Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[N:6]([CH3:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc2[nH]cc(C(C)=O)c(=O)c2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1ccc2c(c1)c(=O)c(C(C)=O)cn2C
Temperature: 90 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a suspension of ethyl 3-acetyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (5.74 g, 22.14 mmol) in N,N-dimethylformamide (120 ml) was added potassium carbonate (9.18 g, 66.4 mmol) and methyl iodide (4.2 ml, 67.2 mmol). The mixture was stirred at 90° C. for 1 h. After cooling, the reaction was filtered, concentrated under high vacuum, diluted with dichloromethane/ethyl acetate, and filtered through a silica plug to afford ethyl 3-acetyl-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (3.64 g, 13.32 mmol, 60.2% yield. LCMS: (M+H)+: 274.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CC(C)([O-])C.[K+].[C:18]([O:22][C:23]([N:25]1[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28]OS1(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl>CN(C=O)C>[C:18]([O:22][C:23]([NH:25][C:30]([CH3:31])([CH3:32])[CH2:29][CH2:28][N:8]1[C:9]2[C:5](=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Reactant: CSc1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc2c(ccn2CCC(C)(C)NC(=O)OC(C)(C)C)c1

Procedure:
Under a nitrogen atmosphere 500 mg (2.6 mmol) 5-(methylsulphanyl)-indole (Yang et al., Heterocycles, 1992, vol. 34, No. 6, page 1169-1175) are dissolved in 6 ml DMF and combined with 357 mg (3.2 mmol) potassium-tert-butoxide with stirring and cooling with ice. Then the mixture is stirred for 10 minutes at 0° C. 768 mg (2.9 mmol) N-tert-butoxycarbonyl-4,4-dimethyl-[1,2,3]oxathiazinane-2,2-dioxide (Component XI) are added. The mixture is then stirred for three hours at ambient temperature. Then the reaction solution is poured onto water and hydrochloric acid (1.2 mmol) and extracted with ethyl acetate. The organic phases are combined, dried on sodium sulphate and freed from the solvent in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH2:10].[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])C=C>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(C)cc1C
Product: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(C)c1
Yield: 74 %

Procedure:
The representative procedure was followed using 2,4-dimethyl-1-vinylbenzene (66 mg, 0.50 mmol), tert-butyl acrylate (128 mg, 1.00 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel (eluting with 2% EtOAc/hexanes) afforded the product as a colorless oil (86 mg, 74%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[OH:27][CH2:28][C:29]([NH:38]C(=O)OC(C)(C)C)([CH2:36][OH:37])[CH2:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]>C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[NH2:38][C:29]([CH2:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1)([CH2:28][OH:27])[CH2:36][O:37][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)Cc1ccsc1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1cc(COCC(N)(CO)Cc2ccsc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (50 mg, 0.11 mmol) in 1 mL CH2Cl2 cooled to 0° C. was added intermediate III tert-butyl 2-hydroxy-1-(hydroxymethyl)-1-(thien-3-ylmethyl)ethylcarbamate (81 mg, 0.28 mmol), silver triflate (72 mg, 0.28 mmol) and 2,6-ditert-butylpyridine (76 μL, 0.34 mmol). The reaction mixture was stirred at 0° C. for 40 min and purified by flash chromatography (20 g silica, 30->80% EtOAc/hexanes) and by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl 2-({3-({[(1R)-1-(4-fluorophenyl)ethyl]amino}carbonyl)-5-[methyl(methylsulfonyl)amino]benzyl}oxy)-1-(hydroxymethyl)-1-(thien-3-ylmethyl) contaminated with 2,6-ditert-butylpyridine. Treatment with 10% TFA in CH2Cl2 for 30 min, followed by concentration under a stream of nitrogen, and purification by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) afforded 3-{[2-amino-3-hydroxy-2-(thien-3-ylmethyl)propoxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide as a TFA salt. 1H NMR (400 MHz, d4-MeOH) δ 8.86 (d, J=7.9 Hz, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.48-7.36 (m, 3H), 7.17 (s, 1H), 7.10-7.00 (m, 2H), 6.95 (d, J=5.0 Hz, 1H), 5.30-5.20 (m, 1H), 4.68 (A of AB, d, J=12.0 Hz, 1H), 4.63 (B of AB, d, J=12.0 Hz, 1H), 3.57 (s, 2H), 3.51 (A of AB, d, J=11.0 Hz, 1H), 3.45 (B of AB, d, J=11.0 Hz, 1H), 3.09 (s, 3H), 3.04 (A of AB, d, J=13.6 Hz, 1H), 3.45 (B of AB, d, J=13.6 Hz, 1H), 2.94 (s, 3H), 1.58 (d, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.Cl.C([OH:26])C>>[CH3:15][C:14]1[C:3]2[C:2](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[N:13]=1
Reactant: Cc1cccc(-n2nc(C)c3c(Cl)c4ccccc4nc32)n1
Reactant: CCO
Agent: Cl
Product: Cc1cccc(-n2nc(C)c3c(=O)c4ccccc4[nH]c32)n1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 4-chloro-3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.00 g, 6.48 mmol) in ethanol (90 mL), 6N hydrochloric acid (3 mL, 18.0 mmol) was added and the mixture was heated under reflux for 4 hours. The reaction solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol, air dried, and recrystallized from ethanol to give the title compound (1.55 g, 82% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>C(O)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:19](=[N:18][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOCc1nc2cnc3ccccc3c2n1N=Cc1ccccc1
Temperature: 120 °C
Yield: 59.2 %

