Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[I:22]I>C1COCC1>[I:22][C:11]1[O:10][C:9]([CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: II
Reactant: C(=Cc1ccco1)c1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Ic1ccc(C=Cc2cccnc2)o1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a stirred -78° C. solution of 2-[2-{3-pyridyl}ethenyl]furan (0.95 g, 5.5 mmol), prepared as in step 4, in THF (25 mL) was added lithium diisopropylamide (4 mL, 6 mmol, 1.5M in hexanes). The cold reaction mixture was stirred 1 hour, followed by the addition of a THF (3 mL) solution of iodine (1.39 g, 5.5 mmol). The ice bath was removed and the reaction mixture allowed to stir at ambient temperature overnight. Saturated NH4Cl was added and the mixture diluted with ether. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel eluting with 40% ethyl acetate-hexanes to afford 1.1 g of 2-iodo-5-[2-{3-pyridyl}ethenyl]furan.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH3:15])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9].[F:16][B-:17]([F:20])([F:19])[F:18].[CH2:21]([O+](CC)CC)[CH3:22]>>[F:16][B-:17]([F:20])([F:19])[F:18].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH3:15])=[C:7]([CH:11]=1)[C:8](=[NH:10])[O:9][CH2:21][CH3:22]
Reactant: CC[O+](CC)CC
Reactant: CCCOc1ccc(OC)cc1C(N)=O
Agent: F[B-](F)(F)F
Product: CCCOc1ccc(OC)cc1C(=N)OCC
Yield: 124.6 %

Procedure:
reaction of 5-methoxy-2-propoxybenzamide (10.88 g) with triethyloxonium tetrafluoroborate (0.07 mol) yielded ethyl 5-methoxy-2-propoxybenzimidate tetrafluoroborate (21.0 g);
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1.[C:18]([Zn]C#N)#[N:19]>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:10]1[CH:11]=[C:12]([CH:13]=[O:14])[CH:15]=[CH:16][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:18]#[N:19])[CH:7]=1
Reactant: O=Cc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(Oc2ccc(C=O)cc2F)ccn1
Yield: 30.4 %

Procedure:
To a solution of 4-((2-chloropyridin-4-yl)oxy)-3-fluorobenzaldehyde (580 mg, 2.31 mmol) and dicyanozinc (271 mg, 2.31 mmol) in N,N-dimethylacetamide (DMA) (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (266 mg, 0.230 mmol). The reaction mixture was sealed in a microwave vial and irradiated with a microwave using initial normal to 100° C. for 1 h, and then filtered. Direct purification via reversed phase chromatography (acetonitrile/water: 5%-95%, 0.25% NH4OH) afforded the title product (170 mg) as a white solid.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].C([Li])CCC.CCCCCC.CN(C)[CH:28]=[O:29].Cl>O1CCCC1>[OH:4][C:5]1[C:6]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:8]=[CH:9][C:10]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: COCOc1ccccc1C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(C(F)(F)F)c1O
Reaction time: 1 h

Procedure:
1-methoxymethoxy-2-trifluoromethylbenzene (64.13 g) was dissolved in tetrahydrofuran (500 mL), and a 2.77M n-butyllithium-n-hexane solution (123 mL) was added to the solution over 45 minutes under an argon gas flow at −70° C., and then the mixture was stirred for 1 hour. N,N-dimethylformamide (28.5 mL) was added, followed by stirring at room temperature for 30 minutes. 4N hydrochloric acid (310 mL) was added, followed by stirring at 60° C. for 19 hours. The organic solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (59.16 g) as a yellow crystal.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:17])([CH3:16])[O:4][C:5]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:6]=12.[Na].[S:19]1(=[O:25])(=[O:24])[CH2:23][CH2:22][CH2:21][NH:20]1.O>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([N:20]2[CH2:21][CH2:22][CH2:23][S:19]2(=[O:25])=[O:24])[C:6]2[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][C:3]1([CH3:17])[CH3:16]
Reactant: O=S1(=O)CCCN1
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2C2OC21
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N2CCCS2(=O)=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
To a solution of 3,4-dihydro-3,4-epoxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (1.5 g) in dimethyl sulfoxide (30 ml) was added sodium salt of isothiazolidine 1,1-dioxide (1.7 g). The mixture was stirred at room temperature overnight. Water was carefully added to the reaction mixture and the whole was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (50 g) with a mixture of chloroform and methanol (50:1) as eluents to give trans-3,4-dihydro-3-hydroxy-4-(1,1-dioxoisothiazolidin-2-yl)-6-mesyl-2,2-dimethyl-2H-1-benzopyran (0.47 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(-n2cccc2)c1
Yield: 81.5 %

