Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][CH:9]([CH2:17][OH:18])[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[ClH:1].[ClH:1].[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH:9]([OH:8])[CH2:17][OH:18])[CH2:16][CH2:15]1
Reactant: OCC(O)CN1CCNCC1
Reactant: Clc1ccccn1
Product: Cl
Product: OCC(O)CN1CCN(c2ccccn2)CC1
Yield: 53.6 %

Procedure:
Operation was carried out in a manner similar to the one previously described, using 2-chloropyridine and 1-(2,3-dihydroxypropyl) piperazine. The residue obtained after evaporation to dryness was dissolved in a small amount of concentrated hydrochloric acid and diluted with isopropanol. After resting, 3-[4-(pyridin-2-yl) piperazin-1-yl]propane-1,2-diol dihydrochloride melting at 238°-242° C., was obtained with the 53.6% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].I[CH:20]([CH3:22])[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH:20]([CH3:22])[CH3:21])[C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2C(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 46.5 %

Procedure:
To a solution of 7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (prepared in Preparation 1) (6.1 g) in dimethylformamide (120 ml) were added 60% sodium hydride (in oil) (1.1 g) and 2-iodopropane (4.3 g) and the mixture was stirred at 60° C. for 5 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 7-methoxycarbonyl-2-methyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1.[CH:10](=O)[CH3:11].C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(O)(=O)C>[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([NH:1][CH2:10][CH3:11])[CH:3]=1)#[N:9]
Reactant: N#Cc1cncc(N)c1
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNc1cncc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a solution of 5-amino-3-cyanopyridine (300 mg, 2.52 mmol) in methanol (10 ml) was added acetaldehyde (1.42 ml, 25.1 mmol), and the mixture was stirred at room temperature for 10 minutes. Next, sodium cyanoborohydride (950 mg, 15.1 mmol) was added, and acetic acid was further added to adjust the pH of thereaction mixture to about 6. The mixture was stirred for 5 hours. After the reaction was completed, the reaction mixture was neutralized with an aqueous sodium carbonate solution and extracted with diethyl ether (30 ml×3). The diethyl ether layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (Wako Gel C-200, 20 g; eluted with chloroform:methanol=200:1) to give 3-cyano-5-ethylaminopyridine (200 mg, 1.36 mmol, yield 54%).
Reaction SMILES: [CH3:1][C:2]12[CH2:17][CH:5]([C:6]3([CH3:16])[C:10]1([CH3:11])[C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[Br:18]N1C(=O)CCC1=O>O1CCCC1.CN(C)C=O>[Br:18][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]3([CH3:16])[CH:5]4[CH2:17][C:2]([CH3:1])([C:10]3([CH3:11])[C:9]=2[CH:12]=1)[CH2:3][CH2:4]4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC12CCC(C1)C1(C)Oc3ccccc3C21C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC12CCC(C1)C1(C)Oc3ccc(Br)cc3C21C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.42 g (50 mmol) of (-)-1,2,3,4-tetra-hydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran obtained in Example 1 were dissolved in 110 ml of tetrahydrofuran and were treated dropwise with a solution containing 8.9 g of N-bromosuccinimide (NBS) in 50 ml of dimethylformamide (DMF). The reaction mixture was maintained under stirring at room temperature for 2 h, 30 min, and was then poured into ice-cold water and extracted with 500 ml of ethyl ether. After rinsing with water, drying over magnesium sulfate, filtering and evaporating, 13.8 g (90%) of the expected derivative, melting at 119.8° C., were isolated after chromatography on silica in hexane.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][CH:8]([NH2:16])[CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])(C)(C)C.[ClH:18]>>[ClH:18].[NH2:16][C@@H:8]([CH2:9][C:10]([CH3:14])([CH3:15])[CH2:11][CH2:12][CH3:13])[CH2:7][C:6]([OH:17])=[O:5]
Reactant: CCCC(C)(C)CC(N)CC(=O)OC(C)(C)C
Agent: Cl
Product: CCCC(C)(C)C[C@H](N)CC(=O)O

