Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=O.[C:11]([C:14]1[CH:15]=[C:16]2[C:21](=CC=1O)[N:20]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:18][C:17]2=[O:30])(=[O:13])[CH3:12].[O-]CC.[Na+].C(Cl)(Cl)Cl>C(O)C.Cl.O>[O:30]=[C:17]1[C:16]2[C:21](=[CH:6][C:5]3[O:4][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[CH:12][C:11](=[O:13])[C:14]=3[CH:15]=2)[N:20]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:18]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)c1nc2cc(O)c(C(C)=O)cc2c(=O)[nH]1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc2cc3oc(C(=O)OCC)cc(=O)c3cc2c(=O)[nH]1
Yield: 73 %

Procedure:
A mixture of diethyl oxalate (4.4 ml) and the product of step (a) (1.1 g; 3.98 mmole) in ethanol (50 ml) was added slowly to freshly prepared sodium ethoxide (0.68 g; 9.99 mmole) in ethanol (80 ml) to give instantly a yellow suspension. After the addition, the mixture was heated to reflux on the steambath for half an hour to give a brown suspension. The mixture was cooled and neutralised with dilute hydrochloric acid to give a bright orange precipitate. This was extraced into chloroform, dried and evaporated to give a bright orange solide. The solid was redissolved in ethanolic hydrogen chloride. The solution was heated to reflux on a steambath for 3 hours. The mixture was cooled and was treated with water. After concentration, this was extracted into chloroform. The organic extract was washed with water, dried and evaporated to give a brown solid (0.95 g, 73%) whose structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:14])[CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(F)ccc1C(C)=O
Temperature: 75 °C
Yield: 103.1 %

Procedure:
1-(4-fluoro-2-hydroxyphenyl)ethanone (12.0 g, 77.9 mmol), iodomethane (6.38 ml, 101 mmol), potassiumcarbonate (14.0 g, 101 mmol) were heated at 75° C. in ACN (200 ml) for 8 h. The reaction mixture was brought to ambient temperature, filtered and then evaporated under reduced pressure to dryness. New ACN (150 ml), iodomethane (2 ml, 32 mmol) and potassiumcarbonate (4 g, 29 mmol) was added. The reaction mixture was heated at 75° C. for 3 h. The reaction mixture was concentrated, EtOAc (100 ml) was added and the mixture was filtered and evaporated to give the title product (13.5 g, 100%). MS m/z (rel. intensity, 70 eV) 168 (M+, 11), 153 (bp), 110 (23), 95 (21), 82 (12).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[I:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18]>CCOCC>[I-:11].[C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][SH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH+:6]=[C:2]1[CH3:1])(=[O:19])[CH3:18]
Reactant: Cc1nc2ccccc2s1
Reactant: CC(=O)OCCCCI
Solvent: CCOCC
Product: CC(=O)OCCCC[SH]1C(C)=[NH+]c2ccccc21
Product: [I-]

Procedure:
10 mmol (1.49 g) 2-methyl-benzothiazole and 10 mmol (2.42 g) 4-iodobutylacetate are heated for 4 h at 120° C. and after cooling mixed with ether sucked off, again washed with ether and dried in vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[CH:32](CN)[C:33]([OH:35])=[O:34])=O)(C)(C)C.F[C:39]1C=CC=CC=1[N+]([O-])=O.C(=O)(O)[O-].[Na+]>O.CN(C)C=O>[CH3:39][O:35][C:33](=[O:34])[CH2:32][N:21]1[C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: CC(C)(C)OC(=O)NC(CN)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 80 °C
Yield: 83 %

