Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[N:11][C:12]([O:22][CH3:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH:14]=2)=[CH:4][N:3]=1.C(#N)C.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31].C(N(C(C)C)C(C)C)C>CCOC(C)=O>[Cl:21][C:17]1[CH:16]=[C:15]([C:13]2[CH:14]=[C:9]([CH2:8][C:5]3[CH:4]=[N:3][C:2]([NH:31][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[N:7][CH:6]=3)[CH:10]=[N:11][C:12]=2[O:22][CH3:23])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ncc(Cc2cnc(Cl)nc2)cc1-c1cccc(Cl)c1
Reactant: CN(C)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ncc(Cc2cnc(NCCN(C)C)nc2)cc1-c1cccc(Cl)c1
Temperature: 180 °C
Yield: 28 %

Procedure:
A 5 mL microwave vial was charged with 2-chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine (Example 2, 50.00 mg, 0.14 mmol), ACN (1.44 mL), N1,N1-dimethylethane-1,2-diamine (0.03 mL, 0.29 mmol), and N-ethyl-N-isopropylpropan-2-amine (77.13 μL, 0.43 mmol). The vial was sealed, and the reaction mixture was heated at 180° C. for 15 minutes. EtOAc (5 mL) was added to the reaction mixture, and the reaction mixture was extracted with water (3×). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-15% MeOH/DCM) afforded the title compound (15.6 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 2H), 8.09 (s, 1H), 7.67 (br s, 2H), 7.58 (s, 1H), 7.51-7.34 (m, 2H), 6.79 (br s, 1H), 3.84 (s, 3H), 3.72 (s, 2H), 2.42-2.37 (m, 4H), 2.17 (s, 6H). [M+H]=398.20.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.O1CCOCC1.B([C:38]1[CH:39]=[CH:40][C:41]([Cl:47])=[C:42]([CH:46]=1)[C:43]([OH:45])=[O:44])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O>[Cl:47][C:41]1[CH:40]=[CH:39][C:38]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=3[CH:26]=2)=[CH:46][C:42]=1[C:43]([OH:45])=[O:44]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: O=C(O)c1cc(B(O)O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(Cl)c(C(=O)O)c3)cc12
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 31.4 %

Procedure:
Alternative Procedure: To a 150 mL sealed tube was added 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.0 g, 2.4 mmol), dioxane (14.4 mL), water (2.9 mL), tetrakis(triphenyl phosphine)palladium(0) (0.055 g, 0.048 mmol), 5-borono-2-chlorobenzoic acid (0.720 g, 3.59 mmol), and cesium carbonate (1.171 g, 3.59 mmol). The tube was sealed and heated in an oil bath overnight at 85° C. The reaction mixture was cooled, diluted with 150 mL of ethyl acetate, washed sequentially with 20 mL of 0.5M HCl then brine. The product solution was filtered through a plug of celite then evaporated to dryness. The resulting solid was taken up in 10 mL of 1:1 DMF and acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/trifluoroacetic acid where solvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 3.5 μm C18 4.6×150 mm column at a gradient of 50-100% B and a flow rate of 40 mL/min. over 20 minutes with a 5 minute hold. Solvent was evaporated giving 319.5 mgs (32% yield) of 2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid as a white powder. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 10 μm C18, 3.0×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 4 minutes with a 1 minute hold at a rate of 5 mL/minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83-2.91 (m, 3H), 7.35-7.45 (m, 2H), 7.65 (d, J=8.53 Hz, 1H), 7.69-7.75 (m, 1H), 7.76-7.82 (m, 1H), 7.85-7.93 (m, 2H), 7.98-8.05 (m, 2H), 8.08 (d, J=2.26 Hz, 1H), 8.43-8.53 (m, 1H), 13.50 (br. s., 1H). LCMS m/z 424.0 (M+H), Rt=3.105 min., 100% purity.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+].Br[C:26]1[C:31]([O:32][CH2:33][CH2:34][CH:35]=[CH2:36])=[CH:30][CH:29]=[C:28]([Br:37])[N:27]=1>[N+](CC)(CC)(CC)CC.[Cl-].CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:37][C:28]1[N:27]=[C:26]2[C:35](=[CH2:36])[CH2:34][CH2:33][O:32][C:31]2=[CH:30][CH:29]=1
Reactant: C=CCCOc1ccc(Br)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C1CCOc2ccc(Br)nc21
Temperature: 105 °C

