Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[CH:19]([CH2:36]C([O-])=O)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=1>CS(C)=O.[Na+].[Cl-]>[C:1]([O:5][C:6]([C:8]1[N:9]([CH2:36][CH:19]([O:7][C:6](=[O:5])[CH3:8])[CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCc1ccc(OCC(CBr)CC(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)c1cc2ccccc2[nH]1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(Cn2c(C(=O)OC(C)(C)C)cc3ccccc32)OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
0.325 g (1.50 mmol) tert-butylindole-2-carboxylate is dissolved in 15 ml absolute DMSO, mixed with 0.184 g (1.64 mmol) potassium-tert-butylate and stirred at 110° C. for 15 min. A solution of 0.576 g (1.50 mmol) [1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 15 ml absolute DMSO is added drop-wise. Following 30 minutes of heating at 110° C. and subsequent cooling, hydrolysis is carried out in saturated NaCl solution. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 99:1) and yields the product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[CH:6][C:5]=1[CH3:15].[H-].[Na+].[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[C:7]([O:14][C:21](=[S:22])[N:20]([CH3:24])[CH3:19])=[CH:6][C:5]=1[CH3:15]
Reactant: COC(=O)c1cc(C(C)(C)C)c(O)cc1C
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(C)(C)C)c(OC(=S)N(C)C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-tert-butyl-4-hydroxy-2-methylbenzoic acid methyl ester from Example BBB (15.1 g, 68 mmol) in DMF (150 mL) was added NaH (3.3 g of a 60% dispersion, 82 mmol), and the mixture was stirred at room temperature for 1 hour. N,N-Dimethylthiocarbamoyl chloride (10.1 g, 82 mmol) was added all at once; the reaction mixture was stirred at 55° C. for 36 hours and then cooled to room temperature. H2O (200 mL) was added, and the solution was extracted with EtOAc. The combined extracts were washed with 1N NaOH, 1N HCl, and brine. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed on silica gel, eluting with 6:1 hexane:EtOAc, to give the title compound. 1H NMR (CDCl3) δ 1.37 (s, 9 H), 2.55 (s, 3 H), 3.39 (s, 3 H), 3.49 (s, 3 H), 3.89 (s, 3 H), 6.90 (s, 1 H), 8.01 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[C:8]([NH:10][CH3:11])=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[CH2:8][NH:10][CH3:11]
Reactant: CNC(=O)c1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CNCc1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1

Procedure:
Under N2, a mixture of 0.313g (1.0 mmol) of 2-(3,4-dichlorophenoxy)-5-fluoro-N-methyl benzamide in 5.0 mL of anhydrous tetrahydrofuran (THF) was treated via syringe with 4.0 mL (4.0 mmol) of 1.0 M BH3 in THF (Aldrich Chem. Co.). and the mixture was heated to reflux for a total of 48 hr. The reaction was quenched by the addition of 25 mL of 6N HCl and heating to reflux until the free amine could be detected by tic (CHCl3:CH3OH:TEA, (95:5:1)). The cooled mixture was then diluted with water, basified with K2CO3and extracted with EtOAc. The combined organic layers were washed with water and saturated NaCl, then dried with MgSO4, filtered and concentrated in vacuo to the free base as a light brown oil, 0.164 g, 54%). This compound was converted to the hydrochloride salt as described previously, m.p. 200–202°.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].Cl.NO.C[O-].[Na+].CO.Cl>O1CCOCC1>[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=2)[CH2:11][CH2:12]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cnc(N2CCN(C(=O)c3ccccc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: NO
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cnc(N2CCN(C(=O)c3ccccc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 22b (100 mg, 0.321 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (222 mg, 3.191 mmol) and a freshly prepared solution of sodium methoxide in methanol (110 mg, 4.712 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 23b. HPLC: Rt=3.69 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15](O)[CH2:16][N+:17]([O-:19])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]\[N+:17]([O-:19])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1cc(C(O)C[N+](=O)[O-])ccc1-c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(/C=C\[N+](=O)[O-])ccc1-c1ccccn1

