Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH2:49][CH3:50])[CH3:45])=O>>[CH2:8]([O:10][CH2:41][CH2:42][N:44]([CH3:45])[CH2:46][CH2:47][O:48][C:49]1[CH:50]=[CH:6][C:5]([CH2:14][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:4][CH:9]=1)[CH3:7]
Reactant: CCOCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCOCCN(C)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 27.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-(2-ethoxyethyl)-N-methylacetamide (9.8 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.3 mg) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[CH:23]=[CH:24][CH:25]=[N:26][C:15]2=3)[CH:2]=1.Br[C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3[C:45]4[S:46][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=5[C:44]=4[CH:43]=[CH:42][CH:41]=3)[CH:35]=2)[CH:31]=[CH:32][CH:33]=1.CC(C)([O-])C.[Na+]>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=C(C3C(OC)=CC=CC=3OC)C=CC=2)CCCCC1>[CH:43]1[C:44]2[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[S:46][C:45]=2[C:40]([C:36]2[CH:35]=[C:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([N:12]4[C:13]5[CH:1]=[CH:2][C:3]([N:14]6[C:22]7[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=7)[C:16]7[CH:23]=[CH:24][CH:25]=[N:26][C:15]6=7)=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:29]=3)[CH:39]=[CH:38][CH:37]=2)=[CH:41][CH:42]=1
Reactant: c1ccc2c(c1)[nH]c1ccc(-n3c4ccccc4c4cccnc43)cc12
Reactant: Brc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1cccc(P(C2CCCCC2)C2CCCCC2)c1
Solvent: Cc1ccccc1C
Product: c1cc(-c2cccc(-n3c4ccccc4c4cc(-n5c6ccccc6c6cccnc65)ccc43)c2)cc(-c2cccc3c2sc2ccccc23)c1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
A solution of 9-(9H-carbazol-3-yl)-pyrido[2,3-b]indole (2.50 g, 7.50 mmol), 4-(3′-bromo-[1,1′-biphenyl]-3-yl)dibenzo[b,d]thiophene (3.11 g, 7.50 mmol), Pd2(dba)3 (0.137 g, 0.150 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-3-yl)phosphine (0.123 g, 0.30 mmol), and sodium tert-butoxide (1.44 g, 15.00 mmol) in xylene (150 mL) was refluxed in nitrogen overnight. After cooling to room temperature, the reaction mixture was washed with water, dried over Na2SO4 and the solvent was evaporated. The residue was dissolved in hot toluene, mixed with celite, and purified by column chromatography with hexane:toluene (1:9 to 0:10, v/v) as eluent. The product was precipitated in ethanol, and further purified by thermal sublimation under vacuum (<105 torr) to yield 9-(9-(3′-(dibenzo[b,d]thiophen-4-yl)-[1,1′-biphenyl]-3-yl)-carbazol-3-yl)-pyrido[2,3-b]indole as a white glassy solid (3.21 g).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:10]\[C:11]2[C:12]([O:22][CH2:23][C:24]3[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]CC)=[O:44])=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=3)=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:10]\[C:11]2[C:12]([O:22][CH2:23][C:24]3[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:37]=[CH:38][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:40][CH:41]=5)[O:33][C:34]=4[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=3)=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4csc(C(C)C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\c2csc(C(C)C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(Z)-2-(2-isopropyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.11 g), tetrahydrofuran (2 mL) and ethanol (0.64 mL) was added 1N aqueous sodium hydroxide solution (0.60 mL), and the mixture was stirred at 50° C. for 3 hrs. To the reaction mixture were added 1N hydrochloric acid (0.60 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {4-[4-({4-[({4-[(Z)-2-(2-isopropyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as crystals (0.10 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 156-157° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[NH:23][CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[NH:23][CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([CH:39]3[CH2:40][CH2:41][O:36][CH2:37][CH2:38]3)[CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1
Reaction time: 12 h

Procedure:
