Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[N:6]=[C:7](Cl)[C@H:8]1[CH2:12][O:11][C:10]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9]1)(=O)=O.N1C=CC=CC=1.[S-:25][C:26]#[N:27].[Na+].[Br:29][C:30]1[CH:31]=[C:32]([O:37][C:38]2[C:39]([CH3:45])=[N:40][N:41]([CH3:44])[C:42]=2[CH3:43])[C:33]([NH2:36])=[N:34][CH:35]=1>C(#N)C>[Br:29][C:30]1[CH:31]=[C:32]([O:37][C:38]2[C:39]([CH3:45])=[N:40][N:41]([CH3:44])[C:42]=2[CH3:43])[C:33]([NH:36][C:26]2[S:25][N:6]=[C:7]([C@H:8]3[CH2:12][O:11][C:10]4([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]4)[O:9]3)[N:27]=2)=[N:34][CH:35]=1
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Reactant: N#C[S-]
Reactant: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1N
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Temperature: 40 °C
Yield: 92.7 %

Procedure:
A flask was charged with (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (1.53 g. 5.15 mmol), pyridine (1.25 ml, 15.4 mmol), sodium thiocyanate (0.417 g, 5.15 mmol) and acetonitrile (15 mL). The solution was heated to 40° C. for 40 minutes. 5-Bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine (1.02 g, 3.43 mmol) was added and the reaction was heated to 70° C. overnight. The reaction was cooled to ambient temperature, partitioned between EtOAc and water, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (10% MeOH/EtOAc) to afford (S)-N-(5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (1.66 g, 3.18 mmol, 92.7% yield) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:15][CH2:16]O>>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:15][CH3:16])=[O:9])[CH2:4][CH2:3]1
Reactant: CCO
Reactant: NC1CCC(C(=O)O)CC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCC(N)CC1
Temperature: 80 °C

Procedure:
To an ice-cold solution of 4-aminocyclohexanecarboxylic acid (5.0 g, 34.92 mmol) in EtOH (20 mL) was added thionyl chloride (7.60 mL, 104.76 mmol). The mixture was heated at 80° C. for 3 h. The solvent was evaporated in vacuo to obtain i (7.23 g). 1H NMR (400 MHz, DMSO-d6): δ 4.19 (q, J=7.20 Hz, 2H), 3.71 (m, 1H), 2.71 (m, 1H), 2.06 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.55 (m, 2H), and 1.25 (t, J=7.20 Hz, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[CH2:12][C@H:11]([OH:21])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)C.Cl>C1(C)C=CC=CC=1>[CH3:14][C@@:13]12[CH2:15][CH2:16][C@H:17]3[C@@H:8]([CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([OH:2])[CH:20]=[CH:19][C:18]=43)[C@@H:9]1[CH2:10][C@@H:11]([OH:21])[CH2:12]2
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C[C@H](O)C[C@@H]12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Yield: 69.2 %

Procedure:
0.55 g of 3-methoxy-13α-estra-1,3,5(10)-trien-16α-ol is dissolved hot under a cover gas in 10 ml of toluene. A mixture of 2.3 ml of diisobutylaluminum hydride and 5.4 ml of toluene is added in drops to this solution and refluxed until the reaction is completed (about 4 hours). 2.1 ml of ethanol is added to the cooled batch, and 6 ml of semi-concentrated hydrochloric acid is carefully added while being cooled. After extraction with ethyl acetate, the organic phase is washed neutral and dried on magnesium sulfate. 362 mg of 13α-estra-1,3,5(10)-triene-3,16α-diol is obtained. The recrystallization from methanol yields colorless crystals; flash point 224 . . . 231° C.; [α]D=+61° (pyridine, c=1.13).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10](O)=O.[CH3:14][NH:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:23]>O1CCCC1>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]1[N:15]([CH3:14])[C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]=1
Reactant: CNc1c(N)cccc1N
Reactant: Cc1cc(C)c(CC(=O)O)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(Cc2nc3cccc(N)c3n2C)c(C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of mesityleneacetic acid (904 mg, 5.08 mmol) in tetrahydrofuran (20 mL) was added N,N′-carbonyldiimidazole (823 mg, 5.08 mmol) at room temperature. After the mixture was stirred for 1 hr at 50° C., N2-methylbenzene-1,2,3-triamine (700 mg, 5.08 mmol) in tetrahydrofuran (8 mL) was added to the mixture and the mixture was refluxed for further 18 hr. After the mixture was cooled, the solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography eluting with a 60-80% ethyl acetate/n-hexane gradient mixture to give the title compound (340 mg, 1.22 mmol, 24%) as a colorless solid. The resulting solid was recrystallized from n-hexane/tetrahydrofuran to give the title compound (254 mg, 0.85 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31]O)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:31][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: COc1ccc(CO)cc1OC
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1OC
Reaction time: 0.08 h

