Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].N[C:10]1[CH:21]=[CH:20][C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:12]=2[C:11]=1[S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[S:29](=[O:33])(=[O:32])([OH:31])[OH:30].N([O-])=[O:35].[Na+].N(O)=O.NC(N)=O>>[S:29]([OH:33])([OH:32])(=[O:31])=[O:30].[OH:35][C:10]1[CH:21]=[CH:20][C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:12]=2[C:11]=1[S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=N[O-]
Reactant: CN1CCc2ccc(N)c(Sc3ccccc3)c2CC1
Agent: NC(N)=O
Agent: O=NO
Agent: O=S(=O)(O)O
Product: CN1CCc2ccc(O)c(Sc3ccccc3)c2CC1
Temperature: 0 °C

Procedure:
Following the procedures outlined in Example 9, the isomeric 6-chloro-3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine is treated with sodium thiophenolate to give the 6-phenylthio intermediate and the nitro group is reduced with sodium hydrosulfite. To a solution of 2.6 g. (0.0125 mole) of the resulting 7-amino-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine in 25 ml. of 3 N sulfuric acid at 0°-3° C., a solution of sodium nitrite (1 g. in 5 ml. of water) is added dropwise until a positive test for nitrous acid is obtained. Excess nitrous acid is decomposed by adding 0.2 to 0.3 g. of urea and stirring for 10 minutes. The diazonium solution is added dropwise with stirring to 200 ml. of 50% sulfuric acid at 70° C. and maintained at 70° C. until all of the diazonium salt is decomposed. On cooling the warm solution in an ice bath a crystalline precipitate is formed. After being chilled for 30 minutes at 0° C., the mixture is filtered. The solid is washed with a small volume of ice/water. Recrystallization affords 7-hydroxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine sulfate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:51][C:52]1[N:57]=[CH:56][N:55]=[C:54]2[N:58]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[C:67]([F:70])([F:69])[F:68])[N:59]=[CH:60][C:53]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[OH:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:51][C:52]1[N:57]=[CH:56][N:55]=[C:54]2[N:58]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[C:67]([F:70])([F:68])[F:69])[N:59]=[CH:60][C:53]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=1)=[O:43]
Reactant: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1C(F)(F)F)C(=O)Nc1ccccn1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccccn1)[C@H](COCCO)Oc1ncnc2c1cnn2-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (1.275 mL, 1.28 mmol) was added in one portion to a stirred solution of (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(pyridin-2-yl)-2-(1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (0.927 g, 1.28 mmol) (Intermediate AQ1) in tetrahydrofuran (15 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated NH4Cl (10 mL), and diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (50 mL), The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane to afford the product (0.226 g, 36.3%). 1H NMR: (400 MHz, CDCl3) δ 2.90 (1H, s), 3.75-3.80 (4H, m), 4.16-4.25 (2H, m), 6.09 (1H, t), 7.06-7.10 (1H, m), 7.53-7.92 (5H, m), 8.18-8.20 (1H, m), 8.28-8.30 (1H, m), 8.41 (1H, s), 8.57 (1H, s), 9.01 (1H, s); m/z (ES+) (M+H)+=489.31; HPLC tR=1.74 min.
Reaction SMILES: [F:1][CH:2]([C:8](=O)[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH3:14]>C1(C)C=CC=CC=1>[NH2:14][C:8]([C:9]([F:12])([F:11])[F:10])=[C:2]([F:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)C(=O)C(F)(F)F
Reactant: N
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)=C(N)C(F)(F)F

Procedure:
Ethyl 2,4,4,4-tetrafluoro-3-oxobutanoate (81 g.) in toluene (60 ml) was stirred and heated to 70° C. whereupon ammonia gas was bubbled in until an uptake of 6.8 g. was recorded. The reaction was then set for reflux and water removed azeotropically. Approximately 10 ml of water was removed. After cooling, the solvent was removed under reduced pressure and the residue distilled to give ethyl 3-amino-2,4,4,4-tetrafluoro-2-butenoate b.p. 79°-86° C./20 mm, 44 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[O:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)=[CH:22][CH:23]=2)[O:18][CH2:17]1>>[O:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][N:26]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[C:13]([CH:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)=[O:15])=[CH:22][CH:23]=2)[O:18][CH2:17]1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc3c(c2)OCO3)cc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc3c(c1)OCO3)c1ccc(C(C)C)cc1)CCC2
Yield: 58.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(1,3-dioxaindan-5-yl)methyl](4-isopropylphenyl)amine (1.3 g) as starting materials, N-[(1,3-dioxaindan-5-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.3 g) was obtained. melting point: 97-98° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=[CH:16][C:15]([CH:18]([C:20](C(Br)C2C=CC(C3C=CC=CC=3)=CC=2)=O)Br)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:12]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:13]=[CH:14][C:15]([C:18]2[N:1]=[C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]3[CH:20]=2)=[CH:16][CH:17]=1
