Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26]
Reactant: Brc1c(OCc2ccccc2)ccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)c(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
To a solution of 4-bromo-5-benzyloxy-1H-indole (Intermediate 2, 3.85 g, 12.7 mmol) in DCM (30 mL) was added benzenesulfonyl chloride (2.47 g, 14.0 mmol), tetrabutylammonium hydrogensulphate (0.41 g, 1.3 mmol) and 3 M NaOH (13 mL, 39 mmol) and the mixture was stirred vigorously at room temperature for 30 minutes. The organic phase was washed with water and brine, dried (MgSO4) and concentrated to dryness to give the title compound (5.7 g) as a solid. MS m/z 442/444 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]N.[C:13]([BH3-])#[N:14].[Na+]>CO.C1COCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:14][CH2:13][C:8]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CNCc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,4-dimethoxybenzaldelyde (1 g, 6 mmol) in anhydrous methanol (10 ml) was added 3,4-dimethoxybenzylamine (1 g, 5.9 mmol) and the solution stirred under nitrogen at room temperature for 3 hours. The methanol was removed under reduced pressure to afford the crude imine, 1.9 g. The imine was dissolved in THF (10 ml) and acetic acid (4 ml), and sodium cyanoborohydride (0.38 g, 6 mmol) was added portionwise over 30 minutes. The solution was stirred for an additional 30 minutes at room temperature, and the solvents were removed under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate, and the solid crude product was isolated by filtration, and dried under vacuum at 50° C. overnight, yield 0.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[Al].[Br:14]N1C(=O)CCC1=O>O>[Br:14][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:12]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: O
Product: COc1ccc2c(c1Br)CCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methoxy-indane-1-one (17.2 g, 106.05 mmol) is suspended in 100 mL of water. The flask is covered with an aluminium foil to create a dark environment. N-Bromo-succinimide (18.87 g, 106.05 mmol) is added portionwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture is extracted with 200 mL of ethyl acetate, the organic phase is collected, dried over sodium sulfate and concentrated under vacuum. The crude product obtained (20 g) is used in the next step without any further treatment.
Reaction SMILES: ClN1C(=O)CCC1=O.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[Li].C([Li])CCC.S1C=CC=C1>C1C=CC=CC=1.O1CCCC1>[C:9]1([S:15][C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: [Li]c1cccs1
Agent: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: c1ccsc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: c1ccc(Sc2cccs2)cc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a suspension of N-chlorosuccinimide (7.8 g) in benzene (30 ml) was added dropwise, a solution of thiophenol (5.51 g) in benzene (20 ml) at room temperature. After 1 hour, the suspension was filtered, the filter pad washed with benzene and the filtrate evaporated under reduced pressure to give an orange oil. The oil was dissolved in dry tetrahydrofuran (20 ml) and added dropwise to a solution of 2-thienyl-lithium (prepared by the addition of n-butyllithium (20 ml, 2.5M) to thiophene (4.2 g) in dry tetrahydrofuran (30 ml) at -15° C. under nitrogen and stirred for 2 hours) at -15° C. under N2. The solution was stirred for 1 hour, allowed to warm to room temperature and stirred overnight. The reaction mixture was poured on to ice, extracted with ether (3×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using petroleum ether (40°-60° C.) to give a colourless oil, b.p. 161° C./20 mm pressure.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:21])=[C:16]([F:34])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4]>O1CCCC1>[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:1][NH2:2])=[O:21])=[C:16]([F:34])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Reactant: NN
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)NN)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrazine (0.041 ml, 1.30 mmol) was added dropwise with stirring to a solution of 5-(S)-acetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one (0.500 g, 1.08 mmol) in tetrahydrofuran (3 ml). The mixture was stirred at r.t. for 2 h, and the heavy white precipitate filtered, washed with ether, and dried under vacuum. Yield 0.295 g (88%). MS (m/z): [M+H]+=311.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[C:29](O)(=O)[CH3:30].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH2:29][CH3:30])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: CC(=O)O
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCNc1cc(CC(C)C)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of the compound of Example 32 (0.16 g, 0.4 mmol) and acetic acid (0.06 g, 1 mmol) in dichloroethane (2.5 mL) at 0° C., acetaldehyde (24 mg, 0.55 mmol) and sodium triacetoxyborohydride (212 mg, 1 mmol) were added. The mixture was stirred at 0-15° C. for 2 hours, diluted with ethyl acetate, extracted with water and brine, dried and concentrated. The residue was chromatographed on silica gel with 4:1 hexanes/ethyl acetate to afford the title compound (90 mg, 53%) as a light yellow gum.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:14]1([N:20]2[C:24]3([CH2:25][CH2:26][N:27]([CH2:8][C:7]4[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=4[C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH2:28][CH2:29]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccccc1-c1nccs1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1ccccc1-c1nccs1)CC2