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (275 mg, 1 mmol), (3,4-dimethoxyphenyl)methanol (201 mg, 1.2 mmol), N,N,N,N-tetramethylazodicarboxamide (344 mg, 2 mmol) were dissolved in 2 mL anhydrous THF. Tributylphosphine (404 mg, 2 mmol) was added and the reaction mixture was placed in a microwave reactor for 5 minutes at 90° C. The reaction was filtered, concentrated and purified by HPLC (10-95% Acetonitrile/Water, 25 minutes) to afford the title compound. Yield: 25 mg, 6%. 1H NMR (DMSO, 400 MHz): δ2.119 (s, 3H), 2.385 (s, 3H), 3.724 (J=6.4 d, 6H), 3.946 (s, 2H), 4.435 (s, 2H), 5.178 (s, 2H), 6.885 (m, 3H), 7.776 (s, 1H), 8.166 (s, 1H). MS M+H calculated 426.1; found 426.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.1 g) and 4-chlorobenzenesulphonyl chloride (0.13 g).
Reaction SMILES: C=O.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:15][CH2:14]1.[C:30]([O-])(=O)C.[Na+]>C(O)(=O)C.O>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:30][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH2:15][CH2:14]2)=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1c2ccccc2C(=O)N1C1CCNCC1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1C1CCN(Cc2c[nH]c3ccccc23)CC1

Procedure:
Formaldehyde (0.84 cm3, 40% aq. w/v, 11.3 mmol) was added to a stirred and cooled mixture of indole (1.32 g, 11.3 mmol), 2-(piperid-4-yl)-1H-isoindol-1,3-(2H)-dione, hydrochloride (3.0 g, 11.3 mmol), and sodium acetate (0.93 g, 11.3 mmol) in glacial acetic acid (10 cm3). The suspension was stirred at room temperature for 5 hours, then poured into water and a gummy precipitate filtered off. The mother liquors were basified by addition of 0.880 ammonia to precipitate the title compound, which was collected and dried (2.52 g, 62.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)[Cl:23]>>[Cl:23][CH2:22][CH:24]([OH:26])[CH2:25][N:17]1[CH2:16][CH2:15][N:14]([CH:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Reactant: ClCC1CO1
Product: OC(CCl)CN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
4,4'-Dichlorobenzhydrylpiperazine ((6.0 g, 18.7 mmol) was reacted as above with epichlorohydrin to give the title compound as an amber oil, 3.67 g (49.8%). 100 MHz 1H NMR (CDCl3)δ:7.3 (s, 8H), 4.2 (s, 1H), 3.9 (m, 1H), 3.6 (d, 2H,J=10 Hz), 2.9 (m, 2H), 2.7-2.4 (m 10H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH2:13]([O:15][CH2:16][CH2:17]Br)[CH3:14]>C(O)C>[CH3:14][CH2:13][O:15][CH2:16][CH2:17][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCOCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOCCOc1ccc(C(=O)O)cc1
Yield: 29.6 %

