Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].[CH2:14]([N:16]([CH2:29][CH3:30])[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH3:28])[CH3:15].C(N(C(C)C)C(C)C)C>ClCCl>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][N:16]([CH2:29][CH3:30])[CH2:14][CH3:15])=[C:21]([O:27][CH3:28])[CH:22]=1)=[O:7]
Reactant: CCN(CC)CCOc1ccc(N)cc1OC
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1OC

Procedure:
A solution of 70 mg (0.290 mmol) of (2,4-dichloro-phenoxy)-acetylchloride in 0.5 mL dichloromethane was added to a solution of 66 mg (0.278 mmol) of 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine (intermediate product Z6b) and 96 μL (0.56 mmol) of ethyl-diisopropylamine in 1.5 mL abs. dichloromethane and the mixture was stirred for 15 hours at RT. The reaction mixture was evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane/MeOH 9:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])[CH2:9]2)=[CH:4][CH:3]=1.[NH3:18]>>[CH3:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C@H:10]1[CH2:11][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:2]3[CH:7]=[CH:6][C:5]([C:8]#[N:18])=[CH:4][CH:3]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: N
Reactant: C[C@@H]1CCCN1[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Product: CC1CCCN1[C@H]1C[C@H](c2ccc(-c3ccc(C#N)cc3)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 2B except substituting the product from the Example 4A for the product from Example 2A. 1H NMR (300 MHz, CD3OD) δ 1.24 (d, J=6 Hz, 3 H), 1.60 (m, 1 H), 1.90 (m, 2 H), 2.12 (m, 1 H), 2.41 (m, 1 H), 2.53 (m, 1 H), 2.70 (m, 3 H), 2.92 (m, 1 H), 3.24 (m, 1 H), 3.62 (m, 2 H), 7.46 (d, J=9 Hz, 2 H), 7.67 (d, J=9 Hz, 2 H), 7.80 (s, 4H); (DCl/NH3) m/z 317 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:22]([Si:19]([CH3:21])([CH3:20])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: OCCCCCCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The procedure used was similar to that described by Corey and Venkateswarlu (Corey, E. J.; Venkateswarlu, A., J. Am. Chem. Soc., 1972, 94, 6190-6191). 6-Phenyl-1-hexanol (14.0 g) and imidazole (13.36 g) were dissolved in dry DMF (40 mL). tert-Butyldimethylsilyl chloride (14.20 g,) was then added in one portion. The resulting solution was allowed to stir for 8 hours at room temperature. Aqueous sodium bicarbonate (100 mL, 10% by wt.) was then added and the resulting solution was allowed to stir for 15 minutes. The desired product was then extracted from the mixture with petroleum ether (3×250 mL). The petroleum ether extract was then washed with distilled H2O (7×300 mL), dried over MgSO4 and roto-evaporated to give the desired product as a clear oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:6][CH:5]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][CH:34]=[C:35]([CH2:37]Cl)[N:36]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][CH:34]=[C:35]([CH2:37][O:3][C:4]3[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]4[CH:17]=[CH:16][N:15]=[CH:14]4)=[CH:6][CH:5]=3)[N:36]=2)=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2)cc1
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
Sodium hydride (440 mg) was added, at room temperature, to a solution of 1-[3-(4-hydroxyphenyl)propyl]imidazole (2.02 g) in N,N-dimethylformamide (50 ml). The mixture was stirred for 1.5 hour, to which was added 2-(4-benzyloxyphenyl)-4-chloromethyloxazole (3.60 g). The mixture was stirred for further 3 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. A crystalline product obtained from the fraction eluted with ethyl acetate-methanol (50:1, v.v) was recrystallized from ethanol to give 2-(4-benzyloxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (2.88 g, 62%) as colorless prisms, mp 133-134° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+].[N:27]#[C:28]Br>O1CCOCC1.O>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]2[O:13][C:28]([NH2:27])=[N:15][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2ccccc2Nc2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.7 %

Procedure:
To a room temperature solution of 2-[(3-trifluoromethylphenyl)amino]benzoic acid hydrazide (532.7 mg, 1.81 mmoles) in 5 ml of dioxane is added sodium bicarbonate (155.0 mg, 1.84 mmoles) in 5 ml of water. After stirring at room temperature for five minutes, cyanogen bromide (192.0 mg, 1.81 mmoles) is added, and stirring is continued for 2.5 hours. The tan precipitate is removed by filtration and washed with 10 ml of 50% aqueous dioxane. Drying in vacuo provides 398.0 mg (69%) of 5-[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]-1,3,4-oxadiazol-2-amine, mp 185°-187° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]=O)=[CH:17][CH:16]=1.[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]=[C:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1ccc(/C=C/C=C/C=O)cc1
Reactant: O=C1COC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1CCc1ccc(/C=C/C=C/C=C2OC(=O)NC2=O)cc1

