Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][CH2:9][CH:10](O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(Cl)(Cl)Cl.CO>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:23]=[C:22]2[C:6](=[CH:5][CH:4]=1)[CH2:7][NH:8][CH2:9][CH:10]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: COc1ccc(CNCC(O)c2ccc(OC)c(OC)c2)cc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(c1ccc(OC)c(OC)c1)CNC2
Yield: 88.2 %

Procedure:
α-[[(4-methoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (950 mg) was dissolved in 7.2 ml of trifluoroacetic acid, and after adding thereto 0.22 ml of conc. sulfuric acid under ice cooling, the reaction was allowed to react for 45 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding chloroform, the mixture was basified by addition of 28% aqueous ammonia under ice cooling. By a separating procedure, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue obtained was subjected to silica gel column chromatography (chloroform-methanol-28% aqueous ammonia=15:1:0.1), giving 790 mg of 6-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline as oily matter.
Reaction SMILES: CN(C=O)C.[CH3:6][CH:7]([OH:16])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>O>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([O:16][CH:7]([CH3:6])[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CC(O)CCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
To 100 mL of DMF is added α-methyl-4-morpholinepropanol (15.9 g, 0.1 mol) and 7.2 g (50% in mineral oil, 0.15 mol) of NaH followed by 14.1 g (0.1 mol) of 1-fluoro4-nitrobenzene. Heat the reaction at 80° C. and monitor the reaction by thin-layer chromatography. Upon completion of the reaction add 100 mL of water and extract with ether. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[CH2:8][C:7](=O)[C:6]=2[C:5]([CH3:18])=[CH:4][C:3]1=[O:19].[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[CH3:1][N:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[CH2:8][C:7](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[C:6]=2[C:5]([CH3:18])=[CH:4][C:3]1=[O:19]
Reactant: Cc1cc(=O)n(C)c2c1C(=O)CC(c1ccsc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cc(=O)n(C)c2c1C(=NNC(=N)N)CC(c1ccsc1)C2
Yield: 93.4 %

Procedure:
To a mixture of 1,4-dimethyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.1 g) and aminoguanidine hydrochloride (41 mg) were added ethanol (3 ml) and 2N hydrochloric acid (0.2 ml), and the mixture was refluxed for 4 hours and concentrated under reduced pressure. To the residue was added ethanol (1 ml), and precipitated crystals were filtered, washed with ethanol and dried to give 1,4-dimethyl-5-guanidinoimino-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 137) (0.125 g) as colorless crystals.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].C=O.C1(N[CH:17]2[CH2:22]CCCC2)CCCCC1.[CH2:23]([SH:25])C>O1CCOCC1>[CH2:22]([S:25][CH2:23][C:2](=[CH2:1])[C:3]([OH:5])=[O:4])[CH3:17]
Reactant: CCS
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=C(O)CC(=O)O
Agent: C=O
Solvent: C1COCCO1
Product: C=C(CSCC)C(=O)O
Temperature: 70 °C
Yield: 52 %

Procedure:
A mixture of malonic acid (5.2 g, 50 mmol), paraformaldehyde (3.3 g, 110 mmol), dicyclohexylamine, 9.95 ml, 50 mmol) and ethanethiol 4.06 ml, 55 mmol) in dioxane (120 ml) was heated at 70° C. for 2 hours. The solvents were removed under reduced pressure, the residue was redissolved in ethyl acetate and the solution was extracted with saturated aqueous sodium hydrogen carbonate (4×20 ml). The combined aqueous layers were washed with ethyl acetate (20 ml) then acidified with 1 M hydrochloric acid. The resulting suspension was extracted into dichloromethane and the solution was dried over anhydrous magnesium sulfate, filtered and evaporated to provide the title compound as a white solid (3.76 g, 52%). 1H-NMR; δ (CDCl3), 9.89 (1H, brs), 6.35 (1H, s), 5.77 (1H, s), 3.39 (2H, s), 2.49 (2H, dd, J=7.4, 14.5 Hz) and 1.25 (3H, t, J=5.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH3:21].[Li]CCCC.[C:27]([O:31][C:32](=O)[O:33]C(C)(C)C)([CH3:30])([CH3:29])[CH3:28].O>C(Cl)Cl.CCCCCC>[C:27]([O:31][C:32]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:18][CH:17]=2)[C:12]([CH3:21])=[CH:13][C:14]1([CH3:20])[CH3:19])=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COc1ccccc1-c1ccc2c(c1)C(C)=CC(C)(C)N2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1-c1ccc2c(c1)C(C)=CC(C)(C)N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
A mixture of 2.4 g of 6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (see Example 1) in 35 mL of CH2Cl2 was cooled down to −78° C. To this mixture, 13.1 mL of 1.6 M n-BuLi in hexane was added dropwise. The mixture was warmed to 0° C. and 2.9 g of (di-tert-butyl)carbonate was added. The mixture was allowed to stir at 0° C. for 1 hour. The reaction was then worked up by adding water and extracting with EtOAc three times. The organic layers were combined, washed sequentially with 1 N HCl, water, saturated aqueous sodium bicarbonate solution, water, saturated aqueous NaCl solution, dried over magnesium sulfate, and the solvent evaporated in vacuo. The residue was purified by flash chromatography to yield 1.4 g of 6-(2-methoxyphenyl)-2,2,4-trimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:13][C:12]2[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)=[C:17]([Cl:30])[CH:16]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1.Cl.[CH3:32][N:33]([CH3:40])[CH2:34]/[CH:35]=[CH:36]/[C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[Cl:30][C:17]1[CH:16]=[C:15]([NH:14][C:11]2[C:12]3[NH:13][C:5]([CH2:4][NH:3][C:37](=[O:38])/[CH:36]=[CH:35]/[CH2:34][N:33]([CH3:40])[CH3:32])=[CH:6][C:7]=3[N:8]=[CH:9][N:10]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Reactant: CN(C)C/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Yield: 64.3 %

