Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:45]=[CH:46][CH:47]=1)[O:12][C:13]1[CH:44]=[CH:43][C:16]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:42])([CH3:41])[C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=4)=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1.CN(C)C=O.P(=O)(O)(O)O>[C:1]1(=[O:7])[N:40]([C:36]2[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=2)[O:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:17]([CH3:19])([CH3:18])[C:16]4[CH:15]=[CH:14][C:13]([O:12][C:11]5[CH:45]=[CH:46][CH:47]=[C:9]([N:8]6[C:1](=[O:7])[CH:2]=[CH:3][C:4]6=[O:5])[CH:10]=5)=[CH:44][CH:43]=4)=[CH:25][CH:24]=3)([CH3:42])[CH3:41])=[CH:28][CH:29]=2)[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(c1ccc(Oc2cccc(N)c2)cc1)c1ccc(C(C)(C)c2ccc(Oc3cccc(N)c3)cc2)cc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Oc2cccc(N3C(=O)C=CC3=O)c2)cc1)c1ccc(C(C)(C)c2ccc(Oc3cccc(N4C(=O)C=CC4=O)c3)cc2)cc1
Yield: 97.4 %

Procedure:
In the same reactor used in Example 2D, there were placed 26.5 g (0.27 mole) of maleic anhydride, 0.7 g of phosphoric acid and 150 ml of mixed xylene. A solution was then added dropwise thereto, the solution having been prepared by thermally dissolving 52.8 g (0.1 mole) of 1,4-bis[4-(3-aminophenoxy)-α,α-dimethylbenzyl]benzene obtained in Example 1D in a mixture of 100 ml of mixed xylene and 50 ml of N,N-dimethylformamide. A dropping time of 5 hours and an aging time of 2 hours were used in order to carry out the reaction. The reaction solution was concentrated to about 1/2 the original amount and then cooled. When a temperature of 80° C. had been reached, 50 g of water was added thereto. Afterward, the solution was slowly cooled, so that crystals precipitated. The precipitated crystals were then cooled to room temperatures filtered; and washed with cold methanol. 67.1 g of desired crude 1,4-bis[4-(3-maleimidophenoxy)-α,α-dimethylbenzyl]benzene was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]2=[O:21])=O)=[CH:6][CH:5]=1.CC(O)=O.[BH4-].[Na+]>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:12]2[C:13](=[O:21])[O:14][C:15]([CH3:19])([CH3:20])[O:16][C:17]2=[O:18])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)C2C(=O)OC(C)(C)OC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
The mixture of crude 4-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-benzoic acid methyl ester from step A was dissolved in DCM (50 mL) and AcOH (5 mL) and chilled to ice-bath temperature. To the solution was added portion-wise, over 30 min, NaBH4 (722 mg, 19.1 mmol). The reaction mixture was allowed to warm to RT overnight. The mixture was quenched with water, stirred for 10 min then extracted with DCM. The organic solution was dried over Na2SO4 and concentrated to afford an off-white solid that was suspended in Et2O to give pure 4-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-benzoic acid methyl ester as a white solid (2.24 g, 60%). 1H NMR (500 MHz, DMSO-d6): δ 7.87 (d, J=8 Hz, 2H), 7.43 (d, J=8 Hz, 2H), 4.86 (t, 7.87 (d, J=5 Hz, 1H), 2H), 3.84 (s, 3H), 3.35 (d, J=5 Hz, 2H), 1.83 (s, 3H), 1.64 (s, 3H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[C:10]#[N:11]>CN(C=O)C>[F:16][C:13]1[CH:14]=[CH:15][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: C1CNCCN1
Reactant: N#Cc1cc(F)ccc1F
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1N1CCNCC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
