Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([CH3:15])=[C:11]([I:14])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:16](#[N:20])[CH2:17][C:18]#[N:19]>C(Cl)CCl>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([CH3:15])=[C:11]([I:14])[C:12]=1[OH:13])[CH:8]=[C:17]([C:16]#[N:20])[C:18]#[N:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C=O)cc(C(C)(C)C)c(O)c1I
Reactant: N#CCC#N
Solvent: ClCCCl
Product: Cc1c(C=C(C#N)C#N)cc(C(C)(C)C)c(O)c1I

Procedure:
In a similar manner as described in Example 2 reaction of 3-tert-butyl-4-hydroxy-5-iodo-6-methylbenzaldehyde and malononitrile gave 3-tert-butyl-4-hydroxy-5-iodo-6-methylbenzylidenemalononitrile as prisms from ethylenedichloride m.p. 158°.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reaction time: 20 h
Yield: 90.5 %

Procedure:
7-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (13 g, 33.8 mmol) was dissolved in methanol (50 mL) and palladium hydroxide (20% wt. % (dry basis) on carbon) was added (5.0 g). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 20 hours. The mixture was filtered through celite and evaporated to give 9.0 g of material as a grey solid (91%). 1.5 g of this material was purified on alumina in 10% MeOH-DCM to give 600 mg of the pure compound as an off white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].C([O-])(=O)C.[K+].B(O)(O)B(O)O.C(=O)([O-])[O-].[K+].[K+].O.Br[C:40]1[C:41]2[CH:49]=[CH:48][N:47]([S:50]([C:53]3[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=3)(=[O:52])=[O:51])[C:42]=2[C:43](=[O:46])[NH:44][CH:45]=1>C(O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[O:12][C:3]1[C:4]2[N:8]=[CH:7][N:6]([CH3:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[C:40]1[C:41]2[CH:49]=[CH:48][N:47]([S:50]([C:53]3[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=3)(=[O:52])=[O:51])[C:42]=2[C:43](=[O:46])[NH:44][CH:45]=1
Reactant: Cn1cnc2c(Oc3ccc(F)cc3F)c(Br)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)c[nH]c(=O)c32)cc1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(ncn5C)c4Oc4ccc(F)cc4F)c[nH]c(=O)c32)cc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 52.6 %

Procedure:
A suspension of 5-bromo-4-(2,4-difluorophenoxy)-1-methyl-1H-benzimidazole (0.300 g, 0.885 mmol) and potassium acetate (0.260 g, 2.65 mmol) in ethanol (6.63 mL) was degassed with nitrogen for 5 min, treated with tetrahydroxydiborane (0.238 g, 2.65 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0056 g, 0.012 mmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0035 g, 0.0044 mmol). The resultant reaction mixture was degassed with nitrogen for another 5 min, warmed to 80° C. and stirred at that temperature for 17 h, after which time the reaction mixture was cooled to RT, degassed with nitrogen for 5 min, treated with previously degassed 1.8M solution of potassium carbonate in water (1.47 mL, 2.65 mmol), followed by addition of 4-bromo-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.108 g, 0.295 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0046 g, 0.0059 mmol). The resultant reaction mixture was degassed with nitrogen for another 5 min, and heated at 90° C. for 2 h. The reaction mixture was diluted with saturated sodium bicarbonate solution and ethyl acetate. The precipitate was collected by filtration, layers of filtrate were separated and the organic layer was dried with sodium sulfate, filtered, and concentrated to give a crude residue. This crude residue was combined with the previously collected solid precipitate and purified by flash column chromatography (100% CH2Cl2 to 12% MeOH/CH2Cl2) gave the desired product (84.8 mg, 53%) as a yellow solid. LCMS calculated for C28H21F2N4O4S (M+H)+: m/z=547.1. found: 547.0.
Reaction SMILES: [Cr](O)(O)(=O)=O.[Cl-].[Ca+2:7].[Cl-].[P:9]([O-:13])([O-:12])([OH:11])=[O:10].[Na+].[Na+]>Cl.O>[P:9]([O-:13])([O-:12])([O-:11])=[O:10].[Ca+2:7].[P:9]([O-:13])([O-:12])([O-:11])=[O:10].[Ca+2:7].[Ca+2:7]
Reactant: O=P([O-])([O-])O
Agent: O=[Cr](=O)(O)O
Agent: Cl
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
To 1800 ml of distilled water in a 2 liter volumetric flask, previously cleaned with hot chromic acid, is added 20 ml of the calcium chloride solution, followed by 2 drops of concentrated hydrochloric acid. 40 ml of the disodium hydrogen phosphate solution is then added. The volume of the mixture is brought to 2 liters with distilled water. 100 ml aliquots of the mixed solution are placed in a small (112 ml) glass bottle fitted with a screw cap. To this solution is added sufficient of the solution of the test compound to provide the required concentration of the test compound in the final volume of test solution (100 ml). Thus, 1.0 ml of 0.1% solution of test compound gives a concentration of the test compound in the final solution of 10 ppm.
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[O:9])[CH2:4]1)#[N:2].[N:25]1([CH2:30][C:31](O)=[O:32])[CH:29]=[N:28][CH:27]=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:25]1([CH2:30][C:31]([N:6]2[CH2:7][C@H:3]([C:1]#[N:2])[CH2:4][C@H:5]2[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)=[O:9])=[O:32])[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: O=C(O)Cn1cncn1
Reactant: N#C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.7 %