Procedure:
2(S)-tert-Butoxycarbonylamino-3-(2-nitrophenyl-amino)-propionic acid. 2-tert-Butoxycarbonylamino-3-aminopropionic acid (10 g, 49 mmol), 2-fluoronitrobenzene (5.7 ml, 54 mmol), and sodium bicarbonate (8.25 g, 98 mmol) was taken into 130 ml of dimethylformamide and heated at 80° C. for 18 hours. The reaction was evaporated in vacuo to give a viscous orange residue that was dissolved in 300 ml of water and extracted with diethyl ether (3×150 ml). The aqueous solution was acidified to pH 5 with 10% sodium hydrogen sulfate and extracted with ethyl acetate (3×250 ml). The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to give 12.64 g (83 %) of the title compound as an orange amorphous solid. 1H NMR (CD3OD) δ8.15-8.10 (1H,d), 7.54-7.48 (1H,t), 7.13-7.08 (1H, d), 6.73-6.65 (1H, t), 4.45-4.35 (1H, m), 3.9-3.8 (1H, dd), 3.65-3.55 (1H, dd), 1.45 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 4-(4-chlorophenyl)piperidine-1-carboxylate (compound 42.3, 5.00 g, 16.9 mmol) in dichloromethane (100 mL), trifluoroacetic acid (9.6 g, 84 mmol). The resulting solution was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was carefully diluted with ethyl acetate (100 mL) and aqueous sodium bicarbonate was added until a pH of 8 was attained. The resulting mixture was washed with brine (100 mL) and the organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a light yellow solid (2.30 g, 70%).
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][S:11][C:5]2=[N:4][C:3]=1/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29].[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:25][O:24][C:20]1[C:19]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:18](/[CH:17]=[CH:16]/[C:3]2[N:4]=[C:5]3[S:11][CH:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:6]3[C:7](=[O:8])[C:2]=2[C:37]2[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1cccc(/C=C/c2nc3scc(C(F)(F)F)n3c(=O)c2I)c1OCC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3scc(C(F)(F)F)n3c(=O)c2-c2ccc(C#N)cc2)c1OCC(C)(C)C
Yield: 65.9 %

Procedure:
This compound was prepared from Intermediate 21 (100 mg, 0.197 mmol) and 4-cyanophenylboronic acid (35 mg, 0.204 mmol) using Pd[(C6H5)3P]4 (8 mg, 0.007 mmol) and sodium carbonate (112 mg, 1.053 mmol) in toluene (10 ml) and ethanol (5 ml) and water (4 ml) according to the procedure outlined in Example 1 to afford crude residue which was purified by column chromatography using 1% ethyl acetate in chloroform to afford 70 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 9H), 3.53 (m, 2H), 3.77 (m, 2H), 6.72-6.77 (m, 1H), 6.98-7.02 (m, 2H), 7.52-7.55 (m, 2H), 7.91-7.94 (m, 2H), 8.24 (s, 1H), 8.30 (s, 2H); ESI-MS (m/z) 540.53 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([Cl:22])[N:16]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:22][C:17]1[N:16]=[C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)[C:20]([CH3:21])=[CH:19][CH:18]=1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Cc1ccc(Cl)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Cl)nc1-c1ccc2c(cnn2C)c1
Temperature: 110 °C