A mixture of piperazine (Aldrich; 1.28 g), 2,5-difluorobenzonitrile (Lancaster; 0.422 g), and DMF (4 mL) is stirred at 80° C. for 1.5 h, after which the mixture is cooled and partitioned between dichloromethane, water, and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue is crystallized from dichloromethane/ethyl ether/hexane to give 0.282 g of 5-fluoro-2-(piperazin-1-yl)benzonitrile; mp 83-83.5° C.; 1H NMR (CDCl3) δ3.10, 7.00, 7.21, 7.27.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH:11]=[CH:12][N:13]([CH:16]([CH3:18])[CH3:17])[C:14]=2[CH:15]=1.[OH-].[Na+].CN([CH:28]=[O:29])C>O>[Br:6][C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[C:11]([CH:28]=[O:29])=[CH:12][N:13]([CH:16]([CH3:18])[CH3:17])[C:14]=2[CH:15]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1c(C=O)cn2C(C)C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
To a stirred solution of DMF (1.04 lit) POCl3 (40.3 g, 263 mmol) was added at 0° C. and stirred for 20 min. Then methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (65 g, 2119.5 mmol) in DMF (260 mL) was added to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 3 h. Diluted the reaction mixture with cold water and adjusted PH˜8 using with 2N NaOH solution, extracted with ethylacetate (4×1 lit). The organic layer washed with cold water, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford desired product methyl 6-bromo-3-formyl-1-isopropyl-1H-indole-4-carboxylate (65 g, 91.3%). 1H NMR (CDCl3, 400 MHz): δ 1.588 (d, 6H, J=6.8 Hz), 3.994 (s, 3H), 4.634-4.701 (m, 1H), 7.760 (d, 1H, J=1.6 Hz), 7.958 (d, 1H, J=1.6 Hz), 8.122 (s, 1H), 10.446 (s, 1H). LC-MS (ES+) m/z=324.02 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]=O)[CH:4]=1.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]=[CH:17][N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc2c1OCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(C=C[N+](=O)[O-])cc2c1OCO2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
3-Methoxypiperonal (50.0 g) is combined with 71.9 mL of nitromethane in 250 mL of acetic acid; 36 g of ammonium acetate is added, and the mixture is heated to 50° C. for 4 hrs. Solvents are removed in vacuo; the residue is taken up in water and stirred for 20 min. The solution is filtered; the filtrate is washed with water, then ether, to give 51.8 g of a yellow solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH2:17][CH:18]([OH:21])[CH2:19][OH:20]>C(O)(C)C>[CH2:3]([S:15][CH2:17][CH2:18][CH2:19][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:20][CH2:19][CH:18]([OH:21])[CH3:17]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCCCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(O)CO
Product: CCCCCCCCCCCCSCCCCCCCCCCCC
Temperature: 80 °C

Procedure:
Approximately 97 g of 50% aqueous sodium hydroxide solution was added dropwise over a period of 7 hours to a solution of n-dodecyl mercaptan (1000 g) and 1-chloropropane-2,3-diol (547 g) in isopropanol solvent (2000 cc) at ambient temperature. The reaction temperature rose from 21° to 56° C. during the addition. The reaction was refluxed for 5 hours at 80° C. and then filtered hot through paper to remove the precipitated salt. The isopropanol solvent was removed by distillation. The product residue was dissolved in about 4000 cc of toluene and washed with water several times. The toluene solution was dried over magnesium sulfate and filtered through diatomaceous earth. Toluene was removed by high speed rotary evaporation under reduced pressure to yield a white solid product.