Procedure:
Into a 1 l three-neck flask were introduced 400 ml of 90% ethanol, 25 g of potassium hydroxide, 40 g of p-hydroxybenzoic acid and 45 g of β-ethoxyethyl bromide, and the contents were heated under reflux for 10 hours. After removing ethanol by distillation, 100 ml of a 10% aqueous solution of potassium hydroxide was added and the contents were heated under reflux for additional two hours. After acidifying with hydrochloric acid, separated acid was collected and recrystallized from benzene and then ethanol to obtain 18 g of p-(β-ethoxy)ethoxybenzoic acid. The melting point of the resulting product was 130° C.-132° C. and the elemental analysis values thereof were as follows, which accorded with the calculated values very well.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.O=S(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:10]
Reactant: Cc1cc(F)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(F)ccc1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(4-Fluoro-2-methylphenyl)methanol (11.5 g, 82 mmol) was dissolved in CH2Cl2 (100 mL). The mixture was cooled to 0° C. before adding SOCl2 (10.7 g, 90 mmol), then stirred for 30 min at 0° C. and then at room temperature for 1.5 h. The solvent and excess of SOCl2 were removed by evaporation followed by the addition of CH2Cl2. The solvent and remaining traces of SOCl2 were evaporated once more. There was obtained 13.0 g (100%) of 1-(chloromethyl)-4-fluoro-2-methylbenzene as an oil. 1H NMR (300 MHz, CDCl3): 2.4 (s, 3H), 4.6 (s, 2H), 6.8-7.0 (m, 2H), 7.3 (m, 1H).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(S(C)(=O)=O)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (Example 149) (115 mg, 0.279 mmol) and NEt3 (43 μL, 0.307 mmol) in DMF (2 ml) was added methanesulfonyl chloride (24 μL, 0.307 mmol). Reation mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (75 mg, 55%).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=1.[C:22](O)(=O)C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:10]([CH2:13][CH2:14][N:15]([C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[CH2:22]2)=[CH:11][CH:12]=1
Reactant: CC(=O)O
Reactant: O=C(NCCc1ccc(Br)cc1)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Into acetic acid (42 ml) were added dropwise under ice cooling sulfuric acid (28 ml), subsequently N-(2-(4-bromophenyl)ethyl)trifluoroacetamide (7.8 g) and paraformamide (1.27 g) and the resulting mixture was stirred overnight under a nitrogen atmosphere. The reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate, water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (8.1 g) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[O:14][C:13]3[C:15]([C:18]([O:20]C)=[O:19])=[CH:16][S:17][C:12]=3[C:11](=[O:22])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCOCC1.O>[CH:3]1([C:9]2([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:14][C:13]3[C:15]([C:18]([OH:20])=[O:19])=[CH:16][S:17][C:12]=3[C:11](=[O:22])[CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1csc2c(=O)cc(C3CCCCC3)oc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1csc2c1OC(c1ccccc1)(C1CCCCC1)CC2=O
Temperature: 50 °C
Yield: 114.8 %

Procedure:
0.3 mL of 1N sodium hydroxide and 1.0 mL of water were added to a solution of 0.040 g of Compound 3D in 1.8 mL of MeOH and 0.9 mL of 1,4-dioxane at 20-25° C., while stirring. The mixture was heated at 50° C. for 3.5 hours. After cooling to 20-25° C., the mixture was diluted with water and acidified to pH 1 with 3N hydrochloric acid. The precipitated solid was collected by filtration and washed with water to afford 0.028 g (73.5%) of the title compound, melting at 269-275° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]3[C:17]([O:19][C:20](=O)[C:8]=23)=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([N:25]2[C:17](=[O:18])[C:9]3[CH:10]=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]4=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]=3[C:20]2=[O:19])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: O=C1OC(=O)c2c1cc1ccccc1c2-c1ccccc1
Product: O=C1c2cc3ccccc3c(-c3ccccc3)c2C(=O)N1C1CC1

