Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])=[CH2:12])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1C=CN=C1.[N+](=C[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C1(C)C=CC=CC=1>[C:1]([C:5]1[N:6]=[CH:7][C:8]([CH:11]2[CH2:13][CH:12]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1ccc(C(C)(C)C)nc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1ccc(C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
To a toluene (60 ml) solution of 2-tert-butyl-5-isopropenylpyridine (5.96 g, 34 mmol), Co(TPP) (0.69 g, 1.0 mmol) and 1-methyl-1H-imidazole (8.37 g, 102 mmol), ethyl diazoacetate (5.4 g, 48 mmol) was added and the mixture was stirred for 5 minutes at room temperature followed by additional stirring for 1 hour at 80° C. Then, evaporation of the solvent and purification by silica gel column chromatography, eluting with gradually from hexane to hexane/ethylacetate (30:1), gave the title compound (3.51 g, 39%, trans) as white solids.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[CH:6]=[CH:7][C:8](/[C:13](/[C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:14]/[C@@H:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:18](=[O:31])[CH2:17][CH2:16]2)=[N:9][C:10]=1[O:11][CH3:12].O>CN(C)C=O>[C:38]([C:35]1[CH:36]=[CH:37][C:32](/[C:13](/[C:8]2[CH:7]=[CH:6][C:5]([S:2][CH3:1])=[C:10]([O:11][CH3:12])[N:9]=2)=[CH:14]\[C@@H:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:18](=[O:31])[CH2:17][CH2:16]2)=[CH:33][CH:34]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(SC)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34 %

Procedure:
Sodium thiomethoxide (44 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (150 mg) in N,N-dimethylformamide (1.5 mL), and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:10) to give (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[6-methoxy-5-(methylsulfanyl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (53 mg, 34%).
Reaction SMILES: [C:1]([N:6]1[C@H:10]([C:11]2[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=2[F:19])[CH2:9][CH2:8][C@@H:7]1/[CH:20]=C/C(OCC)=O)(=[O:5])[CH2:2][CH:3]=C.C(N(CC)CC)C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[F:17][C:16]1[CH:15]=[C:14]([F:18])[CH:13]=[C:12]([F:19])[C:11]=1[C@H:10]1[N:6]2[C@@H:7]([CH:20]=[CH:3][CH2:2][C:1]2=[O:5])[CH2:8][CH2:9]1
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OCC)CC[C@H]1c1c(F)cc(F)cc1F
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC=C[C@H]2CC[C@@H](c3c(F)cc(F)cc3F)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
A solution of ethyl (E)-3-[(2R,5S)-1-(3-butenoyl)-5-(2,4,6-trifluorophenyl)pyrrolidin-2-yl]acrylate (1.35 g) and Grubbs catalyst 2nd generation (155 mg) in methylene chloride (70 mL) was heated under reflux for two hours. The reaction solution was left to cool to room temperature. Then, triethylamine (0.5 mL) was added to the reaction solution, and the mixture was stirred for one hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1->ethyl acetate) to obtain 548 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:27]2[CH:31]=[C:30]([C:32]3[C:33]4[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=4[N:35]=[CH:36][N:37]=3)[CH:29]=[N:28]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:16]([F:26])=[C:17]([C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:18]#[N:19])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:27]2[CH:31]=[C:30]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH:29]=[N:28]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:16]([F:26])=[C:17]([C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:18]#[N:19])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2]
Reactant: CN(C)c1ccc(CN2CCC(N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)c(F)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(CN2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)c(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a reaction vial were added 3-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile (56 mg, 0.1 mmol), trifluoroacetic acid (1.5 mL) and methylene chloride (1.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated in vacuum. The residue was dissolved in 5 mL of a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the mixture was purified by HPLC (method B) to give the title compound. LC-MS: 539.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 8.79 (s, 1H), 8.67 (s, 1H), 8.39 (s, 1H), 7.59 (d, J=3.6 Hz, 1H), 7.42 (t, J=8.8 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 3.68 (d, J=8.4 Hz, 2H), 3.51 (m, 4H), 3.38 (s, 2H), 3.01 (s, 6H), 2.67 (m, 2H), 2.17 (m, 1H), 1.97 (m, 2H), 1.63 (m, 2H), 1.15 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[C:4]=1[CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23]>CC#N>[CH2:21]([NH:25][CH2:2][C:3]1[N:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[C:4]=1[CH2:12][CH2:13][CH3:14])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CN
