Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19](OC)=[C:18](OC)[CH:17]=3)[C:12]3[CH:26]=[CH:27][C:28]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:31])=[CH:29][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2].N>C(OCC)(=O)C.C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:7][CH2:8][CH2:3][CH2:4][CH2:5][CH3:6])[C:12]3[CH:26]=[CH:27][C:28]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:31])=[CH:29][C:11]=3[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C#N)cc1)n2CCc1ccc(OC)c(OC)c1
Agent: N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCCCCCCCCn1c(-c2ccc(C#N)cc2)nc2cc(C(=O)NCCC(=O)OC)ccc21

Procedure:
The same procedure is used as in (1) Rf value: 0.60 (silica gel; ethyl acetate/ethanol/conc. ammonia=50:2:0.02)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28][C@H:29]([OH:32])[C:30]#[CH:31]>C1COCC1.CCOC(C)=O.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:31]#[C:30][C@@H:29]([OH:32])[CH3:28])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: C#C[C@H](C)O
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](O)C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 44.3 %

Procedure:
A solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (86 mg, 0.174 mmol), (2S)-3-butyn-2-ol (30.5 mg, 0.436 mmol), palladiumbisdichlorobistriphenylphosphine (12.23 mg, 0.017 mmol), copper(I) iodide (1.659 mg, 8.71 μmol) and TEA (0.121 ml, 0.871 mmol) in THF (3 ml) was irradiated in the microwave for 10 minutes at 120° C. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(3S)-3-hydroxy-1-butyn-1-yl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide (37 mg, 0.077 mmol, 44% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.54-7.94 (m, 1H), 7.26-7.47 (m, 2 H), 7.11 (s, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 4.24-4.71 (m, 3H), 1.41 (d, 3H). LC-MS (ES+) m/z 481.95, [M+H].
Reaction SMILES: C[Si]([C:5]#[C:6][CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([CH:7]1[CH2:16][CH2:15][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:9][CH2:8]1)#[CH:5]
Reactant: C[Si](C)(C)C#CC1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 16.7 grams (0.07 mole) of 8-trimethylsilylethynyl-1,4-dioxaspiro[4.5]decane and 1.1 grams (0.07 mole) of potassium carbonate in 200 mL of methanol is stirred at ambient temperature for about one hour. The reaction mixture is then concentrated under reduced pressure to a residue. The residue is stirred in about 150 mL of water, and the mixture is extracted with three 150 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 8-ethynyl-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCOCCO
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCOCC(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
To a stirred solution of 2-allyloxy-ethanol 7 (10.9 mL, 100 mmol, 1.0 equiv.) in THF (200 mL) was carefully added NaH (60%, 4.8 g, 120 mmol, 1.2 equiv.) in small portions at room temperature. The reaction was then refluxed for 1 h (until H2 release ceased) then cooled to 0° C. Methyl bromoacetate (11.4 mL, 120 mmol, 1.2 equiv.) was then added dropwise. After 15 min at 0° C., the reaction was submitted to a EtOAc/H2O extraction. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered then evaporated under reduced pressure. Purification was achieved by Kugelrohr distillation under reduced pressure and provided 9.77 g (55%) of ester (8) as a colorless oil; bp=130-145° C. (water tap vacuum); 1H NMR (400 MHz, CDCl3) δ 5.91 (m, 1H), 5.28 (m, 1H), 4.99 (m, 1H), 4.19 (s, 2H), 4.02 (m, 2H), 3.76 (s, 3H), 3.75 (m, 2H), 3.64 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.1, 134.8, 117.3, 72.4, 71.2, 69.7, 68.9, 51.9; IR (neat) 1755 cm−1; HRMS (ESI, m/z) calcd. for C8H15O4 (MH+) 175.0964. found 175.0960.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[NH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:7]=[C:3]([C:2]([F:1])([F:12])[F:13])[N:4]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:5]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Cn1nc(C(F)(F)F)cc1C(F)(F)F)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3,5-Bis-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.94–7.0 (m, 2H), 6.92 (s, 1H), 6.82–7.90 (dd, 2H), 5.2 (s, 2H), 3.72–3.8 (t, 2H), 3.58–3.66 (t, 2H), 3.12–3.18 (t, 2H), 3.02–3.12 (t, 2H). 13C NMR (400 MHz, CDCl3): 162.2, 158.2, 156.4, 146.5, 118.4, 116.2, 115.8, 113.2, 60.4, 53.2, 50.6, 50.2, 45.2, 42.2, 21.2, 14.2.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Mg]Cl)C.C(O[CH:15]1[NH:18][C:17](=[O:19])[CH2:16]1)(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH:15]1[NH:18][C:17](=[O:19])[CH2:16]1
Reactant: CC(=O)OC1CC(=O)N1
Reactant: C#C[Si](C)(C)C
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#CC1CC(=O)N1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylsilylacetylene (1715 ml) in tetrahydrofuran (18.0 l) was added ethyl magnesium chloride (2.0M solution in tetrahydrofuran; 6.19 l) was added dropwise below −30° C. under nitrogen atmosphere. The reaction mixture was allowed to 0° C. and stirred for 1 hour. After cooling to −30° C., 4-acetoxy-2-azetidinone (320 g) was added and warmed to room temperature, and stirred for 2 hours. After cooling to −20° C., saturated ammonium chloride (4.0 l) was added. Ethyl acetate (20 l) was added and washed with water (10 l×2) and brine. The organic layer was dried over magnesium sulfate, filtered off and evaporated in vacuo to give 4-(2-trimethylsilylethynyl)-2-azetidinone (425 g), which was essentially pure, so it was used to the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:15]([C:20](O)=[O:21])=[N:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[C:4]1[CH3:23])[CH3:2].[C:24]1([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)C)(=O)C>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]3=[N:19][CH:18]=[CH:17][N:16]=[C:15]3[C:20](=[O:21])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2nccnc2C(=O)O)c2ccccc21
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(N(c3ccccc3)c3ccccc3)OC(=O)c3nccnc32)c2ccccc21