Procedure:
A flask was charged with (2S,4R)-4-cyano-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.88 g, 2.69 mmol), prepared as in Reference 8, 2-(1H-1,2,4-triazol-1-yl)acetic acid (340 mg, 2.69 mmol), DIEA (3.0 mL, 17 mmol), HATU (1.12 g, 2.96 mmol) and DMF (10 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by chromatography (EtOAc to EtOAc/MeOH (9:1)+1% NEt3) to give (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-cyano-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.72 g, 1.66 mmol, 62% yield) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.20 (s, 1H), 8.46 (s, 1H), 7.97 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.22-7.17 (m, 2H), 7.03-6.95 (m, 4H), 5.38-5.26 (m, 2H), 4.59-4.55 (m, 1H), 4.08-3.94 (m, 2H), 3.84-3.50 (m, 2H), 2.39-2.32 (m, 1H). MS (EI) for C22H19FN6O3. found 517.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][NH:12][C:11](=[O:14])[CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:36]1(/[CH:35]=[CH:34]/[C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C1C[C@H](c2ccc(Cl)cc2Br)CN1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1C[C@H](c2ccc(Cl)cc2/C=C/c2ccccc2)CN1
Temperature: 90 °C
Yield: 79 %

Procedure:
To a solution of (4R)-4-(2-bromo-4-chlorophenyl)pyrrolidin-2-one (140 mg, 0.51 mmol), Pd(OAc)2 (34 mg, 0.15 mmol) and triphenylphosphine (0.3 mmol) in DMF (1 mL) was added styrene (0.17 mL, 2 mmol) followed by diisopropylethylamine (0.17 mL, 1.02 mmol) under a N2 atmosphere. The reaction mixture was heated to 90° C. overnight. The mixture was then cooled to room temperature and diluted with 1N HCl aq. solution (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (3×30 mL) and dried over MgSO4. The solvent was removed in vacuo to provide 4-[2-((1E)-2-phenylvinyl)-4-chlorophenyl](4R)pyrrolidin-2-one (3a) (120 mg). MS (ESI) m/z 284.02 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:32])[CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[N:28]1>>[OH:32][CH:25]([CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[N:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: NCC(O)Cn1ccnn1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCC(O)Cn1ccnn1

Procedure:
5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (126.6 mg, 0.4 mmol) was condensed with 1-amino-3 (1,2,3)triazole-1-yl-propan-2-ol (85 mg, 0.48 mmol) to precipitate 5-[5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-amide (48 mg, 27%). 1H NMR (DMSO-d6) δ 2.42, 2.44 (2×s, 6H, 2×CH3), 3.27 (m, 2H), 3.99 (m, 1H), 4.28 (dd, J=7.8, 14 Hz, 1H), 4.51 (dd, J=3.2, 14 Hz, 1H), 5.39 (d, J=6.0 Hz, 1H, OH), 6.85 (d, J=8.4 Hz, 1H), 7.12 (dd, J=2.0, 8.2 Hz, 1H), 7.70 (m, 2H), 7.74 (s, 1H), 7.97 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 10.99 (s, 1H, CONH), 13.65 (s, 1H, NH). LC-MS (m/z) 439.4 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](=[O:17])[CH:16]=[CH:23][C:22]3[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)c1cccnc1Nc1ccc(Cl)cc1
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(C=CC(=O)c2cccnc2Nc2ccc(Cl)cc2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
To a solution of 1-(2-(4-chlorophenylamino)pyridin-3-yl)ethanone (100 mg, 0.406 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 3,4,5-trimethoxybenzaldehyde (79.65 mg, 0.406 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (7h) (147 mg, 85% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[O:10][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:5]=[O:6]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=Cc1cc(F)c(O)c(F)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](Oc1c(F)cc(C=O)cc1F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
30.0 g (190 mmol) of 3,5-difluoro-4-hydroxybenzaldehyde [CAS 118276-06-5] are dissolved under argon in 600 ml of dichloromethane and, at 0° C., 44.7 g (417 mmol) of 2,6-lutidine are added. Then 87.2 g (284 mmol) of triisopropylsilyl trifluoromethanesulfonate are added dropwise, and the mixture is stirred at RT for 12 h. The solvent is distilled out in vacuo, and the residue is mixed with ammonium chloride solution and stirred for 5 min, and the organic phase is separated off. A further extraction with dichloromethane is carried out, and the organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and washed with dichloromethane, and the solvent is distilled off in vacuo. Chromatography on silica gel 60 (mobile phase: cyclohexane) results in 34.9 g (111 mmol, 58% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:28]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:34][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccnc2)cc1
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(CCc2cccnc2)CC1
Temperature: 150 °C
Yield: 12.8 %

