Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][NH:6][C:7](=[O:17])[O:8][CH:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1>>[N:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=2)[CH2:5][NH:6][C:7](=[O:17])[O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:24]=[N:23][CH:22]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(NCc1cccc(Br)c1)OC1CN2CCC1CC2
Product: O=C(NCc1cccc(-c2cncnc2)c1)OC1CN2CCC1CC2
Yield: 54.2 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromobenzylcarbamate (203 mg, 0.600 mmol), pyrimidin-5-ylboronic acid (149 mg, 1.2 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a viscous semi-solid (110 mg, 54%). 1H NMR (500 MHz, CDCl3) δ 9.20 (s, 1H), 8.94 (s, 2H), 7.51 (m, 3H), 7.40 (m, 1H), 5.62 (m, 1H), 4.81 (m, 1H), 4.50-4.40 (m, 2H), 3.30 (m, 1H), 2.97-2.65 (m, 5H), 2.12 (m, 1H), 1.92-1.82 (m, 1H), 1.79-1.69 (m, 1H), 1.65-1.56 (m, 1H), 1.50-1.42 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 157.6, 156.2, 154.9, 140.1, 134.7, 134.1, 129.8, 128.2, 126.2, 70.9, 55.2, 47.2, 46.2, 44.8, 25.2, 23.8, 19.0 ppm. Purity: >95% LCMS (214 nm & 254 nm); retention time 1.22 min; (M+1) 339.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[CH3:22][N:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[C:24]1[N:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]>C1COCC1>[CH3:22][N:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[C:24]1[C:25]([CH:26]([OH:27])[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: CN(c1cccnc1)c1ncccc1C=O
Reactant: c1cncc(Cc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1cccnc1)c1ncccc1C(O)C(c1cccnc1)c1cccnc1
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
A solution of bis-(3-pyridyl)methane (61 mg) in 3 mL THF was cooled to 0 C, and LDA (1.5 M in cyclohexane, 0.240 mL) was added dropwise via syringe. After the mixture had been stirred for 30 min, a solution of 2-[methyl(pyridin-3-yl)amino]nicotinaldehyde (73 mg) in 3 mL THF was added dropwise over 30 min. After 3 h stirring at 0 C, the reaction was quenched with water, then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (Na2SO4) and purified by reverse phase HPLC to give 40 mg of 1-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-2,2-dipyridin-3-ylethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1.[CH3:43][Zn]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:42][C:28]1[C:29]([NH:33][S:34]([C:37]2[CH:41]=[CH:40][O:39][CH:38]=2)(=[O:36])=[O:35])=[CH:30][CH:31]=[CH:32][C:27]=1[C:9]1[N:10]=[C:11]([C:13]2([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[S:12][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:43])[N:7]=1
Reactant: C[Zn]C
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1,1-dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate (130 mg, 0.205 mmol) was dissolved into 1,4-dioxane (3 mL) and the solution was degassed for 10 min. PdCl2(dppf)-CH2Cl2 adduct (8.37 mg, 10.25 μmol) and dimethylzinc (0.205 mL, 0.410 mmol) were added the reaction mixture. The reaction mixture was stirred at 80° C. for 1 h. The reaction was quenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (40% to 100% EtOAc/hexane) to the title compound (100 mg). MS (ESI): 557.7 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=[O:12]>>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)(=[O:12])[CH3:10]
Reactant: Fc1ccc(I)c(F)c1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Product: CC(=O)c1ccc(-c2ccc(F)cc2F)c([N+](=O)[O-])c1