Procedure:
To a mixture of 2-(2-thiazolyl)benzaldehyde (200 mg, 1.06 mmol) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.232 mg, 1.00 mmol) in 1,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (376 mg, 1.79 mmol). The resultant mixture was stirred at room temperature for 18 h, quenched with aqueous NaHCO3 (50 mL) and extracted with CHCl3 (2×50 mL). The organic solution was dried over Na2SO4, filtered and concentrated. The crude product was dissolved in 1:1 CHCl3:CH3OH (30 mL) and treated with 2 mL of 1N HCl in Et2O. The HCl salt was precipitated by addition of Et2O, collected by filtration and dried in the vacuum oven at 60° C. for 18 h to yield the product as an amorphous solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.CNN>C(Cl)Cl.CO>[NH2:3][O:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)C1
Agent: CNN
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(ON)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To an ice-cold solution of tert-butyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]pyrrolidine-1-carboxylate (0.96 g, 2.8 mmol) in CH2Cl2 (16 mL) and MeOH (4 mL) was added methylhydrazine (0.70 mL, 13 mmol) dropwise. The stirred reaction mixture was allowed to slowly warm to ambient temperature. After 2 h, the reaction mixture was concentrated under reduced pressure. To the residue was added CH2Cl2 (20 mL) and with the aid of sonication a solid formed and was collected by vacuum filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 75:25 hexanes/EtOAc to 25:75 hexanes/EtOAc) to afford tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (440 mg, 76%): 1H NMR (500 MHz, CDCl3) δ 1.46 (9H, s), 1.82-1.98 (1H, m), 2.04-2.10 (1H, m), 3.31-3.65 (4H, m), 4.24-4.27 (1H, m), 5.37.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]([CH3:27])([O-])[CH3:25].[K+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O:9][C:24]([CH3:27])([CH3:25])[CH3:23])=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-bromo-2-chlorobenzoic acid (1 eq.) and anhydrous DMF (1.2 eq.) was taken up in toluene (0.9 M). To this was then added, dropwise over 5 min, oxalyl chloride (1.2 eq.) and the reaction mixture was stirred at RT for 1 h. The volatiles were then removed in vacuo and the resulting residue was taken up in toluene (0.9 M). At 0° C., potassium tert-butoxide (2.5 eq.) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into H2O and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→85:15 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c1C
Yield: 45.9 %

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (80 mg, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.1 g) using method B to give 79 mg (46%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>COCCOC>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)[CH:24]=1
Reactant: Oc1cccnc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2cccnc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 3-hydroxypyridine, using dry DME as reaction solvent: 1H NMR (300 MHz, CDCl3) δ 8.14 (dd, J=5.1, 1.6 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.59 (ddd, J=8.5, 6.8, 1.7 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 7.04 (dd, J=8.8, 2.5 Hz, 1H), 6.91 (dd, J=6.8, 5.4 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 4.56 (t, J=6.1 Hz, 2H), 4.11 (q, J=8.5 Hz, 2H), 3.96 (t, J=6.1 Hz, 2H).
Reaction SMILES: [Si]([O:8][CH:9]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH3:11])(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[CH3:11][CH2:10][CH:9]([OH:8])[CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCC=CC(CC)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC=CC(O)CC
Reaction time: 0.5 h
Yield: 228 %

Procedure:
Compound 18E (23 mg, 0.0245 mmol) was dissolved in 2 ml of THF and 60 μl (0.060 mmol) of a 1M solution of nBu4NF in THF was added thereto at room temperature. After stirring for 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over Glauber's salt and concentrated under reduced pressure. Then the resulting residue was dissolved in 2.3 ml of THF and 100 μl of 12M hydrochloric acid was added thereto. The reaction mixture was stirred at room temperature for 1 hour and then neutralized with sodium hydrogencarbonate. After concentration, the residue was dissolved in ethanol-chloroform (1:5) and the salt was filtered off. The resulting product was purified by silica gel column chromatography (2 g of K-60 manufactured by Katayama Kagaku, eluent; methanol:chloroform=1:5). Thus 15 mg of compound 19E was obtained (yield: 99%). The properties of compound 19E were as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH:25]([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC.CCO.O>[F:26][CH:25]([F:27])[C:21]1[CH:20]=[C:19]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:32]4[CH:33]=[N:28][CH:29]=[N:30][CH:31]=4)[CH:3]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:24]=[CH:23][N:22]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: NC1=NC(c2cccc(-c3cncnc3)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Temperature: 150 °C
Yield: 68.4 %

