Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B-](F)(F)(F)[F:30].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N.[Cl-].[Na+].O>[F:30][C:10]1[CH:9]=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=2)[N:13]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c(F)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 22.8 %

Procedure:
A mixture of 3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (49.0 mg, 0.128 mmol) and selectfluor (45.4 mg, 0.128 mmol) in MeCN (1 mL) was stirred at room temperature for 6 days. To the mixture was added selectfluor (45.4 mg, 0.128 mmol) at room temperature. The mixture was stirred at room temperature for 1 day. To the mixture was added selectfluor (45.4 mg, 0.128 mmol) at room temperature. The mixture was stirred at room temperature for 1 day. To the mixture was added selectfluor (45.4 mg, 0.128 mmol) at room temperature. The mixture was stirred at room temperature for 1 day. To the mixture was added selectfluor (272 mg, 0.768 mmol) at room temperature. The mixture was stirred at room temperature for 3 days. The mixture was diluted with brine, extracted with AcOEt, dried over MgSO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=50/50 to 0/100) and crystallized with AcOEt/hexane to yield the title compound (11.7 mg, 23% yield) as a pale yellow solid: mp 156-158° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.67 (1H, d, J=8.2 Hz), 7.33-7.50 (5H, m), 7.63-7.83 (4H, m), 7.97 (1H, d, J=4.1 Hz), 8.96 (1H, d, J=8.0 Hz).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:13]=[N:12][C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21](=[O:32])[NH:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][C:4]2[CH:13]=[N:12][C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:27][CH2:28]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: COc1cccc2ncc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
Sodium hydride (98% purity, 148 mg, 6.10 mmol, 1.5 eq) is added at room temperature to a stirred solution of 2-chloro-8-methoxy-quinoxaline (800 mg, 4.07 mmol, 1.0 eq) in N,N-dimethylformamide (80 mL), followed by [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (1.17 g, 4.07 mmol, 1.0 eq). After 15 hours stirring at room temperature and 4 hours at 80° C., solvent is evaporated, and the residue is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:9:1, v/v/v) to afford {1-[2-(8-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as an orange solid (825 mg, 48% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH:19]([CH3:21])[CH3:20])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][C:6]([OH:22])=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32].C(Cl)(Cl)Cl>CN(C=O)C.C(Cl)Cl>[CH:19]([C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][C:6]([O:22][CH2:30][C:31]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:32])=[CH:7][CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1)([CH3:20])[CH3:21]
Reactant: CC(C)[C@H]1COCc2nc3c(N)nc4cc(O)ccc4c3n21
Reactant: O=C(CBr)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H]1COCc2nc3c(N)nc4cc(OCC(=O)N5CCOCC5)ccc4c3n21
Temperature: 65 °C
Reaction time: 18 h
Yield: 42.3 %

Procedure:
A solution of (11S)-6-amino-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (0.30 g, 1.0 mmol) dissolved in 5 mL of DMF was treated with cesium carbonate (1.0 g, 3.0 mmol) and 4-(bromoacetyl)morpholine (0.23 g, 1.1 mmol). After stirring for 18 hours at 65° C., the reaction mixture was concentrated under reduced pressure to give a solid. The solid was dissolved in CH2Cl2 (100 mL) and washed with H2O (100 mL). The organic layer was concentrated under reduced pressure to give a solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid which was crystallized from acetonitrile to give 0.18 g of the title compound as white crystals, mp 137-139° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:44].[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([NH:53][C:54]([C:56]1[S:57][C:58]3[C:64](Br)=[CH:63][CH:62]=[CH:61][C:59]=3[CH:60]=1)=[O:55])[CH2:46]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:44].[ClH:44].[N:45]12[CH2:50][CH2:49][CH:48]([CH2:51][CH2:52]1)[C@@H:47]([NH:53][C:54]([C:56]1[S:57][C:58]3[C:64]([C:2]4[CH:3]=[CH:4][C:5]([N:8]5[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]5)=[CH:6][CH:7]=4)=[CH:63][CH:62]=[CH:61][C:59]=3[CH:60]=1)=[O:55])[CH2:46]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(N4CCNCC4)cc3)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
165.6 mg (0.49 mmol) of tert-butyl 4-(4-bromophenyl)-1-piperazinecarboxylate, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 ml of DMF are reacted by general method D. The compound purified by preparative HPLC is dissolved in 3 ml of methanol and, after addition of 3 ml of 4 M hydrogen chloride in dioxane, stirred at room temperature for 30 min. The contents of the flask are concentrated in vacuo, and the residue is azeotropically distilled with toluene twice. Drying under high vacuum results in 54 mg (28% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(Cl)(C)=O.[NH3:23]>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=[NH:23])[NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: N#CCCc1ccc(Oc2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Solvent: CO
Product: N=C(N)CCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 3-(4-(4-fluorophenoxy)phenyl)propanenitrile (4.4 g, 18.24 mmol) in toluene (25 mL) and methanol (5.94 mL) was added dropwise AcCl (6.48 mL, 91 mmol) at 0° C. in 5 min. The mixture was stirred at room temperature for 2 h. The mixture was cooled to 0° C. in an ice bath, and ammonia (26.1 mL, 182 mmol) in methanol was added dropwise in 5 min. The mixture was stirred at room temperature overnight. The mixture was filtered to remove the solid, and the solid was washed with toluene (40 mL) and methanol (40 mL). The combined filtrate was concentrated in vacuo, the residue was triturated with diethyl ether, the resulting white solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound (5.4 g, 16.12 mmol, 88% yield) as white solid. LCMS: rt=1.03 min, [M+H+]=259
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([OH:17])=[O:16].[N:18]12CCCN=C1C[CH2:22][CH2:21][CH2:20][CH2:19]2.BrCCCC#N.CN(C)C=O>O>[C:19]([CH2:20][CH2:21][CH2:22][O:16][C:15]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[OH:1])=[O:17])#[N:18]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)ccc1O
Agent: N#CCCCBr
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCOC(=O)c1cc(-c2ccc(O)cc2)ccc1O
Temperature: 75 °C
Yield: 70.6 %

