Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCCCCC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromobenzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromobenzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (1.36 g, 2.3 mmol) dissolved in THF:methanol (50:50 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 660 mg (51%); off white solid; mp 199° C.; MS: 562 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[O:33]1[CH2:38][CH2:37][CH:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:39]([CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=C(Cl)C1CCOCC1
Product: Cc1c(N2CCN(C(=O)C3CCOCC3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure R using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone. 1H NMR (DMSO-d6) δ ppm 1.55-1.67 (m, 4H), 2.10 (br s, 3H), 2.91-2.96 (m, 1H), 3.05 (t, J=4.4 Hz, 4H), 3.24 (br s, 2H), 3.33-3.43 (m, 3H), 3.64 (br s, 2H), 3.69 (t, J=4.0 Hz, 7H), 3.85-3.88 (m, 2H), 6.51 (d, J=2.0 Hz, 1H), 7.13-7.19 (m, 1H), 7.25-7.29 (m, 1H,), 7.52 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=553.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[C:23](C)[CH:22]=1.[C:31]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:31][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[O:26])=[CH:28][CH:29]=2)[C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccc1C(N)=O
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Chloro-N-((R)-2-oxo-azepan-3-yl)-benzenesulfonamide (0.18 g, 0.60 mmol), 4-bromo-methyl-benzamide (0.19 g, 0.90 mmol), K2CO3 (0.83 g, 6 mmol), KI (0.02 g, 0,12 mmol) were added to dry DMF (15 ml) and the resultant reaction mixture was shaken overnight at 60° C. under an argon atmosphere. The solvent was removed under reduced pressure and the residue dissolved in acetonitrile and purified using preparative RP(C18) chromatography: lyophilisate 52 mg; MS: m/e=436.4 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccccc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and benzoic acid to yield (3aR,4S,7aR)-methyl 4-(benzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=6.370 min; LC-MS Method II
Reaction SMILES: CO.[CH:3]([C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21](C)C)=[O:19])[CH2:12][CH2:13]2)[CH2:7][C@H:6]1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)=O.[C:31](=O)([O-])[O-].[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>C(OCC)(=O)C>[C:3]([C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:13]2)[CH2:7][C@H:6]1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)#[CH:31]
Reactant: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@@H]2OC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#C[C@@H]1[C@H]2CC[C@H](CCCC(=O)OC)CO[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 28.4 %

Procedure:
To a methanol solution (2.3 mL) of the compound (180 mg) produced in Example 13, potassium carbonate (94 mg) and a Bestmann reagent (dimethyl-1-diazo-2-oxopropyl phosphonate) (105 mg) were added, followed by stirring at room temperature for 6 hours. Further, potassium carbonate (47 mg) and the Bestmann reagent (53 mg) were added, followed by stirring at room temperature overnight. The reaction mixture was cooled to 0° C.; diluted with ethyl acetate; and then separated by adding water. The organic layer was washed with water and a saturated saline; dried with magnesium sulfate; then filtered; and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→65:35) to obtain a titled compound (47 mg) having the following physical property values.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=2)[N:11]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1.[ClH:82]>C(Cl)Cl.CO>[ClH:82].[CH2:21]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]([NH:58][C@@H:59]([CH2:73][C:74]3[CH:75]=[C:76]([F:81])[CH:77]=[C:78]([F:80])[CH:79]=3)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=3)=[O:20])[CH:13]=2)[NH:8][CH2:9][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CCCCN1CCNc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h
Yield: 21.4 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-butyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (120 mg), HBTU (204 g), and diisopropylethylamine (100 μL) was stirred in methylene chloride (2.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (146 mg) and diisopropylethylamine (100 μL) in methylene chloride (2.0 mL) was added and the mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (10 mL), saturated sodium bicarbonate (10 mL), and brine. The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided a clear solid. The solid was dissolved in methanol (1 mL), and treated with hydrochloric acid (0.5 mL, 1.0 M diethyl ether, 0.5 mmol). The resulting precipitate was collected by filtration to provide 45 mg of the title compound: ESI MS m/z 551 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[S:37])=[C:31]([CH3:39])[CH:30]=1>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:2]([NH:1][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[N:15]=[CH:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=4)[N:12]=3)[CH:6]=2)=[O:3])=[S:37])=[C:31]([CH3:39])[CH:30]=1
Reactant: COc1ccc(NC(N)=S)c(C)c1
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: COc1ccc(NC(=S)NC(=O)NCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(4-methoxy-2-methylphenyl)thiourea and isolated as an off-white solid (0.212 g, 50%).
Reaction SMILES: ClC([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)=O.[CH2:32]([NH2:35])[CH2:33][NH2:34].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:21][CH:19]([CH2:18][CH2:17][CH2:16][C@H:15]([C@@H:14]1[C@:23]2([CH3:31])[C@H:11]([C@H:10]3[C@H:26]([CH2:25][CH2:24]2)[C@:27]2([CH3:30])[C:7]([CH2:6][C@H:5]([CH2:29][CH2:28]2)[OH:4])=[CH:8][CH2:9]3)[CH2:12][CH2:13]1)[CH3:22])[CH3:20].[CH2:32]([NH2:35])[CH2:33][NH2:34]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: NCCN
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
Solid cholesterol chloroformate (10 mmol) was dissolved in 100 mL of dichloromethane (DCM). In a separate flask 0.5 mol ethylenediamine was diluted with 200 mL of DCM and 20 mmol diisopropylethylamine. While stirring, the cholesterol chloroformate solution was drop-wise added to the ethylenediamine solution over a 30 minute period at room temperature (R.T.). Following an overnight R.T. stir, organic solvent was roto-evaporated away using medium vacuum until a minimal sample volume remained. Approximately 400 mL of acetonitrile was added to precipitate the crude product. The solid was then collected by filtration onto a Whatman #5 filter apparatus, rinsed several times with acetonitrile and then air-dried. The crude solid was dissolved in a minimal volume of chloroform and chromatographically purified using a silica column. The purified product presented a single TLC spot (4:1 chloroform/methanol), and a single peak (parent ion M+H=474) was identified by positive mode electrospray.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1.N1C=CC=CC=1>ClC(Cl)C>[C:35]([O:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[CH2:16][CH2:17]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C(Oc1ccc2c(c1)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2)c1cccnc1
Yield: 95 %

