Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ncc(Br)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (15.0 mmol), benzenesulfonyl chloride (11.9 g, 8.61 mL, 67.5 mmol) and triethylamine (9.61 g, 13.2 mmol) in dry THF (100 mL) was heated under reflux for 19 h. The resultant suspension was allowed to cool to ambient temperature and diluted with saturated aqueous sodium carbonate solution (50 mL) and extracted with DCM (2×50 mL) and THF (1×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 50 g cartridge, Si-SPE, 0-100% DCM in pentane). The relevant fractions were concentrated in vacuo and the residue was triturated with pentane (10 mL) to afford the title compound as a white solid (5.25 g, 88%). LCMS (Method B): RT=4.11 min, M+H+=395/397.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:3]=1[CH3:19].[NH2:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>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].COCCOC>[NH2:20][C:21]([C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:3]=2[CH3:19])[CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)ccc1Br
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cc(OCCNC(=O)OC(C)(C)C)ccc1-c1cccc(C(N)=O)c1
Temperature: 80 °C
Reaction time: 5.5 h

Procedure:
A mixture of 1,1-dimethylethyl {2-[(4-bromo-3-methylphenyl)oxy]ethyl}carbamate (0.102 g, 0.31 mmol; Example V-15), 3-(aminocarbonyl)phenylboronic acid (0.056 g; 0.34 mmol), PdCl2(dppf).CH2Cl2 (0.0075 g; 0.01 mmol), DME (2 mL) and 2M Na2CO3 (2 mL) was degassed by sparging with N2, (5-10 min) then stirred at 80° C. for 5.5 h. Upon cooling, the mixture was diluted with EtOAc washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless foam. LC/MS (method A) 2.59 min, m/z 371 (M+1, 2%), 392 (M+Na, 53%), 271 ([M−Boc]+H, 100%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[C:10]([C:18]([F:21])([F:20])[F:19])=[N:11][NH:12][C:13]=2[NH:14]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[OH-].[Na+]>[C:1]1([C:7]#[C:8][C:9]2[C:10]([C:18]([F:20])([F:21])[F:19])=[N:11][NH:12][C:13]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1[nH]nc(C(F)(F)F)c1C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1[nH]nc(C(F)(F)F)c1C#Cc1ccccc1
Yield: 84.5 %

Procedure:
A solution of N-[4-(2-phenylethynyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]acetamide (900 mg, 3.07 mmol) in ethanol (12 mL) and 25% NaOH (9 mL) was heated to 70° C. for 1.5 h. The organic layer was separated and the aqueous extracted with EtOAc (×2). The combined organics were washed with water and the wash extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated, yielding the title compound as a red oil (652 mg) which was used in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Br:19]N1C(=O)CCC1=O>C(OCCCC)(=O)C>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: Cc1ccc(NC(=O)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCOC(C)=O
Product: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of 60.9 g (224.6 mmol) of N-(4-methyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide in 830 ml n-butyl acetate under a nitrogen atmosphere, 44 g (247 mmol) N-bromosuccinimide and 830 mg (5 mmol) azo-iso-butyronitrile are added. The suspension is heated up to 60° C. and then illuminated for 30 min by a Phillips low-voltage lamp (500 W; 10500 lm), whereby the temperature rises to 70-75° C. and a clear brown solution is formed. There is still remaining educt detectable, therefore another 22 g N-bromosuccinimide are added in 3 portions. After totally 6 h illumination, the resulting solid is filtered off and discarded and the filtrate concentrated. The residue is distributed between 2 l CH2Cl2 and 1 l H2O and the aqueous layer extracted with 1 l CH2Cl2. The organic phases are washed 4 times with 1 l H2O, 0.5 l brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/CH2Cl2 2:1→1:1) and crystallization from CH2Cl2/hexane yields the title compound: m.p.: 119-120° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C(C)C)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (76 mg, 86%), MS (ISP) m/z=353.5 [(M+H)+], mp 194.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-isopropyl-phenylboronic acid (53.3 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8]O)[CH2:2][CH3:3].P(Br)(Br)[Br:16]>C(OCC)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][Br:16])[CH2:2][CH3:3]
Reactant: CCCOc1cc(CO)ccc1OC
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCCOc1cc(CBr)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 193.9 %

