Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1([CH2:16][CH:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=3)[CH:20]=2)[CH3:18])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N1CCOCC1)C>C(Cl)Cl.CCOCC>[C:1]([N:13]1[CH2:12][CH2:11][N:10]([CH2:16][CH:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=3)[CH:20]=2)[CH3:18])[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2cc(C(C)CN3CCNCC3)ccc2c1
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2cc(C(C)CN3CCN(C(=O)c4ccccc4)CC3)ccc2c1
Reaction time: 3 h

Procedure:
Benzoyl chloride (0.58 ml, 5 mmols) is added, at 0° C., to a solution of 2-(2-piperazino-1-methylethyl)-6-methoxynaphthalene (1.42 g, 5 mmols) and N-ethylmorpholine (0.65 ml, 5 mmols) in 15 ml of methylene chloride. The mixture is allowed to return to ambient temperature and stirred for 3 hours. The reaction medium is washed with water and dried over sodium sulphate. Concentration of the mixture yields an oily residue which dissolves in ether and crystallises. The compound is recrystallised from ethyl acetate (15 ml).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16](B(O)O)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]([C:34]1[CH:38]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:36][N:35]=1)([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:30]([C:34]1[CH:38]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:36]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:20][CH2:19]3)[N:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: O=C(OCc1ccccc1)N1CCc2cc(B(O)O)ccc2C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 40 h
Yield: 48.4 %

Procedure:
To a stirring suspension of 2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (0.640 g, 2.06 mmol, 1.00 eq) and 4 ÅMS (0.64 g) in CH2Cl2 (20 ml) was added pyridine (0.168 ml, 2.06 mmol, 1.00 eq) followed by ethyl 3-t-butyl-1H-pyrazole-5-carboxylate (0.404 g, 2.06 mmol, 1.00 eq) and Cu(OAc)2 (0.374 g, 2.06 mmol, 1.00 eq). The resulting blue-green mixture was stirred at 25° C. After 40 h, the mixture was diluted with H2O and decanted away from the molecular sieves. The layers were separated and the organic phase was washed with H2O (2×). The combined aqueous phases were extracted with CH2Cl2 (1×). The combined organic phases were dried (MgSO4), concentrated in vacuo and purified by flash chromatography (EtOAc/hexanes) to afford benzyl 6-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.46 g, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.28 (m, 5H), 7.24-7.20 (m, 3H), 6.96 (s, 1H), 5.15 (s, 2H), 4.67 (brm, 2H), 4.17 (q, 2H, J=7.2 Hz), 3.66 (brs, 2H), 2.86 (t, 2H, J=6.0 Hz), 1.29 (s, 9H), 1.18 (t, 3H, J=7.2 Hz); MS (ESI) m/z: 462.3 (M+H+).
Reaction SMILES: [OH:1][C@@H]1CN2C(=O)[C@@H](NC(=O)CC3C=CC=CC=3)[C@H]2SC1.[CH:21]1([N:27]=[C:28]=[N:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.FC(F)(F)C(O)=O.N1C=CC=CC=1.C(O)(=O)C>CS(C)=O.C(OCC)(=O)C.O>[C:28]([NH:27][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)([NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:1]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@@H](O)CS[C@H]12
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h
Yield: 218.3 %

