Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][O:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11].CCN(C(C)C)C(C)C.[Br:26][CH2:27][C:28](Br)=[O:29]>C(#N)C>[CH2:8]([N:12]([O:13][CH2:14][CH2:15][CH3:16])[C:28](=[O:29])[CH2:27][Br:26])[CH2:9][CH2:10][CH3:11]
Reactant: O=C(Br)CBr
Reactant: CCCCNOCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCN(OCCC)C(=O)CBr
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The salt of Example 538B (0.60 g) was dissolved in acetonitrile (5 mL) and cooled to −20° C. Hünig's base (5.5 mL) was added slowly. Bromoacetyl bromide (0.5 mL) was added dropwise over five minutes. The solution was stirred at −20° C. for 30 minutes. The bath was removed and the solution was stirred for six hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1×25 mL), 1N phosphoric acid (3×25 mL), and brine (1×25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.65 g) which was used without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH:21]([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])=[CH2:22].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][CH:8]=[C:7]2[CH:22]=[CH:21][N:23]2[C:24](=[O:33])[C:25]3[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:28])=[CH:12][CH:13]=1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc2cccc(C=CN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 25 °C
Yield: 80 %

Procedure:
In a reactor, 2 g of the compound obtained in Step A, 2 eq. of N-vinylphthalimide, 1.25 eq. of diisopropylethylamine and 0.05 eq. of palladium tetrakis(triphenylphosphine) are introduced into toluene and heated at reflux. The reaction is continued at reflux for 12 hours and then the reaction mixture is cooled to ambient temperature. Ethyl acetate is added, and then washings with water and IN HCl solution are carried out. After evaporating off the solvents, the residue obtained is purified by chromatography on silica gel (eluant:dichloromethane/heptane 1/1, and then dichloromethane) to yield the title product in a yield of 80% and with a chemical purity of more than 95%.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)(C)(C)C.ClCCl.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O>[CH3:29][S:30]([O:15][CH2:14][C@H:12]1[O:11][C:10]([CH3:17])([CH3:16])[O:9][C@@H:8]([CH2:7][C:6]([OH:5])=[O:18])[CH2:13]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)O[C@H](COS(C)(=O)=O)C[C@H](CC(=O)O)O1
Reaction time: 1 h
Yield: 92 %

Procedure:
tert-Butyl-2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]acetate (10.0 g) and dichloromethane (60.0 mL) were added to a reactor. The reaction mixture was cooled to 0˜5° C. Triethylamine (12.9 mL) and methanesulfonyl chloride (3.6 mL) was added to the reaction mixture, which was then stirred at 0˜5° C. for 1 hour. Water (500.0 mL) was added to the reaction mixture under stirring. The separated organic layer was concentrated under reduced pressure. Methanol (40.0 mL), water (20.0 mL), and sodium hydroxide (3.4 g) were added to the resulting residue. The reaction mixture was stirred at 40° C. for over 12 hours and then concentrated under reduced pressure. Water (30.0 mL) and ethyl acetate (60.0 mL) were added to the resulting residue and then the pH of the reaction mixture was adjusted to 2.0˜4.0 using 6N hydrochloric acid solution. The separated organic layer was concentrated under reduced pressure to obtain [(4R,6S)-6-methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid as a gel form (10.0 g, yield 92%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:14][NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>ClCCl>[CH3:14][N:15]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:4]([C:3]1[CH:7]=[C:8]([OH:13])[C:9]([O:11][CH3:12])=[CH:10][C:2]=1[Br:1])=[O:5]
Reactant: COc1cc(Br)c(C(=O)Cl)cc1O
Reactant: CNCCc1ccc(O)cc1
Solvent: ClCCl
Product: COc1cc(Br)c(C(=O)N(C)CCc2ccc(O)cc2)cc1O
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
The previously prepared 2-bromo-5-hydroxy-4-methoxy benzoyl chloride (B13-Cl) in dichloromethane solution was transferred into the slurry of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine at about 5° C. and then stirred for about 0.5 hours under an atmosphere of nitrogen. The solution was concentrated under vacuum and then cooled to between 25 to 35° C. To this was then added a 15% w/v solution of NaOH in methanol (0.173 Kg sodium hydroxide in methanol 0.910 Kg) and was then heated to between 25 to 35° C. The solution was stirred for about 8 hours and then the pH was adjusted to between 2 to 5 with 32% hydrochloric acid (˜0.6 Kg). The solution was concentrated and the residue was cooled to about 30° C. Dichloromethane (6.628 Kg) and water (15 Kg) were added into the above mixture and then cooled to about 5° C. and was then stirred for about 2 hours. The solidified product was filtered and washed twice with dichloromethane (0.663 Kg each) to provide crude N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][NH:35][CH:36]1[CH2:38][CH2:37]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(OS(OCCC)(=O)=O)CC>>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][N:35]([CH:36]1[CH2:37][CH2:38]1)[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)(=[O:3])=[O:4])=[O:28])([CH3:25])([CH3:23])[CH3:24].[CH2:18]([C:19]([O-:21])=[O:20])[CH2:8][CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNC1CC1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Agent: CCCOS(=O)(=O)OCCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN(C1CC1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Product: CCCC(=O)[O-]

Procedure:
(S)-8-[(1-tert-butoxycarbony-pyrrolidin-2-ylmethyl)-cyclopropyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate is prepared according to synthesis 111, from 326 mg (1 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid and 288 mg (1.2 mmol) of (S)-1-tert-butoxycarbonyl-2-cyclopropylaminomethyl-pyrrolidine to give, after esterification according to general method C (using di-n-propylsulfate as the dialkylsulfate) and purification by chromatography on silica (eluent dichloromethane/methanol 99/1 then 95/5), 99 mg (17% in two stages) of (S)-8-[(1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl)-cyclopropyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate in the form of a white solid.
