Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[P:48]([O-])([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>ClCCl.C(#N)C.[Ag]=O>[CH2:59]([O:58][P:48](=[O:49])([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[O:10][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[C:31]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCO
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: O=[Ag]
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mix 2-{2-tert-butyl-5-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-phenoxy}-ethanol (240 mg, 0.5 mmol) and triethyl amine (60 mg, 0.6 mmol) in dichloromethane 10 ml and add methanesulfonyl chloride (60 mg, 0.5 mmol). Stir the solution at room temperature for 1 hour and evaporate to dryness. Re-dissolve the residue in acetonitrile, add dibenzyl phosphate (278 mg, 1.0 mmol) and silver oxide (231 mg, 1.0 mmol) and heat at 70° C. for 24 hours. Filter the mixture through a plug of Celite and evaporate the filtrate to dryness. Partition the residue between ethyl acetate and sodium bicarbonate solution and extract with further ethyl acetate. Dry the combined extracts (MgSO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>COC(C)(C)C>[C:25]([NH3+:29])([CH3:28])([CH3:27])[CH3:26].[CH3:23][O:22][C:18]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]([S:12]([CH2:11][C:5]3[C:6]([CH3:10])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[CH:3][N:4]=3)=[O:24])=[N:21][C:20]=2[CH:19]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Reactant: CC(C)(C)N
Solvent: COC(C)(C)C
Product: CC(C)(C)[NH3+]
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C

Procedure:
Omeprazole (1.0 g, 2.9 mmol) was dissolved in tert-butyl methyl ether (10 ml) at 60-70° C. Tert-butylamine (0.60 g, 8.1 mmol) was added and the mixture was then cooled to room temperature whereupon the product crystallised. The formed precipitate was filtered off and washed with in tert-butyl methyl ether. The title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.CO.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[H][H]>[Pd].O>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C=O)=Cc1ccccc1
Reactant: [H][H]
Reactant: C1CCNCC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(Cc1ccccc1)CN1CCCCC1

Procedure:
A mixture of 1000 g of α-methyl-cinnamaldehyde, 10 liters of methanol and 640 g of piperidine are placed under a nitrogen atmosphere and 50 g of palladium/carbon are added thereto. The mixture is then hydrogenated while cooling with water to 30° C. internal temperature. Hydrogenation continued until the hydrogen uptake has been completed. The catalyst was filtered off and the methanol was distilled under vacuum. Distillation of the crude produce yielded pure 1-(2-methyl-3-phenyl-propyl)-piperidine, b.p. 92° C./0.04 Torr.
Reaction SMILES: [OH:1][C@H:2]([CH2:28][OH:29])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[C:14]([OH:24])[C:15]([C:22]#[N:23])=[CH:16][CH:17]=4)[NH:12][C:11]=3[C:10]([CH3:26])([CH3:25])[C:9]=2[CH:27]=1.[CH3:30][Si](C=[N+]=[N-])(C)C.C(N(C(C)C)CC)(C)C>CO.C(Cl)(Cl)Cl>[OH:1][C@H:2]([CH2:28][OH:29])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[C:14]([O:24][CH3:30])[C:15]([C:22]#[N:23])=[CH:16][CH:17]=4)[NH:12][C:11]=3[C:10]([CH3:26])([CH3:25])[C:9]=2[CH:27]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C)c2cc(OC[C@H](O)CO)ccc2C(=O)c2c1[nH]c1c(O)c(C#N)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)ccc2c3c([nH]c12)C(C)(C)c1cc(OC[C@H](O)CO)ccc1C3=O
Temperature: 25 °C
Reaction time: 31 h
Yield: 61.5 %