Procedure:
1-Phenyl-2,3-naphthalenedicarboxylic anhydride (3.0 g) and cyclopropylamine (5 ml) were shaken for 5 minutes. The reaction mixture became very warm and excess cyclopropylamine was evaporated in vacuo. The solid remaining was then heated at 220° to 240° for 5 minutes in a nitrogen atmosphere. The solid formed was allowed to cool and was recrystallised from light petroleum (b.p. 40°-60°)/chloroform to give 2-cyclopropyl-1,3-dioxo-4-phenylbenz[f]isoindoline, (2.7 g, m.p. 198°).
Reaction SMILES: [CH:1]1([C:4]([CH:6]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]=2[S:29]([CH3:32])(=[O:31])=[O:30])=[O:15])C(OC(C)(C)C)=O)=[O:5])[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:5])[CH2:6][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]=2[S:29]([CH3:32])(=[O:31])=[O:30])=[O:15])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(C(=O)c1cccc(Sc2ccccc2)c1S(C)(=O)=O)C(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1c(Sc2ccccc2)cccc1C(=O)CC(=O)C1CC1
Yield: 92.4 %

Procedure:
A mixture of t-butyl 2-cyclopropylcarbonyl-3-(2-methylsulphonyl-3-phenylsulphenylphenyl)-3-oxopropionoate (8.5 g) and para-toluene sulphonic acid (0.25 g) in toluene was heated at reflux for six hours. Water and ethyl acetate were then added and the organic phase was dried over anhydrous sodium sulphate, filtered and evaporated. The residue was crystallised from ether to give 1-cyclopropyl-3-(2-methylsulphonyl-3-phenylsulphenylphenyl)propan-1,3-dione (6.2 g) as a beige powder,
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[NH:11])OCC)=[C:4]([C:12]2(Cl)[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH2:13]2)[C:3]=1[C:20]#[N:21].[ClH:22].Cl.N[CH:25]([CH2:30][NH2:31])[C:26]([O:28][CH3:29])=[O:27]>C(O)C>[Br:1][C:2]1[S:6][C:5]([C:7]2[NH:11][CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:30][N:31]=2)=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][C:17]=2[Cl:22])[C:3]=1[C:20]#[N:21]
Reactant: COC(=O)C(N)CN
Reactant: Cl
Reactant: CCOC(=N)c1sc(Br)c(C#N)c1C1(Cl)C=CC(Cl)=CC1
Solvent: CCO
Product: COC(=O)C1CN=C(c2sc(Br)c(C#N)c2-c2ccc(Cl)cc2Cl)N1
Temperature: 80 °C
Reaction time: 4 h
Yield: 35.6 %

Procedure:
To a solution of ethyl 5-bromo-4-cyano-3-(1,4-dichlorophenyl)thiophene-2-carboximidoate (0.548 g, 1.36 mmol) in ethanol (26 mL) was added methyl 2,3-diaminopropanoate dihydrochloride (0.313 g, 1.64 mmol). The solution was stirred at 80° C. for 4 hours. The solvent was evaporated, and column chromatography was performed to yield the title compound (0.222 g, 36%). LCMS: (FA) ES+ 460. 1H NMR (400 MHz, d4-methanol) 7.70 (s, 1H), 7.55-7.43 (m, 2H), 3.76-3.66 (m, 4H), 1.36-1.26 (m, 3H).
Reaction SMILES: Br[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[C:13]1([C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCN1CCNCC1
Reactant: CCOC(=O)C(Br)(C(=O)OCC)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)(c1ccccc1)N1CCN(CCO)CC1
Yield: 33.5 %

Procedure:
A solution of diethyl 2-bromo-2-phenylmalonate (16.8 g) in 150 ml of dimethylsulfoxide is heated to 90-100° C., then N-(2-hydroxyethyl)piperazine (27.9 g) is added and the reaction mixture is heated for additional 4 hours. The mixture is poured into water and extracted with ethyl acetate three times. The pooled organic extracts are washed with 1 N hydrochloric acid. The aqueous phase is basified with 1 N sodium hydroxide to pH=8-9 and it is extracted twice with ethyl acetate. The organic extracts are collected and are washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After removal of the solvent under reduced pressure, the residue is crystallized from diethylether petroleum ether 1:1 to give 6.5 g of the product, m.p. 63-64° C.
Reaction SMILES: C(C1CCCN([CH2:14][C:15]([C:17]2[CH:27]=[CH:26][C:20]3[NH:21][C:22](=[O:25])[CH2:23][O:24][C:19]=3[CH:18]=2)=[O:16])C1)C1C=CC=CC=1.O1C2C=CC=CC=2NC(=O)C1.[Cl:39]CC(Cl)=O>>[Cl:39][CH2:14][C:15]([C:17]1[CH:27]=[CH:26][C:20]2[NH:21][C:22](=[O:25])[CH2:23][O:24][C:19]=2[CH:18]=1)=[O:16]
Reactant: O=C1COc2cc(C(=O)CN3CCCC(Cc4ccccc4)C3)ccc2N1
Reactant: O=C(Cl)CCl
Agent: O=C1COc2ccccc2N1
Product: O=C1COc2cc(C(=O)CCl)ccc2N1

