Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:24]=[C:25]1[O:29][C:27](=[O:28])[CH2:26]1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:27](=[O:28])[CH2:26][C:25]([OH:29])([CH3:24])[C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=C1CC(=O)O1
Reactant: CCOC(=O)C(NCc1ccc(OC)cc1OC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)N(Cc2ccc(OC)cc2OC)C(=O)CC1(C)O
Yield: 59.3 %

Procedure:
39.6 g (0.122 moles) of diethyl (2,4-dimethoxybenzyl-amino)-malonate prepared according to Example (1c) are boiled with 12.3 g (11.2 ml, 0.146 moles) of diketene in 80 ml of glacial acetic acid for half an hour. The glacial acetic acid is distilled off on a water bath, in vacuo; the residual oil is crystallized by trituration with 150 ml of water, whereupon the substance is dissolved in 60 ml of ethyl acetate and recrystallized by addition of petroleum ether. 29.6 g (60%) of diethyl N-(2,4-dimethoxybenzyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or the tautomer thereof are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][OH:28])[CH:22]=2)=[N:17][C:16]([Cl:29])=[CH:15][N:14]=1)(=[O:11])=[O:10]>O1CCCC1.ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=2)=[N:17][C:16]([Cl:29])=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccc(CO)c1)c1cccc(Cl)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)c1

Procedure:
2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 106) (0.6 g) and manganese dioxide (1.0 g) in tetrahydrofuran (5 mL) was stirred at room temperature for 16 h. The mixture was diluted with dichloromethane and filtered through celite. The solution was evaporated to dryness and the product crystallised from diethyl ether (0.4 g). Used directly.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:42])[C:23]#[C:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4([NH:34]C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:42])[C:23]#[C:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4([NH2:34])[CH2:32][CH2:33]4)=[CH:27][CH:26]=3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Reaction time: 24 h

Procedure:
1 mL (12.92 mmol) of trifluoroacetic acid is added to a solution of 0.24 g (0.49 mmol) of 3-[4-(1-tert-butoxycarbonylaminocyclopropyl)phenyl]propynoic acid-(4′-chlorobiphenyl-4-yl)amide in 20 mL dichloromethane and stirred for 24 hours. Then the solvent is eliminated by rotary evaporation and the residue is combined with toluene and again subjected to rotary evaporation. This residue is then triturated with dichloromethane, suction filtered and dried in the air. Yield: 0.22 g (89% of theory); C24H19ClN2O*C2HF3O2 (M=500.90); calc.: molecular ion peak (M+H)+: 387 (Cl); found: molecular ion peak (M+H)+: 387 (Cl); melting point: 160° C.-164° C.
Reaction SMILES: [OH:1][C@:2]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C1COCC1.[BH4-].[Na+].[OH-].[Na+]>[Hg](OC(C)=O)OC(C)=O.CCOC(C)=O.O>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C@@:2]1([C:3]([O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:4])[CH2:18][CH2:19][C:20]([CH3:22])([CH3:21])[O:1]1
Reactant: COC(=O)C[C@](O)(CC=C(C)C)C(=O)OCc1ccccc1
Agent: CC(=O)O[Hg]OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C[C@@]1(C(=O)OCc2ccccc2)CCC(C)(C)O1
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
To a solution of alcohol 77 (183.6 mg, 0.599 mmol, 1.00 equiv) in 1:1 THF:H2O (9.2 mL) was added Hg(OAc)2 (382 mg, 1.199 mmol, 2.00 equiv). The resulting solution was stirred at 23° C. for 45 minutes. A 0.5M solution of NaBH4 in 3M NaOH (1.2 mL, 0.599 mmol, 1.00 equiv) was then added by syringe, resulting in an immediate precipitation of Hg0. After stirring for 5 minutes, the suspension was partitioned between 20 mL sat'd NH4Cl soln. and 20 mL EtOAc. The phases were separated and the aqueous phase was extracted with 2×20 mL EtOAc. The combined organic phases were dried over MgSO4 and solvent removal yielded a grey suspension that was purified by silica gel column chromatography (5:1 hex:EtOAc) to yield tetrahydrofuran S12 (141.6 mg, 77%) as a clear, colorless oil. Rf=0.58 (2:1 hex:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.34 (m, 5H, aryl H), 5.21 (d, 1H, J=12.3 Hz, PhCH2), 5.17 (d, 1H, J=12.3 Hz, PhCH2), 3.59 (s, 3H, OCH3), 2.91 (d, 1H, J=15.4 Hz, C(O)CH2), 2.81 (d, 1H, J=15.4 Hz, C(O)CH2), 2.41 (m, 1H, CH2), 2.16 (m, 1H, CH2), 1.85 (m, 1H, CH2), 1.78 (m, 1H, CH2), 1.30 (s, 3H, C(CH3)2), 1.24 (s, 3H, (CCH3)2); 13C NMR (125 MHz, CDCl3) δ 173.70, 170.54, 135.93, 128.59, 128.43, 128.32, 84.26, 83.96, 67.10, 51.80, 43.93, 37.88, 35.58, 29.09, 28.33; IR (neat film) 3036 (w), 2973 (m), 1743 (s), 1500 (w), 1458 (m), 1440 (m), 701 (m) cm−1; LRMS (ESI) calc'd for C17H22O5Na (M+Na+) 329.2; found 329.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]([OH:11])[C:8]([CH3:13])([CH3:12])[C:7]=2[CH:14]=1)#[N:2].[OH-].[Na+].[BH4-].[Na+]>CO.O>[OH:10][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]=1[C:8]([CH3:13])([CH3:12])[CH2:9][OH:11]
Reactant: CC1(C)c2cc(C#N)ccc2OC1O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CO)c1cc(C#N)ccc1O
Yield: 59.4 %

