Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[CH3:56][N:57]1[CH2:64][C@@H:63]2[C@@H:59]([CH2:60][NH:61][CH2:62]2)[CH2:58]1.C(O)=O>CN(C=O)C.CS(C)=O>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:61]3[CH2:62][C@@H:63]4[C@@H:59]([CH2:58][N:57]([CH3:56])[CH2:64]4)[CH2:60]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: CN1C[C@H]2CNC[C@H]2C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3C[C@H]4CN(C)C[C@H]4C3)cn2)c1O
Reaction time: 17 h

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50 mg, 0.156 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (90 mg, 0.468 mmol) and HOBT (21.09 mg, 0.156 mmol) in DMF (0.8 mL) and added N-ethyl-N-isopropylpropan-2-amine (0.056 mL, 0.468 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (79 mg, 0.624 mmol). After 17 hours, the reaction mixture was diluted with DMSO (100 uL) and purified by preparative HPLC (ACN/water with formic acid) to give the title compound as a 0.63 formic acid salt (60 mg, 0.131 mmol, 84%) as a tan solid. MS: 429 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3H) 2.48 (s, 3H) 2.77 (br. s., 2H) 2.91 (br. s., 4H) 3.43 (br. s., 2H) 3.67 (dd, J=11.5, 6.4 Hz, 2H) 7.43-7.49 (m, 1H) 7.51 (s, 1H) 7.87 (s, 1H) 7.94 (dd, J=8.7, 2.4 Hz, 1H) 8.02 (d, J=8.1 Hz, 1H) 8.41 (d, J=8.6 Hz, 1H) 8.49 (d, J=1.8 Hz, 1H) 11.91 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[CH2:14][N:13]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][N:10]2[C:23]2[CH:28]=[CH:27][C:26]([C@:29]([OH:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH2:4][CH2:3]1.FC1(F)CCN(C[C@@H]2CN(S(C3SC=CC=3)(=O)=O)CCN2C2C=CC([C@@](O)(C)C(F)(F)F)=CC=2)CC1.FC1(F)CCN(C[C@H]2CN(S(C3SC=CC=3)(=O)=O)CCN2C2C=CC([C@@](O)(C)C(F)(F)F)=CC=2)CC1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:36][C:2]1([F:1])[CH2:3][CH2:4][N:5]([CH2:8][C@@H:9]2[CH2:14][N:13]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:17])[CH2:12][CH2:11][N:10]2[C:23]2[CH:28]=[CH:27][C:26]([C@:29]([OH:35])([CH3:34])[C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=2)[CH2:6][CH2:7]1
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCC(F)(F)CC2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCC(F)(F)CC2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CCC(F)(F)CC2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CCC(F)(F)CC2)cc1)C(F)(F)F

Procedure:
(2R)-2-(4-((2S)-2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-((4,4-difluoro-1-piperidinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.08-8.06 (dd, J=5.1, 1.1 Hz, 1H), 7.70-7.68 (dd, J=3.7, 1.1 Hz, 1H), 7.38-7.34 (d, J=9.2 Hz, 2H), 7.32-7.30 (m, 1H), 6.89-6.87 (d, J=9.2 Hz, 2H), 4.15-4.11 (m, 1H), 3.46-3.38 (m, 3H), 3.15-3.08 (m, 1H), 2.69-2.63 (m, 1H), 2.59-2.52 (m, 2H), 2.46-2.38 (m, 4H), 2.30-2.25 (m, 1H), 1.79-1.73 (m, 4H), 1.61 (s, 3H). m/z (ESI, +ve ion) 554.2 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=1.05 μM; GK-GKRP EC50 (LC MS/MS)=1.53 μM.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14](Cl)[C:13]=3[F:20])=[CH:6][CH:5]=1.[CH2:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[Li+].[OH-]>O1CCOCC1.[Pd].C(OCC)(=O)C>[CH2:22]([C:26]1[CH:31]=[CH:30][C:29]([C:14]2[C:13]([F:20])=[C:12]3[C:17]([CH:18]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:21])=[CH:5][CH:6]=4)[NH:11]3)=[CH:16][CH:15]=2)=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(-c2cc3ccc(Cl)c(F)c3[nH]2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCc1ccc(-c2ccc3cc(-c4ccc(C(=O)O)cc4)[nH]c3c2F)cc1
Temperature: 120 °C