Procedure:
Under nitrogen atmosphere, 8-((R)-2,3-dihydroxy-propoxy)-4-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound U8-4-2, 8.0 mg, 20.39 μmol) was dissolved in methanol (2.0 mL) and chloroform (2.00 mL), added with trimethylsilyldiazomethane (diethyl ether solution, 2 M, 15.3 μL, 30.58 μmol) and diisopropylethylamine (0.05 mL), and then stirred at room temperature for 31 hr. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (methanol/dichloromethane) to obtain the title compound (5.1 mg, 62%).
Reaction SMILES: [C:1]([CH:3]1[CH:5]([CH:6]=[C:7]([Cl:9])[Cl:8])[C:4]1([CH3:11])[CH3:10])#N.S(=O)(=O)(O)[OH:13].[CH2:17]([OH:19])[CH3:18]>O>[Cl:8][C:7]([Cl:9])=[CH:6][CH:5]1[CH:3]([C:1]([O:19][CH2:17][CH3:18])=[O:13])[C:4]1([CH3:11])[CH3:10]
Reactant: CCO
Reactant: O=S(=O)(O)O
Reactant: CC1(C)C(C#N)C1C=C(Cl)Cl
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 80 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
The procedure described in Example 2 is repeated up to the point at which the mixture of 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane, sulphuric acid and water has been heated and stirred at 80° C. for 6 hours and then cooled below 30° C. 16 Parts of ethanol are added to the reaction mixture below 50° C. The mixture is then heated at 100° C. for a further 12 hours, cooled to 20° C. and drowned into 100 parts of water. The aqueous mixture is extracted with toluene (2×50 parts), the toluene extracts are combined and the solvent is removed by evaporation under reduced pressure. There are obtained 17.6 parts of ethyl 3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate as a brown oil containing 40.4% of the cis-isomer and 21.8% of the trans-isomer. The overall yield is 92.4%.
Reaction SMILES: C(OC([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[CH2:21]([N:23](CC)[CH2:24]C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC.C(Cl)[Cl:59]>>[ClH:59].[CH3:21][N:23]([CH3:24])[C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[O:20]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: ClCCl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)C(=O)[C@@H]1Cc2ccccc2CN1
Product: Cl
Reaction time: 18 h

Procedure:
A solution of 5 g of (3S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (commercial) in 50 ml of DCM is cooled to 0° C. and 5.45 g of triethylamine and then 8 g of BOP are added. Dimethylamine gas is then added by sparging for 5 minutes and the mixture is left stirring for 18 hours at AT. The reaction mixture is taken up in a water/DCM mixture, after separation by settling the organic phase is washed with a 5% KHSO4 solution and with a 5% Na2CO3 solution and dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a DCM/AcOEt (70/30, v/v) mixture. 4 g of the expected product are obtained in the form of an oil, which crystallizes.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[C:17]([O:20][C:21](=[O:23])[CH3:22])(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([OH:20])(=[O:19])[CH3:18].[C:17]([OH:20])(=[O:19])[CH3:18].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:21](=[O:23])[CH3:22])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2csc(NC(=N)N)n2)c1
Reaction time: 18 h