Procedure:
A mixture containing 4 g. of 3-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-2-pyrazinecarboxylic acid, 1.7 g. of diphenylamine and 15 ml. of acetic anhydride was stirred 1 hour at room temperature and then 30 minutes with gentle warming. The product, 7-(1-ethyl-2-methyl-3-indolyl)-7-(diphenylamino)furo[3,4-b]pyrazine-5(7H)-one was isolated by column chromatography as a red solid, m.p. 98°-100° C. A toluene solution of this product contacted with acidic clay or phenolic resin developed an orange image.
Reaction SMILES: O[C@H:2]([C:17]([O:19]CC)=[O:18])[C@H:3]([C:12]([O:14]CC)=[O:13])[CH2:4][C:5]([O:7]C(C)(C)C)=[O:6].Cl>C(O)(=O)C>[O:6]=[C:5]1[O:7][C@H:2]([C:17]([OH:19])=[O:18])[C@H:3]([C:12]([OH:14])=[O:13])[CH2:4]1
Reactant: CCOC(=O)[C@@H](O)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)O)O1
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
16.49 g of 3-tert-butyl 1,2-diethyl (1S,2R)-1-hydroxy-1,2,3-propanetricarboxylate prepared in Reference Example 5(1), 100 ml of acetic acid and 50 ml of concentrated hydrochloric acid were mixed and stirred at 70° C. for 5 hours. The acetic acid and the hydrochloric acid were distilled off under reduced pressure, and the residue was dissolved in 100 ml of acetic acid and 50 ml of concentrated hydrochloric acid again and stirred at 70° C. for 12 hours. The acetic acid and the hydrochloric acid were distilled off under reduced pressure, and the residue was mixed with 100 ml of trifluoroacetic acid and stirred at 60° C. for 5 hours. The trifluoroacetic acid was distilled off under reduced pressure, and the residue was crystallized from hexane-ethyl acetate to give 9.38 g of the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]1)=[O:11].O.[OH-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)C1CCN(C(=O)Cc2cc(C)ccc2C)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)c(CC(=O)N2CCC(C(=O)O)CC2)c1
Temperature: 0 °C