Procedure:
Steps 2 and 3: To a mixture of 4-(6-chloro-7-fluoro-1H-indol-2-yl)-benzoic acid methyl ester (37 mg, 0.122 mmol) from the previous step, 4-n-butylphenyl-boronic acid (43 mg, 0.244 mmol), and cesium carbonate (159 mg, 0.487 mmol) in dioxane (4 mL), is added CombiPhos-Pd6 palladium catalyst (Combiphos Catalysts Inc., 3 mg). The mixture is purged with N2 for 5 minutes and heated at 120° C. for 7 hours in a sealed tube. After cooling to room temperature, the reaction is diluted with ethyl acetate and sequentially washed with 1 N HCl, H2O, and saturated aqueous NaCl. The organics are then dried over Na2SO4, filtered, and concentrated. The resulting residue is treated with ethanol/H2O (2 mL/1 mL) followed by LiOH (26 mg, 0.609 mmol). This mixture is heated at 50° C. for 1 hour. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous HCl. The organic layer is dried over Na2SO4 and filtered. After concentration, the crude product is purified by preparative RP LC-MS to give 4-[6-(4-Butyl-phenyl)-7-fluoro-1H-indol-2-yl]-benzoic acid as a white solid: 1H NMR (400 MHz, Acetone-d6) δ 11.13 (bs, 1H), 8.10-8.05 (m, 4H), 7.59 (d, 2H), 7.52 (d, 1H), 7.32 (d, 2H), 7.18-7.12 (m, 2H), 2.71 (t, 2H), 1.70-1.63 (m, 2H), 1.49-1.40 (m, 2H), 0.98 (t, 3H); ESMS m/z 388.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][CH3:78])([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[CH2:77]([C:74]1([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:26])[CH:68]=[CH:69][C:70]1=2)[CH3:78]
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5.0 mL) can be stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (113 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified on column chromatography and prep-HPLC to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1>>[CH:1]1([CH2:7][CH2:8][O:9][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCCC1CCCCC1
Product: CCOC(=O)c1ccc(OCCC2CCCCC2)cc1

Procedure:
2-Cyclohexylethanol 15-1 (3.2 g, 25 mmol) and ethyl 4-hydroxybenzoate 15-2 (4.15 g, 25 mmol) were reacted as in Example 14. The product 15-3 was obtained as a waxy solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[OH:16].[C:17]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])([CH3:20])([CH3:19])[CH3:18]>C(#N)C.O>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][C:23]([CH3:25])([CH3:24])[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:27])=[C:9]([O:8][CH3:7])[CH:14]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: COc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(F)ccc1OC(C)(C)C(=O)OC(C)(C)C

Procedure:
Potassium carbonate (0.97 g) was added to a solution of 2-methoxy-4-fluorophenol (1.0 g) and tert-butyl-2-bromoisobutyrate (1.31 ml) in acetonitrile (20 ml) and heated under reflux for 26 h. The mixture was diluted with water and extracted with ethyl acetate, the organics were dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with using isohexane:diethylether 3:1, yield 0.83 g.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11]>O=[Mn]=O>[CH2:3]([C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=[O:12])[CH:2]([CH3:13])[CH3:1]
Reactant: CC(C)CC(O)c1ccccc1F
Agent: O=[Mn]=O
Product: CC(C)CC(=O)c1ccccc1F
Reaction time: 20 h
Yield: 84.6 %

