Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](O)=[O:6].CC[N:17](CC)CC.ClC(OCC)=O.N>C1COCC1>[CH3:3]/[C:4](=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:5]([NH2:17])=[O:6]
Reactant: CC(=Cc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Agent: N#N
Solvent: C1CCOC1
Product: C/C(=C\c1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of alpha-methylcinnamic acid (19.0 g, 116 mmol) and Et3N (17.1 mL, 122 mmol) in dry THF (500 mL) was treated with ethyl chloroformate (11.4 mL, 117 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min then aq. NH3 (250 mL) in THF (150 mL) was added. The reaction mixture was vigorously stirred at 0° C. for 30 min and at rt for 1 h30. The layers were then separated, the aq. layer extracted with CH2Cl2 (2×) and the combined organic extracts were concentrated under reduced pressure. The residue was partitioned between water and CH2Cl2, the layers separated and the aq. layer extracted with CH2Cl2 (2×). The combined org. extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound as a white solid. LC-MS-conditions 01: tR=0.75 min; [M+H]+=162.07.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Mg].[C:14](=[O:16])=[O:15].Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]([OH:16])=[O:15])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1
Reactant: O=C=O
Reactant: FC(F)(F)c1cc(Cl)ccc1I
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: O=C(O)c1ccc(Cl)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of 4-chloro-2-trifluoromethyliodobenzene (100 g) in ether was added to a suspension of magnesium (8 g) in ether at a such a rate as to maintain the mixture at reflux. The mixture was stirred at reflux for 1 hour and then cooled to 0° C. Carbon dioxide was then passed into the stirred mixture for 3 hours. Hydrochloric acid (2M) was added and the resulting layers separated. The organic layer was washed with water and then extracted into aqueous sodium carbonate solution and this aqueous extract was acidified to pH 1 and extracted with ether. The ether layer was washed with saturated sodium chloride solution, dried (anhydrous magnesium sulphate) and the solvent evaporated to give 4-chloro-2-trifluoromethylbenzoic acid (57.1 g) as a brown solid, m.p. 106.5°-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@@H]1CCN(C(OC(C)(C)C)=O)C1)=O)C1C=CC=CC=1.IC>>[CH2:1]([O:8][C:9]([N:11]([C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)C1
Solvent: CI
Product: CN(C(=O)OCc1ccccc1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 130, starting from tert-butyl (R)-3-benzyloxycarbonylaminopyrrolidine-1-carboxylate (prepared according to Zhou et al, US 2008 0293771) and iodomethane, as a pale coloured oil.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].N([O-])=O.[Na+].[I-:14].[Na+]>Cl.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([I:14])[CH:7]=1
Reactant: [I-]
Reactant: Nc1cc(Cl)ccc1O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
2-Amino-4-chlorophenol (50 g, 0.35 mol) was dissolved in 500 ml of 2.5 N hydrochloric acid, to which an aqueous solution of 25.25 g (0.37 mol) of sodium nitrite in 50 ml of water was gradually added dropwise with cooling at 0° C. After stirring for 30 minutes, the reaction mixture was confirmed to show "positive" in an iodostarch reaction and an aqueous solution of 70 g (0.42 mol) of sodium iodide in 100 ml of water was added slowly. The temperature of the reaction mixture was allowed to rise to room temperature, at which the reaction mixture was stirred overnight and then extracted with ethyl acetate. The ethyl acetate layer was concentrated, whereby 89.7 g of 4-chloro-2-iodophenol were obtained as a purple solid (yield: 99%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>N1C=CC=CC=1.Cl.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=[S:17])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cccc(Br)n2)COCC(=O)N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1(c2cccc(Br)n2)COCC(=S)N1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 5-(6-bromo-pyridin-2-yl)-5-methyl-morpholin-3-one (4.65 g, 17.15 mmol) and P2S5 (4.57 g, 20.58 mmol) in pyridine (60 ml) was stirred at 80° C. under N2 for 6 h. The reaction mixture was cooled to rt and diluted with 0.5N aq. HCl and EtOAc. The phases were separated and the aq. phase was twice extracted with EtOAc. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. The title compound was obtained as a pale yellow solid after flash chromatography on silica gel (cyclohexane/EtOAc 100:0 to 75:25). HPLC RtH4=0.89 min; ESIMS: 287, 289 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 7.86-7.82 (m, 1H), 7.61 (dd, 1H), 7.39 (dd, 1H), 4.44-4.34 (d, 2H), 4.13 (d, 1H), 3.74 (d, 1H), 1.52 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=2[CH:24]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=2[CH:24]=1)[CH3:2]
Reactant: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1OCC
Temperature: 65 °C
Reaction time: 20 h
Yield: 64.7 %

Procedure:
Into a solution of methyl 7-[3-ethoxy-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.45 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (1.8 ml), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain 7-[3-ethoxy-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (283 mg) as light yellow crystals.
