Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]1[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][C:41](B(O)O)=[C:40]([O:50][CH3:51])[CH:39]=1>C1COCC1>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:41]4[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:38]([F:37])=[CH:39][C:40]=4[O:50][CH3:51])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 32 °C
Yield: 78 %

Procedure:
To (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 32) (460 mg, 0.889 mmol) in THF (10 mL) was added potassium carbonate (2 M in water, 1.3 mL, 2.67 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (57.9 mg, 0.089 mmol) and (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (INTERMEDIATE 59) (283 mg, 1.33 mmol). The reaction was degassed with nitrogen and heated at 32° C. for 16 hr. The reaction was then poured into brine and extracted with ethyl acetate (2×10 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified via flash chromatography on silica gel to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({6-chloro-3-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyridin-2-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (419.4 mg, 0.693 mmol) LCMS calc.=605.1. found=605.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.CC(C)([O-])C.[Na+].[NH2:18][C:19]1[C:27]2[C:22](=[C:23]([C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[N:35]=[C:34]([NH:39][CH3:40])[N:33]=[CH:32]4)[C:24]([CH3:28])=[CH:25][CH:26]=2)[N:21]([CH3:41])[N:20]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:41][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=2[C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[C:34]([NH:39][CH3:40])[N:33]=[CH:32]3)[C:19]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)=[N:20]1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(N)nn(C)c34)ccc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(C(F)(F)F)c5)nn(C)c34)ccc2n1
Temperature: 130 °C

Procedure:
A mixture of 1-bromo-3-(trifluoromethyl)benzene (19 μL, 138 μmol), tris(dibenzylideneacetone)dipalladium (0) (3.5 mg, 3.8 μmol), sodium t-butoxide (17 mg, 176 μmol), 6-(3-amino-1,6-dimethyl-1H-indazol-7-yl)-N-methylquinazolin-2-amine (40 mg, 126 μmol) and X-Phos (6.7 mg, 14 μmol) in toluene (3 mL) was purged with nitrogen and heated in a microwave reactor at 130° C. for 33 min. Solvent was removed in vacuo and the residue was purified by flash chromatography (25-50% EtOAc hexane) to give the title compound. MS (M+H)+ 463.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[N:6]=[CH:5]2.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[F:32].C([O-])(O)=O.[Na+].CN(C=O)C>O>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][N:7]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:3][C:2]=1[O:1][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[F:32])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc2c(cnn2C2CCCCO2)cc1O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A mixture of ethyl 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carboxylate (10.8 g, 37 mmol), 1,2-difluoro-4-nitrobenzene (7.1 g, 44 mmol), NaHCO3 (7.4 g, 88 mmol) and DMF (100 mL) is stirred at 80° C. for 2 hours. After it is cooled to RT, water (400 mL) and PE (50 mL) are added and the mixture is stirred for 20 min. The precipitate is collected and dried under vacuum at 50° C. to afford the product (15 g, 95% yield). MS (m/z): 430.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:38][CH2:39]O.FC(F)(F)C1C=CC(C=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:39][CH2:38][C:24]2[N:25]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=3)[O:27][C:23]=2[CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=Cc1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol (prepared by conversion of the 4-trifluoromethyl-benzaldehyde into 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol in analogy to the sequence described in examples 21 a] to 21 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([NH2:15])[CH:9]=1)=[O:6].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([NH:15][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=2)=[S:30])[CH:9]=1)=[O:6]
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: Nc1cc(NC(=O)c2ccc(Cl)c(Cl)c2)ccc1F
Product: O=C(Nc1ccc(F)c(NC(=S)Nc2cccc(C(F)(F)F)c2)c1)c1ccc(Cl)c(Cl)c1
Yield: 46 %

