Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:29]2[CH2:41][C:32]3[NH:33][C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][C:39]=4[C:31]=3[CH2:30]2)([F:28])[C:11]2[O:15][N:14]=[C:13]([CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>CCO>[C:1]1([S:7]([C:10]([CH:29]2[CH2:41][C:32]3[NH:33][C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][C:39]=4[C:31]=3[CH2:30]2)([F:28])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Agent: NN
Solvent: CCO
Product: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
To a suspension of 420 mg (0.7 mmol) of (RS,SR)-2-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-isoindole-1,3-dione in 50 mL EtOH at RT, was added 0.1 mL (2.1 mmol, 3 eq) hydrazine. The reaction mixture was heated at 80° C. over 3 hours 30 minutes. After cooling down, the reaction was quenched with a 1M solution of HCl, and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (CH2Cl2/MeOH 95/5) yielded 210 mg (64%) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine as a light brown powder, MS: 461 (MH+).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:21])[N:7](CCCN3CCOCC3)[C:8]2=[O:11])=[CH:4][C:3]=1S(N)(=O)=O.ClC1C=C2C(=O)NC(=O)C2=CC=1S(=O)(=O)N.NCCCN1CCOCC1>>[O:21]=[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:8](=[O:11])[NH:7]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(CCCN1CCOCC1)C2=O
Agent: NCCCN1CCOCC1
Agent: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Product: O=C1NC(=O)c2ccccc21
Yield: 92 %

Procedure:
6-Chloro-2,3-dihydro-2-[3-(4-morpholinyl)propyl]-1,3-dioxo-1H-isoindole-5-sulfonamide. Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide and N-(3-aminopropyl)morpholine according to the procedure of Example 1(a) afforded a 92% yield of the 1,3-dioxoisoindole intermediate. Crystallization of this material from 80% aqueous ethanol provided analytically pure 6-chloro-2,3-dihydro-2-[3-(4-morpholinyl)propyl]-1,3-dioxo-1H-isoindole-5-sulfonamide, m.p. 190°-191°.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9])(=O)C.CO[C:16]1C=CC(CN2N=NC(CC(OCC)=O)=N2)=C[CH:17]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([O:10][CH2:16][CH3:17])=[O:9]
Reactant: CCOC(=O)Cc1nnn(Cc2ccc(OC)cc2)n1
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccnc(N)c1
Temperature: 105 °C

Procedure:
2-(Acetylamino)isonicotinic acid (13 g, 73.60 mmol) synthesized by the method of Example 7, (A) was added with ethanol (50 ml) and toluene (150 ml) and heated to 100-110° C. The mixture was added dropwise with concentrated sulfuric acid (7 ml) and heated for 11 hour with stirring. The reaction solution was returned to room temperature and poured into saturated aqueous sodium hydrogencarbonate cooled with ice. The mixture was extracted with chloroform and the collected organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 7.6 g (23% for the two steps) of the title compound as pale yellow crystals without purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=2)[C:7](=[O:18])[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:9]([OH:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)[C:7](=[O:18])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:9]([OH:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(O)c(CC(=O)OCC)c(=O)n1Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(O)c(CC(=O)O)c(=O)n1Cc1ccc(C(=O)O)cc1
Reaction time: 4 h
Yield: 70.7 %

