Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C1(C[O:6][C:7]2[CH:8]=[C:9]([F:37])[CH:10]=[C:11]3[C:16]=2[N:15]=[C:14]([C:17]2[N:21]4[CH:22]=[C:23]([C@@H:26]([N:31]5[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32]5)[C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:25][C:20]4=[N:19][N:18]=2)[CH:13]=[CH:12]3)CC1>Cl.CC(O)C>[ClH:1].[NH2:36][C@H:33]1[CH2:34][CH2:35][N:31]([C@H:26]([C:23]2[CH:24]=[CH:25][C:20]3[N:21]([C:17]([C:14]4[CH:13]=[CH:12][C:11]5[C:16](=[C:7]([OH:6])[CH:8]=[C:9]([F:37])[CH:10]=5)[N:15]=4)=[N:18][N:19]=3)[CH:22]=2)[C:27]([F:29])([F:28])[F:30])[CH2:32]1
Reactant: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)cc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Agent: Cl
Solvent: CC(C)O
Product: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)cc(O)c5n4)n3c2)C(F)(F)F)C1
Yield: 66.3 %

Procedure:
(S)-1-((R)-1-(3-(8-(cyclopropylmethoxy)-6-fluoroquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride (Example 158; 200 mg, 0.400 mmol) was stirred in 5-6N HCl (2 mL) in IPA in a sealed tube at 60° C. for 14 hours. The reaction mixture was concentrated under reduced pressure to provide 2-(6-((R)-1-((S)-3-aminopyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol hydrochloride (128 mg, 71.8% yield) as a solid. LCMS APCI (+) m/z 447 (M+H).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:33][CH:34]([CH3:39])[CH2:35][C:36]([OH:38])=[O:37].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>CN(C=O)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([NH:33][CH:34]([CH3:39])[CH2:35][C:36]([OH:38])=[O:37])=[O:16])=[CH:8][CH:9]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: CC(N)CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CC(=O)O)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 1 h
Yield: 27.5 %

Procedure:
An aliquot of 4-[[4-(aminoiminomethyl)phenyl]-amino]-4-oxobutanoic acid prepared in Example 1, Step 1 (2 g) was added to dry DMF (65 ml) followed by N-methylmorpholine (0.75 g, 1 eq.) and isobutyl chloroformate (1 g) at 25° C. The mixture was stirred for 5 rain. 3-Aminobutyric acid (1.1 g, 1.1 eq. ) was added followed by triethylamine (1.5 g, 1.3 eq. ) and dimethylaminopyridine. After 1 h, the solvent was removed under reduced pressure and the product was purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to give 750 mg of white solid: 1H NMR (d6 -DMSO) δ 1.06 (d, 3H, J=7 Hz), 2.2-2.6 (m, 6H), 4.05 (m, 1H), 7.8 (m, 4H), 7.85 (d, 1H, J=8 Hz), 9.05 (bs, 2H), 9.15 (bs, 2H), 10.4 (s, 1H); MS (FAB) m/z 321.1 (MH+), 236.
Reaction SMILES: [Na].ClC1N=NN=C(Cl)C=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1.[CH2:21]([OH:23])[CH3:22]>>[Cl:10][C:11]1[N:16]=[C:15]([O:23][CH2:21][CH3:22])[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: CCO
Reactant: CN(C)c1nc(Cl)nc(Cl)n1
Agent: Clc1cc(Cl)nnn1
Agent: [Na]
Product: CCOc1nc(Cl)nc(N(C)C)n1
Temperature: 0 °C

Procedure:
A solution of sodium (0.46 g.) in ethanol (50 ml.) was added with stirring and waterbath cooling (25° C.) to a solution of the dichlorotriazine (3.86 g.) from (a) in ethanol (50 ml.). Following the addition the solution was poured into ice water (250 ml.) and the product collected, dried and crystallised from petroleum as needles (2.5 g.) having a melting point of 124° C.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([CH3:11])[C:5]2=[N:4][C:3]=1[CH2:12][CH2:13][CH3:14].[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]([OH:35])[C:2]3[N:6]4[CH:7]=[CH:8][N:9]=[C:10]([CH3:11])[C:5]4=[N:4][C:3]=3[CH2:12][CH2:13][CH3:14])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]
Reactant: CCCc1nc2c(C)nccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: CCCc1nc2c(C)nccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 108.9 %

