Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)C>[CH2:18]([O:8][C:5]1[CH:4]=[C:3]([C:2]([Cl:1])=[CH:7][CH:6]=1)[NH2:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-3-nitrophenol (0.13 g) was dissolved in N,N-dimethylformamide (3 mL). To the solution were added potassium carbonate (0.31 g) and benzyl bromide (0.14 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). To the solution were added methanol (3 mL), nickel(II) bromide (8 mg) and sodium borohydride (85 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.15 g).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)C.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH:28]([F:30])[F:29]>CN(C=O)C.C(OCC)(=O)C>[F:29][CH:28]([F:30])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:8][CH:9]=1
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)F)cc1

Procedure:
A solution of Step 1 intermediate, Intermediate 10 (400 mg, 1.548 mmol) in DMF (15 ml) was treated with Cs2CO3 (1.513 g, 4.645 mmol) slowly at room temperature. The reaction temperature was raised to 80° C. at which the chloro-difluoro-methane (ClCHF2) gas was passed into the reaction mixture till TLC indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 and purified using column chromatography to afford the desired compound; 1H NMR (300 MHz, CDCl3) δ 2.20 (s, 3H), 7.18-7.22 (m, 2H), 7.25 (s, 1H), 7.37-7.40 (m, 2H), 7.55 (d, J=5.1 Hz, 1H), 7.99 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 309.45 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:12]1[S:16][C:15]([CH2:17][NH:18][C:19](=[O:39])[C@H:20]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:13]=1)[CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(N(C(C)C)CC)(C)C.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1)([O-:51])=[O:50]>ClCCl>[Si:5]([O:4][CH2:3][C@H:2]([C:12]1[S:16][C:15]([CH2:17][NH:18][C:19](=[O:39])[C@H:20]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:13]=1)[NH:1][S:58]([C:55]1[CH:54]=[CH:53][C:52]([N+:49]([O-:51])=[O:50])=[CH:57][CH:56]=1)(=[O:59])=[O:60])([C:8]([CH3:9])([CH3:10])[CH3:11])([CH3:7])[CH3:6]
Reactant: COC(=O)N[C@H](C(=O)NCc1ccc([C@H](N)CO[Si](C)(C)C(C)(C)C)s1)C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)s1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-({5-[(1R)-1-amino-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-thiophen-2-yl}methyl)-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (125 mg, 0.220 mmol) in dichloromethane (4.4 mL) was treated with diisopropylethylamine (0.046 mL, 0.264 mmol) and solid p-nitrobenzensulfonyl chloride (59 mg, 0.264 mmol) and the mixture was stirred at room temperature for 18 hours, quenched with saturated NaHCO3 (0.5 mL), diluted with DCM, washed with sat. NaHCO3, dried over MgSO4, filtered and concentrated. The crude was purified on silica gel 10%-50% ethyl acetate in hexane to provide the title compound. 1H NMR (CD3)2CO) δ 8.39 (2H), 8.05 (2H), 7.67 (1H), 7.41 (5H), 7.30-7.15 (6H), 6.65 (1H), 6.42 (1H), 6.30 (1H), 5.10 (1H), 4.72 (1H), 4.50 (1H), 4.23 (1H), 4.13 (1H), 3.82 (2H), 3.49 (3H), 0.84 (9H), 0.01 (6H).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH:27]([Mg]Cl)([CH3:29])[CH3:28]>C1COCC1>[CH3:28][CH:27]([CH3:29])[C:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:14]2[CH:15]=[N:16][C:17]3[NH:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:23]=1)([OH:26])[CH3:25]
Reactant: CC(C)[Mg]Cl
Reactant: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Product: CC(C)C(C)(O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of 6-(5-acetyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (125 mg, 0.35 mmol) in THF (2 mL) is added a solution of isopropylmagnesium chloride in THF (1.3M, 816 μL, 1.1 mmol). The resultant mixture is stirred warming to room temperature for 1 h. The reaction is quenched with saturated aqueous ammonium chloride solution and is extracted with EtOAc. The combined organic extracts are washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is taken up in MeOH (3 mL) and 4N HCl in 1,4-dioxane (3 mL) is added. The reaction is stirred at room temperature for 16 h and is concentrated to provide 3-methyl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-butan-2-ol (131 mg) as the dihydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:5][C:4]([CH3:24])([CH3:23])[NH:3]1.C(N(C1CC(C)(C)NC(C)(C)C1)[P:31]1[O:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][O:32]1)CCC>>[CH3:37][C:34]1([CH3:38])[CH2:35][O:36][P:31]([N:8]([CH:6]2[CH2:7][C:2]([CH3:25])([CH3:1])[NH:3][C:4]([CH3:24])([CH3:23])[CH2:5]2)[CH2:9][CH2:10][CH2:11][N:12]([P:31]2[O:32][CH2:33][C:34]([CH3:37])([CH3:38])[CH2:35][O:36]2)[CH:13]2[CH2:14][C:15]([CH3:22])([CH3:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH2:18]2)[O:32][CH2:33]1
