Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([NH:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20])=[C:13]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([CH3:32])=[C:11]([CH3:33])[N:10]=1>C(O)C>[CH2:17]([C:16]1[N:22]([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[C:12]([CH3:32])=[C:11]([CH3:33])[N:10]=[C:9]([Cl:8])[C:14]=2[N:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Nc1c(Cl)nc(C)c(C)c1NCCOc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(Cl)nc(C)c(C)c2n1CCOc1ccccc1

Procedure:
Triethylamine (1.93 ml), anhydrous ethanol (35 ml), and N-{2-chloro-5,6-dimethyl-4-[(2-phenoxyethyl)amino]pyridin-3-yl}pentanamide (1.32 g) from Part A were combined and heated to reflux for 24 hours. The reaction stalled, so the mixture was cooled and the solvent was removed under reduced pressure. Pyridine (75 ml) and an equivalent of pyridine HCl was added and the reaction mixture was heated to reflux for 16 hours. TLC analysis indicated that the reaction was complete. The reaction was allowed to cool and the solvent was removed under reduced pressure. The resulting product was dissolved in ethyl acetate and washed 4 times with water (150 ml each) to remove the pyridine HCl. The organic layer was dried with magnesium sulfate and the solvent was removed under reduced pressure. NMR analysis of the dried brown solid indicated sufficient purity for use of the product in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:35].C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)Oc5ccc(F)cc5)c4c(c23)C1=O
Temperature: 20 °C
Yield: 72.8 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmol) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 105 mg (2 molar equivalents) of 4-fluorophenyl chloroformate were respectively added. The reaction mixture was maintained at 20° C. for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica, (eluent: CH2Cl2/methanol in a 95/5 volume ratio) to provide 103 mg (yield=66%) of the desired product (formula below) as an orange powder.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][C:12]([O:18][CH2:19][CH3:20])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15].[CH:21]([O:23]CCCC)=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([C:9]1[CH:10]=[N:11][C:12]([O:18][CH2:19][CH3:20])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])(=[O:23])[CH3:22]
Reactant: C=COCCCC
Reactant: CCOc1ncc(Br)cc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCOc1ncc(C(C)=O)cc1C(=O)O
Reaction time: 16 h
Yield: 6.3 %

Procedure:
Triethylamine (354 ml, 2.54 mol), was added to a slurry of 5-bromo-2-ethoxynicotinic acid (250 g, 1.02 mol) in acetonitrile (1 L). To this reaction mixture was added palladium (II) acetate (4.56 g, 20.3 mmol), butyl vinyl ether (305 g, 3.05 mol) and tri-o-tolyl phosphine (12.4 g, 40.6 mmol), each addition being washed in with acetonitrile. Further acetonitrile (1 L) was then added and the reaction mixture heated to reflux under nitrogen for 22 hours. The reaction mixture was left at room temperature for 16 hours, and then the precipitate removed by filtration. The filtrate was concentrated in vacuo to give a brown gum, which was then stirred for 1 hour in water (1 L) and concentrated HCl (1 L). The reaction mixture was diluted with water (6.25 L), and extracted with dichloromethane (6×500 mL). The combined organic layers were extracted with 5% sodium bicarbonate solution (1.2 L, 2×400 ml). The basic aqueous extracts were washed with dichloromethane (250 ml), and then acidified to pH 3. After stirring for 30 minutes the precipitated product was removed by filtration, washed with water (250 ml) and dried at 50° C. in vacuo to yield the target compound as a white solid (134 g, 64.1 mmol, 63%).
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([OH:40])[CH:34]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([OH:40])[CH:34]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)c(O)c3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(O)c2)c1
Yield: 85.7 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-[6-(5-ethanesulfonyl-4′-fluoro-3′-hydroxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (218 mg, 0.32 mmol) and 1.0 N aqueous sodium hydroxide (5 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-ethanesulfonyl-4′-fluoro-3′-hydroxy-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (173 mg, 87%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C33H39FO9S (M+Na)+ 653.2191, found 653.2194.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([CH3:22])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:19]=[C:20]([CH3:22])[CH:21]=[C:16]([CH3:15])[CH:17]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: Cc1cc(C)cc(B(O)O)c1
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: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2nc3cc(F)ccc3c(Cl)c2C)c1
Temperature: 120 °C

