Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([NH:20][C@H:21]([C:29](O)=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:13]([NH:20][C@H:21]([C:29]([NH:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14]
Reactant: NCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1cccc2ccccc12
Yield: 78.3 %

Procedure:
In substantially the same manner as Working Example 2, 1-naphthalenemethylamine (4.32 g) was condensed with Boc-L-phenylalanine (6.63 g) to give N-(Boc-L-phenylalanyl)-1-naphthalenemethylamine (7.92 g) (yield 91%). The Boc group of the product was deprotected in substantially the same manner as Working Example 91 to give N-(L-phenylalanyl)-1-naphthalenemethylamine hydrochloride (4.24 g) (yield 64%). The compound thus obtained (0.75 g) was condensed, in substantially the same manner as Working Example 8, with monoethyl ester of (2S,3S)-N-benzylaziridine-2,3-dicarboxylic acid (0.50 g) obtained in Working Example 95 to give the above-titled compound (Compound 99; 0.79 g) as white crystals (yield 74%).
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)C.FC(F)(F)C1C=C([C@H](O[C@@H:23]2[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27](C=O)[CH2:26][CH2:25][O:24]2)C)C=C(C(F)(F)F)C=1.O>CS(C)=O.O1CCCC1>[C:29]1([C:28]2[CH2:23][O:24][CH:25]=[CH:26][CH:27]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C1=COCC(c2ccccc2)=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethylsulfoxide (10 mL) was added to sodium hydride (60% dispersion in mineral oil, 385 mg, 9.6 mmol) and the mixture was stirred at room temperature for 30 minutes. Tetrahydrofuran (20 mL) was added and the mixture was cooled to −10° C. Trimethylsulfonium iodide (2.13 g, 10.4 mmol) in dimethylsulfoxide (10 mL) was added and the mixture was stirred at 0° C. for 10 minutes. (2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde (WO 00/56727A1; 3.58 g, 8.0 mmol) in tetrahydrofuran (10 mL) was added and the mixture was stirred at 0° C. for 30 minutes, then at room temperature for 30 minutes. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with water (4×100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (85:15 increasing to 80:20), to give (2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2R or S)-oxiranyl]-3-phenyl-2H-pyran (Isomer A; single diastereoisomer; epoxide stereochemistry unassigned) as a colorless oil (1.37 g, 37%); 1H NMR (500 MHz, CDCl3): δ 7.67 (1H, s), 7.23 (5H, m), 7.01 (2H, m), 4.97 (1H, q, J 6.6 Hz), 4.28 (1H, d, J 8.4 Hz), 4.16 (1H, br d, J 11 Hz), 3.53 (1H, br t, J 11 Hz), 2.65 (1H, dd, J 8.4 Hz), 2.60 (1H, m), 2.34 (1H, t, J 4.5 Hz), 1.95 (1H, dd, J 4.5, 2.7 Hz), 1.84 (1H, br d, J 11 Hz), 1.68 (1H, m), 1.57 (1H, m), 1.37 (3H, d, J 6.6 Hz); and
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][N:22]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCN(CC(=O)OC(C)(C)C)C4)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCN(CC(=O)O)C4)no2)cc1Cl
Reaction time: 24 h
Yield: 38.1 %

Procedure:
1,1-Dimethylethyl [8-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]acetate (Preparation 37) (0.13 g, 0.260 mmol) was dissolved in 1,4-dioxane (1 ml) and 4M HCl (4 ml, 16.00 mmol) in dioxan was added and the reaction mixture was left at room temperature for 24 hours. Then the reaction mixture was evaporated, triturated with ether and the resulting solid filtered off. The solid was dissolved in 5 ml of 2M sodium hydroxide and acidified with acetic acid when solid separated. Attempted to dissolve in EtOAc but insoluble so filtered off and washed well with water, acetone and ether to give the title compound (44 mgs) as a white solid. δH (400 MHz, d6DMSO) 1.36 (6H, d), 3.13 (2H, br. s), 3.96 (2H, s), 4.08 (2H, br. s), 4.89 (1H, m), 7.38 (1H, d), 7.44 (1H, d), 7.61 (1H, s), 7.72 (1H, d), 8.11 (1H, d), 8.18 (1H, d), (remaining 2H signal obscured by solvent peak); MS (ES) C22H2235ClN3O5 requires 443; found 444 [M+H]+.
Reaction SMILES: C(O)(=O)C.[C:5]1([C@H:11]([NH:13][C:14]2[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][C:15]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.CCOC(C)=O.[Pt]>[C:5]1([C@H:11]([NH:13][C@@H:14]2[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][C@@H:15]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CCC2(C1)OCCO2
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1CC2(CC[C@H]1N[C@H](C)c1ccccc1)OCCO2
Reaction time: 16 h
Yield: 54 %

