Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:13]([NH:20][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCCCN
Product: CCCCCCC/C=C/C(=O)NCCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and heptylamine as starting materials to give the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([CH3:28])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[OH:27])[C:9](=[O:10])[C:4]=2[CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:35][CH2:36][F:37])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([CH3:28])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[O:27][CH2:35][CH2:36][F:37])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1OCCF
Temperature: 80 °C
Reaction time: 10 h
Yield: 76.8 %

Procedure:
6-chloro-3-[2-hydroxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]-pyrimidin -4(3H)-one (10 mg), 2-fluoroethyl tosylate (7.6 mg) and potassium carbonate (16 mg) were mixed in dimethylformamide (2 mL) and stirred at 80° C. for 10 hours. Distilled water was added, the mixture extracted with ethyl acetate, and dried with anhydrous sodium sulfate. The product was purified by silica gel thin layer chromatography (chloroform/methanol=10/1), and the title compound (8.5 mg, 77%) was obtained as a colorless solid.
Reaction SMILES: [O:1]([CH:8]1[CH2:12][NH:11][CH2:10][CH:9]1[OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][CH2:17][N:11]2[CH2:12][C@@H:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@H:9]([OH:13])[CH2:10]2)=[CH:26][CH:25]=1
Reactant: OC1CNCC1Oc1ccccc1
Reactant: CN(C)CCC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCN1C[C@@H](O)[C@H](Oc2ccccc2)C1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 3.6 g. (0.02 mole) of 4-phenoxy-3-pyrrolidinol, 5 g. (0.0215 mole) of β-dimethylamino-p-fluoropropiophenone hydrochloride, 10 g. of potassium carbonate and 50 ml. of dimethylformamide was heated with stirring at 70° C. for 6 hr. while nitrogen gas was bubbled through the reaction mixture. The mixture was poured into water and extracted twice with benzene. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 6.1 g. of an oil as residue. The oil was chromatographed on 130 g. of silica gel. The desired compound was eluted with 20% acetone in benzene and 2.6 g. (39%) of an oil which gradually crystallized upon standing was obtained. This solid was recrystallized from petroleum ether diethylether to yield a white solid, m.p. 77°-80° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:22][CH:23]([F:27])[C:24](Cl)=[O:25]>>[F:22][CH:23]([F:27])[C:24]([C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)=[O:25]
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)cc2)CC1
Reactant: O=C(Cl)C(F)F
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)C(F)F)cc3)cc2)CC1

Procedure:
The preparation is carried out analogously to Example 4 from 0.5 mol of 4-(trans-4-propylcyclohexyl)biphenyl and 0.5 mol of difluoroacetyl chloride.
Reaction SMILES: [C:1]([NH:5][CH3:6])([NH:3][CH3:4])=[O:2].[CH:7]([CH:9]=[O:10])=[O:8].[OH-].[Na+]>>[OH:8][CH:7]1[CH:9]([OH:10])[N:5]([CH3:6])[C:1](=[O:2])[N:3]1[CH3:4]
Reactant: O=CC=O
Reactant: CNC(=O)NC
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=O)N(C)C(O)C1O
Temperature: 25 °C