Procedure:
98 mg of the product of Example 13 were introduced into 3 ml of ethanol and 0.48 ml of 2N sodium hydroxide and the mixture was refluxed with stirring for 4 hours, then evaporated to dryness under reduced pressure. The residue was added to 4 ml of water, neutralized by the addition of 0.48 ml of 2N hydrochloric acid, separated and washed with water. After taking up in 4 ml of hot isopropanol with 0.4 ml of water added to it, it stood at rest for 16 hours, then separated to obtain 62 mg of the expected product melting at 260° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]>C1COCC1>[C:8]1([C:7](=[N:6][C:5]([CH2:15][CH2:14][CH2:7][CH:8]=[CH2:9])([CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C=CCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCC(CCCC=C)(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A procedure previously described for dialkylation of N-(diphenylmethylene)glycine ethyl ester was used after modifications (see Denmark, S. E.; Stavenger, R. A.; Faucher, A.-M.; Edwards, J. P. J. Org. Chem. 1997, 62, 3375-3389): To a stirred solution of N-(diphenylmethylene)glycine ethyl ester 10 (13.63 g, 51 mmol) in THF (250 mL) was added a solution of KHMDS (11.2 g, 56.1 mmol, 1.1 equiv.) in THF (56 mL) via a cannula at −78° C. over 15 min. After stirring at −78° C. for 1 h, the resulting orange-colored solution was treated with 5-iodo-1-pentene (12 g, 61.2 mmol, 1.2 equiv.). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting suspension was cooled to −40° C. and another solution of KHMDS (15.3 g, 76.5 mmol, 1.5 equiv.) in THF (77 mL) was added via a cannula over 15 min and stirred for 1 h. 5-iodo-1-pentene (16 g, 81.6 mmol, 1.6 equiv.) was then quickly added to the burgundy-colored mixture, and the reaction was left to warm to room temperature overnight (16 h). The reaction was quenched by addition of saturated NH4Cl solution in water (100 mL). The organics were extracted with ethyl acetate (2×150 mL), washed with Na2S2O3 solution and then with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was dried in vacuo overnight and used for the next reaction without further purification: 1H-NMR (400 MHz, CDCl3) δ 7.83-7.12 (m, 10H), 5.80 (m, 2H), 5.02 (dd, J=17.2, 1.6 Hz, 2H), 4.96 (dd, J=10.4, 1.6 Hz, 2H), 3.74 (q, J=6.8 Hz, 2H), 2.05 (dd, J=14.0, 7.2 Hz, 4H), 1.92 (m, 4H), 1.45 (m, 4H), 1.13 (t, J=6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 174.8, 166.0, 141.3, 138.9, 128.5, 128.2, 127.9, 115.0, 69.2, 60.5, 37.5, 34.4, 23.3, 14.2; HRMS (ESI) m/z for C27H34NO2 [M+H]+ calcd 404.2589. found 404.2577.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C([O-])(=O)C.[Na+].[Br:17]Br>CO>[Br:17][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([OH:11])=[CH:3][C:2]=1[Cl:1]
Reactant: BrBr
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cc(Br)c(Cl)cc1O
Temperature: -70 °C
Yield: 50.1 %

Procedure:
Methanol (2.1 liters) was added to 4-chlorosalicylic acid (60 g) and sodium acetate (120 g), and the mixture was cooled to -70° C. and stirred. To this mixture was added dropwise a solution of bromine (55.7 g) in methanol (557 ml) over 1.5 hours. After the reaction mixture was allowed to warm to room temperature, the solvent was distilled off under reduced pressure. The residue was acidified by addition of dilute hydrochloric acid (2 liters). The precipitate was filtered off, dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was concentrated. The deposited crystals were recrystallized from hydrous ethanol to obtain 5-bromo-4-chlorosalicylic acid (43.8 g, mp. 208°-213° C.). According to the same manner as that described in Reference Example 1, by using this compound as the starting compound, 6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazin-4-one (29.2 g) (Compound A-26) was obtained. The physical properties are shown in Table 1.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]([O:13][C:14]([NH:16][C:17]([CH3:22])([C:19](O)=[O:20])[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C)CCCN=C=NCC>ClCCl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19](=[O:20])[C:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])([CH3:22])[CH3:18]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)ON1C(=O)CCC1=O

