Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[NH2:11][C:12]1[C:17]([NH2:18])=[C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:21]=2)[CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1>C1COCC1>[O:2]=[C:1]1[NH:11][C:12]2=[N:13][CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:24][CH:25]=3)=[C:17]2[NH:18]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Method E2 (with phosgene and pyridine). tert-Butyl 4-(2,3-diaminopyridin-4-yl-oxy)phenyl-carbamate (1 g, 3.16 mmol) was dissolved in dry THF (32 mL, 10 mL/mmol). The solution was cooled in an ice bath under nitrogen. Pyridine (0.59 mL, 7.27 mmol) was added and followed by dropwise addition a phosgene solution 1.93 M in toluene (2 mL, 3.79 mmol) under vigourous stirring. The ice bath was removed and the mixture was stirred at room temperature overnight, then at 60° C. during 2 hours. The solvent was evaporated under reduced pressure and the solid residue was washed with water and dried to afford the title compound (952 mg, 88%) as a brown solid. 1H-NMR (δ, ppm, DMSO-d6): 1.48 (9H, s, t-Bu), 6.29 (d, 1H, HPy,5, J=6.0 Hz), 7.09 (d, 2H, Harom,Ph,3+5, J=9.0 Hz), 7.51 (d, 2H, Harom,Ph,2+6, J=9.0 Hz), 7.73 (d, 1H, HPy,6, J=6.0 Hz), 9.43 (bs, 1H, NHBoc), 11.16 (bs, 1H, NHPy3) 11.34 (bs, 1H, NHPy2).; LC-MS (m/z): 343 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][C:30]4[N:35]=[CH:34][C:33]5[O:36][CH2:37][CH2:38][O:39][C:32]=5[CH:31]=4)C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:6]=2[CH:40]=1.Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([NH:21][CH2:29][C:30]4[N:35]=[CH:34][C:33]5[O:36][CH2:37][CH2:38][O:39][C:32]=5[CH:31]=4)[CH2:19][CH2:20]3)[C:6]=2[CH:40]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1n[n+]([O-])c2ccc(Cl)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Yield: 167.1 %

Procedure:
A solution of 1,1-dimethylethyl {1-[2-(6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]-4-piperidinyl}(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)carbamate (81 mg, 0.141 mmol) in chloroform (1 ml) and MeOH (1 ml) was added 4M HCl in 1,4-dioxane (1 ml) and the reaction was stirred at rt for 0.5 h before evaporation, treatment with sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound as a yellow foam (60 mg, 90%).
Reaction SMILES: [OH-].[K+].N1C=CC=CC=1C1C=CC=CN=1.[CH:15](=[CH:22][C:23](=[O:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H][H]>CC(O)C>[C:16]1([CH2:15][CH2:22][C:23](=[O:25])[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: CC(=O)C=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC(C)O
Product: CC(=O)CCc1ccccc1
Reaction time: 18 h
Yield: 87.7 %

Procedure:
RuClCp* (cod) (3.8 mg, 0.01 mmol), KOH (0.04 mmol), 2,2′-bipyridyl (3.1 mg, 0.02 mmol) and benzalacetone (730.95 mg, 5.0 mmol) were dissolved into 10 ml of 2-propanol, and deaerated by argon substitution, after which the total amount of the resulting mixture was transferred into a 100-milliliter metallic autoclave. Hydrogen was then charged to a predetermined pressure (4 atm), and the reaction was started at room temperature (28° C.) After the reaction solution was stirred for 18 hours, the reaction pressure was brought back to atmospheric pressure, and the reaction product, 4-phenyl-2-butanone (yield 87.7%), was identified and quantitatively determined by TLC monitor (silica gel: n-hexane/ethyl acetate=4/1) and gas chromatography of the reaction solution. At this time, 12.3% of the raw material, benzalacetone, was recovered.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=C)[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.C[OH:17]>>[OH:1][CH2:2][C@H:3]1[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:5][C:6](=[O:17])[CH2:7]1
Reactant: C=C1C[C@@H](CO)[C@H](c2cccc(F)c2)C1
Reactant: CO
Product: O=C1C[C@@H](CO)[C@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (+)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane from Step C (1.87 g, 9.0 mmol) in methanol (75 mL) was cooled in a dry ice/acetone bath and ozone was bubbled into the solution until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (5 mL) was added. After 10 min, the bath was removed and the reaction was allowed to warm to rt over 2 h. The mixture was treated with 10 drops of sulfuric acid (c) in water (2 mL) for 1 h before most of the methanol was removed in vacuo. The mixture was diluted with water and extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (50% ethyl acetate in hexanes) to give the title compound (1.87 g), [α]D=+132 (MeOH, c=1.2).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([NH:16][NH2:17])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NN