Procedure:
A solution of 1-(3-methoxy4-pyridin-2-ylphenyl)-2-nitroethanol (290 mg, 1.06 mmol) in anhydrous dichloromethane (5 mL) was treated with triethylamine (0.24 mL, 1.69 mmol), followed by methanesulfonyl chloride (0.10 mL, 1.27 mmol), 1 hr later, the mixture was partitioned between sat. NaHCO3 (10 mL) and dichloromethane (20 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to afford a yellow solid.
Reaction SMILES: P(Cl)(Cl)[Cl:2].[N:5]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][C:11](=O)[CH:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[N+:6]=[N-:7]>CN(C)C=O.C1(C)C=CC=CC=1>[N:5]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][C:11]([Cl:2])=[C:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Reactant: ClP(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Reaction time: 5 h

Procedure:
Phosphorus trichloride (1 mmol) is added to a solution of benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (0.5 mmol) in anhydrous dimethylformamide (2.5 ml) and the mixture is left to stand at room temperature. After 5 hr, the mixture is diluted with toluene, washed with water, 1 N hydrochloric acid, 5% sodium bicarbonate solution, and brine, dried over magnesium sulfate, and filtered. Evaporation of the solvent under vacuum yields benzyl 6-azido-3-chloro-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=[C:7]2[CH:6]=1)=[O:4].[NH3:38]>CO>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:12]3[N:13]=[C:7]4[CH:6]=[C:5]([C:3](=[O:4])[NH2:38])[CH:10]=[CH:9][N:8]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C(N)=O)ccn4c3-c3ccccc3)cc2)CCC1

Procedure:
A mixture of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (150 mg) and a solution of ammonia in methanol (7M, 2.15 mL) was heated at 130° C. for 90 minutes under microwave irradiation. On cooling, the reaction mixture was concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[N:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30]([C:27]4[N:26]=[CH:25][C:24]([C:20]5[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=5)=[CH:29][N:28]=4)=[O:31])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ncc(-c2cccc(F)c2)cn1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ncc(-c4cccc(F)c4)cn3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 5-(3-fluorophenyl)-2-pyrimidinecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([OH:26])[CH3:25].OS([O-])(=O)=O.[K+]>O>[CH2:1]([NH:8][C:9]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:26][CH2:24][CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1F
Reactant: CCO
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product obtained at (655b) (15.5 g, 2.97 mmol) was combined with a mixture of potassium tert.-butylate (6.00 g, 53.5 mmol) and 400 mL ethanol, that was stirred at ambient temperature already for 15 min. After stirring for 1 h, 400 mL ethanol were added. After further 1 h of stirring, potassium tert.-butylate (500 mg, 4.46 mmol) was added. After further 1.5 h, the mixture was poured into water and acidified with KHSO4 (aq). After stirring for 20 min, the precipitate was filtered off, washed with water and dried at 55° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][S:11][CH2:12][CH3:13]>C(OCC)(=O)C>[CH2:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH2:7][S:8][CH2:9][CH2:10][S:11][CH2:12][CH3:13]
Reactant: CN=C=O
Reactant: CCSCCSCCN
Solvent: CCOC(C)=O
Product: CCSCCSCCNC(=O)NC

