Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.CCN(C(C)C)C(C)C>CCO>[Br:15][C:16]1[C:17]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: CNC(=O)C(C)(C)CNC1CCCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C)(C)CN(c1nc(Cl)ncc1Br)C1CCCC1
Yield: 23.4 %

Procedure:
3-(cyclopentylamino)-N,2,2-trimethyl-propanamide (665 mg, 3.353 mmol) and 5-bromo-2,4-dichloro-pyrimidine (666 mg, 373.7 μL, 2.921 mmol) were dissolved in EtOH (10 mL) and DIPEA (511.4 mg, 691.9 μL, 3.957 mmol) was added. The reaction was allowed to stir at reflux temperature overnight. The solvent was removed in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc/Petrol) to give the sub-title product as a brown oil (266 mg, 23%); 1H NMR (400.0 MHz, DMSO) d 1.03 (s, 6H), 1.54-1.83 (m, 8H), 2.57 (s, 3H), 3.68 (s, 2H), 4.23 (quin, 1H), 7.53 (d, 1H), 8.63 (s, 1H); MS ES(+) 391.0, ES (−) 389.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14](OC)=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>C1COCC1.[Cl-].[NH4+]>[OH:15][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: COC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSCCC(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)methioninate (47.7 g, 0.181 mol) in THF (500 mL) was added lithium borohydride (16.0 g, 0.734 mol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl [1-hydroxy-4-(methylsulfanyl)butan-2-yl]carbamate. MS ESI calc'd. for C10H22NO3S [M+H]+ 236. found 236. 1H NMR (400 MHz, CD3OD) δ 3.68-3.64 (m, 1H), 3.54-3.47 (m, 2H), 2.59-2.48 (m, 2H), 2.10 (s, 3H), 1.88-1.64 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [N:1]1[C:6]2[O:7][CH2:8][C:9](=O)[NH:10][C:5]=2[CH:4]=[N:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:1]1[C:6]2[O:7][CH2:8][CH2:9][NH:10][C:5]=2[CH:4]=[N:3][CH:2]=1
Reactant: O=C1COc2ncncc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ncc2c(n1)OCCN2
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
In a 10 ml flask, the mixture of 5H-pyrimido-[4,5-b][1,4]oxazin-6-one (107 mg, 0.58 mmol) was dissolved in tetrahydrofuran (3 ml) and then cooled to 0° C. 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (1.15 ml, 1.2 mmol) was added thereto dropwise and the temperature was raised to room temperature and then stirred for additional 2 hours. After cooling to low temperature again, water, 10% sodium hydroxide solution and water were added in this order to quench the reaction. The mixture was filtered and the filtrate was extracted with ethyl acetate and the combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica gel eluting with a solvent of dichloromethane to obtain white solid (20 mg, 25%).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>O1CCOCC1>[O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
tert-Butyl 4-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate was dissolved in 1:1CH2Cl2:methanol and 4N HCl in dioxane added and stirred for 1 hour at room temperature. The reaction was concentrated and the residue was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to afford 3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine (238 mg, 52.5% yield over 2 steps) as a white solid
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][C:28](OC)=[O:29])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCc1cccnc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(pyridin-3-yl)butanoate (1.3 eq., prepared in Synthetic Example 7) and LDA (1.3 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(pyridin-3-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 221 to 223° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([CH3:13])=[N+:11]([O-:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:15].[Br:16]Br>CO>[Br:16][CH2:13][C:12]1[C:3]([CH2:2][OH:1])=[N+:4]([O-:15])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N+:11]=1[O-:14]
Reactant: Cc1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: BrBr
Solvent: CO
Product: [O-][n+]1c(CO)c(CBr)[n+]([O-])c2ccccc21
Reaction time: 120 h

Procedure:
2-Hydroxymethyl-3-methylquinoxaline-1,4-dioxide (1 mole) was suspended in 5 liters of methanol and stirred while bromine (1.06 moles) was added dropwise over 1.5 hours. The reaction mixture was stirred for 5 days. The product was collected by filtration and washed with 1 liter of ether/400 ml methanol and then with 1 liter of ether. Yield, 175 grams (61%); m.p. 149°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[BH4-].[Na+]>CO>[NH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Br:1])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N)cc(Br)c1
Reaction time: 0.01 h
Yield: 98.4 %