Reactant: O=C(C(Br)c1ccc(-c2ccccc2)cc1)C(Br)c1ccc(-c2ccccc2)cc1
Reactant: Nc1nccc2ccccc12
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2ccc(-c3cn4ccc5ccccc5c4n3)cc2)cc1
Temperature: 100 °C

Procedure:
A solution of 4.32 g. (0.03 mole) of 1-amino-isoquinoline and 8.25 g. (0.03 mole) of [(1,1'-biphenyl)-4-yl]-bromomethyl-ketone in 100 ml. of chloroform was heated on a boiling water bath for about 10 minutes until a precipitate separated. The solvent was distilled off at atmospheric pressure and the residue was heated under vacuum for 30 minutes at 100° C. It was subsequently taken up with 50 ml of water and the resulting solution was made alkaline by means of 70 ml. of aqueous 10% sodium hydroxide. After extracting with 500 ml. of methylene chloride and evaporating the solvent, a residue was obtained which was re-crystallized from ethylene glycol monomethylether. Yield 3.0 g. M.p. 221°-22° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:28]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]2=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](CC3C=CC(OC)=CC=3)[N:16]=[C:17]([CH3:18])[C:10]=12.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([N:28]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]2=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[C:17]([CH3:18])[C:10]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N5Cc6ccccc6NC5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nccc(Oc3ccc(N4Cc5ccccc5NC4=O)cc3F)c12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a reaction tube were added 3-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3,4-dihydroquinazolin-2(1H)-one (17.6 mg, 0.035 mmol) and excess trifluoroacetic acid (0.5 mL). The solution was stirred at 80° C. for 30 minutes in a sealed tube under nitrogen. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude residue was triturated with diethylether. The resulting solid was filtered, washed with ether, and dried to afford the desired product as an off-white solid as the mono-TFA salt (12.8 mg, 74%). LRMS (APCI pos) m/e 390.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.30 (d, J=5.5 Hz, 1H), 7.60 (d, J=12.5 Hz, 1H), 7.50 (t, J=9.0 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.20 (d, J=7.4 Hz, 2H), 6.96 (t, J=7.0 Hz, 3H), 6.90 (d, J=8.2 Hz, 2H), 6.23 (d, J=5.5 Hz, 1H), 4.89 (s, 2H), 2.64 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[C:16]([CH2:27][O:28][CH3:29])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.Cl.C([O:35][C:36](=[O:40])[CH2:37][NH:38][CH3:39])(C)(C)C.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O>[CH3:29][O:28][CH2:27][C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:38]([CH3:39])[CH2:37][C:36]([OH:40])=[O:35])[CH:8]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]
Reactant: COCc1cc(-c2nc(-c3ccnc(CCl)c3)no2)ccc1-c1ccccc1C
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3ccnc(CN(C)CC(=O)O)c3)no2)ccc1-c1ccccc1C
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of 3-(2-(chloromethyl)pyridin-4-yl)-5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazole (0.097 g; 0.24 mmol), sarcosine t-butyl ester hydrochloride (0.037 g; 0.27 mmol) and K2CO3 (0.043 g; 0.27 mmol) in dioxan (3 mL) was heated at 70° C. for 7 days. DCM and water were added to the reaction mixture. The mixture was poured through a hydrophobic frit. The solvent was evaporated in vacuo. The material was purified by SCX chromatography and the material treated with HCl solution in dioxan (5 M; 3 mL) and the reaction mixture stirred at 70° C. for 18 hours. The solvent was evaporated in vacuo and the residue purified by preparative HPLC, affording the title product as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.78 (1 H, d, J=5.1 Hz), 8.42 (1 H, s), 8.16 (1 H, dd, J=8.2, 2.0 Hz), 8.08 (1 H, s), 8.04 (1 H, dd, J=5.2, 1.5 Hz), 7.38-7.21 (4 H, m), 7.12 (1 H, d, J=7.4 Hz), 5.39 (1 H, br s), 4.23 (2 H, dd, J=17.0, 12.7 Hz), 4.17 (2 H, s), 3.54 (2 H, s), 3.34 (3 H, s), 2.66 (3 H, s), 2.08 (3 H, s). LC/MS: 388 (M+H)+. HPLC (Method B) Rt 2.97 min (Purity: 99.2
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:47])/[C:16](/[N:21]2[CH:24]([S:25]S(C3C=CC(C)=CC=3)(=O)=O)[CH:23]([NH:36][C:37](=[O:45])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:22]2=[O:46])=[C:17](\[O:19][CH3:20])/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCOC.N12CCCCC1C=NCCC2>C1(C)C=CC=CC=1>[C:8]1([CH:7]([O:14][C:15]([C@@H:16]2[N:21]3[C:22](=[O:46])[C@@H:23]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@H:24]3[S:25][CH:18]=[C:17]2[O:19][CH3:20])=[O:47])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO/C(C)=C(\C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)Cc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: COC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 670 mg (1 mmol) of 