Procedure:
2,4-Difluoroiodobenzene and 4-bromo-3-nitroacetophenone were reacted under Ullmann conditions to give 4-acetyl-2',4'-difluoro-2-nitrobiphenyl, b.p. 150°-158° C./0.2 mm., and this was reduced with stannous chloride to give 4-acetyl-2-amino-2',4'-difluorobiphenyl, m.p. 93°-95° C. By similar methods there were obtained 4-acetyl-2'-chloro-4'-fluoro-2-nitrobiphenyl, b.p. 178°-190°/0.2 mm m.p. 62°-64° C. and 4-acetyl-2-amino-2'-chloro-4'-fluorobiphenyl, m.p. 84°-86° C; 4-acetyl-4'-chloro-2'-fluoro-2-nitrobiphenyl, b.p. 174°-180°/0.2 mm., m.p. 85°-86° C. and 4-acetyl-2-amino-2'-fluoro-4'-chlorobiphenyl, m.p. 115° C; 4-acetyl-2',4'-dichloro-2-nitrobiphenyl, m.p. 72°-74° C. and 4-acetyl-2-amino-2',4'-dichlorobiphenyl, m.p. 75°-76° C; 4-acetyl-2' ,4'-dibromo-2-nitrobiphenyl, b.p. 210° C./0.3 mm. and 4-acetyl-2-amino-2',4'-dibromobiphenyl, m.p. 107°-109° C; 4-acetyl-4'-bromo-2'-fluoro-2-nitrobiphenyl, m.p. 116°-117° C. and 4-acetyl-2-amino-4'-bromo-2'-fluorobiphenyl, m.p. 120°-121° C; 4-acetyl-2'-bromo-4'-fluoro-2-nitrobiphenyl, b.p. 188°-200° C./0.3 mm., m.p. 75°-77° C. and 4-acetyl-2-amino-2'-bromo-4'-fluorobiphenyl, m.p. 98°-100° C; 4-acetyl-4'-bromo-2'-chloro-2-nitrobiphenyl, b.p. 185°-190° C./0.2 mm. and 4-acetyl-2-amino-4'-bromo-2'-chlorobiphenyl, m.p. 93°-95° C; and 4-acetyl-2'-bromo-4'-chloro-2-nitrobiphenyl, m.p. 84°-86° C; and 4-acetyl-2-amino-2'-bromo-4'-chlorobiphenyl, m.p. 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([CH:17]=O)[CH:3]=1.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[C:4](/[CH:17]=[C:24]2\[C:25](=[O:29])[NH:26][C:27]3[C:23]\2=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=3)[CH:3]=1
Reactant: N#CC1(COc2ccc(Cl)cc2C=O)CCCC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: N#CC1(COc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CCCC1
Yield: 90.1 %

Procedure:
In a manner similar to the method described in Example 1b, 1-(4-chloro-2-formyl-phenoxymethyl)-cyclopentanecarbonitrile (17.4 g, 66 mmol) was reacted with 6-chlorooxindole (8.5 g, 51 mmol) and pyrrolidine (4.69 g, 66 mmol) in methanol to give the title compound as a yellow solid (19 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[O:33][CH3:34])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1)(=O)=O>>[Cl:23][C:21]1[C:20]([C:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:41][CH2:42][CH:43]=2)=[CH:19][C:18]([O:33][CH3:34])=[C:17]([CH:22]=1)[C:15]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:16]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Reactant: O=S(=O)(Oc1cccc2ccccc12)C(F)(F)F
Product: COc1cc(C2=CCCc3ccccc32)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Yield: 87.8 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[5-chloro-2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 1 Step E (0.170 g, 0.355 mmol) and naphthalen-1-yl trifluoromethanesulfonate (0.109 g, 0.391 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 40% ethyl acetate in hexane followed by recrystallization from diethyl ether/pentane afforded the title compound (0.150 g) as white crystals, m.p.: 209–210° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:33][CH2:34][CH2:35][N:36]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:4]1[CH:3]=[C:2]([O:1][CH2:33][CH2:34][CH2:35][N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5]1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCOc1cc(=O)oc2ccccc12
Temperature: 0 °C
Yield: 75.2 %

Procedure:
4-hydroxycoumarin (6.17 mmol, 1.0 g), PPh3 (6.48 mmol, 1.70 g), and 2-(3-hydroxy-propyl)-isoindole-1,3-dione (6.48 mmol, 1.33 g) is disolved in 20 mL THF and is cooled to 0° C. DIAD (6.79 mmol, 1.33 mL) is added dropwise at 0° C. A precipitate is formed immediately and the reaction mixture thickens. The precipitate is filtered, is washed with Et2O and is dried to afford the title compound (1.62 g, 75%). 1H NMR (DMSO-d6, 300 MHz) δ 7.82 (4H, m), 7.61 (2H, m), 7.37 (1H, m), 7.21 (1H, m), 5.83 (1H, s), 4.28 (2H, t, J=5.75 Hz), 3.83 (2H, t, J=6.25 Hz), 2.19 (2H, m); MS (ESI, Pos.) calcd for C20H15NO5 m/z [M+H]=350.1, found 350.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[F:25])[N:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH2:36])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2([NH:36][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])[N:5]=[C:4]([NH:14][C:15]4[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=4[F:25])[N:3]=3)[CH2:34][CH2:35]2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)c(F)c1
Reactant: NC1(c2ccc(Cl)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
To a solution of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate (0.93 g, 2.45 mmol) in THF (10 mL) was added 1-(4-chlorophenyl)cyclopropanamine (0.5 g, 2.45 mmol) and Hunig's Base (1.71 mL, 9.8 mmol). The resulting mixture was refluxed at 80° C. for 16 hs. The precipitate was filtrated through a plug washing with THF to give a crude product that was purified by Biotage eluting with 4/1 to 3/2 hexane/ethyl acetate to give 1.2 g of methyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoro ethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate as product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[NH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]1([S:34]([CH2:37][C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[CH2:40]Br)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[CH2:37][S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[N:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n[nH]c21
Reactant: O=S(=O)(Cc1ccccc1CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n(Cc3ccccc3CS(=O)(=O)c3ccccc3)nc21
Yield: 41.8 %