Procedure:
To a stirred solution of methyl 3-bromo-5-nitrobenzoate (1.0 g, 3.8 mmol) in methanol (30 mL) was added NiCl2-6H2O (1.8 g, 7.6 mmol) and NaBH4 (430 mg, 11 mmol) successively at 0° C. The reaction mixture was stirred for 30 seconds and was then quenched by the addition of water. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford methyl 3-amino-5-bromobenzoate (860 mg, 97% yield). 1H NMR (400 MHz, d-DMSO) δ 7.14 (dd, J=2.0, 2.4 Hz, 1H), 7.11 (t, J=2.4 Hz, 1H), 6.94 (t, J=2.8 Hz, 1H), 5.72 (brs, 2H), 3.79 (s, 3H).
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:12][C:11]=1[C:28](=[O:30])[CH3:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:31](OCC)(=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>C(O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31](=[O:37])[CH2:29][C:28]([C:11]1[CH:12]=[C:13]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][C:10]=1[O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:30])[CH3:36]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(CC(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cc(CC(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Sodium (3 eq) was added to ethanol under nitrogen at room temperature and stirred until complete dissolution occurred. 1-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-ethanone (1 eq) was added, followed by diethyl oxalate (1.5 eq) and the reaction mixture heated to reflux for 4 hours. The mixture was allowed to cool to room temperature and acidified with 2M HCl (aq) to give a yellow precipitate of 4-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-2,4-dioxo-butyric acid ethyl ester, which was obtained by filtration.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1)([O-:3])=[O:2].[H-].[Na+].I[CH3:31].O>CN(C=O)C.C(OCC)C>[CH3:31][N:20]([C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15]1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an orange solution of (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate (1.50 g, 3.9 mmol) in DMF at 0 deg. C was added sodium hydride, 60% dispersion in mineral oil (0.19 g, 4.8 mmol). Bubbling was observed, and the solution became darker orange. After about 20 min, iodomethane (0.30 ml, 4.8 mmol) was added dropwise via syringe. The orange mixture was allowed to warm to room temperature over 30 min. Water was added, followed by diethyl ether. The organics were washed 1×H2O, 1×brine, dried over anhydrous Na2SO4, filtered, and concentrated to give (S)-tert-butyl methyl(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-yl)carbamate as an orange semi-solid which was used without further purification. MS m/z=404 [M+H]−. Calc'd for C18H24F3N3O4: 403.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)([CH3:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:28][N:27]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: CC(C)c1ccc(N)nc1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a stirred solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (500 mg, 1.66 mmol) in pyridine (5 mL) at 25° C. was added 5-isopropylpyridin-2-amine (226 mg, 1.66 mmol). The reaction mixture was stirred at 25° C. for 2 hours, then left to stand at this temperature overnight. The crude reaction mixture was then purified by flash silica (Si) chromatography (0-50% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and concentrated in vacuo to give the title compound (454 mg) as an orange solid. LCMS (2 min, formic) Rt 1.00 min, m/z (ES+) 402 (M+H).
Reaction SMILES: Br[CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(#N)C>O>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]2[C@H:11]([OH:12])[C@H:2]([CH2:3][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[S:4][C:5]=2[CH:6]=1
Reactant: c1c[nH]cn1
Reactant: OC1c2ccc(Cl)cc2SCC1Br
Solvent: CC#N
Solvent: O
Product: O[C@H]1c2ccc(Cl)cc2S[C@H]1Cn1ccnc1

Procedure:
Add 3-bromo-7-chlorothiochroman-4-ol (5.27 g., 18.8 mmole) and imidazole (12.8 g., 188 mmole) to acetonitrile (100 mL.), and reflux for 4 hours. Pour the reaction mixture into water (500 mL.), and extract with chloroform (500 mL.). Wash the organic layer with water (500 mL.), dry it over anhydrous magnesium sulfate, filter and evaporate in vacuo. Triturate the residue with anhydrous ether, filter and recrystallize from acetonitrile to give (±)-cis-6-chloro-2,3-dihydro-3-hydroxy-2-(1H-1-imidazolylmethyl)benzo[b]thiophene, m.p. 164°-165° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Cl[CH2:45][C:46]1[N:51]=[C:50]([O:52][CH3:53])[CH:49]=[C:48]([O:54][CH3:55])[N:47]=1.ClCC1C=NC(OC)=NC=1>>[CH3:53][O:52][C:50]1[CH:49]=[C:48]([O:54][CH3:55])[N:47]=[C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[N:51]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: COc1cc(OC)nc(CCl)n1
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: COc1cc(OC)nc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)n1