Procedure:
A solution of 2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19 mmol) in 50 mL of isopropanol was treated with benzaldehyde (0.66 mL, 6.50 mmol) and 10 mg of p-toluenesulfonic acid. The reaction mixture was heated to 120° C. for 3 d. The reaction mixture was cooled, and a precipitate started to form. The reaction mixture was treated with Et2O and then filtered to give N-benzylidene-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.21 g) as a gray solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:30]I.O>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([O:7][CH3:30])=[O:6]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Reaction time: 1 h

Procedure:
A solution of 7.20 g of 3-fluoro-4-(hexadecylamino)benzoic acid in 25 ml of hexamethylphosphoramide is added to a stirred mixture of 0.800 g of sodium hydride (57% in mineral oil) and 25 ml of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g of methyl iodide and is then stirred at 25° C. for 18 hours Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 3-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8]C=1F)(=[O:3])[NH2:2].[NH2:26]C1C=CN=C(C(N)=O)C=1.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][N:26]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc(N)ccn1
Reactant: COc1ccc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)cc1OC
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2ccnc(C(N)=O)c2)C(=O)O)cc1OC
Yield: 63 %

Procedure:
99C was prepared in a procedure similar to that of 13A using 99B, 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 63%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.83 (s, 3H) 3.84 (s, 3H) 5.45 (s, 1H) 6.95-7.01 (m, 2H) 7.05-7.11 (m, 3H) 8.11 (d, J=6.59 Hz, 1H); LCMS: 331 (M+1).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:2]=1.C1(C2C=CC(C(OC)=O)=CC=2)C=CC=C(C(OC)=O)C=1.C(O)CO>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:11]12[C:1]3[CH:6]=[CH:5][C:4](=[CH:3][CH:2]=3)[C:7](=[O:8])[O:9][CH2:10][CH2:20][O:19][C:17](=[O:18])[C:14]([CH:15]=[CH:16]1)=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: COC(=O)c1ccc(-c2cccc(C(=O)OC)c2)cc1
Solvent: OCCO
Product: O=C1OCCOC(=O)c2ccc(cc2)-c2ccc1cc2
Temperature: 260 °C
Reaction time: 2.7 h