Procedure:
A mixture of 4,4′-dihydroxy-3-biphenylcarboxylic acid (2.3 g; 10 mmol), 1,8-diaza-bicyclo[5.4.0]undec-7-ene (1.7 g; 11.2 mmol), 4-bromobutyronitrile (1.7 g; 11.2 mmol) and N,N-dimethylformamide (40 ml) was heated at 75° C. for 4 h. The reaction mixture was cooled, poured into water (300 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and with water (2×100 ml), dried over magnesium sulphate and filtered. The organic solvent was removed in vacuo. The residue (3.0 g) was purified by flash chromatography using a silica gel column and toluene/ethyl acetate (97:3) as eluent to give 2.1 g (70%) of 3-cyanopropyl-4,4′-dihydroxy-3-biphenylcarboxylate.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[O:14][C:13]=2[CH:23](O)[CH3:24])[CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Br:2][CH:23]([C:13]1[O:14][C:15](=[O:22])[C:16]2[C:21]([C:12]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[CH:7]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:24]
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 M PBr3 in DCM (2.3 ml, 2.332 mmol) was added to a solution of 4-(3-fluorophenyl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate B7, 390 mg, 1.372 mmol) in DCM (7.8 ml) and the mixture stirred at RT for 2 hrs. The reaction mixture was then evaporated under reduced pressure and purified on a silica Biotage SNAP 100 g, eluting with a gradient of hexane and EtOAc to give the title (227 mg, 47.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[BH4-].[Na+].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:13]
Reactant: O=C1CCc2c(Cl)cc(Cl)c(I)c21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC1CCc2c(Cl)cc(Cl)c(I)c21
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 95.1 %

