Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:12])=O)=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH2:1])[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccc(Br)cc1
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(N)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.0 M of ammonia in ethanol (117 mL, 235 mmol, Aldrich, Cat. No. 392685) and titanium tetraisopropoxide (27.7 mL, 93.9 mmol, Aldrich, Cat. No. 377996) was added 1-(4-bromophenyl)acetone (10.0 g, 46.9 mmol, Alfa Aesar, Cat. No. A19028). The reaction mixture was stirred at r.t. under nitrogen overnight. Sodium tetrahydroborate (2.66 g, 70.4 mmol) was added. The mixture was stirred at r.t. for additional 3 h. The reaction mixture was quenched with 2M ammonia in water, and filtered. The solid was washed with AcOEt. The filtrate was concentrated to remove most ethanol, and then was washed with AcOEt twice. The combined organic layers were extracted with 1N HCl aqueous solution (twice). The aqueous HCl solutions were combined, and adjusted with ammonia aqueous solution to pH=10. The result solution was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=214.2.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:18]2[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S1(=O)CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCS(=O)(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
8.6 g (40 mmol) of 4-nitrobenzylbromide are dissolved in 100 ml of acetone. 6.9 g (50 mmol) of potassium carbonate and 5.4 g (40 mmol) of thiomorpholine-1,1-dioxide are added. The reaction solution is stirred for 7 hours at ambient temperature. After the undissolved solids have been filtered off, the solution is concentrated by evaporation. The residue is divided between ethyl acetate and water. The organic phases are freed from solvent in vacuo. The product is triturated with ether and dried.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][C:21]([NH:33][C:34]([NH:36][CH2:37][CH3:38])=[O:35])=[CH:22][C:23]=3[C:24]3[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40](O)=[O:41])=[CH:9]1)[CH2:5][O:6][CH3:7].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.[NH2:77][CH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>CN(C=O)C.O>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][C:21]([NH:33][C:34]([NH:36][CH2:37][CH3:38])=[O:35])=[CH:22][C:23]=3[C:24]3[S:25][CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[N:28]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([NH:77][CH:78]2[CH2:83][CH2:82][O:81][CH2:80][CH2:79]2)=[O:41])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C(COC)COC)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NC2CCOCC2)cn3C(COC)COC)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(1,3-Dimethoxypropan-2-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4, 0.112 g, 0.18 mmol) was suspended in DMF (1 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.105 g, 0.28 mmol) was added, followed by diisopropylethylamine (0.193 mL, 1.11 mmol). The reaction mixture was stirred for 15 min at RT. The 4-aminotetrahydropyran hydrochloride (0.038 g, 0.28 mmol) was added in one portion and the mixture was stirred at RT for 2 days. Water was added and the resultant solid was purified by column chromatography (silica, 95:5 methylene chloride/methanol) to provide the product as a solid. The solid was further purified by trituration with CH2Cl2 and hexanes.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)([CH3:9])([CH3:8])[CH3:7]>[O-2].[Fe+3].[O-2].[O-2].[Fe+3].[Fe](Cl)(Cl)Cl.ClCCl>[C:6]([C:2]1[O:1][C:5]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:4][CH:3]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)Cl
Reactant: c1ccoc1
Agent: Cl[Fe](Cl)Cl
Agent: [Fe+3]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(C)(C)C)o1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 35.5 %

