Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][O:31][C:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3([CH3:45])[O:44][CH2:43][CH2:42][O:41]3)[CH:35]=2)=[N:29]1)=[O:27]>C(Cl)Cl.[Cu](Br)Br>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3([CH3:45])[O:44][CH2:43][CH2:42][O:41]3)[CH:35]=2)[O:31][CH:32]=1)=[O:27]
Reactant: COC(=O)C1COC(Cc2cccc(C3(C)OCCO3)c2)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: N#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(Cc2cccc(C3(C)OCCO3)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethylenetetramine (1.10 g, 7.79 mmol) and DBU (1.17 mL, 7.75 mmol) were added to a stirred suspension of copper (II) bromide (1.73 g, 7.75 mmol) in deoxygenated dry CH2Cl2 (15 mL). After 20 min, a deoxygenated solution of 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (951 mg, 3.12 mmol) in CH2Cl2 (15.0 mL) was added and the reaction mixture was stirred at rt for 45 min. The solvent was removed under reduced pressure and the residue was partitioned between EA (50 mL), and 50 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH. The aq. layer was extracted with EA (50 mL) and the combined organic layers were washed with 50 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH followed by 10% citric acid (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1:1 hept-EA)=0.37. LC-MS-conditions 02: tR=0.93 min, [M+H]+=304.34.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=2)=[N:7][C:2]([NH:18][C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(O)c1
Reactant: OCc1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: OCc1cccc(Nc2nc(Nc3cccc(O)c3)ncc2Cl)c1
Yield: 85 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using {3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}methanol and 3-aminophenol as the starting materials in 85% yield. LCMS for C17H16ClN4O2 (M+H)+: m/z=343.1.
Reaction SMILES: [C:1]([C:5]1[C:13]([N+:14]([O-])=O)=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(O)C>[Fe].O>[C:1]([C:5]1[C:13]([NH2:14])=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc2c(cc1N)OCO2
Reaction time: 2 h
Yield: 24.8 %

Procedure:
The above prepared 5-tert-Butyl-6-nitrobenzo[d][1,3]dioxole (1.1 g, 5 mmol), Fe (5.5 g, 100 mmol) and HCl (2 ml) was added into ethanol (6 ml) and water (18 ml). The mixture was stirred for 2 h at refluxed temperature. The PH was adjusted to 7-8 and the mixture was filtered and washed with methanol. The filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate 1%-5%) to give 6-tert-butylbenzo[d][1,3]dioxol-5-amine (240 mg, 25%) as a red solid. LCMS: 194 [M+1]+; 1H NMR (400M): (DMSO-d6) δ 1.28 (s, 9H), 4.46 (s, 2H), 5.77 (s, 2H), 6.32 (s, 1H), 6.63 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C@@H:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=O)[C:14]2=[O:30])=[CH:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:43]1([S:49]([NH2:52])(=[O:51])=[O:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C1CCN2C(=NCCC2)CC1.Cl>O.C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C@@H:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([NH:52][S:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:51])=[O:50])=[O:26])[C:14]2=[O:30])=[CH:3]1
Reactant: CCC[C@@H](CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCC[C@@H](CC(=O)NS(=O)(=O)c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
(S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (25 mg, 0.062 mmol) is dissolved THF (0.5 mL) and CDI (22 mg, 0.14 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, Benzenesulfonamide (19 mg, 0.12 mmol) is added and after 10 min, DBU (0.018 mL, 0.12 mmol) is added. The mixture is then stirred for 16 hr at room temperature. 1 mL of 1.0 M HCl is added followed by 10 mL of water. The mixture is extracted with EtOAc (3×20 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by Preparative TLC affords 16 mg (47%) of N-{(S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoyl}-benzenesulfonamide. LCMS (ESMS): m/z 545.32 (M+H+).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20](N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:45]1([C:51]2[N:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=3)=[CH:53][N:52]=2)[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:48]1[CH2:49][CH2:50][N:45]([C:51]2[N:52]=[CH:53][C:54]([C:57]3[CH:58]=[CH:59][C:60]([C:63]([F:64])([F:66])[F:65])=[CH:61][CH:62]=3)=[CH:55][N:56]=2)[CH2:46][CH2:47]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: FC(F)(F)c1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 86 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 2-piperazin-1-yl-5-(4-trifluoromethylphenyl)-pyrimidine, dihydrochloride (0.250 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)-oxazolidin-2-one (0.360 g), to yield the title compound as an off-white solid (0.480 g, 86%).
Reaction SMILES: [F:1][C:2]([P:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=O)[OH:9])([F:7])[C:3]([F:6])([F:5])[F:4].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C:2]([P:8]([Cl:19])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:9])([F:7])[C:3]([F:6])([F:5])[F:4]
Reactant: O=P(O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=P(Cl)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
30.0 g (99.3 mmol) of bis(pentafluoroethyl)phosphinic acid and 20.7 g (99.4 mol) of phosphorus pentachloride are mixed with one another and stirred at room temperature for 30 minutes. Bis(pentafluoroethyl)phosphinyl chloride is isolated from the reaction mixture by fractional distillation. The boiling point is 118-119° C. 23.1 g of a colourless liquid are obtained. The yield is 72.6% of the calculated yield of bis(pentafluoroethyl)phosphinyl chloride.
Reaction SMILES: N[C:2]1[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[S:16]([OH:19])(=[O:18])=[O:17].[Na:20].[BrH:21].N([O-])=O.[Na+]>O>[Br:21][C:2]1[C:7]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[S:16]([OH:19])(=[O:18])=[O:17].[Na:20]
Reactant: Br
Reactant: Nc1c(S(=O)(=O)O)cc(S(=O)(=O)O)cc1S(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c(Br)c(S(=O)(=O)O)c1