Secondary amine 24 (200 mg, 0.41 mmol) was dissolved in 1,2-dichloroethane (4 mL) at ambient temperature and tetrahydro-4H-pyran-4-one (84 μL, 0.90 mmol), HOAc (50 μL, 0.82 mmol), and sodium triacetoxyborohydride (172 mg, 0.78 mmol) were added. After 12 h, the reaction mixture was diluted with EtOAc, washed successively with saturated aqueous NaHCO3 (3×), and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude orange mixture was purified by reverse-phase HPLC (2″ Dynamax® C18, 10-100% ACN/water containing 0.1% HOAc over 25 min; Flow: 40 mL/min) to give 100 mg of 24 and 90 mg of 25 as a colorless oil. Mass spectrum, m/z [572.0] (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[CH2:29]([O:36][C@H:37]([C:64]([F:67])([F:66])[F:65])[C@@H:38]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[C:56]([Cl:62])[C:55]=1[CH3:63])[C:39]([NH:41][NH:42][C:43](=O)[C:44]1[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=1)=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.C1COCC1>[CH2:29]([O:36][C@H:37]([C:64]([F:65])([F:67])[F:66])[C@@H:38]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[C:56]([Cl:62])[C:55]=1[CH3:63])[C:39]1[O:40][C:43]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[N:42][N:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of triphenylphosphine (180 mg, 0.69 mmol) in DCM (10 mL) was added I2 (174 mg, 0.69 mmol) at 0° C. After all the Iodine was dissolved completely, Et3N (0.20 mL, 1.43 mmol) was added, followed by a solution of N′-((2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoyl)-4-cyanobenzohydrazide (180 mg, 0.32 mmol) in DCM (2 mL) and THF (2 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 min. The reaction was quenched with saturated aq. sodium thiosulfate (1 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound 4-((1R,2S)-2-(benzyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-3,3,3-trifluoropropylamino)-2-chloro-3-methylbenzonitrile (170 mg, 98%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.98 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.09˜7.17 (m, 5H), 6.45 (d, J=8.4 Hz, 1H), 5.22 (b, 2H), 5.01 (d, J=11.5 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.52 (m, 1H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:35]=[C:36]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[C@H:45]([CH:51]([CH3:53])[CH3:52])[NH:46][C:47]([O:49][CH3:50])=[O:48])[NH:37][CH:38]=5)=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[N:21]=2)[CH2:15][C:14]2([CH2:59][CH2:58][N:57](C(OC(C)(C)C)=O)[CH2:56][CH2:55]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:52][CH:51]([CH3:53])[C@H:45]([NH:46][C:47](=[O:48])[O:49][CH3:50])[C:44]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:36]1[NH:37][CH:38]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:20]4[N:21]=[C:17]([CH:16]5[CH2:15][C:14]6([CH2:55][CH2:56][NH:57][CH2:58][CH2:59]6)[CH2:13][N:12]5[C:10](=[O:11])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:8])[CH3:9])[NH:18][CH:19]=4)=[CH:27][CH:26]=3)=[CH:29][CH:30]=2)[N:35]=1)=[O:54]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCN(C(=O)OC(C)(C)C)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1CC2(CCNCC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 1,1-dimethylethyl 2-{N-[(methyloxy)carbonyl]-L-valyl}-3-(4-{4′-[2-((2S)-1-{N-[(methyloxy)carbonyl]-L-valyl}-2-pyrrolidinyl)-1H-imidazol-4-yl]-4-biphenylyl}-1H-imidazol-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (68 mg, 0.08 mmol) in anhydrous CH2Cl2 (1 mL) was added trifluoroacetic acid (0.3 mL) and the reaction stirred at room temperature for 2 h. The reaction was concentrated in vacuo and purified by HPLC eluting with 10-90% acetonitrile/water/0.2% NH4OH to afford the title compound as a tan solid (49 mg, 81% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.56-7.83 (m, 10H) 7.31 (br. s., 2H) 5.00-5.22 (m, 2H) 4.12-4.30 (m, 3H) 4.01 (br. s., 1H) 3.80-3.91 (m, 1H) 3.57-3.70 (m, 6H) 2.76-3.07 (m, 4H) 1.89-2.48 (m, 10H) 1.69-1.81 (m, 1H) 1.61 (br. s., 2H) 0.82-1.09 (m, 15H). HRMS for C44H58N9O6 (M+H)+ calc: 808.4510, found: 808.4509. Purity (LC-MS): 94%.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH:13]1[CH2:16][N:15]([CH:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH2:14]1)=[O:11])=[O:7].CC[N:40]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.O1CCOCC1>[C:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH:20]2[CH2:21][CH2:22][CH:17]([N:15]3[CH2:16][CH:13]([NH:12][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]4[CH:33]=[CH:34][CH:35]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=4)=[O:11])[CH2:14]3)[CH2:18][CH2:19]2)=[CH:28][CH:27]=1)(=[O:31])[NH2:40]