Procedure:
In a round bottom flask (100 ml) was placed 3-methyl-1-(2-fluoro phenyl)butylalcohol 12 (1.85 gm, 0.0103 mole) and dichloromethae (35 ml). MnO2 (12.52 gm) was added to it. The reaction mixture was stirred for 20 hrs. After the completion of reaction (monitored by TLC or GC), the reaction mire was filtered through cilite, the filtrate was concentrated under reduced pressure to yield 1.57 gm (86%) of isobutyl-(2-fluoro-phenyl)-ketone 13 (GC purity 95%). 1HNMR CDCl3: (spectrum 12) 0.96(d, 6H), 2.30(m, 1H), 2.85(m, 2H), 7.15(m, 2H), 7.45(m, 1H), 7.85(m, 1H).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13](OC)=[O:14])[CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2cnc(C(C)C)n2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ncc2ccc(CO)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To an ice-cold solution of methyl 3-isopropylimidazo[1,5-a]pyridine-6-carboxylate (Preparation 27, 234 mg, 1.07 mmol) in THF (4 mL) was added lithium aluminium hydride solution in THF (2 M, 61 mg, 804 μL, 1.61 mmol). The mixture was allowed to warm to room temperature. After 3 hours the reaction was cooled again in an ice bath and quenched with a saturated solution of sodium sulfate (1 mL). The mixture was stirred for 30 minutes and then filtered through Celite. The filtrate was evaporated to low volume and the aqueous residue extracted with DCM (3×5 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated. The resulting residue was purified by silica gel chromatography eluting with 10 to 100% EtOAc in pentane to yield the title compound as a yellow gum (120 mg, 59%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:28]([OH:30])=[O:29])[CH:24]=4)[N:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:33]([O-])([O-])=O.[K+].[K+].[OH-].[K+].COS(OC)(=O)=O>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[CH3:33][N:17]([C:15]([C:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=2)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]([OH:30])=[O:29])[CH:24]=2)[N:19]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1)c1ccc2cc(C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (F-1a2, 200 mg, 0.46 mM) in toluene (3.0 mL) was added Bu4NHSO4 (15.6 mg, 0.046 mM) and freshly powdered K2CO3 (127 mg, 0.92 mM), and KOH (128 mg, 2.28 mM). The resulting suspension was stirred at room temperature for 1 h. The mixture was heated to 70° C. and (CH3)2SO4 (95 uL, 1.01 mM) was added dropwise. The mixture was stirred at 70° C. for 2 h. LC/MS analysis revealed the residue to be a mixture of the acid F-1b2 and the corresponding methyl ester. After cooling to room temperature the mixture was concentrated and the residue was taken up in 5 mL of THF/methanol/H2O (3:1:1) and the resulting mixture was stirred until the methyl ester had been completely consumed (2 h). The mixture was diluted with H20 (5 mL) and the pH was adjusted to 2.0 with 1 N HCl. The mixture was extracted 3 times with EtOAc. The combined EtOAc fractions were dried (MgSO4), filtered and concentrated to provide F-1b2 (180 mg) as a colorless solid.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[CH3:6].[OH-].[Na+]>S(=O)(=O)(O)O>[OH:2][CH:3]1[C:13]2[C:8](=[C:9]([O:17][CH3:18])[C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[CH2:7][N:5]([CH3:6])[CH2:4]1
Reactant: COc1c(CN(C)CC(OC)OC)ccc2c1OCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1c2c(cc3c1OCO3)C(O)CN(C)C2
Temperature: 5 °C
Yield: 78.2 %

Procedure:
5.67 g (20 mmol) of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde dimethylacetal (5) was dissolved in 40 ml of 6N sulfuric acid and the solution was stirred under heating at 76°-77° C. for 1.5 hour. The solution was cooled and added with 25% aqueous solution of sodium hydroxide at a temperature below 30° C. to make the pH of the solution about 11. The solution was extracted with 35 ml and then with 10 ml of methylene chloride successively, and the extracts were joined, washed with 20 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was added with 12 ml of ethanol and dissolved by heating. Then, the solution was cooled to 5° C. to be crystallized. The crystals were filtered out, washed with 3 ml of cold ethanol and then dried under reduced pressure to obtain 3.71 g of 4-hydroxy-8-methoxy-2-methyl-6,7 -methylenedioxy-1,2,3,4-tetrahydroisoquinoline (6). Yield: 78%, melting point: 152°-153° C.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][C:4]([N:6]([C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16]1)C1C=CC=C(OC)C=1)=[O:5].[CH:26]1[C:31]([CH:32]=O)=[CH:30][C:29]2[O:34][CH2:35][O:36][C:28]=2[CH:27]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.ClCCCl>[O:36]1[C:28]2[CH:27]=[CH:26][C:31]([CH2:32][N:18]3[CH2:19][C@H:15]([N:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:25])[CH3:24])[CH2:32][C:31]4[CH:26]=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[CH2:16][C@H:17]3[C:20]([O:22][CH3:23])=[O:21])=[CH:30][C:29]=2[O:34][CH2:35]1
Reactant: COC(=O)[C@@H]1C[C@@H](N(C(=O)CC(C)(C)C)c2cccc(OC)c2)CN1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of the crude amine (9b) (140 mg) prepared above, piperonal (74 mg, 0.49 rmnol) and glacial acetic acid (2 drops) in 1,2-dichloroethane (0.5 mL) was stirred for 30 min at room temperature. 95% Sodium cyanoborohydride (32 mg, 0.48 mmol) was added in small portions and stirring was continued for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution (2 mL), extracted with dichloromethane, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane-ethyl acetate (90:10-75:25) to give the title pyrrole (10) (115 mg, 71.4%) as a pale yellow oil:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.Cl.[CH3:38][NH:39][CH3:40].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:38][N:39]([CH3:40])[CH2:30][CH2:29][CH2:28][NH:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:36])=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 50 °C
Reaction time: 39 h
Yield: 69.2 %

Procedure:
709 mg (1.35mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.10 g (13.5 mmol) of dimethylamine hydrochloride and 1.86 g (13.5 mmol) of potassium carbonate were added and the mixture was stirred at 50° C. for 39 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 444 mg of 5-(3-dimethylaminopropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 69%).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C1[CH:18]2[CH:13]([CH2:14]CCC2)[CH2:12]CC1.C(Cl)C(=C)C.C(=O)([O-])[O-].[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[CH2:14]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[C:13](=[CH2:12])[CH3:18]
Reactant: Oc1ccccc1O
Reactant: C1CCC2CCCCC2C1
Agent: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: CCO
Product: C=C(C)COc1ccccc1O
Reaction time: 3 h