Procedure:
A solution of 6-(aminomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (105 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (244 mg), 1-hydroxybenzotriazole monohydrate (196 mg) and triethylamine (0.30 mL) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, methanol:ethyl acetate=1:9→1:4) to give the title compound (104.2 mg) as pale-brown powder crystals.
Reaction SMILES: [NH2:1][C:2]1C=CC=C2C=1CNCC2.C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([S:25](Cl)(=[O:27])=[O:26])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1)(=O)C.CN>>[CH3:2][NH:1][S:25]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH2:16][NH:15][CH2:24][CH2:23]2)(=[O:27])=[O:26]
Reactant: Nc1cccc2c1CNCC2
Reactant: CC(=O)N1CCc2cccc(S(=O)(=O)Cl)c2C1
Agent: CN
Product: CNS(=O)(=O)c1cccc2c1CNCC2

Procedure:
By the procedure of Example 15, 8-amino-1,2,3,4-tetrahydroisoquinoline is converted to 2-acetyl-8-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline. Reacting with methylamine by the procedure of Example 27 and hydrolyzing to remove the 2-acetyl group gives 8-methylsulfamoyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5]1
Reactant: COc1cccc2c1CC(c1ccccc1)C=C2CN
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cccc2c1C[C@@H](c1ccccc1)C[C@H]2CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To 0.22 g (0.73 mmol) of 1-aminomethyl-5-methoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride, from Step 2, of Example 2, in 5 mL of absolute ethanol, was added 0.05 g of 10% palladium supported on carbon. The reaction mixture was sealed under a blanket of hydrogen and stirred overnight at ambient temperature. The reaction mixture was flushed with nitrogen before it was filtered through Celite filter aid and washed with 15 mL of absolute ethanol and 15 mL of methylene chloride. The filtrate was concentrated to give 0.16 g (79% yield) of [1R,3S] 1-aminomethyl-5-methoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene hydrochloride, m. p. 235°-237° C.; 1H NMR (d6-DMSO) δ2.15-2.25 (m, 2H), 2.5-2.65 (m, 1H), 2.8-2.95 (m, 2H), 3.0-3.1 (m, 1H), 3.1-3.4 (m, 1H), 3.45-3.5 (m, 1H), 3.72 (s, 3H), 6.43 (d, 1H), 6.62 (d, 1H), 6.94 (t, 1H), 7.2-7.3 (m, 1H), 7.35-7.45 (m, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=O)[CH2:9][C:8](=[O:13])[CH2:7]1.C([O-])(=O)C.[NH4+:18]>C(O)C>[NH2:18][C:10]1[CH2:11][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8](=[O:13])[CH:9]=1
Reactant: O=C1CC(=O)CC(c2ccco2)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2ccco2)C1
Yield: 76.3 %