Procedure:
To a stirred mixture of PPh3(67.6 g, 0.258 mol), KOAc (42 g, 0.43 mol), Pd(OAc)2 (1.94 g, 8.6 mmol) and Et4NCl (28.6 g, 0.172 mmol), was added 2,6-dibromo-3-(but-3-enyloxy) pyridine (26.4 g, 0.086 mol) in anhydrous DMF (300 ml). The mixture was heated at 105° C. overnight. After cooling to rt, the mixture was dissolved in EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum) to afford the title compound as an oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]([O:39][Si](C(C)(C)C)(C)C)[CH3:38])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:47][O:48][C:49](=[O:51])[CH3:50])[CH2:7][O:8]2)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(=O)C.C1COCC1.O>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH:37]([OH:39])[CH3:38])=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:47][O:48][C:49](=[O:51])[CH3:50])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(C)O[Si](C)(C)C(C)(C)C)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(C)O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Yield: 65 %

Procedure:
A solution (1R,2S,3S,4R,55)-1-(acetoxymethyl)-5-(3-(4-(2-(tert-butyldimethylsilyloxy)propoxy)benzyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (350 mg, 0.46 mmol) in Acetic acid:THF:Water (3:1:1, 5.0 mL) was stirred at r.t. for 48 h. After completion of the reaction, as confirmed by TLC, sat. solution of NaHCO3 (10 mL) was added dropwise to the reaction mixture and organic layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1:1 Ethyl acetate:Pet. Ether) to afford title compound (190 mg, 65.7%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]1[C:14]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([C:35]#[N:36])[CH:12]=[N:11]1)[CH2:8][CH3:9].[F-].[Na+].O>O1CCCC1>[NH2:36][CH2:35][C:13]1[CH:12]=[N:11][N:10]([CH2:7][CH2:8][CH3:9])[C:14]=1[NH:15][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCn1ncc(C#N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1ncc(CN)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 81.1 %

Procedure:
To a suspension of lithium aluminum hydride (8.94 g) in tetrahydrofuran (600 ml) was added 1-propyl-5-tritylamino-1H-pyrazole-4-carbonitrile (37 g) at room temperature. The mixture was refluxed for 7 days. After cooling on an ice bath, sodium fluoride (40 g) and water (17 ml) were added to the reaction mixture. The insoluble materials were removed by filtration. To the filtrate was added ethyl formate, and the mixture was refluxed for 24 hours. After evaporation of the solvent in vacuo, the residue was triturated with diisopropyl ether and dried in vacuo to give 4-aminomethyl-1-propyl-5-tritylaminopyrazole (30.3 g).
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.O[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([C:14]3=[O:21])[CH2:12]1)[CH2:18]2.[Na+].[Cl-].[CH:24]([OH:26])=[O:25]>>[O:21]=[C:14]1[CH:15]2[CH2:20][C:11]3([C:24]([OH:26])=[O:25])[CH2:18][CH:17]([CH2:19][CH:13]1[CH2:12]3)[CH2:16]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: O=CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Cl-]
Product: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Temperature: 50 °C

Procedure:
A 5 L 4-neck flask equipped with N2 inlet/bubbler with H2O trap, overhead stirring, and an addition funnel was charged with 30% oleum (˜10.5 volumes, 2.2 L, 8×500 g bottles+100 mL), and heated to 50° C. under a slight N2 flow. 5-Hydroxy-2-adamantanone (220 g, 81 wt % purity, 1.07 mol) was dissolved in 5 volumes HCO2H (˜98%, 1.10 L) and added drop-wise to the warm oleum solution over 5 hours. The addition rate was adjusted to maintain the internal temperature between 70–90° C. After stirring an additional 2 hours at 70° C. The reaction solution was cooled to 10° C. in an ice bath. 20 volumes of 10% NaCl aq (4 L) were cooled to <10° C., the crude reaction mixture was quenched into the brine solution in batches, maintaining an internal temperature <70° C. The quenched reaction solution was combined with a second identical reaction mixture for isolation. The combined product solutions were extracted 3×5 volumes with CH2Cl2 (3×2.2 L) and the combined CH2Cl2 layers were then washed 1×2 volumes with 10% NaCl (1 L). The CH2Cl2 solution was then extracted 3×5 volumes with 10% Na2CO3 (3×2.2 L). The combined Na2CO3 extracts were washed with 1×2 volumes with CH2Cl2 (1 L). The Na2CO3 layer was then adjusted to pH 1–2 with concentrated HCl (˜2 volumes, product precipitates out of solution). The acidic solution was then extracted 3×5 volumes with CH2Cl2 (3×2.2 L), and the organic layer was washed 1×2 volumes with 10% NaCl. The organic solution was then dried over Na2SO4, filtered, concentrated to ˜¼ volume, then chase distilled with 2 volumes EtOAc (1 L). Nucleation occurred during this distillation. The suspension was then chase distilled 2×5 volumes (2×2 L) with heptane and cooled to room temperature. The suspension was then filtered, and the liquors were recirculated 2× to wash the wet cake. The resultant material was dried overnight at 50° C., 20 mm Hg to afford the title compound.
Reaction SMILES: [Cl-].[Li+].[BH4-].[Na+].C([O:7][C:8]([CH2:10][CH:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])[OH:12])=O)C>C1COCC1.C(O)C>[OH:12][CH:11]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:19])[CH2:10][CH2:8][OH:7]
Reactant: CCOC(=O)CC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Lithium chloride (0.678 g) and sodium borohydride (0.605 g) were added to a solution of (S)-2-[[(S)-2-[2-(ethoxycarbonyl)1-hydroxyethyl]-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (3.36 g) in THF-ethanol (1:1, 50 ml), under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered with suction, and the filtrate was concentrated. The residue was dissolved in chloroform, and poured into ice water for separation. The aqueous layer was saturated with sodium chloride and extracted with chloroform. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (2.50 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=1
Reactant: Cc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: CN1CCNCC1
Solvent: CCO
Product: Cc1ccc(-c2nc(Cl)cc(N3CCN(C)CC3)n2)cc1