Procedure:
Dichloromethane (1275 g), iron (III) oxide (200 g) and iron (III) cloride (5.0 g) were charged to a reaction vessel and the stirred mixture was heated to reflux temperature (ca. 40° C.). A mixture of furan (85.1 g) and tert.butyl chloride (289.3 g) was then run into the solvent/catalyst mixture during about 1.5 hours, and the mixture was then maintained at reflux temperature, with stirring, for a further 1.5 hours after the addition was complete. The reaction mixture was then filtered to remove the catalyst, which was washed on the filter with dichloromethane (2×100 g). The filtrate and washings were combined and the dichloromethane was distilled off until the internal temperature of the mixture reached 60°-65° C. Glycerol (125 g) was then added and the mixture was subjected to distillation under reduced pressure to give 2,5-di-tert.butylfuran (80 g at 85.9% strength=32% of theoretical based on furan charged) b.p. 85° C./15 mm Hg pressure (20 mbar).
Reaction SMILES: [I:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.CC1NC2C=CC(OC)=CC=2C=1CCNC(C)=O>C1COCC1>[I:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH:6][C:19]([CH:16]1[CH2:18][CH2:17]1)=[O:20]
Reactant: COc1ccc2[nH]c(I)c(CCN)c2c1
Reactant: O=C(Cl)C1CC1
Agent: COc1ccc2[nH]c(C)c(CCNC(C)=O)c2c1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(I)c(CCNC(=O)C3CC3)c2c1

Procedure:
A solution of 2-iodo-5-methoxytryptamine (0.316 g, 1 mmol), in THF (3 mL) and TEA (0.14 mL) was acylated with cyclopropanecarbonyl chloride (0.09 mL) at room temperature for 1.5 h using the procedure described for 4a. The desired product 4m was obtained as amorphous solid (0.34 g, 89% yield), IR νmax :3450, 3300, 1650. 1H NMR: 0.71(m, 2H, CH2cyclopropyl), 0.96(m, 2H, CH2cyclopropyl), 1.21(m, 1H, cyclopropyl-CH), 2.90(t, 2H, β -CH2), 3.55(q, 2H, α-CH2), 3.85(s, 3H, OCH3), 5.62(br s, 1H, NH), 6.78-7.27(m, 3Harom), 8.21(br s, 1H, NHindole).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:48])[NH:21][C@@H:22]([C:34]1[S:35][C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:37]([C:39](=[O:41])[NH2:40])[N:38]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([NH:21][C@@H:22]([C:34]1[S:35][C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:37]([C:39]([NH2:40])=[O:41])[N:38]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(N)=O)c(-c2ccccc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nc([C@@H](Cc2ccc3ccccc3c2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
((1R)-1-((1R)-1-(4-Carbamoyl-5-phenyl-1,3-thiazol-2-yl)-2-(2-naphthyl)ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester (0.22 g; 0.328 mmol) was dissolved in methylene chloride (2.5 ml) and trifluoroacetic acid (2.5 ml) was added. The reaction mixture was stirred 1 h at room temperature and the solvent was removed in vacuo. The residue was dissolved in methylene chloride and evaporated (2×5 ml). The residue was dissolved in methylene chloride (10 ml) and washed with sodium hydrogencarbonate (satd; 10 ml), water (10 ml) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.155 g of 2-((1R)-1-((2R)-2-amino-3-(2-naphthyl)propionylamino)-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](N2C=CN=N2)[CH:6]=[N:7][CH:8]=1.[N:16]1(C2C=NC=CC=2)[CH:20]=[CH:19][N:18]=[N:17]1.ClC1C=C(N2C=CN=N2)C=C(Cl)N=1.ClC1C=C(N2C=CN=N2)C=C(C(F)(F)F)N=1.ClC1C(Cl)=C(N2C=CN=N2)C(Cl)=C(Cl)N=1>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)=[N:7][CH:8]=1
Reactant: FC(F)(F)c1cncc(-n2ccnn2)c1
Reactant: c1cncc(-n2ccnn2)c1
Agent: Clc1cc(-n2ccnn2)cc(Cl)n1
Agent: Clc1nc(Cl)c(Cl)c(-n2ccnn2)c1Cl
Agent: FC(F)(F)c1cc(-n2ccnn2)cc(Cl)n1
Product: FC(F)(F)c1ccc(-n2ccnn2)nc1

