Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:34][CH:35]([CH3:37])[CH3:36])[C:26]([CH3:33])=[N:27]4)=[CH:15][C:16]=2C(OCC)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.NC1(C2NC(C3C(F)=CC=C4C=3N=C(NC(C)C)C(C)=N4)=CC=2C(O)=O)CC1.Cl.NC1(C2NC(C3C=CC=C4C=3N=C(NC(C)(C)C)C(C)=N4)=CC=2C(O)=O)CC1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[F:32][C:31]1[C:22]([C:14]2[NH:13][C:12]3[C:9]4([CH2:10][CH2:11]4)[NH:8][C:6](=[O:5])[C:16]=3[CH:15]=2)=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:33])[C:25]([NH:34][CH:35]([CH3:36])[CH3:37])=[N:24]2
Reactant: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)C
Agent: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(F)c(-c3cc4c([nH]3)C3(CC3)NC4=O)c2nc1NC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (330b) (1.0 g, 1.95 mmol) was converted to 2-(1-aminocyclopropyl)-5-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (330c: m/z (ESI, +ve) 384.1 (M+H)+) in a fashion similar to that described for Intermediate 324c. This material was used as crude. A suspension of 2-(1-aminocyclopropyl)-5-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (330c) (798 mg, 1.9 mmol) in DMF (10 mL) and DCM (10 mL) at 0° C. was treated with DIEA (1.98 mL, 11.40 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.29 g, 2.47 mmol). The ice bath was removed and the resulting mixture was stirred at RT for 1 h. The mixture was poured onto 150 G of ice. The insoluble brown solid was filtered, rinsed with 2×5 mL of water followed by 3×10 mL of DCM. The solid was collected, dried in a vacuum oven at 45° C. for 1 h to give 425 mg of 2′-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (330) as a yellow crystalline solid. The filtrate was transferred to a separatory funnel, extracted with 50 mL of DCM. The organic layer was washed with 10 mL of 1 N NaOH followed by 10 mL of brine, dried over Na2SO4 and concentrated. The residue was stirred in 50 mL of EtOAc for 30 min. The insoluble yellow crystalline solid was filtered to give additional 165 mg of 2′-(6-fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (330). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (1H, br.), 7.68 (2H, m), 7.29 (1H, m), 7.02 (1H, br.), 6.73 (1H, s), 4.26 (1H, m), 2.52 (3H, s) 11.40 (4H, m), 1.29 (6H, m). 19F NMR (377 MHz, DMSO-d6) δ ppm −110.86. m/z (ESI, +ve) 366.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[O:15]=[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1COCC1>[F:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[C:16]1([OH:15])[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23]
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1(O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-bromo-1,4-difluorobenzene (5.15 g, 25.9 mmol) in dry THF (77 ml, 15 v) at −78° C. was added i-PrMgCl (2M, 19.5 ml, 38.8 mmol) drop wise and stirred for 1 h at room temperature then cooled again to −78° C. and added tert-butyl 2-oxopiperidine-1-carboxylate (dissolved in dry THF) (6.0 g, 31.0 mmol) drop wise and reaction mixture was stirred for 2 h at room temperature. After completion of reaction, quenched with sat.NH4Cl solution and diluted with ethyl acetate. Organic layer was separated and water layer was extracted with ethyl acetate. Combined organic layer were washed with water, brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude Int-17 (9.4 g) which was directly used for the next step.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][NH:31][C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]=3[N:34]3[CH2:35][CH2:36][C@H:32]([NH:31][CH3:30])[CH2:33]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN[C@H]1CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C4CC4)oc23)C1
Temperature: 90 °C
Reaction time: 13 h
Yield: 62.8 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-phenylbenzoxazole-4-carbonitrile (I-173) (250 mg, 0.86 mmol) was dissolved in dimethyl sulfoxide (5 ml), then at room temperature, triethylamine (155 μl, 1.11 mmol) and (3S)-3-(methylamino)pyrrolidine (119 μl, 1.11 mmol) were added. After stirred under nitrogen atmosphere at 90° C. for 13 hours, this was cooled to room temperature. The reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=93:7, v/v) to obtain the entitled compound (201 mg, 63%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[C:16]([I:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>CCO>[C:4]([C:6]1[C:7]([C:12]2[CH:17]=[C:16]([I:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2cc(I)ccc2F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2cc(I)ccc2F)c1C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 4-ethoxycarbonyl-5-methyl-3-(2-fluoro-5-iodophenyl)isoxazole (1.04 g, 2.77 mmol) in EtOH (14 ml) was added 5N NaOH (1.11 ml, 5.6 mmol, 2 eq.) and stirred in a 50° C. oil bath for 1 hr. Rxn was cooled to room temperature, poured into ice H2O and extracted with Et2O. Acidified aqueous layer to pH 2 using conc. HCl and extracted with ethyl acetate. The combined organic solution was washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound (0.85 g, 86%).