Procedure:
In a 10 mL reaction vial, the 1-methyl-1H-indazol-5-ylboronic acid (500 mg, 2.84 mmol) and the 2-bromo-6-chloro-3-methylpyridine (585 mg, 2.84 mmol) were dissolved in dioxane (7 mL) and water (1.7 mL) under argon atmosphere. The mixture was bubbled with argon for 5 min. Then potassium carbonate (979 mg, 7.1 mmol) and Pd(PPh3)4 (49 3 mg, 0.428 mmol) were added sequentially. The resulting reaction mixture was then sealed and heated in oil bath at 110° C. for 2.5 h. Reaction was then partitioned between EtOAc (30 mL) and water (30 mL).The organic phase was washed with water (3×20 mL) and was concentrated. Residue was purified on silica gel column with 0-50% EtOAc/Hex to afford the title compound. LCMS-ESI+: calc'd for: C14H12ClN3: 258.1 and 260.1 (M+H+); found: 258.0 and 260.0 (M+H+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][N:8]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:7]1=[O:30].O>CN(C)C=O>[C:16]([O:15][C:13]([N:11]1[CH2:12][C@@H:6]([N:1]=[N+:2]=[N-:3])[C:7](=[O:30])[N:8]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH2:9][C@@H:10]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(Br)C(=O)N(CC2CC2)CC1c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C(=O)N(CC2CC2)C[C@@H]1c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium azide (0.841 g, 12.9 mmol) was added to a solution of tert-butyl 6-bromo-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate (0.609 g, 1.43 mmol) in N,N-dimethylforamide (10 mL) and heated to 70° C. After 1 h, the mixture was allowed to cool to ambient temperature and water was added. The mixture was extracted with ethyl acetate, washed with water (3×), saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (20% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave 170 mg of the trans isomer and 24 mg of the cis isomer. MS 386 (M+1).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@@H:20](O)[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].[F:26]C(N(CC)CC)(F)C(F)F>ClCCCl>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:26])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4]
Reactant: CCN(CC)C(F)(F)C(F)F
Reactant: O=C1[C@H]2C[C@@H](O)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: ClCCCl
Product: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In a Teflon® flask, a suspension of (6R-trans)-1-chloro-N-[2-chloro-4-fluoro-5-(tetrahydro-6-hydroxy-1,3-dioxo-1H-pyrrolo[1,2-c]imidazol-2(3H)yl)phenyl]methanesulfonamide (8.24 g, assay 94.5% pure, 18.9 mmol) in 1,2-dichloroethane (40 mL) was heated to reflux and then 1,1,2,2-tetrafluoroethyldiethylamine (3.8 g, 26 mmol) was added over 1-2 minutes. Refluxing was continued for 1 hour, then 20 mL of the solvent was distilled out of the reaction mixture at atmospheric pressure. The reaction mixture was cooled to 50° C., 1-propanol (1 mL) was added, the pressure was reduced to about 20 kPa (150 mm Hg) for 10 minutes, and then the remaining solvent was distilled off at 55-60° C. at 20 kPa (150 mm Hg). More 1-propanol (15 mL) was added at 60° C., then the mixture was cooled slowly to room temperature, and stirred overnight at room temperature to complete the crystallization. The mixture was filtered and the solids were rinsed with several portions of 1-propanol (10 mL total) and dried to afford 6.57 g (79.3% crude yield) of the title compound as a white powder melting at 166-168° C. (purity: 97.3% by HPLC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:30].O.C[N:33]1CCCC1=O>>[NH2:33][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:13]2[CH:12]=[CH:11][C:10](=[O:30])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CN1CCCC1=O
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: O
Product: Nc1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (432 mg, 1 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added NaNH2 (195 mg, 5 mmol, 5 eq) and the mixture was heated to 50°. After 1 h, H2O (20 mL) was added then Et2O (20 mL) The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and solvent was removed in vacuo. The yellow residue was then purified by Flash chromatography to afford 2-amino-8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (100 mg, 53% yield). 1H-NMR (CDCl3) δ 5.51 (br s, 2H), 6.42 (d, 1H, J=9.8 Hz), 7.08 (m, 2H), 7.30 (m, 2H), 7.50 (m, 4H), LC MS (m/e)=369 (MH+). Rt=1.77 min
Reaction SMILES: [CH2:1]([C:4]1([C:20]([O:22][CH3:23])=[O:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)[CH:2]=C.C1C=C[NH+]=CC=1.[O-:30][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl.CCOCC>[O:30]=[CH:2][CH2:1][C:4]1([C:20]([O:22][CH3:23])=[O:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:6][CH2:5]1
Reactant: C=CCC1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1(CC=O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate from Step B (4.45 g, 14.0 mmol) in THF (70 mL) at 0° C. was added borane-methyl sulfide complex (28.0 mL of a 2M solution in THF, 56.1 mmol). The reaction mixture was slowly warmed to ambient temperature and stirred for 16 h, then quenched with water and concentrated in vacuo. The residue was dissolved in CH2Cl2 (140 mL) and added drop wise to a solution of PCC (6.65 g. 30.8 mmol) and 4 Å molecular sieves (6.65 g) in CH2Cl2 (50 mL) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 16 h, then diluted with ether (200 mL) and filtered through a pad of celite. Additional ether was used to wash the celite. The combined organics were concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=356 (M+Na).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[Si:19]([O:26][CH2:27][CH2:28][C@@H:29]1[CH2:40][CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32](Cl)[C:31]=3[C:30]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][CH2:28][C@@H:29]1[CH2:40][CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32]([O:3][CH:4]4[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:6][CH2:5]4)[C:31]=3[C:30]1=2)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.96 g, 49.00 mmol, 4.02 equiv) was treated with tert-butyl N-(4-hydroxycyclohexyl)-N-methylcarbamate (3.92 g, 17.09 mmol, 1.40 equiv) in distilled THF (50 mL) at 0° C. for 1 h under nitrogen. Then a solution of 22.1 (4.5 g, 12.20 mmol, 1.00 equiv) in 15 mL of THF was added to the reaction mixture, which was stirred for a further 2 h at 60° C. The reaction was then quenched by the addition of 20 mL of water at 0° C. and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:5) and purified to afford tert-butyl N-(4-[[(3S)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (22.2, 6.5 g, 95%) as yellow oil. MS: m/z 562 (M+H)+.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(C2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 72.6 %