Reaction SMILES: [C:1]1([CH3:11])[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:26]=[C:25]2[C:20]([C:21](=[N:28][OH:29])[CH:22]([CH3:27])[CH2:23][O:24]2)=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH3:11])[C:2]([S:7]([O:29][N:28]=[C:21]2[C:20]3[C:25](=[CH:26][C:17]([C:13]4[O:12][CH:16]=[CH:15][CH:14]=4)=[CH:18][CH:19]=3)[O:24][CH2:23][CH:22]2[CH3:27])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC1COc2cc(-c3ccco3)ccc2C1=NO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1S(=O)(=O)ON=C1c2ccc(-c3ccco3)cc2OCC1C
Reaction time: 6 h
Yield: 57.1 %

Procedure:
Toluenesulfonyl chloride (397 mg, 2.08 mmol) was added to a 0° C. solution of 7-furyl-3-methyl-4-chromanone oxime (61) (461 mg, 1.89 mmol) and pyridine (0.5 mL) in CH2Cl2 (10 mL). After 6 hours, the mixture was diluted with CH2Cl2 (30 mL) and washed with 5% HCl (20 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified via flash chromatography using 5:1 hexanes:EtOAc as the eluent, to provide 7-furyl-3-methyl-4-chromanone O-(toluenesulfonyl)-oxime (62) (429 mg) as a pink solid, m.p. 163-164° C. (dec).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[N:15]1([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([CH:32]=O)=[CH:26]3)[CH2:19][CH2:18][CH2:17][CH2:16]1.N1CCCCC1>C(O)C>[O:1]=[C:2]1[C:10](=[CH:32][C:27]2[NH:28][C:29]3[C:25]([CH:26]=2)=[CH:24][C:23]([O:22][CH2:21][CH2:20][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:31][CH:30]=3)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=2)[NH:3]1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCCC4)ccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 79.9 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide (28 mg, 0.13 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (34 mg, 0.13 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 90° C. for 2 hours. The reaction was cooled at 0° C. for overnight. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 47 mg (80%) of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:16]([O:26][CH2:27][CH3:28])=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:16]([O:26][CH2:27][CH3:28])=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3ccccc3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A mixture of ethyl 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (490 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (3 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionic acid (430 mg, yield: 94%) was obtained. This was recrystallized from acetone-hexane. Melting point: 115–116° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:42])([F:41])[C:9]1[CH:10]=[C:11]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:12][NH:13][CH2:14][C:15]1[C:16]([N:25]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][CH3:27])=[N:17][C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=2[CH:24]=1.Cl[C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[CH3:47][O:46][C:44](=[O:45])[N:13]([CH2:12][C:11]1[CH:10]=[C:9]([C:8]([F:41])([F:7])[F:42])[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=1)[CH2:14][C:15]1[C:16]([N:25]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][CH3:27])=[N:17][C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=2[CH:24]=1
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCC2
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)CCCC2
Reaction time: 1 h
Yield: 15 %

Procedure:
To a suspension of potassium carbonate (0.269 g, 1.949 mmol) in dry THF (5 mL) was added a THF solution (10 mL) of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-5,6,7,8-tetrahydro-quinolin-2-yl}-cyclopentylmethyl-ethylamine (0.25 g, 0.3 mmol), which was then stirred for 1 h. Methyl chloroformate (0.137 g, 1.46 mmol) was then added and stirring was was continued at RT for 8 h. The solvent was then evaporated, water was added, and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated to afford a residue. This crude residue was purified over silica gel (100-200 mesh) and eluted with 2% ethyl acetate and petroleum ether to afford (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopentylmethyl-ethyl-amino)-5,6,7,8-tetrahydro-quinolin-3-ylmethyl]-carbamic acid methyl ester as light green, pasty compound (0.05 g), yield: 15%.