Reactant: CCCCN(C1CC(C)(C)NC(C)(C)C1)P1OCC(C)(C)CO1
Reactant: CC1(C)CC(NCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Product: CC1(C)COP(N(CCCN(C2CC(C)(C)NC(C)(C)C2)P2OCC(C)(C)CO2)C2CC(C)(C)NC(C)(C)C2)OC1

Procedure:
If N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)trimethylenediamine is used as the amine in an analogous procedure, N,N'-bis(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)trimethylenediamine is obtained, which melts at 102° (Compound No. 4).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[Li]CCCC.[O:13]1[CH2:15][CH2:14]1>CCOCC>[Br:7][C:5]1[CH:6]=[C:2]([CH2:15][CH2:14][OH:13])[S:3][CH:4]=1
Reactant: C1CO1
Reactant: Brc1csc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OCCc1cc(Br)cs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dibromothiophene (1 g, 4.13 mmol) in anhydrous ether was added n-BuLi (1.66 mL, 4.13 mmol) at −78° C. dropwise. After stirring at −78° C. for 0.5 hr, oxirane (0.32 mL, 19.28 mmol/mL in ether) was added to the reaction mixture quickly. After stirring at 0° C. for 1.5 hr, the reaction mixture was quenched with aqueous NH4Cl solution, extracted with EtOAc, concentrated and purified to give the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)[CH:5]=1.[Li]CCCC.[Cl:21]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:21][C:13]1[O:14][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH:2][CH3:1])=[O:15])=[CH:11][N:12]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CNC(=O)c1cccc(-c2cnco2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(-c2cnc(Cl)o2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
To a round bottom flask was added N-methyl-3-(oxazol-5-yl)benzamide (0.50 gm, 2.47 mmol) and THF (25 mL). The reaction was cooled to −78° C. and 1.6 M nBuLi (3.86 mL, 6.18 mmol) was added dropwise. The reaction turned orange-red in color. After 60 min, a solution of hexachloroethane (0.88 gm, 3.71 mmol) in THF (5 mL) was slowly added. The reaction was slowly warmed to rt over 30 min. After 2 h at rt the reaction was quenched by slow addition of sat. NH4Cl (10 mL). The mixture was concentrated to remove most of the THF. The mixture was then partitioned between EtOAc (40 mL) and water (20 mL). The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, 3-(2-chlorooxazol-5-yl)-N-methylbenzamide, (123 mg, 0.52 mmol, 21% yield) as a light yellow solid. Anal. Calcd. for C11H9ClN2O2 m/z 236.0, found: 237.0 (M+H)+.
Reaction SMILES: ClC(Cl)C(F)(F)C(F)(F)C(F)(F)F.[F:14][C:15]([F:25])([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][OH:17].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:14][C:15]([F:25])([C:18]([F:23])([F:24])[C:19]([F:20])([F:21])[F:22])[CH2:16][O:17][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: FC(F)(F)C(F)(F)C(F)(F)C(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)C(F)(F)F)cc1

Procedure:
For example, to prepare 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane, 2,2,3,3,4,4,4-heptafluorobutanol and p-toluenesulfonyl chloride are reacted to form 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate are reacted to form 1-chloro-2,2,3,3,4,4,4-heptafluorobutane. Finally, chlorine and the 1-chloro-2,2,3,3,4,4,4-heptafluorobutane are reacted to form the 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 4-fluorophenol (1.06 g) in anhydrous DMF (10 mL) were added anhydrous potassium carbonate (2.07 g) and 4-fluorobenzaldehyde (1.2 g) at room temperature. The reaction was stirred at 100° C. for 16 h, then cooled to room temperature and diluted with ether. The organic layer was washed with 1N sodium hydroxide, and then with water, dried over sodium sulphate, and concentrated under reduced pressure. The crude aldehyde obtained was purified by flash-column chromatography on silica-gel using 20% EtOAc in hexanes to provide the pure aldehyde.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>CN(C)C=O.CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:3]1=[O:12]
Reactant: Brc1cccnc1
Reactant: Cn1c(=O)[nH]c2nc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2cccnc2)c2nc(Cl)ccc21
Temperature: 30 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