Procedure:
The 2-amino-benzene-1,3,5-trisulfonic acid, sodium salt can be dissolved in water and treated with 48% hydrobromic acid (5 equivalents). A solution of sodium nitrite (2 equivalents) in water can be added dropwise and stirred until the precipitation of the diazonium salt is complete. A solution of cuprous bromide (1 equivalent) in 48% hydrobromic acid (5 equivalents) can be added in one portion and the mixture stirred until gas evolution ceases followed by heating to a reflux. The solution can be evaporated and the residue dissolved in water followed by neutralization to pH 7 using sodium bicarbonate. The solids can be filtered off, the filtrate evaporated, and the solids dried under vacuum. The product can be recrystallized from water by addition of ethanol to give 2-bromo-benzene-1,3,5-trisulfonic acid, sodium salt.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[Si:19]([O:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Yield: 95.6 %

Procedure:
10% palladium on activated carbon (1.32 g) was added to 1-(benzyloxycarbonyl)-3-(tert-butyldimethylsilyloxymethyl)piperidine (13.2 g, 36.3 mmol) in methanol (130 mL). The mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. Subsequently, the mixture was filtered through Celite, followed by evaporation of the solvent to give 7.96 g (96%) of the desired compound as a colorless oil.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[S:25][C:26]([CH3:30])=[C:27]([CH3:29])[N:28]=1>C(Cl)CCl>[CH3:29][C:27]1[N:28]=[C:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])[S:25][C:26]=1[CH3:30]
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1nc(N)sc1C
Solvent: ClCCCl
Product: Cc1nc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)sc1C
Yield: 31 %

Procedure:
N-(4,5-Dimethyl-2-thiazolyl)-4-hydroxy-2-methyl-2 H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-4,5-dimethyl-thiazole. Yield: 31% of theory; m.p. 264°-265° C (decomp.; from ethylene chloride).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:17][CH3:18])=[N:11][N:12]2[CH2:15][CH3:16])=[CH:8][CH:7]=1)=[O:5].[CH3:20][Mg]Cl>O1CCCC1>[CH2:15]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4](=[O:5])[CH3:20])[CH:14]=2)[C:10]([CH2:17][CH3:18])=[N:11]1)[CH3:16]
Reactant: CCc1nn(CC)c2cc(C(=O)N(C)OC)ccc12
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CCc1nn(CC)c2cc(C(C)=O)ccc12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
1,3-Diethyl-1H-indazole-6-carboxylic acid methoxy-methyl-amide (0.22 g, 0.86 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to −70° C. Methylmagnesium chloride (2 mL, 3M in tetrahydrofuran, 0.06 mol) was added dropwise and the resulting mixture was stirred for 30 minutes at −70° C. After warming to room temperature, the mixture was stirred for a further 3 minutes, then quenched by the addition of a chilled saturated solution of ammonium chloride. Ethyl acetate (150 mL) and water (40 mL) were then added and the product was extracted. The aqueous layer was re-extracted with ethyl acetate (75 mL). The organic layers were combined, dried, filtered, and concentrated to afford 200 mg of 1-(1,3-Diethyl-1H-indazol-6-yl)-ethanone.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[CH2:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH2:6]1.[H][H].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]>[Pd].C(O)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28].[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([CH3:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH2:6]1
Reactant: [H][H]
Reactant: C=C1c2ccccc2CC(CCN(C)C)c2ccccc21
Agent: [Pd]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC1c2ccccc2CC(CCN(C)C)c2ccccc21

