Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Ca:1].C(=O)([O-])[O-:3].[Ca+2].[O-:7][Si:8]([O-:11])([O-:10])[O-:9].[Ca+2].[Ca+2]>O>[O-:7][Si:8]([O-:11])([O-:10])[O-:9].[Ca+2:1].[Ca+2:1].[OH-:3].[Ca+2:1].[OH-:3]
Reactant: [Ca]
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: O
Product: [OH-]

Procedure:
Table 7 is directed to the valuation of synthetic calcium and magnesium silicates versus the limestone or calcium carbonate fillers currently utilized in the trade. In this regard, "Micro-Cel®" is the registered trade name of the Celite Corporation of Lompoc, Calif. The "Micro-Cel®" products comprise of synthetic, hydrous, calcium silicates produced by the hydro-thermal reaction of diatomite, hydrated lime, and water. According to the Celite Corporation, the different grades of "Micro-Cel®" have the following typical physical and chemical properties:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7]OS(C)(=O)=O)[CH:4]=[N:3]1.[C:13]([NH:17][C:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH:39]([F:41])[F:40])[CH:36]=4)[NH:31][N:30]=3)[N:27]=2)[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:13]([NH:17][C:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH:39]([F:40])[F:41])[CH:36]=4)[N:31]([CH2:7][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:30]=3)[N:27]=2)[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: Cn1cc(COS(C)(=O)=O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)cn1
Temperature: 90 °C
Yield: 50.5 %

Procedure:
To a solution of methanesulfonic acid 1-methyl-1H-pyrazol-4-ylmethyl ester (108 mg, 0.57 mmol) in DMF (2 mL) were added 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (100 mg, 0.19 mmol) and Cs2CO3 (184 mg, 0.57 mmol). The bright yellow reaction mixture was heated at 90° C. for 2 h then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) dried over MgSO4 and concentrated. The residue was chromatographed with 50% to 100% EtOAc/hexanes to afford 60 mg (51%) of 2-[5-difluoromethoxy-1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:22][CH2:23][S:24][CH3:25])[C:16](N(OC)C)=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].S([O-])(O)(=O)=O.[K+]>CCOCC.O>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:22][CH2:23][S:24][CH3:25])[CH:16]=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CON(C)C(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CSCC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of lithium aluminum hydride (5.02 g, 0.132 mol) in ether (500 mL) was stirred at room temperature for one hour. The solution was cooled to −50° C. under nitrogen, and a solution of the product from Step F (39.8 g, ca. 0.120 mol) in ether (200 mL) was added over 30 min, maintaining the temperature below −40° C. When the addition was complete, the reaction was warmed to 5° C., then recooled to −45° C. Analysis by tlc revealed incomplete reaction. The solution was rewarmed to 5 ° C., stirred for 30 minutes, then cooled to −50° C. A solution of potassium hydrogen sulfate (72 g, 0.529 mol) in 200 mL water was slowly added, maintaining the temperature below −20° C. The mixture was warmed to 5° C., filtered through Celite, and concentrated in vacuo to provide the title aldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.C(O[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)(C)C>C1COCC1>[CH3:30][C:25]1([CH3:31])[C:26]([CH3:29])([CH3:28])[O:27][B:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:13][CH:12]4[CH:10]([CH2:11]4)[CH2:9]3)[CH:5]=[CH:6][CH:7]=2)[O:24]1
Reactant: Brc1cccc(N2CC3CC3C2)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2cccc(N3CC4CC4C3)c2)OC1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
3-(3-Bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane (2.0 g, 8.4 mmol) was dissolved in 40 mL of THF and cooled to −78° C. in a dry ice acetone bath. tert-Butyl lithium (1.7 M solution in pentane, 14.8 mL, 25.2 mmol) was added dropwise and the reaction was stirred at −78° C. for 15 min. 2-Isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.4 mL, 16.8 mmol) was added and the reaction was stirred at −78° C. for 2 h. The reaction was quenched with saturated aqueous ammonium chloride and warmed to room temperature. Water was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried, filtered and concentrated. The crude residue was chromatographed using a gradient of 0% to 10% ethyl acetate/heptane to give 1.93 g (81%) of 3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-aza-bicyclo[3.1.0]hexane as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([NH:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:40](C(OC(C)(C)C)=O)[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([N:27]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:28][CH2:29][O:30][CH3:31])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COCCNC(CO[Si](C)(C)C(C)(C)C)c1cccc(NC(=O)OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(C(=O)OC(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)c1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Yield: 32.8 %