Procedure:
5% Pt/C (Sigma-Aldrich catalog #205931, 0.80 g, 30.2 mmol) was carefully wetted down under argon with ethanol. Acetic acid (5.30 mL, 93 mmol) was added thereto followed by (R)-ethyl 8-(1-phenylethylamino)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate (prepared in a similar manner as that described in International Patent Application No. WO 2005/048932, 10.0 g, 30.2 mmol) in ethanol (50 mL). The reaction was then hydrogenated at 50 psi for about 16 hours with stirring in a Parr Shaker apparatus. The catalyst was carefully filtered under argon and the filtrate concentrated to yield an amber oil. The oil was dissolved in EtOAc then rinsed with 5% Na2HPO4 until pH=8-9 (5 rinses). The EtOAc layer was dried over sodium sulfate and concentrated to give (7S,8R)-ethyl 8-((R)-1-phenylethylamino)-1,4-dioxaspiro[4.5]decane-7-carboxylate (5.40 g, 16.2 mmol, 54% yield) as an amber oil. MS (ESI+)=334.25 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([O:27][CH2:28][CH2:29][N:30]([CH2:34][C:35]([NH2:37])=[S:36])[C:31](=[O:33])[CH3:32])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:37]=[C:35]([CH2:34][N:30]([CH2:29][CH2:28][O:27][C:24](=[O:26])[CH3:25])[C:31](=[O:33])[CH3:32])[S:36][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Reactant: CC(=O)OCCN(CC(N)=S)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CN(CCOC(C)=O)C(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, by reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-[N-(2-acetoxyethyl)-N-acetylamino]thioacetamide in ethanol gave 1-ethyl-6-fluoro-1,4-dihydro-7-[2-[[N-(2-acetoxyethyl)-N-acetylamino]methyl]-4-thiazolyl]-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 148°-152° C., resolidified and melted 164°-165° C., which was hydrolyzed with refluxing 6N hydrochloric acid to afford the titled compound, mp 290° C. (dec).
Reaction SMILES: [N+](C1C=CC(N2CCC(=O)CC2)=C(C=1)C#N)([O-])=O.CNCCO.[OH:24][CH2:25][CH2:26][N:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:42]=[CH:41][C:40]([N+:43]([O-])=O)=[CH:39][C:36]=2[C:37]#[N:38])[CH2:31][CH2:30]1)[CH3:28]>>[NH2:43][C:40]1[CH:41]=[CH:42][C:35]([N:32]2[CH2:33][CH2:34][CH:29]([N:27]([CH2:26][CH2:25][OH:24])[CH3:28])[CH2:30][CH2:31]2)=[C:36]([CH:39]=1)[C:37]#[N:38]
Reactant: CN(CCO)C1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: CNCCO
Agent: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Product: CN(CCO)C1CCN(c2ccc(N)cc2C#N)CC1

