Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=O)NC3C=CC=CC=3SC=2C=CC=1.OCCOCC[C:23]1[C:33]2[S:32][N:31]=[CH:30][C:29]3[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=3[C:27]=2[C:26](N2CCCCC2)=[CH:25][CH:24]=1.P(Cl)(Cl)([Cl:46])=O>>[Cl:46][C:37]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:33]=3[S:32][N:31]=[CH:30][C:29]=2[CH:34]=[CH:35][CH:36]=1
Reactant: OCCOCCc1ccc(N2CCCCC2)c2c1SN=Cc1ccccc1-2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C1Nc2ccccc2Sc2ccccc21
Product: Clc1cccc2c1-c1ccccc1SN=C2

Procedure:
EP 0282236-A1 describes that a dibenzothiazepine derivative of the above-mentioned formula (5) can be processed to give 11-[4-(2-(2-hydroxyethoxy) ethyl]-1-piperadinyldibenzothiazepine derivative which is of value as an antipsychotic pharmaceutical. In more detail, dibenzo-[b,f] [1,4]thiazepin-11-one, which is a representative compound of the dibenzothiazepine derivatives of the formula (5), is reacted with phosphorus oxychloride to yield a 11-chloro-dibenzothiazepine derivative; and to the 11-chloro-dibenzothiazepine derivative is added piperazine to yield a 11-piperazinyl-dibenzothiazepine derivative, which is subsequently reacted with 2-chloro-ethoxyethanol under basic conditions to give the desired 11-[4-(2-(2-hydroxyethoxy)ethyl]-1-=piperadinyldibenzothiazepin.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][C:14](=[O:23])[N:13]=[C:11]3[S:12][C:8]=2[CH:7]=1)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[O:23]=[C:14]1[CH:15]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]2[C:11]([S:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:26])=[O:3])[CH:25]=[CH:24][C:9]=32)=[N:13]1
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Yield: 75.4 %

Procedure:
A stirred mixture of 2.47 g of ethyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate, 100 ml of methanol and a solution of 2.47 g of potassium carbonate in 20 ml of water was kept at ambient temperature overnight. The methanol was evaporated and the residue was diluted with water, then acidified with concentrated hydrochloric acid. The precipitate was collected, dried, and crystallized twice from methanol to obtain 1.72 g (75% yield) of 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetic acid as yellow plates.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]=2[F:24])[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH2:28][CH3:29].[Si:30]([O:37][CH2:38][C:39]([CH3:51])([CH3:50])[O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=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].ClCCl>[Si:30]([O:37][CH2:38][C:39]([CH3:51])([CH3:50])[O:40][C:41]1[CH:42]=[CH:43][C:44]([C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][C:11]=3[F:24])[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=2[CH2:28][CH3:29])=[CH:45][CH:46]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Oc1ccc(B(O)O)cc1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 90.3 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.6 g), [4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]boronic acid (0.84 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution (6 mL) and 1,4-dioxane (6 mL) was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.78 g, 90%).
Reaction SMILES: [ClH:1].C([O:6][C:7]1[CH:46]=[CH:45][C:10]([C:11]([NH:13][C@H:14]2[C@H:20]([O:21][C:22](=[O:37])[C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[O:12])=[CH:9][CH:8]=1)(C)(C)C>C(OCC)(=O)C>[ClH:1].[OH:6][C:7]1[CH:46]=[CH:45][C:10]([C:11]([NH:13][CH:14]2[CH:20]([O:21][C:22](=[O:37])[C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:36])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)=[O:12])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(C(=O)c3ccccc3)cc2)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NC1CNCCCC1OC(=O)c1ccc(C(=O)c2ccccc2)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 ml of 5N HCl in ethyl acetate were added at room temperature while stirring to 922 mg of the azepine prepared in Example 19 in 4.0 ml of ethyl acetate. The reaction mixture was stirred at room temperature overnight and the precipitate was filtered off, washed three times with 2 ml of ethyl acetate and dried at 50° C./25 mbar for 16 hours yielding 0.70 g of 3-(4-hydroxy-benzoylamino)-4-(4-benzoyl-benzoyloxy)-hexahydroazepine hydrochloride.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:22]1([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=23)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCc3nc4ccccc4c(-c4ccccc4)c3C2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc(-c2c3c(nc4ccccc24)CCNC3)cc1
Reaction time: 9 h
Yield: 49 %

