Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[S:31][C:30]([CH2:32]O)=[CH:29][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:26][C:27]1[S:31][C:30]([CH2:32][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: OCc1ccc(Cl)s1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (5-chloro-2-thienyl)methanol (88 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (EtOAc/MeOH), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from IPE-IPA to give the title compound (29.1 mg) as an off-white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([N:23]([CH3:32])[C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>CSC.C(S)(S)C>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([N:23]([CH3:32])[C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:40][C:41]([C:42]([OH:44])=[O:43])([F:46])[F:45]
Reactant: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: CC(S)S
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Yield: 79 %

Procedure:
Condensation of BocLeuOH (5.00 g.) and HMeMetNH2 (4.00 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocLeu-MeMetNH2 in 81% yield. De-t-butoxycarbonylation of BocLeu-MeMetNH2 (5.96 g.) using hydrogen chloride in ethyl acetate gave HLeu-MeMetNH2 hydrochloride salt in 98% yield. Condensation of BocDTrpOPFP (7.56 g.) and HLeu-MeMetNH2 hydrochloride salt (5.00 g.) by the activated ester method gave BocDTrp-Leu-MeMetNH2 in 56% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MeMetNH2 (2.0 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HDTrp-Leu-MeMetNH2 trifluoroacetate salt in 79% yield.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:31])[S:22](=O)(=O)[C@@H:21]2[CH2:25][C:26](=[O:27])[N:20]2[C@H:19]1[C:28]([OH:30])=[O:29]>>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:31])[S:22][C@@H:21]2[CH2:25][C:26](=[O:27])[N:20]2[C@H:19]1[C:28]([OH:30])=[O:29]
Reactant: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Agent: c1ccc(CCNCc2ccccc2)cc1
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O

Procedure:
The 1:2 N,N'-dibenzylethylenediamine salt of penicillanic acid 1,1-dioxide is the salt formed from N,N'-dibenzylethylenediamine and two molar equivalents of penicillanic acid 1,1-dioxide; the N-benzyl-2-phenylethylamine salt of penicillanic acid 1,1-dioxide is the salt formed from N-benzyl-2-phenylethylamine and one molar equivalent of penicillanic acid, 1,1-dioxide; and the dibenzylamine salt of penicillanic acid 1,1-dioxide is the salt formed from dibenzylamine and one molar equivalent of penicillanic acid 1,1-dioxide. N,N'-dibenzylethylenediamine is also known as benzathine and as DBED; N-benzyl-2-phenylethylamine is also known as benethamine.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[N:22]=[CH:21][N:20]=[C:19](NC3C=CC(F)=C(Cl)C=3)[C:6]2=[CH:7][C:8]=1OCCCN1CCOCC1.OC1C=C(C=CC=1OC)C#N.O1CCN(CCCCl)CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(N)=O>>[N:22]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=2)[CH:19]=[N:20][CH:21]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCOCC1
Agent: COc1ccc(C#N)cc1O
Agent: ClCCCN1CCOCC1
Agent: O=S([O-])S(=O)[O-]
Solvent: NC=O
Product: c1ccc2ncncc2c1

Procedure:
WO 2004/024703 discloses a process for the preparation of gefitinib starting from 3-hydroxy-4-methoxy benzonitrile which involves condensation of 3-hydroxy-4-methoxy benzonitrile with morpholino propyl chloride, nitration, reduction with sodium dithionite to amino compound, hydrolysis of nitrile to amide, cyclisation in the presence of formamide to obtain quinazoline, chlorination with phosphorous oxychloride and finally condensation with chloro-fluoro aniline to obtain gefitinib. The process involves multiple steps and hence is time consuming.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[N:11]=[CH:10][C:9]([NH:8][CH2:7][C:6]([OH:22])=[O:5])=[CH:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CNc1ccc(-c2ccc(F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNc1ccc(-c2ccc(F)cc2)nc1
Reaction time: 8 h

