Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[CH2:23](O)[CH2:24][CH3:25].O>CN(C=O)C>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([O:22][CH2:23][CH2:24][CH3:25])=[O:21]
Reactant: CCCO
Reactant: O=C(O)c1ccccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
CDI (2.34 g, 14.48 mmol) was added to a solution of salicylic acid (2.00 g, 14.48 mmol) in DMF (40 mL). The reaction mixture was stirred at 50° C. for 4 h and PrOH (2.72 mL, 36.20 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 16 h and allowed to reach r.t. It was poured into H2O (20 mL) and extracted with Et2O (2×40 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 2.05 g of propyl 2-hydroxybenzoate (colourless oil, yield: 79%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:18])[CH3:17]>O1CCCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:18])[CH3:17])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(=O)Cl
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Solvent: C1CCOC1
Product: CC(=O)NCC(C)c1ccc(-c2ccsc2)cc1
Reaction time: 6 h

Procedure:
To a solution of 1.0 mL (0.088 mmol) of a 0.088 M solution of 2-(4-(3-thienyl)phenyl)propylamine in tetrahydrofuran was added 37 mg (0.132 mmol) of piperidinylmethyl polystyrene. To the mixture was added 10.4 mg (0.132 mmol) of acetyl chloride and the mixture was shaken for 6 hours. To this mixture was added 0.15 g (0.3 mmol) of aminomethyl polystyrene and the vessel was shaken for 12 hours. The reaction mixture was filtered through a cotton plug and concentrated to afford the title compound. The NMR spectrum was consistent is with the proposed title structure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.[Li+].[OH-].C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:13][C:14]([OH:16])=[O:15])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)Cn1c(=O)oc2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
(6-Chloro-2-oxo-benzooxazol-3-yl)-acetic acid was prepared by heating 6-chloro-3H-benzooxazol-2-one and ethyl chloroacetate in the presence of cesium carbonate in DMF at 60° C. The crude residue was dissolved followed in 1N LiOH in THF and stirred at rt. The resultant mixture was acidified with 1N HCl to pH ˜1. The desired product precipitated out of solution and was isolated by filtration, and used directly in subsequent reactions without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][N:11]3C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.O1CCOCC1.[ClH:28]>O1CCOCC1>[ClH:28].[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][NH:11]3)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc(I)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Ic1ccc(N2CC3CC2CN3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl 5-(4-iodophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (335 mg, 0.84 mmol) in anhydrous dioxane (3 ml) was added 4M-hydrogen chloride dioxane solution (4 ml, 16 mmol). After stirring at room temperature for 2 hrs, the mixture was concentrated under reduced pressure, dichloromethane was added and the mixture was concentrated again. The residue was washed with diethyl ether and dichloromethane, and dried to give 5-(4-iodophenyl) -2,5-diazabicyclo[2.2.1]heptane hydrochloride (272 mg, 96%) as a pale-green solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:29]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1
Reactant: NCCOCC(O)c1ccccc1
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCOCC(O)c1ccccc1)c1cccnc1
Reaction time: 0.08 h
Yield: 23.6 %