Procedure:
A mixture of (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]-2,4-pentadien-1-al (2.3 g), 2,4-oxazolidinedione (2.0 g), piperidine (0.596 g) and acetic acid (50 ml) was refluxed under heating conditions for 15 hours. The reaction mixture was concentrated; water was added to the residue, followed by acidification with 2N HCl and subsequent extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was subjected to silica gel chromatography to yield 5-[(E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]-2,4pentadienylidene]-2,4-oxazolidinedione [mixture of the (E)- and (Z)-configurations](1.0 g, 33%) from the fraction eluted with chloroform-ethyl acetate (9:1, v/v), which was then recrystallized from chloroform-methanol to yield light yellow prisms having a melting point of 208°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Cl:16][C:17](Cl)([Cl:21])[CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:17]([Cl:21])=[CH:18][CH2:19][O:15][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[C:6]([Cl:14])[CH:5]=1
Reactant: ClCCC(Cl)(Cl)Cl
Reactant: OCCCCOc1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 61.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 1, using 9.3 grams (0.036 mole) of 3,5-dichloro-4-(4-hydroxybutoxy)phenol, 7.7 grams (0.042 mole) of 1,1,1,3-tetrachloropropane and 11.7 grams (0.080 mole) of potassium carbonate in 300 mL of DMF. The crude product was purified with column chromatography on silica gel using mixtures of 1:4 and 1:1 ethyl acetate and hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 8.0 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][C:5]([CH:6]=[N:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[C:25]([CH3:28])([CH3:27])[CH3:26].C([BH3-])#N.[Na+]>C(O)(=O)C>[OH:1][C:2]1[C:20]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:19][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1cc(C=Nn2ccnc2N2CCOCC2)cc(C(C)(C)C)c1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(CNn2ccnc2N2CCOCC2)cc(C(C)(C)C)c1O
Reaction time: 8 h

Procedure:
1.92 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-morpholinoimidazole are dissolved in 30 ml of glacial acetic acid and treated portionwise within 30 minutes with 0.7 g of 90% sodium cyanoborohydride. The reaction mixture is stirred overnight. The solvent is removed by evaporation in a vacuum and the residue is treated with 20 ml of water. Saturated sodium carbonate solution is added up to an alkaline reaction and the mixture is extracted three times with 20 ml of methylene chloride each time. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is boiled up briefly with 20 ml of n-hexane. After cooling, the crystalline colorless product is removed by filtration and recrystallized from methanol/water. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)-2-morpholinoimidazole of m.p. 161°-163°.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.C=[O:11].[NH2:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:28])[C:17]=2[C:16](Br)=[CH:15][C:14]=1[Br:30]>O>[NH2:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:28])[C:17]=2[C:16]([OH:11])=[CH:15][C:14]=1[Br:30]
Reactant: C=O
Reactant: Nc1c(Br)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: Nc1c(Br)cc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
Hydrolysis is carried out by adding 195.3 parts of 66% oleum and 16 parts of paraformaldehyde to the reaction mixture and heating it to 110° C. The mixture is heated in a stream of nitrogen to 110° C. until the presence of 1-amino-2,4-dibromoanthraquinone can no longer be detected. The reaction time is from 1 to 2 hours. Upon completion of the reaction, the reaction mixture is cooled to room temperature and diluted with 523 parts of water. The precipitated crystals of 1-amino-2-bromo-4-hydroxyanthraquinone are isolated by filtration and washed with water until neutral, affording 149 parts of product, corresponding to a yield of 93.7%, based on 1-aminoanthraquinone. Melting point: 226°-228° C. (lit.: 231°-232° C.). According to elemental analysis, the bromine content is 25.0% (calculated: 25.2%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26]O)[CH:19]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:19]=1
Reactant: OCCCc1cccnc1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(OCCCc3cccnc3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (50 mg, 0.196 mmol, Description 3) and 3-pyridinepropanol (0.028 ml, 0.215 mmol) in dichloromethane (1 ml) was added diisopropyl azodicarboxylate (0.038 ml, 0.196 mmol) followed by triphenylphosphine (51.4 mg, 0.196 mmol). The reaction mixture was stirred at 25° C. overnight. Solvent was removed under vacuum and the crude product was purified by reverse phase chromatography using the MDAP. Relevant fractions were combined and concentrated to give 34 mg of material which was dried in the vacuum oven overnight. This solid was then dissolved in DCM (10 ml) and washed with water (2*10 ml). The organic phase was dried over MgSO4 and concentrated. This product was purified by MDAP a second time. This material was dissolved in MeOH and loaded on to a SCX cartridge, washed with MeOH and eluted with methanolic ammonia. Relevant fractions were combined and concentrated to give the title compound as a white solid (2 mg).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[CH2:10][CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: OCCCl
Product: OCCOc1ccccc1O

