Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([O:14]C)=O)[CH:6]=1)=[O:4].[NH2:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19]>CO>[NH2:11][C:9]1[CH:10]=[C:5]([C:3]([NH:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19])=[O:4])[CH:6]=[C:7]([C:12]([NH:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19])=[O:14])[CH:8]=1
Reactant: NC(CO)CO
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: CO
Product: Nc1cc(C(=O)NC(CO)CO)cc(C(=O)NC(CO)CO)c1
Temperature: 105 °C
Yield: 90 %

Procedure:
5-Amino-1,3-benzenedicarboxylic acid dimethyl ester (40.0 g, 191 mmol) and 2-amino-1,3-dihydroxypropane (104.5 g, 1.147 mol) are loaded into a 1 L vessel equipped with a mechanical stirrer, a thermometer and a refluxing refrigerator. The suspension is heated up to 105° C., and is maintained at this temperature for 150 minutes to yield a solution. After cooling to 50° C., methanol (0.7 L) is added and the obtained suspension is maintained for 4 hours at room temperature. The solid that separates is filtered, washed with methanol (0.3 L), and dried in the oven at 45° C. for 4 hours yielding the compound of the title (56.3 g, 0.172 mol, yield: 90%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[F:22][C:23]([F:40])([F:39])[C:24]1[N:29]=[C:28]([N:30]2[CH2:34][C@@H:33]3[C@@H:35]([NH2:38])[CH2:36][CH2:37][C@@H:32]3[CH2:31]2)[CH:27]=[CH:26][CH:25]=1.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:38][C@@H:35]2[C@@H:33]3[C@@H:32]([CH2:31][N:30]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:40])([F:39])[F:22])[N:29]=4)[CH2:34]3)[CH2:37][CH2:36]2)=[O:8])=[CH:9][CH:10]=1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
p-Fluorobenzoic acid (56.8 mg, 0.405 mmol), 1-hydroxybenzotriazole hydrate (62.1 mg, 0.405 mmol 1), and (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (100 mg, 0.369 mmol) were combined in dichloromethane (1.2 mL) to give a colorless solution. After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.072 mL, 0.405 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with 2×2 mL of dichloromethane. The combined extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.90 (d, J=6.9, 1H), 8.29-8.19 (m, 2H), 7.56-7.47 (m, 1H), 7.17 (ddd, J=9.7, 5.9, 2.5, 2H), 6.99 (d, J=7.2, 1H), 6.53 (d, J=8.6, 1H), 4.64-4.52 (m, 1H), 3.80 (dd, J=11.0, 3.7, 1H), 3.63 (dd, J=10.9, 8.2, 1H), 3.51 (dd, J=10.8, 8.4, 1H), 3.30 (dd, J=10.9, 4.6, 1H), 2.90-2.77 (m, 1H), 2.77-2.64 (m, 1H), 2.23 (ddd, J=19.5, 7.1, 4.7, 1H), 1.93 (dtd, J=12.7, 8.0, 4.6, 1H), 1.81 (ddd, J=16.4, 12.7, 8.1, 1H), 1.40 (dt, J=13.2, 7.6, 1H); MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:15][CH3:14])[CH2:19][CH2:20]1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: COCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN1CCN(c2cc(OC)c([N+](=O)[O-])cc2C)CC1
Temperature: 130 °C
Yield: 86.1 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (prepared according to Example 113, Step B) (1 g, 5.4 mmol) in 10 mL of DMSO was added, 1-[2-(methyloxy)ethyl]piperazine (1 g, 7 mmol), and K2CO3 (1.27 g, 4.2 mmol). The mixture was heated to 130° C. for 24 h. The mixture was then poured into 100 mL of H2O and extracted with EtOAc. The product was isolated by flash chromatography to give the title compound of step A (1.44 g, 4.65 mmol, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (s, 1H), 6.68 (s, 1H), 3.88 (s, 3H), 3.44 (t, J=5.68 Hz, 2H), 3.22 (s, 3H), 2.95-3.01 (m, 4H), 2.50-2.58 (m, 6H), 2.17 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=[CH:17][C:16]([C:27](O)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=[CH:17][C:16]([C:27]([NH2:38])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(C(N)=O)ccc2c1=O
