Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:19]1[S:18][C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:20]=1
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(Cl)sc2-c2ccc(OC)cc2)cc1
Reaction time: 0.75 h

Procedure:
A solution of N-chlorosuccinimide (2.92 g, 22 mmole) in 50 ml methylene chloride was added to a solution of 2,3-bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) in 70 ml methylene chloride and 75 ml acetic acid. After 45 minutes at room temperature, the reaction mixture was heated at reflux for 18 hours. The cooled reaction mixture was then concentrated in vacuo.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3.ClC1C=CC=C(C(OO)=[O:23])C=1.[OH2:26]>ClCCl>[CH3:1][S:2]([C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3)(=[O:23])=[O:26]
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc2c(c1)C(=O)C1(CC1)O2
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)C(=O)C1(CC1)O2

Procedure:
To a solution of 5-methylthiospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (103.1 mg.) in dichloromethane (2.1 ml.) was added in small portions of m-chloroperbenzoic acid (215.7 mg.) under stirring. After stirring for one hour, the reaction mixture was diluted with water and extracted with chloroform. The extract was washed with aqueous solution of sodium hydrogen carbonate, aqueous solution of sodium hydrosulfite and water in that order, and after drying the solvent was removed by evaporation under reduced pressure. The residue was recrystallized from ethanol-water to give colorless needles of 5-methylsulfonylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (85 mg.). This product was identical with the compound of Example 64 in melting point and spectral data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[I-].[Na+].S(=O)(O)[O-:44].[Na+]>C1(C)C(C)=CC=CC=1>[C:29]1([P:28]([CH2:14][C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:44])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: O=S([O-])O
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Temperature: 136 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
502.6 mg (1.42 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 8 ml of xylene (isomer mixture) and admixed with 96.6 mg (2.21 mmol) of sodium hydride (55 percent dispersion in mineral oil). After 1 hour, 340.8 mg (1.47 mmol) of chlorodiphenylphosphine in 2.5 ml of xylene was added at room temperature with vigorous stirring over a period of 5 min. The mixture was admixed with 34.6 mg (0.23 mmol) of sodium iodide and heated at 136° C. for 19 h. After 3 h, a further 25.1 mg of sodium iodide were added. After cooling to room temperature, the mixture was admixed with 30 ml of dilute sodium bisulfite solution and extracted with 50 ml of ethyl acetate. The organic phase was separated off and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phases were subsequently concentrated under reduced pressure. This gave 906 mg of crude product which was purified by silica gel chromatography (mobile phase: ethyl acetate), and 315.9 mg (41.3 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:31][CH2:30][CH2:28][OH:29]
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: NCCO
Product: COc1cc(NCCO)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 72 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using ethanolamine instead of thiomorpholine to the title compound (160 mg, 72%) which was obtained as an off-white solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCOCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43 mL, 0.308 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a bright yellow solid. Recrystallization from ethyl acetate/hexanes gave 43.6 g of tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate as bright yellow crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH3:6].[Br:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.Cl>ClCCl>[Br:16][C:17]1[S:18][C:19]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=2)=[O:12])=[CH:20][CH:21]=1
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: Brc1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2ccc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aluminum chloride (8.9 g) and 4-ethylbenzoylchloride (5.96 g) were added to a solution of 2-bromothiophene (3.2 ml) in dichloromethane (50 ml) at 0° C., and the mixture was stirred for four hours at room temperature. 10% hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (5-bromo-2-thienyl)(4-ethylphenyl)methanone (8.97 g). Borontrifluoride diethyl ether complex (1.57 ml) and triethylsilane (3.83 ml) were added to a solution of (5-bromo-2-thienyl)(4-ethylphenyl)methanone in acetonitrile (20 ml) at −40° C., and the mixture was stirred for two hours. Aqueous solution of saturated potassium carbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-bromo-(4-ethylbenzyl)thiophene (6.78 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=3[F:23])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:38])=[CH:18][C:17]=3[F:23])[CH:12]=[CH:11][N:10]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(N)cc3F)n2)cc1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of N-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)pyrimidin-2-amine (Compound C of Example 14, 34 mg, 0.10 mmol) in THF (1 ml) was treated with 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.31 mL, 0.11 mmol) and the mixture stirred at RT for 1 h. The mixture was concentrated in vacuo and the solid obtained was triturated first with 3:1 isopropyl ether/EtOAc and then CH2Cl2 to give the title compound (32 mg, 62%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.26 (s, 1H), 8.15 (s, 1H), 7.76 (d, 1H, J=12.6 Hz), 7.61 (dd, 3H, J=9.1, 5.0 Hz), 7.29 (s, 2H), 7.31-7.21 (m, 3H), 6.81 (s, 3H), 6.24 (s, 1H), 4.32 (s, 1H), 3.96 (s, 1H), 3.68 (s, 3H), 3.48 (s, 2H); MS(ESI+) m/z 520.14 (M+H)+.
Reaction SMILES: [H-].[Na+].FC(F)(F)C(O)=O.[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:18][S:19][C:20]1[N:25]=[C:24]([NH:26][S:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[C:22]([O:36][CH3:37])[N:21]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1COCC1.O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:33]1[CH2:32][CH2:31][N:30]([S:27](=[O:29])(=[O:28])[NH:26][C:24]2[CH:23]=[C:22]([O:36][CH3:37])[N:21]=[C:20]([S:19][CH2:18][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=3[F:10])[N:25]=2)[CH2:35][CH2:34]1)[CH3:44]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)CC1