Procedure:
To a solution of 3-(propyloxy)-4-methoxybenzyl alcohol (2.28 g, 11.62 mmol) in anhydrous diethyl ether (30 mL) was slowly added PBr3 (0.55 mL, 5.81 mmol) via syringe, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with diethyl ether (150 mL) and washed with saturated aqueous NaHCO3 (2×75 mL) and brine (2×75 mL). The organic layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford 3-(propyloxy)-4-methoxybenzyl bromide (2.92 g, 97%) as a white solid.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1
Reactant: ClCc1ccccn1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.9 %

Procedure:
To an N,N-dimethylformamide (250 mL) solution of 4-hydroxybenzaldehyde (20 g, 164 mmol) and 2-picolyl chloride (27 g, 165 mmol) was added potassium carbonate (68 g, 492 mmol), which was stirred for 3 days at room temperature. This mixture was partitoned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (29 g, 83%). The title compound was not purified but used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+].[Br:20]Br>CO>[Br:20][C:4]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: BrBr
Reactant: Nc1cc(-c2ccccc2)c(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1nnc(Cl)c(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a suspension of 6-chloro-5-phenylpyridazin-3-amine (1.01 g, 4.9 mmol) from 1a in methanol (25 mL) under nitrogen was added NaHCO3 (1.09 g, 13.0 mmol). At 0° C., bromine (0.55 M in methanol, 10 mL, 5.5 mmol) was added over 5 min. After 1 h, the cold bath was removed, and the reaction mixture was stirred at room temperature for 6 h. After concentrating in vacuo, the residue was taken up in CH2Cl2 and saturated aqueous Na2S2O5, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude 4-bromo-6-chloro-5-phenylpyridazin-3-amine (1.28 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)=[O:16].[OH-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][CH3:13])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS)cc1
Reactant: CCC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(SCc2ccc(OC)cc2)cc1
Reaction time: 0.17 h

Procedure:
To (4-methoxyphenyl)methane thiol (20 g) in N,N-dimethylformamide (200 ml) solution, sodium hydride (60% mineral oil dispersion) was added under ice cooling and the mixture was stirred for 10 minutes. 4-fluoropropiophenone was added to the reaction solution and the mixture was stirred at room temperature for 3 hours. 1N sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over with anhydrous sodium sulfate, then concentrated. Methanol was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (37.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4](OC(=O)C)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CN(C=O)C.[CH2:23](Br)[CH:24]=[CH2:25]>Cl.CCCCCC.CCOC(C)=O.[Zn]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([CH2:25][CH:24]=[CH2:23])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: C=CCBr
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCN(CC(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of acetyloxy[[(1,1-dimethylethoxy)carbonyl]amino]acetic acid methyl ester (Ref. Tetrahedron Lett. 1994, 35 3669, 21.1 g, 85.7 mmol), zinc (11.2 g, 171.42 mmol) and DMF (100 mL) at 0° C. is added allylbromide (14.8 mL, 171.4 mmol) dropwise. The reaction is warmed to room temperature and stirred overnight. The mixture is diluted with 0.1N HCl and hexane/EtOAc (2:1), filtered, the reaction mixture is then extracted three times with hexane/EtOAc (2:1). The combined EtOAc layer is washed twice with 0.1 N HCl, brine/H2O, brine, dried over MgSO4, and concentrated under reduced pressure to give an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH2:10].[O-]CC.[Na+].Cl[C:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: NCCSCc1nccs1
Reactant: O=C(O)c1cccnc1Cl
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccnc1NCCSCc1nccs1

Procedure:
An intimate mixture of 2-(2-thiazolylmethylthio)ethylamine [prepared from 6.73 g; 0.020 moles of the dihydrobromide salt and sodium ethoxide (from 0.92 g; 0.040 g. atom of sodium in ethanol)] and 2-chloropyridine 3-carboxylic acid (3.15 g; 0.020 moles) was heated to 150° for 3 hours. The resulting brown residue was cooled, dissolved in a little water, and basified to pH5 by dropwise addition of 2 N sodium hydroxide solution, to precipitate an oil. The latter was separated and dried, and chromatographed on a column of silica-gel using chloroform/ethyl acetate, (1:1). The crude product was then recrystallised from isopropanol to give 2-[2-(2-thiazolylmethylthio)ethyl]amino pyridine 3-carboxylic acid as a cream-coloured solid (0.36 g, m.p. 133°-4° (softening above 123°).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-])[CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:18]>ClCCCl>[Cl:18][C:8]1[C:9]2[C:4](=[C:3]([N+:13]([O-:15])=[O:14])[C:2]([CH3:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c[n+]([O-])ccc2c1[N+](=O)[O-]
Solvent: ClCCCl
Product: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 55.2 %