Procedure:
A stirred solution of N-hydroxysuccinimide (112 g, 0.973 mol), N-t-butoxycarbonyl-α-methylalanine (197 g, 0.969 mol), and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (186 g, 0.970 mol) in anhydrous dichloromethane (1.4 L) was stirred at room temperature for about 18 hours under nitrogen atmosphere. The reaction mixture was washed three times each with saturated sodium bicarbonate solution and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound of part 1-D as a white solid (256 g, 88%): PBMS (M+18)+ 318; 1H NMR=250 MHz (CDCl3) δ: 4.91 (NH, br s, 1H), 2.84 (—CO(CH2)2CO—, s, 4H), 1.67 (Me, s, 6H), 1.48 (BOC, s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][CH2:21][O:22][CH3:23])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:37][OH:38]>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][CH2:21][O:22][CH3:23])[N:16]=2)[CH2:11][C:12]([NH:37][OH:38])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: COCCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of ((3R)-6-cyclohexyl-3-[3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 51) (245 mg, 0.76 mmol) in anhydrous tetrahydrofuran (10 ml) was treated with 1,1′-carbonyldiimidazole (123 mg, 0.76 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 1 hour. Hydroxylamine hydrochloride (53 mg, 0.76 mmol) was then added and the mixture stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5). The residue was dissolved in ethyl acetate, washed with hydrochloric acid (1M), dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil (100 mg)
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C[Si](CC(N)=O)(C)C.C(Cl)Cl.[O:32]=[C:33]([CH2:38][Br:39])[CH2:34][C:35](Br)=[O:36]>C(Cl)(Cl)(Cl)Cl.O>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:35](=[O:36])[CH2:34][C:33](=[O:32])[CH2:38][Br:39])[C@H:5]2[S:4]1
Reactant: O=C(Br)CC(=O)CBr
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (0.38 g.), trimethylsilylacetamide (1.1 g.) and methylene chloride (10 ml.) was stirred for 30 minutes at room temperature, and thus obtained solution was cooled to -15° C. To the solution was added dropwise 3-oxo-4-bromobutyryl bromide (1.0 m mole) in carbon tetrachloride (13 ml.) under cooling to -15° C., and the mixture was stirred for 1.5 hours at the same temperature and for 30 minutes without external cooling. The mixture was poured into cold water, and then the organic layer was separated therefrom. The organic layer was washed with 2 N hydrochloric acid (8 ml×3) and water (10 ml×2) in turn, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was pulverized in diisopropyl ether, collected by filtration and then dried to give pale brown powder of 2,2,2-trichloroethyl 2-methyl-7-(3 -oxo-4-bromobutyramido)-3-cephem-4-carboxylate (0.31 g), mp 78° to 83° C. (dec.).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15][N:16]([C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)[CH2:17][C:18]([N:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH:2]([N:35]1[CH2:36][CH2:37][C@@H:33]([N:16]([CH3:15])[CH2:17][C:18]([N:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:34]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(CC(=O)N(c1ccccc1)c1ccccc1)[C@@H]1CCNC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(CC(=O)N(c1ccccc1)c1ccccc1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of bromodiphenylmethane (0.33 g, 1.34 mmol) in butanone (10 ml) was added (R)-2-(methyl-pyrrolidin-3-yl-amino)-N,N-diphenyl acetamide(0.5 g, 1.61 mmol), K2CO3 (0.18 g, 1.34 mmol) and KI (0.22 g, 1.34 mmol). The mixture was, heated under reflux for 18 hours, then filtered and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (10 ml). Drying over MgSO4 and removal of solvent under reduced pressure followed by column chromatography using Hex:EtOAc (1:1) gave the desired product.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([Cl:18])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][C@@H:10]([CH3:12])[C:9]=2[C:13]=1[Cl:18]
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNCCc2ccc(Cl)c(Cl)c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.8 %

Procedure:
A solution of (S)-N-trifluoroacetyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.270 g, 1.2 mmol) in methanol (10 mL) was treated with 15% aqueous NaOH (10 mL), and stirred for 3.5 hours at 25° C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (25 mL), dried with Na2SO4 and concentrated to give 0.270 g of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 4.17 (m, 1H), 3.55 (m, 2H), 3.5-3.3 (m, 2H), 3.2-3.0 (m, 2H), 1.43 (d, J=7 Hz, 3H). MS calculated for C11H13Cl2N+H: 230, observed: 230.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(=[O:5])[CH3:4]>C(O)C>[OH:5][C:3]1[CH:4]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[C:7](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:6]=1
Reactant: CC(=O)Nc1ccccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(-c2ccccc2)c2ccccc2n1
Temperature: 25 °C