Procedure:
A mixture of intermediate (9) (0.025 mol) in methanol (250 ml) was hydrogenated at 50° C. overnight with palladium on carbon (10%; 2 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 7.7 g of N-[4-(4-piperidinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 10).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH3:23].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH3:23]
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Reactant: CC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC=C1OC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.527 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 0.311 ml (5.0 mmol) of acetaldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 17 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=3/1) to yield 77 mg (4.65%, yellow oily substance) of the desired product.
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:11]1[C:16]([I:17])=[CH:15][CH:14]=[C:13]([N:18]2[CH2:22][C@H:21]([O:23]C)[C@H:20]([O:25][C:26](=O)C)[CH2:19]2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CO>[CH2:4]([C:11]1[C:16]([I:17])=[CH:15][CH:14]=[C:13]([N:18]2[CH2:19][C@H:20]([O:25][CH3:26])[C@H:21]([OH:23])[CH2:22]2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A 28% solution of sodium methoxide in 0.33 ml of methanol was added to a mixture of 7.5 g of 2-benzyl-3-iodo-6-[(3R,4S)-3-acetoxy-4-methoxypyrrolidine-1-yl]pyridine and 30 ml of methanol, followed by stirring at room temperature for 30 minutes in a nitrogen atmosphere. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 20-50% ethyl acetate, to give 6.7 g of the target compound.
Reaction SMILES: [C@@H:1]1([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:23](O)=[O:24])[C:18](=[O:22])[O:19]3)=[CH:14][CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]([CH2:58][CH2:59][CH3:60])[C:55]([OH:57])=[O:56].[Si](O)(O)(O)O>CN(C)C=O.O.C(N(CC)CC)C>[C:55]([CH:54]([CH2:58][CH2:59][CH3:60])[CH2:53][CH2:52][CH2:51][CH2:50][NH:49][C:23]([C:17]1[C:18](=[O:22])[O:19][C:20]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C@@H:1]1[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3])[CH:21]=2)=[O:24])([OH:57])=[O:56]
Reactant: O=C(O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Reactant: CCCC(CCCCN)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Agent: O[Si](O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(CCCCNC(=O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of 734 milligrams (mg) [2 millimol (mmol)] of 7-β-galactosylcoumarin-3-carboxylic acid and 210 mg (2 mmol) of N-hydroxysuccinimide in 20 ml of dimethylformamide was cooled to -10° C. while stirring under an inert atmosphere. To this was added 412 mg (2 mmol) of dicyclohexyl carbodiimide. After 15 minutes at -10° C., a clear solution was obtained. The reaction was allowed to warm to room temperature and stirred for 2 hours. It was again cooled to -10° C. and the precipitate of dicyclohexyl urea removed by filtration under vacuum. The filtrate, now containing the activated ester (3), was placed in a dropping funnel and added dropwise over a 15 minute period to a 0° C. solution consisting of 346 mg (2 mmol) of 6-amino-2-n-propylhexanoic acid (2), n=4, and 0.5 ml of triethylamine in 20 ml of water. After 1 hour at 0° C., the reaction was allowed to warm to room temperature and stirred for 2 hours. Ten grams of silicic acid was added and the solvent removed on the rotary evaporator under high vacuum. The impregnated silicic acid was placed atop a column of 120 g of silicic acid packed in 3:2 (v:v) ethyl acetate:ethanol. The column was eluted with this solvent and 15 ml fractions were collected. Fractions 28 to 40 were combined, evaporated, and the residue recrystallized from ethanol to give 365 mg (35% yield) of the labeled conjugate (4), n=4, as cream colored crystals, mp 162° C.