Procedure:
A solution of (3R,6R,7R)-3-hydroxy-7-phenylacetamido cepham (6.0 g., 20.5 mmole) and dicyclohexylcarbodiimide (11.65 g., 56.6 mmole) in dimethyl sulphoxide (50 ml.) was treated with pyridine trifluoroacetate (1.37 g., 7.1 mmole) and the mixture was stirred at 26° for 11/2 hours. Acetic acid (6 ml.) and water (2 ml.) were added and the mixture was stirred for 30 minutes before being diluted with ethyl acetate (250 ml.) and filtered to give dicylohexylurea (10.04 g., 79%) as colourless prisms. The filtrate was washed with saturated aqueous sodium hydrogen carbonate (2 × 200 ml.), dried, and evaporated under reduced pressure to give a brown solid (7.65 g.). The solid was refluxed with acetonitrile (100 ml.) for 5 minutes, filtered to give more dicyclohexyl urea (0.4 g., 3.2%) and the filtrate was evaporated under reduced pressure. The resulting brown solid was dissolved by heating under reflux with isopropyl alcohol (150 ml.) for 15 minutes and on cooling, crystals of (6R,7R)-3-keto-7-phenylacetamidocepham (3.6 g., 60.5% in two crops) separated out; m.p. and NMR were in agreement with standards.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.N#N.FC(F)(F)S(O[Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])(=O)=O>C(Cl)Cl>[O:29]=[C:6]1[CH:5]=[C:4]2[C@:24]([CH3:27])([CH2:25][CH2:26][C@H:2]([O:1][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[CH2:3]2)[C@@H:23]2[C@@H:7]1[C@H:8]1[C@:20]([CH3:28])([CH2:21][CH2:22]2)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: N#N
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of methyl 313-hydroxy-7-oxochol-5-en-24-oate (2) (5.02 g, 12.5 mmoles) and 2,6-1utidine (3.32 ml, 28.5 mmoles) in CH2Cl2 (23 ml) cooled in an ice bath in a N2 atmosphere was added dropwise with magnetic stirring triisopropylsilyl trifluoromethanesulfonate (4.56 g, 17 mmoles). After 2 hrs, the reaction was diluted with CH2Cl2 (150 ml). It was then washed with cold 2N HCl, washed twice with H2O and then with saturated brine before drying with MgSO4. Evaporation in vacuo and purification of the residue by flash chromatography on silica gel with hexane-EtOAc (10:1 ) gave 5.88 g of 3 as a colorless syrup. NMR (CDCl3): δ0.67 (s, 3H, 18-Me); 0.93 (d, 3H, 20-Me); 1.06 (s, 18H, TIPS Me); 1.19 (s, 3H, 19-Me); 3.66 (s, 3H, CO2Me); 3.68 (m, 1H, 3-H); 5.66 (s, 1H, 6-H).
Reaction SMILES: [I:1]I.I(O)(=O)(=O)=O.S(=O)(=O)(O)O.[CH2:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)(=O)C.O>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][C:24]([I:1])=[CH:25][C:20]=1[O:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCOc1ccccc1OCCCCCC
Reactant: II
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCOc1ccc(I)cc1OCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 213.7 %

