Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[O:7][C:6]2[CH:8]=[C:9]([F:15])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[NH:4][C:3]1=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]#[CH:27]>CN(C)C=O.[NH4+].[Cl-]>[F:17][C:2]1([F:1])[O:7][C:6]2[CH:8]=[C:9]([F:15])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[N:4]([CH2:27][C:26]#[CH:25])[C:3]1=[O:16]
Reactant: O=C1Nc2cc([N+](=O)[O-])c(F)cc2OC1(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To 2,2,7-trifluoro-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (6.9 g, 27.8 mmol) and potassium carbonate (4.61 g, 33.4 mmol) in dry N,N-Dimethylformamide at RT was dropwise added 3-bromoprop-1-yne (80 wt % in toluene; 4.96 g, 33.4 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was poured in saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined extracts were washed with aqueous NaCl solution, dried with Na2SO4, concentrated and chased with toluene to yield 7.06 g of the title compound as dark brown solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:12]=[CH:11][C:9]([NH2:10])=[N:8][C:6]2=[O:7])[CH2:3][CH2:2]1.[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([S:21](Cl)(=[O:23])=[O:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(#N)C>C(N(CC)CC)C>[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([S:21]([NH:10][C:9]2[CH:11]=[CH:12][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:7])[N:8]=2)(=[O:23])=[O:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: Nc1ccn(CC2CC2)c(=O)n1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccn(CC3CC3)c(=O)n2)cc1

Procedure:
A mixture of 495 mg. of 1-cyclopropylmethylcytosine, 702 mg. of N-acetylsulfanilyl chloride, 10 ml. of acetonitrile and 322 mg. of triethylamine was stirred and refluxed for 18 hours. The solvent was evaporated under reduced pressure, and the residue triturated with 10 ml. of water and 3 ml. of 10% aqueous sodium hydroxide. The alkaline solution was decanted from the dark insoluble portion and cleared by filtration. Addition of acetic acid to about pH 5 gave a gummy precipitate which solidified only very slowly. The aqueous solution was decanted and the gum triturated with 2 ml. of hot ethanol, and allowed to settle in an ice bath to obtain after filtration 280 mg. of product, melting at 222°-224°. A sample for analysis was recrystallized from aqueous ethanol; m.p. 225°-226°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[NH2:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+].C([Si](C)(C)Cl)(C)(C)C.N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C=O)C.CCOC(C)=O>[C:29]([O:28][C:26](=[O:27])[CH2:25][NH:23][C:10]1[CH:11]=[CH:12][C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:17])[CH3:18])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(OCc2ccccc2)c1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 2-benzyloxy-4-(tert-butyldimethylsilanyloxy)-phenylamine, t-butyl bromoacetate (3.8 mL, 25.7 mmol), and potassium carbonate (7.1 g, 51.4 mmol) in DMF (20 mL) is heated at 60° C. for 18 h. Additional t-butyl bromoacetate (1 mL) is added and the mixture is stirred and heated for an additional 5 h. The mixture is poured into EtOAc and extracted once with water and four times with brine. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to furnish an oil consisting of product and desilylated product. A solution of this material, t-butyldimethychlorosilane (3.87 g, 25.7 mmol), imidazole (2.33 g, 34.2 mmol), and dimethylaminopyridine (3 mg) in DMF (15 mL) is stirred at RT for 18 h. This solution is poured into EtOAc and extracted with water (1×) and brine (5×). The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to afford crude product, which is chromatographed on silica gel to afford the title compound: 1H NMR (CDCl3δ 7.27 (m, 5H), 6.26 (m, 3H), 4.96 (s, 2H), 4.45 (br s, 1H), 3.91 (s, 2H), 1.35 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H); (M+1)+=444.
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([O:25]C)=[O:24])[CH3:22])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CO>CO.O>[NH:1]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
A mixture of tBoc-Lys(Cbz)-Ala-OMe (6.4545 g, 13.86 mmol) 16 and LiOH (1.004 g, 41.8 mmol) in methanol/water (80/10 mL) was stirred at room temperature for 4 h. The reaction mixture was neutralized with 0.5 N citric acid and methanol was removed under reduced pressure. The resulting aqueous solution was diluted with water and extracted with dichloromethane and ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and dried under vacuum to obtain 17 as a white solid (3.445 g, 55%). The product was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:9]=[C:8]([C:18]([O:20]C)=[O:19])[C:7]=2[C:6]([CH3:22])=[CH:5]1)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[C:7]=2[C:6]([CH3:22])=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2nnn[nH]2)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(C(C)C)c2cc(-c3nnn[nH]3)cc(C(=O)O)c12
Temperature: 60 °C
Reaction time: 48 h
Yield: 101 %

