Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8]1.N1C(C)=CC=CC=1C>ClCCl>[CH3:1][S:2]([O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 25 °C

Procedure:
Methansulfonyl chloride (8.2 g; 72.0 mmol) is slowly added to an ice cold solution of commercially available tert-butyl [(1S,3R)-3-hydroxycyclopentyl]carbamate (12.1 g; 60.0 mmol) and 2,6-lutidine (9.6 g; 90.0 mmol) in dry dichloromethane (300 mL). The stirred reaction mixture is allowed to warm to ambient temperature over night. The reaction mixture is extracted with water, ice cold 1N HCl, half saturated brine, and dried over MgSO4. After filtration through a pad of neural alumina (act. 2-3) the solvent is removed under reduced pressure to yield the crude title compound as yellow oil that is processed without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([OH:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanone (Step D, 13 g, 50 mmol) in methanol (100 mL) at 0° C. was added sodium borohydride (3.8 g, 100 mmol). After stirring at 0° C. for 30 min, the reaction was quenched by addition of 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the crude product, which was purified by flash column chromatography on silica gel eluted with 10% ethyl acetate in hexane to afford the pure faster eluting isomer and a mixture containing both the faster eluting isomer and the slower eluting isomer. Faster eluting isomer: 1H NMR (500 MHz, CD3OD): δ 7.25-7.00 (m, 9H), 4.00 (m, 1H), 3.15 (m, 1H), 2.97 (m, 1H), 2.85 (m, 1H), 1.10 (d, 3H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].CN(C)C=O.Br[CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1>O1CCCC1>[S:16]1[CH:17]=[CH:18][C:14]([CH2:13][O:3][CH2:2][CH2:1][OH:4])=[CH:15]1
Reactant: BrCc1ccsc1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCCOCc1ccsc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.3 %

Procedure:
621 mg of ethylene glycol was dissolved in 1 ml of tetrahydrofuran, and 88 mg of 60% oily sodium hydride and 0.5 ml of dimethylformamide were added. After the mixture was stirred at room temperature for 5 minutes, a tetrahydrofuran solution(1 ml) of 200 mg of 3-bromomethylthiophene was added. The mixture was stirred at 60 ° C. for 2 hours, and then the solvent was evaporated. The residue was worked up in a customary manner to give 181 mg of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:19]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18][C:26]3[CH:27]=[CH:28][C:23]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=3)=[O:17])[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(O)cc1
Reactant: CCCCCC1CCc2cc(C(=O)O)ccc2C1
Solvent: c1ccncc1
Product: CCCCCC1CCc2cc(C(=O)Oc3ccc(CCCC)cc3)ccc2C1
Yield: 99 %

Procedure:
Analogously to Example 1, 2.0 g of 2-pentyl-1,2,3,4-tetrahydronaphthalene-6-carboxylic acid are converted into the acid chloride and this is reacted with 1.202 g of p-butylphenol in 5 ml of absolute pyridine. There are obtained 3.0 g of crude p-butylphenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthoate for purification, is chromatographed on 95 g of silica gel. Elution with hexane/toluene (1:1) yields 2.8 g of substance which is recrystallized from ether/hexane up to constant melting point and clearing point and dried up to constant weight in a high vacuum (0.01 mbar). There are obtained colorless crystals of p-butylphenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthoate; m.p. 48.1° C., cl.p. 80.7° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:11]([CH2:13][CH3:14])=[O:12])[CH3:10]>>[C:2]1([CH:1]([OH:8])[CH:9]([CH3:10])[C:11](=[O:12])[CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)CC
Reactant: O=Cc1ccccc1
Product: CCC(=O)C(C)C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0 h
Yield: 72 %

Procedure:
50 mmol (5.1 ml) of benzaldehyde are added at -78° C. to the manganous enolate of diethyl ketone, prepared by the procedure described above. After stirring for 10 seconds at -78° C., the reaction medium is hydroIyzed by the dropwise addition of a saturated solution of (NH4)2SO4. After decantation, filtration on hyflo-supercel and evaporation of the solvents under vacuum, 5-phenyl-5-hydroxy-4-methylpentan-3-one is isolated by low pressure liquid chromatography on 15 μm silica gel using cyclohexane/ethyl acetate (90/10) as the eluent. Yield=72%. Erythro/threo=61/39.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29][C@@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCNC[C@H]1O
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)[C@@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4S*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f11) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20]([O:22]CC)=O)=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20]([NH2:25])=[O:22])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1nn(CCO)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Reactant: N
Product: CCc1c(Sc2cc(Cl)cc(Cl)c2)c(C(N)=O)nn1CCO