Procedure:
Repeating the procedure of Example XX 7.2 g. of 4,6-dichloro-2-(p-tolyl)-pyrimidine and 6.0 g. of N-methylpiperazine are reacted in 40 ml. of absolute ethanol. The crude product (8.4 g.) is separated and twice recrystallized from n-heptane to afford 4-chloro-6-(4-methyl-1-piperazinyl)-2-(4-tolyl)-pyrimidine, m.p. 93°-95°C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH3:27])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH3:27])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1CCCN1c1cnc(C=O)c(Cl)n1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC1CCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
Sodium triacetoxyborohydride (2.09 g) was added to a solution of 3-chloro-5-(2-methylpyrrolidin-1-yl)pyrazine-2-carbaldehyde (1.49 g), N-benzylethanolamine (1.19 g) and acetic acid (1.13 mL) in acetonitrile (12 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→50% ethyl acetate/hexane) to give the title compound (1.82 g, 76%) as a pale-yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 1-phenylpiperazine 2 (2.59 g, 15.98 mmol) was reacted with N-(2-bromoethyl)phthalimide (8.12 g, 31.96 mmol), Et3N (2.0 mL) and K2CO3 (8.0 g) in DMF (40 mL) and stirred at 70° C. under N2 overnight. After the reaction mixture was cooled down, water (100 mL) was added. The mixture was extracted with diethyl ether. The organic phase was combined and dried over Na2SO4. The solvent was removed under vacuo to give the crude product, which was purified by flash chromatography (Hexane/EtOac=1/1) to furnish 3a, 3.81 g (71%) 1HNMR (CDCl3) 2.68-2.72 (m, 6H, N(CH2)2, CONCH2), 3.12-3.15 (t, J=4.8 Hz, 4H, N(CH2)2), 3.84-3.89 (t, J=6.3 Hz, 2H), 6.80-6.82 (t, J=8.1 Hz, 1H, Ar—H), 6.88-6.91 (d, J=8.1 Hz, 2H, Ar—H), 7.21-7.26 (t, J=8.1 Hz, 2H, Ar—H), 7.69-7.86 (m, 4H, Ar—H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH2:17]([O:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)[CH3:18]
Reactant: CCI
Reactant: CN(CCO)c1ccc([N+](=O)[O-])cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCN(C)c1ccc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (197 mg, 1 mmol) in THF (5 mL) and DMF (2 mL) was stirred with 60% NaH in oil (48 mg, 1.2 mmol) for 1 hr. The mixture was cooled and to this was added ethyl iodide (120 uL, 1.5 mmol). The reaction was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness and used without further purification. Yield: 155 mg. ES-MS calcd for C10H15N3O3 (m/e) 225.25, obsd 225.1 (M+H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:28][C:25]=2C=O)=[CH:18][C:17]=1[O:38][CH3:39])([CH3:14])[CH3:13]>C(Cl)Cl>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:28][C:25]=2[OH:6])=[CH:18][C:17]=1[O:38][CH3:39])([CH3:13])[CH3:14]
Reactant: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2C=O)ccc1OC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2O)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
m-Chloroperoxybenzoic acid [1.2 g, ALDRICH, 50% (remainder 3-chlorobenzoic acid and water), ca. 7.0 mmol] was added in portions over 0.25 h to a magnetically stirred mixture of 2-[(4-isopropoxy-3-methoxy-phenyl)ethynyl]5-isopropoxy-4-methoxybenzaldehyde (2.20 g, 5.75 mmol) and KHCO3 (1.73 g, 17.3 mmol) in CH2Cl2 (50 mL) maintained at 0° C. (ice-bath). The resulting slurry was stirred for a further 1 h between 0° C. and 18° C. then filtered through Celite® and the solids thus retained rinsed with CH2Cl2 (1×50 mL). The combined filtrates were concentrated under reduced pressure and the residue treated with NH3 (30 ml of a saturated methanolic solution). After 1 h at 18° C. the reaction mixture was concentrated under reduced pressure and the residue redissolved in CH2Cl2 (200 mL) then concentrated on to silica gel (8 g, 400-200 mesh). The resulting powder was loaded on top of a column of silica (40-10 mesh TLC grade, 10 cm wide×5 cm long) and eluted with 2:1, 1:1 and 1:2 hexane/CH2Cl2 then neat CH2Cl2 (250 ml of each). The appropriate fractions (Rf 0.3 in 1:2 hexane/CH2Cl2) were concentrated under reduced pressure to give the title compound (1.97 g, 92%) as white crystalline masses, mp 130-1° C. IR(KBr disc, cm−1) 3404, 2981,2935, 1620, 1573, 1513, 1467, 1450, 1418, 1383, 1373, 1330, 1269, 1240, 1214, 1166, 1135, 1113, 951. 