Yield: 95.5 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (0.70 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt (0.46 g, 3 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.67 g, 95.7%) as crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=O)N(Cc1ccccc1)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of N-benzyl-2-nitroaniline (1.62 g, 7.1 mmol) and methyl 3-chloro-3-oxopropanoate (1.17 mg, 8.5 mmol), Et3N (1.8 g, 17.8 mmol) in 50 mL of CH2Cl2 was stirred at 80° C. for 2 days. The solvent was evaporated, and the residue was purified by combi-flash to give methyl 3-(benzyl(2-nitrophenyl)amino)-3-oxopropanoate as a yellow solid. LRMS (M+H)+: 328 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.C[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CNCCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCCCO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 43.4 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 4-methylamino-butan-1-ol (44.5 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide (30.5 mg, 43.4%). HRMS (ES+) m/z Calcd for C27H33Cl2N3O2+H [(M+H)+]: 502,2023. found: 502.2020.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32].[OH-].[Na+]>CS(C)=O>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]2[C:15]=1[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH:22]=[CH:21]2
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2C=Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CNCC1C=Cc2cc(F)cc(-c3ccccc3Cl)c2O1
Temperature: 60 °C
Yield: 44.5 %

Procedure:
To a solution of [8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.33 g, 0.748 mmol) in anhydrous dimethyl sulfoxide (1.2 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 3.74 mL, 7.48 mmol) and the mixture heated to 60° C. in a sealed vial for 2 days. The cooled reaction mixture was then poured into 2.0 M aqueous sodium hydroxide solution (40 mL) and the product extracted with ethyl acetate (50 mL). The separated organic extract was washed with water (50 mL), and saturated brine (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown syrup. Purification by flash chromatography using a solvent gradient of 0 to 5% ammonia saturated methanol solution in dichloromethane gave 101 mg (45%) of {[8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl}methylamine as a yellow syrup. The product was dissolved 2-propanol (1 mL) and diethyl ether (2 mL), a solution of hydrogen chloride (1.0 M in diethyl ether, 0.33 mL, 0.33 mmol) was added followed by hexane (3 mL). The resulting precipitate was filtered to afford 100 mg (39%) of {[8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl}methylamine hydrochloride as a tan crystalline solid. HRMS: calcd for C17H15ClFNO+H+, 304.08990. found (ESI, [M+H]+), 304.0891.
Reaction SMILES: [CH2:1]([CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[O:23][CH3:24])[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH3:12].[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].[ClH:30]>CO.Cl.Cl.NNC(N)=N>[ClH:30].[ClH:30].[C:25]([NH:28][N:29]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH2:1][CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[N:29][NH:28][C:25](=[NH:26])[NH2:27])=[CH:17][C:16]=2[O:23][CH3:24])=[C:4]([O:11][CH3:12])[CH:5]=1)(=[NH:27])[NH2:26]
Reactant: COc1cc(C=O)ccc1OCCOc1ccc(C=O)cc1OC
Reactant: N=C(N)NN
Agent: Cl
Solvent: CO
Product: COc1cc(C=NNC(=N)N)ccc1OCCOc1ccc(C=NNC(=N)N)cc1OC
Yield: 98.4 %

Procedure:
4,4'-(ethylenedioxy)di-m-anisaldehyde (0.99 g), aminoguanidine hydrochloride (0.829 g), and aminoguanidine dihydrochloride (0.01 g) were heated in 95% methanol (10.5 mL) under nitrogen for 16 hr. Cooling and filtration gave 1.52 g of 4,4'-(ethylenedioxy)di-m-anisaldehyde bis(amidinohydrazone) dihydrochloride, mp 322°-3° C. dec.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26](=O)[NH:27][CH:28]=1>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:26]1[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=c1ccc(F)c[nH]1