Procedure:
5-Cyano-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (2.0 g), prepared as in Example 10, was dissolved in methanol (10 ml) and added to sodium hydroxide (1.7 g) in water (25 ml) at 10°-15° C. with stirring. To this solution was added sodium borohydride (0.5 g), and the mixture was stirred at ambient temperature for 11/2 hours. After acidification with hydrochloric acid (6 ml) at 8°-12° C., the mixture was filtered and the product washed with water and dried yielding 1.8 g. Recrystallisation from toluene gave 1.2 g of product, mp 129°-130° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:29]=[CH:28][C:11]([O:12][CH:13]([CH3:27])[C:14]([O:16][CH2:17][CH2:18][S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[CH:10][CH:9]=1.Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1>CS(C)=O>[F:38][C:37]([F:40])([F:39])[C:34]1[CH:35]=[CH:36][C:31]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:27])[C:14]([O:16][CH2:17][CH2:18][S:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:15])=[CH:28][CH:29]=2)=[N:32][CH:33]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCSCc1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)OCCSCc1ccccc1
Temperature: 90 °C
Yield: 76.1 %

Procedure:
15.2 g of potassium carbonate were added to a solution of 33.2 g of 2-benzylthioethyl 2-(4-hydroxyphenoxy)-propionate in 100 ml of dimethyl sulfoxide at room temperature whilst stirring. The mixture was heated to 90° C. for 1 hour with stirring. Then, 20.0 g of 2-chloro-5-trifluoromethyl-pyridine were added thereto while maintaining the temperature between 80° and 90° C. After the addition was completed, the reaction mixture was further stirred at this temperature for 2 hours, and then cooled to room temperature. Then the reaction mixture was poured into ice water and extracted with chloroform. After drying the organic phase, the chloroform was removed under reduced pressure. There were obtained 36.3 g of 2-benzylthioethyl 2-[4-(5-trifluoromethyl-2-pyridyloxy)-phenoxy]-propionate in the form of a pale yellow viscous oil. nD20 =1.5505.
Reaction SMILES: N1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:42]=[CH:41][C:32]5OC(F)(F)OC(F)(F)[C:31]=5[CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])C=CN=C1.NCCCN1C=CN=C1.[CH3:52][N:53]1C2C(=CC(NC(NC3C=CC(OC4C=CN=C(C(N)=O)C=4)=CC=3)=O)=CC=2)[CH:55]=[N:54]1.FC1(F)OC2C=CC(NC(NC3C=CC(OC4C=CN=C(C(OC)=O)C=4)=CC=3)=O)=CC=2C(F)(F)O1>>[CH:8]1([NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[C:31]5[C:32](=[CH:41][CH:42]=4)[N:54]([CH3:55])[N:53]=[CH:52]5)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])[CH2:6][CH2:7]1
Reactant: Cn1ncc2cc(NC(=O)Nc3ccc(Oc4ccnc(C(N)=O)c4)cc3)ccc21
Reactant: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCCn3ccnc3)c2)cc1)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Agent: COC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)cc2)ccn1
Agent: NCCCn1ccnc1