Reactant: O=C(O)Cc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)Cc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
A solution of [4-(4-{3-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-azetidin-1-yl}-cyclohexyl)-phenyl]-acetic acid (as prepared in Example 25, 450 mg, 0.87 mmol), EDCI (240 mg, 1.25 mmol), HOBT (130 mg, 0.96 mmol) and TEA (610 μL, 4.35 mmol) in DCM (10 mL) was treated with 2N NH3 in dioxane (5 mL) at room temperature overnight. The solvent was removed in vacuo and the residue was purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the two title compound as white solids.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][OH:16].Cl[C:18]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=1.O>CN(C)C=O.O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:18]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1oc(-c2ccccc2)nc1CO
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccnc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 0.25 h
Yield: 13.5 %

Procedure:
Sodium hydride-(60%, oily, 2.40 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolylmethanol (9.46 g) in N,N-dimethylformamide (50 ml) at 0° C., which was stirred for 15 minutes. A solution of methyl 2-chloro-4-pyridinecarboxylate (8.58 g) in tetrahydrofuran (50 ml) was added to the mixture. After being stirred at room temperature for 1 hour, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridinecarboxylate (2190 mg, yield 14%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 106–107° C.
Reaction SMILES: [CH3:1][C:2]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])([CH2:5][OH:6])[CH2:3][OH:4].C=O.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[CH3:1][C:2]1([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:5][O:6][CH2:18][O:4][CH2:3]1
Reactant: Cc1ccccc1COC(C)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: CCCCCC
Product: Cc1ccccc1COC1(C)COCOC1

Procedure:
This compound was prepared in the manner of Intermediate A using 6.00 g of 2-methyl-2-(2-methylbenzyloxy)-1,3-propanediol (Intermediate R), 1.66 g of paraformaldehyde, and 0.13 g of p-toluenesulfonic acid in 150 ml of dry hexane. The crude reaction product was distilled under reduced pressure using a short path distilling system to give in one fraction 3.64 g of 5-methyl-5-(2-methylbenzyloxy)-1,3-dioxane; bp 106°-108°/0.01 mm; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][CH:30]=1>>[NH2:35][C:33]([C:32]1[CH:36]=[CH:37][C:29]([NH:28]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:30][CH:31]=1)=[O:34]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(C(N)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-aminobenzamide
Reaction SMILES: CCOP(OCC)([CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=O.C([Li])CCC.[C:22]([O:26][C:27]([N:29]1[C@@H:33]([CH:34]=O)[CH2:32][O:31][C:30]1([CH3:37])[CH3:36])=[O:28])([CH3:25])([CH3:24])[CH3:23]>COCCOC>[C:22]([O:26][C:27]([N:29]1[C@@H:33](/[CH:34]=[C:6](/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)\[CH3:7])[CH2:32][O:31][C:30]1([CH3:36])[CH3:37])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: CCOP(=O)(OCC)C(C)c1ccccc1
Agent: [Li]CCCC
Solvent: COCCOC
Product: C/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of diethyl 1-phenylethyl phosphonate (2.35 ml) in 1,2-dimethoxyethane (15 ml) was cooled under an argon atmosphere to 0° C. and treated dropwise with an n-butyllithium solution (5.9 ml; 1.6 M in hexane). The reaction mixture was stirred for 5 min at 0° C., then treated dropwise with a solution of (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.5 g) in 1,2-dimethoxyethane (15 ml). The solution was warmed to r.t., then refluxed overnight. After cooling to r.t., the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was isolated by column chromatography (SiO2; gradient: cyclohexane ->cyclohexane/EtOAc 1:1) to give (S)-2,2-dimethyl-4-((E)-2-phenyl-propenyl)-oxazolidine-3-carboxylic acid tert-butyl ester (720 mg) as light yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4](Cl)[C:3]=1[Cl:13].[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[NH2:16][CH2:15][CH2:14][NH:17][C:4]1[C:5]([Cl:11])=[C:6]([Cl:10])[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[Cl:13]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: NCCN
