Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][C:29]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][CH2:40][CH2:41]O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>C(Cl)Cl.[Al]>[Br:1][CH2:41][CH2:40][O:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]([CH3:31])([CH3:30])[CH3:28])=[CH:33][CH:34]=1
Reactant: CC(C)(C)c1ccc(COCCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(COCCBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution of 2-({[4-(1,1-dimethylethyl)phenyl]methyl}oxy)ethanol (160 mg, 0.768 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (25 mg, 12%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC1CCCO1.[C:26]([O:30][C:31](=[O:51])[N:32]([C:43]1[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][CH:44]=1)[CH2:33]S(C1C=CC=CC=1)(=O)=O)([CH3:29])([CH3:28])[CH3:27]>O>[C:26]([O:30][C:31](=[O:51])[N:32]([C:43]1[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[CH:47][CH:48]=1)[CH2:33][C:13]1[C:14](=[O:17])[CH2:15][CH2:16][C:12]=1[NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:18])([F:19])[F:3])[CH:6]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 1.06 g, 26.5 mmol) is added at room temperature in portions to a mixture of 3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (4.31 g, 17.9 mmol) and 2-methyltetrahydrofuran. After 20 min tert-butyl(4-cyanophenyl)(phenyl-sulfonyl)methylcarbamate (10.0 g, 24.2 mmol based on 90% purity) is added, and the mixture is stirred at room temperature for 1 h. Water is added and the phases are separated. The organic layer is washed with water and concentrated under reduced pressure, and the residue is recrystallized from tert-butyl methyl ether. Yield: 6.92 g. ESI mass spectrum: [M+H]+=472; Retention time HPLC: 0.76 min (X012_S01).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)=[CH:2]1.N1C2[C:15](=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:3]1[CH:4]=[CH:5][N:1]([C:15]2[CH:16]=[C:17]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[CH:13][CH:14]=2)[CH:2]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: c1csc(-c2cc[nH]c2)n1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1cncc(-c2cccc(-n3ccc(-c4nccs4)c3)c2)c1

Procedure:
A solution of 2-(1H-pyrrol-3-yl)-1,3-thiazole (0.100 g, 0.67 mmol) 3-(3-iodophenyl)pyridine (0.224 g, 0.8 mmol), copper(I) iodide (0.038 g, 0.2 mmol), 1,10-phenanthroline (0.360 g, 2 mmol), potassium phosphate (0.440 g, 2.0 mmol) in dioxane (2 mL) was heated at 220° C. for ½ hr under microwave irradiation. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (EtOAc 100%) to afford 3-{3-[3-(1,3-thiazol-2-yl)-1H-pyrrol-1-yl]phenyl}pyridine as a slightly yellow oil. The free base in anhydrous diethyl ether was treated with 1.5 equivalent HCl (1M in Ether) to give HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([NH:20][CH3:21])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([N:20]([CH2:18][CH3:19])[CH3:21])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Reactant: CCNC
Product: CCN(C)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 30 %

Procedure:
The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (390 mg, 1.43 mmol) and ethylmethylamine using General Procedure G and was isolated in 30% yield as a white solid. HPLC Rt=11.66 min; 1H NMR (400 mHz, CDCl3) 7.40-7.30 (m, 2H), 7.10 (dd, J=2.2, 8.4 Hz, 1H), 3.31 (bs, 2H), 2.59 (bs, 3H), 2.30 (d, J=12.5 Hz, 2H), 1.76-1.55 (m, 7H), 1.32-1.25 (m, 2H), 1.00 (bs, 3H); 13C NMR (100 mHz, CDCl3) 147.0, 132.9, 130.8, 130.3, 127.5, 125.2, 51.0, 44.5, 36.8, 25.9, 23.5; GC-MS (SCOUT) 13.01 min, M+ 313.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[Na+].[OH-].[Na+]>O.CO.CO>[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
Except that 200 ml of 0.1 w/v% solution of sodium ascorbate in water-methanol (water/methanol-1/100) was used in place of 200 ml of the solution of sodium hydroxide in methanol in Example 1, a similar treatment to that in Example 1 gave 190 g of ascorbic acid powder of 100 mesh pass. The powder contained about 30 ppm of sodium ascorbate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].[CH3:25][CH2:26][CH2:27][NH:28][C@@H:29]1[CH2:38][C:33]2[S:34][C:35]([NH2:37])=[N:36][C:32]=2[CH2:31][CH2:30]1>C(#N)C>[NH2:37][C:35]1[S:34][C:33]2[CH2:38][C@@H:29]([N:28]([CH2:27][CH2:26][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:7]3=[O:16])[CH2:30][CH2:31][C:32]=2[N:36]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CCCN[C@H]1CCc2nc(N)sc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCCN(CCCCN1C(=O)c2ccccc2C1=O)[C@H]1CCc2nc(N)sc2C1
Yield: 90.3 %

