washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (19.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.31-8.29 (m, 1H), 8.28-8.25 (m, 1H), 7.61 (t, J=1.6 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.42-7.34 (m, 3H), 7.30 (d, J=7.8 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C:12]1[N:13]=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)C.C([O:23][C:24](=O)[CH2:25][C:26]1[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[N:28][N:27]=1)C.O>O1CCCC1>[CH:17]([N:15]1[N:14]=[N:13][C:12]([CH2:11][CH2:10][OH:9])=[N:16]1)([CH3:19])[CH3:18].[CH:31]([N:30]1[C:26]([CH2:25][CH2:24][OH:23])=[N:27][N:28]=[N:29]1)([CH3:33])[CH3:32]
Reactant: CCOC(=O)Cc1nnn(C(C)C)n1
Reactant: CCOC(=O)Cc1nnnn1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1nnc(CCO)n1
Product: CC(C)n1nnnc1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Lithium aluminum hydride (2.1 g, 10 mmol) was added slowly to tetrahydrofuran (30 mL) at 0° C. and a mixture of (2-isopropyl-2H-tetrazol-5-yl)-acetic acid ethyl ester and (1-isopropyl-1H-tetrazol-5-yl)-acetic acid ethyl ester (2 g, 10 mmol) in tetrahydrofuran (20 mL) was added under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 16 h. After the resulting mixture was cooled at 0° C., water (0.3 mL) was added slowly, and the reaction was stirred for 30 minutes and filtered through a short silica gel column, which was rinsed with ethyl acetate followed by 20% methanol/methylene chloride. The solution was concentrated in vacuo to provide 2-(2-isopropyl-2H-tetrazol-5-yl)-ethanol and 2-(1-isopropyl-1H-tetrazol-5-yl)-ethanol (1.5 g, 95% yield).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:12][CH2:11][CH2:10][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NCCN)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-fluorobenzonitrile (167 g, 1.38 mol), ethylenediamine (330 g, 5.5 mol) and potassium carbonate (300 g, 2.17 mol) in 2 1 of toluene is refluxed for 6 hours. After cooling to room temperature, the mixture is filtered and rinsed with toluene, and the filtrate is evaporated to give a yellow oil which is crystallized from toluene. The product is filtered off, rinsed with toluene and dried under vacuum at 50° C. to give 200 g of a slightly yellow solid.
Reaction SMILES: O=[O+][O-].C=[C:5]1[CH2:10][N:9]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][N:7]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:6]1.C(=O)=[O:36].CC(C)=O.CSC>O=O.CC(C)=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:9]2[CH2:10][C:5](=[O:36])[CH2:6][N:7]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:8]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: C=C1CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C=O
Agent: O=O
Agent: O=[O+][O-]
Solvent: CC(C)=O
Solvent: CSC
Product: O=C1CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A stream of ozone in oxygen was bubbled into a solution of hexahydro-5-(methylene)-1,3-bis(4-nitrobenzenesulfonyl)pyrimidine (0.6 g, 1.3 mmol) in 150 mL acetone at −78° C. (dry ice-acetone bath) until a blue color persisted for 5 minutes. The reaction was stirred for 15 minutes under a nitrogen atmosphere. Next, 2.0 mL of dimethyl sulfide was added. After stirring for 10 minutes, the solvent was removed and the solid dried under reduced pressure to give 0.5 g (83%) of tetrahydro-1,3-bis(4-nitrobenzenesulfonyl)pyrimidin-5(4H)-one. [1H NMR (acetone-d6): δ 3.95 (s, 4 H), 5.25 (s, 2 H), 8.20, 8.48 (AB q, J=9.0 Hz, 8 H); 13C NMR (DMSO-d6): δ 53.8, 58.8, 124.8, 129.3, 141.9, 150.4, 196.2].
Reaction SMILES: [C:1]([CH2:9][C:10](OCC)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.Cl.O1CCOCC1>C1(C)C=CC=CC=1.O>[C:2]1([C:1]2[CH:9]=[C:10]([OH:11])[C:20]3[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[N:23]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1cccc(N)c1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a solution of ethyl benzoylacetate (10.00 g, 52.0 mmol., 1 eq) and m-anisidine (7.05 g, 57.2 mmol., 1.1 eq) in toluene (85 mL) was added 4M HCl in dioxane (0.520 mL, 2.08 mmol., 0.04 eq) dropwise. The reaction mixture was refluxed for 15 hours while water was collected in a Dean-Stark apparatus. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was suspended in diphenyl ether (28 mL) and the mixture was heated for 2 h at 240° C. The reaction mixture was then left to cool to ambient temperature and dichloromethane (55 mL) was added, leading to the precipitation of a yellow solid. Stirring was continued at ambient temperature for a further 30 min and the solid collected by filtration, rinsing the cake with a small amount of dichloromethane. The solid was transferred to a 100 mL round bottom flask and stirred with dichloromethane (50 mL) for another 45 min at ambient temperature. After filtration and drying under high vacuum, 2.85 g (22%) of the title compound was isolated as a pale yellow solid. 1H NMR (250 MHz, DMSO-d6) δ ppm 11.54 (s, 1 H), 7.99 (d, J=8.91 Hz, 1 H), 7.73-7.90 (m, 2 H), 7.48-7.64 (m, 3 H), 7.20 (d, J=2.32 Hz, 1 H), 6.94 (dd, J=2.34, 8.97 Hz, 1 H), 6.26 (s, 1 H), 3.86 (s, 3 H). LC-MS: purity 98% (UV), tR 1.52 min, m/z [M+1]+ 252.10.