Reaction SMILES: CS(Cl)(=O)=O.C(N(CC)CC)C.O[C:14]([C:17]1[CH:21]=[C:20]([C:22]2[CH:38]=[CH:37][C:25]([O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][CH:23]=2)[N:19]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[N:18]=1)([CH3:16])[CH3:15].CN(C)C=O>ClCCl>[C:14]([C:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:37][CH:38]=2)[N:19]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[N:18]=1)([CH3:16])=[CH2:15]
Reactant: COc1ccc(-n2nc(C(C)(C)O)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C(C)c1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (367 mg) and triethylamine (649 mg) were added successively to a solution of tert-butyl 2-{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate obtained by Example 6 (1.0 g) and N,N-dimethylformamide (91.5 mg) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 2 hrs. Additional methanesulfonyl chloride and triethylamine were added until all starting material was consumed with stirring at the same temperature.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCCC(O)c2ccccc2N1
Product: CC(=O)OC1CCCCC(=O)Nc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 7-hydroxy-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (9.2 g) in acetic anhydride (200 ml) is maintained at 80° C. for 3 hours. The reaction mixture is cooled to room temperature and the solvents removed under reduced pressure. Ether (300 ml) is added, and the resulting solution washed with water (150 ml) and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 7-acetoxy-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](=[S:8])[NH2:7])[CH:3]=[N:2]1.Br[CH2:10][C:11](=O)[C:12]([OH:14])=O.[NH2:16][C@@H:17]([CH3:33])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=2)=[N:20]1.C(Cl)Cl>C1COCC1>[Cl:32][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:12]([C:11]3[N:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[S:8][CH:10]=3)=[O:14])[CH3:33])[N:20]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)c1cn[nH]c1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cn[nH]c2)n1
Temperature: 60 °C
Yield: 37.7 %

Procedure:
1H-Pyrazole-4-carbothioic acid amide (1.0 g, 7.86 mmol) and 3-bromo-2-oxopropanoic acid (1.44 g, 8.65 mmol) were dissolved in dry THF under nitrogen atmosphere. The reaction mixture was heated at 60° C. for 4.5 h. The reaction mixture was cooled to RT and evaporated to dryness. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.367 g, 5.24 mmol) and DCM were added to the reaction flask and the title compound was prepared using the method of Example 34(d). The product purified by Flash-chromatography and triturated using acetonitrile. Yield 37.7%. 1H-NMR (400 MHz; DMSO): δ 1.11 (d, 3H), 4.25-4.48 (m, 3H), 6.89 (d, 1H), 7.77 (d, 1H), 7.80 (d, 1H), 7.87 (dd, 1H), 7.93 (bs, 1H), 7.99 (d, 1H), 8.01 (s, 1H), 8.31 (d, 1H), 8.33 (bs, 1H), 13.31 (bs, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:23]=[CH:22][C:14]([CH2:15][C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)=[CH:13][CH:12]=1.BrCC(=O)CC1C=CC(Br)=CC=1.NC(N)=S>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:11]2[CH:23]=[CH:22][C:14]([CH2:15][C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)=[CH:13][CH:12]=2)=[CH:3][CH:2]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1nc(Cc2ccc(Br)cc2)cs1
Agent: NC(N)=S
Agent: O=C(CBr)Cc1ccc(Br)cc1
Solvent: CCO
Product: Nc1nc(Cc2ccc(-c3ccncc3)cc2)cs1

Procedure:
In a similar manner to Preparation 6, step 3, the Suzuki coupling reaction of pyridine-4-yl boronic acid and 4-(4-bromo-benzyl)-thiazol-2-ylamine, was prepared via reaction of 1-bromo-3-(4-bromo-phenyl)-propan-2-one and thiourea in ethyl alcohol according to the procedure described in Preparation 1, step 2, gave the title compound 7. LC/MS m/z 268.08 (M+H)+; HPLC Rt: 0.598 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[OH2:11].[OH-:12].[Na+]>O1CCOCC1>[CH2:4]([CH:5]([NH:8][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])[C:6]([OH:12])=[O:11])[C:3]#[C:2][CH3:7]
Reactant: O
Reactant: [OH-]
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC#CCC(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the solid (110 mg, 0.866 mmol) in 1N aq. NaOH (3 mL), a solution of 4-chlorophenyl isocyanate (200 mg, 1.30 mmol) in dioxane (3 mL) was added. The mixture was stirred at room temperature for 16 h. H2O (20 mL) was added. The aqueous layer was washed with Et2O, acidified with 4N HCl to pH 1-2. The product was extracted with EtOAc. The EtOAc solution was dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give the urea acid as a white powder (207 mg). MS 303.3 and 305.2 (M+Na, Cl pattern)