Procedure:
1.23 g of N,N'-dicyclohexylcarbodiimide was added, with ice cooling, to a solution of 1.08 g of 2-(2-aminoethoxy)-1-phenylethanol, 730 mg of nicotinic acid, 810 mg of 1-hydroxybenzotriazole and 0.83 ml of triethylamine dissolved in 5 ml of tetrahydrofuran. The resulting mixture was stirred a the same temperature for 5 minutes and further at room temperature for 1 hour. To the reaction mixture was added 11 ml of ethyl acetate. The insolubles were removed by filtration. To the filtrate was added 5 ml of water and the mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted with 5 ml of water. The extract was combined with the previously separated aqueous layer. The combined aqueous layer was mixed with 20 ml of chloroform and adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=15/1) to obtain 400 mg of oily 2-(2-nicotinoylaminoethoxy)-1-phenylethanol (compound No. 216).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)CCl.CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:40]=[C:41]([N:45]2[S:49](=[O:51])(=[O:50])[NH:48][C:47](=[O:52])[CH2:46]2)[CH:42]=[CH:43][CH:44]=1.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.C1(C)C=CC=CC=1.CCOC(C)=O.C1(C)C=CC=CC=1>[O:51]=[S:49]1(=[O:50])[NH:48][C:47](=[O:52])[CH2:46][N:45]1[C:41]1[CH:40]=[C:39]([NH:38][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=3)=[CH:21][CH:20]=2)=[O:24])[CH:44]=[CH:43][CH:42]=1
Reactant: Nc1cccc(N2CC(=O)NS2(=O)=O)c1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3cccc(N4CC(=O)NS4(=O)=O)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.06 mmol of 4′-(octyloxy)-4-biphenyl-carboxylic acid, 1.06 mmol of EDC and 1.06 mmol DIPEA are added to a mixture of 0.53 mmol of 5-(3-amino-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 0.11 mmol of HOAt in 6 ml of a DMF/toluene-mixture. The mixture obtained is stirred at rt for 18 hours, diluted with EtOAc and toluene and a precipitate is obtained and filtered off. 4′-Octyloxy-biphenyl-4-carboxylic acid [3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-amide in solid form is obtained. The filtrate obtained is washed with HCl (1M) and brine, the organic layer is dried and solvent is evaporated. Further 4′-octyloxy-biphenyl-4-carboxylic acid [3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-amide is obtained.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[F:21][C:22]([F:26])([F:25])[CH2:23][OH:24].Cl>>[C:1]([O:24][CH2:23][C:22]([F:26])([F:25])[F:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: OCC(F)(F)F
Agent: Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(F)(F)F
Yield: 96.1 %

Procedure:
Oleoyl chloride (75 g, 250 mmol) is heated at reflux with 2,2,2-trifluoroethanol (60 g, 600 mmol) for 16 hrs. After the evolution of HCl ceased, excess trifluoroethanol is removed in vacuo. Vacuum distillation of the residue afforded 87.6 g of 2,2,2-trifluoroethyl oleate as colorless liquid, by 150°/0.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.C([Mg]Br)(C)C.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cc(Br)ccc1I
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1C(=O)CCC(=O)O
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of 4-bromo-1-iodo-2-methylbenzene (148 mg, 0.5 mmol) in THF (10 mL) at −25° C. was added isopropylmagnesium bromide (0.5 mL, 0.5 mmol) and stirred 3 h. Succinic anhydride (55 mg, 0.55 mmol) was added and the reaction was stirred 18 h. The mixture was quenched with water (10 mL) and washed with 1N NaOH (10 mL), 1N HCl (10 mL), brine (10 mL) and dried (MgSO4). The organic layer was concentrated in vacuo and the residue purified by flash chromatography (0-100% EtOAc/Hexane) to afford 55A (42 mg, 31%) as a crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.98 (t, 3 H) 2.42 (q, 2 H) 2.73 (t, 2 H) 4.10 (t, 2 H) 6.82 (d, 1 H) 7.02 (d, 1 H) 7.09 (t, 2 H) 7.15 (t, 1 H) 7.36 (d, 1 H) 7.58-7.63 (m, 1 H).
Reaction SMILES: [NH2:1][C@H:2]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[CH:3]=[O:4].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].[Na]>>[C:13]([NH:1][C@H:2]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[CH2:3][OH:4])(=[O:16])[CH:14]=[CH2:15]
Reactant: N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=CC(=O)Cl
Agent: [Na]
Product: C=CC(=O)N[C@@H](CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
An attempt was done to prepare the same compound by reacting 2-amino-2-deoxy-D-glucose and acryloyl chloride, followed by reduction of the product with sodium boronhydride. However, it was not possible to get pure N-acryloyl-2-amino-2-deoxy-D-glucitol in this way.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2([C:38](O)=[O:39])[CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:38]([C:35]4([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:37][CH2:36]4)=[O:39])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)C4(c5ccccc5)CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-[4′-(4-aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-cyclopropanecarboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]C)=[C:10]([Br:17])[CH:9]=2)=[O:5])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Br:17])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)c(Br)cc2[nH]1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)c(Br)cc2[nH]1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
The solution of 8.30 g (27.8 mmol) 6-bromo-5-methoxy-1H-indole-2-carboxylic acid ethyl ester (prepared according to J. Org. Chem. 1974, 39, 3580) in 160 mL dichloromethane was cooled to −78° C. At this temperature, 55.7 mL boron tribromide (55.7 mmol; 1M solution in dichloromethane) were added. The solution was allowed to warm to room temperature and after 30 min. The solution was poured on 10% aqueous sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with n-hexane: ethyl acetate (2:1 v/v) as eluant to give 5.7 g (72%) of the product as a light yellow solid. MS (m/e): 282.2 (M−H+, 100%).
Reaction SMILES: O=O.[CH3:3][C:4]1[C:9]([OH:10])=[C:8]([CH:11]=[O:12])[C:7]([CH2:13][O:14]P(O)(O)=O)=[CH:6][N:5]=1>P([O-])([O-])([O-])=O>[CH3:3][C:4]1[N:5]=[CH:6][C:7]([CH2:13][OH:14])=[C:8]([CH:11]=[O:12])[C:9]=1[OH:10]
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=O
Agent: O=P([O-])([O-])[O-]
Product: Cc1ncc(CO)c(C=O)c1O

