Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]([F:17])=[C:14]([F:16])[F:15].C1(O)C=CC=CC=1.[OH-].[K+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([O:11][C:14]([F:16])([F:15])[CH:13]([F:17])[F:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: FC(F)=C(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)cc1F
Reaction time: 2 h
Yield: 10.6 %

Procedure:
After dissolving 1.15 g of 3-fluoro-4-nitrophenol in 10 ml of dioxane, the resulting solution was violently stirred at about 60° C. for 15 minutes under the stream of a tetrafluoroethylene gas in large excess of said phenol. After quickly adding 0.04 g of potassium hydroxide, the solution was violently stirred for 2 hours under the same condition. The reaction solution was cooled, and after adding water, extracted with two 100-ml portions of diethyl ether. The ether layers were combined, dried and concentrated to obtain a yellow oily product as a residue. This oily product was subjected to chromatography on silica gel to obtain 0.20 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)nitrobenzene.
Reaction SMILES: [CH:1]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O-:10].[Na+]>C(O)C>[CH:1]1([C:6]2[NH:7][C:9](=[O:10])[CH:5]=[C:1]([CH2:2][CH3:3])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[O-]
Reactant: N=C(N)C1CCCC1
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(=O)[nH]c(C2CCCC2)n1
Temperature: 85 °C
Yield: 122.1 %

Procedure:
A solution of cyclopentanecarboximidamide (8.5 g, 75.8 mmol) in ethanol (150 mL) was treated with ethyl propionaylacetate (13.7 g, 94.7 mmol), followed by the addition of sodium methoxide (4.9 g, 90.9 mmol). The mixture was then heated to 85° C. overnight. After this time, the mixture was cooled and concentrated to a volume of approximately 50 mL. Then, 2M HCl in EtOH (68 mL) was added slowly. The resulting precipitate was filtered, washed with water and ether, and the residue was dried on a high vacuum overnight to afford the title compound (8.9 g, crude) as a pink solid. MW=192.26. 1H NMR (DMSO-d6, 500 MHz) δ 12.00 (s, 1H), 6.14 (s, 1H), 3.01 (quin, J=8.0 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 2.13-2.01 (m, 2H), 1.94-1.77 (m, 4H), 1.74-1.63 (m, 2H), 1.22 (t, J=7.5 Hz, 3H); APCI MS m/z 193 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([NH:17][CH:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.C([O-])(O)=O.[Na+].[F:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][NH:50]2)=[C:46]([NH:53][C@H:54]([C:56]2[N:57]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:58](=[O:67])[C:59]3[C:64]([CH:65]=2)=[CH:63][CH:62]=[CH:61][C:60]=3[CH3:66])[CH3:55])[N:45]=1>Cl.CCO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:17][C@H:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.[F:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][NH:50]2)=[C:46]([NH:53][CH:54]([C:56]2[N:57]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:58](=[O:67])[C:59]3[C:64]([CH:65]=2)=[CH:63][CH:62]=[CH:61][C:60]=3[CH3:66])[CH3:55])[N:45]=1
Reactant: Cc1cccc2cc(C(C)Nc3nc(F)nc4c3ncn4C3CCCCO3)n(-c3ccccc3)c(=O)c12
Agent: Cc1cccc2cc([C@H](C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Cc1cccc2cc(C(C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3-(1-(2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5203) (160 mg, 0.32 mmol) was dissolved in HCl/EtOH (3 M, 5 mL) and the resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated NaHCO3 aqueous solution to pH=7-8, and extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate and hexanes. The solid was collected by filtration and dried in vacuo to afford the desired product, 3-(1-(2-fluoro-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5204) (125 mg, 94% yield) as a white solid.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].CC[O-].[Na+]>CC(OC)(C)C.O>[CH3:20][C:8]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:7][CH2:6][CH2:5][C:4]#[CH:3]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC#C[Si](C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: C#CCCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
A 3-N 250 mL flask was charged with trimethyl-(6,10,14-trimethyl-pentadeca-5,9,13-trien-1-ynyl)-silane (Ex-1B-7) (19.38 g, 64.1 mmol) and NaOEt (42 mL of a 21% w/w solution, 112 mmol). The reaction mixture was stirred at 60° C. for 4 h. After cooling to RT, the reaction mixture was diluted with MTBE (100 mL) and water (100 mL) and then filtered to remove solid present at the phase interface. The aqueous layer was extracted with MTBE (3×100 mL). The combined MTBE layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to yield 12.43 g of 6,10,14-trimethyl-pentadeca-5,9,13-trien-1-yne (Ex-1B-8) as a dark orange oil (96%). 1H NMR (400 MHz, CDCl3) δ (ppm): 5.23-5.17 (m, 1H), 5.17-5.07 (m, 2H), 2.29-1.95 (m, 13H), 1.70 (s, 3H), 1.65 (s, 3H), 1.62 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: O=Cc1sccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccsc1C1OCCO1
Yield: 74.1 %

