Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)[CH3:3].C1(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:24]([CH:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)[CH3:3])=[N+:25]=[N-:26]
Reactant: CC(O)c1cnccn1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1cnccn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-(1-hydroxyethyl)pyrazine (0.859 g) and diphenylphosphoryl azide (2.48 g) in dry toluene (12 mL) at 0° C., under argon, was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.35 mL) dropwise. The resulting mixture was allowed to warm slowly to room temperature and stirred for 22 h then quenched with water (8 mL). The organic layer was removed and the aqueous phase extracted with 10 mL ethyl acetate. The combined extracts were concentrated, and the crude product was purified by flash column chromatography, eluting with hexane; 25% ethyl acetate to give 2-(1-azidoethyl)pyrazine (0.88 g) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2.CN(C)C=O>ClCCl.CN(C)C1C=CN=CC=1>[NH2:8][C@H:9]([C:13]([O:15][CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2)=[O:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](COC(=O)[C@@H](N)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of N-Boc-L-valine (528 mg; 2.1 mmol) and N,N′-dicyclohexyl carbodiimide (250 mg; 1.21 mmol) in dichloromethane (20 ml) was stirred over night at room temperature, dicyclohexylurea filtered off and extracted with a small volume of dichloromethane, and the filtrate evaporated in vacuo to a small volume. (R)-9-[2-Hydroxymethyl-4-(stearoyloxy)butyl]guanine (340 mg; 0.654 mmol), 4-dimethylaminopyridine (25 mg; 0.205 mmol), and dry N,N-dimethylformamide (15 ml) were added and the mixture was stirred for 4 h at 50° C. under N2. The solvent was evaporated in vacuo to a small volume. Column chromatography on silica gel, then on aluminum oxide (ethyl acetate:methanol: water 15:2:1 as eluent) gave 185 mg (39%) pure title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]([C:10]([OH:12])=O)[CH3:9])=[O:6])[CH3:3].Cl.[CH3:15][C:16](=[CH2:19])[CH2:17][NH2:18].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>O1CCCC1>[CH3:9][C@H:8]([NH:7][C:5](=[O:6])[O:4][C:2]([CH3:1])([CH3:3])[CH3:13])[C:10]([NH:18][CH2:17][C:16]([CH3:19])=[CH2:15])=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=C(C)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
To a cooled (0° C.) mixture of 18.9 parts of (S)-N-[(1,1-dimethylethoxy)carbonyl]alanine, 10.8 parts of 2-methyl-2-propen-1-amine monohydrochloride, 27.0 parts of 1-hydroxy-1H-benzotriazole hydrate and tetrahydrofuran, there were added 10.1 parts of N-methylmorpholine and, after 20 min, 20.6 parts of N,N-methanetetraylbis[cyclohexanamine] under a nitrogen atmosphere. The whole was kept at 0° C. for 1 hour and at room temperature for 12 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and NaHCO3 (sat.). The organic layer was separated, washed with NaCl (sat.), dried, filtered and evaporated, yielding 24.2 parts (99.9%) of (1,1-dimethylethyl) (S)-[1-methyl-2-[(2-methyl-2-propenyl)amino]-2-oxoethyl]carbamate (interm. 63).
Reaction SMILES: [CH:1]1([C:7]2([O:17][CH3:18])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C(=O)([O-])O.[Na+].C(OCC)C>O>[CH3:18][O:17][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: COC1(C2CCCCC2)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC1(C2CCCCC2)CCC(=O)CC1
Temperature: 25 °C
Yield: 107.1 %