Product: CC(C)(C)CN(CCOc1ccc(F)cn1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 27B from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 61C) and 5-fluoro-2(1H)-pyridinone: 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=3.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.35 (m, 1H), 7.27 (d, J=2.7 Hz, 1H; partially obscured by solvent), 6.96-(dd, J=9.0, 2.7 Hz, 1H), 6.66 (ddd, J=9.1, 3.6, 0.6 Hz, 1H), 4.41 (t, J=6.7 Hz, 2H), 3.87 (t, J=6.7 Hz, 2H), 3.33 (s, 2H), 1.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[C@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21].C(O[C:29]([CH3:32])([CH3:31])[CH3:30])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl>[C:29]([O:24][C@@H:19]([C:3]1[C:4]([CH3:18])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=2)[C:2]=1[Cl:1])[C:20]([O:22][CH3:23])=[O:21])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of (S)-methyl 2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (1.0 g, 2.73 mmol) in CH2Cl2 (100 mL) at room temperature was added tert-butyl acetate (20 mL) followed by perchloric acid (0.282 mL, 3.28 mmol). The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (520 mg, 50%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.07-8.00 (m, 1H), 7.89 (dt, J=6.7, 1.9 Hz, 1H), 7.48-7.37 (m, 2H), 6.93 (s, 1H), 5.68 (s, 1H), 3.75 (s, 3H), 2.69 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([CH:31]([F:33])[F:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:35])([CH3:34])[C:13]32[CH2:37][CH2:36]3)[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([CH:31]([F:33])[F:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:35])([CH3:34])[C:13]32[CH2:37][CH2:36]3)[N:12]=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: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
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).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[N:25]=[N+:26]=[N-:27])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Five grams (12.2 millimoles) of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide was dissolved in 120 ml of DMF, and 15.8 g (243 millimoles) of sodium azide was added with agitation. The reaction mixture was agitated at room temperature for a day and a night while shielded from light. The reaction mixture was added dropwise to 1,000 ml of ice water with agitation, and the insoluble material was extracted using 900 ml of methylene chloride. The organic phase was washed with ice water and dried using anhydrous sodium sulfate. The drying agent was separated by filtration, and the solvent was completely removed by distillation under reduced pressure. The pale yellow solid obtained was washed using diethyl ether, dried and recrystallized from 2-propanol to obtain 3.30 g (79% yield) of 2,3,4,6-tetra-O-acetyl-β-glucopyranosyl azide in the form of white needle shaped crystals. The physical properties of the product are shown below.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][CH2:20][C:21]1([CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:25][CH:24]([OH:26])[CH2:23][CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CCOCC>[CH2:12]([O:19][CH2:20][C:21]1([CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:25][C:24](=[O:26])[CH2:23][CH2:22]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(O)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(=O)O1
Reaction time: 18 h

Procedure:
To a solution of 1.6 g (7.4 mmol) of pyridinium chlorochromate in 25 ml of methylene chloride under a nitrogen atmosphere, was added 13.5 g (6.5 mmol) of the compound prepared in (d) above in 25 ml of methylene chloride. After 18 hours at 25° C., the solution was diluted with 150 ml of ether, filtered through silica gel and the filtrate evaporated to afford an oil. The oil was then flash chromatographed on silica gel employing a mixture of petroleum ether and diethyl ether in a ratio of 7:3 as the eluent to yield colorless oil.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH3:5][C:6](C)([C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9])C.Br>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]([CH3:9])([CH3:10])[CH2:6][CH2:5][P:1]([OH:3])(=[O:2])[OH:4])=[CH:12][CH:13]=1
Reactant: O=[PH](O)O
Reactant: CC(C)(C)C(C)(C)c1ccc(O)cc1
Agent: Br
Product: CC(C)(CCP(=O)(O)O)c1ccc(O)cc1
Reaction time: 1 h

Procedure:
3.0 Parts of dimethyl-3-(4-hydroxyphenyl)-3-methyl-butane phosphonate from Example 23a and 30 parts of 48% hydrobromic acid were heated on a steam--bath for 1 hour and the volatiles then removed at 80° C. under reduced pressure. Crystallisation of the residual solid from water gave 3-(4-hydroxyphenyl)-3-methyl-butane phosphonic acid m.p. 192°-5° C. with the following percentage composition by weight.