1H NMR(300 MHz, CDCl3) δ7.03 (dd, J=1.8, 8.4 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 6.87 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.53 (s, 1H), 5.81 (s, 1H), 4.52 (septet J=6.0 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 1.35 (d, J=6.0 Hz, 12H). 13C NMR+APT (75.5 MHz, CDCl3) δ151.8 (C), 149.7 (C), 149.3 (C), 147.8 (C), 143.6 (C), 124.6 (CH), 115.0 (C), 114.7 (CH), 114.6 (CH), 114.3 (CH), 102.0 (CH), 100.1 (C), 94.7 (C), 82.2 (C), 71.1 (CH), 71.0 (CH), 56.4 (CH3), 55.7 (CH3), 21.9 (CH3), 21.8 (CH3). MS (70eV) m/z (%): 370 (M+•), 355(2, M+•−CH3), 328(18, M+•−CH(CH3)2], 327 (20, M+•CH2CHCH3), 286 (100, M+•−2×CH2CHCH3), 271 (42, M+•−2×CH2CHCH3—CH3). Anal. Calcd for C22H26O5 C, 71.33; H, 7.07. Found: C, 70.91; H. 7.24.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C(O)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCc1cc(Nc2ccc(CC(N)=O)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 108 °C
Yield: 62.4 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g, 0.59 mmol) and 2-(4-aminophenyl)acetamide (0.107 g, 0.71 mmol) and 4M HCl in dioxane (2 drops) in acetic acid (3 mL) was heated for 2 h at 108° C. After this time, the mixture was cooled to rt, neutralized with saturated NaHCO3, extracted with EtOAc, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with methylene chloride and methanol to afford the title compound (0.135 g, 62%) as a white solid. MW=366.84. 1H NMR (DMSO-d6, 500 MHz) δ 9.57 (s, 1H), 8.33-8.29 (m, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.58-7.54 (m, 2H), 7.43 (br s, 1H), 7.27 (d, J=8.5 Hz, 2H), 6.86 (br s, 1H), 6.59 (s, 1H), 3.35 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H); ESI MS m/z 367 [M+H]+.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]2[CH2:17][CH2:16]2)[C:9]=1[NH2:18].C(=O)([O-])[O-].[Na+].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>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.O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:17][CH2:16]3)[C:9]=2[NH2:18])=[CH:28][CH:27]=1
Reactant: Nc1c(Cl)ncnc1NC1CC1
Reactant: OB(O)c1ccc(Cl)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: C1COCCO1
Solvent: O
Product: Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a reactor carousel test tube which had been dried by heating and preheated to 100° C., the degassed diluent mixture dioxane (20 ml)/water (7 ml) was added to 6-chloro-N-cyclopropylpyrimidine-4,5-diamine (10 g, 54.1 mmol) and sodium carbonate (17.22 g, 162 mmol). 5 mol % of tetrakis(triphenylphosphine)palladium(0) and 4-chlorophenylboronic acid (108.2 mmol) were added, and the reaction mixture was stirred at 90° C. overnight. The solution was cooled, filtered and concentrated and the residue was recrystallised from acetonitrile.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:16]2[C:33]([NH2:35])=O)=[CH:11][CH:10]=1>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:16]2[C:33]#[N:35])=[CH:11][CH:10]=1
Reactant: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(N)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C#N)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
To ice-cold DMF (1 ml) under an argon atmosphere was added oxalyl chloride (68 ml, 0.78 mmol). After stirring for 5 min at 0° C., a solution of (1RS, 2SR, 3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxamide (150 mg, 0.39 mmol) in DMF (2 ml) was added, and stirring was continued for an additional 10 min at 0° C. The reaction mixture was partitioned between EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to afford the title compound as a white solid (135 mg, 94%) which was used without further purification.