Procedure:
4,6-Dichloro-7-iodoindan-1-one (14.71 g., 45 mmoles) was suspended and partially dissolved in ethanol (140 ml). Sodium borohydride (1.70 g., 45 mmoles) was added and the mixture was stirred for 50 minutes. Aqueous sodium hydroxide 20% (w/v) (40 ml) was added and stirred for 10 minutes. The reaction mixture was poured into 700 mL of ice-water with vigorous stirring. The crystals were collected, washed with water, sucked dry and dried in a vacuum oven at 50° C. overnight to give 14.08 g of the title compound, mp 95°-100° C. Recrystallization from acetonitrile gave material with mp 99°-102° C.
Reaction SMILES: C[O:2][C:3]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[C:18]([O:25]C)=[C:17]([CH3:27])[C:4]=1[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>C(#N)C.O>[CH3:24][O:23][C:19]1[C:18](=[O:25])[C:17]([CH3:27])=[C:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)[C:3](=[O:2])[C:20]=1[O:21][CH3:22]
Reactant: COc1c(C)c(Cc2ccc(CCC(=O)O)cc2)c(OC)c(OC)c1OC
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
The compound (1.00 g, 2.67 mmol) obtained in Step 6 was dissolved in a mixture of acetonitrile (30 ml) and water (10 ml), to which was added CAN (ceric ammonium nitrate) (2.34 g, 4.27 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ether. After the extract was washed with water and dried, the solvent was distilled off. The residue was purified by a silica gel column chromatography (5% methanol-methylene chloride) and then was crystallized in ethanol/hexane to yield the title compound (662 mg, 1.92 mmol, yield 72%).
Reaction SMILES: [CH:1]([C:3]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH3:18])([CH3:7])[CH:4]([CH3:6])[CH3:5])=[O:2].[CH3:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[OH:2][CH:1]([C:25]1[CH:26]=[C:21]([CH3:20])[CH:22]=[CH:23][CH:24]=1)[C:3]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH3:18])([CH3:7])[CH:4]([CH3:5])[CH3:6]
Reactant: Cc1cccc([Mg]Br)c1
Reactant: COc1cccc(C(=O)NC(C)(C=O)C(C)C)c1C
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NC(C)(C(C)C)C(O)c2cccc(C)c2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
An oven-dried vial equipped with a stir bar was flushed with N2, charged with N-(1-formyl-1,2-dimethyl-propyl)-3-methoxy-2-methyl-benzamide (IX, R1=2-Me-3-MeO-Ph, R2=i-Pr, R3=Me, 131 mg, 0.5 mmol) in dry THF (1 mL) and cooled in dry ice acetone. 3-methylphenyl-magnesium bromide (1.0 M, 2 mL, 2.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous NaHCO3 (5 mL) and poured onto a 10 mL Chem Elut cartridge. After 5 min the cartridge was eluted with CH2Cl2 (25 mL). The eluate was evaporated to leave a secondary alcohol, N-[1-(hydroxy-m-tolyl-methyl)-1,2-dimethyl-propyl]-3-methoxy-2-methyl-benzamide (VIII, R1=2-Me-3-MeO-Ph, R2=i-Pr, R3=Me, R4=3-Me-Ph, 180 mg). 1H and 13C NMR showed complete consumption of aldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:15][CH2:14][O:13][C:5]=2[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[Br:16]Br>C(O)(=O)C>[Br:16][C:6]1[C:5]2[O:13][CH2:14][O:15][C:4]=2[C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: BrBr
Reactant: COC(=O)c1cc(OC)c2c(c1)OCO2
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c2c(c1Br)OCO2
Temperature: 25 °C
Reaction time: 10 h
Yield: 51 %

Procedure:
In 35 ml of acetic acid was dissolved 10.5 g of methyl 5-methoxy-3,4-methylenedioxybenzoate, and a solution of bromine (formed by diluting 8 g of bromine with 25 ml of acetic acid) was dropped into the solution over a period of 1 hour. The mixture was stirred at room temperature for 10 hours and the reaction liquid was poured into ice water, and the formed precipitate was recovered by filtration and recrystallized from ethanol to obtain methyl 2-bromo-5-methoxy-3,4-methylenedioxybenzoate (the yield was 51%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][N:24]=[C:25]=[O:26].[CH:27]([NH2:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][NH:24][C:25]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:26]
Reactant: CC(C)N
Reactant: CC1=C(CN=C=O)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC1=C(CNC(=O)NC(C)C)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 750 %

Procedure:
To a solution of the isocyanate from Step 1 in toluene was added 1.2 equivalent of isopropylamine. The reaction mixture was kept under reflux for 1 h. After having been cooled to room temperature, the mixture was diluted with n-hexane to form a yellow precipitate, which was filtered off, and was recrystallized from CH2Cl2, to give the title compound as a yellow solid (750%), mp: 217° C.
Reaction SMILES: CO.[CH2:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:4].[S:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([OH:13])(=[O:12])=[O:11].C([O:24][C:25](=O)[CH:26]=[C:27]([NH:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)OCC)C>C(O)(=O)C>[CH2:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:4].[C:32]([NH:31][C:27]1[NH:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([S:10]([OH:13])(=[O:11])=[O:12])=[CH:19][CH:18]=2)[C:25](=[O:24])[CH:26]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)C=C(NC(=O)c1ccccc1)OCC
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1cc(=O)n(-c2ccc(S(=O)(=O)O)cc2)[nH]1)c1ccccc1

Procedure:
Into a mixed solution of 50 ml of methanol, 50 ml of triethylamine and 50 ml of glacial acetic acid there was dissolved 18.8 g of p-sulfophenyl hydrazine, to which 26.3 g of ethylβ-benzoylamino-β-ethoxyacrylate was then added. The resulting solution was allowed to stand at room temperature for one week. The crystals which precipitated were collected and recrystallized from methanol; thus, 32 g of pale yellow crystals of the objective compound of a melting point of 275° to 278° C. was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][N:6]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:10]([C:11]#[N:12])=[C:5]2[NH:4][CH2:3]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:30]>>[NH2:1][CH:2]1[CH2:7][N:6]2[N:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][CH:18]=3)[C:10]([C:11]([NH2:12])=[O:30])=[C:5]2[NH:4][CH2:3]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(N)C2
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(N)C2