Procedure:
3-Bromothiophen-2-aldehyde (2) (7.44 g, 39 mmol), ethylene glycol (2.7 ml, 48 mmol), anhydrous benzene (130 ml) and a few crystals of p-toluenesulphonic acid were refluxed in a Dean-Stark apparatus until no more water separated. The benzene layer was washed with a solution of bicarbonate, dried (Na2SO4), and evaporated under reduced pressure to give the derivative 3 (6.8 g, 28.9 mmol, 74% yield) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C)C(N1CCCC1C(=O)[NH:33][CH:34]1[CH2:38][C:37](=[O:39])[O:36][CH:35]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[NH:33][CH:34]1[CH2:38][C:37](=[O:39])[O:36][CH:35]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 57 %

Procedure:
Prepared from piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 99 and 40 following the method used in the preparation of 75 to give the title compound as a yellow solid (2.63 g, 57% yield). 1H-NMR (500 MHz, CDCl3) δ 1.15-1.79 (m, 15H), 2.12-2.50 (m, 2H), 2.56-2.83 (m, 1H), 2.89 (dd, 0.5H), 3.05 (dd, 0.5H), 3.81-4.15 (br s, 1H), 4.36-4.97 (m, 3H), 5.37-5.61 (m, 1H), 6.42-6.89 (br s, 1H), 7.17-7.51 (m, 5H). LC-MS (ES+) m/e=419.4 (MH+).
Reaction SMILES: O.[ClH:2].[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([C:15]([CH3:17])=[O:16])([CH3:14])=[O:13].C(O)(C)C.O.C([O-])(=O)C.[Na+]>O>[ClH:2].[CH3:17][C:15]1([OH:16])[C:12]([CH3:14])([OH:13])[NH:11][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:10]1
Reactant: CC(=O)C(C)=O
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC1(O)N=C(c2ccccc2)NC1(C)O
Reaction time: 4 h

Procedure:
To 56.4 g (0.323 mole) of benzamidine hydrochloride hydrate in 200 ml of warm water is added with vigorous stirring 40 ml of biacetyl. Within a few minutes a heavy precipitate forms and 150 ml of isopropyl alcohol is added followed by 5.0 g of sodium acetate hydrate dissolved in 15 ml of warm water. Stirring is continued for 4 hours after which time the product, 4,5-dimethyl-2-phenylimidazoline-4,5-diol hydrochloride, is filtered off and washed with isopropyl alcohol. Recrystallization from 95% ethanol gives the pure product, m.p. 162°-165° C (dec.).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[CH:22]=[C:21]4[N:24]([CH2:30][CH3:31])[C:25](=[O:29])[N:26]([CH2:27][CH3:28])[C:20]4=[CH:19][C:18]=3[C:17](Cl)=[N:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[N+:40]([C:43]1[CH:48]=[CH:47][C:46]([N:49]=C=O)=[CH:45][CH:44]=1)([O-:42])=[O:41].[Cl-].[Na+]>ClCCl.O>[CH2:27]([N:26]1[C:20]2=[CH:19][C:18]3[CH:17]=[N:16][N:15]=[C:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([NH:49][C:46]5[CH:47]=[CH:48][C:43]([N+:40]([O-:42])=[O:41])=[CH:44][CH:45]=5)=[O:5])[CH2:9][CH2:10]4)[C:23]=3[CH:22]=[C:21]2[N:24]([CH2:30][CH3:31])[C:25]1=[O:29])[CH3:28]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCn1c(=O)n(CC)c2cc3c(N4CCN(C(=O)OC(C)(C)C)CC4)nnc(Cl)c3cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCn1c(=O)n(CC)c2cc3c(N4CCN(C(=O)Nc5ccc([N+](=O)[O-])cc5)CC4)nncc3cc21
Reaction time: 5 h
Yield: 53 %