Procedure:
A solution of 8-cyclohexyl-8-methoxy-1,4-dioxaspiro[4.5]decane (1.15 g) and acetic acid (40 ml) in water was stirred at 100° C. for 6 hours. After cooling to room temperature, the reaction mixture was added to a mixture of sodium hydrogen carbonate solution and diethyl ether. The organic layer was taken, washed with sodium hydrogen carbonate solution and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 1-methoxy-1,1′-bicyclohexane-4-one (1.018 g).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1.[CH2:21]([N:23]([CH2:26]C)CC)C.[CH3:28][S:29]([N:32]=C(SC)SC)(=[O:31])=[O:30]>C(O)C>[NH2:19][C:18](=[N:17][C:14]1[S:15][CH:16]=[C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][NH:4][C:21]([NH:23][CH3:26])=[N:32][S:29]([CH3:28])(=[O:31])=[O:30])[N:11]=2)[N:13]=1)[NH2:20]
Reactant: CCN(CC)CC
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CSC(=NS(C)(=O)=O)SC
Agent: Cl
Solvent: CCO
Product: CNC(=NS(C)(=O)=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.5 g), triethylamine (1.8 ml) and dimethyl N-methanesulfonyl-dithiocarbonimidate (0.8 g) in ethanol (30 ml) was heated under reflux for 5 hours. The solvent was removed by concentration in vacuo. To the residue was added to a mixture of 40% aqueous methylamine (4.0 ml) in N,N-dimethylformamide (13 ml) and the mixture was stirred at ambient temperature for 30 hours. The reaction mixture was added a water and the isolated precipitate was collected by filtration to give 2-(diaminomethyleneamino)-4-[6-(2-methanesulfonyl-3-methylguanidino)methylpyridin-2-yl]thiazole (1.12 g).
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:8]([CH3:22])[CH:7]=[C:6]([O:23][CH3:24])[N:5]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:20]([N:19]1[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11](=[O:12])[NH:10][C:9]2[C:8]([CH3:22])=[CH:7][C:6]([O:23][CH3:24])=[N:5][C:4]1=2)[CH3:21]
Reactant: CCNc1ncccc1C(=O)Nc1c(C)cc(OC)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(OC)nc21
Yield: 47.6 %

Procedure:
Sodium hydride (0.14 g of a 50% dispersion in mineral oil) was added to a solution of N-(2-bromo- 6-methoxy-4-methyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide (0.54 g) in pyridine (4 ml), and the resulting mixture was refluxed for 1.5 hours. The cooled mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The residue was washed with diisopropyl ether and hot ethyl acetate, and then crystallized from ethanol to provide 0.2 g of 5,11-dihydro-11-ethyl-2-methoxy-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one m.p. 249°-251° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([N+:8]([O-])=[O:9])[CH:7]=1.O.NN>ClCCCl.C(O)C.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][OH:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: ClCCCl
Solvent: O
Solvent: CCO
Product: COc1cc(Br)cc(NO)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Bromo-5-nitroanisole (1.5 g, 6.46 mmol) was dissolved in 20 mL of 1,2-dichloroethane and 20 mL of ethanol, and the mixture was cooled to 0° C. Raney-Ni (30 mg) and hydrazine hydrate (0.79 mL, 12.9 mmol) were added within 10 minutes, and the reaction was stirred for 4 hours at room temperature, when 50 mg of Raney-Ni were added. After stirring for 16 hours, another 50 mg of Raney-Ni were added, and after further stirring for 4 hours, another 50 mg of Raney-Ni were added. Stirring was continued for 4 hours at room temperature, when the starting material had completely disappeared. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure to provide N-(3-bromo-5-methoxy-phenyl)-N-hydroxylamine as a solid, which was dissolved in 80 ml of toluene. Sodium bicarbonate (597 mg, 7.11 mmol) was added, followed by acetyl chloride (0.51 mL, 7.11 mol). Stirring at room temperature was continued for 20 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (40 g SiO2; EtOAc/heptane in a gradient from 5/95 to 1/3) to yield the title compound as a solid (360 mg, 21% over 2 steps). LC-MS at 254 nm; [M+H] 260.0/262.1; Rt 0.82 min; (LCMS method 1). 1H-NMR (600 MHz; DMSO-d6): 10.85 (brs, 1H), 7.50 (dd, 1H), 7.26 (dd, 1H), 6.94 (dd, 1H), 3.77 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([O-])(=[O:10])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC=C/C=C/C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCC=C/C=C/CO
Yield: 87.4 %