Procedure:
Dimethylurea (2 moles, 176 parts) and glyoxal (2 moles, 290 parts of 40% aqueous solution) are mixed and the pH adjusted to 7 with sodium hydroxide. The reaction mixture is stirred at room temperature for several hours and the resulting white solid is filtered, washed with methanol and dried. White crystals, m.p. 140° C., are obtained in fine yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[CH:27][C:26]=1[Cl:25]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 151, step 7) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e)=530.1 [M+H+].
Reaction SMILES: [N:1]#[C:2][NH2:3].C([O:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[N:16]=[C:17]=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])C=C>C(#N)C>[OH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])=[N:3][C:2]#[N:1]
Reactant: C=CCOc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Reactant: N#CN
Solvent: CC#N
Product: N#CN=C(Nc1ccc(C#N)cc1O)Nc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
To a stirred mixture of cyanamide (560 mg, 13.33 mmol) and Huinig's base (2.6 ml) in acetonitrile was added a solution of N-(2-Allyloxy-4-cyanophenyl)-N′-(2-bromophenyl)-carbodiimide (600 mg, 1.69 mmol) in acetonitrile (30 ml) dropwise. The reaction was stirred at rt for 15 min, then the solvent was removed under reduced pressure and the residue hydrolyzed with 0.5 M sodium dihydrogen phosphate. Ethyl acetate extractions of the aqueous mixture were washed with 0.5 M sodium dihydrogen phosphate and brine. After drying (MgSO4) filtration and evaporation under reduced pressure afforded a crude tan solid (500 mg). This was chromatographed on silica gel (50/50 ethyl acetate/hexane) to give the title compound (455 mg, 95%). MS(ES−) m/e 394, 396 [M−H]−
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:16]1[C:20]2[N:21]=[C:22]([Cl:28])[CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:19]=2[CH:18]=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:9]([N:16]1[C:20]2[N:21]=[C:22]([Cl:28])[CH:23]=[C:24]([C:25]([O:27][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:26])[C:19]=2[CH:18]=[N:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1cc(Cl)nc2c1cnn2Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(Cl)nc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Benzyl bromide (11 mL/89 mol) is added dropwise to a suspension of 1-benzyl-6-chloro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (27.0 g/93.9 mmol) and potassium carbonate (15.6 g/112 mmol) in 310 mL of DMF. The mixture is stirred at ambient temperature for 2 hours and then run into a saturated aqueous solution of ice-cold NaHCO3. The precipitate formed is filtered, thoroughly washed with water, and dried under vacuum to give 32.6 g of a pale yellow powder (yield: 92%).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=S.[NH2:13][C@@:14]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:18][O:17][C@H:16]([CH3:19])[C@H:15]1[C:20]([O:22]C)=O.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C@:14]12[CH2:18][O:17][C@H:16]([CH3:19])[C@H:15]1[C:20](=[O:22])[N:2]([CH3:1])[C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[N:13]2
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1[C@@H](C)OC[C@@]1(N)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1OC[C@]2(c3ccccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.7 %

Procedure:
tert-Butyl (methylcarbamothioyl)carbamate (2.13 g, 11.2 mmol) was added to a stirred mixture of (2R,3S,4S)-methyl 4-amino-4-(2-fluorophenyl)-2-methyltetrahydrofuran-3-carboxylate (2.27 g, 9.0 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (3.9 mL, 22.4 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1:1) (2.15 g, 11.2 mmol) in dry DMF (18 mL) at RT under nitrogen. The mixture was stirred at RT for 3 days, then partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL) and water (50 mL). The aqueous layer was further extracted with EtOAc (2×50 mL). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 10% to 25% EtOAc in n-hexane) to give the title compound (3.15 g, colourless foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (d, J=6.06 Hz, 3H) 1.54 (s, 9H) 3.28 (s, 3H) 3.40 (dd, J=9.09, 2.02 Hz, 1H) 4.31 (d, J=10.11 Hz, 1H) 4.36-4.45 (m, 2H) 7.10-7.24 (m, 3H) 7.33-7.40 (m, 1H) 10.53 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:25]=1[CH3:35])(=[O:12])=[O:11].[NH:36]1[CH2:40][CH2:39][C@@H:38]([OH:41])[CH2:37]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1]/[C:2](/[CH:7]=[CH2:6])=[C:3](/[C:4]([Cl:8])=[CH2:5])\[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([N:36]2[CH2:40][CH2:39][C@@H:38]([OH:41])[CH2:37]2)=[O:34])[C:25]=1[CH3:35])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Reactant: O[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C=C/C(Cl)=C(/CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(CCC(=O)N3CC[C@@H](O)C3)c1C)C(=O)N2)C(=C)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (267 mg), (R)-pyrrolidin-3-ol (2 eq.), HATU (1.2 eq.) and TEA (0.2 mL) in DMF (2 mL) was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with water (2×), sodium carbonate (2×), dried and concentrated. The residue was purified on a silica gel column to give 16 mg of the titled compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[CH3:20][O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.[I-].[Na+]>CN(C)C=O>[CH3:20][O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8](=[O:9])[C:7]1[CH:18]=[CH:19][C:4]([Cl:3])=[CH:5][CH:6]=1
Reactant: COC(=O)CCCCCCCBr
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
As described in example 1(a), 2.4 g (0.1 mol) of sodium hydride, 25.2 g (0.1 mol) of 4-chloro-N-(4-chlorophenyl)-benzamid, 200 ml dimethylformamide, 23.7 g (0.1 mol) of 8-bromocaprylic acid methyl ester and 3 g (0.02 mol) of sodium iodide are reacted. Reaction time: 5.5 hours; reaction temperature: 110° C. The crude product is used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Br:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH2:29])[CH2:27][OH:28])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Br:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][OH:28])=[N:25][C:21]=2[CH:20]=1
Reactant: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N[C@@H](CO)c2nc3cc(Br)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)benzoic acid, (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(OCC)C>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:11])=[CH:9][CH:8]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.2 G. of p-chlorobenzoic acid methyl ester and 6.25 g. of N-(2-aminoethyl)-morpholine are stirred together for 6 hours at 120° C. The mixture is then cooled to room temperature and 40 ml. of diethyl ether are added. Thereafter, the mixture is allowed to stand overnight in the refrigerator. The crystalline product is removed by filtration, washed with diethyl ether and recrystallized from isopropanol, and 2.6 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(O)C>[N:23]1([CH2:22][CH2:21][NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCCN1CCCCC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCN4CCCCC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
The experiment of Example 1 was repeated in every essential detail except for the following. The suspension was prepared using 2.0 g (6.98 mmol) of the 6-chloropurine riboside in 30 ml of absolute ethanol. 1-(2-Aminoethyl) piperidine (commercially available) was added in an amount of 1.07 g (0.7 ml, 8.3 mmol). Also added to this suspension was 1.5 ml (10.5 mmol) of triethylamine. The reaction mixture was refluxed for 72 hours. The resulting residue was chromatographed on a silica gel column eluting with an eluent of 20 parts methanol, 79 parts dichloromethane and one part ammonium hydroxide. The title product was produced in a yield of 1.1 g (42%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH3:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C.CC(N(C)C)=O>[CH2:13]([O:12][C:10]1[C:9]([O:15][CH3:16])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]=[CH:19][N:20]([CH3:22])[CH3:21])[CH:11]=1)[CH3:14]
Reactant: CCOc1cc(N)c(C(=O)OC)cc1OC
Reactant: COC(OC)N(C)C
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1OC
Temperature: 100 °C
Yield: 97.1 %