Procedure:
To a solution of 758.4 mg (1.65 mmol) of 4-(8-chloro-1,3-diethyl-1,3-dihydro-2-oxo-2H-imidazo[4,5-g]phthalazin-5-yl)-1-piperazinecarboxylic acid tert-butyl ester obtained in Reference Example 21 (5) in 20 ml of dichloromethane was added 50 ml of trifluoroacetic acid under ice-cooling, followed by stirring at the same temperature for 5 hours. After the solvent was evaporated, the residue was subjected to azeotropic distillation with toluene twice. The obtained residue was dissolved in 20 ml of acetic acid, and a suspension of 300 mg of 10% palladium-carbon in 5 ml of water was added thereto, followed by overnight stirring at room temperature in an atmosphere of hydrogen. After the catalyst was separated by filtration using Celite, the solvent was evaporated, and the residue was subjected to azeotropic distillation with triethylamine. The obtained residue was dissolved in 10 ml of dimethylformamide, and 297.3 mg (1.81 mmol) of 4-nitrophenyl isocyanate was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=2[C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[O:28]=[C:27]1[CH:26]([N:25]2[C:21](=[O:23])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:15]2=[O:17])[CH2:32][CH2:31][C:30](=[O:33])[NH:29]1
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1OC
Yield: 85 %

Procedure:
A mixture of 3-(3,4-dimethoxyphenylamino)phthalic acid (0.59 g, 1.9 mmol) and rac-α-aminoglutarimide hydrochloride (0.32 g, 1.9 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.64 g of the product at 96:4 methylene chloride-methanol, in 85% yield: mp>215-217° C.; 1H NMR (CDCl3) δ 2.15-2.19 (m, 1H), 2.74-2.96 (m, 3H), 3.88 (s, 3H), 3.91 (s, 3H), 4.97 (dd, J=11.8 Hz, J=5.1 Hz, 1H), 6.78-6.81 (m, 1H), 6.85-6.91 (m, 2H), 7.16-7.21 (m, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.87 (s, 1H), 8.07 (s, 1H); 13C NMR (CDCl3) δ 22.8, 31.4, 49.0, 56.0, 56.2, 108.6, 110.9, 111.8, 113.2, 116.5, 118.5, 131.7, 132.4, 135.9, 145.2, 147.1, 149.8, 167.4, 168.2, 169.4, 170.8; Anal. calcd for C21H19N3O6: C, 61.61; H, 4.68; N, 10.26. Found: C, 61.47; H, 4.52; N, 10.12.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:40])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=C(C(F)(F)F)[CH:30]=2)[CH:24]=1)(C)(C)C.[C:42](O)([C:44]([F:47])([F:46])[F:45])=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:40])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(C(F)(F)F)c3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (5-chloro-2-{3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M246) (0.24 g, 0.40 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (150 mg, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]12[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C:5]23[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)N=C1N
Product: CC1=NC2(CC3(CCCOC3)Oc3ccc(-c4ccc(F)c(Cl)c4)cc32)N=C1N
Yield: 38 %

