Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:24][CH3:25])(=[O:23])[CH3:22].[CH3:26][C:27]([S@:30]([N:32]=[C:33]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[CH3:34])=[O:31])([CH3:29])[CH3:28]>C1COCC1.O.CCOC(C)=O.Cl[Ti](OC(C)C)(OC(C)C)OC(C)C>[CH3:29][C:27]([CH3:26])([S@:30]([NH:32][C@@:33]([CH:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)([CH3:34])[CH2:22][C:21]([O:24][CH3:25])=[O:23])=[O:31])[CH3:28]
Reactant: COC(C)=O
Reactant: CC(=N[S@](=O)C(C)(C)C)C1CCOCC1
Agent: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@](C)(N[S@](=O)C(C)(C)C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a 0° C. solution of N,N-diisopropylamine (12.7 mL, 90.8 mmol) in THF (120 mL) was added n-butyllithium (2.5 M in hexanes, 35.1 mL) over ˜5 min. The resulting solution was stirred at 0° C. for 10 min, then the cooling bath was removed and the mixture stirred for an additional 10 min before it was finally cooled to −78° C. To this solution of LDA was then added via cannula a −78° C. solution of methyl acetate (6.01 mL, 75.6 mmol) in THF (30 mL) over ˜5 min. This mixture was stirred at −78° C. for 30 min, and then a mixture of chlorotriisopropoxytitanium (27.1 mL, 113 mmol) and THF (30 mL) was added via syringe. After 30 min, a RT solution of (R)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethylidene)propane-2-sulfinamide 4 (7.0 g, 30 mmol) in THF (40 mL) was added via cannula over ˜5 min. The reaction was then stirred at −78° C. for 5 h. At that time, while still at −78° C., the reaction was diluted rapidly with water (300 mL) and agitated. The reaction was allowed to gradually warm to RT overnight with stirring. At that time, the mixture was further diluted with EtOAc and water, and the mixture was filtered with copious EtOAc washes. The phases of the filtrate were separated and the aqueous layer was extracted 2× with EtOAc. The organic portions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude sample was subjected to column chromatography (ISCO, 330 g silica, 100 mL/min, 0% to 25% i-PrOH/hexanes) to give (S)-methyl 3-((R)-1,1-dimethylethylsulfinamido)-3-(tetrahydro-2H-pyran-4-yl)butanoate 5 (6.5 g, 70%). LCMS (conditions D) for 5: tR=1.90 min, m/e=306.2 (M+H, base), 328.2 (M+Na).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][C:21]([OH:23])=O)[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C([N:26](CC)CC)C.ClCCOC=O.[NH4+].[OH-]>C1COCC1>[O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][C:21]([NH2:26])=[O:23])[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C(O)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: CCN(CC)CC
Agent: O=COCCCl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid (100 mg, 0.325 mmol) and triethylamine (58.9 μl, 0.423 mmol) in THF (3.0 ml) was added chloroethylformate (35.7 μl, 0.374 mmol). The mixture was stirred at room temperature for 25 minutes, and then concentrated NH4OH (3.0 ml) was added. After stirring for 8 minutes at room temperature, the reaction was partitioned between 4% HCl aqueous solution, and EtOAc. The organic layer was then washed with saturated NaHCO3 aqueous solution, water, dilute HCl aqueous solution, brine, dried with anhydrous Na2SO4 and rotary evaporated to yield a solid. The solid was recrystallized from CHCl3/MeOH to give 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetamide as a yellow-gold solid (34.4 mg, 35%).
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8]([NH:11][CH3:12])(=[O:10])=[O:9].S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8]([NH:11][CH3:12])(=[O:10])=[O:9]
Reactant: CNS(=O)(=O)c1sccc1CO
Reactant: O=S(Cl)Cl
Product: CNS(=O)(=O)c1sccc1CCl

Procedure:
7.5 g (36.1 mmol) of 3-hydroxymethyl-2-N-methylthiophenesulfonamide are boiled under reflux with 50 ml of thionyl chloride for 15 minutes. Thereafter, the mixture is evaporated to dryness in a water-jet vacuum. The residue is taken up in 150 ml of methylene chloride and stirred with saturated sodium bicarbonate solution until the aqueous phase has an alkaline reaction. The phases are separated. The aqueous phase is extracted with two 50 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated to give an oil which crystallizes out in the cold. There is obtained 3-chloromethyl-2-N-methylthiophenesulfonamide of melting point 52°-53° C.
Reaction SMILES: C(OC([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[O:21][CH3:22])[CH2:8][CH2:7]1)=O)C.Cl>>[CH3:22][O:21][C:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=[C:9]2[CH2:8][CH2:7][NH:6][CH2:20][CH2:19][C:18]=12
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(OC)c2CC1
Agent: Cl
Product: COc1c2c(nc3ccccc13)CCNCC2
Yield: 7 %