Procedure:
A mixture of 15.056 g (66.9 mmol) methyl 2-amino-4-ethoxy-5-methoxybenzoate and 14.1 ml (100 mmol) N,N-dimethylformamide dimethylacetal was heated to 100° C. under N2. At 4.5 hours added 4.7 ml (33.3 mmol) more DMF/DMA and removed heat at 5 hours. Stripped solvent, azeotroped with toluene, and dried in vacuo, giving 18.211 g of grey-brown solid: mass spectrum (electrospray m/e): M+H=281.3.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C([Li])CCC.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCCC1>[OH:6][C:2]([CH3:3])([CH3:1])[C:4]#[C:5][C:12]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#CC(C)(C)O
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CC1(O)CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 2-methyl-3-butyne-2-ol (25 g, 0.297 mol) in tetrahydrofuran (250 ml) is cooled to −78° C. under a nitrogen atmosphere and n-butyl lithium (1.6 molar solution in hexanes, 410 ml, 0.65 mol) is added slowly over 1.5-2.0 hours. The reaction mixture is stirred for 1 hour at −78° C. and a solution of cyclopentanone (39 ml, 0.44 mol) in tetrahydrofuran (39 ml) is added. The reaction mixture is stirred at −78° C. for one hour and allowed to come to ambient temperature and stirred for 2-3 hours. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The mixture is extracted with dichloromethane (3×250 ml), and the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 1-(3-hydroxy-3-methylbut-1-ynyl)-cyclopentanol (17 g) as colourless oil.
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C.Cl>C1CCCCC1>[Cl:14][C:15]1[CH:20]=[C:19]([CH:25]=[O:26])[C:18]([SH:21])=[CH:17][CH:16]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: O=Cc1cc(Cl)ccc1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
Tetramethylethylenediamine (TMEDA) (10.44 mL, 8.035 g, 69.15 mmol) was added via syringe to n-BuLi (43.22 mL of 1.6 M in hexanes, 69.15 mmol) and the solution was chilled to 0° C. A solution of 4-chlorothiophenol (5.00 g, 34.57 mmol) in cyclohexane (25 mL) was added with stirring over 1 hour. The resulting tan slurry was stirred overnight at room temperature, chilled to 0° C., and DMF (2.94 mL, 2.78 g, 38.03 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 30 hours and became a powdery suspension. A mixture of 2 N HCl and ice was added to the reaction mixture until the pH became acidic (pH=1). During this addition, the mixture warmed and became first red and then pale yellow. This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a clear red-brown oil. This oil was triturated with hexanes yielding a red-brown semisolid. This semisolid was purified by plug flash chromatography over silica gel, eluting with 1:1, hexanes:dichloromethane to afford 5-chloro-thiosalicylaldehyde (0.858 g, 14%) as an intensely yellow solid suitable for use without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:21])[CH3:20])[CH2:14]2)=[O:10])=[C:7]([O:24][CH2:25][CH3:26])[CH:6]=1)(=[O:3])[CH3:2].[Cl:27]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([NH:4][C:5]1[C:23]([Cl:27])=[CH:22][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:21])[CH3:20])[CH2:14]2)=[O:10])=[C:7]([O:24][CH2:25][CH3:26])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)NCC1CN(C(C)=O)CCO1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)NCC1CN(C(C)=O)CCO1
Yield: 67.4 %