Procedure:
6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine (Example 45 Isomer 1, 77 mg, 0.21 mmol) and 3-chloro-4-fluorophenylboronic acid (47.9 mg, 0.27 mmol) were reacted using the conditions described for Example 46a Isomer 1, to give Isomer 1 of the title compound (33 mg, 38% yield) with undetermined configuration: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.44-1.52 (m, 1 H), 1.81-1.92 (m, 3 H), 1.97-2.05 (m, 2 H), 2.22 (s, 3 H), 3.41-3.48 (m, 1 H), 3.56 (d, 1 H), 3.67-3.74 (m, 1 H), 3.98 (d, 1 H), 6.57 (s, 2 H), 6.60 (d, 1 H), 6.94 (d, 1 H), 7.38-7.46 (m, 3 H), 7.60 (dd, 1 H); MS (ES+) m/z 414 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].O>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 2-amino-5-chloro-benzoic acid (3.43 g, 20 mmol) in DMF (10 mL) cooled in an ice-water bath was added isobutyryl chloride (2.11 mL, 20 mmol). The reaction was stirred for 2 hours while warming to room temperature. Water (20 mL) was added and the mixture was stirred vigorously for 1 hour. The precipitate was then collected by vacuum filtration to give the product as a pale yellow solid (3.20 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.52 (d, J=9.0 Hz, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.66 (dd, J=9.0, 2.7 Hz, 1H), 2.58 (septet, J=6.9 Hz, 1H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5]2)[CH2:3][O:2]1.[CH2:20]1[O:22][CH2:21]1>CO>[OH:22][CH2:21][CH2:20][N:12]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]2([CH2:3][O:2][CH2:1]2)[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1CO1
Reactant: C1COCCOCC2(COCCOCCN1)COC2
Solvent: CO
Product: OCCN1CCOCCOCC2(COCCOCC1)COC2
Yield: 86.4 %

Procedure:
A mixture of 27.5 g (0.10 mol) of 2,6,9,15,18-pentaoxa-12-azaspiro[3,15]nonadecane, 10 g (0.21 mol) of ethylene oxide and 200 ml of methanol was heated in a bomb tube at 100° for 6 hours under autogenous pressure. Solvent was evaporated, and the product was volatilized in a very short path still at 190° (~20 μ), giving 27.6 g (87%) of N-hydroxyethyl-2,6,9,15,18-pentaoxa-12-azaspiro[3.15]nonadecane as a nearly colorless oil. Ir: 2.90 (OH), 8.7-9.5 (COC, COH), 10.23 and 10.80 μ oxetane). Nmr ((CD3)2CO): 4.29 (singlet, 4, oxetane CH2), 3.74 (singlet, 4, C-CH2O), 3.6-3.3 (multiplet, 15, OCH2CH2O + OH + OCH2CH2N), 2.85-2.5 ppm (multiplet, 6, CH2N).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.CCO.C([O-])([O-])=O.[Na+].[Na+].[CH3:19][C:20]1([CH3:29])[CH2:25][CH2:24][C:23](B(O)O)=[CH:22][CH2:21]1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[Br:1][C:2]1[N:7]=[C:6]([C:23]2[CH2:24][CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21][CH:22]=2)[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: Nc1ccc(Br)nc1I
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: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(c2nc(Br)ccc2N)CC1
Temperature: 80 °C
Yield: 71 %