Product: Cn1ncc2cc(NC(=O)Nc3ccc(Oc4ccnc(C(=O)NC5CC5)c4)cc3)ccc21

Procedure:
The title compound was prepared in the same manner described for N-[3-(1H-imidazol-1-yl)propyl]-4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}-amino)phenoxy]pyridine-2-carboxamide, substituting cyclopropylamine for 1-(3-aminopropyl)imidazole and 4-[4-({[(1-methyl-1H-indazol-5-yl)amino]-carbonyl}amino)-phenoxy]pyridine-2-carboxamide for methyl 4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}amino)phenoxy]pyridine-2-carboxylate. 1H-NMR (MeOH-d4/CD2Cl2) δ 8.42 (d, J=5.5 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.45-7.57 (m, 5H), 7.08 (m, 2H), 7.02 (dd, J=5.5, 2.6 Hz, 1H), 4.04 (s, 3H), 2.84 (m, 1H), 0.81 (m, 2H), 0.65 (m, 2H); MS LC-MS [M+H]+=443.2, RT=2.51 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:25].[CH3:26][C:27]1[CH:39]=[CH:38][C:30]2[N:31]=[C:32](S(C)(=O)=O)[O:33][C:29]=2[CH:28]=1>ClC(Cl)C>[F:25][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:32]1[O:33][C:29]2[CH:28]=[C:27]([CH3:26])[CH:39]=[CH:38][C:30]=2[N:31]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)c(F)c2)cc1
Reactant: Cc1ccc2nc(S(C)(=O)=O)oc2c1
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(C)cc4o3)c(F)c2)cc1
Temperature: 85 °C
Yield: 42.7 %

Procedure:
To a solution of methyl (1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate (800 mg, 2.34 mmol, 78% ee) in dichloroethane (15 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (891 mg, 4.22 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 80:20 hexane/EtOAc) to give methyl (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate (472 mg). This ester intermediate was redissolved in 1:1 dioxane/THF (20 mL), a solution of 1 N aqueous NaOH (7.02 mL, 7.02 mol) was added, and the mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL) were added to the residue. The aqueous layer was separated, acidified to pH 5 by the addition of 1 N aqueous HCl, and then extracted with EtOAc (2×60 mL). The combined organic phases were washed with saturated NaCl and dried (Na2SO4). The solvent was removed by rotary evaporation and the residue was redissolved in DMF (10 mL) and methanol (20 mL). The crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as an off-white solid (161 mg, 15% yield, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (m, 1H), 8.00-7.60 (m, 6H), 7.30 (d, 2H), 7.00 (d, 1H), 4.05 (m, 1H), 3.20 (m, 1H), 2.40 (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.80-1.60 (m, 4H); LC-MS ret. time 3.57 min, m/z 459.3 (MH+).
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.CO[CH:18](OC)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[N:3]1([C:8]2[CH:13]=[C:12]3[C:11](=[CH:10][CH:9]=2)[NH:14][CH:18]=[C:19]3[CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: COC(CCCCN1CCC(O)CC1)OC
Reactant: NNc1ccc(-n2ccnc2)cc1
Agent: Cl
Product: O=C1CCN(CCCc2c[nH]c3ccc(-n4ccnc4)cc23)CC1

