Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[C:7]([O:19][CH:20]2[CH2:23][CH2:22][CH2:21]2)=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[NH:12][C@@H:11]([CH3:18])[CH2:10][CH2:9]2>ClCCl.N1C=CC=CC=1>[Br:5][C:6]1[C:7]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23]2)=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[N:12]([C:1](=[O:3])[CH3:2])[C@@H:11]([CH3:18])[CH2:10][CH2:9]2
Reactant: CC(=O)Cl
Reactant: C[C@H]1CCc2c(c(F)c(F)c(Br)c2OC2CCC2)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2c(F)c(F)c(Br)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Yield: 105.3 %

Procedure:
Acetyl chloride (0.21 mL, 3.02 mmol) was added dropwise to a 0° C. solution of (S)-6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.0 g, 3.02 mmol) in dichloromethane (20 mL) and pyridine (0.6 mL), and the resulting solution was allowed to stir and warm to room temperature overnight. The reaction mixture was diluted with dichloromethane (40 mL), washed with 1 N hydrochloric acid (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.19 g, 99%) as yellow oil. MS (ESI, pos. ion) m/z 374, 376 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([C:25](O)=[O:26])[O:22][C:23]=2[CH3:24])=[CH:13][CH:12]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.O1CCCC1.C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([C:25]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:26])[O:22][C:23]=2[CH3:24])=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)c(OC)c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccccc4)oc3C)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
A stirred solution of 4-(2′,4′-dimethoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (140) (50 mg, 0.136 mmoles), benzenesulphonamide (32 mg, 0.204 mmoles) and 4-(N,N-dimethylamino)-pyridine (5 mg) in a mixture of tetrahydrofuran (8 ml) and acetonitrile (2 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.163 mmoles). The mixture was stirred at room temperature for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 141 (24 mg) as a white solid. LC/MS System C; Rt=8.99 mins, m/z (ES−)=506 (M−H for C27H25NO7S).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Br:23])=[CH:17][C:13]=1[C:14](O)=O>>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[NH:8][C:14]([C:13]1[CH:17]=[C:18]([Br:23])[C:19]([O:21][CH3:22])=[CH:20][C:12]=1[O:11][CH3:10])=[N:1]2
Reactant: Nc1ncnc(Cl)c1N
Reactant: COc1cc(OC)c(C(=O)O)cc1Br
Product: COc1cc(OC)c(-c2nc3ncnc(Cl)c3[nH]2)cc1Br

Procedure:
Prepared analogously to Example 14 from 4,5-diamino-6-chloropyrimidine and 2,4-dimethoxy-5-bromo-benzoic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:11][CH:12]([CH3:16])[C:13]([O-])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:13](=[O:14])[CH:12]([SH:11])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(S)C(=O)[O-]
Reactant: OCCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OCCCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, hot plate (with stirring apparatus contained within) and spin bar are placed 13.6 grams phenylpropyl alcohol; 4.0 grams of 2-mercaptopropionate acid; and 0.1 grams of para-toluene sulphonic acid. The reaction mass is maintained at reflux for a period of 9 hours with stirring. At the end of the 9 hour period, the reaction mass is cooled and fractionally distilled on a micro distillation apparatus yielding the compound having the structure: ##STR64## (as confirmed by GLC, mass spectral, NMR and IR analyses).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([Br:7])[CH:4]=[N:3]1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>CCOC(C)=O.CCCCCCC>[Br:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1
Reactant: On1cc(Br)cn1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)On1cc(Br)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-bromopyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (89%, oil). HPLC-MS m/z=298.0 (M+1), Rt: 3.77 min.
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CN([CH:23]=[O:24])C.Cl>C1COCC1>[CH2:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH:23]=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCc1ccsc1Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccsc1C=O
Temperature: 0 °C
Yield: 54.6 %