Procedure:
According to example 1, 3-amino-5,5-dimethyl-octanoic acid tert-butyl ester was treated with 3N HCl to provide 286 mg of the title compound as a solid. 1HNMR (400 MHz; CD3OD): 0.87–0.93 (m, 9H), 1.18–1.31 (m, 4H), 1.51 (dd, 1H, J=4 Hz, 14.4 Hz), 1.62 (dd, 1H, J=6.8 Hz, 14.4 Hz), 2.60 (dd, 1H, J=8 Hz, 17.6 Hz), 2.73 (dd, 1H, J=4 Hz, 7.6 Hz), 3.55–3.60 (m, 1H). MS (APCI), m/z: 188.1 (M+1)+. 186.1 (M−1)+. Anal. Calc'd for C10H21NO2.HCl.0.12H2O: C: 53.17, H: 9.92, N: 6.20, Cl: 15.69; Found: C: 53.19, H: 10.00, N: 6.08, Cl: 15.25. α=+20° (MeOH). MP: 194.2–195.2° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([Cl:24])=[O:23]>C1C=CC=CC=1>[ClH:24].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:22]([C:18]2[O:17][CH:21]=[CH:20][CH:19]=2)=[O:23])[CH2:15][CH2:16]1
Reactant: Cc1ccccc1CCCN1CCNCC1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccccc1
Product: Cc1ccccc1CCCN1CCN(C(=O)c2ccco2)CC1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of 1-[3-(o-methylphenyl)propyl]piperazine [b.p. 135° - 136°C (2 mmHg), dihydrochloride, m.p. 240° - 245°C], 2-furoyl chloride and benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:24]
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(OC(F)(F)F)c3)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 3-(trifluoromethoxy)benzoyl chloride (37 μL, 0.229 mmol) and mixing for 24 h, 50.4 mg (>100%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:29][C:30]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][C:33]([NH2:34])=[C:32]([O:40][CH3:41])[CH:31]=1>CC(O)CCC>[Br:29][C:30]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][C:33]([NH:34][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: Clc1nccc(-c2cnn3c2CCCC3)n1
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(Br)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 58.7 %

Procedure:
A solution of 3-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (Intermediate 128, 0.893 g, 3.80 mmol), p-toluene sulphonic acid monohydrate (1.034 g, 5.43 mmol) and 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 0.895 g, 3.62 mmol) in 2-pentanol (35 mL) was heated at reflux for 16 h under an atmosphere of N2. The mixture was then allowed to cool, and was concentrated in vacuo. The resulting residue was triturated in CH3CN until a yellow precipitate formed. The solid was collected by filtration and was washed with diethyl ether. The solid then was dissolved in 10% CH3OH in CH2Cl2 and the resulting solution was washed twice with sat. NaHCO3, then with water. The solution was then dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated with CH3CN, the resulting solid collected by filtration, washed with diethyl ether, and then air dried to give the title compound (0.946 g, 59%) as a yellow solid; 1H NMR: 1.80-1.87 (2H, m), 1.96-2.03 (2H, m), 3.11 (2H, t), 4.04 (3H, s), 4.13 (2H, t), 7.17 (1H, d), 7.50 (1H, s), 8.13 (1H, s), 8.21 (1H, s), 8.45 (1H, d), 9.10 (1H, s); m/z: ES+ MH+ 445/447.
Reaction SMILES: [NH2-].[Na+].O1CCCC1.Br[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[CH2:19]([O:21][C:22]([O:24][CH2:25][CH3:26])=[CH2:23])[CH3:20]>O.CCOCC>[CH2:19]([O:21][C:22]1([O:24][CH2:25][CH3:26])[C:9]2=[C:18]3[C:13](=[CH:12][CH:11]=[C:10]2[CH2:23]1)[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH3:20]
Reactant: Brc1cccc2ccccc12
Reactant: C=C(OCC)OCC
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC1(OCC)Cc2ccc3ccccc3c21