Procedure:
Methyl 1-[(2,5-dimethylphenyl)acetyl]-4-piperidinecarboxylate (i.e. the product of Example 9, Step A) (4.95 g, 17.1 mmol) was dissolved in 20 mL of tetrahydrofuran, and 15 mL of water was added. With vigorous stirring the reaction mixture was cooled to 0° C., and 35 mL of a 1 N aqueous sodium hydroxide solution was added dropwise. The reaction mixture was stirred at room temperature for 1 h, diluted with 20 mL of brine, washed with diethyl ether (3×20 mL), and the aqueous phase was acidified with 1 N aqueous hydrochloric acid to pH 3-4. The precipitate was collected and dried to give 4.08 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Na+]>CO>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 80.1 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), water (320.8 g), and methanol (320.8 g) was placed in a 1 l-flask. The mixture was heated to 80° C. with stirring by use of a mechanical stirrer. A 20% aqueous solution of sodium hydroxide was added to the mixture so as to adjust the pH of the mixture at 8.0-8.3. Twenty-four hours after the reaction started, liquid chromatographic analysis revealed that the reaction mixture contained 58.9 g of p-cyanobenzoic acid (yield 80.2%). The reaction mixture was cooled to 30° C., and hydrochloric acid was added thereto to lower the pH to 3.1. The mixture was heated again to 82° C. to dissolve. The resultant mixture was cooled for crystallization, to thereby obtain 57.7 g of p-cyanobenzoic acid crystal (purity 96.8%, yield 76%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)OC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)OC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-cyclohexyloxycarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.C(O[CH:21](OCC)[CH2:22][NH2:23])C>Cl.O1CCOCC1>[NH2:23][CH2:22][CH:21]1[C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:4][C:5]=2[CH2:9][CH2:10][O:11]1
Reactant: CN(c1ccccc1)c1cccc(CCO)c1
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CN(c1ccccc1)c1ccc2c(c1)CCOC2CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
2-{3-[Methyl(phenyl)amino]phenyl}ethan-1-ol (1.0 g, 4.4 mmol) was stirred in 4N HCl/dioxane (8 mL) at 0° C. Aminoacetaldehyde diethyl acetal (880 mg, 6.6 mmol) was added, and the reaction stirred for at r.t. for 1 h and then at 108° C. in the microwave for 1 h. The solution was concentrated and purified by silica gel chromatography (0% to 20% MeOH/DCM) to give 150 mg (13%) of the title compound as a yellow oil. [M+H] Calc'd for C17H20N2O, 269. Found, 269.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>N1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc2ccccc2c1
Yield: 95.7 %

Procedure:
Prepared according to the procedure described for Example 121 using 2-napthalenesulfonyl chloride (2.28 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (4.139 g); m.p. 223-225° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: C([O:8][C@H:9]1[CH2:33][N:12]2[C@@H:13]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=3)[C:15](=[O:16])[C@@H:11]2[CH2:10]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl>C(Cl)Cl>[C:29]([C@@H:13]1[N:12]2[CH2:33][C@H:9]([OH:8])[CH2:10][C@H:11]2[C:15](=[O:16])[N:14]1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)[C@H]1N(c2ccc(C#N)c3ccccc23)C(=O)[C@@H]2C[C@@H](OCc3ccccc3)CN21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[C@H]1N(c2ccc(C#N)c3ccccc23)C(=O)[C@@H]2C[C@@H](O)CN21
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
Compound 33C (94.4 mg, 0.2 mmol) was dissolved in dry CH2Cl2 (5.0 ml), cooled to −75° C., treated with 1.0 M BCl3/CH2Cl2 (1.2 ml, 1.2 mmol) and stirred at −75° C. for 1.5 hr. The reaction mixture was quenched with ice-water (3.4 ml), warmed to room temperature, stirred for 5 min then extracted with CH2Cl2 (50 ml). The organic phase was washed with water (3.4 ml) and brine (3.4 ml) and dried (Na2SO4). Purification using automated flash chromatography (35 g silica gel column, EtOAc/hexane gradient) gave the title compound as a white solid (34.7 mg, 49.6%), m.p. 155-157° C. MS (ES): m/z 350 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([O:5][C:6]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([C:19]#[N:20])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ncc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)OC(=O)c1ncc(C#N)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-3-nitro-pyridine-2-carboxylic acid tert-butyl ester (888 mg, 2.93 mmol) in DMF (8.8 ml) was added zinc cyanide (206 mg, 1.76 mmol) and zinc dust (2 mg, 0.03 mmol). The mixture was purged with nitrogen (3 times) bis(tri-tert-butylphosphine)palladium(0) (150 mg, 0.293 mmol) was added and the mixture was heated to 80° C. for 4 h. After cooling to 0° C. water was added and the mixture extracted with EtOAc, the combined organic layers were washed with half saturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as beige solid.
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[O:6]1)[NH2:2].[Na+].[I-:28].FC(F)(F)C(O)=O>CC(=O)CC>[S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[I:28])[O:6]1)[NH2:2]
Reactant: [I-]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(I)ncnc21
Temperature: -10 °C
Reaction time: 4.5 h
Yield: 81.2 %