Procedure:
480 mg (1.59 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid tert-butyl ester in 5 ml of 90% aqueous TFA were allowed to stand at room temperature overnight. The mixture was concentrated and lyophilized. Yield: 587 mg.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:13][Si](Cl)(C)C>CO>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccc(CBr)cc1
Solvent: CO
Product: COC(=O)Cc1ccc(CBr)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-(bromomethyl)phenylacetic acid (20 g, 87.3 mmol) in MeOH (200 ml) was added trimethylsilylchloride (2 ml) and the reaction stirred for 2 h. The solvent was removed in vacuo and the residue was twice re-dissolved in MeOH (200 ml) and re-concentrated to give the title compound (21.08 g). δH (CDCl3, 250 MHz) 7.36 (2H, d), 7.26 (2H, d), 4.49 (2H, s), 3.69 (3H, s), 3.62 (2H, s).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[CH3:14][N:15]1[C:23]2[C:18](=[C:19]([O:24][CH3:25])[CH:20]=[CH:21][CH:22]=2)[C:17]([CH:26]=O)=[CH:16]1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17]([CH2:26][NH:6][CH3:5])=[CH:16][N:15]2[CH3:14]
Reactant: COc1cccc2c1c(C=O)cn2C
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cccc(OC)c12
Yield: 95 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 1-methyl-4-methoxy-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.0 g, 95%) was obtained as a white solid: MS (ES) m/e 205.2 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Br)C.[C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH3:13].[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([C:34]#[N:35])[CH:31]=[N:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(OCC)C>[NH2:35][C:34]([C:30]1[CH:31]=[N:32][CH:33]=[C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:29]=1)=[CH:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: N#Cc1cncc(OCc2ccccc2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C=C(N)c1cncc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
Diisopropylamine (12.8 mL, 91 mmol) was added at 0° C. to a 3M solution of ethyl magnesium bromide in diethyl ether (15 mL, 45 mmol) and additional diethyl ether (40 mL). After one hour at 0° C. t-butyl acetate was added and stirring was continued for 30 minutes. 5-(benzyloxy)pyridine-3-carbonitrile (2.9 g, 13.8 mmol) in diethyl ether (40 mL) was added at 0° C. After 2.5 hours at 0° C. saturated aqueous ammonium chloride solution was added. Phases were separated and the aqueous phase was extracted with diethyl ether. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 0 to 45%) to yield 1.95 g tert-butyl 3-amino-3-[5-(benzyloxy)pyridin-3-yl]prop-2-enoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:16]Br>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([Br:16])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: N#Cc1cccnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-aminopyridine-3-carbonitrile 1 (0.56 g, 4.6 mmol) was dissolved in 10 mL HOAC, to which one equivalent of Na2CO3 was added. Then, 1.1 equivalent of Br2 was added dropwise and reaction mixture was stirred at room temperature for 30 minutes. Orange precipitation was formed and filtered off to obtain the desired compound 2 in quantitative yield. The compound was carried on without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]=1OS(C(F)(F)F)(=O)=O)[CH2:2][CH3:3].[NH2:29][CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1>>[CH2:1]([C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:15])([F:17])[F:16])[CH2:11][CH2:12][C:6]=2[C:5]=1[NH:29][CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[CH2:2][CH3:3]
Reactant: NCc1cccs1
Reactant: CCCc1ccc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)C(F)(F)F)CC2
Product: CCCc1ccc2c(c1NCc1cccs1)CCN(C(=O)C(F)(F)F)CC2

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-propyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-(aminomethyl)-thiophene. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 and 4:1) to give 7-propyl-6-[(2-thienyl)methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid. MS (ES+) m/z: 397 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(CCCN2CCCC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCCN2CCCC2)(C(=O)O)CC1