Procedure:
9.4 g of sodium amide are introduced into 350 ml of tetrahydrofuran. 25.9 g of 1-bromonaphthalene and 28 g of freshly prepared 1,1-diethoxyethylene are poured in succession into that mixture. The reaction mixture is refluxed for 16 hours and than taken up in water and ether. After washing the organic phase to neutral pH and drying thereof, the expected product is isolated and chromatographed over silica gel (dichloromethane/cyclohexane: 1/1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[CH:35](N(C)C)[N:36]([CH3:38])[CH3:37])(C)(C)C.C(OCC)C.CCCCCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14](=[CH:35][N:36]([CH3:38])[CH3:37])[C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CN(C)C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 97.2 %

Procedure:
To a solution of di-tert-butyl (1S,2S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (15.15 g, 36.82 mmol, See WO03/104217/A2 for synthesis details) in toluene (90.90 mL) is added tert-butoxybis(dimethylamino)methane (12.83 g, 73.63 mmol). This mixture is then heated to 80° C. for 1 hour and then allowed to cool to ambient temperature. The solvent volume is reduced to about 35 ml. The mixture is stirred while diethyl ether and hexane are added to cause a precipitate to form. The solids are collected by filtration, washed with hexanes, and air dried to obtain the title compound (16.7 g, 35.79 mmol, 97.2% yield). MS (m/z): 467.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]([NH:12][C:20](=[O:21])[CH2:19][Br:18])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)O)c1NC(=O)CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 3-methoxy-2-aminobenzoic acid (5.0 g, 30 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL-3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled with an ice-bath to -5° C. Bromoacetyl bromide (6.66 g, 2.90 mL, 30 mmol) was added dropwise, keeping the internal temperature between -5° to 0° C. over a 1/2 h period. After the addition of bromoacetyl bromide was completed, the solution was warmed to room temperature and then stirred overnight. To the solution was slowly added 150 mL of ice-water, causing a pale white solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum oven overnight to afford 6.26 g (72%) of the title compound as a pale-white solid, mp 178°--180° C. (decomp): 1H NMR (DMSO-d6) δ12.80 (bs, 1H), 9.80 (s, 1H), 7.30-7.25 (m, 3H), 4.05 (s, 2H), 3.81 (s, 3H); 13C NMR (DMSO-d6) δ167.37, 164.54, 153.67, 129.76, 126.56, 124.39, 121.18, 114.66, 56.03, 29.63; MS (EI, m/z) 287 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][OH:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:26][C:27]#[N:28].[Na+].[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]([N:9]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([OH:15])[C:27]([NH2:28])=[O:26])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: N#C[O-]
Reactant: Cc1cnc(N(CCCCNO)C2CCCc3cccnc32)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(N(CCCCN(O)C(N)=O)C2CCCc3cccnc32)c(C)c1

Procedure:
N-{4-[(3,5-Dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-hydroxylamine (HBr salt) (180 mg, 0.25 mmol) was dissolved in H2O (2.5 mL) and treated with sodium cyanate (65 mg, 1.0 mmol) for 2 hours. 15% aqueous NaOH solution (0.1 mL) was added and the aqueous was extracted with CH2Cl2 (3×5 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure to afford, after radial chromatographic purification on a silica gel plate (3% NH4OH/CH3CN) N-{4-[(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-N-hydroxyurea (73 mg, 73%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=O)[O:14][C:10]=2[CH:9]=1>ClC1C=CC=CC=1Cl>[Cl:2][C:13]1[O:14][C:10]2[CH:9]=[C:8]([Cl:7])[CH:17]=[CH:16][C:11]=2[N:12]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Clc1ccc2nc(Cl)oc2c1
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
400 ml of o-diohIorobenzene and 1,040 g (5 moles) of phosphorus pentachloride are heated to 150° to 160° C. Then 169.5 g (1 mole) of 6-chlorobenzoxazolin-2-one, suspended in 600 ml of o-dichlorobenzene, are metered in within 2 hours with heating such that the interior temperature does not drop below 150° C. The addition being complete, stirring is continued for a further 10 minutes. working up analogously to Example 8 results in a yield of 145 g of 2,6-dichlorobenzoxazole, corresponding to 77% of theory. GC purity: 99.7%.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH3:9][S:10][CH3:11].[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:41][CH2:40][C:27]3([C:32]4=[CH:33][CH:34]=C[N:31]4[C:30]4[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=4[O:28]3)[CH2:26][CH2:25]2)=[O:23])=[CH:18][C:17]=1[CH3:42])([CH3:14])[CH3:13]>ClCCl.C1(C)C=CC=CC=1>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:41][CH2:40][C:27]3([O:28][C:29]4[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=4[N:31]4[C:9]([S:10][CH3:11])=[CH:34][CH:33]=[C:32]34)[CH2:26][CH2:25]2)=[O:23])=[CH:18][C:17]=1[CH3:42])([CH3:14])[CH3:13]
Reactant: CSC
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1OC(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CSc1ccc2n1-c1ccccc1OC21CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.3 %