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][N:27]([CH2:7][CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCC1CCCCO1
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCCCO3)C2=O)nc1C
Yield: 39 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with (bromomethyl)tetrahydro-2H-pyran to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 39% yield: 1H NMR (300 MHz, CDCl3) δ 4.26 (q, J=7.2 Hz, 2H), 4.11-4.05 (m, 2H), 3.97-3.92 (m, 1H), 3.83-3.62 (m, 2H), 3.55-3.34 (m, 2H), 3.22-3.15 (m, 1H), 2.60 (s, 3H), 1.85-1.82 (m, 1H), 1.57-1.44 (m, 4H), 1.31-1.22 (m, 5H); MS (ES+) m/z 354.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:7][S:8]([O:11][CH2:12][CH:13]([N:15]1[C:28]2[CH:27]=[C:26]([C:29](=[O:34])[NH:30][CH2:31][CH2:32][CH3:33])[CH:25]=[CH:24][C:23]=2[S:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])(=[O:10])=[O:9].C(OCC)C>C(#N)C>[CH3:7][S:8]([O-:11])(=[O:10])=[O:9].[CH3:1][N+:2]1([CH2:14][CH:13]([N:15]2[C:28]3[CH:27]=[C:26]([C:29](=[O:34])[NH:30][CH2:31][CH2:32][CH3:33])[CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCCNC(=O)c1ccc2c(c1)N(C(C)COS(C)(=O)=O)c1ccccc1S2
Reactant: CN1CCCC1
Solvent: CC#N
Solvent: CCOCC
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)C[N+]1(C)CCCC1)c1ccccc1S2
Product: CS(=O)(=O)[O-]
Temperature: 20 °C
Reaction time: 1 h

Procedure:
N-Methylpyrrolidine (2.6 cc) is added to a solution of (2RS)-2-[2-(N-propylcarbamoyl)-10-phenothiazinyl)propyl methanesulphonate (2.1 g) in acetonitrile (40 cc). The mixture is brought to reflux for 120 hours. After cooling, the solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give an oily residue, which is taken up with diethyl ether (50 cc). After one hour's stirring at 20° C., the suspension is filtered and the solid is washed with diethyl ether (3×10 cc) and then dried at 20° C. under reduced pressure (5 mmHg; 0.7 kPa. 1-Methyl-1-{(2RS)-2-[2-(N-propylcarbamoyl)-10-phenothiazinyl]propyl}pyrrolidinium methylsulphonate (2 g) is thereby obtained in the form of an orange-colored solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1>C(#N)C>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Brc1nccs1
Reactant: C1CNCCN1
Solvent: CC#N
Product: c1csc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
Piperazine (3.44 g, 40 mmol) was added to a solution of 2-bromothiazole (1.8 ml, 20 mmol) in acetonitrile (90 ml). The mixture was heated at reflux for 20 h. The reaction was cooled down at RT and the precipitate (disubstituted piperazine) was filtered off. The filtrate was evaporated, the residue was partitioned between water and ethyl acetate, the organic phase was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were extracted with HCl (1 M). The organic phase was discarded, and the aqueous layer was neutralized by addition of NaHCO3 (solid) to pH 8, and then extracted with EtOAc. The organic extracted was dried over sodium sulfate and evaporated, providing 1-thiazol-2-ylpiperazine (intermediate IIIa, 860 mg, 25% yield) as colorless oil. H-NMR (CDCl3): 2.98 (m, 4H), 3.48 (m, 4H), 6.56 (d, 1H, J=3.63 Hz), 7.20 (d, 1H, J=3.63 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1>N1C=CC=CC=1>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[N:2]([CH3:1])[C:3](=[S:6])[NH:4][N:5]=2)=[CH:10][CH:9]=1
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cn1c(-c2ccc(F)cc2)n[nH]c1=S
Temperature: 25 °C

Procedure:
To 4-methylthiosemicarbazid (4.24 g, 40.30 mmol) in pyridine (50 ml) was added dropwise 4-fluorobenzoyl chloride (4.9 ml, 40.00 mmol) and the resulting mixture was stirred at r.t. o.n. The pyridine was removed by evaporation and the residue was heated in aq. sat. NaHCO3 at reflux o.n. After cooling to r.t., the product was collected by filtration, washed with water and dried under vacuum to give 3.22 g (38%) which was used in the next step without further purification. 1H NMR: 3.9 (m, 3 H) 6.98 (t, 2 H) 7.92 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH:26]12[O:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][C:28](=[O:34])[CH2:27]2>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:28]3([OH:34])[CH2:27][CH:26]4[O:33][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: O=C1CC2CCC(C1)O2