Procedure:
A mixture of 5-(2-furyl)cyclohexane-1,3-dione (1.78 g) and ammonium acetate (2.3 g) in ethanol (35 ml) was refluxed for 15 hours, and the reaction solution was concentrated under reduced pressure. To the residue was added water (30 ml), and the resulting crystals were filtered. The crystals were washed with water and ethyl acetate, and dried to give 1-amino-5-(2-furyl)cyclohexen-3-one (1.35 g) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[CH:13]2.[H][H].[CH3:19]I>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[N:15]([CH3:19])[CH:14]=[CH:13]2
Reactant: [H][H]
Reactant: CI
Reactant: COCCOc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cccc2ccn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a slurry of sodium hydride (60% in mineral oil, 0.575 g, 14 mmol) in DMF (40 mL) was added in portions 7-(2-methoxy-ethoxy)-1H-indole (Cuny, Gregory D.; Yuan, Junying; Jagtap, Prakash; Degterev, Alexei. US 2005119260, 2.5 g, 13 mmol) over 5 minutes at 5-10° C. The reaction mixture was stirred at rt for 1 h until hydrogen evolution ceased, and methyl iodide (3.7 g, 26 mmol) was added dropwise over 5 minutes at 10-20° C. The mixture was stirred at rt for 2 h, quenched with ice/water, and extracted with tert-butylmethyl ether. The organics were washed, dried and concentrated. The residue was crystallized from ether/hexane to yield the desired compound (2.28 g) as a yellowish liquid. MS (ISP): m/e 206.3 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:15])[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[CH2:10]O)([O-:3])=[O:2].C[Si](C)(C)N[Si](C)(C)C.[CH:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.N1CCCCC1.C(OCCCC)(=[O:43])C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:15][OH:43])[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[CH:10]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)([O-:3])=[O:2]
Reactant: CCCCOC(C)=O
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cc([N+](=O)[O-])c(CO)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCNCC1
Product: COc1ccc(C=Cc2c([N+](=O)[O-])cc(CO)cc2[N+](=O)[O-])cc1

Procedure:
A solution of 2,6-dinitro-4-hydroxymethyltoluene (9) from Example 7 (3 grams ) and hexamethyldisilazane (2.28 grams) in n-butyl acetate (20 grams) was combined with p-anisaldehyde (1.92 grams) and piperidine (0.384 gram) and the mixture was heated to reflux under a N2 blanket for 14 hours The reaction was cooled, concentrated in vacuo and the crude product analyzed by 1H NMR to reveal the characteristic AB splitting patern of the stilbene protons. The product was confirmed by comparison to an authentic sample prepared according to Example 9 using thin layer chromatography, confirming the presence of structure (10) ##STR10##
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:24]([F:27])([F:26])[F:25])[C:8]2[CH:9]=[C:10]([Br:13])[CH:11]=[CH:12][C:7]=2[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5](=[O:23])[O:4]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O.CN(C=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:5](=[O:23])[O:4][C:3]([CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)([C:24]([F:26])([F:27])[F:25])[C:8]=2[CH:9]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(CN2C(=O)OC(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
While stirring a solution of DMF (50 mL) containing 4-(aminomethyl)-6-bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (13.67 g, 30.7 mmol), 4-fluorobenzoic acid (4.73 g, 33.8 mmol), hydroxybenzotriazole monohydrate (4.7 g, 30.7 mmol) and triethylamine (4.69 mL, 33.8 mmol) at 0° C., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.47 g, 33.8 mmol) was added little by little thereto. After the reaction solution was stirred overnight at room temperature, water was slowly added thereto. After a solid began to precipitate, further excess water was added thereto, and the mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and washed with water and then dried under reduced pressure, whereby the objective compound (15.6 g, 90%) was obtained as a white solid.
Reaction SMILES: [C:1](O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C@:18]2([CH2:32][CH2:33][C:34]([NH2:36])=[O:35])[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20][NH:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[OH-].[Na+].ClCCl.[I:42]C>O>[I-:42].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C@:18]2([CH2:32][CH2:33][C:34]([NH2:36])=[O:35])[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20][NH+:19]2[CH3:1])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: CI
Reactant: COc1ccc(C[C@@]2(CCC(N)=O)NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C[C@]2(CCC(N)=O)c3cc(OC)c(OC)cc3CC[NH+]2C)cc1OC
Product: [I-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
(1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-aminocarbonylethylisoquinoline oxalate (7.0 g, 0.0139 moles) was dissolved in water (30 ml) and 20% aqueous sodium hydroxide solution was added to produce a pH in the range of 9-10. Dichloromethane (100 ml) was added and the mixture was stirred for 15 minutes at ambient temperature. The upper organic layer was separated and washed with 10% sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford an oily residue. Iodomethane (20 ml, 0.321 moles) was added to the oily residue. The mixture was stirred to obtain a solution and kept at ambient temperature overnight. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to afford a mixture of 72% of the cis and 28% of the trans isomers of (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-aminocarbonylethyl-isoquinolinium iodide (7.7 g; 99% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.B(F)(F)F.[CH3:23]COCC.CS(Cl)(=O)=O>CN(C=O)C>[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:18])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:23][O:1]2)=[CH:4][CH:5]=1
Reactant: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1O
Reactant: CCOCC
Agent: CS(=O)(=O)Cl
Agent: FB(F)F
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Temperature: 50 °C