Procedure:
Ethyl m-aminobenzoate (1.6 g) was dissolved in 10 ml of glacial acetic acid, and 1.3 g of 2,5-dimethoxytetrahydrofuran was added. The mixture was refluxed for 2 hours, and the solvent was evaporated. The residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, and then worked up in a customary manner. Finally, recrystallization from hexane gave 1.7 g (yield 82%) of ethyl 3-(1-pyrrolyl)benzoate as colorless needles having a melting point of 64° to 65° C. The resulting pyrrolyl compound (1.1 g) was dissolved in 30 ml of ethyl ether, and with stirring under ice cooling, 0.2 g of lithium aluminum hydride was added. The mixture was stirred for 1 hour. The reaction mixture was extracted by adding water and ethyl ether. The extract was worked up in a customary manner. Recrystallization from a mixture of ethyl acetate and hexane gave 0.80 g (yield 91%) of 3-(1-pyrrolyl)benzyl alcohol as colorless needles having a melting point of 66° to 68° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][O:3]1.[Cl:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21](Cl)[N:20]=[CH:19][N:18]=1.CC(N(C)C)=O>>[Cl:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21]([O:14][C:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][CH2:6]3)=[CH:9][CH:10]=2)[N:20]=[CH:19][N:18]=1
Reactant: CC1(C)OCC(c2ccc(O)cc2)CO1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CC(=O)N(C)C
Product: CC1(C)OCC(c2ccc(Oc3ncnc(Cl)c3[N+](=O)[O-])cc2)CO1
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of 4-(2,2-dimethyl-1,3-dioxan-5-yl)phenol (500 mg, 0.0026 moles) and 4,6 dichloro-5-nitropyrimidine (600 mg, 0.0028 mole) in dimethyl acetamide (10 ml) K2CO3 (776 mg, 0.00577 mole) was added −20° C. The reaction mixture was stirred for about 2 hours at −10° C. to −18° C. The reaction mixture was then poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield crude product which was purified by column chromatography using 15% ethyl acetate in hexane as eluent to yield 500 mg product as pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][OH:22])[C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][OH:22])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CO)c1ccc(OCc2ccccc2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(CO)C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 2-(4-benzyloxy-3-methoxyphenyl)-3-hydroxy-propionate (1.29 g; 3.29 mmol; from step (iii) above) in THF (12.5 mL) was added a solution of LiOH (0.273 g; 6.75 mmol) in H2O (5 mL), and the mixture was stirred at room temperature for 2.5 hours. The resultant mixture was partially concentrated, water (25 mL) was added, the mixture was washed with two portions of CH2Cl2, made acidic with HCl/aq (2M), and extracted with 3 portions of CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), and evaporated to yield 10.55 g (quant.) of a yellow powder. Purity 83.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5]
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C(=O)O)c3)ccc12
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNC(=O)c1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 3-[2-(2,4-dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-benzoic acid (40 mg, 0.09 mmol) in dichloromethane (2 mL) was added 2-methoxyethylamine (0.02 mL, 0.19 mmol), EDCI (20 mg, 0.1 mmol), DMAP (1 mg, 0.01 mmol), and N,N-diisopropylethylamine (0.02 mL, 0.1 mmol). The reaction mixture was stirred at rt overnight, then concentrated in vacuo and purified by prep-HPLC to afford the desired product (11 mg, 25%). 1H-NMR (CDCl3) δ 8.05 (t, J=1.8 Hz, 1H), 7.77-7.75 (m, 3H), 7.69 (m, 1H), 7.60 (dd, J=8.3, 1.0 Hz, 1H), 7.51 (m, 2H), 7.47 (m, 1H), 7.40 (ddd, J=8.2, 1.9, 0.5 Hz, 1H), 6.62 (t, J=4.5 Hz, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.40 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.[S:15]([NH:25][NH2:26])(C1C=CC(C)=CC=1)(=O)=O.S(Cl)(Cl)=O>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:26]=[N:25][S:15][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc(CCCCCl)cc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: ClCCCCc1ccc(-c2csnn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 6.25 g (29.65 mmol) p-(4-chlorobutyl)acetophenone, 5.57 g (29.65 mmol) tosylhydrazine, and 50 ml ethanol. The reaction was refluxed 3.5 hours, cooled, and evaporated. The residue was taken up in 23.4 ml (326 mmol) thionyl chloride and stirred at room temperature for 3 hours. The reaction mixture was evaporated and the residue chromatographed on silica gel using hexane/methylene chloride as eluent to afford an oil, 6.1 g (81.5%). NMR (CDCl3): 1.84 (m, 4H), 2.73 (m, 2H), 3.58 (m, 2H), 7.3 and 7.95 (m, 4H), 8.59 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C@H:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[N:2]1.[Br:16]Br>ClCCl.C(O)(=O)C>[Br:16][C:4]1[C:3]([NH:6][C@H:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH:9]([CH3:10])[CH3:11])=[N:2][S:1][CH:5]=1
Reactant: BrBr
Reactant: COC(=O)[C@H](CC(C)C)Nc1ccsn1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)Nc1nscc1Br
Reaction time: 0.75 h
Yield: 102.3 %