Procedure:
A mixture of Example 46 (407 mg, 1.05 mmol) and 0.880 ammonia solution was heated at 90° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. The precipitate was filtered off and washed with water (5 ml) to afford the title compound (273 mg) as a white solid, m.p. 214-216° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
5.9 g (20.0 mmol) of ethyl 5-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate were dissolved in 140 ml of ethanol, 2.98 g Pd/C (10%) were added and the mixture was hydrogenated in an autoclave at 60° C. at a hydrogen pressure of 50 bar overnight. The reaction mixture was filtered through silica gel. The resulting solution was concentrated under reduced pressure. Water was added to the residue and the solution was adjusted to pH 8 using aqueous 1 N sodium hydroxide solution. The mixture was then extracted with dichloromethane. The organic phase was dried over sodium sulphate and concentrated. Yield: 4.2 g (67% of theory)
Reaction SMILES: C(OC([N:8]1[CH2:20][CH:19]([CH3:21])[N:18]2[CH:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:25])[CH2:23][CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=O)(C)(C)C.[CH:26]1([CH2:29]Br)[CH2:28][CH2:27]1>>[CH:26]1([CH2:29][O:25][CH:22]([C:15]2[N:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C@H:10]2[N:18]3[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]2)[CH2:23][CH3:24])[CH2:28][CH2:27]1
Reactant: BrCC1CC1
Reactant: CCC(O)c1ccc2c(n1)N1C(C)CN(C(=O)OC(C)(C)C)CC1C2
Product: CCC(OCC1CC1)c1ccc2c(n1)N1[C@@H](CNC[C@H]1C)C2

Procedure:
(4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene di-trifluoroacetate (32 mg) was made from 6-(1-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (52 mg), using cyclopropylmethyl bromide (29 μl) in place of methyl iodide, according to the procedures described in Example 63 to afford the product as a colorless oil. HPLC [Xterra; 50/80; 255 nm] 100%, 1.44 min; MS (ES) 302.1 (MH+).
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.C(Cl)(=O)C.[CH3:12][O:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:7][N:5]([CH2:4][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([O:18][C:17]3[CH:28]=[CH:29][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[CH:20]=2)[NH:24][CH:23]=1)[CH3:6]
Reactant: CN(C)CN(C)C
Reactant: COc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2ccc3[nH]cc(CN(C)C)c3c2)cc1
Reaction time: 0.33 h

Procedure:
N,N,N',N'-Tetramethyldiaminomethane (0.29 g, 0.39 mL, 2.82 mmol) was dissolved in CH2Cl2 (dry; 8.5 mL) and the stirred solution cooled in an ice-bath. Acetyl chloride (0.23 g, 0.21 mL, 2.95 mmol) was added dropwise (syringe) over 10 min, to give a white suspension. After stirring for a further 20 min. with cooling maintained, a solution of 5-(4-methoxyphenoxy)indole (0.5 g, 2.09 mmol) in CH2Cl2 (7.2 mL) was added dropwise, over 20 min. The cooling was removed and the resulting clear solution was stirred for 1 hr at room temperature. The solution was then diluted with CH2Cl2, washed with 10% aq. NaOH (2×) followed by saturated aqueous NACl and dried (MgSO4). Evaporation in vacuo gave 3-(N,N-dimethylaminomethyl)-5-(4-methoxyphenoxy)indole as a gum. This material was dissolved in DMF (dry; 7 mL) and potassium cyanide (0.52 g, 8.0 mmol) was added, followed by methyl iodide (1.19 g, 0.52 mL, 8.35 mmol). The mixture became cloudy and eventually opaque. After stirring at room temperature for 36 hr, water was added and the mixture was extracted with Et2O (2×). The combined organic layers were washed with H2O (2×) and then with saturated aqueous NaCl, dried (MgSO4) and evaporated to give an almost colourless gum. This was triturated with Et2O to give: 3-cyanomethyl-5-(4-methoxyphenoxy)indole as a virtually colourless solid, 0.334 g (57%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH:38]([S:41](Cl)(=[O:43])=[O:42])([CH3:40])[CH3:39]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][S:41]([CH:38]([CH3:40])[CH3:39])(=[O:43])=[O:42])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: CC(C)S(=O)(=O)Cl
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NS(=O)(=O)C(C)C)cc1
Temperature: 65 °C