Reactant: CCCc1c(CBr)ncn2ncnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1c(CNCC(C)C)ncn2ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-bromomethyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine (16.58 mmol) in CH3CN (30 ml) is added K2CO3 (9.15 g, 66.3 mmol), isobutylamine (6.6 ml, 66.3 mmol) and the mixture is stirred at room temperature overnight. The solvent is removed in vacuo and to the residue is added water (60 ml) and EtOAc (60 ml). The layers are separated and the organic layer is washed with brine (20 ml) and dried (Na2SO4). Evaporation of the solvent provides a light yellow oil, which is used in next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1.[NH4+:18].[OH-]>CN(C)C=O.O>[Cl:7][C:8]1[C:13]([C:14]([NH2:18])=[O:15])=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cnc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Oxalyl chloride (7.70 mL, 88.3 mmol) was added over 1 hour to a suspension of 4,6-dichloronicotinic acid (8.47 g, 44.1 mmol) in dimethylformamide (200 mL) at room temperature. The reaction mixture was stirred for an additional 3 hours at room temperature then concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) followed by the dropwise addition of NH4OH (8.3 mL, 130 mmol) over 30 minutes [Note: reaction is exothermic upon addition of NH4OH and care was taken to control the rate of addition so that the reaction temperature did not exceed 25° C.]. The reaction mixture was stirred for an additional 1 hour at room temperature then diluted with water (600 mL) and extracted with EtOAc (4×600 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to give the title compound as a light brown solid (8.05 g, 95% yield). This material was carried forward without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH:31](N(CC)C(C)C)([CH3:33])[CH3:32].C(Br)C=C>C(Cl)Cl>[CH2:33]([NH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1)[CH:31]=[CH2:32]
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C=CCBr
Product: C=CCNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1

Procedure:
To a solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.39 mmol) in CH2Cl2 (˜0.4 mL) was added N,N-diisopropylethylamine (90 μL, 0.52 mmol). Allyl bromide (35 μL, 0.40 mmol) was dissolved in CH2Cl2 (˜9.6 mL) and added to the amine mixture at a rate of 5.5 mL/hour. The resultant mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed consecutively with H2O (5 mL), saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL). The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel (200:1:1 followed by 100:1:1—EtOAc:MeOH:NH4OH) followed by radial chromatography on silica gel (250:1:1—EtOAc:MeOH:NH4OH) afforded AMD9725 (36 mg, 21%) as a light yellow foam. 1H NMR (CDCl3) δ 1.56-1.75 (m, 1H), 1.97-2.08 (m, 2H), 2.24-2.31 (m, 1H), 2.65-2.77 (m, 1H), 2.77-2.91 (m, 1H), 3.21 (d, 2H, J=5.7 Hz), 3.69 (s, 2H), 3.73 (s, 2H), 3.97 (d, 1H, J=16.8 Hz), 4.04-4.16 (m, 1H), 4.17 (d, 1H, J=16.8 Hz), 5.07 (d, 1H, J=9.9 Hz), 5.15 (dd, 1H, J=17.1, 1.2 Hz), 5.88 (ddt, 1H, J=17.1, 10.5, 6.0 Hz), 7.10-7.19 (m, 5H), 7.35 (d, 2H, J=7.8 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.45-7.57 (m, 1H), 7.58-7.68 (m, 1H), 8.69 (d, 1H, J=4.2 Hz); 13C NMR (CDCl3) δ 20.83, 22.89, 28.67, 47.95, 51.11, 52.33, 53.17, 59.68, 110.37, 115.39, 118.11, 120.91, 121.66, 127.59, 128.07, 134.13, 136.17, 136.60, 137.48, 138.56, 146.38, 155.80, 156.94. ES-MS m/z 438.3 (M+H). Anal. Calcd. for C28H31N5. 0.8H2O: C, 74.40; H, 7.27; N, 15.49. Found: C, 74.36; H, 7.25; N, 15.31.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][NH:15][C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])[CH:8]=[CH:7]2>CC(O)=O>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH2:14][NH:15][C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])=[CH:10]2
Reactant: BrBr
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2cc(O)ccc2c1
Solvent: CC(=O)O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Bromine (210 μL, 4.02 mmol) in 50 mL of glacial HOAc was added under nitrogen dropwise over 2 h to a solution of 2-butyl-benzofuran-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (1.5 g, 4.02 mmol), prepared in step 2 of Example 8, in 300 mL of glacial HOAc at room temperature. After the addition the reaction was stirred at room temperature for 20 h (overnight). The solid formed was collected by filtration and dried under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (1.41 g, 81%) as a light gray solid, mp 192-193° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[NH2:17])[CH3:14].C(O)=O>CCCCCCC>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[N:17]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11])[CH3:14]
Reactant: CCc1cccc(CC)c1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: O=CO
Solvent: CCCCCCC
Product: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=O)n1
Yield: 41.6 %

Procedure:
10.35 g of 2,6-diacetylpyridine (0.0634 mol), 7.10 g of 2,6-diethylaniline (0.0476 mol) and 2 ml of formic acid were stirred in 300 ml of heptane at room temperature for 71 h. The insoluble solid was filtered off (11.10 g) and dissolved in 150 ml of toluene and the solution was extracted with 10 ml of a saturated Na2CO3 solution. The toluene phase was dried over Na2SO4 and filtered and the solvent was distilled off in vacuo. 5.58 g (0.0198 mol) of the product were obtained in a purity of 99% (GC/MS) in a yield of 40%. The mother liquor of the reaction solution was freed completely from the solvent and the residue was recrystallized from hot heptane. 2.00 g (0.0068 mol) of the product were additionally obtained in a purity of 100% (GC/MS). The total yield was 54%.