Product: CC1(C)CC=C(c2cc(C3(O)CC4CCC(C3)O4)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g)) and 8-oxa-bicyclo[3.2.1]octan-3-one (Liebigs Annalen der Chemie, (1), 1-5 (1987)). 1H-NMR (CDCl3; 400 MHz): δ 11.69 (br s, 1H), 9.56 (s, 1H), 8.36 (d, 1H, J=8.4 Hz), 7.70 (s, 1H), 7.48 (dd, 1H, J=8.4, 2.0 Hz), 7.30 (d, 1H, J=2.0 Hz), 5.79-5.74 (m, 1H), 4.58-4.50 (m, 2H), 2.48-2.41 (m, 2H), 2.40-2.37 (m, 2H), 2.32-2.25 (m, 2H), 2.12-2.07 (m, 2H), 2.05-1.96 (m, 2H), 1.83-1.76 (m, 2H), 1.57-1.53 (m, 2H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O3, 447.2 (M+H). found 447.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]=4[CH:27]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].CCN(C(C)C)C(C)C.Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:26][CH2:25][CH2:24][N:23]([CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:22][C:21]=4[CH:27]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CNCCO4)no2)cc1Cl
Reactant: CCOC(=O)CCCBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCN1CCOc2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc2C1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
7-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.105 g, 0.272 mmol) was stirred in acetonitrile (2 ml). DIPEA (0.095 ml, 0.544 mmol) and ethyl 4-bromobutanoate (0.058 ml, 0.408 mmol) were added and the reaction mixture heated at 80° C. under Argon for 5 hours. Additional DIPEA (0.095 ml, 0.544 mmol) and ethyl 4-bromobutanoate (0.058 ml, 0.408 mmol) were added and the reaction mixture heated at 80° C. overnight. Then the reaction mixture was dissolved in EtOAc (20 ml), washed with NaHCO3 (aq) (15 ml×3) and with water (15 ml×3) and the organics dried (MgSO4) and evaporated. The crude was purified by flash chromatography eluting with EtOAc/iso-Hexane 20/30% (Biotage column), and evaporated to give the title compounds as an oil (80 mg). MS (ES): C26H3035ClN3O5 requires 499; found 500 [M+H]+.
Reaction SMILES: Cl[CH:2]([CH2:6][CH:7]([Cl:10])[CH2:8][CH3:9])[C:3](=[O:5])[CH3:4].[SH:11][CH2:12][CH2:13]O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:10][CH:7]([CH2:8][CH3:9])[CH2:6][C:2]1[S:11][CH2:12][CH2:13][O:5][C:3]=1[CH3:4]
Reactant: CCC(Cl)CC(Cl)C(C)=O
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(Cl)CC1=C(C)OCCS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 26 g (0.14 mole) of 3,5-dichloro-2-heptanone, 12 g (0.15 mole) of 2-mercaptoethanol, and 15 g (0.15 mole) of triethylamine in 200 ml toluene, was stirred at ambient temperature overnight. The mixture was then washed with dilute hydrochloric acid and subsequently refluxed with 0.1 g. p-toluenesulfonic acid with azeotropic removal of water for six hours. Upon cooling, it was washed with aqueous sodium bicarbonate, dried (magnesium sulfate), and the solvent was removed to leave the product.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:33]1([C:39]#[C:40][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:40]([Si:41]([CH2:46][CH3:47])([CH2:42][CH3:43])[CH2:44][CH3:45])[O:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Reactant: CC[Si](C#Cc1ccccc1)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Temperature: 108 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-4-benzyloxy-3-iodo-1H-pyridin-2-one (1.00 g, 2.40 mmol), diisopropylethylamine, (0.51 mL. 2.88 mmol) and Pd(dppf)2Cl2/CH2Cl2 (0.20 g, 0.24 mmol) in DMF (10.0 mL) was slowly added 1-phenyl-2-(triethylsilyl)acetylene (1.50 g, 7.20 mmol) at room temperature under N2. The resulting reaction mixture was degassed and stirred at 108° C. under nitrogen overnight. The reaction was cooled down to room temperature, and the solvent was removed. The residue was dissolved in DCM (250 mL). The solution was washed with NaHCO3 (30×2 mL) and brine (30 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/methanol/100/1, to give the title compound. MS (m/z), M+H+ 416.2.