Procedure:
69.3 g (253 mmol) of iodine, 32.8 g (144 mmol) of periodic acid, 150 mL of distilled water and 22.5 mL of concentrated sulfuric acid were added to 750 mL of glacial acetic acid and stirred for 5 minutes at room temperature followed by the addition of 80.00 g (287 mmol) of 1,2-dihexyloxybenzene and stirring for 24 hours at 40° C. The resulting reaction mixture was cooled to room temperature, washed with aqueous KOH solution (1 M, 1.5 L) and 3 L of distilled water, and then extracted with 800 mL of chloroform. The organic phase was dried with MgSO4 followed by distilling off the solvent. The residue was purified by column chromatography followed by distilling to obtain 218.6 g of a light brown liquid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2](C)[CH3:3].C([Li])CCC.Br[C:13]1[CH:14]=[CH:15][C:16]([Cl:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Cu]C#N.C(Br)C=C>C1COCC1>[CH2:3]([C:13]1[CH:14]=[CH:15][C:16]([Cl:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:1]
Reactant: CC(C)(C)OC(=O)c1cc(Br)ccc1Cl
Reactant: CC(C)C[Mg]Br
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1ccc(Cl)c(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., isobutylmagnesium bromide (2.0 M ether solution, 1.2 eq.) and n-butyl lithium (2.5 M hexane solution, 2.4 eq.) were added to anhydrous THF (0.3 M). After stirring at 0° C. for 30 min, the reaction mixture was cooled to −40° C. and tert-butyl 5-bromo-2-chlorobenzoate from the previous step (1 eq.) was added over 15 min. The now red solution was stirred at −40° C. for 1 h before copper (I) cyanide (30% loading) was added. The resulting suspension was stirred at −40° C. for 15 min and then added allyl bromide (3 eq.). After stirring at −40° C. for another 2 h, the reaction mixture was quenched with sat. aq. NH4Cl and warmed to RT. The biphasic mixture was poured into more sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→19:1 (v/v) Hex:ether) afforded the title compound as a light yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[OH:14][NH2:15]>N1C=CC=CC=1.C(O)C>[C:1](=[N:15][OH:14])([C:4]1[CH:5]=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cnc2ccsc2c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1cnc2ccsc2c1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
To a solution of 6-acetylthieno[3,2-b]pyridine (3.78 g, 21.3 mmol) in pyridine (40 ml) and ethanol (40 ml), under a nitrogen atmosphere, was added hydroxyl amine hydrochloride (5.0 g, 72 mmol). After the reaction mixture was heated at 80° C. for three hours, the solvents were removed under reduced pressure on a rotary evaporator and the residue was diluted with ice water to give crystalline product. This solid was collected by filtration and dissolved in ethyl acetate/methanol, dried over anhydrous sodium sulfate and filtered through charcoal. The solvents were evaporated to give pure product (3.15 g, 77% yield) which was used as is. A small portion was recrystallized from methanol for microanalysis, m.p 210°-213° C.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C:28](=[O:30])[CH3:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C:28]1([CH3:8])[CH2:29][O:30]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2cc(Cl)ccc2OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 60% sodium hydride (1.2 g,30 mmol) in tetrahydrofuran (30 mL)-dimethyl sulfoxide (30 mL) was heated at external temperature of 60° C., and trimethylsulfoxonium iodide (6.5 g, 30 mmol) was added portionwise to the mixture. The resultant mixture was stirred for 1 hour and then cooled to room temperature. A solution of 1-(2-(benzyloxy)-5-chlorophenyl)-1-ethanone [compound (9-1)] (5.0 g, 19 mmol) in tetrahydrofuran (10 mL) was added dropwise to the mixture, and the mixture was stirred for 3 hours at external temperature of 60° C. After the mixture was cooled to room temperature, the mixture was added to ice-water, followed by extraction with diethyl ether. The extracted substance was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure, to thereby yield 2-(2-(benzyloxy)-5-chlorophenyl)-2-methyloxirane as a colorless oily product (yield: 4.4 g). The obtained product was used in the subsequent reaction step without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=O)OC(C)(C)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN[C@@H]1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of (R)-tert-butyl 1-benzylpiperidin-3-ylcarbamate (300 mg, 1.03 mmol) in THF (5 mL) at −30° C., LiAlH4 (0.77 mL of 2 M solution in THF, 1.5 mmol) was added dropwise under inert atmosphere. After addition the reaction mixture was warmed to rt and then heated to reflux for 2 h. After completion of the reaction, a 20% aq. solution of NaOH solution (5 mL) was added dropwise to the reaction mixture. The reaction mixture was diluted with EtOAc (50 mL) and the suspension was filtered over a short pad of celite. The filtrate was dried over Na2SO4 and concentrated in vacuo to give the titled intermediate (200 mg, 94%). The compound was used in the further steps without purification. LC-MS: m/z [M+1]=205.
Reaction SMILES: Br.Br.Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:15]=1)[N:12]=[CH:11][CH:10]=[C:9]2[CH3:29].CC(O)C.[OH-].[NH4+].[C:36]([N:38]=[C:39](SC)[S:40][CH3:41])#[N:37]>O.C1(C)C=CC=CC=1>[C:36]([N:38]=[C:39]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]2[CH:15]=[C:6]([O:5][CH3:4])[CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[C:9]3[CH3:29])[CH2:28][CH2:27]1)[S:40][CH3:41])#[N:37]
Reactant: CSC(=NC#N)SC
Reactant: COc1cc(NCCCCCCN2CCNCC2)c2nccc(C)c2c1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(NCCCCCCN2CCN(C(=NC#N)SC)CC2)c2nccc(C)c2c1
Yield: 66 %

Procedure:
A solution of 5.5 g (0.009 mole) of 6-methoxy-4-methyl-N-[6-(1-piperazinyl)hexyl]-8-quinolinamine, trihydrobromide, compd. with 2-propanol (1:0.3), hemihydrate in 100 ml of water was made basic with concentrated ammonium hydroxide and extracted with dichloromethane. The extract was washed, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under vacuum. A solution of the concentrate and 1.8 g (0.012 mole) of cyanodithioimidocarbonic acid, dimethyl ester in 100 ml of toluene was stirred at room temperature for 64 hours, then washed with water, dried, and concentrated to dryness. Recrystallization from 2-propanol afforded 2.7 g (66%) of the title compound as yellow needles, mp 97°-99°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][NH:11][CH2:10]2)[O:6][N:5]=1)[CH3:2].C(N(CC)CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>ClCCl>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:35])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOc1noc(C2CNCC(c3ccc(CC(F)(F)F)cc3)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 52 mg (0.14 mmol) of the compound from Example 61A in dichloromethane (1.6 ml) was admixed with 0.07 ml (49.7 mg, 0.49 mmol) of triethylamine and then, at 0° C., 28 mg (0.14 mmol) of 4-nitrophenyl chloroformate were added. The mixture was stirred at 0° C. for 2 h, then warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 75.8 mg (95% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][CH2:21][CH:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc2cc(OCc3ccccc3)ccc2c1
Yield: 25.6 %