Procedure:
To a stirred solution of methyl 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylate (0.27 g, 0.902 mmol) in MeOH (15 mL) and tetrahydrofuran (5 mL) was added 1N NaOH (5 mL, 5.00 mmol). The reaction was heated to 60° C. and stirred for 48 hr. LCMS showed that the reaction was complete. The reaction was concentrated to near dryness under vacuum, acidified with 1 N HCl (5 mL), triturated, filtered and washed with a small volume of water, and dried under vacuum to give the product 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylic acid (0.26 g, 0.911 mmol, 101% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br. s., 1H), 8.36 (d, J=1.5 Hz, 1H), 8.13 (d, J=1.3 Hz, 1H), 7.65 (s, 1H), 4.85 (quin, J=6.6 Hz, 1H), 2.36 (s, 3H), 1.50 (d, J=6.6 Hz, 6H). MS (ES)+m/e 286.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[C:18]([NH:17][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)=[O:10])[CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: Cc1cccc(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of 6-methylpyridine-2-carboxylic acid (5.66 g, 41.3 mmol) in tetrahydrofuran (300 mL) were added N,N-dimethylformamide (5 drops) and oxalyl chloride (7.20 mL, 83.0 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (200 mL). A solution of 5-(3-aminophenoxy)pyridin-2-amine (7.90 g, 39.3 mmol) in N,N-dimethylacetamide (20 mL) was added with stirring at room temperature, and the mixture was stirred at room temperature for 65 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give the title compound (10.4 g, 83%) as a pale-brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][NH:5][C:4](=[S:9])[C:3]=1[C:10]#[N:11].C([O-])(=O)C.[Na+].Cl[CH2:18][C:19]#[N:20]>C(O)C.CC(O)C>[NH2:11][C:10]1[C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[N:5][C:4]=2[S:9][C:18]=1[C:19]#[N:20]
Reactant: N#CCCl
Reactant: Cc1n[nH]c(=S)c(C#N)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Product: Cc1nnc2sc(C#N)c(N)c2c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 5,6,-dimethyl-3-thioxo-2,3-dihydropyridazine-4-carbonitrile (99 mg, 0.60 mmol) was stirred in ethanol (6.0 mL). Sodium acetate (50 mg, 0.60 mmol) and chloroacetonitrile (0.040 mL, 0.60 mmol) were added and the mixture was stirred at ambient temperature for 90 minutes. The mixture was then diluted with IPA, stirred for 15 minutes, and filtered. The solute was concentrated in vacuo, and the resulting solid was dried overnight at 60° C. in a vacuum oven to give the product. LC/MS: RT=0.38 min., m/z=205 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][N:35]([CH3:44])[C:36]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br)=[O:37])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>CN(C)C=O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][N:35]([CH3:44])[C:36]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:16][C:13]2[CH:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:15][N:14]=2)=[O:37])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(CCN(C)C(=O)CCCCCBr)cc1OC
Reactant: COc1ccc(C2CC(=O)NN2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)C(=O)CCCCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Temperature: 100 °C
Yield: 84.5 %

Procedure:
3.85 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one were dissolved in 50 ml of anhydrous dimethylformamide. 3.15 g of finely ground potassium carbonate were added to the solution, and the reaction mixture was heated under a nitrogen atmosphere to 100° C. with stirring. A solution of 5.6 g of 5-{N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminocarbonyl}-pentyl bromide in 10 ml of anhydrous dimethyl formamide was slowly added dropwise to the solution, and the reaction mixture was stirred at 100° C. for a further 2 hours. In order to work up the reaction mixture, it was cooled and then the precipitated salts were filtered out and the filtrate was concentrated by evaporation. The oily residue which remained was dissolved in ethyl acetate and washed with 7% strength sodium hydroxide solution in order to remove unreacted 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one. The organic phase was separated, dried with sodium sulfate and concentrated by evaporation. 6.5 g of 3-{5-[N-(2-(3,4-dimethyloxyphenyl)-ethyl)-N-methylaminocarbonyl]-pentyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole were obtained as an oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][NH:39][C:40]([CH2:42][CH3:43])=[O:41])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@@H](C(NCC(O)=O)=O)[C@H](C)O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][NH:39][C:40]([CH2:42][CH3:43])=[O:41])=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: C[C@H](O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Product: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Yield: 55.2 %