Procedure:
6-Methyl-5-nitroquinoline (46.5 g, 0.228 mol) obtained in Step (3) was dissolved in 1,2-dichloroethane (1.8 L), added with POCl3 (107 mL, 1.14 mol) at room temperature, and refluxed for 7 hours or more. The reaction solution was cooled to room temperature and concentrated by distilling the solvent under reduced pressure. The concentrated solid was dissolved in dichloromethane, added with an ice water, and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated solid was added with a mixed solution of ethyl acetate/hexane=1/1 (v/v), and stirred for 2 hours or more at room temperature. The solid thus obtained was filtered under reduced pressure, and washed with a mixed solution of ethyl acetate/hexane=1/1 (v/v). The filtered solid was dried with warm wind in an oven (40° C.) for over 3 hours or more to obtain the title compound (28 g, 55%).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1>>[N:29]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33][CH:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Reactant: C1CC(C2CCNCC2)CCN1
Product: c1cncc(-c2cc3c(-c4cccc(N5CCC(C6CCNCC6)CC5)n4)n[nH]c3cn2)c1

Procedure:
Following the procedures of Example 143, and starting with 3-(6-Fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 4,4′-bipiperidine, 273 was obtained and purified via reverse phase HPLC using a gradient of MeCN in water with 0.1% HCOOH to afford 25 mg (20%) over two steps. ESI MS m/z 440.2 (M+1). 1H NMR (400 MHz, DMSO): 9.23 (s, 1H), 8.97 (s, 1H), 8.61 (s, 1H), 8.39 (s, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J=7.3 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 4.54 (d, J=11.1 Hz, 2H), 2.97 (s, 2H), 2.66 (s, 2H), 1.88-1.71 (m, 4H), 1.46 (s, 1H), 1.31 (s, 5H)
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]2[C:10]([C:11]3[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:21][N:22](C)C=O>>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[N:5]3[CH:4]=[N:3][C:2]([C:21]#[N:22])=[C:6]3[N:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(-c2ccnc3c(Br)ncn23)c1
Product: N#Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 1.0 g. of 8-bromo-4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine, 0.45 g. of cuprous cyanide and 25 ml. of N,N-dimethylformamide is refluxed for 16 hours. The solvent is removed under reduced pressure. The residue is extracted with methylene chloride and the solution passed through a column of hydrous magnesium silicate. The eluent is collected, concentrated and n-hexane added while heating. The product separates as crystals, m.p. 168°-169° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:25]1([P:31]([O-:35])[O:32][CH2:33][CH3:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:33]([O:32][P:31]([CH2:1][CH:2]1[O:6][C:4](=[O:5])[CH2:3]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:35])[CH3:34]
Reactant: CCOP([O-])c1ccccc1
Reactant: C=C1CC(=O)O1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOP(=O)(CC1CC(=O)O1)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 8.4 parts of diketene, 2.5 parts of benzoyl peroxide and 20.0 parts of ethyl phenylphosponite were added dropwise over 1 hr to 48.1 parts of vigorously stirred ethyl phenylphosphonite which was heated at 120° C. in an atmosphere of nitrogen. The excess phosphonite was removed by passing the reaction mixture down a wiped wall still at 80° C. at a pressure of 0.013 mb. The residue was distilled on a wiped wall still at a temperature of 110° C. and a pressure of 0.013 mb and the product, ethyl(2-oxo-4-oxetanylmethyl)phenylphosphinate, was obtained as a colourless oil which was shown by 31P NMR to be a nearly equal mixture of diastereoisomers having chemical shifts at δ-37.5 and δ-37.7 and which had the following elemental analysis by weight.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: COc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Yield: 65 %