Procedure:
After magnesium (0.63 g; 25.8 mmol) and anhydrous THF (25 ml) were put into a flask, 2-bromo-3-dodecylthiophene (7.78 g; 23.5 mmol) was slowly added thereto. After starting Grignard reaction, the solution was refluxed until magnesium was almost removed. The purified DMF (3.65 g; ˜4 ml; 50 mmol) was slowly added dropwise to the reaction solution. The reaction solution was refluxed for one day, and cooled to 0° C., and 5% HCl (100 ml) was added thereto to terminate the reaction. An organic layer was extracted by using ethyl ether, and the obtained organic layer was washed sequentially with NaHCO3, a saturated NaCl aqueous solution, and water. The residual moisture was removed over anhydrous magnesium sulfate. After removing the solvent, the residue was subjected to a column separation process by using silica gel (ethyl acetate/hexane=1/9) to obtain 3-dodecylthiophene-2-carboaldehyde (3.6 g; 55%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Product: CCOC(=O)c1cnc(N(CC)CC)c(Cl)c1
Temperature: 80 °C
Reaction time: 72 h
Yield: 86.1 %

Procedure:
A mixture of 5,6-dichloronicotinic acid ethyl ester (2.91 g, 15.2 mmol) and diethyl-amine (11.1 g, 152 mmol) is stirred in a sealed vessel at 80° C. for 72 h. The mixture is cooled to rt and concentrated. The residue is dissolved in DCM (15 mL) and washed with 1 N aq. KHSO4 solution (2×50 mL). The washings are extracted back with DCM (50 mL). The combined org. extracts are dried over Na2SO4, filtered, concentrated and dried to give 5-chloro-6-diethylamino-nicotinic acid ethyl ester (3.36 g) as a yellow oil; LC-MS: tR=1.08 min, [M+1]+=257.12; 1H NMR (CDCl3): δ 1.26 (t, J=7.0 Hz, 6H), 1.39 (t, J=7.3 Hz, 3H), 3.62 (q, J=7.0 Hz, 4H), 4.36 (q, J=7.3 Hz, 2H), 8.07 (s, 1H), 8.70 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.3 %