Procedure:
N-(4-bromobutyl)-phthalimide (2.25 g, 7.98 mmol), cesium carbonate (2.6 g, 7.98 mmol), and sodium iodide (1.80 g, 12 mmol) were added to a solution of pramipexole 1 (1.53 g, 7.25 mmol) in acetonitrile (50 mL). After refluxing for 3 hours, the mixture was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, and dried over anhydrous Na2SO4. Flash column chromatography (MeOH/EtOAc, 5:95) gave 13 as a colorless oil (2.7 g, 90.4%). 1H NMR (CDCl3, 300 MHz) δ 7.88-8.00 (m, 2H), 7.78-7.60 (m, 2H), 4.90 (s, 2H), 3.70 (t, J=7.2 Hz, 2H), 3.10-2.95 (m, 1H), 2.78-2.30 (m, 8H), 2.05-1.90 (m, 1H), 1.77-1.60 (m, 3H), 1.56-1.40 (m, 4H), 0.87 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ168.89, 165.83, 145.53, 134.28, 132.53, 123.58, 117.96, 57.59, 52.97, 50.41, 38.34, 27.01, 26.81, 26.71, 26.05, 25.33, 22.64, 12.24.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:11][C:12]1[C:13]2[N:14]([C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH:15]=[CH:16][N:17]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].[OH-].[K+]>ClCCl.C(O)(=O)C.CO.O>[CH3:11][C:12]1[C:13]2[N:14]([C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:7]4[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]4)[CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH:15]=[CH:16][N:17]=1
Reactant: Cc1nccn2c(C3CCNCC3)ncc12
Reactant: CC(=O)N1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCC(N2CCC(c3ncc4c(C)nccn34)CC2)CC1
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
To 1-acetyl-4-piperidone (0.877 mmol, 0.109 ml) in dichloromethane (3 ml) and acetic acid (0.143 ml) under nitrogen atmosphere was added 8-methyl-3-(piperidin-4-yl)imidazo[1,5-a]pyrazine (0.797 mmol, 172 mg) in dichloromethane (4 ml) and methanol (1 ml). After 20 minutes, sodium cyanoborohydride (0.877 mmol, 55.1 mg) was added. After stirring at room temperature for one hour 1-acetyl-4-piperidone (0.877 mmol, 0.109 ml) and acetic acid (0.05 ml) were added. After 1.5 hours water was added to the reaction mixture and saturated aqueous sodium hydrogencarbonate solution were added to the water layer and made basic (pH 10) with potassium hydroxide. This aqueous basic mixture was extracted with dichloromethane/methanol (9/1) and the organic extracts concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane containing 1% triethylamine with gradient 0 to 10% of methanol) to give 1-(4-(8-methylimidazo[1,5-a]pyrazin-3-yl)-1,4′-bipiperidin-1′-yl)ethanone (174 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Br)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 595.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][C@H:6]1[C:11]([O:13]C)=O)=[O:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCCO)C>[CH2:15]([N:22]1[CH2:2][C:3](=[O:4])[N:5]2[CH2:9][C@H:8]([OH:10])[CH2:7][C@H:6]2[C:11]1=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)CCl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCCO
Product: O=C1[C@@H]2C[C@@H](O)CN2C(=O)CN1Cc1ccccc1

Procedure:
To a solution of Example 19B (75 g, 0.34 mol, 1 equivalent) in 2-ethoxyethanol (1.2 L), benzylamine (44 mL, 0.41 mol, 1.2 equivalents) was added. Triethylamine (60 mL, 0.43 mol, 1.28 equivalents) was then added, and the resultant mixture was refluxed for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure. This crude material was purified by column chromatography on silica gel using a gradient of 0-10% methanol-ethyl acetate to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.93-2.03 (m, 1H), 2.1-2.17 (m, 1H), 3.23 (d, 1H, J=12.3 Hz), 3.55 (d, 1H, J=4.2 Hz), 3.63 (d, 1H, J=16.5 Hz), 4.15 (m, 1H), 4.32 (bs, 1H), 4.47-4.59 (m, 3H), 5.16 (s, 1H), 7.24-7.37 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8](Cl)=[CH:9][C:10]=1[CH3:11])=[O:4].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(CC)CC.CCOC(C)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1c(C)cc(Cl)nc1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(C)cc(N2CCOCC2)nc1OC
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 5.0 g (21.8 mmol) 6-chloro-2-methoxy-4-methylpyridine-3-carboxylic acid methylester, 2.0 g (24.0 mmol) morpholine and 6.0 ml (43.5 mmol) NEt3 in NMP (21 ml) was heated at 90° C. for 2 d. After cooling to RT the mixture was partiotionated between EtOAc and a 1M aq. NaHCO3 sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 2.7 g (9.8 mmol, 45%) 2-methoxy-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:24](OCC)[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]2[CH2:17][O:18][CH:24]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:16][CH2:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(CCCNC(C)=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)NCCCC1OCC(Oc2ccc(OCc3ccccc3)cc2)CO1