Procedure:
Ethyl 1-(tert-butoxycarbonyl)-4-(3-pyrrolidin-1-ylpropyl)piperidine-4-carboxylate (0.12 g, 0.33 mmol) prepared according to Process Step 2 was mixed with ethanol (1.8 mL) and aqueous sodium hydroxide solution (2.0 mol/L, 1.6 mL, 3.3 mmol), followed by stirring under reflux for fifteen hours. After adjusting the pH to 7.8 by adding diluted hydrochloric acid (6.0 mol/L) added under ice-cooling, the reaction mixture was extracted with n-butanol. The organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was dried under reduced pressure and thereby yielded 1-(tert-butoxycarbonyl)-4-(3-pyrrolidin-1-ylpropyl)piperidine-4-carboxylic acid (0.10 g, 91%).
Reaction SMILES: [CH3:1][C:2]12[C:9](=[O:10])[O:8][C:6](=[O:7])[CH:3]1[CH2:4][CH2:5]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([N:15]=[C:9]([C:2]2([CH3:1])[CH2:5][CH2:4][CH:3]2[C:6]([OH:8])=[O:7])[OH:10])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC12CCC1C(=O)OC2=O
Solvent: Cc1ccccc1
Product: CC1(C(O)=Nc2cc(Cl)cc(Cl)c2)CCC1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
10 g (0.07 mol) of 1-methyl-cyclobutane-1,2-dicarboxylic acid anhydride are dissolved in 50 ml of toluene, and 11.6 g (0.07 mol) of 3,5-dichloroaniline are added. After 24 hours' stirring at room temperature, the amide acid (m.p. 106°-108° C.) which has precipitated is separated. This amidocarboxylic acid is suspended in 40 ml of acetic anhydride, and the suspension is stirred for 24 hours at room temperature, in the course of which everything goes into solution. The acetic anhydride is evaporated off in a water-jet vacuum, and the pulverulent residue is recrystallised from dichloromethane/n-hexane to yield 15 g (73% of theory) of 1-methyl-cyclobutane-1,2-dicarboxylic acid-(3,5-dichlorophenyl)-imide, m.p. 110°-111° C. NMR Spectrum (100 MHz) δ in ppm: 1.55 (s,3H, CH3), 2.0-3.2 (m, 5H, --CH2CH2 --CH--), 7.2-7.5 (m, 3H, aromat.). Compound No. 7.
Reaction SMILES: [CH:1]1(/[CH:7]=[N:8]/[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.CC(C)([O-])C.[K+]>>[CH:7](=[N:8]/[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1)\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=CCC(/C=N/Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C1=CCC(C/N=C/c2ccccc2)CC1

Procedure:
In another aspect, a process is described for preparing a compound, or a salt of a compound, or a solvate thereof, of Formula (III). The process comprises steps of: (a) condensing benzylamine with cyclohex-3-enecarbaldehyde to form (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine; (b) contacting (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine with potassium tert-butoxide present in an amount ranging from about 0.05 molar equivalents to about 3.0 molar equivalents of potassium tert-butoxide to (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine to form (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine; (c) contacting (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine with paraformaldehyde present in an amount ranging from about 2.0 molar equivalents to about 5.0 molar equivalents of paraformaldehyde to (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine, in presence of formic acid and a reaction medium to form a compound of Formula (I); (d) contacting a compound of Formula (I) with an a hydrogen halide solution to form an acid addition salt of a compound of Formula (II); (e) contacting aminothiourea and benzoic acid in presence of polyphosphoric acid to form a 2-amino-5-phenyl-1,3,4-thiadiazole phosphate salt; (f) contacting a 2-amino-5-phenyl-1,3,4-thiadiazole salt, CuBr2 and iso-amyl nitrite, in presence of acetonitrile, to form 2-bromo-5-phenyl-1,3,4-thiadiazole; and (g) contacting the acid addition salt of a compound of Formula (II) with 2-bromo-5-phenyl-1,3,4-thiadiazole, in presence of a sodium bis(trimethylsilyl)amide and a reaction medium, to form a reaction mixture, and optionally contacting the reaction mixture with citric acid. In another aspect, the reaction mixture comprises
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>O1CCCC1>[Cl:21][C:16]1[CH:15]=[C:14]([C:10]2([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2cc(F)cc(Cl)c2)CCN(C(=O)OC(C)(C)C)C1
Yield: 71.4 %