Reaction SMILES: CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[CH3:22][O:23][C:24]1[C:29]([C:30]2[C:34]3[N:35]=[C:36](S(C)(=O)=O)[N:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:43]([O:45][CH3:46])=[O:44])=[CH:28][CH:27]=[C:26]([CH3:47])[N:25]=1.[CH3:48][C:49]1[C:50]([N:62]2[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]2)=[CH:51][C:52]([O:58][CH:59]([CH3:61])[CH3:60])=[C:53]([NH:55][CH:56]=[O:57])[CH:54]=1>CN(C=O)C>[CH:56]([N:55]([C:53]1[CH:54]=[C:49]([CH3:48])[C:50]([N:62]2[CH2:63][CH2:64][N:65]([CH3:68])[CH2:66][CH2:67]2)=[CH:51][C:52]=1[O:58][CH:59]([CH3:61])[CH3:60])[C:36]1[N:37]=[CH:38][C:33]2[S:32][C:31]([C:43]([O:45][CH3:46])=[O:44])=[C:30]([C:29]3[C:24]([O:23][CH3:22])=[N:25][C:26]([CH3:47])=[CH:27][CH:28]=3)[C:34]=2[N:35]=1)=[O:57]
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1ccc(C)nc1OC
Reactant: Cc1cc(NC=O)c(OC(C)C)cc1N1CCN(C)CC1
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cnc(N(C=O)c3cc(C)c(N4CCN(C)CC4)cc3OC(C)C)nc2c1-c1ccc(C)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
0.7 ml of 1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine (BTPP) is added to a mixture of 300 mg of methyl 7-(2-methoxy-6-methylpyridin-3-yl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate and 231 mg of N-[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide in 8 ml of anhydrous DMF. The mixture is stirred at ambient temperature for 16 h, and then evaporated under vacuum at a temperature of 55° C., and the residue is diluted with ethyl acetate and water. The aqueous phase is extracted three times with ethyl acetate. The organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is purified on 25 g of silica, elution being carried out with 50-100% of acetone in dichloromethane so as to obtain 422 mg of methyl 2-{formyl[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxy-6-methylpyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of an orangey-coloured solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)=[CH:5][C:4]=1[O:20][CH2:21][C:22]#[CH:23].[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1I.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.[Cu](I)I>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:23]#[C:22][CH2:21][O:20][C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: Clc1ccc(I)c(Cl)c1
Reactant: C#CCOc1cc(-c2cccc(CC(=O)OC)c2)ccc1OC
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(OCC#Cc3ccc(Cl)cc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
9 mg of methyl (4′-methoxy-3′-(2-propynyloxy)biphenyl-3-yl)acetate was dissolved in 0.1 ml of N,N-dimethylformamide, 30 mg of 2,4-dichloroiodobenzene, 2 mg of copper iodide, 2 mg of tetrakistriphenyl phosphine palladium and 0.05 ml of triethylamine were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was concentrated to give methyl {3′-[3-(2,4-dichlorophenyl)-2-propynyloxy]-4′-methoxybiphenyl-3-yl}acetate. This product was dissolved in 0.5 ml of ethanol, then 0.1 ml of 5N sodium hydroxide was added thereto, and the mixture was left overnight at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography to give 4.24 mg of the title compound.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:20])[O:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][O:19][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1.[S-]CC.[Na+].O>CN(C)C=O>[OH:2][C:3]1[C:8]2[C:9](=[O:20])[O:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][O:19][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1
Reactant: COc1cc(OC)c2c(c1)OCCCC=CCCCOC2=O
Agent: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O)c2c(c1)OCCCC=CCCCOC2=O
Yield: 22.8 %

Procedure:
A solution of 1,3-dimethoxy-6,7,8,11,12,13-hexahydro-5,14-dioxa-benzocyclotridecen-15-one (95 mg, 0.30 mmol) and sodium thioethoxide (31 mg, 0.37 mmol) in dimethyl formamide was heated at 140° C. for 4 h whereby it was poored into water (100 ml). Extraction and chromatography gave 1-hydroxy-3-methoxy-6,7,8,11,12,13-hexahydro-5,14-dioxa-benzocyclotridecen-15-one (20 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[C:6]4[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:9][N:8]=3)[CH2:15][CH2:14]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(F)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.3 g, 5 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (example 1, intermediate C) (1.6 g, 6 mmol), triethylamine (0.64 mL, 5 mmol) in 1,2 dichloroethane (27 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (1.9 g, 9 mmol) was added slowly and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 2.3 g (5.1 mmol, 100% yield) of a off-white solid. MS (m/e): 446.3 (M+H+).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2S[C:15]([C:19](O)=O)=[C:16](C)[N:17]=2)N=N1)C1C=CC=CC=1.[F:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[S:34][C:35]([C:39]([OH:41])=O)=[C:36]([CH3:38])[N:37]=3)[N:30]=[N:29]2)=[CH:25][CH:24]=1.N1C=CC=C(CN)C=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[S:34][C:35]([C:39]([NH:8][CH2:12][C:11]4[CH:13]=[N:17][CH:16]=[CH:15][CH:19]=4)=[O:41])=[C:36]([CH3:38])[N:37]=3)[N:30]=[N:29]2)=[CH:42][CH:43]=1
Reactant: Cc1nc(-c2cn(Cc3ccc(F)cc3)nn2)sc1C(=O)O
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(-c2cn(Cc3ccc(F)cc3)nn2)sc1C(=O)NCc1cccnc1
Yield: 64 %

Procedure:
Following the procedure as described in Example 4, making variations as necessary to replace 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 64% yield: mp 212-213° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.54 (br s, 1H), 8.46 (br s, 1H), 7.95 (s, 1H), 7.72-7.69 (m, 1H), 7.34-7.18 (m, 3H), 7.09-6.97 (m, 2H), 6.85 (t, J=5.6 Hz, 1H), 5.49 (s, 2H), 4.58 (d, J=5.6 Hz, 2H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.1, 161.9, 157.9, 157.2, 149.2, 148.9, 142.9, 135.8, 133.9, 130.3, 129.6, 129.5, 124.1, 121.5, 116.4, 53.9, 41.6, 17.3; MS (ES+) m/z 409.3 (M+1).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[O:4][C:5]1=[O:11].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[CH2:13]([O:20][C:5]([CH:6]1[CH:2]([C:3]([OH:12])=[O:4])[CH:1]2[O:10][CH:7]1[CH2:8][CH2:9]2)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1OC(=O)C2C3CCC(O3)C12
Reactant: OCc1ccccc1
Solvent: C1COCCO1
Product: O=C(O)C1C2CCC(O2)C1C(=O)OCc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of 4,10-dioxa-tricyclo[5.2.1.02,6]decane-3,5-dione (8, 3.7 g, 22.0 mmol) and benzyl alcohol (9) (4.5 mL, 44.0 mmol) in dioxane was heated at 80° C. for 16 h. Cooled to room temperature and evaporated to remove solvent. Residue obtained was triturated with diisopropyl ether (20 mL) to give white solid of 10 which was filtered, washed with diisopropyl ether (10 mL) and dried. Yield: 3.6 g (59%). 1H NMR (300 MHz, CDCl3) δ 1.45-1.55 (m, 2H); 1.78-1.81 (m, 2H); 3.05 (s, 2H); 4.91 (d, J=9.4 Hz, 2H); 5.02 (d, J=6.3 Hz, 1H); 5.13 (d, J=6.3 Hz, 1H); 7.28-7.40 (m, 5H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.Cl>CS(C)=O.O.CCOCC>[C:3]1([C:9]2([C:10]#[N:11])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: N#CC1(c2ccccc2)CCCC1
Yield: 86.7 %

Procedure:
To a suspension of NaH (11.3 g, 281.7 mmol, 60%) in DMSO (75 ml) were added dropwise a mixture of phenyl-acetonitrile (15 g, 128.0 mmol) and 1,4-dibromo-butane (18 ml, 128.0 mmol) dissolved in DMSO:Ether (150 ml, 1:1) at 0° C. and the reaction mixture was stirred at room temperature (RT) for 2 to 3 h. After completion of the reaction, water and 10% HCl solution were added to the crude mass. It was extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (10% EtOAc-hexane) to get 1-phenyl-cyclopentanecarbonitrile (2) (19 g, 86.64%) as a yellow solid. MS: m/z=171 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:25]=[CH:26][CH:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:11](O)[CH:10]=2)=[N:6][CH:7]=1.FC1C=CC([N+]([O-])=O)=C([OH:40])C=1>>[F:1][C:2]1[C:3]([NH:21][C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:25]=[CH:26][CH:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:13][C:14]=2[OH:40])=[N:6][CH:7]=1
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)c(O)c3)ncc2F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)cc3O)ncc2F)c1

Procedure:
The synthesis of N-(3-((5-fluoro-2-((3-hydroxy-4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide was achieved as described above for N-(3-((5-fluoro-2-((3-hydroxy-4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (I-13) in Example 7 using 5-fluoro-2-nitrophenol in place of 2-fluoro-5-nitrophenol in the first step.