Procedure:
Prepared according to procedure F using 2,4-dichloro-7-fluoro-3-methylquinoline (500 mg, 2.173 mmol), 3,5-dimethylbenzeneboronic acid (326 mg, 2.173 mmol), sodium carbonate (1.15 g, 10.87 mmol) and Pd(PPh3)4 (251 mg, 0.217 mmol) in toluene/water (4 mL:1 mL) and heating in the microwave for 90 min at 120° C. After purification 4-chloro-2-(3,5-dimethylphenyl)-7-fluoro-3-methylquinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=300 (M+1).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].P([O-])([O-])(O)=[O:8].[Na+].[Na+].[Cl:14][C:15]1[C:16]([O:23][C:24]2[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=2)=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19]>CC(C)=O>[Cl:14][C:15]1[C:16]([O:23][C:24]2[N:25]=[C:26]([O:32][CH3:33])[CH:27]=[C:28]([O:30][CH3:31])[N:29]=2)=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]([OH:8])=[O:19]
Reactant: O=P([O-])([O-])O
Reactant: COc1cc(OC)nc(Oc2c(Cl)cccc2C=O)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(Oc2c(Cl)cccc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
An aqueous solution of potassium permanganate (1.3 g) and disodium hydrogenphosphate (1 g) was dropwise added to a solution of 3-chloro-2-(4,6-dimethoxypyrimidin-2-yl)oxy benzaldehyde (1.7 g) in acetone (50 ml). The mixture was stirred at room temperature for 12 hours, and the precipitated manganese dioxide was filtered off. The filtrate was adjusted with hydrochloric acid to a pH of about 4 and then extracted with chloroform. The chloroform layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue thus obtained was recrystallized from carbon tetrachloride to obtain the above identified compound as a white solid (1.1 g). (Melting point: 151°-152° C.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>C(Cl)Cl>[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:41]([C:33]1[C:32]2[C:36](=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=1)=[O:43]
Reactant: Nc1nccs1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(F)cc21
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.3 %

Procedure:
A solution of triphenylphosphine (771 mg, 2.94 mmol) in methylene chloride (7 mL) cooled to 0° C. was treated with N-bromosuccinimide (523 mg, 2.94 mmol). The reaction was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid (500 mg, 2.26 mmol). The reaction was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 15 min. The reaction was then treated with 2-aminothiazole (521 mg, 5.20 mmol) and stirred at 25° C. for 18 h. At this time, the mixture was partitioned between water (75 mL) and ethyl acetate (75 mL) and treated with a 1N aqueous hydrochloric acid solution (50 mL). The organic layer was then washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (160 mg, 23%) as pink solid: mp 203-204° C.; EI-HRMS m/e calcd for C15H14FN3OS (M+) 303.0842, found 303.0844.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ON1C2C=CC=CC=2N=N1.[CH3:40][N:41]1CC[O:44][CH2:43][CH2:42]1.Cl.CN(C)CCCN=C=NCC.CNCCO>CN(C)C=O.O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:41]([CH2:42][CH2:43][OH:44])[CH3:40])=[O:25])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CNCCO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(C(=O)N(C)CCO)cn1
Reaction time: 0.5 h

Procedure:
6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinic acid (from step 2) (230 mg, 0.5 mmol) was added into the 1-hydroxybenzotriazole (101 mg, 0.75 mmol) in 5 ml of N,N-dimethylforamide. 4-methyl morpholine (0.16 ml, 1.5 mmol) was added into the mixture followed by addition of 1-(3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (143 mg, 0.75 mmol). Stirred the mixture for 30 minute to become homogenous solution. To that homogenous solution, was added 2-(methylamino) ethanol (0.06 ml, 0.75 mmol) and the mixture was stirred for 20 hours. Water (150 ml) was added into the reaction mixture and the product was extracted using ethyl acetate (400 ml X2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (app br s, 1H), 7.80 (br d, J=7.92 Hz, 1H), 7.64 (app q, J=6.58 Hz, 1H), 7.30 (m, 2H), 7.15 (m, 1H), 6.56 (s, 1H), 5.39 (s, 2H), 5.28 (s, 2H), 3.46 (m, 2H), 3.23 (m, 2H) 2.93 (m, 3H), 2.36 (s, 3H); LC/MS, tr=2.29 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-HRMS m/z 522.0850 (M+H calcd for C23H23BrF2N3O4 requires 522.0835).
Reaction SMILES: C1C2C(=CC=CC=2)[C@H](N)[C@@H]1O.[N+:12]([C:15]1[CH:16]=[C:17]([C:21](=[O:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>O1CCCC1>[N+:12]([C:15]1[CH:16]=[C:17]([C@H:21]([OH:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: N[C@H]1c2ccccc2C[C@H]1O
Solvent: C1CCOC1
Product: C[C@@H](O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of (1S,2R)-(−)-cis-1-amino-2-indanol (1.49 g, 10 mmol) in tetrahydrofuran (100 mL), cooled to 0° C., was added borane-N,N-diethylaniline complex (17.8 mL, 100 mmol) and the mixture was stirred at 0° C. for 1 hour. After this time a solution of 3′-nitroacetophenone (16.5 g, 100 mL) in tetrahydrofuran (300 mL) was added dropwise over 4 hours and the mixture was allowed to warm to room temperature over night with stirring. After this time the mixture was quenched by stirring with acetone (40 mL) for 1 hour after which it was concentrated under reduced pressure. The yellow residue was dissolved in toluene (250 mL) and washed sequentially with dilute aqueous sulfuric acid (1M, 4×100 mL), water (100 mL), saturated aqueous sodium hydrogen carbonate (100 mL), water (100 mL) and brine (100 mL). The organic solution was dried over MgSO4 and concentrated under reduced pressure to give (1R)-1-(3-nitrophenyl)ethanol (14.3 g, 86%).
Reaction SMILES: [NH4+].[Cl-].[CH2:3]([C:6]1([CH2:26][O:27][CH3:28])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH:12]=2)[C:7]1=[O:25])[CH:4]=[CH2:5]>C(O)C.O.[Fe]>[CH2:3]([C:6]1([CH2:26][O:27][CH3:28])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH:12]=2)[C:7]1=[O:25])[CH:4]=[CH2:5]
Reactant: C=CCC1(COC)CCc2cc(-c3ccc([N+](=O)[O-])cc3)ccc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C=CCC1(COC)CCc2cc(-c3ccc(N)cc3)ccc2C1=O
Yield: 80.8 %