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7]C=[CH:9][C:4]=2[C:3]([OH:10])=N1.P(Cl)(Cl)([Cl:13])=O.C([N:18]([CH2:21][CH3:22])CC)C>>[Cl:13][C:21]1[C:22]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=2[O:10][N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: Oc1noc2ccccc12
Product: Cc1cccc2c(Cl)noc12
Temperature: 135 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a stirred mixture of 114 parts of 1,2-benzisoxazol-3-ol and 230 parts of phosphoryl chloride were added dropwise 160 parts of N,N-diethylethanamine (exothermic reaction). Upon complete addition, the reaction mixture was stirred overnight at 135° C. The mixture was poured into crushed ice and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was boiled in 2,2'-oxybispropane. The solvent was decanted (this was repeated twice) and the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 60 parts (51.1%) of 3-chloro-7-methyl-1,2-benzisoxazole as a residue (int. 1).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH2:19]([N:22]1[C:26]([SH:27])=[N:25][N:24]=[N:23]1)[C:20]#[CH:21].B(F)(F)F.CCOCC.N>C(#N)C.O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:26]3[N:22]([CH2:19][C:20]#[CH:21])[N:23]=[N:24][N:25]=3)[CH2:15][S:14][C@H:9]12
Reactant: C#CCn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: N
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 47 °C
Reaction time: 1.5 h
Yield: 79.5 %

Procedure:
To a suspension of 7-aminocephalosporanic acid (0.35 g) and 1-(2-propynyl)-1H-tetrazole-5-thiol (0.20 g) in acetonitril (1.8 ml) was added boron trifluoride etherate (0.55 g) at room temperature and the resulting mixture was stirred for 1.5 hours at 47° C. To the reaction mixture was added water (1.8 ml) and the mixture was adjusted to pH 3.5 with conc. aqueous ammonia under ice-cooling. The precipitates were collected by filtration, washed successively with water and acetone and then dried to give 7-amino-3-[1-(2-propynyl)-1H-tetrazole-5-yl]thiomethyl-3-cephem-4-carboxylic acid (0.36 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].O[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: OCCOc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCOc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (193 mg, 0.6 mmol), (prepared as described in Example 49), 4-(2-hydroxyethoxy)pyridine (166 mg, 1.2 mmol), (J. Chem. Soc. Perkin II, 1987, 1867), in methylene chloride (5 ml) containing triphenylphosphine (330 mg, 1.26 mmol) and diisopropyl azodicarboxylate (255 mg, 1.26 mmol) was stirred at ambient temperature for 2 hours. The precipitate was filtered, triturated with ether followed by ethyl acetate, and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline (142 mg, 54%).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:44][CH:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46]([NH2:48])=[O:47])(=[O:43])=[O:42])=[CH:37][CH:36]=1.[CH3:56][O:57][C:58](=[O:66])[C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][CH:60]=1>O1CCCC1>[CH3:56][O:57][C:58](=[O:66])[C:59]1[CH:64]=[CH:63][C:62]([CH2:1][N:44]([CH:45]([C:46](=[O:47])[NH2:48])[CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[S:41]([C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)(=[O:42])=[O:43])=[CH:61][CH:60]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: NC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C(Cc2ccccc2)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (110 mmg, 0.4 mmol) in 0.7 mL of tetrahydrofuran is added diisopropyl azodicarboxylate (0.08 mL, 0.4 mmol) and the reaction stirred for 30 min. To the reaction is added 0.4 mL of tetrahydrofuran, (2-(4-chloro-benzenesulfonylamino)-3-phenyl-propionamide (75 mg, 0.2 mmol), and methyl-4-hydroxybenzoate (73 mg, 0.4 mmol). The reaction is allowed to warm to room temperature (rt) and stirred overnight. The solvent is removed and the resultant residue purified by silica gel chromatography to provide the title compound. C13 NMR (100 MHz, CDCl3) 35.5, 48.7, 52.4, 61.4, 127.1, 128.8, 128.9, 129.0, 129.3, 129.6, 129.9, 136.8, 138.1, 139.8, 141.7, 166.9, 171.0. MS 487.1 m/z (M+1).