Procedure:
from 7-(2-(3-benzylpiperidino)-1-oxoethyl)-2,3-dihydro-1,4-benzoxazin-3-one ("F"; obtainable by reaction of 2,3-dihydro-1,4-benzoxazin-3-one with chloroacetyl chloride to give 7-chloroacetyl-2,3-dihydro-4H-1,4-benzoxazin-3-one ("G"), then reaction with 3-benzylpiperidine):
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][S:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][S:5]([C:6]1[NH:10][CH:9]=[CH:8][N:7]=1)=[O:23]
Reactant: Nc1ccccc1CSc1ncc[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ccccc1CS(=O)c1ncc[nH]1
Temperature: 0 °C
Yield: 12.7 %

Procedure:
To a solution of 2.5 g of 2-(2-aminobenzylthio)imidazole in a mixture of 25 ml of chloroform and 10 ml of methanol was dropwise added under stirring and under chilling with ice 2.6 g (12.1 mmol) of m-chloroperbenzoic acid. The mixture was further stirred for 15 min. Thus precipitated crystalline product was collected by filtration, washed twice with water and placed in 40 ml of saturated aqueous sodium hydrogencarbonate. The aqueous mixture was stirred, and then the crystalline product was collected by filtration. The obtained solid product was stirred in a mixture of 30 ml of chloroform and 10 ml of 1N aqueous NaOH. The aqueous portion was taken out and made ammonia-alkaline by addition of 20% aqueous ammonium chloride. The mixture was chilled after addition of sodium chloride, to give a crystalline precipitate. The precipitate was collected by filtration, washed successively with two portions of water and one portion of acetone, and dried under reduced pressure to give 340 mg of the desired compound as a pale brown crystalline powder, yield 12.7%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[Br:17][C:18]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Br)(Oc1cccc2[nH]ccc12)C(=O)OCC
Product: CCOC(=O)C(Oc1cccc2[nH]ccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %
Yield: 34 %

Procedure:
A solution of 4-hydroxyindole (266 mg, 2 mmol) in acetone (20 mL) was cooled to 0° C. under nitrogen and anhydrous potassium carbonate (414 mg, 3 mmol) was added. A solution of freshly distilled pure diethyl bromomalonate (574 mg, 2.4 mmol) in acetone (20 mL) was added dropwise and the mixture was stirred at room temperature overnight. Work up and flash chromatography as above afforded 7 (101 mg, 13%) and 8 (199 mg, 34%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[Li]CCCC.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=[O:21])[CH2:14]2>O1CCCC1>[OH:21][C:15]1([CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1
Reactant: Cc1cc(C)on1
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(CC2(O)CN3CCC2CC3)on1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3,5-dimethylisoxazole (9.71 g, 100 mmol) in dry tetrahydrofuran (30 ml) cooled to -78° C. was added n-BuLi (2.5M in hexane, 100 mmol). The reaction mixture was stirred at -78° C. for 1 h. A solution of 3-quinuclidinone (6.25 g, 50 mmol) dissolved in dry tetrahydrofuran (50 ml) was added. The reaction mixture was stirred for 2 h at -78° C., then quenched with water (100 ml) and acidified with concentrated hydrochloric acid. The water phase was extracted with ether (2×50 ml), then basified with solid potassium carbonate and extracted with methylene chloride (4×100 ml). The methylene chloride phases were collected and dried over magnesium sulfate. After evaporation of the solvent the title compound was isolated in 10.04 g. 90% yield.