Procedure:
The following were prepared analogously and identified by NMR spectroscopy and elemental (CHN) analysis: 5-(trifluoromethyl)-3-(1H-1,2,3-triazol-1-yl)pyridine, m.p. 129.5°-131° C.; 3-(1H-1,2,3-triazol-1-yl)pyridine, m.p. 80.5°-83° C.; 2,6-dichloro-4-(1H-1,2,3-triazol-1-yl)pyridine, m.p. 80°-83° C.; 2-chloro-6-(trifluoromethyl)-4-(1H-1,2,3-triazol-1-yl)pyridine, and 2,3,5,6-tetrachloro-4-(1H-1,2,3-triazol-1-yl)pyridine, m.p. 161°-162.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([S:6][CH2:7][C:8](Cl)=C)=[CH:4][CH:3]=1.[CH2:13](N(CC)C1C=CC=CC=1)C>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]([CH3:8])=[CH:13][C:11]=2[CH:12]=1
Reactant: C=C(Cl)CSc1ccc(Br)cc1
Reactant: CCN(CC)c1ccccc1
Solvent: CCOCC
Product: Cc1cc2cc(Br)ccc2s1
Yield: 46 %

Procedure:
According to the procedure of W. K. Anderson, J. Chem. Soc., Perkin, 1, 1 (1976), a mixture of 3-(4-bromothiophenoxy)-2-chloro-1-propene (37.4 g, 0.142 mol) and N,N-diethylaniline (180 mL) was heated to 210°-215° C. for 2 days, cooled, and diluted with ether. The ethereal layer was washed with 10% HCl (3×200 mL), dried (MgSO4), and concentrated. Purification by column chromatography (eluant: hexane) gave 15.0 g (46%) of product as a white solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([C:11]#[N:12])[CH2:9][OH:10]>C1(C)C=CC=CC=1>[C:11]([CH2:8][CH2:9][O:10][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])#[N:12]
Reactant: O=C1CCC(=O)O1
Reactant: N#CCCO
Solvent: Cc1ccccc1
Product: N#CCCOC(=O)CCC(=O)O
Yield: 101.8 %

Procedure:
5.00 g (50 mmol) of succinic anhydride, 3.55 g (50 mmol) of ethylene cyanohydrin and 61 mg (0.5 mmol) of N,N-dimethylaminopyridine were dissolved in 40 mL of toluene, and heated under reflux for 10 hours. After the reaction, the reaction liquid was concentrated under reduced pressure to give 8.71 g of 4-(2-cyanoethoxy)-4-oxobutanoic acid as a mixture.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:18]([OH:20])=O)[C:9]2[CH:10]=[CH:11][N:12]([CH:15]([CH3:17])[CH3:16])[C:13]=2[CH:14]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:53][CH2:54][C:55]1[C:56](=[O:65])[NH:57][C:58]([CH3:64])=[CH:59][C:60]=1[CH2:61][CH2:62][CH3:63]>CN(C=O)C.O>[CH3:64][C:58]1[NH:57][C:56](=[O:65])[C:55]([CH2:54][NH:53][C:18]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]([CH:15]([CH3:16])[CH3:17])[C:13]=3[CH:14]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH:7]=2)=[O:20])=[C:60]([CH2:61][CH2:62][CH3:63])[CH:59]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(C)n1ccc2c(C(=O)O)cc(OCCN(C)C)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN(C)C)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.4 %

Procedure:
To a cooled (0° C.) mixture of 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (400 mg, 1.37 mmol) in DMF (10 mL) was added EDC.HCl (310 mg, 1.65 mmol) and HOBt.H2O (250 mg, 1.65 mmol). The reaction was stirred for 15 min, then DIPEA (1.2 mL, 6.89 mmol) and 3-aminomethyl-6-methyl-4-propyl-1H-pyridin-2-one (240 mg, 1.37 mmol) were added. The reaction was allowed to warm to RT and stirred for 16 h, at which time it was diluted with water (20 mL) and extracted with DCM (2×15 mL). The combined DCM layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography eluting with 3% MeOH in chloroform and then further purified by preparative HPLC to furnish 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide (120 mg, 19%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.92-0.88 (t, 3H), 1.43-1.41 (d, J=6.8 Hz, 6H), 1.56 (m, 2H), 2.12 (s, 3H), 2.22 (s, 6H), 2.55-2.53 (m, 2H), 2.06 (m, 2H), 4.11-4.09 (t, 2H), 4.36-4.34 (d, J=4.8 Hz, 2H), 4.76-4.73 (m, 1H), 5.90 (s, 1H), 6.74-6.73 (d, J=2.8 Hz, 1H), 7.04 (s, 1H), 7.20 (s, 1H), 7.43-7.42 (d, J=3.2 Hz, 1H), 8.10-8.07 (bs, 1H), 11.55 (bs, 1H). LCMS (ES+): m/z=453.23 [M+H].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=O)=[CH:15][CH:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=[S:39])=[CH:15][CH:14]=1
Reactant: NC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1