Procedure:
A further 72.8 g of pyrocatechol, 616 ml of decalin, 264 ml of ethyl alcohol, 135.8 g of methallyl chloride, 116.6 g of sodium carbonate and 1.8 g of sodium hydrosulphite are added to the previously separated lower phase (140 g) which is constituted essentially by 48.2 g of pyrocatechol and the quaternary ammonium salt. The mixture is heated to 80° under stirring in a nitrogen atmosphere for 3 hours, to obtain practically the same results in o.methallyloxyphenol as obtained in the first cycle.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=C(OC)C=2)=CC=1)[C:29](OC)=[O:30]>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:30][CH3:29])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CSc2cccc(OC)c2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(OC)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 68, starting from methyl 3-bromo-2-methoxy-6-(3-methoxyphenylthiomethyl)benzoate (Intermediate 105).
Reaction SMILES: C([Li])CCC.CC1CCCN(C)C1(C)C.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[N:19][C:18]=1[O:25][CH3:26].[CH:27](OCC)=[O:28].[NH4+].[Cl-]>C1COCC1>[Cl:16][C:17]1[C:22]([CH:27]=[O:28])=[C:21]([O:23][CH3:24])[N:20]=[N:19][C:18]=1[O:25][CH3:26]
Reactant: COc1cc(Cl)c(OC)nn1
Reactant: CCOC=O
Agent: CC1CCCN(C)C1(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nnc(OC)c(C=O)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium (1.6 M in hexanes, 0.39 mL, 0.63 mmol) was added to a cold solution of THF (10 mL) at −78° C. Tetramethylpiperidine (0.11 L, 0.63 mmol) was introduced and the solution was warmed to 0° C. and kept at this temperature for 20 min; it is then cooled to −78° C. A solution of 4-chloro-3,6-dimethoxy-pyridazine (100 mg, 0.57 mmol) in 20 THF (5 mL) was added slowly and the mixture was stirred at −78° C. After stirring for 45 min at −78° C., ethyl formate (0.07 mL, 0.86 mmol) was added and stirring was continued at −78° C. for 15 min. Saturated aqueous NH4Cl was added and the mixture was warmed to room temperature. The mixture was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo to give the crude product, which was purified by flash chromatography, eluting with 20-30% EtOAc in hexanes to afford, after evaporation, the title compound as a light yellow solid (51 mg, 44%): IR (KBr, cm−1) 1702, 1474, 1388, 1022; 1H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 4.17 (s, 3H), 4.16 (s, 3H); LCMS (+ESI, M+H+) m/z 203.
Reaction SMILES: COC1C=CC(CO)=CC=1.CC1(C)C2(C)C(O)CC1CC2.[Cl:22][C:23]([Cl:27])([Cl:26])[CH2:24][OH:25].COC1C=CC(C[O:35][C:36]([NH:38][CH:39]2[C:42](=[O:43])[N:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH3:54])[CH:40]2[C:55]([O:57][CH3:58])=[O:56])=O)=CC=1.C(OC(NC1C(=O)N(CC2C=CC(OC)=CC=2OC)C1C(OC)=O)=O)C1C=CC=CC=1>C(O)(C)(C)C>[Cl:22][C:23]([Cl:27])([Cl:26])[CH2:24][O:25][C:36]([NH:38][CH:39]1[C:42](=[O:43])[N:41]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[CH:40]1[C:55]([O:57][CH3:58])=[O:56])=[O:35]
Reactant: COC(=O)C1C(NC(=O)OCc2ccc(OC)cc2)C(=O)N1Cc1ccc(OC)cc1OC
Reactant: OCC(Cl)(Cl)Cl
Agent: CC1(C)C2CCC1(C)C(O)C2
Agent: COC(=O)C1C(NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: COc1ccc(CO)cc1
Solvent: CC(C)(C)O
Product: COC(=O)C1C(NC(=O)OCC(Cl)(Cl)Cl)C(=O)N1Cc1ccc(OC)cc1OC

Procedure:
When p-methoxybenzyl alcohol, isoborneol, benzy, alcohol, or 2,2,2-trichloroethanol is substituted for t-butanol in Example 3, methyl 3-(p-methoxybenzyloxy-carbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, methyl 3-(isobornyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, methyl 3-(benzyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate., or methyl 3-(2,2,2-trichloroethoxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate is obtained