Procedure:
The title compound was prepared from 4-(imidazol-1-yl)-phenylhydrazine dihydrochloride and 5-(4-hydroxypiperidin-1-yl)-pentanal dimethyl acetal using a similar method to that described for Example 8 (steps 3 and 4); δH (250 MHz, CDCl3) 1.96 (2H, qn, d=7.5 Hz), 2.46 (4H, t, J=6.1 Hz), 2.56 (2H, t, J=7.4 Hz), 2.76 (4H, t, J=6.1 Hz), 2.84 (2H, t, J=7.5 Hz), 7.13 (1H, d, J=2.2 Hz), 7.18-7.23 (2H, m), 7.30 (1H, t, J=1.2 Hz), 7.44 (1H, d, J=8.5 Hz), 7.58 (1H, d, J=2.1 Hz), 7.84 (1H, t, J=1.0 Hz), 8.41 (1H, br s); m/e (ES) 323 (M+ +1).
Reaction SMILES: C1([O:7][C:8]([C:10]2[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:11]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)=O)C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1.[Pd]>[CH3:15][N:14]1[C:10]2[C:8](=[O:7])[NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:11]=2[C:12]([CH3:16])=[N:13]1
Reactant: Cc1nn(C)c(C(=O)Oc2ccccc2)c1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1nn(C)c2c1Nc1ccccc1NC2=O
Yield: 70.8 %

Procedure:
2.4 g of 1,3-dimethyl-4-[(2-nitrophenyl)amino]pyrazole-5-carboxylic acid phenyl ester are hydrogenated in 150 ml of toluene and 5 ml of glacial acetic acid using 0.75 g of 10% strength palladium-on-charcoal at room temperature for 2.1 hours in a circulatory hydrogenation apparatus. The solution is filtered and concentrated in vacuo; the residue is chromatographed over a silica gel column using 1:1 petroleum ether (50°/70° C.)/ethyl acetate to yield 1.1 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, mp 189° to 190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26]1([C:32]2[S:36][C:35]([C:37](OCC)=[O:38])=[N:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([C:35]4[S:36][C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:33][N:34]=4)=[O:38])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)c1ncc(-c2ccccc2)s1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Temperature: 80 °C
Yield: 29 %

Procedure:
To a solution of the compound of example 6 (405 mg, 1.2 mmol) and ethyl 5-phenylthiazole-2-carboxylate (233 mg, 1 mmol) in toluene (15 mL) in a sealed tube, was added 2M solution of AlMe3 (135 mg, 1.875 mmol) and the reaction mixture was heated at 80° C. for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride. The resulting solution was extracted with ethyl acetate. The ethyl acetate extract was washed with water, brine, dried over anhydrous sodium sulphate and concentrated to obtain a crude material, which was purified using column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound.
Reaction SMILES: ClC1C=C(C=CC=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[N+:83]([C:86]1[CH:87]=[C:88](B(O)O)[CH:89]=[CH:90][CH:91]=1)([O-:85])=[O:84]>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:88]4[CH:89]=[CH:90][CH:91]=[C:86]([N+:83]([O-:85])=[O:84])[CH:87]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2cccc([N+](=O)[O-])c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 7 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 3-nitrophenylboronic acid (44 mg, 0.2625 mmol) to produce the title compound (7 mg, 7% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][NH:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][N:15]([C:30]4[N:31]=[CH:32][C:27]([F:26])=[CH:28][N:29]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Nc1cccc([C@]23CNC[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Yield: 79.3 %