Procedure:
To a solution of methyl N-isothiazol-3-yl-L-leucinate (160 mg, 0.70 mmol) in dichloromethane (3 mL) and acetic acid (0.5 mL) was added bromine (0.04 mL, 0.78 mmol). The solution was stirred for 45 min, then diluted with dichloromethane and washed with saturated aqueous NaHCO3 and brine, filtered through cotton and evaporated to give 220 mg of methyl N-(4-bromoisothiazol-3-yl)-L-leucinate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH:21]5[CH2:23][CH2:22]5)(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][N:33]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)C5CC5)CC4)cc3n2)c(OC)n1

Procedure:
2-Chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (Example 39) was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine via General Procedure A. Purification on silica yielded the desired compound. NMR (400 MHz, CDCl3): 1.01-1.04 (2H, m, CH2), 1.20-1.25 (2H, m, CH2), 2.30 (1H, m, CH), 2.67-2.70 (4H, m, CH2), 3.39-3.41 (4H, m, CH2), 2.87-3.88 (4H, m, CH2), 3.90 (2H, s, CH2), 4.03-4.05 (4H, m, CH2), 4.08 (3H, s, CH3), 4.11 (3H, s, CH3), 7.36 (1H, s, ar), 8.95 (1H, s, ar).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:34][C:35]1[N:39]([CH3:40])[N:38]=[N:37][N:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:34][C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cn1nnnc1S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nnnc1SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) in dry THF (30 mL) were added triphenylphosphine (2.0 g, 7.5 mmol) and 5-mercapto-1-methyl-1H-tetrazole (0.70 g, 6.0 mmol). To the mixture was added diisopropyl azodicarboxylate (1.2 mL, 6.0 mmol) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), which was washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, successively. The solvent was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (50 g, diethyl ether-hexane 1:1) to give the titled compound as a colorless oily substance. (1.11 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24](O)=[O:25])[C:13]2=[O:27])=[O:10])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]([CH3:63])[C@H:58]1[CH2:62][CH2:61][NH:60][CH2:59]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([N:60]3[CH2:61][CH2:62][C@H:58]([N:57]([CH3:63])[CH3:56])[CH2:59]3)=[O:25])[C:13]2=[O:27])[CH:7]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
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: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CC[C@H](N(C)C)C3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial charged with {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (50 mg, 0.11 mmol), HATU (46.6 mg, 0.12 mmol), and dimethyl-(S)-pyrrolidin-3-yl-amine (14.0 mg, 0.12 mmol) DCM (2 ml) is added. The mixture is treated with DIPEA (48.6 μL, 2.79 mmol) and stirred at RT for 1 hour. DCM (5 ml) is added to the mixture and washed with 1M HCl. The acidic aqueous phase is treated with 1M NaOH until the pH is adjusted to pH of 7-8. The product is extracted from the aqueous phase with EtOAc (3×10 ml). The organic portions are combined, washed with water (10 ml), dried (MgSO4), filtered and concentrated to afford the title compound, [M+H]+ 544
Reaction SMILES: [Na+].[NH2:2][C:3]([O:5][CH2:6][CH:7]1[O:11][CH2:10][CH:9]([S:12][C:13]2[CH:19]([CH3:20])[CH:18]3[N:15]([C:16](=[O:24])[CH:17]3[CH:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O-:27])=[O:26])[CH2:8]1)=[O:4].[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(=O)(O)[O-].[I-].[Na+]>>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[O:34][CH2:35][O:26][C:25]([C:14]1[N:15]2[CH:18]([CH:19]([CH3:20])[C:13]=1[S:12][CH:9]1[CH2:8][CH:7]([CH2:6][O:5][C:3]([NH2:2])=[O:4])[O:11][CH2:10]1)[CH:17]([CH:21]([OH:23])[CH3:22])[C:16]2=[O:24])=[O:27]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COC(N)=O)C3)C(C)C12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(SC3COC(COC(N)=O)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 407 using 0.460 g of product from Example 21, 0.24 ml of chloromethyl pivalate, 0,189 g ofsodium bicarbonate and 0,252 g of sodium iodide to give after chromatograph0.32 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16]C(OC(C)(C)C)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(NC(=O)OC(C)(C)C)c2c1C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1oc2cccc(N)c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (624 mg, 1.95 mmol, prepared according to Example 59, Step 1) was added 1,2-dichloroethane (12 mL) and trifluoroacetic acid (TFA, 6 mL). The reaction was stirred at room temperature for 2 hours. Solvent was removed in vacuo to provide 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.7 (s, 3 H) 4.3 (q, J=7.1 Hz, 2 H) 6.5 (dd, J=7.8, 0.8 Hz, 1 H) 6.8 (d, J=8.3 Hz, 1 H) 7.2 (t, J=8.1 Hz, 1 H).
Reaction SMILES: [OH:1]O.[CH:3]1=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1>C(O)(C)(C)C>[CH:3]12[O:1][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: OO
Reactant: C1=CCCCCCC1
Agent: C1=C\CCCCCC/1
Solvent: CC(C)(C)O
Product: C1CCCC2OC2CC1
Temperature: 30 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
Hydrogen peroxide (30%, 2 ml) was added to a mixture of the catalyst from Example 48 (0.04 g) and cis-cyclooctene (1.4 g, 11.5 mmol) in tert-butanol (10 ml) at 30° C. under an atmosphere of nitrogen. The reaction mixture was stirred at 30° C. for 48 h under nitrogen. The catalyst was filtered off and washed well with ether (80 ml). The combined organic layers were washed well with water (2×40 ml) and then dried over magnesium sulphate. After filtration the solvent was removed under reduced pressure—20° C. at 50 mm of Hg—to afford 9-oxabicyclo[6.1.0] nonane as a white solid (0.95 g, 65%). M.p. 51° C., lit. m.p. 53-56° C.
Reaction SMILES: C[Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:18]2[N:22]3[CH2:23][CH2:24][CH2:25][C@:26]([O:32][C:33]4[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=4)(C(OCC)=O)[C:21]3=[N:20][N:19]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:18]2[N:22]3[CH2:23][CH2:24][CH2:25][C@@:26]([C:6]([OH:5])([CH3:7])[CH3:11])([O:32][C:33]4[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=4)[C:21]3=[N:20][N:19]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 129.4 %