2-[4-(p-toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenylmethyl ester, 6.7 ml of 1,2-dimethoxyethane and 0.22 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene is stirred for 25 minutes at room temperature under a nitrogen atmosphere. The reaction mixture is diluted with toluene, washed successively with 2 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue, after preparative thick layer chromatography on silica gel using toluene/ethyl acetate, 1:1, gives 7β-phenylacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid diphenylmethyl ester of melting point 166-169° C. (from methylene chloride/hexane), UV spectrum (ethanol): λmax = 258 mμ (ε = 4,500) IR spectrum (methylene chloride): characteristic bands at 2.93, 5.62, 5.73, 5.93 and 6.66 μ, Rf value~0.54 (silica gel; system toluene/ethyl acetate, 1:1), and amorphous 7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, UV spectrum (ethanol): λmax =258 mμ (ε = 6,350), 264 mμ (ε = 6,350), 282 mμ (ε = 5,600) (shoulder), IR spectrum (methylene chloride): characteristic bands at 2.94, 5.63, 5.83, 5.94, 6.26 and 6.66 μ, Rf value~0.37 (silica gel; system toluene/ethyl acetate, 1:1), in the ratio of 8:1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([CH:11]=O)=[CH:9][NH:8][N:7]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:11][C:10]3[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:7][NH:8][CH:9]=3)[CH2:26][CH2:25]2)[CH:19]=1)=[O:16]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1c[nH]nc1-c1cccs1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]nc3-c3cccs3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(2-thienyl)-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:21])=[CH:23][CH:24]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: OCCN1CCOCC1
Product: O=C(OCCN1CCOCC1)c1ccc(-c2ccccc2)cc1
Yield: 93 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 2-morpholinoethanol was used instead of the triethanolamine, and 4-phenylbenzoyl chloride was used instead of the benzoyl chloride, to give 2-morpholinoethyl 4-phenylbenzoate in a yield of 93%.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C:28]4(OC)[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClC(Cl)C>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=[CH:17][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: COC1(c2ccc(C(C)C)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCO4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC(Cl)Cl
Solvent: CC#N
Product: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To a stirred solution of (3R,4S,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (600 mg, 1.09 mmol) in acetonitrile-dichloroethane mixture (1:1 mixture, 10 mL) was added triethylsilane (0.7 mL, 4.4 mmol) and boron trifluoride diethyletharate complex (0.27 mL, 2.18 mmol) at −20° C. After stirring for 4 h at 0° C., the reaction was quenched with aq. saturated NaHCO3 solution (8 mL). The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with brine (5 mL), dried over sodium sulphate, concentrated to a residuer which was purified by column chromatography to furnish (2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (520 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[N:6]=[N:5]1>C(O)C.[Pd]>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[N:5]1
Reactant: CC(C)(C)Cn1nnc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)Cn1nnc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(2,2-Dimethylpropyl)-5-nitro-1H-1,2,3-benzotriazole (4.46 g, 19.0 mmol, 1.0 equiv.) was dissolved in ethanol (50 ml), sparged under nitrogen, charged with 10% Pd/C (2.03 g, 1.90 mmol, 0.1 equiv.) and then sparged under hydrogen (1 atm). After stirring at room temperature for 5 hrs, the mixture was filtered through Celite and the residue was washed with MeOH. The filtrate was concentrated in vacuo to provide the titled compound. LRMS m/z (M+H) 205.0 found, 205.3 required.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:8])=[CH:4][CH:3]=1.O.[OH-].[Na+:25]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([NH:9][C@H:10]([C:18]([O-:20])=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[S:8])=[CH:21][CH:22]=1.[Na+:25]
Reactant: Cc1ccc(CC(=S)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(CC(=S)N[C@@H](Cc2ccccc2)C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
3.6 G (0.011 mol) of N-(4-methylbenzylthiocarbonyl)-L-phenylalanine was dissolved in 10 ml of acetone. To the mixture were added 30 ml of water and 10 ml of 1N-sodium hydroxide and then the mixture was stirred at room temperature for 1 to 2 minutes to obtain a transparent solution. After the solution was washed with 30 ml of ether twice, the water layer was evaporated under reduced pressure. To remove the remaining amounts of water from the residue, a small quantity of ethanol was added to the residue and then evaporated under reduced pressure. This operation was repeated three times. Thus, the residue was completely dried to obtain 3.4 g of white powder of the desired sodium salt.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[F:9][C:10]1([F:38])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[C@@H:12]([C:23](=[O:37])[NH:24][C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=2)[CH3:26])[CH2:11]1>>[F:38][C:10]1([F:9])[CH2:15][CH2:14][NH:13][C@@H:12]([C:23]([NH:24][C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=2)[CH3:26])=[O:37])[CH2:11]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CCN2)cc1