Reaction SMILES: I[CH2:2][CH2:3][N:4]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5]1.[C:16]([OH:19])(=[O:18])[CH3:17].C1CCN2C(=NCCC2)CC1.CCOC(C)=O>C1(C)C=CC=CC=1>[N:4]1([CH2:3][CH2:2][O:19][C:16](=[O:18])[CH3:17])[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5]1
Reactant: CC(=O)O
Reactant: ICCN1CCn2c1nc1ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(=O)OCCN1CCn2c1nc1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
According to the procedure of N. Ono, et al., Bull. Chem. Soc. Jpn., 51 (8), 2401 (1978), a solution of 1-N-(2-iodoethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (2.20 g, 7.03 mmol), acetic acid (0.060 mL, 10.54 mmol) and DBU (1.57 mL, 10.54 mmol) in toluene (70 mL) was heated under reflux for 4 hours, cooled, and stirred at room temperature overnight. EtOAc (30 mL) was added and the mixture was washed with brine, dried (MgSO4), and concentrated to give 1.68 g (98%) of a brown solid. This material was used without further purification in the next step (hydrolysis).
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:10]([F:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.O>C(O)C>[F:11][C:10]1[C:5]([NH:2][NH2:3])=[N:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncc(C(F)(F)F)cc1F
Reaction time: 2 h

Procedure:
To a solution of hydrazine hydrate (100%) (3.45 ml) in ethanol (150 ml) was added dropwise a solution of 2,3-difluoro-5-(trifluoromethyl)pyridine (4.45 g) in ethanol (50 ml) at room temperature, stirred at the same temperature for 2 hours, and then additionally stirred at 80° C. for 2 hours. Then, the mixture was allowed to cool, water was added thereto, and the organic solvent was evaporated in vacuo. The precipitated solid was collected by filtration, and washed with water to give 3-fluoro-5-(trifluoromethyl)pyridin-2-ylhydrazine as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:13]([F:22])([F:12])[F:21])[CH:19]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccnc(C(F)(F)F)c1
Product: N#Cc1cc(C=O)ccc1Oc1ccnc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-(trifluoromethyl)pyridine-4-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCc1ccccn1
Product: Clc1nc(Cl)nc(NCc2ccccn2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 2-aminomethylpyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[C:3]=1[F:10].C(O[B:15]1[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]1)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)=[C:3]([F:10])[C:4]=1[F:9]
Reactant: Fc1c(Cl)ccc(Br)c1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-4-chloro-2,3-difluorobenzene (720 mg, 3.17 mmol) in tetrahydrofuran (10 mL) was added i-propylmagesiumchloride (1.90 mL, 3.80 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (0.98 mL, 4.75 mmol) in tetrahydrofuran (5.0 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at RT for 1 h. The mixture was used directly in the next step.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11]CCC)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N>CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCCNC1CCC2(CC1)OCCO2
Agent: N
Solvent: CO
Product: NC1CCC2(CC1)OCCO2

Procedure:
1,4-Dioxa-spiro[4.5]dec-8-ylamine (2A) is synthesized as been described for 1A using methanol which has been saturated with ammonia.