7.36 g of 1-methyl-5-chloro-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one were dissolved in 160 ml of hot dimethylformamide and after cooling the solution to 30° C., 4.64 g of a 50% sodium hydride-oil suspension were slowly added thereto. The mixture was stirred at 40°-50° C. for 2 hours and then 80 ml or 128.8 g of 3-bromo-pyridine and 1.5 g of cuprous chloride were added thereto. The mixture was refluxed for 9 hours and was then cooled and evaporated to dryness. The residue was taken up in ammonium hydroxide solution and was filtered. The product was washed with water to obtain 8 g of raw product which was dissolved in acetone. The solution was chromatographed over silica gel and was eluted with acetone. The product was crystallized from 95% ethanol to obtain 5 g of 1-methyl-3-(3-pyridyl)-5-chloro-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one in the form of white needles melting at 206°-208° C.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([C:17]1[NH:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:9])([CH3:8])[CH3:7].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([C:17]1[N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer and nitrogen inlet, is charged with 50 mL of DMF, 3.50 g (10 mmol) of (R)-[1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (the compound of Formula 202 prepared, e.g., as described in Example 6.2), 1.34 mL of benzyl bromide (98%), and 3.04 g of potassium carbonate. The mixture is stirred at room temperature overnight. TLC (hexanes/ethyl acetate 7:3) indicates complete reaction. The mixture is transferred into a Erlenmeyer flask and mixed with 100 mL of water. To the stirring mixture is then added hexanes, 50 mL. The formed white solid is collected by filtration to afford the title compound of Formula 203 (R)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (also corresponding to Formula 107). The layers are separated and the organic is concentrated to dryness. The residue is chromatographed to afford an additional yield of the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:30]1([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32][CH2:31]1
Reactant: c1cnc2c(c1)CCN2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cccnc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 mg (0.42 mmol) 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised. Then the substance was dissolved in DMF and purified again by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (135 mg, 0.43 mmol), 4-[N′-(2-methylphenyl)ureido]-3-methoxyphenylacetic acid (136 mg, 0.43 mmol) and N,N-dimethylaminopyridine (52.9 mg, 0.43 mmol) in DMF (10 ml) was added EDC.HCl (90.8 mg, 0.48 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[N′-(2-methylphenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (271 mg, quant.) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 2.00–2.18 (m, 3 H), 2.31–2.41 (m, 1 H), 2.27 (s, 3 H), 3.31 (s, 2 H), 3.67 (s, 3 H), 3.89 (s, 3 H), 4.35–4.48 (m, 2H), 4.60 (br s, 1 H), 4.92 (t, J=6.8 Hz, 1 H), 6.51 (d, J=8.4 Hz, 1 H), 6.62 (s, 1 H), 6.96 (d, J=8.8 Hz, 1 H), 7.11–7.40 (series of m, 8 H), 7.51 (d, J=8.0 Hz, 1 H), 7.97–8.00 (m, 2 H); MS (ESI) m/z, 608 (M++H).
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH2:73]([O:75][C:76](=[O:80])[CH2:77]CN)[CH3:74]>CN(C)C=O>[CH2:73]([O:75][C:76](=[O:80])[CH2:77][CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36])[CH3:74]
Reactant: CCOC(=O)CCN
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
To a solution of 0.18 g (0.37 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added 0.148 g (0.39 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brown solution 0.060 g (0.39 mmol) beta-alanine ethylester hydrochloride (commercially available, CAS RN 4244-84-2) was added and the solution was stirred at room temperature for 3.5 hours. The solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to afford 0.185 g (85%) of the title compound as a light brown foam. MS (ESI): m/z=583.15 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:29][OH:30].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:30][NH:29][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25](=[O:27])[CH3:26])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(C)=O)cc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ncc(C(=O)NO)s3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of compound (12h) (125 mg, 0.305 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (211 mg, 3.05 mmol) and a freshly prepared solution of sodium methoxide in methanol (105 mg, 4.57 mmol of sodium dissolved in 1 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 13 h (15 mg, yield 12.0%). HPLC: 92.26% (Rt=12.51 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27](=O)[CH2:28][C:29](=[O:31])[CH3:30])[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27](=[S:44])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)NC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=S)NC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21

Procedure:
A solution of the product of Step A (136 mg, 0.26 mmol) and Lawesson's reagent (106 mg, 0.26 mmol) in 5.0 mL of toluene was stirred at 120° C. for 3 h and then concentrated. Chromatography on a Biotage 40+S cartridge using 1:3 v/v EtOAc/hexanes as the eluant afforded the title compound.