Procedure:
To a solution of ethyl trans, trans-2,4-nonadienoate (25 g) in dry ether (250 ml) was added dropwise lithium aluminum hydride (5 g) with stirring under ice-cooling in the course of an hour. The reaction mixture was stirred for an hour at ambient temperature. To the resultant mixture was added ether containing water and then insoluble materials were removed by filtration. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give oily trans, trans-2,4-nonadien-1-ol (20 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[N:19]=[CH:18][N:17]=3)[C:9]=2[N:10]=1)=[O:4].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[N:32]1([CH2:2][C:3]([NH:5][C:6]2[S:7][C:8]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=5)[N:19]=[CH:18][N:17]=4)[C:9]=3[N:10]=2)=[O:4])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Solvent: ClCCl
Product: O=C(CN1CCOCC1)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
This material was prepared according to the procedure described in Example 83(b) using 2-chloro-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 83(a)), (0.17 g, 0.33 mmol) and morpholine (72 uL, 0.82 mmol, Aldrich) in CH2Cl2 (1.5 mL). Purification by silica gel chromatography (1:1 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 516 (M+1). Mp:177.8-181.7° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]([N:8]([CH2:28][CH2:29][CH2:30][S:31]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])[C:9]1[C:10]([C:23](OCC)=[O:24])=[N:11][CH:12]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)=[O:7])[CH3:2].[O-]CC.[Na+]>C(O)C.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:13]2[CH:14]=[C:9]3[C:10]([C:23]([OH:24])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:39])[C:6](=[O:7])[N:8]3[CH2:28][CH2:29][CH2:30][S:31]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)(=[O:32])=[O:33])=[N:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)N(CCCS(=O)(=O)N1CCCC1)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cold (0° C.) solution of ethyl 3-{[3-(ethyloxy)-3-oxopropanoyl][3-(1-pyrrolidinylsulfonyl)propyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (275 mg, 0.488 mmol) in ethanol (5 mL) was added sodium ethoxide (347 μL, 3.09 M in ethanol, 1.07 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred 10 minutes, then poured onto ice. Once the ice had melted, the mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(1-pyrrolidinylsulfonyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1 H), 7.73 (s, 1 H), 7.23 (dd, J=8.3, 5.4 Hz, 2 H), 7.02 (t, J=8.7 Hz, 2 H), 4.51 (q, J=7.1 Hz, 2 H), 4.38 (t, J=7.8 Hz, 2 H), 4.12 (s, 2 H), 3.37-3.33 (m, 4 H), 3.05 (t, J=6.5 Hz, 2 H), 2.18 (m, 2 H), 1.96-1.93 (m, 4 H), 1.48 (t, J=7.2 Hz, 3 H); MS m/z 518 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:11]=2[C:12]([OH:14])=[O:13])=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C>CO>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:8]1([C:7]2[CH:6]=[CH:5][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:24][CH:23]=2)[C:10]2[C:11](=[C:15]([Cl:22])[C:16]([Cl:21])=[C:17]([Cl:20])[C:18]=2[Cl:19])[C:12](=[O:14])[O:13]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Temperature: 90 °C
Yield: 48.2 %

Procedure:
A mixture of 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (8.70 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (3.61 g.) and acetic anhydride (5 ml.) was heated (to 90° C.). Addition of methanol (10 ml.) and slurrying the resulting product with methanol afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=(CH3)2N, Y2 =H, Y4 =(CH3CH2)2N, Z4 =Z5 =Z6 =Z7 =Cl) (5.60 g., m.p. 206°-207.5° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[CH:16][N:15]=1>O1CCOCC1>[F:21][C:20]([F:23])([F:22])[C:18]1[N:17]=[CH:16][N:15]=[C:14]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:19]=1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: Nc1ccc(O)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ccc(Oc2cc(C(F)(F)F)ncn2)cc1
Temperature: 62.5 °C

Procedure:
4-Amino-phenol (1.2 g, 10.9 mmol) is added in one portion to a suspension of NaH (60% free-flowing powder moistened with oil, 0.48 g, 12.0 mmol, 1.1 equiv) in dioxane abs. (18 mL), under an argon atmosphere. When hydrogen evolution subsides, a solution of 4-chloro-6-trifluoromethyl-pyrimidine (2.0 g, 10.9 mmol) in dioxane (2.0 mL) is added. The resulting dark mixture is heated to 60-65° C. (oil bath temperature) for 40 min, allowed to cool to rt, quenched by addition of MeOH and concentrated in vacuo. The residue is purified twice by silica gel (200 g) column chromatography (CH2Cl2/MeOH, 99/1, then 98/2) to afford the title compound as a white solid: ES-MS: 256.0 [M+H]+; single peak at tR=6.35 min (System 2); Rf=0.33 (CH2Cl2/MeOH, 98/2).
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[C:33]=1[OH:40].[NH2:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C@H:68]3[CH2:73][CH2:72][C@@H:71]([N:74]4[CH2:79][CH2:78][N:77]([CH3:80])[CH2:76][CH2:75]4)[CH2:70][CH2:69]3)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]4OC5C=CC=C(C)C=5N=4)=[CH:53][CH:52]=3)[C:43]=12>>[NH2:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C@H:68]3[CH2:73][CH2:72][C@@H:71]([N:74]4[CH2:75][CH2:76][N:77]([CH3:80])[CH2:78][CH2:79]4)[CH2:70][CH2:69]3)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]4[O:40][C:33]5[C:34]([Cl:39])=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=5[N:31]=4)=[CH:53][CH:52]=3)[C:43]=12
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Reactant: Nc1cc(Cl)cc(Cl)c1O
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cc(Cl)cc(Cl)c6o5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
cis-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dichloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and 2-amino-4,6-dichlorophenol (0.044 g, 0.245 mmol) in a manner similar to that used in the synthesis of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine (PH4042235). The compound was formed as an off-white solid (0.008 g, 6%): RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=8.93 min., 95%; m/z 594 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:20]/[C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(Br)c(/C=C/c2cccnc2)nc2ccccn12