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH2:31][C@@H:32]([CH2:40][OH:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([C@@H:32]([NH:31][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH2:40][OH:41])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: N[C@@H](CO)Cc1ccccc1
Product: O=C(N[C@@H](CO)Cc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (R)-phenylalaninol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 392 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.14 (1H, s) 7.98 (1H, d, J=5.47 Hz) 7.72-7.82 (2H, m) 7.40 (1H, d, J=5.37 Hz) 7.28 (1H, dd, J=3.54, 2.22 Hz) 7.14-7.22 (4H, m) 7.10 (1H, ddd, J=6.20, 2.98, 2.73 Hz) 6.73 (1H, d, J=5.52 Hz) 6.39 (1H, dd, J=3.51, 1.66 Hz) 4.82 (1H, t, J=5.56 Hz) 4.13 (1H, ddd, J=14.04, 5.58, 2.98 Hz) 3.42-3.49 (1H, m) 3.38 (1H, t, J=5.78 Hz) 2.84-2.93 (1H, m) 2.73 (1H, dd, J=13.67, 8.93 Hz)
Reaction SMILES: C1COCC1.[C:6]1([CH2:12][OH:13])[CH:11]=[CH:10][CH:9]=[CH:8]C=1.[OH-].[Na+].[Cl:16][C:17]1[C:22]([O:23][CH2:24][CH:25]2[CH2:27][O:26]2)=[CH:21][CH:20]=[CH:19][N:18]=1>O>[Cl:16][C:17]1[C:22]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][O:13][CH2:12][CH2:6]/[CH:11]=[CH:10]\[CH:9]=[CH2:8])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: OCc1ccccc1
Reactant: Clc1ncccc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C/C=C\CCOCC(O)COc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A mixture of THF (915 ml), benzenemethanol (2.96 mol) and NaOH (2.36 mol) was stirred at room temperature for 30 minutes (cooling was required to keep the temperature below 25° C.). Intermediate (19) (1.97 mol) was added. The reaction mixture was stirred at room temperature for 4 days. Water was added dropwise (cooling required) and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was evaporated. The residue was combined with analogously obtained fraction, then purified by HPLC over silica gel (eluent: hexane/ethyl acetate (60/40)). The desired fractions were collected and the solvent was evaporated, yielding 38% of 1-[(2-chloro-3-pyridinyl)oxy]-3-[(3Z)-3,5-hexadienyloxy]-2-propanol (intermediate 20).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][N:9]1[C:15]([O:17]CC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].[CH2:27]([O:34][C:35]([NH:37][CH:38](C)[C:39](O)=O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>[Pd].CO>[C:1]([O:5][C:6]([CH:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][N:9]1[C:15](=[O:17])[CH:38]([NH:37][C:35]([O:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:36])[CH3:39])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C1CC(F)(F)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(NC(=O)OCc1ccccc1)C(=O)N1CC(F)(F)CC1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid-1-benzyl ester-2-tert-butyl ester (113) (Karanewsky, et. al., J. Med. Chem. 33, pp. 1459-1469 (1990)) (0.42 g, 1.23 mmol) and 10% palladium on carbon (0.22 g) in methanol (6 mL) was stirred at 1 atm hydrogen pressure for 3 h. The mixture was filtered through Celite and evaporated. The residue was dissolved in CH2Cl2 (4 mL) and DMF (2 mL) and cooled to 0° C. 2-Benzyloxycarbonylamino-propionic acid (0.30 g, 1.35 mmol), EDC (0.30, 1.54 mmol), DIEA (0.65 mL) and HOBt (0.17 g, 1.23 mmol) was added and the reaction was stirred 0.5 h at 0° C., then 16 h at room temperature under nitrogen. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, then was washed with 10% sodium bisulfate, saturated sodium bicarbonate, water and brine, was dried over sodium sulfate and was evaporated. Purification by flash chromatography on silica, eluted with 25:75 ethyl acetate:hexanes provided 1-(2-benzyloxycarbonylamino-propionyl)-4,4-difluoro-pyrrolidine-2-carboxylic acid tert-butyl ester (0.39 g, 77% yield) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([N:15]([C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH3:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:26]([O:25][C:19]1[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([N:15]([CH3:16])[C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(N(C)C(=O)c2cccc(C)c2OC(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)N(C)C2(C(=O)O)Cc3ccccc3C2)c1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
The mixture of 2-[(2-isopropoxy-3-methyl-benzoyl)-methyl-amino]-indan-2-carboxylic acid ethyl ester (118′) (200 mg, 0.51 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (119) as a pale orange solid (170 mg, 91%).