Procedure:
A mixture of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (100 mg, 0.24 mmol), toluene-4-sulfonic acid 2-pyridin-3-yl-ethyl ester (133 mg, 0.48 mmol), and triethylamine (167 μL, 1.2 mmol) in DMF (2 mL) was heated under microwave irradiation for 60 min at 150° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound C18 as an oil (15 mg, 13%). 1H NMR (CDCl3, 400 MHz) δ 2.15 (s, 3H), 2.18-2.38 (m, 4H), 3.04 (s, 3H), 3.07-3.22 (m, 2H), 3.29-3.43 (m, 4H), 3.44-3.65 (m, 2H), 5.43-5.51 (m, 1H), 7.36 (t, 1H), 7.67-7.79 (m, 3H), 8.11 (s, 1H), 8.35 (d, 1H), 8.58 (d, 1H), 8.91 (s, 1H). Exact mass calculated for C24H27FN4O4S 486.56, found 487.4 (MH+).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)C.[O:8]1[CH2:30][CH:9]1[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24]>O>[OH:8][CH:9]([CH2:30][NH:4][CH2:3][CH2:1][OH:2])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24]
Reactant: CCCCOC(=O)CCCCCCCCCCCOCC1CO1
Reactant: NCCO
Solvent: O
Solvent: CCO
Product: CCCCOC(=O)CCCCCCCCCCCOCC(O)CNCCO
Temperature: 80 °C
Yield: 55.4 %

Procedure:
A 100-ml flask equipped with a stirrer and dropping funnel was charged with 23.7 g (250 mmol) of ethanolamine and 23.7 g of ethanol. While stirring the mixture at 80° C., an ethanol solution of 8.20 g (25 mmol) of butyl 12-(2,3-epoxypropoxy)-dodecanate was added dropwise over 1 hour. After completion of the reaction, water was added to the reaction mixture, followed by extraction with chloroform. The resultant chloroform solution was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 5.40 g (yield: 55.4%) of the title compound (Ia-15).
Reaction SMILES: [C:1]([N:4]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][CH:14]=2)[C@@H:11]2[C:6]([C:7]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:8]=3[CH2:9][CH2:10]2)=[N:5]1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([N:4]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C@@H:11]2[C:6]([C:7]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:8]=3[CH2:9][CH2:10]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C1=NN(C(C)=O)[C@@H](c3ccc(OCc4ccccc4)cc3)[C@H]1CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C1=NN(C(C)=O)[C@@H](c3ccc(O)cc3)[C@H]1CC2
Reaction time: 20 h
Yield: 63.9 %

Procedure:
A mixture of (174) (0.370 mg, 0.86 mmol) and 5% Pd—C (10 mg) in ethyl acetate (20 mL) was stirred under a hydrogen atmosphere for 20 h and then filtered though the pad of celite. The celite was then washed sequentially with ethyl acetate and acetic acid. The combined filtrates were concentrated. The solid obtained was recrystallized from ethyl acetate to give (175) (0.185 g, 63%): mp 240-41° C., 1H NMR (400 MHz, d6-DMSO-CDCl3): δ 0.99-1.11 (m, 1H), 1.72-1.76 (m, 1H), 2.43 (s, 3H), 2.67-2.83 (m, 2H), 3.46-3.53 (m, 1H), 3.87 (s, 3H), 5.61 (d, J=10.8 Hz, 1H), 6.74 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 6.61 (m, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.43-7.46 (m, 1H), 7.52 (d, J=3.2 Hz, 1H). Anal. (C20H20N2O3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22]C)=[O:21])=[C:8]2[CH3:26])=[CH:4][CH:3]=1.[OH-].[K+]>CCO>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([OH:22])=[O:21])=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)c(CC(C)(C)C(=O)O)c(C)n2Cc1ccc(Br)cc1
Yield: 102.8 %