Yield: 88 %

Procedure:
The title compound (D97) (66 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (R)-tert-butyl 4,4-difluoro-2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate (D66) (98 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)#[N:20]>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[N:14]=[C:13]([O:15][CH2:25][C:24]3[CH:27]=[CH:28][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)c1cc(O)nc(-c2cc(Cl)cc(Cl)c2)n1
Product: CC(C)c1cc(OCc2ccc(C#N)cc2)nc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-(3,5-dichloro-phenyl)-6-isopropyl-pyrimidin-4-ol (which was obtained in Intermediate 6) and 4-cyanobenzyl bromide according to Method A; LC retention time 4.22 min; MS: m/z (ESI) 398 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:21]([O-])=O)=[C:7]([C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]>CO.[C].[Pd]>[C:1]([NH:4][C:5]1[C:6]([NH2:21])=[C:7]([C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)/C=C/c1ccc(NC(C)=O)c([N+](=O)[O-])c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(NC(C)=O)c(N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
To a solution of methyl 3-(acetylamino)-6-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-2-nitrobenzoate (686 mg, 2.13 mmol) in methanol (20 mL) was added palladium-carbon powder (20 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (516 mg, yield 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:20]C)[CH:10]=[CH:9]3)[CH:6]([C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=1)[S:5]2.[ClH:37].CC(=CC)C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOCC>[ClH:37].[F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:20])[CH:10]=[CH:9]3)[CH:6]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:35][CH:36]=1)[S:5]2
Reactant: COc1ccc2c3c(ccc2c1)-c1ccc(F)cc1SC3c1ccc(OCCN2CCCCC2)cc1
Agent: BrB(Br)Br
Agent: CC=C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Oc1ccc2c3c(ccc2c1)-c1ccc(F)cc1SC3c1ccc(OCCN2CCCCC2)cc1
Yield: 65 %

Procedure:
Dissolve 1-{2-[4-(8-fluoro-2-methoxy-5H-6-thia-chrysen-5-yl)-phenoxy]-ethyl}-piperidine (330 mg, 0.67 mmol) in methylene chloride (6.0 mL) and add 2M HCl in ether (0.67 mL). Concentrate in vacuo and dissolve in dry methylene chloride (6.0 mL). Add 2-methyl-2-butene (0.71 mL, 6.7 mmol) and cool to 0° C. under nitrogen. Add boron tribromide (0.25 mL, 2.7 mmol) slowly and stir at 0° C. for 20 minutes. Pour the reaction into saturated aqueous sodium bicarbonate and extract with methylene chloride/methanol (4:1). Dry organic layer with sodium sulfate, filter and concentrate in vacuo. Purify the resultant oil over silica gel (0% to 3% methanol in methylene chloride). Dissolve the resultant oil in methylene chloride (3 mL) and add 2M HCl in ether (0.5 mL). Remove the solvent in vacuo and place in a 50° C. vacuum oven overnight to yield 225 mg (65%) of the title compound: mass spectrum (ion spray) m/z=486.3 (M−Cl).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]([OH:7])=[O:6].Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.Cl>CS(C)=O>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:10][CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)CO
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(OCC(=O)O)ccnc2c1
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
A 250-mL, 3-neck, rb flask equipped with a magnetic stirbar, a reflux condenser and a powder funnel was charged with potassium hydroxide (6.0 g, 90 mmol) then 2-hydroxyacetic acid (5.0 g, 65 mmol) with stirring. The solid reactants gradually reacted and liquified as significant heat was generated. Upon dissolution of all the reagents, flask containing the hot syrupy liquid was immersed in a 170° C. oil bath, then a solution of 4-chloro-7-methoxyquinoline (5.0 g, 26 mmol) in anhydrous DMSO (20 mL, 4 vol wrt quinoline) was added dropwise over 20-30 min via addition funnel. The resulting brown solution was maintained in the oil bath with stirring. After 2.5 h, the flask was removed from the oil bath, then quenched by the addition of water (100 mL, 5 vol wrt DMSO). The resulting brown solution was immersed in an ice bath, and the mixture was neutralized by the dropwise addition of 6 N HCl (15 mL, 1 equiv to KOH), which resulted in the formation of a thick yellow ppt and brought the mixture to pH 3. The mixture was filtered and washed with water and ACN. The solid products were dried under vacuum to yield 2-(7-methoxyquinolin-4-yloxy)acetic acid (2.16 g, 36% yield) as a yellow solid. (ESI, pos. ion) m/z: 234.1 (M+H).