Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:13][CH:4]([C:5]3[C:6]([OH:12])=[CH:7][CH:8]=[C:9]([OH:11])[C:10]=31)[CH2:3][CH2:2]2.B(F)(F)F.CCOCC.[Cl:23][CH2:24][CH2:25][C:26]([CH3:30])(O)[CH:27]=[CH2:28].O>O1CCOCC1>[Cl:23][CH2:24][CH2:25][C:26]1([CH3:30])[CH2:27][CH2:28][C:7]2[C:6](=[C:5]3[CH:4]4[CH2:13][CH:1]([CH2:2][CH2:3]4)[C:10]3=[C:9]([OH:11])[CH:8]=2)[O:12]1
Reactant: Oc1ccc(O)c2c1C1CCC2C1
Reactant: C=CC(C)(O)CCCl
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: CC1(CCCl)CCc2cc(O)c3c(c2O1)C1CCC3C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of, 1,2,3,4-tetrahydro-1,4-methano-naphthalene-5,8-diol (1.34 g, 794 mmol), 11.0 ml 3.97 mmol) of BF3.Et2O and 25 ml of dioxane was heated up to 110° C. under a nitrogen atmosphere. A solution of 5-chloro-3-methyl-pent-1-en-3-ol (1.12 g, 8.6 mmol) in 24 ml of dioxane was added slowly to the mixture. The addition was completed after two hours and the mixture was continued to reflux for an additional 3 hours. After cooling down to room temperature, the mixture was poured to water, extracted with ethyl acetate, washed with water and dried over MgSO4. After the removal of solvents, the residue was mixed with methanol/HCl and let stirred overnight at room temperature. After the removal of the solvents the residue was purified via flash column chromatography on silica gel (1:3 EtOAc/Hex) twice to give 1.30 g of 2-(2-chloro-ethyl)-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-6-ol. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.39 (s, 1H), 4.27 (s, 1H), 3.63-3.47 (m, 4H), 2.73-2.70 (m, 2H), 2.00-1.47 (m, 8H), 1.43-1.15 (m, 4H); MS: 307 (M+H+, 100%).
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2)CC1.[CH2:53]([N:55]=[C:56]=[O:57])[CH3:54].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:53]([NH:55][C:56](=[O:57])[O:52][C:43]1[CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=[C:41]([CH2:40][N:7]([C:8](=[O:39])[CH:9]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:31]([Cl:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=3[Cl:36])=[CH:24][CH:25]=2)[CH2:10][NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:18])[CH:4]2[CH2:6][CH2:5]2)[CH:42]=1)[CH3:54]
Reactant: CCN=C=O
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1cc(CCCOC)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in dichloromethane (0.08 M) was added ethyl isocyanate (3 eq.), triethylamine (3 eq.) and a few crystals of DMAP. The resulting solution was stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo and directly subjected to purification by way of column chromatography (SiO2, 3:2 (v/v) Hex:EtOAc→2:3 (v/v) Hex:EtOAc). The title compound was isolated as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([C:20]1[N:21]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:22]=[CH:23][C:24]=1[C:25]([O:27]C(C)(C)C)=[O:26])[NH:12]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[NH2:12][C@@H:11]([C:20]1[N:21]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=2)(=[O:34])=[O:33])[CH:22]=[CH:23][C:24]=1[C:25]([OH:27])=[O:26])[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2[C@@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2[C@H](N)CCOCc2ccccc2)cc1
Temperature: 40 °C

Procedure:
An orange solution of (R)-tert-butyl 2-(3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)propyl)-1-tosyl-1H-pyrrole-3-carboxylate (504c, 5.85 g, 10.00 mmol) in DCM (15 mL) was treated with TFA (15 mL, 202 mmol) and heated at 40° C. for 2 h. The TFA and DCM was removed in vacuo affording (R)-2-(1-amino-3-(benzyloxy)propyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (724d) as a dark orange viscous oil which was used for the next step without purification. m/z (ESI, +ve) 429.2 (M+1)′.
Reaction SMILES: O[CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C1C=CC=CC=1>[Cl:29][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2SC(c2ccccc2)C1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C1Nc2ccccc2SC(c2ccccc2)C1CCl
Yield: 84 %