Procedure:
[step 3] Using 3-iodo-8-methyl-2-propylimidazo[1,2-a]pyrazine (0.5 g, 1.7 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (0.3 g, 1.0 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 14A, step 3, (E)-2-{3-fluoro-8-[hydroxy(8-methyl-2-propylimidazo[1,2-a]pyrazin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (0.51 g, quantitative) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(O)cc1
Solvent: CC#N
Product: CCOC(=O)COc1ccc(N)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
4-amino phenol (500 mg, 4.58 mmol) was suspended in acetonitrile (60 mL), the mixture cooled to 0° C. and ethyl 2-bromoacetate (0.53 mL, 4.81 mmol) added. CsCO3 (1.9 g, 10 mmol) was added in portions and the mixture stirred for 16 h, allowing to warm to RT. The mixture was filtered, the residue washed with acetonitrile and the filtrate evaporated to dryness. The crude product was suspended in DCM (˜30 mL), filtered and this filtrate evaporated to dryness to afford ethyl 2-(4-aminophenoxy)acetate (860 mg) as a dark oil that solidified on standing. 1H NMR (400 MHz, CDCl3) δ 6.79-6.74 (m, 2H), 6.66-6.60 (m, 2H), 4.53 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.CN(C=O)C.[C:26]([CH:28]=[CH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)#[N:27].C1CCN2C(=NCCC2)CC1>CCOC(C)=O>[C:26]([CH2:28][CH:29]([CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[N:15]1[CH:14]=[C:13]([C:11]2[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:12]=2)[CH:17]=[N:16]1)#[N:27]
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=CC#N)CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)cn1
Temperature: 45 °C
Yield: 61.9 %

Procedure:
To 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation K; 50 mg, 0.19 mmol) was added DMF (950 μL, 0.19 mmol), tert-butyl 4-(2-cyanovinyl)piperidine-1-carboxylate (Table 1, compound 1; 67 mg, 0.28 mmol) and DBU (185 μL, 1.3 mmol). The reaction mixture was heated to 45° C. for 8 hours, then diluted in EtOAc and washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated down to a yellow oil. Purification of the resulting crude material by reverse phase HPLC using a 0-100% acetonitrile/water gradient afforded tert-butyl 4-(2-cyano-1-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (59 mg, 62% yield). MS (apci) m/z=502.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].CN(C)C(=O)C.[Cl:33][CH2:34][C:35](Cl)=[O:36].[OH-].[Na+]>O>[OH:25][CH:22]([CH2:23][OH:24])[CH2:21][NH:20][C:18](=[O:19])[C:4]1[C:3]([I:26])=[C:2]([NH:1][C:35](=[O:36])[CH2:34][Cl:33])[C:15]([I:16])=[C:6]([C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8])[C:5]=1[I:17]
Reactant: O=C(Cl)CCl
Reactant: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I

Procedure:
The general procedure for the process of the invention involves reacting 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with N,N-dimethylacetamide and chloroacetyl chloride. The resulting product is hydrolyzed with a base (such as sodium hydroxide). A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. Alternately, 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is reacted with N,N-dimethylacetamide, acetonitrile, and chloroacetyl chloride. The resulting product is hydrolyzed with a base. A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. This product is combined with an aqueous base and deionized water. 2-Chloroethanol is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. Alternately, N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide plus metal halide and deionized water are combined. Ethylene oxide is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. This product is suspended in water with acetate ions and hydrochloric acid added. This suspended solution can take place at or above atmospheric pressure. Generally about 1 to about 2 atmospheres above atmospheric pressure is used. After adding aqueous sodium hydroxide to, maintain the pH, the reaction yields N,N′-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisopthalamide. Finally, salts and low molecular weight impurities are removed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[C:6]([CH:9]=1)[CH2:7][OH:8]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: OCc1cc(Cl)ccc1Sc1cccs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1cc(Cl)ccc1Sc1cccs1

Procedure:
To a solution of 51.4 g (0.2 mole) of 5-chloro-2-(2-thienylthio)-benzyl alcohol in 400 ml of toluene is added 173.9 g (2.0 mole) of manganese (IV)-oxide, and stirring is maintained at 20°-25° for 25 hours. The precipitate is then filtered off with suction, and the filtrate is concentrated in vacuo to yield 5-chloro-2-(2-thienylthio)-benzaldehyde as yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1>>[Br:12][C:13]1[CH:14]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1cccc(Br)c1
Product: O=Cc1ccc(-c2cccc(Br)c2)cc1

Procedure:
For example, as shown in Scheme 42, Example 1,4-formylbenzeneboronic acid 42.1 is coupled with 1,3-dibromobenzene 42.9 to give 3′-bromo-4-formylbiphenyl 42.10. The product is then coupled, as described above, with a dialkyl phosphite 42.4 to give the biphenyl phosphonate ester 42.11.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][O:9][C:10](=[NH:12])[NH2:11].O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:12][C:10](=[NH:11])[O:9][CH3:8])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=N)NC(=O)Nc1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 6 h