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (250 mg, 1.045 mmol) and pyridine-3-aldehyde (168 mg, 1.561 mmol) in the presence of sodium ethoxide (142 mg, 2.086 mmol) in absolute ethanol (25 ml) as described in Intermediate 1 to give 203 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.11 (t, J=6.9 Hz, 1H), 7.32-7.36 (m, 1H), 7.63-7.76 (m, 3H), 7.98-8.05 (m, 2H), 8.57 (d, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.97 (d, J=6.6 Hz, 1H).
Reaction SMILES: S(Cl)(Cl)=O.C1(CCC(O)=O)C=CC=CC=1.C1(CCC(Cl)=O)C=CC=CC=1.[C:27]1([CH2:33][CH2:34][C:35]([N:37]=[C:38]=[S:39])=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][C:56]=1[F:62]>C(O)C.C1(C)C=CC=CC=1>[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:38]([NH:37][C:35](=[O:36])[CH2:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[S:39])=[CH:57][C:56]=1[F:62]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(CCc1ccccc1)N=C=S
Agent: O=C(Cl)CCc1ccccc1
Agent: O=C(O)CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCc4ccccc4)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-phenylpropanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-phenylpropanoyl isothiocyanate was prepared using the resultant 3-phenylpropanoyl chloride as a starting compound according to the description of the literature. 3-Phenylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (57 mg, yield 71%).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:11][C:10]2[C:5](=[N+:6]([O-:22])[CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[Si](C)(C)c1cc2ncccc2o1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc2c(ccc[n+]2[O-])o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Trimethylsilyl)furo[3,2-b]pyridine (14.68 g, 76.7 mmol) was dissolved in 80 mL DCM and cooled to 0° C. m-CPBA (33.1 g, 192 mmol) was dissolved in 160 mL DCM and slowly added to the reaction vessel. Upon complete addition, the reaction was warmed to RT and stirred for three hours. Reaction was diluted with DCM and washed twice with saturated sodium bicarbonate solution. 30 g of carbonate scavenger beads (˜30 mmol) were added to the organic layer and the solution was stirred for 30 minutes. The reaction was filtered, washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-10% MeOH:DCM) to afford 2-(trimethylsilyl)furo[3,2-b]pyridine N-oxide as a light brown oil that solidified under high vacuum. MS: M+H+=208.2
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].O>COCCOC.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>[F:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Cc1cc(F)nc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
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: O
Solvent: COCCOC
Product: Cc1cc(F)nc(-c2ccc(F)cc2)c1
Yield: 36.1 %

Procedure:
A mixture of 2-bromo-6-fluoro-4-methylpyridine (9.5 g, 50 mmol), 4-fluorobenzeneboronic acid (7.8 g, 56 mmol), sodium bicarbonate (12.6 g, 150 mmol), water (200 mL) and catalytic amounts of tetrakis(triphenylphosphine)palladium(0) in DME under nitrogen is heated to reflux overnight. After filtration of the reaction mixture the solvents are removed under reduced pressure. The residue is partitioned between water and ethyl acetate. The layers are separated and the aqueous layer is washed with ethyl acetate. After drying of the combined organic layers with anhydrous magnesium sulphate, the solvent is removed in vacuo. The crude product is purified by flash column chromatography (silica gel, pentane/ethyl acetate 9/1) yielding colorless crystals of 2-fluoro-6-(4'-fluorophenyl)-4-methylpyridine (3.7 g, 36.1% of th.) with mp 49° C.