Procedure:
5.7 g of 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one prepared as described in Reference Example 1 and 1.6 g of pyridine were dissolved in 30 ml of benzene, and 3.6 g of thionyl chloride was added to the solution, followed by heating under refluxing for 1 hour. The solvent was then distilled off and water was added to the residue. The precipitated crystals were filtered, washed with methanol and recrystallized from benzene to obtain 5.1 g of 3-chloromethyl-2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one as colorless needles having a melting point of 233° C. (with decomposition).
Reaction SMILES: Br[CH2:2][CH2:3]Br.Cl.[CH3:6][O:7][C:8](=[O:15])[C@@H:9]([C:11]([SH:14])([CH3:13])[CH3:12])[NH2:10].N12CCCN=C1CCCCC2.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:12][C:11]1([CH3:13])[S:14][CH2:3][CH2:2][NH:10][C@H:9]1[C:8]([O:7][CH3:6])=[O:15]
Reactant: COC(=O)[C@H](N)C(C)(C)S
Reactant: BrCCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@@H]1NCCSC1(C)C
Reaction time: 2.5 h
Yield: 87.1 %

Procedure:
To a stirred solution of 5.15 mL (59.8 mmol) of 1,2-dibromoethane in 50 mL of DMF at room temperature was added over 45 min a solution of 10 g (50 mmol) of D-penicillamine methyl ester hydrochloride and 22.5 mL (150.45 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 mL of DMF. The reaction was stirred for 2.5 h, poured into a solution of saturated NaHCO3 and extracted with ethyl acetate. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 8.24 g (87%) of methyl(3S)-2,2-dimethyl-3-thiomorpholine carboxylate as a pale yellow oil. Electrospray Mass Spec: 190.1 (M+H)+.
Reaction SMILES: [NH3:1].Cl[C:3]([C:5]([F:16])([F:15])[CH:6]([O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[CH2:7][CH3:8])=[O:4]>>[NH2:1][C:3]([C:5]([F:16])([F:15])[CH:6]([O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[CH2:7][CH3:8])=[O:4]
Reactant: N
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)Cl
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(N)=O
Yield: 90.9 %

Procedure:
In a 25-mL glass flask with a dropping funnel, 5.0 g (82.2 mmol/4.0 eq) of 28% aqueous ammonia solution was added and stirred. Subsequently, 5.0 g (purity: 98%, 20.4 mmol) of methacrylic acid 1-chlorocarbonyl-1,1-difluoro-2-butyl ester was dropped into the glass flask. The resulting solution was stirred for 10 minutes at room temperature. The completion of the reaction was confirmed by 19F NMR. After that, the solution was separated into an organic layer and an aqueous layer with the addition of 5 mL of water and 5 mL of diisopropyl ether. The thus-obtained aqueous layer was concentrated under a reduced pressure. With this, 4.1 g of methacrylic acid 1-aminocarbonyl-1,1-difluoro-2-butyl ester was obtained as a white crystalline substance (yield: 86%, purity: 96%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.C(Cl)Cl>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)c1ccc(OC2CCCCO2)cc1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
Into a 300 ml three neck flask were charged 25.4 g of 2,3-dihydropyran (reagent, manufactured by Tokyo Kasei Kogyo Co., Ltd.), 41.4 g of p-hydroxybenzoic acid (reagent, manufactured by Tokyo Kasei Kogyo Co., Ltd.), and 3.7 g of pyridinium p-toluenesulfonate (reagent, manufactured by Tokyo Kasei Kogyo Co., Ltd.). The mixture was dissolved after addition of 20 ml of methylene chloride and 80 ml of absolute ether. After the mixture was vigorously stirred for about 3 hours, it was extracted 3 times with 70 ml of a 10% sodium hydroxide aqueous solution. The resulting extracted solution was neutralized with 1 N of hydrochloric acid until the pH is made to 6. The resulting precipitate was filtered and dried in a vacuum thereby obtaining 57.4 g of crude p-tetrahydropyranyloxy benzoic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Li]CCCC.[CH:12]([O:15][B:16]1[O:20][C:19](C)(C)[C:18]([CH3:24])([CH3:23])O1)(C)C>C1COCC1.[NH4+].[Cl-]>[CH3:24][C:18]1([CH3:23])[CH2:12][O:15][B:16]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[O:20][CH2:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1cccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nccc1B1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 1-methylpyrazole (4.1 g, 50 mmole) in THF (100 mL) at 0° C. was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at −78° C., the reaction was allowed to warm to 0° C. over 1 hour. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organic fractions were washed with H2O (2×100 mL), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77%) which was used without further purification.
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17].N1C=NN=N1.C(N([CH:31]([O:39][P:40]([O-])[O-:41])N(C(C)C)C(C)C)C(C)C)(C)C>N1C=CC=CC=1.C(#N)C>[F:1][C@:2]1([CH3:18])[C@@H:6]2[O:7][P@:40]([O:39][CH3:31])(=[O:41])[O:9][CH2:8][C@H:5]2[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17]
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: CC(C)N(C(C)C)C(OP([O-])[O-])N(C(C)C)C(C)C
Agent: c1nnn[nH]1
Solvent: CC#N
Solvent: c1ccncc1
Product: CO[P@@]1(=O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (730 mg, 2.8 mmol) in dry pyridine (15 mL) was added a 0.45M solution of tetrazole in acetonitrile (15 mL) followed by bis(N,N-diisopropylamino)methylphosphite (0.971 mL, 3.3 mmol) at room temperature. After 2 h, TLC indicated disappearance of the starting material and two non-polar products. The reaction mixture was concentrated under reduced pressure at room temperature and the residue was triturated with EtOAc (30 mL). Tetrazole salts precipitated were filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed using 0-40% EtOAc/hexanes gradient to give pure product 2 (92 mg) and mixture of product 1&2 (102 mg). 1H NMR confirmed that the product 2 is a single isomer of the required compound. Stereochemistry is not determined.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH:21]4[CH2:24][O:23][CH2:22]4)[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH:21]4[CH2:24][O:23][CH2:22]4)[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CN(C4COC4)C3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C5COC5)C4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 49.1 %