Procedure:
Prepared according to the procedure described for Example 60 using 3,4-dichloro-N-(3-amino-4-fluorophenyl)-benzamide from Example 22 (0.69 g, 2.3 mmol) and 3-trifluoromethylphenyl isothiocyanate (0.47 g, 2.3 mmol) to afford the product (0.532 g); m.p. 172-174° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: Oc1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1COc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 10.76 g (55 mmol) of N-chloromethylphthalimide in 80 ml of DMF, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene was added. The mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the reaction mixture was poured into water and extracted with ethyl acetate. The precipitate was filtered off. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.67 g of the desired compound (yield: 21%, colorless crystals).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1>>[O:11]1[CH2:12][CH:13]=[C:14]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1C1=CCOCC1
Yield: 65 %

Procedure:
Following Example 231, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester gave 5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (167 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 5.99-5.94 (m, 1H), 4.37 (q, J=2.8 Hz, 2H), 3.99 (t, J=5.3 Hz, 2H), 3.84 (s, 3H), 2.40-2.35 (m, 2H)
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14](C=O)=[CH:13][C:12]([I:17])=[C:11]2[C:7]=1[CH:8]([O:28][CH3:29])[N:9]([C:19]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:10]2=[O:18])(=[O:4])=[O:3].[CH:30]([O:35][CH3:36])([O:33][CH3:34])OC.C(=O)([O-])O.[Na+].O>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][S:2]([O:5][C:6]1[C:14]([CH:30]([O:33][CH3:34])[O:35][CH3:36])=[CH:13][C:12]([I:17])=[C:11]2[C:7]=1[CH:8]([O:28][CH3:29])[N:9]([C:19]([CH3:20])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:27])[C:10]2=[O:18])(=[O:3])=[O:4]
Reactant: COC1c2c(OS(C)(=O)=O)c(C=O)cc(I)c2C(=O)N1C(C)(C)c1ccccc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1cc(I)c2c(c1OS(C)(=O)=O)C(OC)N(C(C)(C)c1ccccc1)C2=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
4-Methanesulfonyloxy-5-formyl-3-methoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (220 mg, 0.416 mmol) was dissolved in methanol (4 mL), and the solution was added with trimethyl orthoformate (0.091 mL, 0.83 mmol) and p-toluenesulfonic acid monohydrate (1.0 mg, 0.0058 mmol), followed by stirring at 50° C. for 5 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-methanesulfonyloxy-5-dimethoxymethyl-3-methoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (231 mg, yield 96%).
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[C:42]([CH3:44])[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=1>>[CH3:45][N:41]1[C:42]([CH3:44])=[CH:43][C:38]([C:17]2[CH:16]=[CH:15][C:14]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:36])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:19][CH:18]=2)=[CH:39][C:40]1=[O:46]
Reactant: Cc1cc(Br)cc(=O)n1C
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(=O)n1C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-bromo-1,6-dimethylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.173 min, m/z=475.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.16 (s, 3H), 1.51 (d, 3H),2.18 (m, 3H), 2.21 (m, 1H), 2.42 (m, 4H), 2.86 (m, 1H), 3.54 (s, 3H), 5.66 (m, 1H), 6.21 (s, 1H), 6.60 (s, 1H), 6.97 (m, 2H), 7.23-7.34(m, 7H).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[H+].[B-](F)(F)(F)F.[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27]>O.C(O)C>[CH2:30]([O:29][C:25](/[CH:26]=[CH:27]/[C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:28])[CH3:31]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: C=CC(=O)OCC