Procedure:
2.0 g (0.0052 mol) of the compound from Example II and 1.3 g (0.0031 mol) of Lawesson's reagent were heated at the boiling point with 15 ml of toluene under an argon atmosphere for 3 hours. The mixture was then separated by column chromatography (silica gel 60, toluene/tetrahydrofuran 100:5). A slightly yellowish product which could be recrystallised from diisopropyl ether was obtained (Rf =0.45).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:25][CH2:24]2)=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(Cc3ccc(F)cc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.050 g (0.112 mmol) of {3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-piperazin-1-yl-methanone, hydrochloride salt was dissolved in 3 ml of DMF. 61.9 mg (0.448 mmol) of potassium carbonate was added to the solution, followed by 0.021 g (0.11 mmol) of 1-Bromomethyl-4-fluoro-benzene. The reaction solution was shaken for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with water and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), and DCM/MeOH (10/1).
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC1CCCc2cccnc21
Yield: 102.5 %

Procedure:
To 10 g of 8-acetoxy-5,6,7,8-tetrahydroquinoline in 30 mL of methanol was added 30 mL of 30% sodium hydroxide in water. The mixture was heated to reflux for 2 min and the methanol was removed in vacuo. The residual organic product was extracted with chloroform. The chloroform extracts were dried over sodium sulfate and evaporation of the solvent gave 8 g of product as an oil, characterized by its NMR.
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:39])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([N:32]4[C:36](=[O:37])[CH2:35][NH:34][C:33]4=[O:38])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)(=O)C.O>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:39][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([N:32]2[C:36](=[O:37])[CH2:35][NH:34][C:33]2=[O:38])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(N4C(=O)CNC4=O)c3)ccc2O1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CNC(=O)N1c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Yield: 135.2 %

Procedure:
A solution of 3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine2,4-dione (414 mg) in acetic acid (20 ml) and water (5 ml) was heated to 75° C. for 30 min before evaporating to dryness. The residue was purified by chromatography on Biotage (40 g) eluting with CH2Cl2:MeOH:2M NH3 in MeOH (85:10:5). Appropriate fractions were combined and evaporated to dryness. Acetone (10 ml) was added and the mixture was re-evaporated under reduced pressure to give the title compound (290 mg). LCMS RT=2.44 min, ES+ve 514 (MH)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[OH-].[Na+].Cl[C:19]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=1[C:21]#[N:22].O>CS(C)=O>[CH2:14]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:19]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=2[C:21]#[N:22])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:15]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCN(CC)S(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCN(CC)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 60 °C
Yield: 87.8 %