Procedure:
1-(3-Bromophenyl)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1H-isoindol-3-amine (0.168 g, 0.39 mmol), 5-pyrimidinylboronic acid (0.063 g, 0.51 mmol), [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (0.016 g, 0.02 mmol), cesium carbonate (0.093 mL, 1.17 mmol) and DME:EtOH:water (6:3:1) (10.0 mL) were added to a microwave vial and heated at 150° C. in a microwave reactor for 20 min. Additional 5-pyrimidinylboronic acid (0.048 g, 0.39 mmol) was added. The reaction mixture was heated at 150° C. in a microwave reactor for 20 min. The reaction mixture was filtered through a syringe filter, concentrated in vacuo, redissolved in methanol and purified by preparative HPLC to afford the title compound (0.115 g, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11](O)=[O:12])[N:10]=1)=[O:5])[CH3:2].C1COCC1>CO>[OH:12][CH2:11][C:9]1[N:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][CH:8]=1
Reactant: CCOC(=O)c1nc(C(=O)O)cs1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1nc(CO)cs1
Yield: 51.6 %

Procedure:
A mixture of 2-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (2 g), boran-THF complex (1.0 M in THF, 45.2 ml) and THF (50 ml) was heated under reflux overnight. After MeOH (2.0 ml) was added to the mixture at the same temperature, the mixture was concentrated in vacuo to dryness. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (0.96 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][C:10](=[C:12]1C(=O)O[C:15](C)([CH3:19])[O:14][C:13]1=[O:21])[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[CH2:15]([O:14][C:13](=[O:21])[CH2:12][C:10](=[O:11])[CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:22])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCC(O)=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CCOC(=O)CC(=O)CCNC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 87 %

Procedure:
A stirred solution of [3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxin-5-ylidene)-3-hydroxy-propyl]-carbamic acid tert-butyl ester in absolute ethanol (112 ml) was heated to reflux at 70° C. overnight, and cooled to room temperature. The mixture was filtered and concentrated under reduced pressure to give 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (11.22 g, 87%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[Cl:27][C:28]1[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[C:29]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:35]([C:29]3[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:28]=3[Cl:27])(=[O:36])=[O:37])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: CCOc1ccc(Cl)cc1-c1ccc(C(C)N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(Cl)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2c(C)nn(C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([O-:4])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25]Cl.O>CN(C)C=O>[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[N+:2]([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: Cn1ccnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1COc1ccccc1[N+](=O)[O-]
Yield: 41.9 %

Procedure:
A solution of 1.92 g (11.97 mmol) of o-nitrophenol sodium salt, 3.8 g (35.9 mmol) of sodium carbonate, 2 g (11.97 mmol) of 1-methyl-2-chloromethylimidazole hydrochloride in 30 ml of N,N-dimethylformamide were heated at 50° C. for 2 hours. The mixture was then poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated, affording 1.17 g of the title compound, recrystallized from diethylether.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[N:13][C:14]=2[CH3:16])[C:9](=[N:18]O)[CH2:8][CH:7]1[CH2:20][CH3:21])=[O:5])[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[N:13][C:14]=2[CH3:16])[CH:9]([NH2:18])[CH2:8][CH:7]1[CH2:20][CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2c(cc(C)nc2C)C(=NO)CC1CC
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)N1c2c(cc(C)nc2C)C(N)CC1CC

Procedure:
This compound can be prepared by reacting a solution of 2-ethyl-4-hydroxyimino-6,8-dimethyl-3,4-dihydro-2H-[1,7]naphthyridine-1-carboxylic acid ethyl ester in acetic acid with Zn (5 to 10 eqv), typically at reflux temperature, for about 1 h to about 5 h, followed by a typical workup procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([OH:11])=[N:7][NH:8][C:9]=1[CH3:10].[C:30]([O:35][CH3:36])(=[O:34])[C@H:31]([CH3:33])O.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(OCC)(=O)C.C1(C)C=CC=CC=1.CCCCCC>[CH3:36][O:35][C:30]([C@H:31]([O:11][C:6]1[C:5]([O:4][C:3]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:2]=2[Cl:1])=[C:9]([CH3:10])[NH:8][N:7]=1)[CH3:33])=[O:34]
Reactant: Cc1[nH]nc(O)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: COC(=O)[C@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)Oc1n[nH]c(C)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a solution of 0.13 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole in 2.0 ml of ethyl acetate were added 0.10 g of (S)-(−)-methyl lactate, 0.26 g of triphenylphosphine and 0.5 ml of a 40% solution of diisopropyl azodicarboxylate in toluene, and the mixture was stirred for 3 hours at room temperature. 6 ml of n-hexane was poured into this reaction solution, and the precipitated insoluble substance was filtrated off. This solution was subjected to silica gel column chromatography to obtain 0.09 g of (R)-3-{1-(methoxycarbonyl)ethoxy}-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin -1-yl]phenoxy}-5-methylpyrazole [R optical isomer of present compound 5-12, hereinafter, represented as 5-12-R].