Procedure:
According to Tetrahedron, vol. 38, No. 3, p. 413 (1982) and using 5-nitro-2-(4-oxopiperidino) benzonitrile and N-methylethanolamine, 2-[4-(N-2-hydroxyethyl-N-methylamino) piperidin-1-yl]-5-nitrobenzonitrile was synthesized, which was subjected to reduction according to Starting Material Synthesis Example 40 to give the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][NH:16][CH2:17]2)[CH2:13][CH2:12]1)=[O:9].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O.C(O)(=O)C.C([BH3-])#N>ClCCl>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:27]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCCS1(=O)=O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(2S)-2-(1,1-Dioxidoisothiazolidin-2-yl)-4-methyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]pentanamide (204 mg, 0.594 mmol) and 3-(trifluoromethyl)benzaldehyde (0.158 mL, 1.188 mmol) were dissolved in dichloromethane (3 mL). Acetic acid (1 mL) was added. The reaction was stirred at ambient temperature for 20 min, then PS-cyanoborohydride (487 mg, 1.188 mmol) was added. The reaction was stirred at room temperature overnight, then filtered, and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane to the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.79 (d, J=7.0, 1H), 7.75 (d, J=10.3, 1H), 7.61-7.54 (m, 2H), 7.44 (t, J=7.7, 1H), 4.52 (dd, J=6.6, 8.9, 1H), 4.38 (dq, J=6.4, 12.6, 1H), 3.94 (dd, J=7.3, 16.2, 1H), 3.57 (dd, J=9.1, 13.5, 1H), 3.50-3.37 (m, 2H), 3.31-3.19 (m, 2H), 2.79 (ddd, J=3.0, 9.1, 19.0, 1H), 2.62-2.54 (m, 1H), 2.54-2.45 (m, 1H), 2.43-2.36 (m, 1H), 2.31-2.16 (m, 4H), 2.13-2.03 (m, 1H), 1.94-1.78 (m, 3H), 1.77-1.59 (m, 2H), 1.39 (dt, J=6.5, 19.8, 1H), 0.88 (d, J=6.6, 3H), 0.82 (dd, J=2.3, 6.5, 3H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[C:25]3=[C:26]4[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][C:18]([C:27]2[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=2)=[C:17]4[CH:16]=[CH:15][C:14]3=[CH:13][CH:12]=1.C1C(=O)N([Br:44])C(=O)C1.O.CCCCCC.C1(C)C=CC=CC=1>CN(C=O)C>[Br:44][C:20]1[CH:19]=[C:18]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[C:17]2[C:26]3=[C:25]4[C:14]([CH:13]=[CH:12][C:11]([C:2]5[CH:3]=[CH:4][C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[CH:1]=5)=[C:24]4[CH:23]=[CH:22][C:21]=13)=[CH:15][CH:16]=2
Reactant: c1ccc2cc(-c3ccc4ccc5c(-c6ccc7ccccc7c6)ccc6ccc3c4c65)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Brc1cc(-c2ccc3ccccc3c2)c2ccc3ccc(-c4ccc5ccccc5c4)c4ccc1c2c34
Yield: 90.5 %

Procedure:
8.0 g of 1,6-dinaphthalene-2-yl-pyrene prepared by a well known method was dispersed into 80 ml of DMF, and 3.2 g of NBS in DMF solution was dropped therein at room temperature. After 3 days reaction, 150 ml of water was added to it and the deposited crystal was filtrated, followed by water and ethanol washing of the crystal. The crystal obtained was refined through a silica gel chromatography (a developing solvent: hexane/toluene=2/1) and then 8.5 g of 3-bromo-1,6-dinaphthalene-2-yl-pyrene was obtained as the intermediate (the yield: 90%). 8.5 g of 3-bromo-1,6-dinaphthalene-2-yl-pyrene obtained and 2.3 g of phenyl boronic acid were dissolved in 100 ml of DME. Subsequently, 0.55 g of tetrakistriphenylphosphinepalladium and 25 ml of 2M-sodium carbonate aqueous solution were added therein, followed by argon displacement. After heating and refluxing over 8 hours, it was stood to cool and then the deposited crystal was filtrated. After washing the crystal by water and methanol it was refined through a silica gel chromatography (a developing solvent: toluene), and then 5.4 g of 1,6-dinaphthalene-2-yl-3-phenylpyrene of the light-yellow crystalline was obtained (the yield: 64%).
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.Cl.[OH2:16]>C(Cl)Cl>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][C:9]=1[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:16]
Reactant: COc1ccc(C)cc1
Reactant: O
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C)cc1C(=O)c1ccccc1
Yield: 78 %