Procedure:
To a solution of 6.73 g (0.0294 moles) of N,N-diethyl-4-hydroxybenzenesulfonamide in 150 ml of DMSO was added 1.18 g (0.0294 moles) of NaOH. The mixture was heated to 60° C. and 4.88 g (0.0267 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 3 hrs. The reaction mixture was cooled and poured into a solution of 400 ml of 2 N aqueous NaOH and 300 ml of water. The product was collected by filtration, washed well with water and dried to obtain 8.8 g of product (88% yield). Recrystallization from ethanol afforded purified N,N-diethyl-4-(2-cyano-4-nitrophenoxy)benzenesulfonamide, mp 163°-164° C.
Reaction SMILES: [Na].Cl[C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:19]([C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCSc1ccc(Cl)nn1
Reactant: Oc1ccccc1
Agent: [Na]
Product: C=CCSc1ccc(Oc2ccccc2)nn1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
0.11 g(0.005 mol) of metallic sodium was dissolved in 30 g of dry phenol. To the resulting solution was added 0.93 g(0.005 mol) of 3-chloro-6-allylthiopyridazine and then the reaction solution was stirred for 3 hours at 160±5° C. After the reaction was allowed to stop, the reaction solution was cooled and adjusted to alkaline (pH 14) with 2N--NaOH, thereby precipitating the crystals. The precipitated crystal was extracted with diethyl ether and then treated according to the same manner as Example 1 to obtain the title compound as a crystal.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Br-:12].[Li+].CCOCC>C1COCC1>[Br:12][CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [Br-]
Reactant: CCCCCC#CCCCCl
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC#CCCCBr

Procedure:
1-Bromodec-4-yne was prepared from 1-chlorodec-4-yne. The 1-chlorodec-4-yne (10.6 g, 61 mmol) and 25 g of lithium bromide were refluxed in 80 ml of THF for 21 hours. The conversion was 74%. Ether was added, the reaction mixture was washed with water (2×) and brine, dried over magnesium sulfate and stripped. The product was dissolved in 70 ml of THF and refluxed for 8 hours with an additional 25 g of lithium bromide. This gave 95% conversion of the chloride to the bromide. The same workup provided 11.36 g of 1-bromodec-4-yne.
Reaction SMILES: CI.[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[C:9]([OH:16])[CH:8]=1)=[O:6].[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[C:9]([O:16][CH3:17])[CH:8]=1)=[O:6]
Reactant: COC(=O)c1cc(O)c2cc[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(OC)c2cc[nH]c2c1
Yield: 49 %

Procedure:
Methyl iodide (0.72 mL, 11.5 mmol, 1.1 equiv.) was added dropwise, over 10 minutes, to a stirred solution of 4-hydroxy-1H-indole-6-carboxylic acid methyl ester (2 g, 10.5 mmol, 1 equiv.) and potassium carbonate (1.3 g, 15.7 mmol, 1.5 equiv.) in acetone (20 mL) at room temperature and the mixture was heated at reflux for 16 hours. The solvent was removed under vacuum, the residue dissolved in ethyl acetate (20 mL) and washed with saturated aqueous solution of NaHCO3 (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and the solvent removed under vacuum to afford 4-methoxy-1H-indole-6-carboxylic acid methyl ester, 1.1 g (49% yield). LC @215 nm; Rt 1.23: 91%, m/z (ES+): 206 (M+H+.); δH (400 MHz; MeOD) 7.74 (1H, s), 7.15 (1H, m), 7.03 (1H, d), 6.46 (1H, m), 3.86 (3H, s), 3.80 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])=[CH:4][CH:3]=1.CO[CH:16](OC)[CH2:17][NH:18][C:19](=[O:21])[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:12][O:13][CH:16]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(CNC(C)=O)OC
Reactant: OCC(CO)Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)NCC1OCC(Cc2ccc(Cl)cc2)CO1
Temperature: 75 °C
Yield: 30 %

Procedure:
4 g (20 mmol) of 2-[(4-chlorophenyl)methyl]propane-1,3-diol, 2.94 g (20 mmol) of N-(2,2-dimethoxyethyl)acetamide, 0.3 g of paratoluenesulphonic acid and 4 ml of diethyl ether saturated with hydrogen chloride are added to 150 ml of diethyl ether. The mixture is evaporated in vacuo, then 150 ml of benzene are added twice to the residue, it is heated to 70-80° C. under a slight vacuum and the solvent is evaporated. The residue is cooled, 150 ml of dichloromethane are added, and the solution is washed with a saturated solution of sodium hydrogen carbonate then with water and dried over magnesium sulphate. The residue is purified twice by chromatography on a silica gel column eluted with chloroform, and it is finally recrystallised in a 70:4 mixture of cyclohexane/ethyl acetate. 1.7 g (6 mmol) of product are obtained.