Procedure:
Palladium black (125 mg) was added to a solution of 2-benzyl-10-phenyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine (1.25 g, 3.57 mmol) in acetic acid (9 ml), and the resulting mixture was stirred under a hydrogen atmosphere for 9 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was made basic with 1N sodium hydroxide and extracted with diethyl ether. The extract solution was dried over anhydrous sodium sulfate and concentrated under reduced pressured to be freed of the solvent, and the residue was washed with diethyl ether to obtain the desired compound (0.45 g, 1.75 mmol, 49%).
Reaction SMILES: CN1CCCC1=O.[CH2:8]([NH:15][C:16]1[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:35]1[CH2:36][CH2:37][N:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:18]3[N:17]=[C:16]([NH:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1)[CH3:44]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1cnc(Nc2ccc(N3CCNCC3)cc2)nc1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CN1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCc4ccccc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 5 ml portion of 1-methyl-2-pyrrolidone solution of 400 mg of 4-benzylamino-2-[(4-piperazin-1-ylphenyl)amino]pyrimidine-5-carboxamide was mixed with 0.12 ml of ethyl bromoacetate and 200 mg of potassium carbonate, followed by stirring at room temperature for 30 minutes. The reaction mixture was mixed with water, and the organic layer was extracted with ethyl acetate-THF mixed solvent. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the residue obtained by evaporating the solvent was washed with methanol to obtain ethyl[4-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]acetate as a pale brown solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]#[N:13])[N:9]=[CH:8]1.[CH3:16][CH2:17][Mg+].[Br-].O>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2([NH2:13])[CH2:17][CH2:16]2)[N:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1cnc(C#N)c1
Reactant: CC[Mg+]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(C2(N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a round bottom flask was added 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (310 mg, 3.19 mmol) in THF (10 ml), followed by the addition Ti(OiPr)4 (0.9 ml, 3.05 mmol) Next, EtMgBr (3.0 M in ether) (1.85 ml, 5.55 mmol) was added slowly. The clear solution changed to dark and gas evolved was found. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was added with water (10 ml). The solid precipitate was filtered through celite. The filter cake was washed with THF (10 ml), EtOAc (10 ml). The combined solvent was concentrated to afford 400 mg of 1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-cyclopropylamine, m/z 254.6 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(-c2cccc3c2CC(CC2CCCCC2)=C3)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
82.3 g (229 mmole) 7-(4′-tert-Butyl-phenyl)-2-cyclohexylmethyl-indan-1-one were dissolved in 292 ml toluene in a 1 l—roundbottom flask equipped with a reflux condenser. 9.5 g (1.1 eq.) sodium borohydride were added. Then 40 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 3 h at 50° C. An additional 1 g of sodium borohydride and 5 ml methanol were added and the mixture was stirred another 2 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 350 ml of toluene. After addition of 0.7 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate, evaporation of the solvent and crystallization from 800 ml ethanol afforded 67.3 g (86%) of the desired indene as white crystals. 1H-NMR (400 MHz, CDCl3): δ=7.45, 7.33, 7.25, 7.14 (4×m, 7H, aromatic), 6.69 (s, 1H, ═CH), 3.35 (s, 2H, benzylic), 2.34 (d, 2H, aliphatic), 1.71-1.50 (m, 6H, aliphatic), 1.39 (s, 9H, C(CH3)3), 1.24-0.87 (m, 5H, aliphatic) ppm.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3]>[Pd].C(O)C>[CH3:8][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:9][CH2:10][OH:11]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCCC(C)CCO
Reaction time: 21 h
Yield: 54.5 %