Procedure:
A clear solution of 243.3 g (0.900 mole) of dimethyl 4,4'-biphenyldicarboxylate, 81.2 g of dimethyl 3,4'-biphenyldicarboxylate, 150.5 g (2.43 mole) of ethylene glycol and 50 μL of titanium tetraisopropoxide is stirred at 217° C. under nitrogen in a 1-L round bottom flask equipped with a paddle stirrer, Vigreaux column, distillation head, condenser, receiver and nitrogen inlet. The apparatus is heated in a molten salt bath until methanol begins to distill. After 2.7 hours, the temperature is slowly increased to 260° C. where it is held for 45 minutes. The distillate (104 mL) that has collected is discarded. Over the next 48 minutes the temperature is increased to 300° C. and the pressure is slowly reduced to 1 mm Hg. More liquid is distilled. The viscosity of the clear reaction mass slowly increases. After 8 minutes at 300° C., the heating bath is lowered and nitrogen is admitted. The polymer solidifies to an opaque creamy white solid when it cools. It is ground to coarse granules in a Wiley mill. The copolyester has an inherent viscosity of 0.72 dL/g, a Tg of 122° C. and a Tm of 293° C. The molecular weight of this polymer is advanced in the solid state by stirring the granules at 240° C. and 1 mm Hg for 3.2 hours. The advanced polymer has an inherent viscosity of 1.05 dL/g. It is injection molded into standard one eight-inch thick test bars at 316° C. into a mold held at 65° C. using an Arburg 170CDM injection molding machine. The tensile modulus and impact strength of these test bars are measured using procedures described in ASTM Test Nos. D638 and D256, respectively. The tensile modulus is 578 kpsi and the notched Izod impact strength is 1.2 ft. lb./in.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>CN1CCCC1=O.C(OCC)(=O)C>[F:27][C:26]([F:28])([F:29])[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:20][CH:21]=1)([OH:34])[C:30]([F:31])([F:33])[F:32]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C(=O)C1
Reaction time: 14 h
Yield: 31.6 %

Procedure:
To a stirring solution of tert-butyl 3-oxopiperazine-1-carboxylate (9.99 mmol, 2 g) in dry N-methyl-2-pyrrolidinone (2 mL) was added sodium hydride (30.0 mmol, 1.198 g). The mixture was stirred at room temperature under nitrogen for 20 min before the addition of 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (10.99 mmol, 3.70 g). The mixture was stirred for a further 14 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (4×75 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with dichloromethane—3.5% methanol/96.5% dichloromethane gradient) to afford the title compound (1.44 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH2:22][CH:23]([C:28]([O:30]C)=[O:29])[C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]([C:24]([OH:26])=[O:25])[C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(OCCOc3ccc(CC(C(=O)O)C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of dimethyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylmalonate (1.50 g, 3.21 mmol) in a mixture of methanol (12.9 ml) and tetrahydrofuran (6.4 ml) is added a 2 mol/L aqueous solution of sodium hydroxide (8.01 ml, 16.03 mmol). The mixture is stirred for 2 hours at room temperature, and then the solvent was removed under a vacuum. The residue is dissolved in water and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (1.38 g, 98%). HRMS calcd for C26H32O6: 440.5365. Found: 440.5363. MA calcd for C26H32O6: C, 70.89%; H, 7.32%. Found: C, 70.72%; H, 7.36%.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C@H:10]2[CH2:15][C@@H:14]([C:16](=[O:23])[CH2:17][C:18](OCC)=[O:19])[CH2:13][CH2:12][N:11]2[C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[C:1]([C:5]1[S:9][C:8]([C@H:10]2[CH2:15][C@@H:14]([C:16]3[O:23][NH:30][C:18](=[O:19])[CH:17]=3)[CH2:13][CH2:12][N:11]2[C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(C)(C)C)s2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(C)(C)C)s1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
Cis-methyl 2-(5-tert-butylthiophen-2-yl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (963 mg, 2.43 mmol) was dissolved in methanol (15 mL) and cooled to −40° C. NaOH (0.641 mL, 2.43 mmol) dissolved in water (1 mL) was added and stirred for 20 min. Hydroxylamine (50% by weight in water, 0.149 mL, 2.43 mmol) was added and the reaction stirred at −40° C. for 3 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M HCl (12.58 mL, 75.48 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (150 mL) and water (150 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (150 mL). The combined organic phase were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(5-tert-butylthiophen-2-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (436 mg, 49.1%) was isolated as a white solid. MS m/z 363 (M−H)−
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[Br:21][CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1
Reactant: COc1cc2nc(CCCO)sc2c(OC)c1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1cc2nc(CCCBr)sc2c(OC)c1OC
Reaction time: 1 h