Procedure:
The subtitle compound was prepared by adding 60% sodium hydride (0.18 g) portionwise to a solution of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, trifluoroacetate salt (the product from example 36) (0.53 g) and ethyl 2-bromoacetate (0.36 mL) in THF (10 mL). The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine and evaporated to give the subtitle compound as an oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[C:24]2[CH2:23][CH2:22][N:21]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][C:15]=1[Cl:31]>C(Cl)Cl>[Cl:31][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][CH2:20][N:21]([C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])[CH2:22][CH2:23][C:24]=2[C:14]=1[O:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)Nc1ccccc1

Procedure:
Combine phenyl isocyanate (16.3 mg, 0.137 mmol), 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature for 16 h. Concentrate in vacuo. Purify by reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1% trifluoroacetic acid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5μm, 12 nm, 100×20 mm) to give 7-chloro-6-[2-(3-phenyl-ureido)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2].C(N(C(C)C)CC)(C)C.[ClH:41].[N:42]1([C:47](N)=[NH:48])C=CC=N1>CN(C)C=O>[ClH:41].[ClH:41].[CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:47](=[NH:42])[NH2:48])[CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CNCC3)CC1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=N)N)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.2 %

Procedure:
To a solution of 3-[4-[4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester (70 mg) in dimethylformamide (1 ml) were added diisopropylethylamine (0.032 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (27 mg), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and to the obtained residue was added diethyl ether and the supernatant was removed. This procedure was repeated twice and hydrogen chloride-ethanol solution was added to the obtained residue and insoluble material was removed. The solution was concentrated and dried under reduced pressure to give the title compound (50 mg).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH3:9])([OH:3])=[O:2].[N+:10]([O-])([OH:12])=[O:11].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[C:1]([C:4]1[S:5][C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[CH3:9])([OH:3])=[O:2]
Reactant: Cc1ccsc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])sc1C(=O)O
Yield: 53 %

Procedure:
To a solution of 2-carboxy-3-methylthiophene (10 g, 70.3 mmol) in 80 mL of trifluoroacetic acid at 0° C. was added HNO3 (1.2 mL, 1.0 eq.) dropwise. The reaction mixture was warmed to ambient temperature and after 4 hours another 1.0 eq. of HNO3 was added. The reaction mixture was made basic with aqueous sodium bicarbonate and washed with ethyl acetate. The aqueous layer was acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 5.75 g (53%) of 2-carboxy-3-methyl-5-nitrothiophene and 2-carboxy-3-methyl-4-nitrothiophene, as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18]O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)(Cl)[Cl:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18][Cl:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(-c2ccccc2)c2ccc(O)cc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc2c(-c3ccccc3)cc(CCl)cc2c1

Procedure:
To a solution of the alcohol from Step 1 (1.46 g, 5.8 mmoL) in CH2Cl2 (50 mL) was added CCl4 (5.7 mL, 58 mmoL, 10 eq.) followed by Ph3P (3 g, 11.7 mmoL, 2 eq.). The resulting mixture was refluxed for 2 hr. The solvent was evaporated and a purification by flash chromatography on silica gel (hexanes: EtOAc; 8:2) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][OH:25])[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:33]([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][O:25][CH3:33])[O:15][C:14]3=[O:26])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: O=C1O[C@@H](CO)[C@H](c2ccccc2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one (14 mg, 0.035 mmol) in THF (1 mL) was added NaH (˜5 mg) and the reaction was stirred for 10 min. at room temperature. Iodomethane (˜0.01 mL) was added and the reaction was stirred for an additional 2 h. NaHCO3 aqueous solution was added to quench, followed by dilution with water and ethyl acetate. The organic phase was washed with brine, dried (MgSO4), and concentrated. Flash chromatography (0-30% ethyl acetate/hexanes) yielded 8 mg (57%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ (ppm) 7.23-7.32 (m, 7H), 7.16-7.19 (m, 2H), 6.78-6.82 (m, 4H), 5.16 (d, 1H, J=5.7 Hz), 4.36 (dd, 1H, J=9.3, 3.9 Hz), 3.63 (ddd, 2H, J=18.4, 11.0, 4.1), 3.41 (s, 3H). HPLC-MS calculated C23H20ClNO4 (M+H+): 410.1, found: 410.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:25]3[CH2:27][CH2:26]3)[C:16]2=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1n(-c2ccc(OCc3ccccc3)cc2)c2ncccc2n1C1CC1
Temperature: 140 °C
Yield: 35.5 %