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
520 mg of NaNO2 (7.6 mmol) were dissolved in 2 ml of water and added dropwise at 0° C. to a solution of 1.3 g of 2-amino-4-trifluoromethylbenzoic acid (6.5 mmol) in 2.6 ml of a 48% aqueous HBF4 solution and 30 ml of ethanol. The mixture was then stirred at 0° C. for 10 minutes, then warmed to RT. A further 0.3 ml of a 48% aqueous HBF4 solution was then added, then 30 ml of ethanol, 0.9 g of ethyl acrylate (9.0 mmol) and 26.9 mg of Pd (OAc)2 (0.12 mmol). Subsequently, the mixture was stirred at 50-60° C. for 1 h. The solvent was then removed under reduced pressure, and the residue taken up with 25 ml of EA and washed initially with 25 ml of a 1N aqueous HCl solution then with 25 ml of a saturated aqueous NaCl solution. The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. The residue was suspended in 25 ml of heptane and the precipitated product was filtered off. Yield: 1.3 g (69%) of a pale brownish solid. An analytical sample was purified by crystallization from heptane/ethyl acetate.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([N:7]1[C:11]2=[N:12][C:13]([CH3:19])=[C:14]([C:16](O)=[O:17])[CH:15]=[C:10]2[CH:9]=[C:8]1[C:20](=[O:37])[NH:21][CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[C:23]([F:26])([F:25])[F:24])[CH3:6].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[CH:1]1([NH:4][C:16]([C:14]2[CH:15]=[C:10]3[CH:9]=[C:8]([C:20]([NH:21][CH:22]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=4)[C:23]([F:24])([F:25])[F:26])=[O:37])[N:7]([CH2:5][CH3:6])[C:11]3=[N:12][C:13]=2[CH3:19])=[O:17])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)O)c(C)nc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3CC3)c(C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Cyclopropylamine (0.0217 g, 0.380 mmol) was dissolved in N,N-dimethylformamide (2.3 ml) and 1-ethyl-6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.150 g, 0.317 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (0.120 g, 0.317 mmol) and 4-methylmorpholine (0.105 ml, 0.951 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then water was added. The aqueous phase was extracted three times with ethyl acetate, dried over sodium sulphate, adsorbed on silica gel and chromatographed with cyclohexane/ethyl acetate (1:1). This gave 0.033 mg (18% of theory) of N5-cyclopropyl-1-ethyl-6-methyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-2,5-dicarboxamide. HPLC-MS: log P=3.52; mass (m/z): 513.1 (M+H)+; 1HNMR (D6-DMSO): δ 0.57 (m, 2H), 0.71 (m, 2H), 1.20 (t, 3H), 2.89 (s, 3H), 3.32 (s, 3H), 4.02 (q, 1H), 4.59 (q, 2H), 6.29-6.33 (m, 1H), 7.35 (s, 1H), 7.70-7.83 (m, 2H), 7.95 (s, 1H), 8.06 (m, 1H), 8.21 (s, 1H), 8.41 (d, 1H), 9.78 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1(CO)[CH2:55][OH:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[CH:45][CH:46]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:55][OH:56])[CH2:32][O:31]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.9 %