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 13, Step C) and isopropylsulfonyl chloride according to the procedure of Example 14, except that the mixture was heated overnight at 65° C. Flash chromatography of the crude product on silica gel gave the title compound as a glass; satisfactory purity by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 659 (M+Na)+, 675 (M+K)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCC(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
9-Bromo-nonanoic acid (3.82 g, 17 mmol) was dissolved in DMF (30 mL) and sodium azide (1.11 g, 17 mmol) was added. The solution was heated to 80° C. and stirred overnight. The reaction was poured onto ice and extracted with DCM (3×200 mL). The combined extracts were washed with water (3×200 mL), brine (200 mL), and dried over MgSO4. The solvent was removed in vacuo to give a clear oil 2.83 g (84% yield);
Reaction SMILES: [N:1]1([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:24][CH2:23]4)=[N:19][C:18]=3[C:34]([F:37])([F:36])[F:35])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.ClC1[O:49][C:50]2[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=2[N:52]=1>CN(C=O)C>[O:49]1[C:50]2[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=2[N:52]=[C:5]1[N:4]1[CH2:3][CH2:2][N:1]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:23][CH2:24][CH:25]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:26][CH2:27]4)=[N:19][C:18]=3[C:34]([F:36])([F:35])[F:37])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: Clc1nc2ccccc2o1
Reactant: O=C(Nc1ccc(N2CCCNCC2)nc1)c1oc(N2CCC(c3ccccc3)CC2)nc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2CCN(c3nc4ccccc4o3)CC2)nc1)c1oc(N2CCC(c3ccccc3)CC2)nc1C(F)(F)F
Yield: 42 %

Procedure:
Compound C-18 was prepared by the general procedure for compound 84. Compound C-18 (150 mg, 0.30 mmol), Hunigs base (78 mg, 0.10 mL, 0.60 mmol), and 2-chlorobenzoxazole (92 mg, 0.60 mmol) in dry DMF (3 mL) was heated at 100° C. for 24 h. The reaction mixture was cooled and concentrated. Water (15 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined extracts were dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant:10-30% EtOAc—CH2Cl2) gave the product 236 (77 mg, 42% yield) as a beige foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(F)cccc1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)cccc1F
Yield: 77.9 %