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)-4,6-dimethoxypyrimidine to replace 5-(chloromethyl)-2-methoxypyrimidine, 1′-[(4,6-dimethoxypyrimidin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (90%): mp 169-170° C.; 1H NMR (300 MHz, CDCl3) δ7.21-7.11 (m, 2H), 7.06-6.95 (m, 1H), 6.81-6.67 (m, 1H), 6.49 (s, 1H), 6.37 (s, 1H), 5.89 (s, 1H), 4.98 (ABq, 2H), 4.80 (ABq, 2H), 4.23-4.00 (m, 4H), 3.80 (s, 6H); MS (ES+) m/z 447.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14](=[O:25])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1)=[O:35].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:33][C:34](=[O:35])[NH:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1)[N:9]=[C:8]2[C:14](=[O:25])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]1)=[O:4]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc2[nH]nc(C(=O)NC3CCN(C(C)C)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(C(=O)NC1CCN(C(C)C)CC1)nn2CC(=O)Nc1ccc(Cl)cn1
Reaction time: 48 h

Procedure:
To a solution of 4 g 3-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-indazole-5-carboxylic acid methyl ester in 35 mL DMF, 3.8 g Cs2CO3 and 2.9 g 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added at RT and the reaction mixture was stirred for 2 d. After addition of 50 mL water the mixture was extracted with ethyl acetate (3×150 mL), the combined organic layers were dried over MgSO4 and filtered. The solvents were removed under reduced pressure and the residue was recrystallized from diisopropylether. Yield: 3.8 g MS (ES+): m/e=513, chloro pattern.
Reaction SMILES: B1(C2C=CC(O)=CC=2)O[C:4](C)(C)[C:3](C)(C)O1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][O:26][C:25]=2[C:29]([OH:31])=[O:30])=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][O:26][C:25]=2[C:29]([O:31][CH2:3][CH3:4])=[O:30])=[CH:20][CH:19]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: O=C(O)c1occc1-c1ccc(O)cc1
Product: CCOC(=O)c1occc1-c1ccc(O)cc1

Procedure:
Using 4-hydroxyphenylboronic acid pinacol cyclic ester, a reaction and treatment was carried out in the same manner as in Reference Example 2, thereby giving 3-(4-hydroxyphenyl)-2-furancarboxylic acid. A reaction and treatment was further carried out in the same manner as in Reference Example 1, thereby giving the desired compound.
Reaction SMILES: C(O[CH:4]=[N:5][NH:6][C:7]([O:9][CH3:10])=[O:8])C.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>C(O)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][CH:4]=[N:5][NH:6][C:7]([O:9][CH3:10])=[O:8])=[CH:15][CH:14]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC=NNC(=O)OC
Solvent: CCO
Product: COC(=O)NN=CNCc1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Methyl 2-(ethoxymethylene)hydrazinecarboxylate (prepared according to the method of N. Shao et al., Tetrahedron Lett. 2006, 47, 6743-6746; 5.00 g, 34.2 mmol) and 4-methoxybenzylamine (4.44 mL, 34.2 mmol) were dissolved in ethanol (20 mL), and the reaction was heated to 50° C. for 2 hours, then allowed to stir at room temperature for 18 hours. Filtration provided the product as a solid. Yield: 4.80 g, 20.2 mmol, 59%. 1H NMR (400 MHz, CD3OD) δ 3.69 (br s, 3H), 3.78 (s, 3H), 4.27 (br s, 2H), 6.80 and 7.62 (2 br s, 1H), 6.89 (br d, J=8.5 Hz, 2H), 7.19-7.28 (br m, 2H).
Reaction SMILES: O[CH2:2][NH:3][CH:4]=[O:5].[CH2:6]([O:8][P:9]([O:13]CC)[O:10][CH2:11][CH3:12])[CH3:7]>>[CH2:6]([O:8][P:9]([CH2:2][NH:3][CH:4]=[O:5])(=[O:13])[O:10][CH2:11][CH3:12])[CH3:7]
Reactant: O=CNCO
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CNC=O)OCC