Procedure:
2-(4-Benzyloxyphenoxy)propane-1,3-diol (98 mg, 0.36 mmol), N-(4,4-diethoxybutyl)acetamide (73.06 mg, 0.36 mmol) and p-toluenesulfonic acid (61.89 mg, 0.36 mmol) were stirred in 6 ml of toluene at 60° C. for 2 h and concentrated. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 30.8 mg (22%) of cis-N-{3-[5-(4-benzyloxyphenoxy)-[1,3]dioxan-2-yl]propyl}acetamide, M+H+: 386.15 and 29.8 mg (22%) of trans-N-{3-[5-(4-benzyloxyphenoxy)-[1,3]dioxan-2-yl]propyl}acetamide, M+H+: 386.19.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[C:4]([CH3:12])([CH2:5][CH2:6][O:7][C:8]2([CH3:11])[CH3:10])[CH:3]1[CH:13]([CH3:15])C.C(Br)[C:17]1[CH:22]=[CH:21]C=[CH:19][CH:18]=1>>[O:1]=[C:2]1[N:9]2[C:4]([CH3:12])([CH2:5][CH2:6][O:7][C:8]2([CH3:10])[CH3:11])[CH:3]1[CH2:13][C:15]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C1C(=O)N2C(C)(C)OCCC12C
Product: CC1(C)OCCC2(C)C(Cc3ccccc3)C(=O)N12

Procedure:
Following the procedure described for the preparation of 8-oxo-3-oxa-2,2,6-trimethyl-7-isopropyl-1-azabicyclo[4.2.0]octane from 8-oxo-3-oxa-2,2,6-trimethyl-1-azabicyclo[4.2.0]-octane (Example 4a, above) and using benzyl bromide instead of isopropyl iodide there is obtained 8-oxo-2,2,6-trimethyl-7-benzyl-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [O:1](CC1C=CC(N)=CC=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>CO.[Pd]>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: Nc1ccc(CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: [Pd]
Solvent: CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
4-Aminobenzyl β-D-glucopyranoside (110 mg, 0.40 mmol) was hydrogenated over Pd/C (10%) (50 mg) in MeOH (5 ml) at room temperature for 4 hours. The catalyst was filtered off and the filtrate was evaporated affording D-glucose in quantitative yield.
Reaction SMILES: FC([C:4]([O:10][C:11]([C:14]([C:17]([C:20]([C:23]([C:26](F)=[O:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:6]([F:9])([F:8])[F:7])[F:5])=O.FC(F)(F)C1(F)[O:35]C1(F)F.FC(F)(C(F)(F)C(F)(F)C(F)(F)C(F)=O)C(F)=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O.S(=O)(=O)(O)O>COCCOCCOC.O>[C:6]([CH:4]([O:10][C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([OH:35])=[O:27])([F:24])[F:25])([F:21])[F:22])([F:19])[F:18])([F:15])[F:16])([F:12])[F:13])[F:5])([F:9])([F:7])[F:8]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(C(=O)F)C(F)(F)F
Reactant: FC(F)(F)C1(F)OC1(F)F
Agent: O=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(=O)F
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: COCCOCCOC
Solvent: O
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)C(F)(F)F
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A sample of diacid fluoride, FCOCF(CF3)—O—(CF2)5COF (500 g, 1.1 mol) prepared from the hexafluoropropylene oxide (HFPO) coupling of perfluoroadipoyl fluoride as described in U.S. Pub. No. 2004/0116742 and was added over 2 hours to a stirred slurry of sodium carbonate (500 g, 4.7 mol) in 500 g of diglyme at 85° C. to make the disalt. The reaction liberated CO2 gas. Distilled water (25 g, 1.4 mol) was added at 85° C. The mixture was heated up to 168° C. with CO2 off-gassing and held for 30 minutes. Reaction was cooled down and sulphuric acid (350 g, 3.6 mol) in 1100 g of water was added to make the reaction mixture acidic. Bottom phase was washed with 400 g of 50% sulfuric acid and vacuum distilled to give CF3—CFH—O—(CF2)5COOH 426 g, 1.0 mol for a 95% yield having a boiling point of 132-135° C./15 mm. This was followed by the addition of 46 g NaOH in 63 g of water. Dried salts in vacuum oven at 112° C./15 mm Hg to give 386 g of slight yellow sticky solids. To the salt was added sulphuric acid and the lower fluorochemical phase was vacuum distilled. The previous process was repeated two more times to yield a colorless acid. The surfactant CF3—CFH—O—(CF2)5COONH4 having a melting point of 159-165° C. was made quantitatively from the reaction of 200 g of acid reacted with excess ammonium hydroxide and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]2[C:23](I)=[C:22]([CH3:25])[N:21]=[C:20]([NH2:26])[N:19]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[CH:36])=[CH:31][N:30]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]2[C:23]([C:36]#[C:35][C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)=[C:22]([CH3:25])[N:21]=[C:20]([NH2:26])[N:19]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(N)nc(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)c1I
Reactant: C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 733 mg (1.5 mmol) [3-(2-amino-5-iodo-6-methyl-pyrimidin-4-yl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (A-41) and 262 mg (2.2 mmol) 2-amino-5-ethynyl-pyridine (A-15) using 28 mg (0.15 mmol) CuI, 104 mg (0.15 mmol) PdCl2(PPh3)2 and 2 mL (15 mmol) triethylamine in 14 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica gel (DCM/MeOH gradient). Yield: 632 mg (88%).
Reaction SMILES: C(N(C1C2N=C([N:26]3[CH2:31][CH2:30][CH:29]([CH2:32][N:33]([CH3:35])[CH3:34])[CH2:28][CH2:27]3)N=C(N3CCOCC3)C=2N=CN=1)C)C1C=CC=CC=1.ClC1N=C(N2CCOCC2)C2N=CN=C(N(CC3C=CC=CC=3)C)C=2N=1>>[CH3:34][N:33]([CH2:32][CH:29]1[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]1)[CH3:35]
Reactant: CN(C)CC1CCN(c2nc(N3CCOCC3)c3ncnc(N(C)Cc4ccccc4)c3n2)CC1
Agent: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: CN(C)CC1CCNCC1
Yield: 30.6 %