Procedure:
To a solution of 2-guanidino-4-(3-aminophenyl)thiazole (0.24 g.) in acetic acid (5 ml.) was added acetic anhydride (0.25 g.). The mixture was allowed to stand for 18 hours and the white solid precipitate (0.25 g.) was filtered off to give 2-guanidino-4-(3-acetylaminophenyl)thiazole diacetate, m.p. 171°-173° C., solidifies and remelts at 258°-261° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[Cl-].[Li+].C([Li])CCC.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1Cc2cccc(F)c2N1
Reactant: BrCCCCCBr
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2c(F)cccc2C12CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
7-Fluoro-1,3-dihydro-indol-2-one (EXAMPLE 99, step 4) (1.16 g, 7.68 mmol) and lithium chloride (0.81 g, 19.2 mmol) were dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. n-Butyllithium (6.14 mL, 15.4 mmol) was added dropwise and the mixture was stirred 15 minutes. 1,5-Dibromopentane (1.05 mL, 7.7 mmol) was added slowly and stirring was continued for 2 hours at o° C. then warmed to 25° C. After 16 hours the reaction was quenched with a saturated aqueous solution of ammonium chloride. The mixture was diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5% to 40% ethyl acetate in hexane) to afford 0.90 g (54%) of 7′-fluorospiro-[cyclohexane-1,3′-indol]-2′(1′H)-one. HPLC purity 95.9% at 210-370 nm, 19.2 min.; Xterra MSC18, 5u, 150×3.0 mm column, 0.5 mL/minutes, 95/5-5/95 (0.1% formic acid in H2O/MeOH) for 20 minutes, hold 3 min.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([OH:10])=[CH:5][CH:4]=1)[CH3:2].Br[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C@H:21]([CH2:25][C:26]([O-:28])=[O:27])[CH2:20][CH2:19]2.[C:29](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C@H:21]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:20][CH2:19]3)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C([O-])C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: O=C([O-])[O-]
Reactant: CCc1ccc(O)c(C)n1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(OCCCOc2ccc3c(c2)CC[C@H]3CC(=O)OC)c(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
6-Ethyl-2-methyl-3-pyridinol (40.6 mg, 0.30 mmol) and [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (101.0 mg, 0.30 mmol) (Example 45) were dissolved in DMF (4 mL) and cesium carbonate (193 mg, 0.59 mmol) and 4 drops of water were added. The mixture was stirred at rt for 16 h. The DMF was removed in vacuo and the residue was suspended in EtOAc and filtered. This filtrate was concentrated to give the pure title compound as a yellow oil (73 mg, 62%) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.08-6.99 (m, 2H), 6.90 (d, 1H), 6.78 (s, 1H), 6.62 (dd, 1H), 4.20-4.08 (m, 4H), 3.72 (s, 3H), 3.58-3.48 (m, 1H), 2.96-2.70 (m, 6H), 2.51-2.34 (m, 4H), 2.30-2.23 (m, 2H), 1.80-1.68 (m, 1H), 1.21 (t, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[O:10][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[C:27]([Cl:40])[CH:26]=2)=[CH:12][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[C:27]([Cl:40])[CH:26]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
(5-(4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl)-furan-2-ylmethyl)-carbamic acid tert-butyl ester (0.0218 g, 0.0379 mmol) is dissolved in DCM (2 ml) and TFA (2 ml) is added dropwise. The reaction mixture is stirred at room temperature for 1 hour. The solvent is removed under a nitrogen stream and to the residue are added consecutively saturated aqueous potassium carbonate solution and DCM. The resulting mixture is extracted with DCM containing 5% THF, the combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 17.6 mg (0.037 mmol, 98%) of the clean desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35].O>CN(C=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])[CH2:12][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
1-(2,3-Dichlorophenyl)piperazine hydrochloride (3.16 g, 11.8 mmol) and potassium carbonate (4.08 g, 29.5 mmol) were added to the solution of 2-(2-bromoethyl)isoindoline-1,3-dione (3 g, 11.8 mmol) in DMF (20 ml). The reaction mixture was stirred for overnight at room temperature. After reaction complete, water (40 ml) was added and then normal work-up was taken. The residue was purified with normal phase preparative column to afford title compound (3.87 g, 81% yield) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC#N>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 78 °C

Procedure:
Amine preparation: To a solution of piperidine-4-carboxylic acid ethyl ester (3.0 g) stirring in dry MeCN (30 mL) was added potassium carbonate (2.90 g) followed by benzyl bromide (2.5 mL). The mixture was warmed to 78° C. After 3 h the mixture was cooled, poured into water (100 mL) and extracted into ethyl acetate, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to give 1-benzyl-piperidine-4-carboxylic acid ethyl ester (2.17 g) as a pale yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH3:31])[C:10]([N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C@H:22]4[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[N:11][CH:12]=1.C(N(CC)C(C)C)(C)C>C(#N)C.CO>[OH:28][C@@H:25]1[CH2:26][CH2:27][C@H:22]([N:19]2[CH2:18][CH2:17][C:16]3([CH2:29][CH2:30][N:13]([C:10]4[N:11]=[CH:12][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[CH:8][C:9]=4[CH3:31])[CH2:14][CH2:15]3)[C:20]2=[O:21])[CH2:23][CH2:24]1
Reactant: Cc1cc(N)cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Reactant: COC(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)Nc1cnc(N2CCC3(CC2)CCN([C@H]2CC[C@@H](O)CC2)C3=O)c(C)c1
Reaction time: 2 h