Reaction SMILES: [Mg].CCOCC.BrBr.ClC1C=CC(C[O:15][C:16]2[C:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=[O:19])=CC=1>C1C=CC=CC=1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:24][C:23]2[C:16]([OH:15])=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:19])=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(OCc2ccc(Cl)cc2)c1OCc1ccc(Cl)cc1
Agent: BrBr
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=Cc1cccc(OCc2ccc(Cl)cc2)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To magnesium (0.098 g, turnings, 4.0 mmol) in a mixture of anhydrous ether (20 mL) and benzene (20 mL) at 0° C., bromine (0.10 mL, 2.0 mmol) was added dropwise. When the reaction had started, stirring was commenced and the addition of bromine continued until complete. The ice bath was removed and the reaction mixture was heated until the solution was almost colorless. After cooling down, the reaction mixture was slowly added to a solution of 2,3-bis-(4-chloro-benzyloxy)-benzaldehyde (62, 0.78 g, 2.0 mmol) in benzene (60 mL) at room temperature while stirring vigorously. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight, then refluxed for 36 hours. After the reaction mixture was cooled down to room temperature, a solid was collected by filtration and washed with benzene, then boiled in hydrochloric acid (100 mL, 1.0 M) for 30 minutes. After cool down, the solution was extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. An off-white solid was obtained after removal of the solvent (63, 0.32 mg, 60%). MS (ESI) [M−H+]−=261.25.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:23]=[C:24](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:33])([F:34])[F:19])[CH:23]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][CH3:27])[N:20]=1>ClCCl>[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH3:27])[C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:12])=[O:13])=[O:16])[N:20]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CNc1nc(C)nc(OC)n1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)N(C)c1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To a solution of 2-carbomethoxybenzenesulfonyl isocyanate (22.4 g 93.0 mmol) in dichloromethane (100 mL) was added 2-methoxy-4-methyl-6-methylamino-1,3,5-triazine (10.7 g, 69.6 mmol), followed by a catalytic amount of 1,4-diaza[2.2.2]bicyclooctane. After stirring overnight at ambient temperature under a nitrogen atmosphere, the reaction mixture was concentrated in vacuo. The residue was triturated with diethyl ether and then washed with 1-chlorobutane to yield the title compound as a white powder (27.8 g, m.p. 126°-131° C.).
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)C.[H-].[Na+].[CH3:16][C:17]#[N:18]>C1(C)C=CC=CC=1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:4](=[O:13])[CH2:16][C:17]#[N:18])[CH:10]=[CH:9][CH:8]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cccc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)CC#N)c1
Temperature: 90 °C
Yield: 50 %

Procedure:
To a solution of commercially available 3-methoxy-benzoic acid ethyl ester (3.2 g, 18 mmol) in dry toluene (25 mL), under N2, NaH (50-60% dispersion in mineral oil, 1.44 g, 36 mmol) was carefully added. The mixture was heated at 90° C. and anhydrous CH3CN was added dropwise (4.45 mL, 85.2 mmol). The reaction was heated for 18 hours and the product precipitated from the reaction mixture as Na salt. The reaction was allowed to cool down to room temperature and the solid formed was filtered and washed with ether, then it was redissolved in water and the solution acidified with 2N HCl solution to pH 3 when precipitation of title compound was observed. Filtration of the solid from the aqueous solution afforded 1.57 g of title product (50% yield).
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[C:2]1=2>CCO>[O:1]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[C:2]1=2
Reactant: OCc1cc2ccc3ccc4ccccc4c3c2o1
Solvent: CCO
Product: O=Cc1cc2ccc3ccc4ccccc4c3c2o1
Yield: 91.2 %

Procedure:
Using the procedure outlined in Example 14B, phenanthro[4,3-b]furan-2-methanol (18A) gave a 91.2% yield of phenanthro[4,3-b]furan-2-carbaldehyde, mp 169°, (C,H), (95% EtOH/Ch2Cl2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13](=[O:24])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[F:23])[N:9]1[C:25](=[O:39])[NH:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([C:36](=[O:38])[NH2:37])[CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40](O)([C:42](F)(F)F)=[O:41].C(OC([N:54]1[CH2:58][CH2:57][C@H:56]([C:59](=[O:70])[NH:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[C:63]=2[F:69])[NH:55]1)=O)(C)(C)C>>[Cl:68][C:64]1[C:63]([F:69])=[C:62]([CH:67]=[CH:66][CH:65]=1)[CH2:61][NH:60][C:59]([C@@H:56]1[N:55]([C:40](=[O:41])[CH2:42][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([C:36]([NH2:37])=[O:38])[CH:28]=2)[NH:54][CH2:58][CH2:57]1)=[O:70].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13](=[O:24])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[F:23])[N:9]1[C:25](=[O:39])[NH:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([C:36](=[O:38])[NH2:37])[CH:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)NCc2cccc(Cl)c2F)N1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)OC(=O)N1CC[C@H](C(=O)NCc2cccc(Cl)c2F)N1C(=O)Nc1cn(C(N)=O)c2ccccc12