Reaction SMILES: [OH-].[K+].Br[CH2:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)=[O:6].Cl.[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)=[O:6])[CH3:24]
Reactant: CCO
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 16 h

Procedure:
Under inert atmosphere 8.4 g (150 mmol) of potassium hydroxide is dissolved in 150 ml of ethanol. After adding 10.0 g (31 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-tert-butylphenyl)-ethanone in portions at room temperature stirring is continued for 16 hours. Then the reaction mixture is acidified with 10% HCl and extracted with ethylacetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 3.8 g of compound 113, m.p. 73-75° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH:21]1([C:24]2[S:28][C:27]([NH2:29])=[N:26][N:25]=2)[CH2:23][CH2:22]1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH:21]1([C:24]2[S:28][C:27]([NH:29][C:15]([CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[O:17])=[N:26][N:25]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: Nc1nnc(C2CC2)s1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COC(Cc1ccc(OCC(=O)Nc2nnc(C3CC3)s2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 5-cyclopropyl-[1,3,4]thiadiazol-2-ylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C17H19N3O5S [M−H]−: 376.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3][C:2]2=[O:11].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:39][CH3:40])=[C:36]([Pb+3])[CH:37]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1.ClCCl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:39][CH3:40])=[C:34]([CH:3]2[C:2](=[O:11])[CH:1]3[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]3)[C:4]2=[O:10])[CH:33]=1
Reactant: O=C1CC(=O)C2CCC1CC2
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1ccc(Br)cc1C1C(=O)C2CCC(CC2)C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
A solution of bicyclo[3.2.2]nonane-2,4-dione (0.12 g, 0.79 mmol), prepared by the method of W. Childers et al., US2006/0004108, in dry chloroform (4 ml) is stirred at room temperature then thoroughly flushed with nitrogen. To this mixture is then added 4-dimethylaminopyridine (0.482 g, 3.95 mmol) and anhydrous toluene (1 ml), followed by heating to 80° C. 5-Bromo-2-ethylphenyllead triacetate (0.673 g, 1.18 mmol) is added in one portion, and the mixture is further heated at this temperature for a further 4 hours then left to stand overnight. Dichloromethane (10 ml) and 2M hydrochloric acid (10 ml) are added, and the resulting biphasic mixture is filtered to remove any inorganic salts (washing with additional dichloromethane, 10 ml). The organic phase separated, and the aqueous phase is extracted again with dichloromethane (10 ml×2). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a yellow gum. This crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio) to afford 3-(5-bromo-2-ethylphenyl)-bicyclo[3.2.2]nonane-2,4-dione (0.130 g, 49%) as a yellow solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:37](=[O:38])[C:16]2=[CH:17][N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:28][CH:27]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]2=[N:14]1)(=O)=O.[N-:39]=[N+:40]=[N-:41].[Na+].C(=O)(O)[O-].[Na+]>CS(C)=O>[N:39]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:37](=[O:38])[C:16]2=[CH:17][N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:28][CH:27]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]2=[N:14]1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
[2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)phenyl]methyl methanesulfonate (0.21 g, 0.51 mmol) was dissolved in dimethyl sulfoxide (10 mL) and treated with sodium azide (0.33 g, 5.1 mmol, 10 equiv). The mixture was stirred for 45 minutes at ambient temperature and then placed into a preheated oil bath at 80° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (100 mL, aqueous saturated) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.17 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.23 (1H, d, J=7.8 Hz), 7.83 (2H, d, J=8.6 Hz), 7.79 (1H, d, J=8.6 Hz), 7.72 (1H, m), 7.65-7.61 (1H, m), 7.57-7.54 (3H, m), 7.51 (1H, br d, J=7.6 Hz), 7.49-7.45 (3H, m), 6.53 (1H, m), 5.78 (2H, s), 4.60 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 473.1823 [(M+H)+; calculated for C27H21N8O: 473.1833].