Procedure:
In a solution of 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-ethanone (2 mmol) in DMF (6 mL), freshly destilled BF3.OEt2 (6.3 mL) was added under argon. The mixture was heated at 50° C., and a solution of methanesulphonyl chloride (1 mL) in dry DMF (1.5 mL) was added slowly. After reaction at 80° C. for 1 h, the mixture was cooled to rt and poured into a large volume of ice cold aq. sodium acetate (12 g/100 mL), then extracted with EtOAc, and the organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH to give 7-hydroxy-3-(4-hydroxyphenyl)-chromen-4-one.
Reaction SMILES: [CH2:1]([C:4]1([CH:33]([CH3:35])[CH3:34])[CH2:8][CH:7]([OH:9])[N:6]([CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2O[Si](C(C)C)(C(C)C)C(C)C)[C:5]1=[O:32])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C1COCC1.CCOC(C)=O>[CH2:1]([C:4]1([CH:33]([CH3:34])[CH3:35])[C:5](=[O:32])[N:6]2[CH:7]([O:9][C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]=3[CH2:10]2)[CH2:8]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(C)C)CC(O)N(Cc2cc(C(F)(F)F)ccc2O[Si](C(C)C)(C(C)C)C(C)C)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1(C(C)C)CC2Oc3ccc(C(F)(F)F)cc3CN2C1=O
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A solution of 3-allyl-5-hydroxy-3-isopropyl-1-(5-(trifluoromethyl)-2-(triisopropylsilyloxy)benzyl)pyrrolidin-2-one (approximately 525 mg, 1.02 mmol) in THF (13 mL) was charged with tris(dimethylamino)sulfonium difluorotrimethylsilicate (366 mg, 1.33 mmol) and the resulting mixture was stirred for 30 min. At this time the mixture was charged with TFA (0.394 mL, 5.11 mmol) and 4 angstrom molecular sieves (500 mg). This solution was stirred for 12 h, at which time it was diluted with EtOAc and washed 2× with brine. The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified using a 12 g silica gel cartridge and 20:1 Hex/EtOAc to 3:1 Hex/EtOAc to elute 2-allyl-2-isopropyl-7-(trifluoromethyl)-2,3,3a,9-tetrahydro-1H-benzo[e]pyrrolo[2,1-b][1,3]oxazin-1-one (177 mg, 0.52 mmol, 51% yield) as a clear oil, 1:1 mixture of diastereomers. LC/MS [M+H]+=340.15, HPLC tR=1.99 min [Waters Sunfire C18 4.6×50 mm column, 3 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate]. 1H-NMR (400 MHz, CDCl3) δ=7.26 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 6.80 (d, J=8.0 Hz, 1H), 5.56 (m, 1H), 5.2-4.8 (m, 3H), 4.16 (m, 1H), 2.3-1.8 (m, 5H), 0.8-0.6 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:8][N:9]=1
Reactant: COc1ccc2c(-c3cccnc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3cccnc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(pyridin-3-yl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [C:1]1([CH2:7][OH:8])([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.O[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.O[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=1>>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:6][CH2:5][C:1]2([CH2:7][O:8][C:21]3[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=3)[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: OCC1(CO)CCC1
Product: CC#CC(CC(=O)O)c1ccc(OCC2(COc3ccc(C(F)(F)F)cc3)CCC2)cc1

Procedure:
Analogously to example 1, cyclobutane-1,1-diyldimethanol, 4-hydroxybenzotrifluoride and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-{4-[1-(4-trifluoromethylphenoxymethyl)cyclobutylmethoxy]phenyl}hex-4-ynoic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=2)=[O:31])[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CN)c1
Reactant: Cc1cccc(N=C=O)c1
Product: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc2cccc(C)c2)c1
Yield: 65.9 %

Procedure:
The procedure used is similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(3-methoxyphenyl)acetamido]acetate (2.3 g) and 3-methylphenyl isocyanate (1.1 g). The product obtained is purified by chromatography on silica (0.04-0.063 mm) (150 g) contained in a column 3.5 cm in diameter [eluent: cyclohexane/ethyl acetate (70:30 by volume)], using an excess pressure of nitrogen of 40 kPa and collecting 20-cc fractions. Fractions 10 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in diisopropyl ether, tert-butyl 2-{N-(3-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (2.2 g), m.p. approximately 60° C., is obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1ccc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
To a suspension of 4,5-diphenylimidazole (500 mg, 2.27 mmol) in 5 mL CH2Cl2 at rt were added TEA (348 μL, 2.50 mmol) and trityl chloride (664 mg, 2.38 mmol). The mixture was stirred at rt for 18 h, then was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 692 mg of Intermediate 19.1 as a pale green solid.