Procedure:
A solution of 19 (1.78 g, 4.9 mmol) and N-chlorosuccinimide (0.687 g, 5.1 mmol, 1.05 equiv) in DMF (30 mL) was stirred for 1 h at 70° C. The reaction mixture was then concentrated under reduced pressure to dryness. The residue was triturated with H2O and the resulting solids were removed by filtration and recrystallized from CH3OH to yield 20 (1.314 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H-].[Na+].[CH:13]1([S:19](Cl)(=[O:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C=O.C(O)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[S:19]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: CNCCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(CCc1ccncc1)S(=O)(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
N-Methyl-2-(4-pyridyl)ethylamine (5 g) was added dropwise over 15 minutes to a stirred suspension of sodium hydride (1.77 g, 50% dispersion in oil) in dry N,N-dimethylformamide (80 ml) (DMF) containing absolute ethanol (2 drops) under dry nitrogen at room temperature. Upon gentle warming to 50° for 1 hour the coloured anion was generated. After cooling to 0°, cyclohexanesulphonyl chloride (6.71 g) was added dropwise over 45 minutes then the stirred mixture allowed to attain room temperature over 18 hours. The yellow solution was then added to ice-water (200 ml), filtered, extracted with chloroform (25 ml×4), the organic phase dried (MgSO4) and concentrated in vacuo. Residual DMF was distilled from the product at 0.7 mm.Hg and the remaining viscous oil column-chromatographed upon silica (150 g) by elution with chloroform. Evaporation of the primary fractions (200 ml×3) afforded crystalline N-methyl-N-(2-[4-pyridyl]ethyl)cyclohexanesulphonamide (8.67 g), m.p. 94°- 6°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]3[C:17]([C:18]=2[CH:19]=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][CH2:5]1.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28]>>[CH:19]([C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]=1[N:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][O:1][P:27](=[O:28])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH2:9][CH2:8]1)=[O:20]
Reactant: O=Cc1c(N2CCN(CCO)CC2)n(-c2ccccc2)c2ccccc12
Reactant: CCOP(=O)(Cl)OCC
Product: CCOP(=O)(OCC)OCCN1CCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 71 %

Procedure:
2-[4-(2-Hydroxyethyl)piperazin-1-yl]-1-phenyl-1H-indole-3-carboxaldehyde is reacted with diethyl chlorophosphate as described in Step 1 of Example 31 to afford phosphoric acid diethyl ester 2-[4-(3-formyl-1-phenyl-1H-indol-2-yl)piperazin-1-yl]ethyl ester (71% yield) as a yellow solid. ESI/MS 486 (M+H); RT 2.94 min; NMR 10.15 (1H, s); 8.13 (1H, d, J=9 Hz); 7.68 (5H, m); 7.20 (2H, m); 6.91 (1H, d, J=6 Hz), 4.04 (6H, m); 3.28 (6H, m); 2.49 (4H, br s); 1.23 (6H, t).