Procedure:
Sodium hydroxide (5 M, 1.8 g, 43.9 mmol) was added to a mixture of 2-acetamidobenzophenone (10.5 g, 43.9 mmol) in ethanol (439 mL). The mixture was heated to reflux for 3 hours, then cooled to room temperature and concentrated. Water and methylene chloride were added while stirring to form a white precipitate. The solid was collected by vacuum filtration and washed with methylene chloride to yield 2-hydroxy-4-phenylquinoline.
Reaction SMILES: [Cl-].C(OC([P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(OCC)=O)C.C([O:37]C1C=CC(C=O)=CC=1)C1C=CC=CC=1.CN(C)C(=N)N(C)C>C(Cl)Cl>[CH:27]1[CH:28]=[CH:29][C:24]([P:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:37])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
The crystals of (1,2-diethoxy-2-oxoethyl)(triphenyl)phosphonium chloride in the reactor were dissolved in CH2Cl2 (290 L) followed by the addition of 4-benzyloxybenzaldehyde (44.2 kg, 208 mol, yield is based on this chemical). To this solution tetramethylguanidine (25.4 kg, 220 mol) was added in 1 hour. The solution was then stirred for 20 hours at 20° C. CH2Cl2 (200 L) was distilled off and at an Ti of 30° C. replaced TBME (280 l). The crystals of TPPO formed were filtered off at 20° C. and the mother-liquor was concentrated until a new precipitate was formed. The TPPO was filtered off again and the mother-liquor was concentrated until no more solvents distilled. 2-Propanol (260 L) and seeding crystals (ethyl 3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate) (50 g) were added before cooling to 0° C. The resulting suspension was filtered and the isolated material dried at 40° C./160 mbar. The overall yield was 44.5 kg, 65% (GLC: 99% area).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][C:21]#[N:22])=[CH:10][CH:9]=1.[OH-].[Na+].C(O)(=O)/C=C\C(O)=O>CO.O.CCOCC>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][NH2:22])=[CH:23][CH:24]=1
Reactant: N#CCc1ccccc1CCc1ccc(Br)cc1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: NCCc1ccccc1CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride, 0.61 g. (0.016 mole), is weighed under nitrogen, transferred to a dry, nitrogen-flushed reaction flask and suspended in 50 ml. of absolute ether. The mixture is stirred at reflux for 30 minutes, then cooled to room temperature and a solution of 2.4 g. (0.008 mole) of 2-(4-bromophenethyl)-phenylacetonitrile in 30 ml. of absolute ether is added dropwise. After 16 hours at reflux, the cooled mixture is hydrolyzed by the successive dropwise addition of 0.7 ml. of water, 0.7 ml. of 20% aqueous sodium hydroxide, and 1.5 ml. of water. The ethereal layer is separated and stirred with 18 ml. of 3N hydrochloric acid. The hydrochloride salt of the product separates, m.p. 148°-153° C. (cloudy melt). Repeated recrystallizations from absolute ethanol-ether and from water yield purified material, m.p. 148°-150° C. (cloudy melt). The hydrochloride is converted to the base by rendering an aqueous solution strongly alkaline. The oily base is extracted into benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the product as the residual oil. The base may be converted to the hydrogen maleate salt by treating a solution in methanol with a slight excess of maleic acid. Dilution with absolute ether precipitates the hydrogen maleate in white crystals, m.p. 158°-160° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([S:55][C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:58][CH:57]=2)=[C:51]([NH:70][C:71]2[C:72]3[CH:80]=[CH:79][C:78]([CH:81]([CH3:83])[CH3:82])=[N:77][C:73]=3[N:74]=[CH:75][N:76]=2)[CH:50]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:48][C:49]3[CH:54]=[CH:53][C:52]([S:55][C:56]4[CH:61]=[CH:60][C:59]([NH:62][C:63]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:69])=[CH:58][CH:57]=4)=[C:51]([NH:70][C:71]4[C:72]5[CH:80]=[CH:79][C:78]([CH:81]([CH3:83])[CH3:82])=[N:77][C:73]=5[N:74]=[CH:75][N:76]=4)[CH:50]=3)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(N)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)c1ccc2c(Nc3cc(NC(=O)c4ccc(Sc5ccc(NC(=O)OC(C)(C)C)cc5)c(Nc5ncnc6nc(C(C)C)ccc56)c4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
To a solution of the product from Example 1E (50 mg, 0.094 mmol) in DMSO (0.5 mL) at room temperature were added Hunig's base (49.3 μl, 0.282 mmol), the product from Example 2A (47.3 mg, 0.094 mmol), and HATU (42.9 mg, 0.113 mmol) and the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with water. The organic was dried over MgSO4, filtered and concentrated. The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:30][C:31]#[CH:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][O:17][CH2:32][C:31]#[CH:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCCl
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC=C(C(=O)NCCc1ccc(OC)c(OC)c1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Yield: 63 %

Procedure:
Six hundred milligrams (600 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (1.57 mmol), 0.14 g (1.89 mmol) of 3-chloropropyne, 280 mg (2.05 mmol) of potassium carbonate and 10 ml of anhydrous N,N-dimethylformamide were mixed and stirred at room temperature. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=1:1) to give 415 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(2-propynyloxy)-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1196).