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Mg].B(OC)(OC)OC.Br[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.C1(P([Pd-4](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)C=CC=CC=1.C1(C)C=CC=CC=1>[CH:24]([C:23]1([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=2[CH3:2])[CH:22]=[CH:29][CH:28]=[CH:27][CH2:26]1)=[O:25]
Reactant: O=Cc1ccccc1Br
Reactant: ClCc1cccc2ccccc12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1c(C2(C=O)C=CC=CC2)ccc2ccccc12
Temperature: -78 °C

Procedure:
The corresponding Grignard compound is prepared from 88.3 g (500 mmol) of 1-chloromethylnaphthalene and 12.2 g (500 mmol) of magnesium in 500 ml of ether. After the Grignard solution has been cooled to −78° C., 59 ml (530 mmol) of trimethyl borate are added, the mixture is then allowed to warm to room temperature, the solvent is removed in vacuo, 500 ml of toluene, 92.5 g (500 mmol) of 2-bromobenzaldehyde, 2.9 g (2.5 mmol) of tetrakis(triphenylphosphino)palladium(0) and 300 ml of 2 M sodium carbonate solution are added to the residue, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, washed twice with 500 ml of water each time, filtered through silica gel and then evaporated to dryness, and the residue is recrystallised from toluene/acetonitrile. Yield: 93.1 g (378 mmol), 75.6%, purity about 97% (NMR).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[H-].[Na+].[Br-].C(O[C@@H:46]1[C@@H:52](OC(=O)C)[C@H:51](OC(=O)C)[C@@H:50]([CH2:61]OC(=O)C)O[C@@H:47]1O)(=O)C>>[C:16]([O:15][C@H:9]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:7][C@@H:8]1[O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]1[CH:27]=[C:26]([C:47]2[CH:46]=[CH:52][CH:51]=[CH:50][CH:61]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(=C/c1cccc(-c2ccccc2)c1)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 16 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(3-arylphenyl)-2-oxopropanoate (B14) (100 mg, 0.373 mmol), sodium hydride (9.0 mg, 0.373 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucose bromide (153 mg, 0.373 mmol). The compound was isolated in the form of white solid in 16% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)(Cl)[Cl:9])=[CH:4][N:3]=1>[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cn1
Agent: [Zn]
Product: ClCc1ccc(Cl)nc1

Procedure:
The method according to claim 1, wherein 2-chloro-5-trichloromethylpyridine is reduced at a reaction temperature of from -20° C. to +100° C. with from 2 to 15 equivalents of the proton donor and from 2 to 15 equivalents of zinc, relative to 1 mol of 2-chloro-5-trichloromethylpyridine and from 0.5 to 50 parts by weight of the solvent, relative to 1 mol of 2-chloro-5-trichloromethylpyridine, to obtain 2-chloro-5-chloromethylpyridine.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].C[O-].[Na+].CO.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Cl:27])[C:22]=1[C:23](Cl)=[N:24]O>C1COCC1.O>[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Cl:27])[C:22]=1[C:23]1[C:4]([C:3]([OH:2])=[O:10])=[C:5]([CH:6]([CH3:8])[CH3:7])[O:9][N:24]=1
Reactant: ON=C(Cl)c1c(Cl)cncc1Cl
Reactant: COC(=O)CC(=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cncc2Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