Procedure:
{3-[2-(tert-Butyl-dimethyl-silanyloxy)-1-(2-methoxy-ethylamino)-ethyl]-phenyl}-carbamic acid benzyl ester (1 g) was dissolved in dry DCM (10 mL) and stirred under argon at 0° C. Triethylamine (0.4 g) and (BOC)2O (0.52 g) were added and the reaction mixture was stirred at room temperature for 2 days. The reaction was quenched by addition of water and the mixture extracted with DCM. The organic phase was separated, dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography to give the title compound (400 mg).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH2:13][OH:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(F)cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (0.223 g) was added to a solution of the product from step (ii) (1.07 g) in dry ethanol (30 ml) and the mixture was stirred at RT overnight. The mixture was partitioned between 2M hydrochloric acid/ethyl acetate, the organics separated, dried and evaporated under reduced pressure, yield 1.08 g.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1>Br[Zn]CCCCC#N>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][C:2]#[N:3])[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: N#CCCCC[Zn]Br
Product: N#CCCCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Yield: 210.8 %

Procedure:
Prepared according to the method of example 67(a), using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (500 mg) and bromo(4-cyanobutyl)-zinc (30 mL, 0.5 M solution in tetrahydrofuran). Purification (SiO2, methanol:dichloromethane 1:99 as eluant) gave the sub-title compound (600 mg).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.CN(C(O[N:47]1N=[N:54][C:49]2C=CC=N[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:48]([CH2:49][NH:54][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)#[N:47]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 35 mg, 0.081 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.054 mL, 0.487 mmol), 2-aminoacetonitrile, HCl (15.02 mg, 0.162 mmol), and HATU (61.7 mg, 0.162 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=33.2 min) to give single enantiomer N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (18.3 mg, 0.038 mmol, 46.6% yield): LCMS=470.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15-8.23 (2 H, m), 7.65-7.76 (4 H, m), 7.53-7.64 (3 H, m), 5.21 (1 H, s), 4.19 (2 H, d, J=2.86 Hz). HPLC Peak RT=9.5 min (Analytical Method A).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].O.[N+:19]([CH3:22])([O-:21])=[O:20]>>[N+:19]([CH:22]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1)([O-:21])=[O:20]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)cc1
Yield: 43 %

Procedure:
4-Trifluoromethylbenzaldehyde (3.00 g, 17.2 mmol) was dissolved in nitromethane (10 ml), to which ammonium acetate (1.341 g, 17.4 mmol) was added, and the mixture was heated under reflux for 2 hours. Water was added to the mixture, which was extracted with methylene chloride twice, and the extracts were combined and washed with brine, and dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1) to afford 1-(2-nitrovinyl)-4-trifluoromethylbenzene (1.596 g, yield 43%) as a pale yellow crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][OH:12])[NH:8]2)=[CH:4][CH:3]=1>C1COCC1.O=[Mn]=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:11]=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OCc1cc2ccc(Br)cc2[nH]1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: O=Cc1cc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
To a suspension of (6-bromo-1H-indol-2-yl)methanol (696 mg, 3.00 mmol) in THF (25.0 mL) was added MnO2 (3.20 g, 37.0 mmol) at 0° C. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (371 mg, 55%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 9.86 (s, 1H), 9.07 (br s, 1H), 7.64 (s, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.29 (dd, J=8.5, 1.5 Hz, 1H), 7.24 (d, J=1.0 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH2:10])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:21](=O)[O:22]C2C=CC=CC=2)[N:14]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:21]([NH:20][C:15]1[N:14]=[C:13]([O:12][CH3:11])[CH:18]=[C:17]([CH3:19])[N:16]=1)=[O:22])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3]
Reactant: COc1cc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: CN(S(C)(=O)=O)S(N)(=O)=O
Solvent: Clc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
37.6 g of (N-methylsulfonyl-N-methylamino)sulfonamide are dissolved in 500 ml of chlorobenzene, 51.8 g of phenyl 4-methoxy-6-methyl-2-pyrimidylcarbamate are added dropwise at room temperature to the solution, and the mixture is stirred for 5 hours at 100° C. The mixture is cooled to 0° C., the precipitate is then filtered off, and, after washing with 100 ml of chlorobenzene, 68.8 g of the desired product of a purity of 98.7% are obtained. This corresponds to a yield of 96.4% of theory. The melting point of the product is 118-120° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH:11]=[CH:10]2>CO>[Br:1][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[N:13]2
Reactant: COc1cccc2ccc(-c3cccnc3)nc12
Reactant: BrBr
Solvent: CO
Product: COc1ccc(Br)c2ccc(-c3cccnc3)nc12