Procedure:
A flask containing a stirring suspension of geraniol (10 ml, 58 mmol) and palladium on carbon (10% Pd, 0.494 g, 0.08 eq) in ethanol (70 ml) was evacuated, and then filled with hydrogen. The reaction mixture was then stirred under an atmosphere of hydrogen for 21 hours. After this time the reaction was filtered and the filtrate concentrated in vacuo to give 43 (5 g, 55%) as a colourless oil.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][CH:35]([CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])[CH2:36][CH:37]=O>>[CH3:34][CH:35]([CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])[CH2:36][CH:37]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)=CCCC(C)CC=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)=CCCC(C)CC=CCc1ccccc1
Yield: 51.4 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.48 g, 7.78 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.9 mL, 7.78 mmol, 1.0 equiv.) and 3,7-dimethyloct-6-enal (1.80 g, 11.7 mmol, 1.5 equiv.), 0.97 g (51%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[C:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([N:21]4[CH:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)[N:23]=[CH:22]4)=[C:15]3[C:14]([CH:32]([CH3:34])[CH3:33])=[N:13]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].[OH:35]O.[OH-].[Na+].O>CS(C)=O>[CH2:1]([NH:3][C:4]1[CH:11]=[C:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([N:21]4[CH:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)[N:23]=[CH:22]4)=[C:15]3[C:14]([CH:32]([CH3:33])[CH3:34])=[N:13]2)[CH:9]=[CH:8][C:5]=1[C:6]([NH2:7])=[O:35])[CH3:2]
Reactant: OO
Reactant: CCNc1cc(-n2nc(C(C)C)c3c(-n4cnc(-c5cnn(C)c5)c4)ccnc32)ccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCNc1cc(-n2nc(C(C)C)c3c(-n4cnc(-c5cnn(C)c5)c4)ccnc32)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Compound (100b) (1.00 g), copper iodide (0.248 g), cesium carbonate (2.12 g), and 4-bromo-2-(ethylamino)benzonitrile (0.932 g) were suspended in 1,4-dioxane (10 mL), and N,N′-dimethylethylenediamine (0.560 mL) was added to the suspension, followed by stirring at 150° C. for 20 hr. The reaction solution was distributed between chloroform and water. The organic layer was washed with a 2 N aqueous sodium hydroxide solution and dried over magnesium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (1.13 g, 77%) as a white solid. 2-(Ethylamino)-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (0.700 g) was dissolved in DMSO (10 mL), and a 30% hydrogen peroxide solution (0.310 mL) and a 4 N aqueous sodium hydroxide solution (1.16 mL) were added to the resulting solution, followed by stirring at room temperature for 10 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (109) (0.655 g, 90%) as a white solid.
Reaction SMILES: [CH:1]([S:4]([CH3:7])(=[O:6])=[O:5])([CH3:3])[CH3:2].CO.C[O-].[Na+].[C:13]([O:18][CH3:19])(=[O:17])[C:14]([O-])=[O:15].Cl>C1COCC1>[CH:1]([S:4]([CH2:7][C:14](=[O:15])[C:13]([O:18][CH3:19])=[O:17])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C(=O)[O-]
Reactant: CC(C)S(C)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(=O)CS(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a mixture of i-propylmethylsulfone (5.17 g, 42.3 mmol) and THF (20 mL) was added 28% sodium methoxide methanol solution (8.58 g, 44.5 mmol) at room temperature, and then methyl oxalate (5.0 g, 42.3 mmol) was gradually added to the mixture at room temperature. The resulting mixture was stirred at room temperature overnight. To the reaction mixture was added ice-water (200 mL), and the pH of the resulting mixture was adjusted pH3 or less than pH3 with 2 mol/L hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL). The extract was washed with brine (200 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (ethyl acetate/n-hexane) to give methyl 3-(i-propylsulfonyl)-2-oxopropanoate (2.7 g, yield: 28%) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([CH2:14][OH:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (4.7 g) in tetrahydrofuran (40 ml), a borane-tetrahydrofuran complex (0.95 M solution in tetrahydrofuran, 31.6 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ice water and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (4.2 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[C:27]1[C:31]([C:32](O)=[O:33])=[C:30]([CH3:35])[O:29][N:28]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>C1COCC1>[C:12]1([CH2:11][CH2:10][CH2:9][C:8]([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:32]([C:31]3[C:27]([C:21]4[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=4[Cl:19])=[N:28][O:29][C:30]=3[CH3:35])=[O:33])[CH2:3]2)=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)O
Reactant: NC1CCCN(C(=O)CCCc2ccccc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NC1CCCN(C(=O)CCCc2ccccc2)C1
Yield: 66 %