Procedure:
To a mixture of methylmagnesium bromide (1 M THF solution, 6.81 mL) in THF (6 mL) was added a mixture of ethyl (8R)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1 g) in THF (6 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (0.63 g) as a solid.
Reaction SMILES: C1[C@H](N)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)[C@H]([O:20][C@@H:21]2[O:25][C@H:24](CO)[C@@H:23](O[C@H]3O[C@@H](CN)[C@@H](O)[C@H](O)[C@H]3N)[C@H:22]2[OH:40])[C@@H](O)[C@@H]1N.OS(O)(=O)=O.[CH2:48]([O:55][C:56]([NH:58][C:59]([N:71]1C=CC=N1)=[N:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:56]([N:58]([CH2:24][CH2:23][C@H:22]([OH:40])[C:21]([OH:25])=[O:20])[C:59]([NH2:71])=[N:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[O:62])([O:55][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:57]
Reactant: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O
Reactant: O=C(N=C(NC(=O)OCc1ccccc1)n1cccn1)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)OCc1ccccc1)N(CC[C@H](O)C(=O)O)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2(S)-hydroxy-4-amino-butyric acid (1, 0.059 g, 0.50 mmol) in DMF (2 ml) was added N,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.26 g, 0.70 mmol) followed by DIPEA (0.87 mL, 4.99 mmol) and the reaction was heated to 80° C. and stirred overnight. The crude mixture was purified on a 2-inch reverse-phase HPLC column to yield N,N′-bis-Cbz-2(S)-hydroxy-4-guanidino-butyric acid (2): MS: m/z (M+H)+ calc. 430.15, obs. 430.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH2:11]Br>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)CCBr
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)CCN1CCCC1

Procedure:
Pyrrolidine (5.4 mL, 66 mmol) was dissolved in toluene (40 mL). 4-Bromo-2-methyl-butyric acid methyl ester (4.3 g, 22.0 mmol) was added and the reaction stirred at reflux for 2.5 hours. Removal of the solvent and of the excess amine at reduced pressure gave 2-methyl-4-(pyrrolidin-1-yl)-butyric acid methyl ester as a thick oil. The crude product was diluted with MeOH (3 mL) and 1.0M NaOH aq solution (22 mL) was added and the reaction stirred at reflux for 18 hours.