Procedure:
Prepared according to the method described in Example 24b) from 6-(benzyloxy)-2-naphthol (2.2 g; Chem. Ber., (1965) 98, 1233), (±)-α-(chloromethyl)-3-pyridinepropanol (1.89 g; from Example 24a) above) and sodium hydroxide (0.8 g) in ethanol (30 ml) and water (10 ml) with heating at reflux for 6 hours to give the title compound as a solid (0.9 g).
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[OH-].[Ca+2:16].[P:17](=[O:21])([OH:20])([OH:19])[OH:18].[OH-].[K+]>>[P:17]([O-:21])([O-:20])([O-:19])=[O:18].[Ca+2:16].[P:17]([O-:21])([O-:20])([O-:19])=[O:18].[Ca+2:16].[Ca+2:16]
Reactant: O=P(O)(O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Ca+2]
Agent: [K+]
Product: O=P([O-])([O-])[O-]
Reaction time: 0.08 h

Procedure:
0.05 mol of 50% citric acid was added dropwise to 1 mol of a 11% calcium hydroxide slurry regulated at 15° C. over 300 seconds under stirring, thereafter, a mixture of 0.66 mol of 30% phosphoric acid and 0.05 mol of 40% KOH was added dropwise over 600 seconds and, thereafter, this was stirred at 80° C. for 3 hours to obtain a white slurry. The slurry was concentrated to a solid matter of 50% using an ultracentrifuge, and water was added again to obtain a slurry having-the same concentration as that before concentrated. The aforementioned concentration and re-slurrying were repeated three times to obtain calcium phosphate V. It was confirmed by X-ray diffraction that the resulting white cake is amorphous calcium phosphate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@@H:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.[Br:23][C:24]1[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@@H:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)=[O:30])[N:28]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@H](c2ccncc2N)C1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@H](c2ccncc2NC(=O)c2csc(Br)n2)C1
Reaction time: 17 h

Procedure:
A solution containing 1 eq each of tert-butyl (1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexylcarbamate, 2-bromothiazole-4-carboxylic acid, HOAT and EDC in DMF, at a concentration of 0.3 M, was stirred for 17 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding tert-butyl (1S,3R,5S)-3-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate, LCMS (m/z): 495.1/497.1 (MH+); LC Rt=3.17 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH:18]=[CH:19][C:20]=1[Cl:21]>N1C=CC=CC=1>[Cl:21][C:20]1[CH:19]=[CH:18][C:17]([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:16][C:15]=1[NH:14][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Nc1cc(NC(=O)c2ccccc2[N+](=O)[O-])ccc1Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc2Cl)cc1OC
Temperature: 80 °C
Yield: 69.5 %

Procedure:
3,4-Dimethoxybenzoyl chloride (1.55 g) was added to a stirred mixture of N-(3-amino-4-chlorophenyl)-2-nitrobenzamide (1.5 g) and pyridine (20 ml) and the mixture was stirred and heated to 80° C. for 16 hours. The mixture was cooled to ambient temperature and evaporated. The residue was partitioned between methylene chloride and 1N aqueous hydrochloric acid solution. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and evaporated. The residue was triturated under ethyl acetate. The resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried under vacuum at 40° C. There was thus obtained the title compound (1.63 g);
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Yield: 42.3 %

Procedure:
1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole was prepared by coupling of 1-benzyl-5-bromo-1H-indole (5.2 g, 18 mmol) and 4-trifluoromethoxyphenylboronic acid (4.7 g, 23 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.88 g, 1.1 mmol), and potassium carbonate (3.8 g, 27 mmol) in dioxane (135 mL) and water (13.5 mL) according to the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using hexane as an eluant yielded the title compound as a light yellow solid (2.8 g, 42%), mp: 62-63° C. 1HNMR (300 MHz, DMSO-d6): δ 7.85 (s, 1H), 7.75 (d, 2H, J=7.7 Hz), 7.5-7.6 (m, 2H), 7.4 (d, 3H, J=7.7 Hz), 7.2-7.35 (m, 5H), 6.6 (d, 1H, J=3.9 Hz), and 5.45 ppm (s, 2H).