Procedure:
To a solution of 3-hydroxypyridine(5 g) in DMF(50 ml) was added slowly sodium hydride(2.1 g) under ice cooling. After the addition was completed, the reaction mixture was warmed up to room temperature and stirred at the same temperature for 30 minutes. The mixture was cooled with ice and methyl bromoacetate (8.1 g) was added slowly. After the addition was completed, the reaction mixture was stirred at room temperature for 15 hours and poured into ice water. The product was extracted with ethyl acetate, washed with brine, dried(MgSO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel (chloroform: methanol=20:3) to obtain methyl 2-(3-pyridyloxy)acetate(1.7 g).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:35])=[C:15]([NH:18][C:19]([C:21]3[C@H:26]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH2:25][C:24](=[O:34])[NH:23][CH:22]=3)=[O:20])[CH:16]=2)[CH:11]=[N:10]1)(C)(C)C>C(O)(=O)C.O.C1COCC1>[OH:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:35])=[C:15]([NH:18][C:19]([C:21]3[C@H:26]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[CH2:25][C:24](=[O:34])[NH:23][CH:22]=3)=[O:20])[CH:16]=2)[CH:11]=[N:10]1
Reactant: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2cnn(CCO)c2cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-amide (46 mg, 0.09 mmol) was dissolved in 3 ml of a 3:1:1 mixture of acetic acid, water and THF. The mixture was allowed to stir overnight at room temperature. The solution was concentrated in vacuo, and the residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 24 mg (70.6%) of (S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [1-(2-hydroxy-ethyl)-5-methyl-1H-indazol-6-yl]-amide white crystalline solid; MS (ES+) m/z 409 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:31])[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:32]1([CH:30]([N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=3[CH3:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:28])=[O:29])[CH3:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(C2=NN(C(C)c3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(C(C)c3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(1-Phenyl-ethyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.11 (d, 1H), 7.91 (t, 1H), 7.81 (t, 1H), 7.36 (m, 8H), 6.91 (m, 1H), 5.72 (m, 1H), 4.52 (s, 2H), 2.07 (s, 3H), 1.85 (d, 3H) ppm. MS calculated for C26H22FN3O4S—H: 490, observed: 490.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][C@@H:25]([CH3:29])[NH:24]1>CN(C)C=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:26][C@H:25]([CH3:29])[NH:24][C@H:23]([CH3:22])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In the same manner as described in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-2,6-dimethylpiperazine, and dimethylformamide was stirred at room temperature for 24 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 258°-260° C.
Reaction SMILES: [I-:1].[K+].N([O-])=O.[Na+].N[C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].O>C(#N)C>[I:1][C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(C(F)(F)F)cc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Potassium iodide (5.6 g, 34 mmol) and sodium nitrite (2.4 g, 35 mmol) were added to a solution of 2-amino-4-trifluoromethyl-benzonitrile (2.58 g, 14 mmol) in acetonitrile (60 mL). The resultant mixture was cooled to 0° C. in an ice-water bath with magnetic stirring. Ice-cold concentrated HCl (14 mL) was added slowly drop-wise to the reaction mixture, causing the reaction mixture to become cloudy and deep red in color. The reaction mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature. Stirring at room temperature proceeded for 3 hours. The reaction mixture was poured into water, and the resulting suspension was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated to give a purple liquid. A solution of this crude product and dichloromethane (200 mL) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a silica gel column. Manual flash chromatography using 5% ethyl acetate in hexanes afforded 2-iodo-4-trifluoromethyl-benzonitrile as 3.58 g (87%) of a purple, crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[F:12].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:51]([C:53]([C:72]1[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]([C:86]([F:89])([F:88])[F:87])([OH:85])[C:81]([F:84])([F:83])[F:82])=[C:74]([CH3:90])[CH:73]=1)([C:56]1[CH:61]=[CH:60][C:59](B2OC(C)(C)C(C)(C)O2)=[C:58]([CH3:71])[CH:57]=1)[CH2:54][CH3:55])[CH3:52]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:59]2[CH:60]=[CH:61][C:56]([C:53]([CH2:54][CH3:55])([C:72]3[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]([OH:85])([C:86]([F:88])([F:89])[F:87])[C:81]([F:84])([F:83])[F:82])=[C:74]([CH3:90])[CH:73]=3)[CH2:51][CH3:52])=[CH:57][C:58]=2[CH3:71])=[CH:7][C:6]=1[F:12]
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
(4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 26.5 mg, 0.131 mmol), palladium acetate (2.0 mg, 0.009 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (7.2 mg, 0.018 mmol), potassium phosphate (56 mg, 0.263 mmol) and water (0.1 mL) were added to a solution of (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 50 mg, 0.088 mmol) in toluene (1 mL). After replacement with nitrogen, the mixture was stirred at 100° C. overnight. Then, the reaction mixture was filtered through amino silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (26.6 mg, 50%).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(Cc2ccccc2)c1C