Procedure:
11-methoxy-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline was prepared from 11-methoxy-1,2,4,5-tetrahydro-3-azepino[4,5-b] quinoline-carboxylic acid ethyl ester by hydrolysis with semiconcentrated hydrochloric acid. Yield: 7% of theory; m.p. 112° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18][CH2:17]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(NCCN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 40 °C

Procedure:
A mixture of 2-chloro-6-(methyloxy)-3-nitropyridine (1.9 g, 10 mmol), 1,1-dimethylethyl [1-(2-aminoethyl)-4-piperidinyl]carbamate (2.43 g, 10 mmol) and potassium carbonate (1.4 g, 10 mmol) in acetonitrile (35 ml) and DMF (10 ml) was heated at 40° C. for 30 minutes. The mixture was filtered, washing with acetonitrile, and evaporated. The residue was dissolved in the minimum volume of DCM (15 ml) and washed with water (1 ml). The organic extract was added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording a yellow solid (3.1 g, 78%).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][CH2:25][CH2:26]O)=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]([Cl:42])([Cl:41])[CH2:30][O:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[O:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][CH2:25][CH2:26][N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[C:32]([O:31][CH2:30][C:29]([Cl:28])([Cl:41])[Cl:42])=[O:33])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCO)ccc12
Reactant: O=C(Nc1ccccn1)OCC(Cl)(Cl)Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCN(C(=O)OCC(Cl)(Cl)Cl)c3ccccn3)ccc12

Procedure:
500 mg (1.36 mmol) of 5 and 550 mg (2.04 mmol) of 2-(2,2,2-trichloroethoxycarbonylamino)pyridine and 907 mg (2.72 mmol) of triphenylphosphine (polymer-bound) are introduced into 7.5 ml of anhydrous THF, and a solution of 0.32 ml (2.04 mmol) of azodicarboxylic acid diethyl ester (diethyl azodicarboxylate, DEAD) in 7.5 ml of THF is added dropwise at room temperature over the course of 30 minutes. The TLC check shows complete conversion after 1.5 hours. The polymer is filtered off, and the solution is washed with a little water, dried and evaporated. The residue can be purified by chromatography on silica gel (eluent gradient toluene/acetone 20:1→4:1), giving ethyl 3-phenyl-3-(6-{3-[(pyridin-2-yl)(2,2,2-trichloroethoxycarbonyl)amino]propoxy}indol-3-yl)propionate.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1.C(O[CH2:15][CH3:16])(=O)C>>[CH:9](=[O:10])/[CH:6]=[CH:5]/[CH2:4][CH2:3][CH2:8][CH2:7][CH2:5][CH2:4][CH2:3][CH2:8][CH2:7][CH2:6][CH2:9][CH2:15][CH3:16]
Reactant: CCOC(C)=O
Reactant: COc1ccc(C=O)cc1
Product: CCCCCCCCCCCCC/C=C/C=O

Procedure:
RF =0.5, petroleum ether (boiling point 35°-80° C./ethyl acetate 9:1; UV: blue coloration with anisaldehyde reagent (0.5 ml anisaldehyde, 50 ml glacial acetic acid, 1 ml H2SO4); boiling point (10-3Torr): 115° C.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]([O-:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl-2-pyrrolidine-carboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 mL), and methanol (50 mL) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87t) of snow-white solid which did not require further purification. 1H NMR (CDCl3): d 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22]([C:28]([OH:30])=[O:29])[CH2:23][S:24][C:25](=[O:27])[CH3:26])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][C:32](=[CH2:34])[CH3:33]>ClCCl>[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22]([C:28]([O:30][C:32]([CH3:34])([CH3:33])[CH3:31])=[O:29])[CH2:23][S:24][C:25](=[O:27])[CH3:26])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=C(C)C
Reactant: CC(=O)SCC(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)SCC(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 60 %

Procedure:
Sulfuric acid (1.15 ml) was added slowly to a solution of 4-(2-acetylsulfanyl-1-carboxy-ethyl)-piperidine-1-carboxylic acid benzyl ester (20.32 g) in dichloromethane (60 ml). The mixture was cooled in an acetone/dry ice bath and cooled isobutylene (60 ml) added. The mixture was transferred to a Parr high pressure apparatus and left to stir overnight then washed with water (30 ml), saturated sodium bicarbonate solution (30 ml) and brine (30 ml). After drying (Na2SO4) and filtering the solvent was removed under reduced pressure and the residue purified by column chromatography (SiO2, 20% ethyl acetate in hexane) to give the title compound (11.22 g, 60%) as an orange oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7](CC2C=CC(OC)=CC=2)[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>ClCCl>[NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2
Reactant: COc1ccc(CN2C(=O)[C@@H](N)c3ccccc3-c3ccccc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 97.5 %