Procedure:
Methyl chloroformate (6.0 μL) was added to a mixture of 8-(5-amino-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (18.0 mg) and N,N-diisopropylethylamine (20.0 μL) in acetonitrile (1.0 mL). The mixture was stirred for 2 h, and was diluted with methanol. The resulting solution was purified by prep-HPLC under basic condition to afford methyl {6-[2-(cis-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]dec-8-yl]-5-methylpyridin-3-yl}carbamate. LCMS: (M+H)+=416.2.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[C:4]([F:18])[C:3]=1[O:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([Cl:28])[CH:21]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1>ClCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]([C:10]2[N+:11]([O-:37])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:4]([F:18])[C:3]=1[O:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([Cl:28])[CH:21]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3ccccn3)c2F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cccc[n+]3[O-])c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of N-[4-Chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl]pyridine-2-carboxamide (0.064 g, 0.154 mmol) in 4 mL of dichloromethane was added mCPBA (0.026 g, 0.154 mmol). The resulting mixture was stirred overnight at RT. The reaction mixture was washed with 15% Na2CO3 and the organic layer separated and evaporated. The solid was dissolved in DMF and diluted with MeOH to a volume of 2 mL. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.006 g, 9%) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.74-11.85 (m, 1H), 8.44 (dd, 1H), 8.26-8.30 (m, 1H), 7.46-7.52 (m, 1H), 7.40-7.45 (m, 1H), 7.32-7.38 (m, 2H), 7.24-7.29 (m, 1H), 7.16 (t, 1H), 7.01-7.04 (m, 1H), 4.74 (d, 2H). LCMS: m/z 431.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O-:12].[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(Br)ccc1C#N
Yield: 79.6 %

Procedure:
In a 1 L round-bottomed flask, 53.94 g (270 mmol) of 4-bromo-2-fluorobenzonitrile was dissolved in 500 mL of THF. Sodium methoxide (21.99 g, 407 mmol) was added and the mixture was heated to reflux until TLC (SiO2: CH2Cl2) showed complete consumption of starting material. The mixture was poured into 1N HCl and the THF was evaporated in vacuo. The remaining mixture was extracted with diethyl ether. The extract was dried (MgSO4) and filtered over a plug of silica gel. The plug was eluted with CH2Cl2 and the filtrate was evaporated in vacuo to afford 45.56 g (80%) of the product as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.42 (d, 1H), 7.17 (dd, 1H), 7.14 (d, 1H), 3.95 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][OH:13]>CC(N(C)C)=O.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:6]3[CH2:7][CH2:8][CH2:9][C@@H:10]([CH2:12][OH:13])[CH2:5]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: CO
Reactant: Fc1ccc2nnc(Cl)n2c1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: OC[C@@H]1CCCN(c2nnc3ccc(F)cn23)C1
Yield: 29 %

Procedure:
A brown solution of Intermediate 24b (565 mg, 3.29 mmol) and R-3-hydroxymethyl piperidine (Chess GmbH, 948 mg, 8.23 mmol) in DMA (10 mL) was irradiated at 175° C. for 3 h in the microwave. The cooled solution was concentrated in vacuo, suspended in water (10 mL) and brine (10 mL), and then extracted with DCM (2×20 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown oil. FCC, using 4-5% MeOH in DCM, gave the title compound as a viscous yellow oil (237 mg, 29%). LCMS (Method 3): Rt 2.11 min, m/z 251 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18](Br)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1Br)OCCN(Cc1ccccc1)C2
Reactant: OB(O)c1ccoc1
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+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc2c(c1-c1ccoc1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
A mixture of 4-benzyl-9-bromo-8-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine (500 mg, 1.49 mmol), 3-furanboronic acid (250 mg, 2.23 mmol), potassium carbonate (206 mg, 1.49 mmol), tetrakis(triphenylphosphine)palladium(0) (172 mg, 0.149 mmol), 1,2-dimethoxyethane (5 ml) and water (0.5 ml) was stirred under an argon atmosphere at 100° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and preparative HPLC to give the desired product (104 mg, 21.7%) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH2:9]([O:11][CH2:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]=[C:33]=[S:34])[CH2:26][CH2:25]1)[CH3:10]>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:33]([NH:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][C:15]2[N:14]([CH2:13][CH2:12][O:11][CH2:9][CH3:10])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:25][CH2:26]1)=[S:34]
Reactant: CCOCCn1c(CC2CCN(CCN=C=S)CC2)nc2cccnc21
Reactant: Nc1ccncc1N
Solvent: C1CCOC1
Product: CCOCCn1c(CC2CCN(CCNC(=S)Nc3cnccc3N)CC2)nc2cccnc21
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 3.3 parts of 3,4-pyridinediamine, 11.2 parts of 3-(2-ethoxyethyl)-2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-3H-imidazo[4,5-b]-pyridine and 90 parts of tetrahydrofuran was stirred overnight at reflux temperature. The reaction mixture was evaporated, yielding 14.5 parts (100%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]thiourea as a residue (compound 138).