Procedure:
A mixture of 5.54 g. (0.02 mole) 10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene and 0.6 g 5% palladium on carbon in 60 ml. ethanol is hydrogenated at atmospheric pressure and room temperature. The hydrogenation is stopped after 1 equivalent of hydrogen is absorbed, the catalyst is removed by filtration and the filtrate concentrated to a small volume in vacuo. The concentrated filtrate is treated with 2.32 g. (0.02 mole) maleic acid in ethanol and the resulting solid is filtered and washed with cold ethanol to give 10,11-dihydro-10-(2-dimethylaminoethyl)-5-methyl-5H-dibenzo[a,d]cycloheptene maleate, m.p. 120°-122° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)=[O:10])C1C=CC=CC=1.CO>[OH-].[Pd+2].[OH-].[Pd]>[NH:17]1[C:14]2=[N:15][CH:16]=[C:11]([C:9]([OH:10])=[O:8])[CH:12]=[C:13]2[CH:19]=[CH:18]1
Reactant: O=C(OCc1ccccc1)c1cnc2[nH]ccc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Into a round bottom flask was added compound 22 (55.0 mg, 0.000218 mol) and palladium hydroxide, 20 wt. % Pd on carbon, wet (20.0 mg, 0.000142 mol) and Methanol (5.0 mL, 0.12 mol) under an atmosphere of Hydrogen. The reaction mixture was stirred at room temperature overnight. Filtration and concentration gave product 15 (35 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][CH3:16])[CH2:11][CH2:10]2)[N:5]=[N:4][C:3]=1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C(N(CC)CC)C.[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([Cl:40])=[O:39])=[CH:36][CH:35]=1)#[N:33].Cl>C(Cl)Cl.CO>[ClH:40].[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:5]=[N:4][C:3]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)=[C:2]([CH3:1])[C:7]=3[CH3:8])[CH2:10][CH2:11]2)[CH3:16])=[O:39])=[CH:36][CH:35]=1)#[N:33]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CNC1CCN(c2nnc(-c3ccc(C#N)cc3)c(C)c2C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1c(-c2ccc(C#N)cc2)nnc(N2CCC(N(C)C(=O)c3ccc(C#N)cc3)CC2)c1C
Yield: 95.3 %

Procedure:
Treat a solution of 4-(4,5-dimethyl-6-(4-(methylamino)piperidin-1-yl)pyridazin-3-yl)benzonitrile (90 mg, 0.28 mmol) and triethylamine (0.12 mL, 0.84 mmol) in CH2Cl2 (2.8 mL) with 4-cyanobenzoyl chloride (56 mg, 0.34 mmol). Stir the reaction at ambient temperature overnight. Wash with H2O and separate the layers. Directly purify the organic layer by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2). Concentrate to afford a white solid. Dissolve the material in MeOH and add 1.1 eq of methanolic HCl (preform by dripping acetyl chloride into MeOH). Concentrate the mixture under a stream of N2 gas and dry the residue in a vacuum oven at 45° C. to obtain the title compound as yellow solid (130 mg, 95%). ES/MS m/z 451.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[C:25]([Si:29]([CH3:40])([CH3:39])[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([Si:29]([CH3:40])([CH3:39])[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH:38][C:13](=[O:15])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=3[F:1])[CH:6]=[N:7]2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: CC(C)CC(C(=O)Nc1ccn(CCO[Si](C)(C)C(C)(C)C)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Yield: 68 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (Intermediate 28) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide as an off-white solid (1.15 g, 68%); ES+-HRMS m/e calcd for C27H37N5O4SiF2 [M+H+] 562.2656 found 562.2658. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.06 (s, 6H) 0.81 (s, 9H) 0.84-0.92 (m, 6H) 1.45 (m, 1H) 1.70-1.87 (m, 1H) 2.09-2.24 (m, 1H) 3.86 (t, J=5.1 Hz, 2H) 4.07 (t, J=5.1 Hz, 2H) 5.53 (dd, J=11.2, 4.2 Hz, 1H) 6.04 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.0 Hz, 1H) 7.31-7.52 (m, 3H) 7.54 (d, J=2.0 Hz, 1H) 8.28 (d, J=2.7 Hz, 1H) 10.82 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Br[CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:25]=2)[C:20]1=[O:36]>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[C:7]([NH:6][C:3](=[O:5])[CH3:4])([CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:25]=2)[C:20]1=[O:36])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:12]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCc1ccc2c(c1)CC(Br)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)CC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2=O
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a stirring solution of 60% NaH (1.194 g, 29.85 mmol) in DMF (5 mL) was added diethyl acetamidomalonate (6.484 g, 29.85 mmol) via cannula at 0° C. The solution was allowed to stir for 3 hours for anion to form. A solution of 3 (3.22 g, 9.95 mmol) in DMF (10 mL) was then added to then transferred to anion solution at 0° C. and left to stir over night at room temp. The reaction mixture was then poured over ice and extracted with EtOAc. The organic layer was washed with brine, dried with NaSO4 and concentrated. The product was then purified with silica gel chromatography eluding with 70% hexanes-30% EtOAc. The reaction provided 4 (2.842 g, 6.184 mmol, 65%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:4])=[O:3].CN(C)C=O.S(Cl)([Cl:28])=O>>[CH3:1][S:2]([C:5]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:28])=[O:8])(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1c(Sc2ccccc2)cccc1C(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1c(Sc2ccccc2)cccc1C(=O)Cl