Procedure:
Preparation according to Preparation 2. Tert-butyl-3-(3-chloro-5-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (2.1 g, 6.67 mmol) in dry tetrahydrofuran (50 mL), sodium hydride (60% dispersion in mineral oil, 0.40 g, 10 mmol), iodomethane (0.83 mL, 13.3 mmol). Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (1.57 g, 71%). MS m/z (rel. intensity, 70 eV) 275 (33), 273 (bp), 256 (42), 228 (32), 57 (77).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[C:26]1([CH2:32][C:33](O)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][C:33](=[O:34])[CH2:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(N)c2)Cc2ccccc2C1
Reactant: O=C(O)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(NC(=O)Cc3ccccc3)c2)Cc2ccccc2C1
Reaction time: 8 h

Procedure:
The compound of step 2 (0.042 g, 0.12 mmol) and phenylacetic acid (0.013 g, 0.092 mmol) were dissolved in DCM (3 ml) and DMF (1 ml), NMM (0.031 ml, 0.28 mmol), HOBT (0.016 g, 0.12 mmol) and EDC (0.021 g, 0.12 mmol) were added, and the mixture was stirred overnight. LC/MS analysis showed complete conversion. The mixture was filtered, the filtrate subjected to preparative RP HPLC (water/ACN gradient), and the fractions containing the title compound freeze-dried. Yield: 0.042 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH:25][P:26](=[O:29])([OH:28])[OH:27])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[OH-].[Na+:33]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH:25][P:26]([O-:28])([O-:29])=[O:27])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[Na+:33].[Na+:33]
Reactant: O=P(O)(O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=P([O-])([O-])Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Yield: 90 %