Procedure:
To a room temperature solution of the methyl ester from Step 2 (24 mg, 0.052 mmol) in 10 mL EtOH was added 1 mL of 4N KOH. The solution was heated to reflux for 22 h, then cooled and concentrated in vacuo. The residue was partitioned between 1M HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and evaporated to provide 23 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:9](=[O:18])[NH:8][C:7]1=[O:19].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>C(Cl)Cl>[CH3:17][C:16]1[CH:15]=[CH:14][S:13][C:12]=1[C:10]1[C:9](=[O:18])[NH:8][C:7](=[O:19])[N:6]([CH2:5][CH2:4][CH2:3][CH:2]=[O:1])[CH:11]=1
Reactant: Cc1ccsc1-c1cn(CCCCO)c(=O)[nH]c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccsc1-c1cn(CCCC=O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
1-(4-Hydroxy-butyl)-5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 31, 30 mg, 0.11 mmol) was dissolved in dry DCM (2 mL), the solution was cooled to 0° C. and Dess-Martin periodinane (113 mg, 0.26 mmol) was added portionwise under nitrogen. The mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added and the solution washed with aqueous saturated Na2S2O3 (3 mL) and NaHCO3 (3 mL). The organic phase was dried (Na2SO4) and evaporated to give 30 mg of the title compound that was used in the next step without further purification (98% yield).
Reaction SMILES: [C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[Cl:17]>C(O)CC>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[Cl:17].[C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)c1ccccc1
Agent: COC(=O)C(CC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: CCCO
Product: C[C@H](N)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1.21 g (10.0 mmol) of (−)-1-phenylethylamine and 25 ml of 1-propanol were added to 2.77 g (10.0 mmol) of (±)-3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid and dissolved by heating. Then the solution was cooled to an internal temperature of 90° C. and inoculated with the separately prepared seed crystals. The solution was then cooled to an internal temperature of 70 to 72° C. and stirred in a suspended state for 8 hours. Then the solution was further cooled to an internal temperature of 20° C. and stirred at this temperature for 0.5 hour, and the precipitated crystals were filtered out, washed with a small quantity of 1-propanol and dried to obtain 2.13 g (53.6% yield) of (+)-3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid·(S)-1-phenylethylamine salt.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Cl)ncn2)C1

Procedure:
A solution of 4,6-dichloropyrimidine (0.1 g, 0.671 mmol), 3-amino-Boc-piperidine (0.16 g, 0.80 mmol) and DIPEA (0.086 g, 6.71 mmol) in n-butanol (5.0 mL) was heated in a pressure tube (120° C., 12 h). The solution was cooled, was quenched with water (2 mL) and was extracted with EtOAc (2×15 mL). The combined EtOAc extract was washed with water (5 mL), brine (5 mL), was dried over Na2SO4 and was concentrated under reduced pressure to give tert-butyl 3-(6-chloropyrimidin-4-ylamino)piperidine-1-carboxylate, which was dried under high vacuum and was used as such for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.[CH2:10]([S:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH2:10]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[F:8])=[CH:17][CH:16]=1)(=[O:13])=[O:14])[CH3:11]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Fc1ccc(Br)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(Br)ccc2F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a degassed, room temperature solution of 4-bromo-1-fluoro-2-iodobenzene (2.80 g, 9.30 mmol) and 4-(ethylsulphonyl)benzeneboronic acid (2.27 g, 10.6 mmol), in anhydrous 1,4-dioxane (120 mL) was added aqueous Na2CO3 solution (1M, 46.5 mL, 46.5 mmol) followed by the tetrakistriphenylphosphine palladium(0) (537 mg, 0.465 mmol). The slightly yellow solution was degassed 3 times by vacuum/nitrogen refill then was heated to 100° C. with stirring for 2 hours. The reaction mixture was cooled then suspended in CH2Cl2 (50 mL) and filtered through a pad of celite. The pad was rinsed well with CH2Cl2 (100 mL) and the filtrate was washed with water (2×50 mL) then dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to give crude product as a yellow oil. Purification by silica gel column chromatography eluting with heptane:EtOAc 1:1 afforded the title compound as a colourless oil in 84% yield, 2.696 g.