Procedure:
Bromine (200 μl) was added in a dropwise manner to a stirred and cooled (0°-5° C.) solution of 8-methoxy-2-(3-pyridyl)quinoline (780 mg) in methanol (30 ml) under a nitrogen atmosphere. The reaction mixture was stirred for 15 minutes then quenched by the addition of 5% aqueous sodium metabisulfite solution (7ml). The reaction mixture was evaporated in vacuo and the residue partitioned between 0.5N sodium hydroxide solution (65 ml) and dichloromethane (75 ml). The aqueous phase was reextracted with dichloromethane (2×75 ml) and the combined organic phases were dried (magnesium sulfate), filtered and evaporated in vacuo. Trituration with diethyl ether afforded the title compound (570 mg) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]C(=O)C)=[CH:10][CH:9]=1)=[O:4].C[O-].[Na+]>CO>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)NC=Cc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)NC=Cc1ccc(O)cc1
Temperature: 50 °C

Procedure:
A suspension of 23.5 g (0.1 mol) of p-(2-methoxycarbonylaminovinyl)-acetoxybenzene in 300 ml of absolute methanol, which is mixed with a solution of 5.4 g of sodium methoxide in 30 ml of methanol, is warmed to 50° C. for 15 minutes. Thereafter the mixture is evaporated to dryness under reduced pressure. The resulting crude sodium salt of [2-methoxy-carbonylaminovinyl]-phenol is dissolved in 100 ml of water, 50 ml of 2 N hydrochloric acid are added to the solution and the phenol which has separated out is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated in vacuo. Crude p-(2-methoxycarbonylaminovinyl)-phenol is obtained as an oil. This can be used, as shown below, without further purification. A sample crystallised from ether showed a melting point of 169°-170° C.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][CH:37]=[N:38][CH:39]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:25][CH2:24][CH2:23][O:22][C:3]1[C:2]([C:34]2[CH:35]=[N:36][CH:37]=[N:38][CH:39]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OCCO)c(Br)c1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OCCO)c(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-bromo-6-(2-hydroxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 52.1, 50 mg, 0.119 mmol), Pd(Ph3P)4 (14 mg, 0.012 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (37 mg, 0.178 mmol) in toluene (0.5 mL) was stirred for 15 min. at RT. K3PO4 (76 mg, 0.356 mmol) was added and the RM was stirred at 110° C. for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative SFC (Column DEAP, from 12% to 17% in 6 min.) to afford the title compound as an off-white powder. UPLC-MS (Condition 2) tR=0.93 min, m/z=419.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.74 (q, J=4.83 Hz, 2H) 4.48 (t, J=4.71 Hz, 2H) 4.90 (t, J=5.27 Hz, 1H) 7.39 (d, J=8.66 Hz, 2H) 7.87 (d, J=8.85 Hz, 2H) 8.50 (d, J=1.51 Hz, 1H) 8.81 (s, 1H) 9.19 (s, 2H) 9.21 (s, 1H) 10.46 (s, 1H).
Reaction SMILES: [C:1]([NH:4]C1C=C(C=CC=1N=NC1C([N+]([O-])=O)=CC(Br)=CC=1Br)N(CC)CC)(=O)C.Br[C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[N:39]=[N:40][C:41]1[CH:59]=[CH:58][C:44]([N:45]([CH2:52][CH2:53][O:54][C:55](=[O:57])[CH3:56])[CH2:46][CH2:47][O:48][C:49](=[O:51])[CH3:50])=[CH:43][CH:42]=1>>[C:1]([C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[N:39]=[N:40][C:41]1[CH:59]=[CH:58][C:44]([N:45]([CH2:52][CH2:53][O:54][C:55](=[O:57])[CH3:56])[CH2:46][CH2:47][O:48][C:49](=[O:51])[CH3:50])=[CH:43][CH:42]=1)#[N:4]
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Br)cc1
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc(Br)cc2[N+](=O)[O-])c(NC(C)=O)c1
Product: CC(=O)OCCN(CCOC(C)=O)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2C#N)cc1
Reaction time: 7 h
Yield: 15.95 %