Procedure:
A solution of 1-chloropyrrolidine-2,5-dione (92 mg, 0.70 mmol) in dry dichloromethane (3.2 mL) was added dropwise at −10° C. to a solution of methylsulfanylmethane (82 μL, 1.1 mmol) in dry dichloromethane (800 μL) over a period of 5 minutes. The reaction was allowed to warm to room temperature and was stirred for 30 minutes. The mixture was then cooled to −55° C. and a solution of (4-isopropoxy-3-methyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone (210 mg, 0.49 mmol) in dry dichloromethane (800 μL) was added dropwise. The cooling bath was removed and the mixture was gradually warmed up to room temperature and was stirred overnight. The solvent was removed under vacuum and the pink residue that was obtained was dissolved in dry toluene (7 mL) and was heated at 50° C. for 5 minutes. The solvent was removed to afford (4-isopropoxy-3-methylphenyl)(1-(methylthio)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (250 mg, 78%). ESI-MS m/z calc. 462.2, found 463.5 (M+1)+; Retention time: 2.43 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.C([Li])CCC.CCCCCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1)[CH3:32]
Reactant: COCCOCc1cc(Br)ccc1OC
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC)c(COCCOC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-bromo-1-methoxy-2-(2-methoxy-ethoxymethyl)-benzene (2.88 g, 10.5 mmol) in absolute THF (30 mL) is added at −70° C. a 1.6N solution of n-butyllithium in hexane (7.20 mL, 11.5 mmol) with stirring. After 40 min, ethyl chloroformate (1.14 g, 10.5 mmol) is added, and the mixture is stirred overnight while gradually warming up to room temperature. The mixture is poured into 2N aqueous HCl, extracted with CH2Cl2, the organic layers are dried (Na2SO4) and concentrated. The crude product is purified by flash chromatography on silica gel (hexane/AcOEt 2:1) to give the title compound as liquid. TLC, Rf (hexane/AcOEt 1:1)=0.13.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[CH:2].[C:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:25][NH:26][CH3:27]>O.[Cu]I>[CH3:25][N:26]([CH3:27])[CH:23]([CH:20]1[CH2:21][CH2:22][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:18][CH2:19]1)[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1
Reactant: C#Cc1cccc(C)n1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Cu]I
Solvent: O
Product: Cc1cccc(C#CC(C2CCN(C(=O)OC(C)(C)C)CC2)N(C)C)n1

Procedure:
A mixture of 2-ethynyl-6-methyl-pyridine (0.08 g, 0.7 mmol), 1-Boc-4-piperidinecarboxaldehyde (0.1 g, 0.47 mmol), CuI (0.001 g, 0.11 mmol) and 33% w/w aqueous dimethylamine (0.077 mL, 0.56 mmol) in water (3 mL) was sonicated for 2 h in a laboratory ultrasonic bath. Afterwards, it was extracted with EtOAc and the combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to give a crude, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with EtOAc—Petroleum Ether 1:1 affording the title product (0.11 g).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]2[S:9][C:10]([CH:12]=O)=[CH:11][C:7]=2[CH:6]=1.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])[CH3:18].CO[CH2:25][CH2:26]OC>>[CH2:21]([O:20][C:17](=[O:19])/[CH:18]=[CH:25]/[CH:26]=[CH:12]/[C:10]1[S:9][C:8]2[CH:14]=[CH:15][C:5]([N:4]([CH3:16])[CH3:3])=[CH:6][C:7]=2[CH:11]=1)[CH3:22]
Reactant: CCOC(C)=O
Reactant: CN(C)c1ccc2sc(C=O)cc2c1
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/C=C/c1cc2cc(N(C)C)ccc2s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65 %