Procedure:
Iron powder (0.09 g, 1.7 mmol) and NH4Cl (0.023 g, 0.427 mmol) was added to a solution of 197F (0.3 g, 0.847 mmol) in 25 mL of ethanol-water (2:1) mixture. The reaction mixture was refluxed for 2 h, and solvent was removed under reduced pressure and extracted with ethyl acetate (40 mL). The organic layer was washed with water, dried over sodium sulphate, filtered and removed under reduced pressure to give title compound (0.22 g, %) as yellow solid. 1H NMR (300 MHz, DMSO-d6): 7.83 (d, J=8.4 Hz, 1H), 7.53-7.44 (m, 4H), 6.64 (d, J=9.0 Hz, 2H), 5.75-5.65 (m, 1H), 5.42 (s, 2H), 5.09-5.03 (m, 2H), 3.62 (d, J=9.0 Hz, 1H), 3.21 (s, 3H), 2.99-2.5 (m, 2H), 2.44-2.27 (m, 1H), 2.25-2.12 (m, 2H), 2.00-1.94 (m, 2H).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:16]([O:17]CC2C=CC=CC=2)[C@H:15]([O:25]CC2C=CC=CC=2)[C:12]2([CH2:14][CH2:13]2)[O:11][C@H:10]1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][CH:10]2[CH:9]([OH:8])[CH:16]([OH:17])[CH:15]([OH:25])[C:12]3([CH2:14][CH2:13]3)[O:11]2)=[CH:46][CH:45]=1
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2OC3(CC3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cc2ccccc2OC2OC3(CC3)C(O)C(O)C2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of (5R,6R,7S,8S)-6,7,8-tris-benzyloxy-5-[2-(4-methoxy-benzyl)-phenoxy]-4-oxa-spiro[2.5]octane (190 mg, 0.29 mmol) in methanol (5 ml) was added 10% Pd/C (60 mg) and stirred under hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered through celite bed, washed with methanol (20 mL). The crude product was purified by preparative HPLC to furnish the title compound (22 mg).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]1.CCN(C(C)C)C(C)C.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@@H]1CCNC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CC[C@@H](O)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 16.4 %

Procedure:
(1-(5-Tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (210 mg, 0.4 mmol) from Example 27B was treated with (R)-(+)-3-pyrrolidinol (65 μL, 0.8 mmol), tetrabutylammonium iodide (148 mg, 0.4 mmol) and N,N′-diisopropylethylamine (69 μL, 0.4 mmol) in N,N′-dimethylformamide (4 mL). The mixture was stirred at 50° C. for 5 h. After cooling to room temperature water (4 mL) was added and the precipitating solid filtered off and dried. The solid residue was purified by preparative HPLC (phenylhexyl reverse phase column). The obtained solid was triturated with water to give (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea (37.76 mg, 16%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.10 (s, 1H), 8.55 (s, 1H), 7.58-7.56 (m, 2H), 7.40-7.38 (m, 2H), 7.25 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.70 (s, 1H), 4.31-4.20 (m, 3H), 3.99 (s, 3H), 3.32 (s, 1H), 2.81-2.69 (m, 2H), 2.40-2.19 (m, 3H), 2.10-1.98 (m, 3H), 1.67-1.4 (m, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].CO.[C:10]1([CH2:16][CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:17]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])[CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CN
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CNCCc1ccccc1
Temperature: 0 °C
Yield: 33.4 %