Procedure:
reaction of catechol with 2-chloroethanol to obtain 2-(2-hydroxyethoxy)phenol of formula: ##STR30## b) reaction of the 2-(2-hydroxyethoxy)phenol obtained in a) with 1,2-dibromethane to obtain 1,2-bis [2-(2-hydroxyethoxy)pbenoxy]etbane and
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+].[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CN1c2cc(Br)ccc2NS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1c2cc(Br)ccc2N(COCC[Si](C)(C)C)S1(=O)=O
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-1-methyl-1,3-dihydrobenzo[c][1,2,5]thiadiazole 2,2-dioxide (557 mmol, 2.10 mmol, as prepared above) in DMF (5 mL), K2CO3 (1.00 g, 7.23 mmol) and SEM-Cl (0.560 mL, 3.20 mmol) were added. The resulting mixture was stirred at 75° C. for 4 h and allowed to cool to rt. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The combined DCM layers were dried over Na2SO4, filtered, concentrated and the resulting residue was purified by flash column chromatography on silica gel (0-50% hexane/EtOAc) to obtain compound 39a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.12-7.17 (m, 2H), 6.60 (d, J=8.6 Hz, 1H), 5.14 (s, 2H), 3.68-3.74 (m, 2H), 3.25 (s, 3H), 0.93-0.99 (m, 3H), 0.01 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N(C(OCC)=O)=NC(OCC)=O.[Cl:31][CH2:32][CH2:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:31][CH2:32][CH2:33][CH2:34][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: OCCCCl
Reactant: Oc1ccccc1C=Cc1cccc2[nH]ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCCOc1ccccc1C=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an inert atmosphere, 235 mg of 2-[(1H-indol-4-yl)-ethenyl]-phenol in 20 ml of tetrahydrofuran with 0.15 ml of diethyl azodicarboxylate, 0.1 ml of 3-chloro-1-propanol, and 262 mg of triphenylphospine were stirred for 5 hours. Then 0.1 ml of 3-chloro-1-propanol, 0.15 ml of diethyl azodicarboxylate and 262 mg of triphenyl phospine were added, and after 15 hours of stirring at ambient temperature, the mixture was concentrated to dryness. The residue was purified by chromatography on silica (eluent: benzene) to obtain 310 mg of 4-[2-[2-(3-chloropropoxy)-phenyl]-ethenyl]-1H-indol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[CH:12].C(=O)(O)[O-:14].[Na+]>CS(C)=O.CCOCC>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[O:14])[CH2:10][C:11]#[CH:12]
Reactant: O=C([O-])O
Reactant: C#CCCOCCCCCCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: C#CCCOCCCCCC=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
6-Bromohexylbut-3-ynyl ether (525 mg) in DMSO (2 ml) was added to a mixture of sodium bicarbonate (1 g) in DMSO (8 ml) at 150° C. with vigorous stirring and nitrogen bubbling through the solution. The mixture was stirred for 20 min at 150° C. and then allowed to cool to room temperature, diluted with Et2O and washed with water. The aqueous layer was extracted with Et2O and the combined ether layers were washed with dilute hydrochloric acid, brine, dried (MgSO4) and evaporated to dryness to give the title compound (325 mg): IR 1726 cm−1 MS(TSP+ve) m/z 186 (M+MH4)+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:32])[C:5]([C:3]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1nc(C#N)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2cc(Cc3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 130.5 %