Reaction SMILES: [C:1]([C:4](=[C:10](SCC1C=CC=CC=1)[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[CH3:27][NH:28][NH2:29]>C(#N)C>[CH3:27][N:28]1[C:10]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([CH3:2])=[N:29]1
Reactant: CCOC(=O)C(C(C)=O)=C(SCc1ccccc1)SCc1ccccc1
Reactant: CNN
Solvent: CC#N
Product: CCOC(=O)c1c(C)nn(C)c1SCc1ccccc1
Yield: 77.2 %

Procedure:
In 60 ml of acetonitrile is dissolved 10.0 g of ethyl 2-acetyl-3,3-bis(benzylthio)acrylate. To the solution is added dropwise, while stirring at room temperature (15° C.), 1.2 g of methyl hydrazine over a period of 10 minutes, followed by heating for 3 hours under reflux. Then, the solvent is distilled off under reduced pressure. The residue is purified by means of silica gel column chromatography (eluent, n-hexane:ethyl acetate=8/1) to give 5.8 g of the title compound as white crystals, m.p. 55° to 56° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C@@H:23]2[C:14]31[C@H:19]([CH2:20][CH2:21][CH2:22]2)[CH2:18][O:17][CH2:16][CH2:15]3.[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@@H:23]2[CH2:22][CH2:21][CH2:20][C@@H:19]3[C@:14]2([OH:13])[CH2:15][CH2:16][O:17][CH2:18]3)=[CH:4][CH:3]=1
Reactant: C1C[C@@H]2COCCC23O[C@H]3C1
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O[C@]12CCOC[C@@H]1CCC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-fluoroaniline (0.119 g, 1.07 mmol) in CH2Cl2 (1 mL) at 0° C. was added trimethylaluminum (2M in toluene, 0.535 mL) dropwise. The mixture was warmed to rt and stirred for 30 min. A mixture of cis and trans octahydrooxireno[e]isochromene (0.033 g, 0.214 mmol) in CH2Cl2 (1 mL) was then added and the mixture was stirred at rt overnight. The reaction mixture was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL). It was diluted with more water and extracted 3× with CH2Cl2. The combined organics were dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.92 (t, 2H, J=8.8 Hz), 6.71 (dd, 2H, J=4.2 Hz, 8.8 Hz), 3.81-3.87 (m, 1H), 3.61 (dd, 1H, J=4.6 Hz, 11.2 Hz), 3.50 (t, 1H, J=11.0 Hz), 3.32 (s, 1H), 2.15-2.26 (m, 1H), 1.89-2.07 (m, 2H), 1.59-1.69 (m, 2H), 1.45-1.58 (m, 1H), 1.20-1.37 (m, 4H). HRMS (ES) m/z M+H calc'd.: 266.1551. found: 266.1549
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH:29]1([CH2:35]Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH:29]1([CH2:35][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=2[OH:28])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OCC2CCCCC2)c1
Yield: 86 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 1.46 ml (10.362 mmol) of cyclohexylmethyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1) to obtain 215 mg (0.4454 mmol, 86%) of 2-cyclohexylmethoxy-2' -hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.6-2.2 (15H, m, cyclohexyl-H, 2CH2), 2.36 (4H, t, 2CH2), 2.65 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 3.81 (2H, d, CH2), 6.52 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 482 (M+)