Procedure:
A cold solution (0° C.) of glycine methyl ester hydrochloride (1.0 g, 8 mmol), methanol (25 mL), glacial acetic acid (0.8 mmol, and phenylacetaldehyde (0.481 g, 4 mmol) was treated with sodium triacetoxyborohydride (1.7 g, 8 mmol) in two portions. The reaction mixture was maintained at 0° C. for 1.5 hr, and then quenched with saturated sodium bicarbonate (15 mL). The solution was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and adsorbed onto silica gel (100 mg) and applied to a column prepacked with silica gel. The column was eluted with CH2Cl2/MeOH (97:3, v:v) to afford titled compound (258 mg).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[CH2:14]I.C([Zn]CC)C.CCCCCC>ClCCCl.CCOC(C)=O.Cl>[CH2:14]1[C:2]2([CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:1]1
Reactant: C=C1CCC(C(=O)OCC)CC1
Reactant: ClCI
Agent: CC[Zn]CC
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC2(CC1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., to a solution of ethyl 4-methylenecyclohexanecarboxylate (0.08 g) in DCE (1 mL) was added chloroiodomethane (0.110 mL, 1.522 mmol), followed by the addition of 1 N diethylzinc in hexane (0.761 mL, 0.761 mmol). The reaction was stirred at 0° C. for 1 hr, then stirred at rt for 18 hrs. The reaction mixture was diluted with EtOAc and 1 N HCl, the organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was charged to a 25 g silica gel cartridge which was eluted with a 20 min gradient of 0-6% EtOAc in hexane to yield ethyl spiro[2.5]octane-6-carboxylate. 1H NMR (400 MHz, CDCl3) δ ppm 4.08-4.18 (2H, m), 2.32 (1H, tq, J=11.01, 3.53 Hz), 1.85-1.93 (2H, m), 1.53-1.74 (4H, m), 1.28-1.35 (2H, m), 1.22-1.28 (3H, m), 0.28 (2H, ddd, J=8.53, 5.52, 1.51 Hz), 0.17-0.25 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]3=[O:26])[CH:9]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>>[O:26]=[C:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3cc(C#N)ccc3c2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2cc(N3CCNCC3=O)cnc2c1
Reaction time: 0.33 h

Procedure:
tert-Butyl 4-(7-cyanoquinolin-3-yl)-3-oxopiperazine-1-carboxylate (0.030 g, 0.099 mmol) was treated with TFA (2 mL) and stirred for 20 minutes. Analysis of the reaction mixture by LC indicated that reaction had gone to completion. The solution was concentrated in vacuo and crude was azetroped with dichloroethane (3×8 mL) to furnish the title product. LC/MS (IE, m/z): [M+1]+=253.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]1[O:14][C@@H:13]1[CH2:15]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C@H:13]2[O:14][CH2:12]2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Nc1ccc(OC[C@@H]2CO2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A solution of 4-amino-3-nitrophenol (2.54 g, 16.5 mmol) and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (4.27 g, 16.5 mmol) in 50 mL of acetone was treated with 1.1 equivalents of K2CO3 (2.50 g, 18.1 mmol) and stirred at reflux for 20 hours. The suspension was cooled to ambient temperature, concentrated in vacuo to dryness. The resulting solids were partitioned between chloroform and water, and the aqueous layer extracted with chloroform. The organic layers were combined and dried over MgSO4 and concentrated in vacuo to provide 3.0 g (87%) of an orange solid. TLC and NMR indicated >95% purity, so the material was used without further purification. NMR.
Reaction SMILES: [CH3:1][N:2]([CH3:12])/[C:3](=[C:5]1/[N:6]=[C:7]([CH3:11])[O:8][C:9]/1=[O:10])/[CH3:4].[H-].[Na+].[CH2:15]([OH:17])[CH3:16]>>[C:15]([NH:6]/[C:5](=[C:3](/[N:2]([CH3:12])[CH3:1])\[CH3:4])/[C:9]([O:8][CH2:7][CH3:11])=[O:10])(=[O:17])[CH3:16]
Reactant: CC1=N/C(=C(\C)N(C)C)C(=O)O1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(NC(C)=O)=C(/C)N(C)C

Procedure:
4-[1-dimethylamino-eth-(Z)-ylidene]-2-methyl-4H-oxazole-5-one (compound 15, 7.54 g, 44.8 mmol) was dissolved in ethanol (50 mL) and sodium hydride (179 mg, 4.5 mmol, 60% dispersion in mineral oil) wad added at room temperature. The solution was refluxed for 1 hr. The solvent was evaporated and the crude product was used without any further purification for the next step.