Procedure:
A solution of 0.55 g (1.6 mmol) (S)-7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one, 3.74 ml (50 mmol) trifluoroacetic acid and 1.4 ml (16 mmol) trifluormethane sulfonic acid in 38 ml dichloromethane was stirred at room temperature for 4 hours. The solvent was distilled off and extraction with aqueous sodium bicarbonate solution/ethyl acetate followed by chromatography on silicagel with ethylacetate/methanol (100-95/0-5) yielded 0.35 g (96%) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one as orange solid; MS: m/e: 225.4 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:38])[C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:28]#[CH:29].COC(=O)C(NC(OC(C)(C)C)=O)CC#C>C1COCC1.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25](=[O:38])[C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][C:28]#[C:29][C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][CH2:12][CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CC#Cc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
Compound 22, [4-(4-iodophenyl)-but-3-ynyl]carbamic acid benzyl ester (0.52 g, 1.283 mmol) was dissolved in a mixture of anhydrous THF and triethylamine (8 mL, 1/1, v/v). To the solution was added copper (I) iodide (0.025 g, 0.128 mmol). The mixture was stirred at room temperature for 15 min. The flask was then evacuated and re-filled with Argon. The procedure was repeated three more times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)palladium(II) (0.09 g, 0.128 mmol) was added into the mixture under Argon protection. The mixture was further stirred at room temperature for 30 min. The other starting material 23, 2-tert-butoxycarbonylamino-pent-4-ynoic acid methyl ester (0.32 g, 1.412 mmol), dissolved in THF (4 mL) was added dropwise over 15 min. The newly formed reaction mixture was further stirred overnight at room temperature. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in dichloromethane and purified by column chromatography, eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%) to afford the product 24 (0.64 g, 99%) as a gummy, yellowish solid. 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 9H), 2.64 (t, J=6.3 Hz, 2H), 2.95 (t, J=4.1 Hz, 2H), 3.42 (m, 2H), 3.79 (s, 3H), 4.56 (m, 1H), 5.12 (s, 2H), 5.38 (br s, 1H), 7.29 (s, 4H), 7.35 (m, 5H). m/z (APCI) 502 [C29H32N2O6−H]+.
Reaction SMILES: C(#N)C.[N:4](=[C:6]([C:15](=O)[CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])O.[NH2:18][CH:19]([CH2:24][CH3:25])C(OC)=O.C(C1NC(CC)=NC=1C1C=CC=CC=1)(=O)C>C(O)C.[OH-].[Na+]>[C:7]([C:6]1[NH:4][C:19]([CH2:24][CH3:25])=[N:18][C:15]=1[CH3:16])(=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)C(=NO)C(=O)c1ccccc1
Reactant: CCC(N)C(=O)OC
Agent: CCc1nc(-c2ccccc2)c(C(C)=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: CCc1nc(C)c(C(=O)c2ccccc2)[nH]1
Yield: 42 %

Procedure:
An acetonitrile solution (15 ml) of 2-oximino-1-phenyl-1,3-butanedione (1.38 g, 7.22 mmoles) and methyl 2-aminobutyrate (0.85 ml, 7.22 mmol) was refluxed under nitrogen for 26.4 h. After concentrating the cooled reaction mixture, the residue was dissolved in 10 ml of ethanol and 20 ml of 10% aqueous sodium hydroxide. This mixture was refluxed 4.9 h, cooled, then extracted with ethyl acetate. Removal of the solvent in vacuo gave 0.65 g (42% yield) of 5-benzoyl-2-ethyl-4-methylimidazole and 5-acetyl-2-ethyl-4-phenylimidazole (86:14 respectively).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][O:10][CH:11]([CH:33]=[CH2:34])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].Cl.[NH2:42][OH:43]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:9][O:10][CH:11]([CH2:12][O:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:33]1[CH2:34][O:43][NH:42]2
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)c1ccccc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Fc1ccccc1C12COC(COC(c3ccccc3)(c3ccccc3)c3ccccc3)C1CON2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A reactor was charged with 1-(2-fluorophenyl)-2-((1-(trityloxy)but-3-en-2-yl)oxy)ethanone (61.2 g, 1.0 equiv), toluene (428 mL) and sodium acetate (16.1 g, 1.5 equiv). Upon complete addition, the reaction mixture was stirred at ambient temperature for 5 minutes. Hydroxylamine hydrochloride (10.0 g, 1.1 Eq) was added and the suspension was heated to 111° C. After stirring for >20 hours at 111° C., the reaction mixture was allowed to cool down to ambient temperature, and the suspension was filtered and the solids rinsed with toluene (245 mL) and then THF (10 volumes) The filtrate was concentrated under reduced pressure (bath temp. <40° C.) and chased with 2-propanol (275 mL). 2-Propanol (428 mL) was added to the solids and the suspension was heated to 83° C. After stirring for 1 hour at 83° C., the mixture was allowed to cool down to ambient temperature. The slurry was cooled to 0° C. over a 1 hour period and stirred at 0° C. for 1 hour. The suspension was filtered and the solids rinsed in two portions with cold 2-propanol (490 mL) to give 6a-(2-fluorophenyl)-4-((trityloxy)methyl)hexahydrofuro[3,4-c]isoxazole (42.3 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([N:16]([CH:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Yield: 33.1 %