Procedure:
6 g of methyl isocyanate in 15 ml of ethyl acetate were added dropwise at room temperature to a solution of 16.5 g of 1-amino-3,6-dithiaoctane in 40 ml of ethylacetate. The urea precipitated was recrystallised twice from methanol/water.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.[BH4-].[Na+]>C1COCC1.CO>[N:1]1[N:2]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:12][CH:13]=2)[N:3]=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(-n2nccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(-n2nccn2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 42.26 g (244 mmol) of 4-[1,2,3]-triazol-2-yl-benzaldehyde in 140 ml of THF and 420 ml of MeOH, 9.23 g (244 mmol) of NaBH4 are added portionwise at 0–5° C. and the mixture is stirred for 30 min. at the same temperature. The reaction is quenched with sat. NH4Cl at 0–5° C. and the mixture is extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O.C([BH3-])#N.[Na+].Cl>CO.O>[O:19]=[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCC(=O)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCCCN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.4 g (42 mmol) of 4-nitrobenzaldehyde are dissolved in 150 ml of methanol and combined with 4.9 g (42 mmol) of 5-aminovaleric acid and 1.8 g (29 mmol) of sodium cyanoborohydride. The mixture is stirred for 18 hours at ambient temperature and then carefully mixed with 20 ml of conc. hydrochloric acid. The solvent is eliminated in vacuo, the residue is taken up in water and extracted with dichloromethane. The residue obtained after evaporation is chromatographed on silica gel (dichloromethane/methanol, 4:1). A mixture of methyl 5-(4-nitrobenzylamino)-pentanoate and 4-(2-oxopiperidinomethyl)-nitrobenzene is obtained which is dissolved in 100 methanol and combined with 50 ml of 1 N sodium hydroxide solution. The mixture is stirred for one hour at ambient temperature, 50 ml of 1 N hydrochloric acid are added and the reaction solution is evaporated down to 100 ml. The aqueous phase thus obtained is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:26][NH:27][O:28][CH3:29]>CN(C=O)C.CCOC(C)=O.O>[CH3:29][O:28][N:27]([CH3:26])[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: CNOC
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2ncccc2c1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of quinoline-6-carboxylic acid (10 g, 57.75 mmol) in DMF (200 mL) was added carbonyl diimidazole (10.3 g, 62.5 mmol) under nitrogen. The reaction was stirred for 1 hour. To the solution was added N,O-dimethyl hydroxylamine (5.6 g, 57.75 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was diluted with EtOAc (150 mL) and water (150 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (5×100 mL). The organics were combined and washed with water (3×100 mL), brine (2×100 mL), dried over Na2SO4, filtered and concentrated to give quinoline-6-carboxylic acid methoxy-methyl-amide (11.97 g, 97% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.Cl.[OH2:31]>C(#N)C>[OH:23][CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:14]=1)[CH2:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:31]
Reactant: c1ccc(C2=NCC(c3cccc(OCc4ccc5ccccc5n4)c3)O2)nc1
Reactant: O
Agent: Cl
Solvent: CC#N
Product: O=C(NCC(O)c1cccc(OCc2ccc3ccccc3n2)c1)c1ccccn1

Procedure:
A solution of 3.9 g (0.01 mol) of 4,5-dihydro-5-[3-[(2-quinolinyl)methoxy]phenyl]-2-(2-pyridyl)-1,3-oxazole in 100 ml of acetonitrile, 10 ml of water, and 1 ml of concentrated hydrochloric acid is heated on a steam bath for 5 hours. The solvents are evaporated and the residue is dissolved in a mixture of aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate solution is separated and washed with dilute aqueous sodium chloride solution. The ethyl acetate solution is dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue is dissolved in hot ethyl acetate and the solution is distilled with hexane to obtain crystals (2.2 g), m.p. 126°-129° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][P:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=[O:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][P:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=[O:11])[O:12][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCP(=O)(O)CNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCP(=O)(CNC(=O)OC(C)(C)C)OCc1ccccc1
Yield: 55 %

Procedure:
In analogy to Example 4, the benzyl phosphinate 5 was prepared from the phosphinic acid 1 and benzyl alcohol in a yield of 55%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([NH:14]C(OCC2C=CC=CC=2)=O)([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([NH2:14])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@](C)(NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@](C)(N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.8 %