Procedure:
A 25-ml round-bottomed flask equipped with a reflux condenser was charged with 272a (140 mg, 0.35 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (140 mg, 0.35 mmol), Pd(dppf)Cl2 (28 mg, 0.035 mmol), sodium acetate (58 mg, 0.70 mmol), K3PO4 (148 mg, 0.70 mmol), water (6 drops), and acetonitrile (6 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 272b (114 mg, 46%) as a brown solid. MS-ESI: [M+H]+ 664.4
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][CH2:13][C@@H:14]([OH:26])[CH2:15][C:16](=[O:25])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:11])([CH3:10])[CH3:9].[H][H]>C(O)C>[C:8]([O:12][CH2:13][C@@H:14]([OH:26])[CH2:15][C@@H:16]([OH:25])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:11])([CH3:9])[CH3:10]
Reactant: [H][H]
Reactant: CC(C)(C)OC[C@@H](O)CC(=O)CC(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Yield: 62 %

Procedure:
In the same manner as in Example 5, 15 mg (0.009 mmole) of Ru2Cl4 ((R)-BINAP)2 (NEt3) was weighed, and 500 mg (1.75 mmole) of t-butyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate as synthesized in Example 4 and 50 ml of ethanol were added thereto to form a solution. The solution was transferred to a 100 ml-volume autoclave whose atmosphere had been displaced with nitrogen, and the solution was stirred at 30° C. for 16 hours at a hydrogen pressure of 50 kg/cm2 to conduct hydrogenation. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (diethyl ether/hexane: 5/1 by volume) to obtain 300 mg (yield: 60%) of t-butyl (3R,5S)-6-t-butoxy-3,5-dihydroxyhexanoate.
Reaction SMILES: [CH:1](=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:11]/1([CH3:12])[CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:13])\[CH3:2].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[C:22]([Si:19]([O:13][C@H:7]1[CH2:8][CH2:9][CH2:10][C@@:11]2([CH3:12])[C@H:6]1[CH2:5][CH2:4]/[C:3]/2=[CH:1]/[CH3:2])([CH3:21])[CH3:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: C/C=C1/CC[C@H]2[C@@H](O)CCC[C@]12C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C1/CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 8A (0.74 g, 4.1 mmol) was dissolved in 4 mL of dimethylformamide; 0.4 g of imidazole was added, followed by 0.7 g of tert-butyldimethylsilyl chloride. The resultant mixture was stirred at ambient temperature for 4 hours; equal portions of tert-butyldimethylsilyl chloride and imidazole were added, and the mixture was heated overnight at 60° C. Water was added; the mixture was stirred at ambient temperature for 30 minutes, and then extracted with ether. The organic phase was washed sequentially with 1 N aqueous H3PO4, water, and brine, and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 0% to 10% ethyl acetate in hexanes. The titled compound was isolated contaminated with some unreacted starting material (0.31 g, 42%).
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][C:20]=3[Cl:34])[C:14]2=[O:35])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[N:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[C:1]([Si:5]([CH3:36])([CH3:37])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:20]([Cl:34])=[CH:21][C:22]([C:41]4[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=4)=[CH:23][C:24]=3[Cl:25])[C:14]2=[O:35])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(-c4ccncc4)cc3Cl)C2=O)CC1