Procedure:
320 Parts of a 50% sodium hydroxide solution was added dropwise to 345 parts of 2-methylpseudourea hydrogen sulfate in a mixture of 3500 parts of water and 4000 parts of dichloromethane which mixture was maintained at approximately 5°C. by a cooling bath. 307 Parts of p-chlorophenyl isocyanate was added to the resulting mixture and the cooling bath was removed. The reaction mas was stirred vigorously for 6 hours at room temperature. The dichloromethane layer was separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was triturated in hexane and the solid was collected by filtration affording 400 parts of methyl 4-(4-chlorophenyl)allophanimidate, m.p. 115°-117°C.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:9]=2[NH:8][C:7](=[O:19])[CH2:6]1)C.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30]([NH2:32])=[NH:31])=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30]2[N:32]=[CH:4][C:5]3[CH2:6][C:7](=[O:19])[NH:8][C:9]4[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:10]=4[C:11]=3[N:31]=2)=[CH:21]1
Reactant: N=C(N)Cc1c[nH]c2ccccc12
Reactant: Cc1cc2c(cc1C)C(=O)C(=CN(C)C)CC(=O)N2
Product: Cc1cc2c(cc1C)-c1nc(Cc3c[nH]c4ccccc34)ncc1CC(=O)N2
Yield: 72 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepine-2,5-dione and 2-(1H-indol-3-yl)-acetamidine. Yield: 72%.
Reaction SMILES: [F:1][C:2]([F:20])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1.FC(F)(F)S(O[C@@H:27]([CH3:38])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])(=O)=O.C(O)(=O)C>CN1CCCC1=O.[H-].[Na+].O1CCCC1.C(OCC)(=O)C>[F:20][C:2]([F:1])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C@H:27]([CH3:38])[C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[C:12]2=[O:16])=[CH:7][CH:6]=1
Reactant: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](C(=O)OCc1ccccc1)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
1-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (4 g) was dissolved in 30 ml of 1-methyl-2-pyrrolidone, to which 60% sodium hydride in oil (0.55 g) was added. The mixture was vigorously stirred at room temperature for 30 minutes and then added to a solution of 5.2 g of benzyl (2S)-2-trifluoromethanesulfonyloxypropionate (prepared in Example 3) in 80 ml of tetrahydrofuran under nitrogen atmosphere at -40° to -50° C. over the period of 10 minutes. The mixture was stirred at -20° to -40° C. for 50 minutes, followed by addition of 9.6 ml of acetic acid. Then, the reaction solution was diluted with 100 ml of ethyl acetate, washed with 50 ml of water, 1N-hydrochloric acid (50 ml×2) and 50 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (silica gel: 200 g, eluent; hexane:ethyl acetate=2:3) to give 5.3 g of benzyl (2R)-2-[3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-dihydro-2-oxo-1H-imidazol-1-yl]propionate (yield: 85%) as colorless powdery crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:27])[C:17](=[CH2:26])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH3:14][O:15][C:16](=[O:27])[CH:17]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:26][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:13]
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Product: COC(=O)C(Cn1c(=O)cnc2ccc(OC)cc21)NC(=O)OC(C)(C)C
Yield: 20 %