Procedure:
A solution of N-[(4aR,7aS)-7a-(3-aminophenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (2.49 g, 7.06 mmol), 5-fluoro-2-chloropyrimidine (3.74 g, 28.26 mmol), and diisopropylethylamine (6.16 mL, 35.32 mmol) in 1,4-dioxane (60 mL) is heated to reflux for 4 hours under nitrogen. The reaction is cooled, diluted with water and extracted with ethyl acetate (3×). The combined organic extracts are dried over sodium sulfate, filtered and the solvent is removed in vacuo to give the crude product. The crude product is purified over silica gel with a 25 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (2.51 g, 79%). ES/MS (m/e): 449 (M+H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]([O:11][C:9]([CH2:8][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[Cl:1])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: Clc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1ccnc1Cl

Procedure:
The starting material was prepared by reaction of 2-chloroimidazole with t-butyl bromoacetate in CH2Cl2 /aqueous sodium hydroxide in presence of tetra-n-butyl ammonium hydrogen sulphate to give 1-t-butoxycarbonylmethyl-2-chloroimidazole. Reaction of this compound with trimethyloxonium tetrafluoroborate in CH2Cl2 gave 1-t-butoxycarbonylmethyl-2-chloro-3-methylimidazolium tetrafluoroborate; n.m.r. in d6DMSO: 1.5 (s, 9H); 3.9 (s, 3H); 5.17 (s, 2H); 7.81 (d, 1H): 7.85 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[N+:15]([CH3:18])([O-:17])=[O:16].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=[CH:18][N+:15]([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc2ccccc2c1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ccccc2c1C=C[N+](=O)[O-]
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 2-methoxy-1-naphthaldehyde (1862 mg, 10 mmol) and nitromethane (610 mg, 10 mmol) in methanol (200 ml) is stirred at room temperature until the solids dissolved. The solution is cooled to about 0° C. and a 30% NaOH solution (2 ml, 20 mmol) is added dropwise over 30 min. The resulting solution is added slowly at 60° C. to a 35% HCl solution (200 ml). The amorphous solid that formed is filtered and washed with water. The crude product is recrystallized from ethanol to give pure title compound in 80% yield (1835 mg).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:10]=[CH:11][C:12]=1[CH2:13]Br)(C)(C)C.[C-:26]#[N:27].[Na+]>CN(C=O)C.CCOC(C)=O>[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:26]#[N:27])=[C:7]([OH:6])[CH:8]=1
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-bromomethylphenyl)-1,3-benzoxazole (1.6 g, 3.8 mmol) and sodium cyanide (560 mg, 11.4 mmol) in DMF (10 mL) was stirred at 90° C. overnight. The reaction was cooled to rt and dissolved in EtOAc (200 mL), washed with H2O (2×50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford [4-(1,3-benzoxazol-2-yl)-2-hydroxyphenyl]acetonitrile as yellow solid. MS (ESI) 251 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([O:31]CC)=O)[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:36][CH3:35])=[O:31])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: CN
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine using methods similar to Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.10 (1H, b), 8.53 (1H, s), 8.15 (1H, s), 7.37 (2H, dd, J=6, 8 Hz), 7.11 (2H, t, J=9 Hz), 4.34 (2H, t, J=7 Hz), 4.12 (2H, s), 3.46 (2H, t, J=7 Hz), 3.22 (2H, t, J=6 Hz), 2.88 (3H, d, J=5 Hz), 2.01 (2H, t, J=7 Hz), 1.48-1.62 (4H, m); ES+ MS: 553 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][NH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:20])[CH3:19]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][N:8]2[C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC1(c2ccccn2)CNc2cc(Br)ccc21
Reactant: CC(=O)Cl
Product: CC(=O)N1CC(C)(c2ccccn2)c2ccc(Br)cc21

Procedure:
Following similar methods to those described in Preparation 335 using 6-bromo-3-methyl-3-pyridin-2-yl-2,3-dihydro-1H-indole (1.2 g, 4.1 mmol), acetyl chloride (360 μL, 5 mmol) and TEA (721 μL, 5 mmol) gave the title compound as a pale yellow oil. MS: [M+H]+=331.