Procedure:
The mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), cyclopropylboronic acid (731 mg), TEA (1976 μl), pyridine (1835 μl), copper(II) acetate (1030 mg) and THF (4727 μl) was heated at 140° C. for 30 min under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) as white crystals.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][O:3][CH2:4][C:5]([OH:7])=O.[CH3:10][OH:11].Cl[CH2:13]CCl>>[CH3:10][O:11][C:5](=[O:7])[CH2:4][O:3][CH2:2][C:1]([O:9][CH3:13])=[O:8]
Reactant: ClCCCl
Reactant: O=C(O)COCC(=O)O
Reactant: CO
Product: COC(=O)COCC(=O)OC
Temperature: 25 °C

Procedure:
Diglycolic acid (67.05 g, 0.5 mol) was dissolved in a mixture of methanol (122 ml, 30 mol) and 1,2-dichloroethane (150 ml). KSF-catalyst (Aldrich) (2.5 g) was added and the mixture was refluxed for 15 hours. The mixture was cooled to ambient temperature, filtered through alumina, washed with aqueous saturated sodium hydrogen carbonate (100 ml) and dried over magnesium sulphate. The solvent was evaporated and diglycolic acid dimethyl ester was isolated after distillation as a colourless oil.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: Cc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.70 g, 1.39 mmol) in methanol (13.9 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (40 mg, 0.20 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane) afforded (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.49 g, 77%) as an off-white solid: HR-ES-MS m/z calculated for C23H29N4O5F [M+H]+ 461.2195, observed 461.2194; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H), 1.32-1.48 (m, 1H), 1.48-1.63 (m, 1H), 1.63-1.82 (m, 1H), 2.29 (s, 3H), 3.17-3.30 (m, 2H), 3.68-3.79 (m, 1H), 3.79-3.91 (m, 1H), 4.07 (dd, J=13.4, 3.8 Hz, 1H), 4.18 (d, J=18.4 Hz, 1H), 4.57 (d, J=18.4 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.81-4.89 (m, 2H), 4.92 (d, J=5.4 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 7.08-7.18 (m, 1H), 7.24-7.35 (m, 2H), 7.51 (d, J=2.0 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH2:10]([NH2:13])[C:11]#[CH:12].C(=O)([O-])[O-].[K+].[K+].C1COCC1>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH2:10][C:11]#[CH:12])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: C#CCN
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCNc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
2,4,5-Trichloropyrimidine (500 mg, 2.7 mmol), propargyl amine (149 mg, 2.7 mmol), and potassium carbonate (373 mg, 2.7 mmol) were combined in a 30 ml reaction vial with 5 ml THF and stirred at room temperature overnight. The reaction was poured into 50 ml water and extracted with EtOAc (3×20 ml). The combined organic was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield (2,5-dichloro-pyrimidin-4-yl)-prop-2-ynyl-amine (488 mg, 90%) as a yellow oil that crystallizes upon standing. This was used crude in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C(N(CC)CC)C>>[C:11]1([C:17]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=C(Cl)C1=CCCCC1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)O)cc1)C1=CCCCC1

Procedure:
4-(1-Cyclohexene-1-carbonylamino)-benzoic acid was prepared as described in Example 1 from 16.6 g (0.121 mol) of p-aminobenzoic acid with 22.0 g (0.152 mol) of 1-cyclohexene-1-carboxylic acid chloride and 21.3 ml (0.152 mol) of triethylamine. Recrystallization from THF/n-pentane.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: COc1ccc(F)c(C#N)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-n2cnc(C)c2)c(C#N)c1
Yield: 72 %

Procedure:
As described for example 84a, 2-fluoro-5-methoxy-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 48 h at 100° C. After aqueous workup and crystallization from ethyl acetate/diisopropylether the title compound was obtained as a white solid (yield: 72%). MS: m/e=214.1 [M+H]+.