Procedure:
The compound (yellow solid; 370 mg, 20% yield) was obtained according to procedure H starting from 7-methoxyquinoxalin-2(1H)-one (prepared according to WO 2006/134378) and N-(tert-butoxycarbonyl)dehydroalanine methyl ester.
Reaction SMILES: C([NH:8][CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[NH2:8][CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:15])([CH3:16])[N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNCc2ccccc2)COC1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CN)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (4S)-4-[(benzylamino)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (810 mg, 2.53 mmol), palladium hydroxide on carbon (81 mg) and methanol (20 mL) was stirred at room temperature under hydrogen atmosphere overnight. The catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by SPE (12 mL tube, 2 gram of DSC-SCX) to afford the pure product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCc2cc(OCCCCCBr)ccc2N1
Reactant: Sc1ccccc1
Product: O=C1CCc2cc(OCCCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(5-bromo-pentoxy)-3,4-dihydro-carbostyril and thiophenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:21]([O:23][C:24]([C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28])=[O:25])[CH3:22].C(N(CC)CC)C.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[C:24]([O:23][CH2:21][CH3:22])=[O:25])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)c1ccccc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a solution of 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol), o-ethoxycarbonylaniline (150 μL, 1 mmol), and triethylamine (280 μL, 2 mmol) in dichloromethane (3 mL) was added N,N-bis(2-oxo-3-oxazolydinyl)phosphinic chloride (254 mg, 1 mmol) at 0° C. The mixture was stirred overnight at room temperature and 0.2N hydrochloric acid was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residual solid was rinsed with diethyl ether and dried in vacuo to give 290 mg of the title compound (58%): mp>265°~267° C.; 1H NMR (270 MHz, DMSO-d6) δ12.05 (bs, 1H), 10.55 (s, 1H), 8.14 (d, 1H, J=8.1 Hz), 7.89 (d, 2H, J=8.1 Hz), 7.60 (t, 1H, J=8.1 Hz), 7.23 (d, 1H, J=2 Hz), 7.22 (t, 1H, J=8.1 Hz), 7.16 (d, 1H, J=2 Hz), 5.14~5.26 (m, 1H), 4.29 (q, 2H, J=7.2 Hz), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.82 (dm, 1H, J=17.1 Hz), 2.62~2.76 (m, 2H), 2.18 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H), 1.32 (t, 3H, J=7.2 Hz).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:9]=[C:10]([OH:18])[C:11](=[CH:16][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH2:19]([O:18][C:10]1[CH:9]=[C:8]([I:7])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(I)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Solid K2CO3 (76.1 g, 0.55 mol) was added to a solution of methyl 4-iodosalicylate (1) (76.5 g, 0.28 mol) in MeCN (550 mL) at RT. Benzyl bromide (32.7 mL, 0.28 mol) was added via syringe, and the resulting reaction mixture was warmed to 80° C. and stirred overnight. The reaction mixture was then cooled to RT and filtered subsequently to remove insoluble salts, which were washed further with EtOAc. The filtrate was concentrated in vacuo, before re-dissolving the residue in fresh EtOAc and filtering a second time. The filtrate was concentrated in vacuo to provide an oil which solidified upon standing to yield 2 (99%, 100.5 g) as a beige solid that required no further purification. 1H NMR (500 MHz, CDCl3, 25° C.): δ=7.54 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.5 Hz, 2H), 7.43-7.35 (m, 4H), 7.33 (t, J=7.5 Hz, 1H), 5.15 (s, 2H), 3.89 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3, 25° C.): δ=166.3, 158.4, 136.2, 133.1, 130.1, 128.8, 128.1, 127.0, 123.3, 120.3, 100.0, 71.0, 52.3 ppm. HRMS (ESI) calculated for C15H14IO3: m/z=367.9909 ([M+H]+); Found m/z=367.9893.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@@H:3]1[OH:7].CCN(C(C)C)C(C)C.[C:17](=O)(OC(Cl)(Cl)Cl)[O:18]C(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:7]1[C@H:3]2[CH2:4][O:5][CH2:6][C@H:2]2[NH:1][C:17]1=[O:18]
Reactant: N[C@@H]1COC[C@@H]1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N[C@@H]2COC[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.9 %

Procedure:
To a solution of (3R,4R)-4-aminotetrahydrofuran-3-ol (1.1 g, 7.88 mmol) and DIEA (4.54 ml, 26.0 mmol) in CH2Cl2 (30 mL) was added (bis(trichloromethyl) carbonate (1.75 g, 5.91 mmol) dissolved in CH2Cl2 (5 mL) at RT over a period of 30 min. After stirring for 0.5 h at 25° C., the reaction mixture was added to aqueous K2CO3 solution, stirred for 1 h and the CH2Cl2 was evaporated. The aqueous phase was washed with Et2O and afterwards evaporated to dryness. The residue was triturated with EtOH/THF 1:1, the inorganic salts removed by filtration through a plug of silica gel, and the filtrate was concentrated to provide the title compound as a beige solid (930 mg, 90%): ESI-MS: 147 [M+NH]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:7](=[CH:11][C:12](=[S:23](=[O:25])=[O:24])[CH:13]([CH3:22])[C:14]=1[C:15]1[CH2:19][CH:18]([CH2:20][Cl:21])[O:17][N:16]=1)[C:8](O)=[O:9]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:5][C:6]1[C:7](=[CH:11][C:12](=[S:23](=[O:25])=[O:24])[CH:13]([CH3:22])[C:14]=1[C:15]1[CH2:19][CH:18]([CH2:20][Cl:21])[O:17][N:16]=1)[C:8]([Cl:3])=[O:9]
Reactant: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)Cl

Procedure:
3.23 g (27.2 mmol) of thionyl chloride were added dropwise to a mixture of 4.5 g (13.6 mmol) of 2-methyl-3-(5-chloromethyl-4,5-dihydroisoxazol-3-yl)-4-methyl-sulfonylbenzoic acid, 100 ml of toluene and three drops of N,N-dimethylformamide. The mixture was refluxed for 4 hours and then cooled, and the solvent was removed. The residue was then taken up in methylene chloride and once more concentrated to dryness. This gave 4.74 g (100% of theory) of the title compound in the form of a pale powder.