Procedure:
To a solution of [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 25k (1.04 g, 13 mmol) in dichloromethane (100 mL) was added p-toluenesulfonic acid monohydrate (123 mg, 0.65 mmol) at 0° C. The mixture was warmed up to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and partitioned. The organic layer was washed with water (30 mL×2) and saturated aqueous sodium chloride (30 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 25l as pale yellow oil (0.59 g, 58.7%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ(ppm): 7.44 (m, 3H), 7.35 (m, 15H), 7.19 (m, 3H), 7.09 (m, 2H), 6.89 (m, 2H), 6.85 (m, 2H), 5.02 (s, 2H), 4.90 (d, 2H), 4.86 (d, 1H), 4.77 (d, 1H), 4.30 (d, 1H), 4.27 (d, 1H), 4.07 (d, 1H), 4.03 (m, 2H), 3.97 (d, 1H), 3.86 (d, 1H), 3.82 (d, 1H), 3.74 (d, 1H), 3.70 (d, 1H), 3.68 (d, 1H).
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[NH:6]1[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: Oc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCN2

Procedure:
4-Hydroxyindole was reduced with sodium cyanoborohydride and acetic acid to give 4-hydroxy, dihydroindole. A mixture of ethyl iodide (40 ml), potassium carbonate (1.09 gm, 7.8 mmole) and 4-hydroxy, dihydroindole (1.06 gm, 7.8 mmole) was refluxed for 2 hr. Excess ethyl iodide was evaporated under vacuum, water was added (10 ml) and the product was extracted with dichloromethane. Silica gel chromatography gave N-ethyl-4-hydroxy-dihydroindole (0.30 gm, 23% yield) as a pale yellow solid.
Reaction SMILES: [CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:9]([OH:12])([OH:11])=[O:10])([P:5]([OH:8])([OH:7])=[O:6])[OH:4].[OH-].[Na+].[Cl-].[Ca+2:18].[Cl-]>>[CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:5]([O-:7])([OH:8])=[O:6])([P:9]([OH:12])([OH:11])=[O:10])[OH:4].[CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:5]([O-:7])([OH:8])=[O:6])([P:9]([OH:12])([OH:11])=[O:10])[OH:4].[Ca+2:18]
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Product: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O

Procedure:
To the alendronate solution, sodium hydroxide and calcium chloride solutions were simultaneously added to keep the pH of the solution at 7.0 until all the calcium chloride solution had been added. The precipitate was collected by filtration and washed with water. The solid was dried in an oven at 120° C. over night to obtain 1.5 g of alendronate calcium, denoted as CakY (where Y is the Alendronate anion). The mean value of k for the generated alendronate calcium at neutral solution (the pH of human blood) was 1.5±0.1. Chemically, Ca1.5Y corresponds to Ca3Y2. The solubility of Ca1.5Y in saline, as alendronic acid, was measured as 247 mcg/mL or 0.0247%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=3)[N:10]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(O)nc(C(O)c3ccc(F)cc3)nc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc2c(O)nc(C(=O)c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
To a solution of 2-((4-fluorophenyl)(hydroxy)methyl)-7-methylquinazolin-4-ol (3 g, 10.56 mmol) in acetonitrile (45 mL) was added Dess-Martin periodinane (5.37 g, 12.67 mmol), and the mixture was stirred at rt for 5 h. Saturated sodium hydrogen carbonate solution was then added and the mixture was stirred at rt overnight. This suspension was then filtered and the resulting solid dried to give crude (4-fluorophenyl)(4-hydroxy-7-methylquinazolin-2-yl)methanone (2.65 g, 89%). LC-MS (ESI) m/z 283 (M+H)+.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])#[N:2].[N-:41]=[N+:42]=[N-:43].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N+:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:30][C:28]([N:4]2[CH2:5][C@@H:6]([S:8][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:7][C@H:3]2[C:1]2[NH:43][N:42]=[N:41][N:2]=2)=[O:29])=[CH:33][CH:34]=1)([O-:40])=[O:39]
Reactant: [N-]=[N+]=[N-]
Reactant: N#C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1c1nnn[nH]1
Yield: 86.2 %

Procedure:
A mixture of (2S,4S)-2-cyano-1-(4-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine (2.00 g) and sodium azide (0.30 g) in dimethylformamide (20 ml) was stirred at 110°-120° C. for 9 hours in the presence of ammonium chloride (0.05 g). The mixture was concentrated under reduced pressure to give a residue. The residue was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of acetone and chloroform (10:90, V/V) to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(1H-tetrazol-5-yl)-4-tritylthiopyrrolidine (1.86 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([N:18]4[CH2:23][CH2:22][CH:21]([NH:24]C=O)[CH2:20][CH2:19]4)[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1>Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:12]2[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[S:10][C:9]=3[N:11]=2)[CH2:19][CH2:20]1
Reactant: CCCc1cc(N2CCC(NC=O)CC2)nc2sc3c(N)ncnc3c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCc1cc(N2CCC(N)CC2)nc2sc3c(N)ncnc3c12
Temperature: 60 °C
Yield: 42.6 %

Procedure:
The above formamide (249 mg, 0.672 mmol) was dissolved in 1 mL of concentrated HCl and 1 mL of water. The reaction mixture was heated in a SmithSynthesizer™ (Personal Chemistry) at 60° C. for 1 h. The solvent was removed in vacuo. The residue was recrystallized from MeOH to give a yellow solid. The solid was stirred in 5 mL of 2 M sodium carbonate solution for 6 h. The resulting yellow solid was collected by filtration, washed with water and air dried to provide the title compound (98 mg, 43%).