N-chlorosuccinimide (1.36 g, 10.2 mmol) was added to a stirred solution of 3,5-dichloro-4-pyridinecarbaldehyde oxime (1.94 g, 10.2 mmol) in dimethylformamide (8 mL) and the solution was heated in a 65° C. oil bath for 1.5 hours. The solution was poured into water and extracted with ether. The organic layer was dried with MgSO4, filtered and concentrated to yield a crude carboximidoyl chloride. A solution of methylisobutyrylacetate (1.7 mL, 12.3 mmol) in THF (2.5 mL) was stirred at 0° C. as 0.5 N solution of sodium methoxide in methanol (24.6 mL, 12.3 mmol) was added. The solution was allowed to stir for ten minutes before the addition of the crude 3,5-dichloro-N-hydroxy-4-pyridinecarboximidoyl chloride in THF (8.1 mL). The solution was allowed to stir at room temperature overnight. The solution was then concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 1:9 ethyl acetate:hexanes). Fractions containing the intermediate were combined and concentrated. The residue was azetroped with methanol then was diluted with THF (11 mL) and methanol (5.5 mL). A 1 N solution of sodium hydroxide (3.3 mL) was added and the solution of heated to 100° C. for 500 seconds in a microwave reactor. The solution was neutralized with 1 N HCl and concentrated to yield a white solid. The residue was slurried in water and filtered to yield 3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylic acid (0.57 g, 18%). 1H NMR (400 MHz, DMSO-d6): δ 13.39 (s, 1H), 8.81 (s, 2H), 3.82 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([NH2:32])[CH2:30][CH3:31])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([NH:32][C:2](=[O:3])[O:4][CH3:5])[CH2:30][CH3:31])=[CH:9][CH:8]=1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(NC(=O)OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl

Procedure:
Methyl chloroformate was added to a mixture of crude 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (192 mg) and triethylamine (0.158 mL, 1.13 mmol) in tetrahydrofuran (3.5 mL) at 0° C. The resultant mixture was stirred at 0° C. for 30 min, diluted with aqueous sodium bicarbonate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 1-30% ethyl acetate/n-hexane gradient mixture and NH silica gel eluting with a 25% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (78.2 mg, 0.156 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:15])[CH2:13]Br)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:15])[CH2:13][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: FC(=CC1(c2ccc(Cl)cc2)CC1)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-(p-chlorophenyl)-1-(3-bromo-2-fluoropropenyl)cyclopropane, (Z)—(0.434 g, 1.5 mmol), 4-fluoro-3-phenoxybenzene-boronic acid (0.452 g, 1.95 mmol), potassium carbonate (1.86 g, 13.5 mmol) and bis(dibenzylideneacetone)-palladium(O) (Pd(dba)2, 4.3 mg, 0.075 mmol) in toluene is heated at 80° C. for one hour, cooled to room temperature, diluted with water, and filtered through diatomaceous earth. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and ethyl acetate extract are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 3:20 methylene chloride/hexanes solution gives the title product as an oil (0.274 g, 63% yield) which is identified by NMR spectral analyses.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]\[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:66][CH2:67][CH2:68][C:69]([OH:71])=[O:70].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:69]([CH2:68][CH2:67][CH2:66][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]\[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:71])=[O:70]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C\c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C\c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
9 mg (10 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3Z)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 18) was dissolved in 0.6 mL dioxane/water (1:1) and reacted with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride in a process similar to the synthesis in Example 1. After lyophilization from dioxane, 5.6 mg (64% of the theoretical) of the title compound was obtained in the form of a white solid.