Procedure:
3-[(3-Hydroxypropyl)thio]-5-methyl-7-(2-methylpropyl)-1H-pyrazolo[3,4-d]-pyrimidine-4,6(5H,7H)-dione (94 mg), potassium carbonate (90 mg) and 2-(phenylsulfonylmethyl)benzyl bromide (105 mg) were combined in dimethylsulfoxide (11 ml). After 5 hours at room temperature the reaction mixture was diluted with ethyl acetate and washed thrice with water, twice with dilute hydrochloric acid, once with brine, then dried over magnesium sulfate and then concentrated in vacuo. Chromatography on silica gel (isohexane:isopropanol 4:1) gave the title compound (70 mg).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na+].[I-].[H-].[Na+].[CH3:18][O:19][C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[C:25]([OH:32])[CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21]>CN(C=O)C.C(Cl)Cl>[CH3:18][O:19][C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[C:25]([O:32][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21]
Reactant: CCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc2cccc(O)c2n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1cccc2ccc(C(=O)OC)nc12
Reaction time: 8 h
Yield: 14 %

Procedure:
In a first step, dodecyl bromide (767 μL, 3.2 mmol), NaI (478 mg, 3.2 mmol) and NaH (76 mg, 3.2 mmol) were added to a solution of 8-hydroxyl-quinoline-2-carboxylic acid methyl ester (2.11 mmol) stirring in DMF (dry, 10 mL), and the red reaction was allowed to stir overnight. The crude material resulting from removal of solvents by rotary evaporation was taken into DCM, washed with water, dried over Na2SO4, and filtered. The resulting solution was evaporated to dryness and the desired intermediate, 8-dodecyloxy-quinoline-2-carboxylic acid methyl ester, was obtained by HPLC (isocratic, 75% acetonitrile, 25% water) yielding 169 mg (about 14% yield). This intermediate was in turn deprotected using LiOH in THF/H2O as described in the method of Example 336 to yield the title compound, which was utilized further without additional purification or characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[NH2:22][CH:23]1[CH2:28][CH:27]2[CH2:29][CH:24]1[CH2:25][CH2:26]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:22][CH:23]3[CH2:28][CH:27]4[CH2:29][CH:24]3[CH2:25][CH2:26]4)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: NC1CC2CCC1C2
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)NC1CC2CCC1C2
Yield: 71 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2-aminonorbornane (21 μL, 0.18 mmol) as the coupling partner. Concentration (no chromatography) yielded 38 mg (71%) of the titled compound. ESI-MS m/z 385 (MH+), 383 (M−H−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][N:12]2[CH:18]=1)=[O:8])[CH3:2].[Cl:20]N1C(=O)CCC1=O.O1CCCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][N:12]2[C:18]=1[Cl:20])=[O:8])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1Cl
Yield: 57.2 %

Procedure:
0.86 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester was suspended in 30 ml of ethyl acetate; 1.2 g of N-chlorosuccinimide was added, followed by thermal refluxing for 20 hours. After cooling, 30 ml of tetrahydrofuran was added; the mixture was washed with an aqueous solution of sodium thiosulfate and saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; ethyl ether was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 0.552 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23]B1OB(C)OB(C)O1>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH3:23])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 15 h
Yield: 69 %