Product: N#Cc1c(Cl)c(Cl)c(NCCN)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
55 g of pentachlorobenzonitrile are introduced into 300 g of ethylenediamine at room temperature in such a way that the temperature does not exceed 30° C. The mixture is then stirred for a further half an hour at room temperature, after which 0.75 l of ice water is slowly added and stirring is continued for 15 minutes. The precipitate is filtered off under suction, washed with water and dried to give 55 g of product which, when recrystallized from toluene with the addition of active carbon, has a melting point of 140°-144° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].S(=O)(=O)(O)O.[N:19](OC(C)C)=[O:20]>O>[CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][C:7]([N:19]=[O:20])=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: CC(C)ON=O
Reactant: CCN(CCO)c1cccc(C)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(CCO)c1ccc(N=O)c(C)c1

Procedure:
360 g of N-ethyl-N-(2-hydroxyethyl)-m-toluidine and 1,250 g of water are initially introduced into a stirred flask. 196 g of concentrated sulfuric acid are added, while stirring and cooling. During this addition, the internal temperature should not rise above 50°. After cooling to 0°, 187 g of isopropyl nitrite is allowed to run in slowly at -2° to +2°. The excess of nitrite is then removed in the customary manner with amidosulfonic acid. The reaction mixture is brought to room temperature and degassed under reduced pressure. 60 g of prereduced Pd/C (5%) is added to this solution as the catalyst and the N-ethyl-N-(2-hydroxyethyl)-3-methyl-4-nitroso-aniline, which has not been isolated, is hydrogenated at 20° to 40° under a gauge pressure of 0.4 bar of hydrogen. When the reaction has ended, the reaction batch is let down, the catalyst is filtered off and the reaction mixture is concentrated.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10]([CH2:15][C:16](OCC)=[O:17])(=O)[CH2:11][CH2:12][CH3:13].FC(F)(F)S(O)(=O)=O>O>[OH:2][C:1]1[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]2[C:3]=1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:15][C:16](=[O:17])[O:5]2
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCCC(=O)CC(=O)OCC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: CCCc1cc(=O)oc2cc(O)cc(O)c12
Temperature: 0 °C
Yield: 99.1 %

Procedure:
A suspension of anhydrous phloroglucinol (20.0 g, 0.159 mol) in ethyl butrylacetate (26.3 g; 0.167 mol) was added over 30 min to 50 g of constantly stirred trifluoromethanesulfonic acid cooled in an ice bath. A drying tube was then fined to the reaction vessel and the mixture was stirred for 16h at 25° C., after which the resulting thick paste was combined with ice (200 g) and water (300 mL) with brisk stirring. After 30 min the solid material was collected by vacuum filtration and recrystallised from 95% ethanol to yield coumarin 15 (34.7 g; 99%) as lemon yellow crystals. mp 236°-238° C. 1H NMR (CDCl3 /CD3OD 3:1): δ6.13(1H, d; J =2.3 Hz), 6.04(1H, d; J=2.3 Hz), 5.68(1H, s), 2.76(2H, t; J=7.4 Hz), 1.47(2H, tq; J =7.7, 7.4 Hz), 0.82(3H, t; J =7.7 Hz). 13C NMR (CDCl3 /CD3OD 3:1): δ163.1, 160.7, 160.6, 157.3, 156.7, 107.8, 102.5, 99.2, 95.0, 37.7, 22.5, 13.4. Anal. calc. for C12H12O4.(H2O): C, 60.50; H, 5.92. Found: C, 60.47; H, 5.92.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[CH:13][C:14]=1[Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@@H:22]([CH3:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)=O.C(=O)([O-])[O-].CN(C)C=O>CCOCC.O>[Br:15][C:14]1[CH:13]=[CH:12][C:11]([O:16][C@H:22]([CH3:32])[CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)c(OCc2ccccc2)c1
Reactant: C[C@@H](CCCc1ccccc1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@H](CCCc1ccccc1)Oc1ccc(Br)c(OCc2ccccc2)c1
Yield: 72 %

Procedure:
A mixture of 21.8 g. (78 mmole) of 3-benzyloxy-4-bromophenol, 20.0 g. (82.6 mmole) of (S)-1-methyl-4-phenylbutyl methane sulfonate and 25.2 g. (200 mmole) of potassijm carbonate in 100 ml. dimethylformamide was heated at 85° C. for 13.5 hours. The reaction was cooled and added to 500 ml. water-500 ml. ether. The organic extract was washed with two 250 ml. portions of water, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chromatography on 750 g. of silica gel eluted with 10% ether-hexane to yield 23.9 g. (72%) of the title compound as an oil.