Procedure:
The desired product was prepared from 6-amino-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) 7.53-7.48 (m, 2H), 7.46-7.40 (m, 2H), 7.22-7.16 (m, 1H), 7.11-7.03 (m, 4H), 6.58 (br s, 1H), 4.15-4.08 (m, 1H), 3.72-3.67 (m, 1H), 3.40-3.30 (m, 2H) and 3.06-2.98 (m, 1H). MS (ESI) m/e [M+1]+ 350.2.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]([C:19]2[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[N:9]=1)=[O:7].Cl.O>CO>[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]([C:19]2[N:20]=[N:21][C:22]([O:2][CH3:1])=[CH:23][CH:24]=2)[N:9]=1)=[O:7]
Reactant: COC(=O)c1cc(-c2ccccn2)n(-c2ccc(Cl)nn2)n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(-c2ccccn2)n(-c2ccc(OC)nn2)n1
Reaction time: 19 h

Procedure:
Sodium methoxide (1.530 g) was added to the above-obtained 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid methyl ester (2.981 g) in methanol (190 mL) at room temperature, followed by stirring for 19 hours. Aqueous 1N hydrochloric acid (19 mL) was added to the reaction mixture. Water was added to the residue obtained by evaporation of methanol under reduced pressure. The insoluble product was recovered by filtration, and dried, to thereby give 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid methyl ester as a solid (2.571 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@H:4]([O:12][C:13]1[C:18]([Br:19])=[CH:17][C:16]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([OH:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:15][C:14]=1[Br:38])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[CH3:44][O:45][C:46](=[O:49])[CH2:47]Br.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:39])[CH:4]([O:12][C:13]1[C:18]([Br:19])=[CH:17][C:16]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([O:37][CH2:47][C:46]([O:45][CH3:44])=[O:49])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:15][C:14]=1[Br:38])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(O)c3sc4ccccc4c23)cc1Br
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c2ccccc2c(-c2cc(Br)c(OC(Cc3ccccc3)C(=O)OC)c(Br)c2)c2c1sc1ccccc12
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of (R)-2-[2,6-dibromo-4-(6-hydroxy-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-phenoxy]-3-phenyl-propionic acid methyl ester (0.60 g, 0.906 mmol) in anhydrous N,N-dimethylformamide was added potassuim carbonate (0.376 g, 2.72 mmol, 3 eq) and methylbromoacetate (0.26 mL, 2.72 mmol, 3 eq) at room temperature under a dry nitrogen atmosphere. After stirring for 24 hours the reaction mixture was combined with water (60 mL) the organics were extracted with diethyl ether (2×100 mL). The extracts were combined and washed with water (2×100 mL) and brine (100 mL). Silica gel was added and the solvents removed. The adsorbate was twice flash chromatographed (eluent 88/12 petroleum ether/ethyl acetate and 85/15 ethyl ether/ethyl acetate) to provide the title compound as a white solid (0.493 g, 73%): NMR (CDCl3); δ8.38 (d, J=8 Hz, 1 H), 7.81 (d, J =Hz, 1 H), 7.64-7.59 (m, 3 H), 7.55 (d, J=8 Hz, 1 H), 7.48 (ddd, J=8, 7, 1 Hz, 1 H), 7.43-7.26 (m, 6 H), 7.16 (ddd, J=8,7,1 Hz, 1 H), 6.79 (d, J=8 Hz, 1 H), 5.25 (dd, J=8, 6 Hz, 1 H), 4.94 (s, 2 H), 3.92 (s, 3 H), 3.76 (s, 3 H), 3.57 (septet, J=7 Hz, 2 H); MS (EI): [M+], 2 bromine isotope pattern, 732 (1.8%), 734 (4%), 736 (0.8%); Anal. Calc. for C35H26Br2O6S:, 57.24, H, 3.57, N, 0.00. Found: C, 57.01, H, 3.42, N, -0.07.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=O)#[N:2].[H-].[Na+].BrC1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-])=O.[Cl-].[NH4+]>CS(C)=O>[NH2:19][C:13]1[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: CCOC(=O)CC#N
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: N#CCc1ccc(Br)cc1N
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl cyanoacetate (3.2 mL) in dimethyl sulfoxide (20 mL) was added sodium hydride (1.22 g) at room temperature, and then 1,4-dibromo-2-nitrobenzene (4.21 g) was added, and the reaction mixture was stirred at 90° C. for 3 hours. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended in an aqueous solution of 1M-sodium hydrogen carbonate (60 mL), and the reaction mixture was stirred at 80° C. for 24 hours. To the reaction mixture was added 2N-hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (20 mL), ethanol (40 mL) and water (20 mL). To the solution were added ammonium chloride (4.03 g) and iron powder (4.22 g), and the reaction mixture was stirred at 100° C. for 5 hours. The reaction mixture was filtered through a cotton plug, and then the filtrate was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (3.03 g) as a yellow solid.