Procedure:
A 3.87 g (0.06 mmol) portion of the thus obtained hemoglobin was dissolved in 0.1 M phosphate buffer (pH 8.0), and the solution was adjusted to a total volume of 25 ml. After de-oxidation of the solution by vigorous blowing of argon until the partial pressure of oxygen reached 2 mmHg or less, addition of pyridoxal 5′-phosphate was effected in accordance with a known method (R. Benesch et al., J. Biol. Chem., 257 (3), 1320-1324, 1982) to obtain pyridoxal-modified hemoglobin. The thus obtained pyridoxal-modified hemoglobin solution was adjusted to a total volume of one liter by adding 0.1 M borate buffer (pH 8.2).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH:5]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>[OH-].[Na+].CO>[O:21]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][N:12]1[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][C:3]([OH:22])=[O:2]
Reactant: COC(=O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acid methyl ester (0.5 mmol, 1 eq) is dissolved in 8 mL 1 M NaOH/MeOH (25% V/V) and stirred at room temperature for 2 h. The solution is acidified with 1 M HCl and extracted with dichloromethane. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acid is obtained as red-orange residue (81% yield); ES-MS (MH+)=282.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>O1CCCC1.CCCCCC.C(OCC)C.O>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([B:15]([OH:20])[OH:16])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(B(O)O)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 g (5.32 mmol) of 5-bromo-2-methoxypyridine is dissolved in 10 ml of absolute tetrahydrofuran and cooled to −78° C. Addition of 0.4 g (6.38 mmol) of a 1.6 M n-butyllithium solution in hexane results in a yellow solution which is stirred at the given temperature for 30 min. Addition of 3 g (15.9 mmol) of triisopropyl borate is followed by stirring for a further hour, during which the solution warms to −20° C. Water is added, and the mixture is stirred overnight. The crude solution is acidified to pH 5 with 1 N hydrochloric acid and extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated, resulting in a pale brown solid which is suspended in diethyl ether and filtered. 0.38 g (47% of theory) of the product is isolated.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31]>CC(C)=O>[OH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]=[N:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(N=Nc2ccc(OCCCCCCO)cc2)cc1