Procedure:
Using Z-Tyr-(D)-His-Gly-Phe-NHNH-COCH2CH3 (0.20 g), the desired compound (90 mg) is obtained in a similar manner to (II) of Example 4.Rf2 =0.15, Amino acid analysis His 0.95, Gly 1.00, Tyr 0.85, Phe 1.02
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:28])[CH2:8][C:9](=[O:27])[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=2)[CH2:12][CH2:11]1)C.C1COCC1.O>CO>[O:27]=[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=2)[CH2:12][CH2:11]1)[CH2:8][C:7]([OH:28])=[O:6]
Reactant: CCOC(=O)CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
LiOH.H2O (93 mg, 2.2 mmol) was added to a solution of 3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionic acid ethyl ester (400 mg, 1.1 mmol) in a mixture of methanol (2 mL), THF (5 mL) and H2O (2 mL). The resulting mixture was stirred for 2 hours at room temperature. The mixture was then concentrated and the residue was diluted with water, washed with diethyl ether and acidified with concentrated HCl. The residue was extracted with ethyl acetate and concentrated to afford 230 mg (62%) of 3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionic acid. LCMS: 331.09 (M+1)+, 90.2%, 1H NMR: (CDCl3): δ 7.0 (t, 2H), 3.7 (s, 4H), 3.5 (m, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][C:6](C(OCC)=O)([C:10]([O:12][C:13](C)(C)[CH3:14])=[O:11])[CH2:7]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH:4]2[CH:8]([CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5]2)[CH2:9]1
Reactant: CCOC(=O)C1(C(=O)OC(C)(C)C)CC2CC(=O)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CC2CC(=O)CC2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-tert-butyl 2-ethyl 5-oxohexahydropentalene-2,2(1H)-dicarboxylate (0.8 g, 2.70 mmol) in DCM (4 mL) was added TFA (2.080 mL) and the reaction mixture was stirred at rt for 4 h. The reaction mixture was evaporated to dryness and the residue was dissolved in pyridine (5 mL) and heated to reflux for 4 h until decarboxylation was complete. Pyridine was evaporated and the residue was purified by silica gel chromatography (10% EtOAC in DCM) to afford ethyl 5-oxooctahydropentalene-2-carboxylate (a mixture of endo/exo isomers) as a clear oil. 1H NMR (500 MHz, CDCl3) δ ppm 4.10-4.18 (2H, m), 2.85-3.02 (2H, m), 2.69-2.80 (1H, m), 2.44-2.56 (2H, m), 2.20-2.36 (2H, m), 2.10-2.20 (1H, m), 2.04 (1H, dd, J=19.45, 4.65 Hz), 1.66-1.80 (2H, m), 1.22-1.31 (3H, m).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][Si:15]([CH3:25])([CH3:24])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH:26]([P:29](Cl)(Cl)=[O:30])([CH3:28])[CH3:27]>CCCCCC.C1CCCCC1>[CH:26]([P:29]1(=[O:30])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:16]1[Si:15]([CH3:25])([CH3:24])[CH3:14])([CH3:28])[CH3:27]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: C[Si](C)(C)NCc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CC(C)P1(=O)c2ccccc2CN1[Si](C)(C)C
Temperature: 26 °C
Reaction time: 16.5 h