Reaction SMILES: Cl[CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=[O:4].[O:15]=[C:16](/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl>[CH2:5]([C@@H:2]1[C:3](=[O:4])[O:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][C@@H:23]1[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC(Cl)C=O
Reactant: CCOC(=O)C(=O)/C=C/c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC[C@@H]1C(=O)OC(C(=O)OCC)=C[C@@H]1c1ccc(C)cc1
Yield: 70 %

Procedure:
Prepared according to the general procedure from 2-chlorododecanal and (E)-ethyl 2-oxo-4-p-tolylbut-3-enoate using 2 mol % 1 as the catalyst in 70% yield as a single diastereomer (colorless oil). [α]D20 (c 1.31, CHCl3)=+154.3; 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 3H), 7.12 (d, 2H, J=8.1 Hz), 6.99 (d, 2H, J=8.1 hz), 6.70 (d, 1H, J=6.5 Hz), 4.32 (q, 1H, J=7.2 Hz), 3.77 (t, 1H, J=6.8 Hz), 2.81 (q, 1H, J=6.8 Hz), 2.33 (s, 3H), 1.72-1.63 (m, 2H), 1.37-1.14 (m, 19H), 0.88 (t, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 169.2, 160.8, 142.3, 138.1, 133.1, 130.0, 128.1, 118.6, 62.1, 43.6, 41.2, 32.1, 29.7, 29.7, 29.5, 27.3, 26.4, 22.9, 21.3, 14.4, 14.3; IR (thin film) ν 3027, 2925, 2854, 1777, 1739, 1659, 1464, 1370, 1316, 1260, 1104 cm−1; HRMS (EI) calcd for C25H36O4 [M]+ 400.2614, found 400.2613; 99% ee (4S,5S)-isomer as determined by HPLC(OD-H, 20:1 hexanes/i-PrOH), tr (4S,5S)=8.0 min, tr (4R,5R)=9.2 min.