Procedure:
Similar to Example 1, equimolar amounts of benzylhydrazine dihydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. The resulting oil was determined to be the named product by 1H-NMR (CDCl3, ppm): 1.35 t (3H); 2.44 s (3H); 2.45 s (3H); 4.38 a (2H); 5.25 s (2H); 7.08 d (2H); 7.29 m (3H).
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:42])[NH:11][CH:12]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:13]([OH:34])[CH2:14][N:15]([S:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH:29]=[C:28]([CH2:31][NH2:32])[C:27]=3[CH:33]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)CC)C>C1COCC1>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:42])[NH:11][CH:12]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:13]([OH:34])[CH2:14][N:15]([S:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH:29]=[C:28]([CH2:31][NH:32][C:43](=[O:50])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:27]=3[CH:33]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2occ(CN)c2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2occ(CNC(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
{3-[(3-Aminomethyl-benzofuran-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester from the previous step (20 mg, 33 umol) was dissolved in 0.5 mL THF. 5.8 uL (50 umol) benzoyl chloride and 7 uL (50 umol) triethylamine were added and the reaction was stirred at room temperature for 1 h. The reaction mixture was purified by prep TLC on the silica gel plate with ethyl acetate/hexanes=2/1 to afford 12 mg (17 umol, 52%) of product. MS 706 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].[CH2:20]([N:27]([CH3:31])[CH2:28][CH2:29]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([N:27]([CH3:31])[CH2:28][CH2:29][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Reactant: CN(CCCl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN1c2ccccc2N(C)C(=O)c2cccnc21)Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
18.1 gm (0.08 mol) of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one were dissolved in 180 ml of dimethylformamide at room temperature, 2.88 gm (0.096 mol) of 80% sodium hydride in mineral oil were added to the solution, and the mixture was stirred at 60° C. for 45 minutes. Then, 17.7 gm (0.096 mol) of 2-(N-benzyl-methylamino)-ethyl chloride were added dropwise, and the resulting mixture was stirred at 120° C. for 30 minutes. After evaporation in vacuo, the residue was dissolved in chloroform/dilute acetic acid, and the aqueous phase was separated and made alkaline with concentrated ammonia. The base, which precipitated as an oil, was taken up in chloroform, the solvent was distilled off in vacuo and the oily residue was distilled, yielding 22.4 gm (75% of theory) of 11-[2'-(N-benzyl-methylamino)-ethyl]-6,11-dihydro-6-methyl-5-H-pyrido [2,3-b][1,5]benzodiazepin-5-one, b.p. 212°-216° C. at 0.05 mm Hg.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[C:6]([O:41][CH2:42][CH3:43])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:44])=[O:2])=[CH:5][C:6]=4[O:41][CH2:42][CH3:43])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:30]2=[CH:29][CH:28]=1
Reactant: CCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-ethoxy-benzoic acid methyl ester (0.12 g, 0.19 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-ethoxy-benzoic acid as a off white powder (Yield, 0.1 g, 85%).
Reaction SMILES: CN.O=[C:4]1[C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1.[BH3-][C:21]#[N:22].[Na+]>>[CH3:21][NH:22][CH:4]1[C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CC(=O)C2(CCCC2)C1
Agent: CN
Agent: [Na+]
Product: CNC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of CH3NH2 (33% [w/w] in EtOH, 11.70 g, 124.3 mmol) was added tert-butyl 4-oxo-2-azaspiro[4.4]nonane-2-carboxylate (5.92 g, 24.7 mmol). After addition, the reaction mixture was stirred at rt overnight, and then NaBH3CN (4.69 g, 74.6 mmol) was added portionwise. The resulting mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc, 100%) to give the product as colorless oil (6.28 g, 100%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:11]2[N:12]=[C:13]([CH3:24])[CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[C:10]2=[N:9][C:8]=1[CH2:25][CH3:26])=[O:6]>C(O)C>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[C:15]1[C:10]2[N:11]([C:7]([C:5]([OH:6])=[O:4])=[C:8]([CH2:25][CH3:26])[N:9]=2)[N:12]=[C:13]([CH3:24])[CH:14]=1
Reactant: CCc1nc2c(-c3ccc(C)cc3C)cc(C)nn2c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2c(-c3ccc(C)cc3C)cc(C)nn2c1C(=O)O

Procedure:
A 5N aqueous sodium hydroxide solution (20 mL) was added to a solution of the resulting 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazin-3-carboxylic acid methyl ester in ethanol (100 mL), and the mixture was heated under reflux for 3 hours. The reaction mixture was evaporated as it was. Water was added thereto, which was extracted with ethyl acetate. 5N Hydrochloric acid (pH=1) was added to the aqueous layer, and the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated, to give 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid as a crude compound (2.8 g).