Procedure:
SnCl4 (47.5 ml, 0.41 mol) was added dropwise to a mixture of 4-methylanisol (100 g, 0.82 mol) and benzoyl (95.15 ml, 0.82 mol) in 500 ml of CH2Cl2 at 0° C. Once the addition is complete, it was allowed to react for 3-4 hours, allowing the mixture to reach room temperature. Once the reaction concluded, the mixture was cooled at 0° C., hydrolyzed with a mixture of concentrated HCl (41 ml) in H2O (376 ml), washed with 2×50 ml of NaOH (10%), dried and evaporated to give 140 g (78%) of the title compound in crystalline solid form.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([F:46])[C:34]=1[O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH2:30]Br.[Cl-].[NH4+]>O1CCOCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([CH2:30][C:29]2[CH:28]=[C:27]([F:26])[C:34]([O:35][Si:36]([CH:40]([CH3:42])[CH3:41])([CH:43]([CH3:45])[CH3:44])[CH:37]([CH3:39])[CH3:38])=[C:33]([F:46])[CH:32]=2)([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)[Si](Oc1c(F)cc(CBr)cc1F)(C(C)C)C(C)C
Reactant: C=CCOC(=O)C(CCc1ccc(C#N)cc1)C(=O)OCC=C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: C=CCOC(=O)C(CCc1ccc(C#N)cc1)(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g (31.91 mmol) of diallyl 2-[2-(4-cyanophenyl)ethyl]malonate are dissolved in 250 ml of dioxane and, at 0° C., 1.4 g (35.1 mmol) of 60% sodium hydride are added in portions, and the mixture is stirred at room temperature for 30 min. After renewed cooling to 0° C., a solution of 14.53 g (38.30 mmol) of 3,5-difluoro-4-triisopropylsilanyloxybenzyl bromide in 250 ml of dioxane is added dropwise, and the mixture is stirred while warming to room temperature for 2 h. The reaction solution is then added to 500 ml of saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 14.3 g (73% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[O:22]C.C(Cl)Cl>>[NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22]
Reactant: COc1c(N)c(F)c(F)c2c1[nH]c(=O)n2-c1ccc(Br)cc1F
Solvent: ClCCl
Product: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(Br)cc2F)c1O
Yield: 51.9 %

Procedure:
Intermediate I-14a was prepared from 5-amino-1-(4-bromo-2-fluoro-phenyl)-6,7-difluoro-4-methoxy-1,3-dihydro-benzoimidazol-2-one (I-12a: 1.7 g, 0.00438 mol) and borontribromide using procedures analogous to those used for the preparation of Intermediate I-13a in DCM (10.9 mL, 0.0109 mol) to afford 850 mg of the product (88% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:7][CH:6]([CH2:8][OH:9])[CH:5]([OH:10])[CH:4]1[OH:11].C(N(CC)CC)C.[C:19]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:23]([CH:8]([OH:9])[C@H:6]1[O:7][C@@H:3]([O:2][CH3:1])[C@H:4]([OH:11])[C@@H:5]1[OH:10])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC1OC(CO)C(O)C1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a mixture of methyl-β-D-ribofuranoside (460 mg, 2.8 mmol, Sigma, St. Louis, Mo.) and anhydrous methylene chloride (20 ml) were added triethylamine (0.468 ml, 3.36 mmol), t-butyldiphenylchlorosilane (0.9 ml, 3.46 mmol), and DMAP (13.7 mg, 0.112 mmol) successively at room temperature. The reaction mixture was stirred at room temperature for 18 h under nitrogen. It was washed with water (20 ml), saturated ammonium chloride (20 ml), and brine (20 ml), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was separated by silica gel column chromatography (CHCl3 --MeOH, 50:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside (618 mg, 54.8%) as a thick syrup. 1H NMR (DMSO-d6) δ0.96 (s, 9H, t-Bu), 3.22 (s, 3H, --OCH3), 3.61 (dd, J=11.0 and 5.3 Hz, 1H), 3.74 (d, J=4.4 Hz, 1H), 3.81 (dd, J=11.0 and 2.7 Hz, 1H), 3.90 (m, 1H), 4.00 (m, 1H), 4.68 (s, 1H, H-1'), 4.84 (br s, 1H, exchangeable with D2O, OH), 5.05 (br s, 1H, exchangeable with D2O, OH), 7.45 and 7.67 (m, 10H, Ph2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:8][C:9]#[N:10].[K+]>Cl>[C:2]1([NH:1][C:9]([NH2:10])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: Nc1ccccc1
Agent: Cl
Agent: [K+]
Product: NC(=O)Nc1ccccc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Aniline (18.6 g, 200 mmol) was dissolved in 100 ml of 2M hydrochloric acid (aq.), cooled down to 2° C. by immersing in ice bath, charged with potassium cyanate (19.5 g, 240 mmol) portion wise in 30 minutes under stirring, the cooling was removed and stirred for 4 h at room temperature, whereby thick white solids precipitated. The reaction mixture was stored at 4° C. for 1 h. The solids were separated by filtration, washed well with ice cold water and dried under vacuum yielding pure white solids (25.6 g, 94%).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5].[CH3:20]COCC>>[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH3:20]
Reactant: CCOCC
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 80 %