Procedure:
A solution of 6-bromo-2-iodo-pyridin-3-ylamine (as prepared in the previous step, 1.00 g, 3.35 mmol) in toluene (27 mL) and EtOH (13.5 mL) was treated with 2.0 M aq Na2CO3 (13.4 mL, 26.8 mmol) and 4,4-dimethyl-cyclohex-1-enylboronic acid (567 mg, 3.68 mmol). The mixture was degassed via sonication, placed under Ar, treated with Pd(PPh3)4 (271 mg, 0.234 mmol), and heated to 80° C. for 5 h. The cooled mixture was diluted with EtOAc (100 mL) and washed with water (2×50 mL). The combined aqueous layers were extracted with EtOAc (1×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-g column with 10% EtOAc-hexane afforded 668 mg (71%) of 6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-ylamine as a tan solid. 1H-NMR (CDCl3; 400 MHz): δ 7.06 (d, 1H, J=8.3 Hz), 6.85 (d, 1H, J=8.3 Hz), 5.95 (m, 1H), 3.86 (br s, 2H), 2.43-2.39 (m, 2H), 1.99-1.97 (m, 2H), 1.51 (t, 2H, J=6.4 Hz), 0.99 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH2:8])[S:5][CH:6]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:13][N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](O)=[O:21])[C:15]1=[O:23].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)(O)[O-]>[Cl-].[Na+].O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:8][C:20]([C:16]2[C:15](=[O:23])[N:14]([CH2:13][C:12]3[CH:24]=[CH:25][C:26]([F:27])=[C:10]([F:9])[CH:11]=3)[CH:19]=[CH:18][CH:17]=2)=[O:21])[S:5][CH:6]=1
Reactant: NCc1cc(Br)cs1
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1cc(Br)cs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reaction time: 2.5 h

Procedure:
C-(4-Bromo-thiophen-2-yl)-methylamine (0.200 g, 0.00104 mol;), 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (0.251 g, 0.000946 mol;), N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.40 g, 0.0010 mol;), N,N-Diisopropylethylamine (800 uL, 0.005 mol;), and Methylene chloride (9.1 mL, 0.14 mol;) were added to a 50 mL round bottom and stirred for 2 to 3 hours. LC-MS showed the formation of product at 1.78 438.92. Workup consisted of dilution with methylene chloride washing 1×with citric acid, 1× with saturated bicarbonate, and 1× with brine before drying and concentration to give the crude material. The crude was then purified by combiflash 0-100 percent hexanes/Ethyl acetate to give pure material. ES (+) MS m/e=438.92
Reaction SMILES: [N:1]1([CH2:8][C:9]2[S:10][C:11]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[OH:19][C:18]1[O:15][C:14]([C:11]2[S:10][C:9]([CH2:8][N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:13][CH:12]=2)=[N:16][N:17]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1nnc(-c2ccc(CN3CCCCCC3)s2)o1
Yield: 94.6 %

Procedure:
760 mg (3.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide was dissolved in 30 ml of tetrahydrofuran and 3 ml of N,N-dimethylformamide, 583 mg (3.6 mmol) of 1,1'-carbonyldiimidazole and 0.84 ml (6.0 mmol) of triethylamine were added, and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated, chloroform was added to the resulting residue, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 793 mg of the title compound.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17](O)=[O:18])=[C:12]2[N:11]=[CH:10][C:9]=1[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].[CH:40]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41]1>>[C:1]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]([NH:46][S:43]([CH:40]3[CH2:42][CH2:41]3)(=[O:45])=[O:44])=[O:18])=[C:12]2[N:11]=[CH:10][C:9]=1[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cnn2c(Nc3ccccc3-c3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: O=C(NS(=O)(=O)C1CC1)c1cnn2c(Nc3ccccc3-c3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 24.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(biphenyl-2-ylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (61 mg, 0.14 mmol) obtained in step 2 and cyclopropanesulfonamide (73 mg, 0.70 mmol), the title compound (21 mg, 27%) was obtained.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:43]([O:47][C:48]([N:50]1[C@H:54]([CH:55]=O)[CH2:53][O:52][C:51]1([CH3:58])[CH3:57])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1(C)C=CC=CC=1>[C:43]([O:47][C:48]([N:50]1[C@H:54]([CH:55]=[CH:9][C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:53][O:52][C:51]1([CH3:57])[CH3:58])=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCOC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1C=C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a suspension of (2-ethoxycarbonylbenzyl)-triphenylphosphonium bromide (9.0 g, 17.77 mmol) in toluene (100 mL) is added potassium bis(trimethylsilyl)amide (0.5M in toluene, 40 mL) followed by the addition of (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (3.4 g, 14.83 mmol) and the mixture is refluxed for 1 h. After cooling to RT, ice/water is added and the solution extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude material is purified by column chromatography to afford the title compound as a yellow oil: (M+1)+=376.