Procedure:
The procedure is as in Example 1, but 0.85 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 1.25 g of di-tert-butyl 2-anilinomalonate and 0.3 cm3 of thionyl chloride are used as starting materials. The product obtained is purified by chromatography on 50 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: methanol/dichloromethane (1.5/98.5 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 25-cm3 fractions. Fractions 6 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 35° C. and the residue obtained is crystallization from 10 cm3 of diethyl ether. 0.67 g of di-tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}malonate melting at 175° C. are then obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:6]#[N:7].C(C1C=C2C(=CC=1)C(=O)OC2)#N.OCC1C=C(C=CC=1C(C1C=CC(F)=CC=1)(C1C=CC(F)=CC=1)O)C#N.[BH4-].[Na+].[OH-].[Na+]>CC#N.O.O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:19])[C:6]#[N:7]
Reactant: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CO)c1
Agent: N#Cc1ccc(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)c(CO)c1
Agent: N#Cc1ccc2c(c1)COC2=O
Agent: [BH4-]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(C(O)c2ccc(F)cc2)c(CO)c1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
The organic phase (950 ml), containing a theoretical quantity of 150 g of 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile, referred to the starting 5-cyanophthalide, and about 14-16% of 3-hydroxymethyl-4-[bis(4-fluorophenyl)hydroxymethyl]benzonitrile, is cooled at 0-5° C., under nitrogen atmosphere. A solution of 23.3 g of NaBH4, 230 ml of water and 1 ml of 30% NaOH is added to the mixture dropwise, in 30 minutes and at a temperature not higher than 15° C. At the end of the addition a control by HPLC [COLUMN: Develosil C18 4.6×250 mm, 5μ; DETECTOR: UV 240 nm; FLOW: 1.5 ml/min; GRADIENT: A: aq. NH4H2PO4+H3PO4-pH=2.85/B: CH3CN/H2O=9/1 (v/v)] detects the disappearance of 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile. The temperature is kept to 25° C., the aqueous phase is eliminated and tetrahydrofuran is evaporated under vacuum at 50° C. 100 ml of ethyl acetate are added to the residue and the solvent is evaporated under vacuum at 50° C., then other 350 ml of ethyl acetate are added. The phases are separated, the organic phase is collected and the aqueous phase is extracted with 230 ml of ethyl acetate. The phases are separated, the aqueous phase is discarded and the organic phases are collected obtaining 720 ml of a solution in ethyl acetate containing 150 g of 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile and the same quantity of 3-hydroxymethyl-4-[bis(4-fluorophenyl)hydroxymethyl]benzonitrile contained into the starting solution.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C@@:23]4([CH2:27][O:26][C:25]([NH:28]C(=O)OC(C)(C)C)=[N:24]4)[C:20]4([CH2:22][CH2:21]4)[C:19]([CH3:37])([CH3:36])[O:18][C:15]3=[CH:16][CH:17]=2)=[O:10])=[N:7][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:28][C:25]1[O:26][CH2:27][C@@:23]2([C:14]3[C:15](=[CH:16][CH:17]=[C:12]([NH:11][C:9]([C:6]4[CH:5]=[N:4][C:3]([CH:2]([F:38])[F:1])=[CH:8][N:7]=4)=[O:10])[CH:13]=3)[O:18][C:19]([CH3:37])([CH3:36])[C:20]32[CH2:22][CH2:21]3)[N:24]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3cnc(C(F)F)cn3)ccc1OC(C)(C)C21CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2ccc(NC(=O)c3cnc(C(F)F)cn3)cc2[C@@]2(COC(N)=N2)C12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of tert-butyl [(4′R)-6′-({[5-(difluoromethyl)pyrazin-2-yl]carbonyl}amino)-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (373 mg, 0.704 mmol) in chloroform (6 ml) was added trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (precolumn: NH-silica gel, main column: neutral silica gel, chloroform/methanol=100:0-10:1). To the purified product was added a mixture of hexane and ethyl acetate (4:1), and the mixture was stirred at room temperature over night. The resulting precipitate was collected, washed with a mixture of hexane and ethyl acetate (4:1), and dried in vacuo to afford N-[(4′R)-2″-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-6′-yl]-5-(difluoromethyl)pyrazine-2-carboxamide (253 mg).