Procedure:
Alternative method (1): To a mixture of (3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-yl)phosphoramidic acid (7.1 mg, 0.016 mmol) described in Example 2 and methanol (2 mL) was added 1 N aqueous sodium hydroxide solution (0.032 mL) at room temperature, and the solvent was evaporated under a reduced pressure. The resulting residue was washed with dimethyl sulfoxide-ethyl acetate (1:1) to obtain the title compound (7.0 mg, 90%).
Reaction SMILES: [CH2:1]([Zn])[C:2]([CH3:5])([CH3:4])[CH3:3].C1COCC1.I[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][C@@H:16]2[NH:23]C(=O)OC(C)(C)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][C@@H:16]2[NH2:23])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCOc2ccc(I)cc21
Reactant: CC(C)(C)C[Zn]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc2c(c1)[C@@H](N)CCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
To a suspension of the 0.3 M neopentyl zinc reagent in THF (60 ml, 15 mmol) was added the tert-butyl (4S)-6-iodo-3,4-dihydro-2H-chromen-4-ylcarbamate (1.8 g, 5.0 mmol) and Pd(dppf)Cl2 (0.2 g, 0.25 mmol) as solids in one portion. The mixture was stirred at r.t. under nitrogen for 48 hours (progress monitored by LC/MS and HPLC). The mixture was quenched with aqueous NH4Cl (20 ml) and extracted with EtOAc (3×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in MeOH(25 ml) and treated with DOWEX® 50WX2-400 ion exchange resin. The mixture was heated to 50° C. for six hours and then the resing was collected by filtration. The resin was washed successively with MeOH and CH2Cl2 these washings were discarded. The resin was then treated with 7 N NH3/MeOH to elute the free amine from the resin. The elutions were concentrated in vacuo to yield a light brown oil (0.63 g, 57%) of (4S)-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamine. This material was consistent with previous preparations and was used as obtained for the subsequent opening of the di-fluoroPhe epoxide. S)-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamine was previously characterized as the mono.HCl salt. 1H NMR (300 MHz, DMSO-d6) δ); 7.25 (s, 1H), 7.02 (m, 1H,), 6.76 (m, 1H), 4.47 (bs, 1H), 4.21 (m, 2H), 2.38 (s, 2H), 2.24 (m, 1H), 2.10 (m, 1H), 0.87 (s, 9H). HRMS (ESI+) calculated for C14H21N1O1 220.1701; found m/z 220.1698 (M+H)+. Anal. Calcd for C14H21NO.HCl: C, 65.74; H, 8.67; N, 5.48. Found: C, 65.62; H, 8.53; N, 5.42. [α]23D=15.6, c=1.17 in CH3OH.
Reaction SMILES: C1C(O)=C(O)C(O)=CC=1C(OC1C=C(C(OC[C@H]2O[C@@H](OC(C3C=C(O)C(O)=C(OC(C4C=C(O)C(O)=C(O)C=4)=O)C=3)=O)[C@H](OC(C3C=C(O)C(O)=C(OC(C4C=C(O)C(O)=C(O)C=4)=O)C=3)=O)[C@@H](OC(C3C=C(O)C(O)=C(OC(C4C=C(O)C(O)=C(O)C=4)=O)C=3)=O)[C@@H]2OC(C2C=C(O)C(O)=C(OC(C3C=C(O)C(O)=C(O)C=3)=O)C=2)=O)=O)C=C(O)C=1O)=O.[CH3:123][C:124]1[CH:129]=[C:128]([OH:130])[C:127]2[C:131]([C:133]3[C:138]([OH:139])=[CH:137][C:136](O)=[CH:135][C:134]=3[C:141](=O)[C:126]=2[CH:125]=1)=[O:132]>C1C=CC=CC=1>[CH3:123][C:124]1[CH:125]=[C:126]2[CH:141]=[C:134]3[C:133](=[C:131]([OH:132])[C:127]2=[C:128]([OH:130])[CH:129]=1)[C:138]([OH:139])=[CH:137][CH:136]=[CH:135]3
Reactant: Cc1cc(O)c2c(c1)C(=O)c1cc(O)cc(O)c1C2=O
Agent: O=C(OC[C@H]1O[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H]1OC(=O)c1cc(O)c(O)c(OC(=O)c2cc(O)c(O)c(O)c2)c1)c1cc(O)c(O)c(OC(=O)c2cc(O)c(O)c(O)c2)c1
Solvent: c1ccccc1
Product: Cc1cc(O)c2c(O)c3c(O)cccc3cc2c1

Procedure:
Phytochemistry: The seeds contain tannic acid, mucilage (36%), fatty acid (2.56%), emodin and a toxalbumin. Chrysarobin (methyl-di hydroxy anthranol. M. P. 203-4° C.) has been isolated from the benzene extract of the seeds. The fatty oil contains: saturated fatty acids 19.7; linoleic acid, 31.4; oleic acid 30.7, linolenic acid, 6.3;volatile constituents, 0.7; un sapon matter 7.4%. Pharmacology: All parts of the plant have similar medicinal properties and are considered purgative, tonic, febrifugal, expectorant and diuretic. The plant is used as a vermifuge and to treat sore eyes, haematuria, rheumatism, dropsy, typhoid, asthma, blood disorders and is reportedly effective against leprosy. A decoction of the plant is used for the treatment of hysteria, dysentery and other stomach troubles. The roots are considered bitter, tonic, purgative, anthelmintic and diuretic. In ayurveda a paste made from the roots is considered specific ringworm and other skin ailments. The leaves are also used externally to relieve inflammatory swellings, rheumatism, wounds and sprains. The root bark is used as a quinine substitute to cure fever, and its decoction is used as a stimulant and as a specific medicine for gonorrhoea and hepatic troubles.