Procedure:
To a mixture of sodium hydride (60% in mineral oil, 128 mg, 3.2 mmol) in ethylene glycol dimethyl ether (4 mL) was added dropwise at 0° C. a solution of triethyl phosphonocrotonate (800 mg, 3.2 mmol) in ethylene glycol dimethyl ether (2 mL). The mixture was stirred at room temperature for 45 min. A solution of 5-dimethylamino-benzo[b]thiophene-2-carboxaldehyde (596 mg, 2.9 mmol) in ethylene glycol dimethyl ether (5 mL) was added in dropwise manner. The mixture was stirred at reflux for 90 min, cooled to room temperature and diluted by addition of ethyl acetate (50 mL). The mixture was washed with water (3×25 mL) and brine (25 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil, that was purified by flash chromatography (10:90:1 ethyl acetate:40-60° C. petroleum ether:triethylamine) to give a solid that was recrystallised from ethanol to give the title compound (567 mg, 65%) as a solid, mp 140-142° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>ClCCl.CO.CCOCC>[ClH:23].[NH:8]1[CH2:13][CH2:12][CH:11]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: O=S(=O)(C1CCNCC1)N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of 4-(morpholine-4-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (10 ml) and methanol (10 ml) was added 2M hydrogen chloride in ether (2 μL). The reaction mixture was stirred overnight. The solvents were removed in vacuo to yield 4-(piperidine-4-sulfonyl)-morpholine hydrochloride salt.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.C(Cl)Cl.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][OH:36])[CH3:32]>C(OCC)C>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:36][CH2:35][CH2:34][N:33]([CH2:37][CH3:38])[CH2:31][CH3:32])=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1
Reactant: CCN(CC)CCO
Reactant: O=C(Cl)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCN(CC)CCOC(=O)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1

Procedure:
A mixture of 9.45 g. (21 mmole) 4-{2-[1-(2-chlorobenzyl)-piperazin-4-yl]-ethyl}-benzoyl chloride dihydrochloride, 50 ml. methylene chloride and 3.3 g. (28 mmole) 2-diethylaminoethanol is maintained at reflux temperature for 3 hours, then cooled and mixed with diethyl ether until turbidity appears. A thick precipitate is slowly deposited. This is filtered off with suction, washed with sec.-butanol and dissolved in a hot mixture of sec.-butanol and ethanol. Upon cooling and partial concentration, there are obtained 5.0 g. (35% of theory) of the desired compound in the form of its dihydrochloride; m.p. 220°-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22])=[CH:4][CH:3]=1
Reactant: CC(C)(CCCl)C(=O)CCl
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CCCl)C(=O)CSc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
86.7 g (0.6 mole) of 4-chlorothiophenol and 82.8 g (0.6 mole) of potassium carbonate in 500 ml of toluene are heated under reflux for 2 hours, using a water separator. 91.5 g (0.5 mole) of 1,5-dichloro-3,3-dimethyl-2-pentanone in 200 ml of toluene are then added at 100° C. The reaction mixture is stirred at 100° C. for 5 hours and is then allowed to cool, and is stirred with 500 ml of water. The organic phase is separated off, washed with dilute sodium hydroxide solution and with water, dried over sodium sulphate and concentrated. 137.4 g (94.4% of theory) of 1-(4-chlorophenylthio)-5-chloro-3,3-dimethyl-2-pentanone of refractive index nD20 1.5628 are obtained. ##STR95##