Procedure:
Heat at reflux for 8 hours, under a nitrogen atmosphere, a solution of 1.37 mmol of 6-hydroxy -2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin, 4.5 mmol of nicotinoyl chloride and 3.42 mmol of anhydrous pyridine in 25 cm3 of dichloroethane. After cooling, the reaction mixture is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate and then concentrated under reduced pressure. The crude product is then purified by chromatography on a silica column (eluant:petroleum ether/ethyl acetate, 70:30). 6-Nicotinoyloxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin is thereby obtained in a yield of 95%.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8]=2[CH:7]=[C:6]([O:19][CH2:20][CH:21]2[CH2:23][O:22]2)[CH:5]=1>C(OCC)(=O)C>[Cl:1][CH2:23][CH:21]([OH:22])[CH2:20][O:19][C:6]1[CH:5]=[C:4]([O:3][CH3:2])[C:17]2[C:16](=[O:18])[C:15]3[C:10]([O:9][C:8]=2[CH:7]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: Cl
Reactant: COc1cc(OCC2CO2)cc2oc3ccccc3c(=O)c12
Solvent: CCOC(C)=O
Product: COc1cc(OCC(O)CCl)cc2oc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Aqueous ethyl acetate 1M-HCl (3 mL) was added to 1-methoxy-3-(oxiran-2-ylmethoxy)-9H-xanthen-9-one (25 mg, 0.08 mmol) prepared in Step 4 of Example 9, followed by stirring at room temperature for 30 minutes, and the reaction solvent was removed under reduced pressure. Ether was added to the residue, followed by sonication, and the solvent was removed to give the title compound (20 mg, 71.3%) as a reddish brown solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[CH2:9][C@@H:10]1[O:15][C:14](=[O:16])[N:13]([CH3:17])[C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH2:11]1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[NH4+:36]>>[CH3:2][O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[CH2:9][C@@H:10]1[O:15][C:14](=[O:16])[N:13]([CH3:17])[C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[N:25][NH2:36])=[CH:20][CH:19]=2)[CH2:11]1
Reactant: COC(=O)CCNC(=O)C[C@H]1C[C@@H](c2ccc(C#N)cc2)N(C)C(=O)O1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: COC(=O)CCNC(=O)C[C@H]1C[C@@H](c2ccc(C=NN)cc2)N(C)C(=O)O1
Temperature: 0 °C
Reaction time: 12 h
Yield: 64.5 %