Procedure:
Combine 1-(3-amino-piperidin-1-yl)-4-phenyl-butan-1-one (250 mg, 1.02 mmol) with 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid (260 mg, 1.02 mmol), 1.3-dicyclohexylcarbodiimide (209 mg, 1.01 mmol) and 1-hydroxybenzotriazole (138 mg, 1.02 mmol) in THF and stir overnight at room temperature. Concentrate and elute over silica gel using THF/dichloromethane to give the desired product (326 mg, 66%). MS(ES): (M+1)+ 484.1, 486.1 m/z.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH:24]([O:26]CCCC)=[CH2:25].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl.CCN(CC)CC>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([C:24](=[O:26])[CH3:25])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CCC(c2cccc(OS(=O)(=O)C(F)(F)F)c2)CC1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN1CCC(c2cccc(C(C)=O)c2)CC1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of trifluoro-methanesulfonic acid 3-(1-propyl-piperidin-4-yl)-phenyl ester (300 mg) in DMF (4 ml) under argon atm at r.t. was subsequently added NEt3 (356 μL), butyl vinyl ether (823 μL), 1,3-bis(diphenylphosphino)propane (50 mg), and Pd(OAc)2 (19 mg). The reaction mixture was then heated to 80° C. and after 2 h the reaction was stopped. 5% Hydrochloric acid solution (6 ml) was added and the combined mixture stirred for 45 min. Then CH2Cl2 was added and the phases were separated. The aqueous layer was then extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash chromatography (MeOH:CH2Cl2 (1:9 (v/v)). Collection of the fractions containing pure product and evaporation of the solvent afforded pure 1-[3-(1-Propyl-piperidin-4-yl)-phenyl]-ethanone (35 mg). MS m/z (rel. intensity, 70 eV) 245 (M+, 4), 216 (bp), 100 (19), 70 (36), 57 (13).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23]Cl)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[I-:26].[Na+]>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23][I:26])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: [I-]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCCl)C(=O)OC)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCI)C(=O)OC)cc1

Procedure:
A solution of 4.80 g of methyl 2-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]-5-chloropentanoate of Step 1 and 15 g of sodium iodide in 25 ml of acetone was stirred at room temperature for 3 days. Solvent was removed under reduced pressure, and the residue was washed with water. The product was dried to give methyl 2-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]-5-iodopentanoate as a pale yellow solid, Electrospray Mass Spec 480.2 (M+H)+.
Reaction SMILES: O1CCOC1[C:6]1[N:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:20]1[CH2:25][CH2:24][O:23][CH:22]1[CH:21]=[CH:12][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][N:11]=1
Reactant: O=Cc1cccc(C2OCCO2)n1
Reactant: C1COCCO1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: C(=CC1OCCO1)c1ccccn1

Procedure:
A mixture of 3.10 g of 6-[1,3]dioxolan-2-yl-pyridine-2-carbaldehyde (17.3 mmol), 9.26 g of (methyl)triphenylphosphonium bromide (25.9 mmol) and 4.80 g of potassium carbonate (34.8 mmol) in 60 ml of 1,4-dioxane is maintained under reflux for 5 hours. The solid is removed by filtration and then the solvent is evaporated off. The residue is taken up in ethyl acetate, the solution is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. After evaporation of the solvent, the title compound is isolated by chromatography on a silica column (eluent: hexane/ethyl acetate; 80:20). 1.63 g of a yellow oil are obtained.