Procedure:
20 g (153.74 mmol) of 2,6-difluorophenol is dissolved in 200 ml of acetone and mixed under nitrogen with 42.5 g (307.48 mmol) of potassium carbonate. After 19.1 ml of methyl iodide (2 equivalents) is added, it is refluxed for three and one-half hours. After cooling, the reaction mixture is filtered, the filter residue is washed with acetone, and the filtrate is spun in until a dry state is reached. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 17.27 g (77.9%) of the desired product is obtained. It should be noted that the product is slightly volatile. The bath temperature should not exceed 30° C., and the vacuum of the rotary evaporator is to be adapted.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:44][CH2:45][C:46]1[N:47]=[CH:48][N:49]([C:51]2[CH:56]=[CH:55][C:54]([N:57]3[CH2:62][CH2:61][CH2:60][CH2:59][C:58]3=[O:63])=[CH:53][CH:52]=2)[CH:50]=1>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:44][CH2:45][C:46]2[N:47]=[CH:48][N:49]([C:51]3[CH:52]=[CH:53][C:54]([N:57]4[CH2:62][CH2:61][CH2:60][CH2:59][C:58]4=[O:63])=[CH:55][CH:56]=3)[CH:50]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cn(-c2ccc(N3CCCCC3=O)cc2)cn1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1cn(-c2ccc(N3CCCCC3=O)cc2)cn1)c1ccc(Cl)s1
Reaction time: 0.08 h
Yield: 60.3 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid 1-5 (43 mg, 0.26 mmol) and triethylamine (0.200 mL, 1.43 mmol) in DMF (2 mL), BOP (130 mg, 0.29 mmol) was added. After 5 min of stirring, the solution was added to a solid sample of 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)piperidin-2-one (54 mg, 0.18 mmol) in a flask. After being stirred at room temperature for 2 h, the mixture was purified by HPLC to give the titled compound (45 mg). MS 415.1 and 417.1 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].CC(C)([O-])C.[K+].[CH:18]([Si:21]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:22][CH2:23][CH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([CH3:20])[CH3:19].O>O1CCCC1>[CH:34]([Si:21]([CH:18]([CH3:20])[CH3:19])([CH:31]([CH3:33])[CH3:32])[O:22][CH2:23][CH:24]1[CH2:29][CH2:28][C:27](=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:26][CH2:25]1)([CH3:35])[CH3:36]
Reactant: CC(C)[Si](OCC1CCC(=O)CC1)(C(C)C)C(C)C
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=C1CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of 6.37 g (35 mmol) of tri methyl phosphonoacetate in 200 mL of tetrahydrofuran (THF) was added 4.28 g (35 mmol) of potassium tert-butoxide. The reaction mixture was stirred at room temperature for 10 minutes. To the resultant slurry was added a solution of 9.3 g (32.7 mmol) of ketone from step C in 20 mL of THF. The mixture was stirred at room temperature under nitrogen overnight, then poured into water and extracted with three 100 mL portions of ether. The combined organic phases were washed sequentially with water, aqueous saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated to give 10.8 g (97%) of the title compound as a clear oil which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 5.63 (s, 1H), 3.78 (m, 1H), 3.69 (s, 1H), 3.53 (m, 2H), 2.32 (m, 1H), 2.21(m, 1H), 1.97 (m, 2H), 1.76 (m, 1H), 1.10–1.03 (m 23H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][CH2:15][OH:16].N1C=CN=C1.[Si:22](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][CH2:15][O:16][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1cc(CCCO)c2cc(Br)ccc2[nH]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCc1cc(=O)[nH]c2ccc(Br)cc12)(c1ccccc1)c1ccccc1

Procedure:
6-Bromo-4-(3-hydroxypropyl)quinolin-2(1H)-one (4.7 g, 16.67 mmoles), imidazole (2.84 g, 41.7 mmoles) and tert-butyldiphenylsilyl chloride (5.14 mL, 20 mmoles) were stirred in dimethylformamide (60 mL) overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:32][CH2:31]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:36]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)(=[O:38])=[O:37])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(COCCNS(=O)(=O)N2CCN(C)CC2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Yield: 43 %

Procedure:
2-(2-Aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g) was dissolved in a mixture of chloroform (dried over alumina) (20 ml) and triethylamine (2 ml) and the mixture stirred at room temperature. 4-Methyl-1-piperazinylsulphonyl chloride (0.25 g) was added in one portion and the mixture stirred at room temperature for 17 hours. After evaporation to dryness, the resultant oil was partitioned between 5% aqueous sodium carbonate and methylene chloride. The organic layer was dried (MgSO4), filtered and evaporated to give 0.3 g of a colourless oil, which was dissolved in diisopropyl ether (15 ml) and kept in a refrigerator for 14 days. The resultant crystals were collected by filtration to afford the title compound (0.1 g), m.p. 137°-139° C. Found: C, 52.58; H, 6.18; N, 9.81%. C25H35ClN4O7S requires C, 53.03; H, 6.14; N, 9.20%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=[CH:11]2.C(OCC)C>C1COCC1>[OH:19][CH2:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:7])[CH:17]=[CH:16]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the slurry of lithium aluminum hydride (2 equi.) in THF (3 mL/mmole), a solution of 6-hydroxy-naphthalene-2-carboxylic acid (15) (1 equi.) in THF (3 ml/mmole) was added at ice temperature over a period of 20 min. The reaction mixture was stirred at room temperature for 24 h, cooled to ice temperature, added diethyl ether (20 mL/mmole), quenched slowly with water (1 mL/g LAH), 15% aqueous sodium hydroxide (1 mL/g LAH), and water (3 mL/g LAH) succesively. MgSO4 (5 g/100 mL reaction solution) was added to the reaction mixture, stirred for 30 min, filtered through celite, and concentrated in vacuo to give 6-hydroxy methyl-naphthalen-2-ol (16), a white solid (79%).