Procedure:
To a solution of ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate (645 mg, 1.59 mmol) in 2-butanone (30.0 mL) was added NaI (4.77 g, 31.79 mmol). The reaction was cooled to −10° C. and trifluoroacetic acid (612 μL, 7.94 mmol) was added. The reaction was stirred for 4.5 hours, quenched with saturated aq NaHCO3 and extracted with DCM. The crude product was purified by flash chromatography (40% EtOAc/DCM) to isolate the title compound (0.642 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:25]1[N:30]2[N:31]=[C:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:47])[C:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:29]2[N:28]=[C:27]([CH3:48])[N:26]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:25]1[N:30]2[N:31]=[C:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:47])[C:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:29]2[N:28]=[C:27]([CH3:48])[N:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 8 h

Procedure:
To a mixture of 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (78 mg, 0.40 mmol) and diisopropylethylamine (0.094 ml, 0.52 mmol) in methylene chloride (2.5 ml) was added 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 135 mg, 0.35 mmol), portionwise. After stirring overnight, the reaction was concentrated, in vacuo, to ½ volume and then purified on a Biotage™ Flash 12M column using 0-3% ethyl acetate in methylene chloride to afford 8A-1 (200 mg, quantitative) as a solid: +APcI MS (M+1) 551.2; 1H NMR (400 MHz, CD3OD) δ 7.50-7.34 (m, 4H), 7.32 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 4.60 (br s, 1H), 2.46 (s, 3H), 2.10-1.99 (br m, 2H), 1.50-1.40 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:9]([C:10](=[O:12])[CH3:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(=O)CC(=O)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCC(C(C)=O)C(=O)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-fluorophenyl)butane-1,3-dione (1.0 g), potassium carbonate (3.84 g), and tetrabutylammonium bromide (90 mg) in toluene (20 ml) was refluxed for 3 hours, then ethyl 6-bromohexanoate (1.18 ml) was added. After stirring at 100° C. for 3 hours, the mixture was partitoned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 7-(4-fluorobenzoyl)-8-oxononanoate (983 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]
Reactant: COC(=O)Cc1ccc(Cl)c(NC(=O)Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(Cl)c(NC(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.98 mmol (990 mg) of methyl 4-chloro-3-[[(phenylamino)carbonyl]-amino]benzeneacetate is taken up in 10 ml of methanol and mixed with 6 mmol of 1N NaOH. After 2 hours of stirring at room temperature, the methanol is distilled off, and the residue is acidified with 1 M HCl to pH 2–3. It is extracted with ethyl acetate, dried with Na2SO4, and solvent is removed. Recrystallization is carried out from boiling isopropanol. Yield: 830 mg of white solid 4.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:30]([C:31](=[O:42])[NH:32][C:33]3[CH:41]=[C:40]4[C:36]([CH:37]=[N:38][NH:39]4)=[CH:35][CH:34]=3)=[CH:29][C:17]3[N:18]=[C:19]([NH:21][C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=4)[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH:39]1[C:40]2[C:36](=[CH:35][CH:34]=[C:33]([NH:32][C:31]([C:30]3[C:14]([N:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)=[CH:15][C:16]4[NH:20][C:19]([NH:21][C:22]5[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=5)=[N:18][C:17]=4[CH:29]=3)=[O:42])[CH:41]=2)[CH:37]=[N:38]1
Reactant: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4cn[nH]c4c3)c(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4cn[nH]c4c3)c(N3CCC(N)CC3)cc2[nH]1

Procedure:
The product from Example 157 was treated with 4M HCl in dioxane employing the procedure described for Example 156 to afford 6-(4-Aminopiperidin-1-yl)-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 521 (M+H)+.