Procedure:
A mixture of 1,3-dibenzyl-8-cyano-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (23 mg, 0.054 mmol), β-alanine (2.57 g, 28.8 mmol) and NaOMe solution (43 mL, 21.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 34 mg of the title compound. MS: (−) m/z 481.13 (M−1).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH2:7]([OH:10])[C:8]#[CH:9]>[Cu]I>[O:4]1[CH:5]=[CH:6][C:2]([C:9]#[C:8][CH2:7][OH:10])=[CH:3]1
Reactant: Brc1ccoc1
Reactant: C#CCO
Agent: [Cu]I
Product: OCC#Cc1ccoc1

Procedure:
To a mixture of 3-bromofuran (10 g, 0.068 mol) and propargyl alcohol (4.3 ml, 0.074 mol) in 200 ml of TEA was added under argon, CuI (0.26 g, 1.4 mmol) and [(C6H5)3P]2PdCl2 (1.05 g, 1.4 mmol) and the mixture was stirred at 0° C. for 2 hours and at room temperature for 72 hours. The reaction mixture was cooled, decanted, and the solid was washed with TEA. The combined TEA solution was concentrated in vacuo and the residue was distilled (Kugelrohr distillation) to afford 1.48 g (17.8%) of 3-(3-furyl-2-propynyl alcohol.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1)([CH2:5][CH:6]([C:11](=[O:27])[NH:12][CH:13]([C:23](=[O:26])[NH:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][P:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1)([CH2:5][CH:6]([C:11](=[O:27])[NH:12][CH:13]([C:23](=[O:26])[NH:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(N)c1)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(NCc2ccccc2)c1)OC
Yield: 74.7 %

Procedure:
(3-Aminobenzyl){2-[2-(4-methoxyphenyl)-1-methylcarbamoyl ethylcarbamoyl]-4-methylpentyl}phosphinic acid methyl ester (prepared as described in Example 4/Step A) (150 mg, 0.30 mmole), benzaldehyde (38 mg, 0.36 mmole), sodium cyanoborohydride (23 mg, 0.357 mmole) and acetic acid (1 drop) in methanol were stirred at room temperature for 3 hours. The reaction was quenched with 1N hydrochloric acid (few ml's) and the reaction mixture concentrated. The residue was dissolved in ethyl acetate (20 ml) and washed with 1N hydrochloric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and dried with magnesium sulfate. Filtration and concentration gave the crude product which was purified by chromatography (3:97--methanol:methylene chloride) yielding 133 mg (75%) of (3-Benzylamino benzyl)-{2-[2-(4-methoxyphenyl)-1-methylcarbamoylethylcarbamoyl]-4-methylpentyl}phosphinic acid methyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH2:30])=[CH:24][NH:25]2)=[CH:21][C:20]=1[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH:30][C:10]([C:7]3[CH:6]=[C:5]([CH2:4][C:3]4[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=4[F:1])[O:9][N:8]=3)=[O:12])=[CH:24][NH:25]2)=[CH:21][C:20]=1[CH3:31]
Reactant: Cc1cc2c(CCN)c[nH]c2cc1Cl
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(CCNC(=O)c3cc(Cc4cc(F)ccc4F)on3)c[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
A mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.180 g, 0.752 mmol), 2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine intermediate 142 (0.157 g; 0.752 mmol), HATU (0.286 g; 0.753 mmol) and N,N diisopropylethylamine (0.324 mL; 1.88 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane and eluent 1 to 10% ethyl acetate in dichloromethane) and by preparative HPLC method 2 to yield 0.0051 g (2%) of N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: FC(F)(F)S([Cl:6])(=O)=O.[C:9]1([C:15](=[O:27])[CH2:16][C:17](=[O:26])[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.Cl>[Cl:6][C:18]1[C:17](=[O:26])[CH:16]=[C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:27][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccccc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Cl
Reaction time: 2 h

Procedure:
Trifluoromethane sulphonyl chloride (3.95 ml) was added over 10 minutes to a stirred solution of ethyl 6-phenyl-2,4,6-trioxohexanoate (8.1 g) and triethylamine (6.5 ml) in dichloromethane (100 ml) at 0° to 5° C. The solution was stirred for 2 hours at 0° to 5° C., then made acidic by passing in hydrogen chloride gas. The mixture was stirred for 3 hours at room temperature, washed with water and evaporated to a brown oil which crystallised from ethanol-water. The product was recrystallised from ethanol-water and from ethyl acetate-petroleum ether 60°-80° C. to give ethyl 3-chloro-4-oxo-6-phenyl-4H-pyran-2-carboxylate (mp 121° C.).