Procedure:
Dry HCl gas was bubled through a solution of 3-[[4(S)-(4-cyanophenyl)tetrahydro-3-methyl-2-oxo-2H-1,3-oxazin-6(R)-yl]acetyl]aminopropionic acid methyl ester (125 mg 0.35 mmol) in dry CHCl3 containing anhydrous methanol (23 mg, 0.70 mmol), cooled with salt ice-water bath, at 0° C. for 5 hrs. The resulting solution was then kept at 0° C. for 6 hrs and at 15° C. for 12 hrs. The flammable portion was removed and the residue was dissolved in anhydrous methanol (3 ml) followed by addition of ammonium bicarbonate (84 mg, 0.88 mmol). After stirring at rt for 4 hrs, the mixture was concentrated and purified by flush chromatography over silica gel using a mixture of methylene chloride and methanol as the eluent to give a white amorphous solid (85 mg, 64% yield).1H NMR (300 MHz, CD3OD) δ1.90 (m, 1H), 1.22(m, 2H), 2.50(t, 2H), 2.60(dd, 1H), 2.66(s, 3H), 3.40(m, 2H), 3.60(s, 3H), 4.80(m, 2H), 7.54(d, 2H), 7.84(d, 2H); MS (ESI) Calc. for (M+1)+: 377. Found: 377.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[CH3:10][C:9]([CH3:12])([OH:11])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)COc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
To a stirred solution of 24.2 g (0.16 mole) of phenoxy-2-propanone (Eastman) in 150 mL of dry ethyl ether was added 56 ml (0.17 mole) of methylmagnesium bromide (3.0M solution in ethyl ether, Aldrich) and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 4 hr. The reaction mixture was treated with 100 ml of saturated ammonium chloride solution and vigorously stirred for 1 hr. The layers were separated and the organic layer was washed twice with 200 ml portions of water, dried (magnesium sulfate) and the solvent evaporated under reduced pressure to yield 24.3 g (91%) of a vicous oil. A 2.3 g sample of the oil was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500 A, PrePAK 500/silica, ethyl acetate-hexanes, 1:20, flow rate 150 ml/min). The desired fractions were combined and the solvents evaporated under reduced pressure to yield 2.1 g (91% recovery) of the title compound as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH:7]([CH3:10])[C:6]1=[O:11])=[O:4].C=O.[C:22](=O)([O-])[O-:23].[K+].[K+]>O>[CH3:1][O:2][C:3]([C:5]1([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:7]([CH2:22][OH:23])([CH3:10])[C:6]1=[O:11])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)C1=O
Agent: C=O
Agent: [K+]
Solvent: O
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 190.1 %

Procedure:
To 1.12 g of 1-(4-chlorobenzyl)-3-methyl-2-oxo-cyclopentancarboxylic acid methyl ester (Compound 1-1), which is a known compound, 0.90 ml of 37% aqueous solution of formaldehyde and 276 mg of potassium carbonate were added, and the resulting mixture was vigorously stirred at room temperature for 4 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was then carried out. The organic layer thus extracted was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 1.180 g of Compound 2-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH2:27])=[S:25]>C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:27][N:26]=[C:24]([C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([F:20])[CH:22]=2)[S:25]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(=S)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Reaction time: 72 h
Yield: 89.8 %

Procedure:
To a solution of (4-oxo-4-phenylbutyl)-carbamic acid tert-butyl ester (2.2 g, 8.5 mmol) in ethanol/DCM (30 mL/10 mL) was added 3-fluorothiobenzoic acid hydrazide (Takasugi, J. J.; Buckwalter, B. L. European patent EP 1004241, 2004) (1.2 g, 7.1 mmol) at room temperature. After stirring for 3 days, the reaction mixture was concentrated and purified by flash column chromatography (20:1 Hexanes/EtOAc) to provide the product (2.65 g, 90%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:2]1.ClN1[C:32](=[O:33])[CH2:31][CH2:30]C1=O.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][O:12][C:10]([C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[N:1]3[CH2:30][CH2:31][CH2:32][O:33][C:2]=23)=[O:11])[CH2:15][CH2:16]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(OCC1CCN(Cc2ccccc2)CC1)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCC1CCN(Cc2ccccc2)CC1)c1c2n(c3ccccc13)CCCO2

Procedure:
(1-Benzyl-4-piperidyl)methyl indole-3-carboxylate was treated initially with N-chlorosuccinimide (1.5 equivalents) for 2 h, then with 3-bromo-1-propanol (2 equivalents) for 16 h, followed by anhydrous potassium carbonate in acetone, using the method described in Example 1b. The crude product was purified by chromatography on silica gel eluting with chloroform/ethanol (19:1) to afford the title compound (E15) as a beige solid following recrystallisation from chloroform/ether (47%) mp 158-160° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:14]#[C:15][NH2:16].C1CCN2[C:20](=[N:21]CCC2)[CH2:19]C1.BrCC#N>C(#N)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[S:13][C:19]([C:20]#[N:21])=[C:15]([NH2:16])[N:14]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: N#CN
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: C1CCC2=NCCCN2CC1
Agent: N#CCBr
Solvent: CC#N
Product: N#Cc1sc(Nc2ccc(S(N)(=O)=O)cc2)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 4-(aminosulfonyl)phenylisothiocyanate (1.12 g, 5.0 mmol) and cyanamide (0.23 g, 5.5 mmol) in acetonitrile (50 ml) was added DBU (0.83 g, 5.5 mmol), and the resulting mixture was stirred at room temperature for 60 minutes. To the reaction mixture was added bromo-acetonitrile (0.66 g, 5.5 mmol) followed by DBU (0.83 g, 5.5 mmol) 30 minutes afterward. The reaction mixture was stirred overnight at room temperature, the solvent was removed at the reduced pressure, and the residue was dissolved in EtOAc (200 ml). The EtOAc solution was washed with 0.1 N HCl (150 ml×3) and brine and dried with MgSO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc) to provide 0.73 g (48%) of 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:62]=[CH:61][CH:60]=[CH:59][C:53]=1[O:54][CH2:55][CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][CH:61]=[CH:62][C:52]=2[F:51])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCCCOc1ccccc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4ccccc4F)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 67.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (72 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (100 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-fluorophenoxy)-1-propanol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (78 mg, yield 63%).