Procedure:
reaction of N-(hydroxymethyl)formamide with triethylphosphite with accompanying heat, to form diethyl-N-(formyl)aminomethylphosphonate,
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([C:31]=3[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=4[O:33][CH3:34])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:35][C:36]([CH3:44])([CH2:40]C(O)=O)[C:37]([OH:39])=[O:38].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(N(C(C)C)CC)(C)C.ClCCl>[CH3:34][O:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:24][C:23]([C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:5])[CH2:35][C:36]([CH3:44])([CH3:40])[C:37]([OH:39])=[O:38])[CH2:13][CH2:12]3)=[CH:19][CH:18]=1)=[O:22])=[C:31]2[CH3:32]
Reactant: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)[nH]c12
Reactant: CC(C)(CC(=O)O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)CC(C)(C)C(=O)O)CC4)cc3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
4-{4-[(7-Methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (139 mg, 0.3 mmol) (see example 1) was stirred in 5 mL of 1:3 TFA/CH2Cl2 at r.t. overnight, then concentrated. The residue was dissolved in 5 mL of 30:70 diisopropylethylamine/anhydrous dichloromethane, 2,2-dimethyl-succinic acid (72 mg, 0.49 mmol), N-hydroxybenzotriazole (61 mg, 0.45 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) were added. The reaction mixture was stirred at room temperature overnight. After the reaction, solvent was evaporated. The resulted mixture was mixed with water and extracted with ethyl acetate twice. The organic layers were collected, combined, washed with brine before dried over sodium sulfate, and then concentrated to give a solid. The crude product was purified by reverse phase HPLC (10%-80% acetonitrile in water) to gave 7 mg of 4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid. LCMS calcd for C27H32N4O5 (m/e) 492, obsd 493 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([C:12]1[CH:13]=[CH:14][C:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:10][CH2:9][C:8]=2[CH:11]=1)=[O:20]
Reactant: CC(=O)N1CCc2ccccc2CC1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(C(=O)CCCCl)cc2CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
In 30 ml of dichloromethane, was dissolved 3.79 g of 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine. To the solution were added 3.38 g of 4-chlorobutyryl chloride and 4.00 g of aluminum chloride. The mixture was stirred for 2 hours at room temperature (about 20° C.). The reaction mixture was poured into 50 ml of ice-water. The organic layer was separated, which was washed successively with 50 ml of 0.5N aqueous solution of sodium hydroxide and 50 ml of pure water, then dried over anhydrous sodium sulfate. The solvent was distilled off to leave 5.40 g of an oily residue. The residue was purified by means of a silica gel column chromatography (developing solvent, ethyl acetate-dichloromethane 1:1 (V/V)) to afford 2.92 g of the title compound as colorless crystals, m.p.103°-106° C.
Reaction SMILES: C([O-])=O.C([NH+](CC)CC)C.C(O)=O.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:26][C:25](=[O:33])[CH:24]=1>O>[CH2:23]([C:24]1[C:25](=[O:26])[O:33][C:20]2[C:15]([C:14]=1[OH:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:32]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: O
Solvent: O=CO
Product: O=c1oc2ccccc2c(O)c1Cc1ccccc1
Temperature: 25 °C

Procedure:
Triethylammonium formate (TEAF) was prepared by adding TEA (20.0 mL) to formic acid (16.5 mL) with ice cooling. To TEAF was added benzaldehyde (3.78 mL) and 4-hydroxy-chromen-2-one (6.0 g) and the resulting mixture was heated to 130–140° C. for 3 hours, cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and conc. in vacuo to give a light yellow solid. The crude solid was recrystallized from EtOH to give 3-Benzyl-4-hydroxy-chromen-2-one as a white solid (1.95 g).
Reaction SMILES: C[O:2][C:3](=[O:16])[C@@H:4]([NH2:15])[CH2:5]/[CH:6]=[CH:7]/[CH2:8][C@H:9]([NH2:14])[C:10]([O:12]C)=[O:11].[ClH:17]>>[ClH:17].[ClH:17].[NH2:15][C@@H:4]([CH2:5]/[CH:6]=[CH:7]/[CH2:8][C@H:9]([NH2:14])[C:10]([OH:12])=[O:11])[C:3]([OH:16])=[O:2]
Reactant: COC(=O)[C@@H](N)C/C=C/C[C@H](N)C(=O)OC
Agent: Cl
Product: N[C@@H](C/C=C/C[C@H](N)C(=O)O)C(=O)O

Procedure:
(S,S)-2,7-Diamino-(E)-oct-4-ene-1,8-dioic acid dimethyl ester (1.65 g, 7.17 mmol) was heated under reflux with 6H HCl (10 ml, 60 mmol) for 2 hours. The solvent was then evaporated, the residue was dissolved in water (10 ml) and ethanol was added (100 ml). The white crystals were filtered off and dried in vacuum at 40° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][C:14](O)=[O:15])[CH2:10][C@@H:9]1[C:17]([O:19][CH3:20])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][OH:15])[CH2:10][C@@H:9]1[C:17]([O:19][CH3:20])=[O:18])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](CC(=O)O)CN1C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](CCO)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To 0.67 g of cis methyl N-t-butoxycarbonyl-4-(carboxymethyl)-pyrrolidine-2-carboxylate in 1 ml THF is added at 0° 3.5 ml of borane (1M) in THF. After stirring 0.5 hour, 1 ml of water is added, the solvent is evaporated and the residue is flash chromatographed with ethyl acetate/hexane (75:25) to afford cis methyl N-t-butoxycarbonyl-4-(2-hydroxyethyl)-pyrrolidine-2-carboxylate.