Procedure:
Using the method of Example 81 and trifluoro-methanesulfonic acid 4-{1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-3-yl methyl}-3,5-dichloro-phenyl ester (Preparation 74) (0.398 g, 0.658 mmol), 4-pyridine boronic acid (0.242, 1.97 mmol) tetrakis(triphenylphosphine)palladium (0.076 g, 0.0658 mmol), dimethoxyethane (5 mL) and sodium carbonate (2M, 1.8 mL) gives the title compound. Purify the crude material over silica gel (3/1 hexane in ethyl acetate to ethyl acetate) to yield 0.189 g (54%) of the title compound: mass spectrum (m/z): 535(M+1).
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[C:8]([S-:10])#[N:9].[K+]>CC(C)=O>[CH3:6][C:2]([S:10][C:8]#[N:9])([CH3:7])[C:3](=[O:5])[CH3:4]
Reactant: N#C[S-]
Reactant: CC(=O)C(C)(C)Br
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C(C)(C)SC#N

Procedure:
16.5 g (0.1 mol) of 3-bromo-3-methyl-2-butanone and 11.6 g (0.12 mol) of potassium rhodanide in 150 ml of anhydrous acetone are heated at reflux for about 11/2 hours. After cooling, the separated potassium bromide is filtered off under suction and backwashed with a small amount of acetone, and the filtrate is evaporated to dryness at 50° C. under reduced pressure. The residue is dissolved in 200 ml of diethyl ether and the solution is washed three times with 100 ml of water each time, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.The crude product is fractionated on a short Vigreux column to yield 3-methyl-3-thiocyanato-2-butanone, b.p. 52° C./0.04 mmHg.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1.O>C1(C)C=CC=CC=1>[CH3:34][O:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27]([CH2:26][N:23]2[CH:24]=[C:20]([CH2:19][OH:18])[N:21]=[CH:22]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](OCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cn2cnc(CO)c2)cc1

Procedure:
A mixture of 4-(tert-butyldiphenylsilyloxymethyl)-1H-imidazole (9.25 g, 27.4 mmol), methyl 4-bromomethylbenzoate (6.297 g, 27.4 mmol) and TEA (2.782 ml, 27.4 mmol) in toluene (250 ml) was refluxed for 1.5 h. Water (500 ml) was added, the mixture was extracted with AcOEt, the organic phase washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the resulting oil was purified by flash chromatography on silica gel (CH2Cl2/MeOH: 100/0 to 98/2) to give:
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55](=[O:59])[CH:56]([NH2:58])[CH3:57])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:41]1[C:42]2[C:37](=[N:36][C:35]3[C:44]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55]([CH:56]([NH:58][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:57])=[O:59])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:38]=[CH:39][CH:40]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 47.8 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dichlorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:22](Cl)(Cl)=[S:23].[OH-].[Na+]>O1CCCC1>[N:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:16][CH:17]=1)=[C:22]=[S:23]
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Triethylamine (4.5 mL, 65.4 mmol) was added to a tetrahydrofuran (500 mL) solution of 4-morpholin-4-ylmethyl-phenylamine (F45-000, 5.16 g, 26.8 mmol). After cooling in ice cold, thiophosgene (2.45 mL, 32.1 mmol) was added. After stirring at room temperature overnight, aqueous sodium hydroxide was added until the reaction mixture became basic. The reaction mixture was extracted with ethyl acetate, washed with water and then washed with saturated sodium chloride. The extract solution was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain a red syrup like substance. The syrup like substance was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 4-(4-isothiocyanatobenzyl)-morpholine (F45-00, brown oil, 5.72 g, 91%).