Procedure:
22.3 g of 4'-cyano-4-hydroxyazobenzene and 14 g of dry potassium carbonate are dissolved in 100 ml of absolute acetone, a pinch of KI is added, and 15.3 g of 6-chlorhexan-1-ol are then added dropwise at the boil. The reaction mixture is refluxed for 6 days. The precipitated potassium chloride is filtered off under suction from the warm mixture, and the solution is evaporated down. 200 ml of CHCl3 are added to the dye obtained, and the chloroform solution is filtered off drom undissolved material, extracted by shaking four times with H2O and evaporated down. The crude product is recrystallized from 300 ml of acetone.
Reaction SMILES: Cl.[C:2]1([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[C:2]1([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([O:11][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1ccccc1)N1CCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCC1
Temperature: 25 °C
Yield: 3.6 %

Procedure:
2-Phenyl-2-(piperidin-1-yl)acetic acid hydrochloride (0.87 g, 3.40 mmol) was suspended in dry THF (34.0 ml) and, while stirring at room temperature, DCC (1.40 g, 6.80 mmol), HOBT (1.04 g, 6.80 mmol) and (R)-quinuclidin-3-ol (1.30 g, 10.21 mmol) were sequentially added. The white suspension was stirred at the same temperature overnight (UPLC-MS: complete conversion). THF was evaporated and the residue was taken up with EtOAc (30 ml) and washed with water (20 ml) and then with a sat. NaHCO3 (20 ml). The organic phase was dried over Na2SO4, filtered was evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=98/2/0.2 to 97/3/0.3) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate (40 mg, 40% yield) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32]C)=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].O=C(CC1C(F)=CC=CC=1[Cl:53])C(OC)=O.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH3:32])=[O:30])=[CH:21]\[C:22]2[C:23]([F:28])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:53])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)Cc1c(F)cccc1Cl
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: COC(=O)/C(=C/c1c(F)cccc1Cl)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 26 %

Procedure:
The title compound was prepared as described for C4 using methyl 2-oxo-3-(2-chloro-6-fluorophenyl)propanoate B14 (Otava, 100 mg, 0.434 mmol), sodium hydride (10.41 mg, 0.434 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (178 mg, 0.434 mmol). The compound was isolated in the form of white solid in 26% yield.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[CH:1]1([C:7]([C:13]2[CH:14]=[CH:15][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
42.6 g (0.291 mol) of cyclohexanecarbonyl chloride and then 30 g (0.277 mol) of anisole are added dropwise at room temperature to a suspension of 44.4 g (0.33 mol) of aluminium chloride in 120 ml of dichloroethane. The reaction mixture is stirred for 1 h and allowed to stand overnight. For working up, the mixture is poured into ice-water and the aqueous phase is extracted with dichloromethane. The organic phase is washed with 1N NaOH and water, dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:13]1[C@@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][N:14]1C(OC(C)(C)C)=O)(=[O:6])=[O:5])([CH3:3])[CH3:2].[ClH:29]>>[ClH:29].[CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:13]1[C@@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][NH:14]1)(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1S(=O)(=O)C(C)C
Agent: Cl
Product: COC(=O)[C@H]1CCN[C@H]1c1ccccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 13B (0.27 g) was added hydrogen chloride (4M in dioxane, 2 mL). The reaction was stirred for 2 h at rt. The solvent was removed to give 0.18 g of 13C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1)=[O:5].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)CC>[CH2:21]([NH:28][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1)=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCBr)cc1
Solvent: CCCO
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCc2ccccc2)cc1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A suspension of 6-[4-(3-bromopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (120 g, 0.355 mol) and benzylamine (152 g, 1.47 mol) in n-propanol (800 ml) was stirred under reflux for 16 hours. The reaction mixture was filtered whilst hot and white solid was collected, which was washed with ether to remove excess benzylamine. The crude material was boiled with ethanol (300 ml) for 2 hours; the mixture was cooled and filtered. The resulting white solid was washed with ether and dried to give 6-[4-(3-benzylaminopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (114 g, 88%) as the hydrobromide salt m.p. 279°-285° C.