Procedure:
A 3-neck, 250 mL round bottom flask was charged with a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (9.9 g) in Et2O (120 mL). The flask was purged with nitrogen and then cooled in a CO2/acetone bath. Methylmagnesium bromide (26.8 mL of a 3.0 M solution in Et2O, 80 mmol) was added dropwise over 10 min to the amide. The resulting thick mixture was warmed to 0° C. and then stirred for 40 min before being poured into 2 M HCl solution (50 mL). The mixture was diluted with Et2O (100 mL), washed with brine, dried (MgSO4) and concentrated on a rotary evaporator to give tert-butyl 4-acetylpiperidine-1-carboxylate (7.3 g, 32.1 mmol, 80% yield) as a colorless oil. The product partly crystallized on standing at RT. 1H-NMR (400 MHz, CDCl3) δ ppm 4.06 (2 H, s), 2.74 (2 H, s), 2.42 (1 H, s), 2.12 (2 H, s), 1.78 (2 H, s), 1.49 (2 H, s), 1.41 (9 H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C@@H:5]([O:9][C:10](=[O:12])[CH3:11])[CH2:6][CH2:7][OH:8])[CH3:2].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(OCC)(=O)C.O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[C@@H:5]([O:9][C:10](=[O:12])[CH3:11])[CH2:6][CH2:7][O:8][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](CCO)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCOS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Yield: 89.3 %

Procedure:
(S)-2-Acetoxy-4-hydroxybutanoic acid ethyl ester (0.5 g, 2.6 mmol) in pyridine (1 ml) was added to a solution of (4-methylphenyl)sulphonyl chloride (0.53 g, 2.76 mmol) in pyridine (1 ml) at 5°. After 16 h at 5° ethyl acetate and water were added, the organic layer was separated, washed with hydrochloric acid (2N), dried (MgSO4) and the solvent evaporated to give the sub-title ester (0.8 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[CH:59]=[CH:58][CH:57]=[C:56]1[S:60](Cl)(=[O:62])=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:60]([C:56]2[O:55][CH:59]=[CH:58][CH:57]=2)(=[O:62])=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=S(=O)(Cl)c1ccco1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccco2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 8 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and furan-2-sulfonyl chloride as starting materials in 8% yield. LCMS for C28H29ClN7O4S (M+H)+: m/z=594.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:25])([CH3:24])[CH:9]=[CH:10][Sn](CCCC)(CCCC)CCCC)=[CH:4][CH:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(OC(=O)C)(=O)C.CCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:25])([CH3:24])[C:9]#[CH:10])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](C=CC(C)(C)c1ccc(Cl)cc1)(CCCC)CCCC
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCC
Product: C#CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
A mixture of 4.0 grams (0.0085 mole) of 3-(4-chlorophenyl)-3-methyl-1-tributylstannyl-1-butene and 4.3 grams (0.0096 mole) of lead tetraacetate in 30 mL of anhydrous acetic anhydride is stirred at ambient temperature for about 18 hours. After this time, the reaction mixture is diluted to 100 mL with pentane. The mixture was then filtered through a pad of diatomaceous earth. The pad of diatomaceous earth is washed with about 300 mL of pentane. The wash and the filtrate are combined and concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding about 1.1 grams of 3-(4-chlorophenyl)-3-methyl-1-butyne. The NMR spectrum is consistent with the proposed structure.