Procedure:
2-(3-Hydroxypropyl)-5,6,7-trimethoxybenzothiazole (388 mg) was dissolved in dichloromethane (5 mL), carbon tetrabromide (590 mg) and triphenylphosphine (431 mg) were added to the solution at room temperature, and the mixture was vigorously stirred for 1 hour. Water was added to conduct extraction with dichloromethane, and the resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9) to obtain the title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH2:14]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[O:14]=[C:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N-(2,3-dihydro-1H-inden-5-yl)acetamide (50 g, 0.29 mol) in 150 mL of acetic acid and 40 mL of acetic anhydride was added dropwise to a solution of chromium trioxide in a mixed solution (30 mL of water and 140 mL of acetic acid) at a temperature of 10° C. (achieved by external cooling). After stirring overnight, the solution was poured into 2 L of ice water with vigorous stirring. The resulting solid was filtered and washed with cooled EtOH to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]=1[O:30][CH3:31]>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([O:28][CH3:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][C:17]=3[O:30][CH3:31])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: COc1cc(C2(OC)CCOCC2)ccc1O
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: COc1cc(C2(OC)CCOCC2)ccc1OCc1ccc2c(ccc(=O)n2C)c1
Yield: 49 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with 4-(4-hydroxy-3-methoxyphenyl)-4-methoxytetrahydropyran to give 4-[4-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)-3-methoxyphenyl]-4-methoxytetrahydropyran in 49% yield, m.p. 172°-173° C. (recrystallised from ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24].C(O)(=O)C(O)=O>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CC(C)CBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CC(C)CN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 51. Enantiomer E1 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.18 g, 0.92 mmol), acetonitrile (6 mL), potassium carbonate (0.25 g, 1.84 mmol), 1-bromo-2-methylpropane (0.1 mL, 0.92 mmol). Flash chromatography on silica gel (ethyl acetate/methanol, 9:1). Yield: 0.18 g. [α]D=+22.6° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 164-165° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 2), 212 (bp), 182 (46), 213 (12), 127 (8), 98 (6) 1-bromo-2-methylpropane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1>>[O:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and tetrahydro-2H-pyran-4-amine (CAN 38041-19-9) as starting materials, MS (LC/MS): 317.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([CH:7]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]=[C:35]=[O:36].C(OCC)(=O)C>CS(C)=O>[CH3:33][NH:34][C:35](=[O:36])[NH:1][C:2]1[O:6][C:5]([CH:7]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][N:3]=1
Reactant: Nc1nnc(C(CCc2ccccc2)NC(=O)OCc2ccccc2)o1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNC(=O)Nc1nnc(C(CCc2ccccc2)NC(=O)OCc2ccccc2)o1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
350 mg of benzyl [1-(5-amino-[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]-carbamate were dissolved in 5 ml of dry dimethyl sulfoxide, treated with 140 mg of potassium carbonate and 140 mg of methyl isocyanate, and stirred at 80° C. for 16 h. The reaction mixture was cooled, treated with ethyl acetate, washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Benzyl {1-[5-(3-methylureido)-[1,3,4]oxadiazol-2-yl]-3-phenylpropyl}carbamate was obtained, which was employed in the next stage (hydrogenolysis) without further purification.