Procedure:
A mixture of (S)-3-benzyloxycarbonylamino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 1, SFC (Table 1, Method 51) Rt=3.693 min, 1.7 g, 5.08 mmol) and Pd/C (10%, 0.2 g, 0.19 mmol) in MeOH (10 mL) was stirred at ambient temperature under an atmosphere of H2 (1 atm) for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give (S)-3-amino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 67%). 1H NMR (400 MHz, CDCl3) δ 3.62-3.06 (m, 4H), 1.88-1.70 (m, 2H), 1.48 (s, 9H), 1.34-1.26 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](Cl)=[O:19])[CH3:14].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18]([NH:1][C:2]1[C:7]([S:8](=[O:9])(=[O:10])[NH2:11])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1)=[O:19])[CH3:14]
Reactant: Nc1ncc(Br)cc1S(N)(=O)=O
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)Nc1ncc(Br)cc1S(N)(=O)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
2-Amino-5-bromo-pyridine-3-sulfonic acid amide (2.5 g, 9.9 mmol) was dissolved in 1,4-dioxane (50 mL). Chlorocarbonyl-acetic acid ethyl ester (1.9 mL, 14.85 mmol) was added and the mixture was heated at 90° C. while stirring for 2 h. Upon cooling to 25° C., the mixture was poured into half-saturated aqueous sodium bicarbonate solution (250 mL). A solid precipitated and was collected by vacuum filtration, rinsed with water (50 mL) and dried in vacuo to afford the desired product, N-(5-bromo-3-sulfamoyl-pyridin-2-yl)-malonamic acid ethyl ester (2.5 g, 6.82 mmol, 69%), as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (3H, t, J=7.0 Hz), 3.67 (2H, s), 4.10 (2H, q, J=7.3 Hz), 7.78 (2H, bs), 8.33 (1H, d, J=2.3 Hz), 8.70 (1H, d, J=2.4 Hz), 9.85 (1H, bs).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10](OCC)=[O:11])[CH:7]=[CH:6][N:5]=1>C(O)C.ClCCl>[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][N:5]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: OCc1ccnc(Cl)c1
Reaction time: 3 h
Yield: 76 %

Procedure:
2.04 g of sodium borohydride are added portionwise to a solution of 1.7 g of ethyl 2-chloropyridine-4-carboxylate in 20 ml of ethanol, under an inert atmosphere of argon at a temperature in the region of 0° C. The reaction mixture is refluxed with stirring for 3 hours and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in dichloromethane and then washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 1 g of 2-chloro-4-(hydroxymethyl)pyridine is thus obtained.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[F-].[Cs+].[CH3:20][C:21]1[N:26]=[C:25]([S:27][CH3:28])[CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=1>O1CCOCC1.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([C:23]2[CH:24]=[C:25]([S:27][CH3:28])[N:26]=[C:21]([CH3:20])[N:22]=2)[C:3]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[N:4][CH:5]=1
Reactant: COc1ccc(Nc2ncc(Cl)nc2Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncc(Cl)nc2-c2cc(SC)nc(C)n2)cn1
Temperature: 140 °C
Yield: 73 %

Procedure:
A glass microwave reaction vessel was charged with 3-bromo-5-chloro-N-(6-methoxypyridin-3-yl)pyrazin-2-amine (83 mg, 0.263 mmol), copper (I) iodide (10 mg, 0.053 mmol, Aldrich), cesium fluoride (80 mg, 0.526 mmol, Alfa Aesar), tetrakis(triphenylphosphine)palladium(0) (30.4 mg, 0.026 mmol) and 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (113 mg, 0.263 mmol) in dioxane (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 10% EtOAc/hexanes to give 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (72 mg, 0.192 mmol, 73.0% yield). 1H NMR (300 MHz, CDCl3) δ 2.63 (s, 3H) 2.78 (s, 3H) 3.95 (s, 3H) 6.79 (d, J=8.77 Hz, 1H) 8.01 (dd, J=8.70, 2.12 Hz, 1H) 8.17 (d, J=5.55 Hz, 2H) 8.39 (s, 1H) 12.21 (s, 1H). m/z (ESI, +ve ion) 375.0 (M+H)+.