Procedure:
When the 3-acetylamino-4-(2',4'-di-bromo-6'-nitrophenylazo)-N,N-diethylaniline employed in Example 9 was replaced by 4-(2'-bromo-4'-nitrophenylazo)-N,N-di(β-acetoxyethyl)aniline (4.8 parts) reaction was effectively complete in 7 hours at 90° C. Isolation of the product by the method of Example 9 gave 4-(2'-cyano-4'-nitrophenylazo)-N,N-di(β-acetoxyethyl)aniline (Found: C, 57.4; H, 5.1; N, 16.1. C21H21N5O6 requires C, 57.4; H, 4.8; N, 15.95%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19]C)=[CH:14][CH:15]=2)[CH2:10]1)[CH2:6][CH2:7][CH3:8])=[O:4].B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:1][C:2]([F:21])([F:22])[C:3]([N:5]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)[CH2:6][CH2:7][CH3:8])=[O:4]
Reactant: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(OC)cc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
To a −78° C. solution of 2,2,2-trifluoro-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-acetamide (3.4 g, 10.9 mmol) and tetrabutylammonium iodide (4.43 g, 12.0 mmol) in dichloromethane (200 mL) under an inert atmosphere boron trichloride (1 M, 27.2 mL) was added dropwise. The reaction was warmed to room temperature and stirred for 2.5 h. The reaction was quenched by the slow addition of water. The organic layer was separated and dried (MgSO4). This was concentrated onto silica (15 g) and placed on top of a flash column. Chromatography eluting with 30% acetone in hexanes afforded 2,2,2-trifluoro-N-(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-acetamide as a foam (3.1 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])[CH:9]=[CH2:10].C1(C)C(C(P(C(C2C(C)=CC=CC=2)=O)C(C2C(C)=CC=CC=2)=O)=O)=CC=CC=1.Br[C:46]1[C:47]([NH:55][CH3:56])=[N:48][CH:49]=[C:50]([N+:52]([O-:54])=[O:53])[CH:51]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH3:56][NH:55][C:47]1[C:46]([CH:10]=[CH:9][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:51][C:50]([N+:52]([O-:54])=[O:53])=[CH:49][N:48]=1
Reactant: CNc1ncc([N+](=O)[O-])cc1Br
Reactant: C=CC(=O)OCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1C(=O)P(C(=O)c1ccccc1C)C(=O)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)C=Cc1cc([N+](=O)[O-])cnc1NC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Triethylamine (32 μl), n-butyl acrylate (33 μl), tri(o-toluoyl)phosphine (24 mg), and palladium acetate (5 mg) were added to a tube containing a DMF (3 ml) solution containing 3-bromo-N-methyl-5-nitropyridin-2-amine (45 mg) and the tube was sealed, followed by stirring at 100° C. for 8 hours. The reaction solution was adjusted to room temperature, and n-butyl acrylate (33 μl), tri(o-toluoyl)phosphine (24 mg), and palladium acetate (5 mg) were added again to the tube and the tube was sealed, followed by stirring at 100° C. for 9 hours. Further, the reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=16:1 to 3:1), and a yellow solid of n-butyl 3-(2-(methylamino)-5-nitropyridin-3-yl)acrylate (44 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:42])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34]CC4C=CC=CC=4)[C@@H:22]([O:23]CC4C=CC=CC=4)[C@@H:13]3[O:14]CC3C=CC=CC=3)[C:6]=2[N:7]=1.B(Cl)(Cl)Cl>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:42])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][OH:34])[C@@H:22]([OH:23])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c2nc(N)nc(Cl)c12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c2nc(N)nc(Cl)c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a precooled (−78° C.) solution of the compound from Step A (0.99 g, 1.7 mmol) in dichloromethane (30 mL) was added borontrichloride (1M in dichloromethane) (17 mL, 17.0 mmol) over a 10 min. The resulting solution was stirred at −78° C. for 1 h, allowed to warm to −15° C. and stirred for another 3 h. The reaction was quenched by addition of methanol/dichloromethane (1:1) (15 mL), stirred at −15° C. for 30 min, and pH adjusted to 7.0 by addtion of NH4OH. The mixture was evaporated in vacuo and the resulting oil purified on silica using methanol/dichloromehane (1:9) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (257 mg) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.061 mMol) propionyl chloride, the title compound was prepared essentially by the procedure described in Example 7.