Procedure:
Using the method described in Example 11, 3-cyclopentyl-2-[4-(2-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 24) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (83.8 mg, 65%); ES+-HRMS m/e calcd for C26H33N5O5 [M+H+] 496.2555 found 496.2552. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.21-1.74 (m, 8H), 1.91 (m, 1H), 2.27 (m, 1H), 3.80 (s, 3H), 3.89 (s, 2H), 4.68 (s, 1H), 5.45 (dd, J=4.2, J=11.2 Hz, 1H), 5.56 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.00-7.11 (m, 1H), 7.20-7.31 (m, 2H), 7.31-7.41 (m, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.7 Hz, 1H), 10.83 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23]C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:32]([O:36][CH:37]([O:39][NH:40][C:41]([C:43]1[S:47][C:46]2[CH:48]=[C:49]([CH:52]=O)[CH:50]=[CH:51][C:45]=2[CH:44]=1)=[O:42])[CH3:38])[CH:33]([CH3:35])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH:19]([CH2:22][NH:23][CH2:52][C:49]2[CH:50]=[CH:51][C:45]3[CH:44]=[C:43]([C:41](=[O:42])[NH:40][O:39][CH:37]([O:36][CH2:32][CH:33]([CH3:34])[CH3:35])[CH3:38])[S:47][C:46]=3[CH:48]=2)[CH2:20][CH2:21]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCC(CN[C@H](C(=O)OC(C)(C)C)c2ccccc2)CC1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(C=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCC3CCC(CN[C@H](C(=O)OC(C)(C)C)c4ccccc4)CC3)cc2s1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
(S)-{[4-(tert-Butoxycarbonylamino-methyl)-cyclohexylmethyl]-amino}-phenyl-acetic acid tert-butyl ester (290 mg, 0.9 mmol) and 6-formyl-benzo[b]thiophene-2-carboxylic acid (1-isobutoxy-ethoxy) amide (Scheme 7) (255 mg, 0.8 mmol) were stirred in DCE (8 ml) for 30 min. Acetic acid (4 ul, 0.08 mmol) and sodium triacetoxyborohydride (504 mg, 2.4 mmol) were added and the reaction mixture was stirred at r.t. for 1 h30. DCM (5 ml) and a saturated solution of NaHCO3 (10 ml) were added and phases were separated. The aqueous phase was extracted with EtOAc (15 ml). The organics were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product (543 mg) was purified on column chromatography (5 to 10% MeOH in DCM) to yield the expected pure product (172 mg, 34% yield). LCMS purity 100%, m/z 638 [M++H]+.
Reaction SMILES: FC1C(S)=CC=CC=1C(OCC)=O.C1C(=O)N(Cl)C(=O)C1.[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:49]=3[F:59])=[C:28](C3CC3)[N:29]2C2C=NN(CCCC(O)=O)C=2)=[CH:25][CH:24]=1>C(Cl)Cl.O>[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:47][C:48]3[C:49]([F:59])=[C:50]([CH:51]=[CH:52][CH:53]=3)[C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:28][NH:29]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)O)c3)c3c(F)c(Cl)ccc23)c1F
Agent: CCOC(=O)c1cccc(S)c1F
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cccc(Sc2c[nH]c3c(F)c(Cl)ccc23)c1F
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a stirred solution of Intermediate A (1.18 g, 5.91 mmol) in CH2Cl2 (30 mL) under inert atmosphere was added NCS (792 mg, 5.91 mmol) at RT and stirred for 1 h. To this, indole 1 (Example 4, Step 1; 1.0 g, 5.91 mmol) in CH2Cl2 (20 mL) was added at RT and stirred for 4 h. After completion of the reaction by TLC, the reaction mixture was diluted with water (40 mL) and extracted with CH2Cl2 (2×60 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel; 10% EtOAc/Hexanes) to afford compound 2 (1.2 g, 55%) as a light brown solid. 1H NMR (500 MHz, DMSO-d6): δ 12.60 (br s, 1H), 8.00 (d, J=4.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.24-7.17 (m, 2H), 7.09 (t, J=8.0 Hz, 1H), 6.90-6.86 (m, 1H), 4.34 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H); MS: m/z 368.6 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[OH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=1[O:40][CH3:41]>C(Cl)Cl>[OH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:37])=[CH:33][C:32]=1[O:40][CH3:41]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
1-Methylpiperazine (0.58 mL, 5.2 mmol), HOBt (0.70 g, 5.2 mmol.) and EDCl (1.0 g, 5.2 mmol) were added to a solution of 4-hydroxy-3-methoxybenzoic acid (0.69 g, 4.0 mmol.) in dry DCM (40 mL). The mixture was stirred at room temperature for 16 h, washed with saturated aqueous sodium bicarbonate (20 mL), brine, dried over sodium sulphate and evaporated to give the title compound (0.96 g, 96%).