Procedure:
To a suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A11) (5.00 g, 14.7 mmol) and tetrakis(triphenylphosphine)-palladium in dioxane/water (9:1; 50 ml) was added at RT trimethylboroxine (2.04 ml, 14.7 mmol). The reaction mixture was stirred under reflux conditions for 15 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1) to yield a light yellow solid (3.25 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[Li].[CH3:14][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].[Cl-].[NH4+]>CCOCC.C1C=CC=CC=1>[CH3:14][NH:15][C:16](=[O:21])[CH2:17][CH2:18][C:19](=[O:20])[C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: [Li]c1cc(C(F)(F)F)ccc1OC
Reactant: CN1C(=O)CCC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CNC(=O)CCC(=O)c1cc(C(F)(F)F)ccc1OC
Reaction time: 8 h

Procedure:
A solution of 2-methoxy-5-trifluoromethylphenyllithium in ether was added to a cold stirred solution of N-methylsuccinimide in benzene. The resultant mixture was allowed to stand overnight and was then decomposed with ammonium chloride solution to give N-methyl 3-(2-methoxy-5-trifluoromethylbenzoyl)propionamide.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH:37]([CH3:39])[CH3:38]>CN(C=O)C.C(OCC)(=O)C>[CH3:18][C@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:16][O:15][CH:12]1[CH2:11][CH2:10][N:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([O:1][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:28]=[CH:27][C:5]=3[N:6]=2)[CH2:14][CH2:13]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2nc(N3CCC(OC[C@H](C)NC(=O)OC(C)(C)C)CC3)oc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.6 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (150 mg) in DMF (5 mL) were added potassium carbonate (210 mg) and 1-iodo-2-methylpropane (190 mg), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (97 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH:11]([N:14](C(C)C)[CH2:15]C)(C)C.CNC.O>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:14]([CH3:15])[CH3:11])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4,6-dichloro-2-methylmercaptopyrimidine (10.0 g, 51 mmol) and diisopropyl ethylamine (17.5 ml, 102 mmol) was dissolved in tetrahydrofuran (400 ml), and a 50% aqueous dimethylamine solution (7.6 ml, 84 mmol) was dripped over the course of 1 hour into this solution under ice cooling. After this mixture liquid was agitated overnight at room temperature, water was added and extraction was carried out 2 times with ethyl acetate. After washing the organic layer with saturated saline, drying was done with MgSO4, the solvent was distilled away under reduced pressure, and 6-chloro-4-dimethylamino-2-methylmercaptopyrimidine was obtained. This was used for the next reaction without separation or refinement. Morpholine (100 ml) was added to this, and it was agitated overnight at 100 degrees Celsius. After allowing to cool, water was added and extraction was carried out 2 times with dichloromethane. After washing the organic layer with saturated saline, drying was done with MgSO4, the solvent was distilled away under reduced pressure. The residue was washed with ether and 11.3 g of coarse crystals of 4-dimethylamino-2-methylsulfanyl-6-morpholinopyrimidine was obtained (2 step yield: 87%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([CH3:31])=[CH:6]2.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[C:8]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:7]([CH3:31])=[CH:6]2
Reactant: COc1ccc2c(Oc3ccc(NS(C)(=O)=O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(NS(C)(=O)=O)cc2)c1-c1ccccc1
Temperature: -20 °C
Reaction time: 0.02 h
Yield: 62.3 %

Procedure:
A stirring solution of 269 (0.27 g, 0.62 mmol) in CH2Cl2 (10 mL) chilled to −20° C. under N2 was added BBr3 (0.47 g, 1.86 mmol), dropwise, via syringe, over 1 minute. The resulting yellow/orange r×n was stirred for 2 h at −20° C. and then poured over 50 g ice followed by addition of EtOAc (50 mL). The resulting slurry was transferred to a separatory funnel and the organic layer washed with brine (50 mL), dried (Na2SO4) and concentrated to a pale yellow foam. The crude product was purified by silica gel column chromatography with 2% MeOH: CH2Cl2 to yield 162 mg (63%) of the title compound 270, as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 2.83 (s, 3H), 6.55 (d, J=9.0 Hz, 2H), 6.97 (d, J=8.3 Hz, 2H), 6.96 (dd, J1=2.3 Hz, J2=9.1 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.21-7.30 (m, 4H), 7.54 (d, J=8.5 Hz, 1H), 7.55 (s, 1H), 9.33 (s, 1H), 9.84 (s, 1H). Anal. Calc for C29H26O3.0.5H2O: C, 67.27; H, 5.18; N, 3.27. Found: C, 67.13; H, 5.04; N, 3.27.