Procedure:
8-(N-benzyl-N-methyl-amino)-2-[4-(N,N-dimethylaminomethyl)-piperidino]-4-morpholino-pyrimido [5,4-d]pyrimidine From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 4-(N,N-dimethylaminomethyl)-piperidine Yield: 30.6% of theory, Melting point: 145°-147° C. C26H36N8O (476.63)
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:3]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1cc(I)ccn1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-iodo-4-difluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.9) (0.43 g, 1.07 mmol) and commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (263 mg, 1.1 mmol) according to the general procedure IVc protocol a. Obtained as an off-white solid (0.20 g, 48%). MS (ISP) 386.0 [(M+H)+]; mp 143.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(O)[CH2:10][CH3:11])=[CH:5][CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][CH3:11])=[CH:18][CH:17]=1
Reactant: CCC(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 97.4 %

Procedure:
Into a reactor were introduced 2.86 g (10.5 mmol) of the 1,1-bis(4-methoxyphenyl)propanol, 40 mL of toluene, and 28 mg of p-toluenesulfonic acid monohydrate under a nitrogen atmosphere. Azeotropic dehydration was conducted for 2 hours with toluene refluxing. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 2.60 g (97%) of the target compound as light-yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[C:14]([CH:15]2OCC[O:16]2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:20][CH3:21])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>C1COCC1>[CH2:1]([C:5]1[C:14]([CH:15]=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:20][CH3:21])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OC)cc2cc1C1OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(OC)cc2cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-butyl-3-(1,3-dioxolan-2-yl)-6-methoxyquinoline SMA 44042 (847 mg, 2.95 mmol) in THF (20 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added a 12 N aqueous HCl solution (5.0 mL, 60.0 mmol) and the mixture was stirred overnight at RT then for 3 h at 70° C. After cooling to RT, THF was removed at 40° C. under vacuum before addition of a 10 N aqueous NaOH solution until neutral pH. The residue was then taken up in CH2Cl2 (50 mL) and the organic layer was isolated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:EtOAc=100:0 to 98:2) gave 2-butyl-6-methoxyquinoline-3-carbaldehyde SMA 44044 as an orange solid (583 mg, 81% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C@H:22]3[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[C:16](=[O:23])[NH:15][N:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:24]([N:15]1[N:14]=[C:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[C:16]1=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reaction time: 0.5 h

Procedure:
6 mmol of a 60% suspension of sodium hydride in mineral oil was added to a suspension of 5 mmol of compound 1 in about 40 ml of dimethylformamide, under a flow of nitrogen at room temperature. After stirring this mixture for 30 minutes, 7 mmol of benzylchloride was added and the resulting mixture was stirred for another 4 hours, after which the solvent was evaporated. The residue was partitioned between ethyl acetate and water, the organic layer was dried over magnesium sulfate and evaporated. The residue was crystallized from methanol. M.p. 117°-118° C.