Product: NC(=O)n1cc(CC(=O)N2NCC[C@@H]2C(=O)NCc2cccc(Cl)c2F)c2ccccc21

Procedure:
The title compound was prepared from (R)-2-(1-carbamoyl-1H-indol-3-ylcarbamoyl)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrazolidine-1-carboxylic acid tert-butyl ester according to the procedure described for the preparation of Example 432 using 10 equivalents of TFA for the Boc deprotection. MS: 459 [M+H]+; tR (HPLC conditions b): 3.73 min. (R)-2-(1-Carbamoyl-1H-indol-3-ylcarbamoyl)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrazolidine-1-carboxylic acid tert-butyl ester was prepared as described in Scheme D5 step C using (R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrazolidine-1-carboxylic acid tert-butyl ester (prepared as described in Scheme B5).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]([C:18]([O-])=[O:19])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:10]=1[CH3:11])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:54]([O:58][C:59](=[O:62])[CH2:60][NH2:61])([CH3:57])([CH3:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]([C:18]([NH:61][CH2:60][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:62])=[O:19])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)[O-])C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
More specifically, a dried methylene chloride solution containing 394 mg (1 mmol) of 1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carboxylate, 309 mg (1.5 mmol) of dicyclohexylcarbodiimide and 134 mg (1.1 mmol) of dimethylaminopyridine was stirred for one hour. To this reaction mixture, 157 mg (1.2 mmol) of glycine t-butyl ester was added and the reaction mixture was refluxed for 2 hours. Insoluble components were removed from the reaction mixture by filtration and the reaction mixture was chromatographed on a silica gel column for purification, whereby 508 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:59]1[C:42](=[CH:43][C:44]3[O:48][N:47]=[C:46]([CH2:49][C:50]4[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=4)[C:45]=3[CH:58]=1)[CH2:41][O:40]2)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.B(Cl)(Cl)Cl.CO>ClCCl>[CH2:56]([C:53]1[CH:54]=[CH:55][C:50]([CH2:49][C:46]2[C:45]3[CH:58]=[C:59]4[C@:10]5([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]5)[O:40][CH2:41][C:42]4=[CH:43][C:44]=3[O:48][N:47]=2)=[CH:51][CH:52]=1)[CH3:57]
Reactant: CCc1ccc(Cc2noc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(Cc2noc3cc4c(cc23)[C@]2(OC4)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
(3′R,4′S,5S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-3-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-spiro[furo[3,4,f]benzoisoxazole-5(7H),2′-[2H]pyran] (86.9 mg, 0.110 mmol) was dissolved in dichloromethane (3.7 mL). Pentamethylbenzene (0.245 g, 1.65 mmol) was added thereto, and then this solution was cooled to −78° C. A solution of boron trichloride in dichloromethane (1.0 M, 0.55 mL) was added dropwise thereto. The resulting mixture was stirred for 2 hours, and then methanol (2.5 mL) was added thereto. The temperature of the mixture was raised to room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution=methanol:dichloromethane (1:12)), to thereby obtain the titled compound (23.0 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][O:15][C:13]2=[O:14])[N:4]=1.[OH-:20].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]([CH3:19])([CH3:18])[CH2:16][OH:15])[C:13]([OH:20])=[O:14])[N:4]=1
Reactant: [OH-]
Reactant: COc1cc(OC)nc(OC2C(=O)OCC2(C)C)n1
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(C)CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To 150 ml of an ethanol solution of 5.4 g of 2-(4,6-dimethoxypyrimidin-2yl)oxy-3,3-dimethyl-γ-butyrolactone, 20 ml of an aqueous solution of 1.2 g of sodium hydroxide was added, and then, the mixture was stirred at room temperature for one hour. Ethanol was evaporated under reduced pressure, and the reaction solution was adjusted to pH 2 to 3 with 5% hydrochloric acid. The reaction solution was extracted twice with ethyl acetate, washed twice with a sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain 4.7 g of the desired product.