Procedure:
A mixture of 2-methylsulphonyl-3-phenylsulphenylbenzoic acid and N,N-dimethylformamide (0.25 ml) in thionyl chloride was heated at reflux for 1.25 hours. The solution was evaporated to give 9.9 g of 2-methylsulphonyl-3-phenylsulphenylbenzoyl chloride as a pale yellow oil which was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[C:22]3[C:23]4=[C:24]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][C:16]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[C:22]3[C:23]4=[C:24]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][C:16]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:3]=[C:2]([C:34]2[CH:33]=[CH:32][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)[CH:7]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5cc(Cl)cc(Cl)c5)ccc5ccc2c3c54)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4c(-c5cc(Cl)cc(-c6ccc7ccccc7c6)c5)ccc5ccc2c3c54)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
A mixed solution of 0.88 g of 1-(3,5-dichlorophenyl)-6-(4-methylphenyl)pyrene, 0.35 g of 2-naphthylboronic acid, 2.9 g of cesium carbonate, 58 mg of (tris-t-butylphosphine)tetrafluoroborate, 0.12 g of bis(dibenzylideneacetone)palladium(0) and 20 ml of 1,4-dioxane was heated and stirred under a nitrogen gas stream at 90° C. for 4 hours. The solution was cooled to room temperature and 50 ml of water was poured into the solution, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 0.40 g of 1-{3-chloro-5-(2-naphthyl)phenyl}-6-(4-methylphenyl)pyrene.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:15])[CH:9]=1.[Cl-].[P:17]([O-])([S:22][CH2:23][CH2:24][CH3:25])([O:19][CH2:20][CH3:21])=[O:18]>C(#N)C>[P:17]([O:14][C:11]1[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][C:10]=1[F:15])([S:22][CH2:23][CH2:24][CH3:25])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCCSP(=O)([O-])OCC
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CCCSP(=O)(OCC)Oc1ccc(Br)cc1F
Reaction time: 24 h
Yield: 61.2 %

Procedure:
5.5 g of potassium carbonate are added to 7.5 g of the resulting 4-bromo-2-fluorophenol in 100 ml of acetonitrile and the mixture is refluxed for one hour, with stirring. 7.5 g of O-ethyl S-n-propyl thiophosphate-chloride are then added dropwise at 50° C. and the mixture is stirred at this temperature for 3 hours and then at room temperature for 24 hours. The solvent is removed on a rotary evaporator, 400 ml of toluene and 100 ml of water are added, the phases are separated, the organic phase is washed with 2N sodium hydroxide solution and then with water and is dried with sodium sulfate, and the solvent and volatile impurities are stripped off under reduced pressure at 40° C./0.13 mbar. 7.5 g of O-ethyl S-n-propyl O-(4-bromo-2-fluorophenyl) thiophosphate are obtained as the residue; nD21 =1.5269.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:24]1>C(#N)C>[C:29]([CH:26]1[CH2:27][CH2:28][N:23]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:24][CH2:25]1)(=[O:30])[NH2:31]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: NC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4 ml). DIPEA (0.28 ml, 1.60 mmol) and piperidine-4-carboxamide (0.21 g, 1.60 mmol) were sequentially added. The reaction was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by flash chromatography (DCM/Acetone=8/2). The solid was triturated with i-Pr2O to obtain ethyl 2-(4-carbamoylpiperidin-1-yl)-2-phenylacetate (239 mg, 66.7% yield) as a pale yellow solid.