Reaction SMILES: O1CCCC1.[C:6]([OH:14])(=[O:13])[C@@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[OH:8].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[CH2:15]([O:13][C:6](=[O:14])[C@@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[OH:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C[C@@H](O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To 150 ml of tetrahydrofurane of 14.50 of D-leucic acid, 15.2 g of triethylamine and then 14.4 ml of benzyl bromide are added, and the solution was stirred for 3 hours while refluxing. The insoluble matter produced from the reaction solution was filtered off, and the filtrate was concentrated in vacuo. The obtained residue was dissolved and extracted in 150 ml of ethyl acetate. The ethyl acetate layer was washed twice with saturated bicarbonate water, twice with 1N hydrochloric acid, and twice with saturated brine sequentially, and dried over sodium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was dried, and the captioned compound was obtained. Yield: 18.34 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:22]1[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Br)s1
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: COc1c(-c2ccc(C(=O)O)s2)cccc1[N+](=O)[O-]
Yield: 85.6 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (10 g, 35.85 mmol), 5-bromothiophene-2-carboxylic acid (6.68 g, 32.2 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.59 g, 71.6 mmol) were dissolved in the solvent mixture of 200 mL of 1,4-dioxane and 30 mL of water. The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 mL of water and adjusted to pH 3 with 1 N hydrochloric acid. The mixture was filtered and the filter cake was washed with 50 mL of the solvent mixture of n-hexane/ethyl acetate (V:V=1/1) and dried to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)thiophene-2-carboxylic acid 12a (7.7 g, yield 77%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COc1ccccc1N
Reactant: CCOC(=O)CBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNc1ccccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a cooled (0° C.) solution of 2-methoxyaniline (13.2 g, 0.108 mol) in CHCl3 (100 mL) was added ethyl bromoacetate (6 mL, 0.05 mol) and the mixture was stirred at room temperature overnight. The resulting solution was washed with 0.5N NaOH and the organic phase was concentrated to a crude product. This was purified by chromatography on silica gel (hexane-EtOAc, 10%) to afford ethyl N-(2-methoxyphenyl)aminoacetate (4.2 g, 40%). This compound was dissolved in MeOH (80 mL), a solution of K2CO3 (4.4 g) in H2O (50 mL) was added and the mixture was refluxed overnight. MeOH was removed and the resulting aqueous solution was extracted with hexane. The aqueous phase was acidified with 5N HCl and extracted with CHCl3 (3×). Evaporation of the solvent afforded the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:23]=2[O:24][C:25]=1[CH2:26][CH3:27])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:28][C:23]=2[O:24][C:25]=1[CH2:26][CH3:27])=[O:20]
Reactant: CCc1oc2cc(O)ccc2c1C(=O)NC
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1oc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NC
Yield: 30.2 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (114 mg, 0.46 mmole) with 6-hydroxy-2-ethylbenzofuran-3-carboxylic acid methylamide 14c (120 mg, 0.55 mmole) and Cs2CO3 (594 mg, 1.82 mmole) in a manner as previously described for example 1 to give 60 mg (30%) of a tan solid. 1H NMR (DMSO-d6) δ 8.49 (1H,d, J=5.6 Hz), 8.00 (1H, d, J=4.6 Hz), 7.89 (1H, s), 7.82 (1H, d, J=8.6 Hz), 7.67 (1H, s), 7.41 (1H, s), 7.26 (1H, d, J=8.6 Hz), 7.03 (1H, s), 6.68 (1H, d, J=5.6 Hz), 3.99 (3H, s), 3.04 (2H, q, J=7.6 Hz), 2.81 (3H, d, J=4.6 Hz), 1.28 (3H, t, J=7.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][Cl:14])[CH:17]=1
Reactant: ClCc1cccc(CCl)c1
Reactant: COC(=O)CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCc1ccccc1OCc1cccc(CCl)c1
Yield: 54.6 %

Procedure:
A mixture of 1.8 g (10 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 14 g (80 mmol) of α,α'-dichloro-m-xylene, 4.25 g (30.8 mmol) of anhydrous, granular potassium carbonate, and 70 mL of acetonitrile was stirred and refluxed for 4 hr. After being cooled, the resulting mixture was diluted with 200 mL of ether and filtered with suction. The solids were washed thoroughly with ether and then the filtrate and washes were combined and concentrated in vacuo. The oily residue was chromatographed on 100 g of silica gel. Elution with 19:1 hexane-ether afforded 1.74 g (54.6%) of 2-[3-(chloromethyl)phenylmethoxy]benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: CN(C)[C:3]([S:5][C:6]1[C:11]2=[N:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=1)=[O:4].[C:23]1([CH2:29]C(Cl)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCCl.[I-].[Zn+2].[I-]>[CH2:29]([C:3]([S:5][C:6]1[C:11]2=[N:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=1)=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)c1cnc2c(SC(=O)N(C)C)cccn2c1=O
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: CCOC(=O)c1cnc2c(SC(=O)Cc3ccccc3)cccn2c1=O
Yield: 58 %

Procedure:
To a solution of 0.129 g of 9-(dimethylcarbamoyl)thio-3ethoxycarbonyl-4H-pyrido[1,2-a]pyrimidin-4-one Ib-85 in 5 ml of 1,2-dichloroethane are added 65 μl of phenylacetyl chloride and 0.13 g of zinc iodide, and the resultant mixture is refluxed in a nitrogen stream for 45 minutes. After cooling, the reaction mixture is shaken with N-hydrochloric acid and the organic layer is washed with saturated brine in order, dried and concentrated in vacuo. The residue is chromatographed on a column of silica gel, eluting with ethyl acetate, whereby 0.118 g of the titled compound Ie-84 is obtained.