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8 g, 0.125 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-trimethylsilylbenzylamine (10.75 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 16.5 hours at 26° C. and then cooled to -72° C. using a solid carbon dioxide-acetone bath. A solution of isopropylphosphonic dichloride (10.3 g, 0.064 mol) in 60 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to -10° C. The reaction mixture was allowed to cool to -72° C., after which time the solid carbon dioxide-acetone bath was removed and the reaction mixture was stirred for 1.5 hours at 26° C. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. The reaction mixture was concentrated under vacuum and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to yield a red oil. The red oil was distilled at 180° C. and 0.2 mm to yield 1-isopropyl-2-trimethylsilyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[CH3:23][CH:24]([CH3:29])[CH2:25]B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][CH:24]([CH3:29])[CH2:25][C:17]1[CH:16]=[C:15]([C:12]([NH:11][C:10](=[O:22])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:14])[CH3:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(Br)c1
Reactant: CC(C)CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)Cc1cccc(C(C)(C)NC(=O)OC2CN3CCC2CC3)c1
Yield: 72.6 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (75 mg, 0.20 mmol), 2-methylpropyl boronic acid (28.1 mg, 0.276 mmol) and palladium (II) acetate gave the title compound as a white solid (50 mg, 71%). 1H NMR (400 MHz, CDCl3) 7.21 (d, J=4.9 Hz, 2H), 7.16 (s, 1H), 7.00 (s, 1H), 5.17 (s, 1H), 4.60 (s, 1H), 3.35-2.10 (m, 6H), 2.45 (d, J=7.1 Hz, 2H), 1.82 (dt, J=6.8, 13.5 Hz, 1H), 2.03-0.94 (m, 5H), 1.65 (s, 6H), 0.89 (d, J=6.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.6, 172.1, 170.8, 170.2, 160.1, 160.0, 157.8, 157.7, 140.4, 139.8, 130.5, 130.4, 130.0, 129.8, 129.5, 129.3, 127.9, 127.7, 120.8, 120.7, 120.3, 113.9, 113.6, 113.2, 113.0, 110.5, 110.4, 66.6, 66.5, 56.8, 56.3, 55.4, 55.4, 54.0, 53.7, 51.1, 46.6, 43.8, 43.7, 42.0, 38.4, 37.8, 37.7, 33.8, 33.2, 27.4, 27.0, 25.7, 25.5, 20.9, 20.9 ppm. Purity: 90% UPLCMS (210 nm): retention time 0.89 min: (M+1) 345.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[C:27]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([C:27]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([CH2:24][O:23][CH2:22][C:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[CH:26]=2)=[CH:40][CH:39]=1)#[N:42]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2-c2ccccc2)CC1
Temperature: 120 °C
Yield: 40.3 %

Procedure:
A mixture of tert-butyl 4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate (100 mg, 0.15 mmol), phenyl boronic acid (19 mg, 0.15 mmol), potassium carbonate (43 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.15 mmol) were placed in a sealable vessel and degassed with nitrogen for 5 min. The vessel was then sealed and heated at 120° C. for 3 h. The reaction was poured into brine (20 mL) and extracted with ethyl acetate (4×5 mL). The combined organic layers were dried (MgSO4) and evaporated to dryness. The resulting residue was purified by chromatography on SiO2 with a ethyl acetate/hexanes gradient from 12% to 100%. The product tert-butyl 4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(5-fluorobiphenyl-2-yl)piperidine-1-carboxylate (39 mg, 39%) was isolated as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.68-7.76 (m, 3H), 7.55 (d, J=8.4 Hz, 2H), 7.44 (m, 3H), 7.18-7.28 (m, 3H), 7.03 (m, 1H), 6.94 m, 2H), 6.67 (m, 1H), 4.52 (s, 2H), 3.52 (m, 2H), 3.47 (s, 2H), 2.90 (m, 2H), 1.91 (m, 2H), 1.45 (m, 2H), 1.38 (s, 9H). Mass spec.: 645.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 66.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (step 1 of example 132) (700 mg, 0.9889 mmol) was deprotected with TFA/DCM (5/20 ml). This afforded 400 mg (66.6% yield) of the titled compound. MS: m/z=608.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[C:8]([Cl:16])[CH:7]=1)=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[C:8]([Cl:16])[CH:7]=2)=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)cc1Cl
Reactant: Nc1ccccc1
Product: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)cc1Cl

Procedure:
2-Chloro-N-(3-chloro-4-sulphamoylphenyl)-acetamide (28.3 g) and aniline (19 ml) were heated together for 30 min on a water bath (90°) and the product worked up as in Example 1(b) to yield 25 g, m.p. 192°-194°.