Procedure:
51.5 g (0.239 mol) of methyl 4-amino-5-chloro-2-methoxybenzoate suspended in 460 ml of ethanol are introduced into a 1 l reactor. 119 g (2.39 mol) of hydrazine hydrate are added, over 15 min, and the mixture is refluxed for 15 h.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:16]([O-:19])(O)=[O:17].[Na+]>N1C=CC=CC=1.CCCCCC>[C:4]([Si:1]([CH3:3])([CH3:2])[O:19][C:16]([O:8][Si:1]([CH3:3])([CH3:2])[C:4]([CH3:7])([CH3:6])[CH3:5])=[O:17])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C([O-])O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC(=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of triethylsilyloxy keto diol 6 (883 mg, 2.31 mmol) in 35 mL of pyridine under nitrogen at 0° C. was added dropwise 0.485 mL (2.771 mmol) of TBSOTf. The solution was then warmed to room temperature. After 2 h at room temperature, the solution was diluted with 100 mL of hexane and poured into 150 mL of a saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with two 100 mL portions of hexane. The organic layers were combined, and washed with 50 mL of a 10% aqueous CuSO4 solution followed by 20 mL of H2O, and dried over anhydrous Na2SO4. Removal of the solvent followed by flash chromatography purification (2.5% EtOAc/hexane) to give 1.122 g of t-butyldimethylsilyloxy ketone 7 (98% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:36][CH2:35][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH2:33][CH3:34])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:19][CH2:18]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([OH:11])=O.CCN(C(C)C)C(C)C.[CH3:46][O:47][CH:48]([O:56][CH3:57])[CH2:49][NH:50][CH:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:18][CH2:19][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH2:33][CH3:34])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:35][CH2:36]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([N:50]([CH:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)[CH2:49][CH:48]([O:56][CH3:57])[O:47][CH3:46])=[O:11]
Reactant: COC(CNC1CCCC1)OC
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)N(CC(OC)OC)C5CCCC5)c4Cl)CC3)C2)cs1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid (9.8 g) in DCM (100 mL) was added Hunig's Base (9.58 mL). The reaction was stirred for 10 mins before the addition of N-(2,2-dimethoxyethyl)cyclopentanamine (4.12 g) followed by HATU (7.65 g). After 1 h, the reaction mixture was diluted with DCM (200 mL) and washed with saturated sodium bicarbonate (300 mL) followed by water (300 mL). The DCM solution was dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by silica chromatography, eluting with 2 to 5% 7N/NH3/methanol in dichloromethane to afford 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)-N-cyclopentyl-N-(2,2-dimethoxyethyl)propanamide (12.0 g) as a pale yellow gum.
Reaction SMILES: FC1C=CC(C2([C:12]3C4C(=CC=C(OCCN)C=4)CC[N:13]=3)CCC2)=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36])=[CH:30][CH:29]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2([C:50](O)=O)[CH2:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1.FC1C=CC(C2(C(O)=O)CCC2)=CC=1>>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2([C:50]3[C:32]4[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH2:26][CH2:12][NH2:13])[CH:33]=4)[C:34]([CH3:38])([CH3:37])[CH2:35][N:36]=3)[CH2:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1
Reactant: COc1ccc(C(C)(C)CN)cc1
Reactant: NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C(O)C1(c2ccc(F)cc2)CCC1
Product: CC1(C)CN=C(C2(c3ccc(Cl)cc3)CCC2)c2cc(OCCN)ccc21

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-4,4-dimethyl-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine was prepared analogously to 2-({1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine (cf. example 65) using 2-(4-methoxyphenyl)-2-methylpropan-1-amine and 1-(4-chlorophenyl)cyclobutanecarboxylic acid in place of 2-(4-methoxyphenyl)ethanamine and 1-(4-fluorophenyl)cyclobutanecarboxylic acid, respectively.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[N+:39]([CH3:42])([O-:41])=[O:40]>>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH2:42][N+:39]([O-:41])=[O:40])[CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[O:26])=[CH:21][CH:22]=2)=[CH:37][CH:38]=1
Reactant: COc1ccc(COC(=O)/C=C/c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Product: COc1ccc(COC(=O)CC(C[N+](=O)[O-])c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1,1,3,3-tetramethylguanidine (0.31 mL, 2.48 mmol) was added to 40.2 (5 g, 12.4 mmol) in nitromethane (20 mL). The mixture was stirred at room temperature for 3 hours, at 50° C. for 3 hours, and at 100° C. for 8 hours. Nitromethane was removed under vacuum and the crude product was purified by flash chromatography to give 40.3 (4.5 g). MS ESI (pos.) m/e: 466 (M+H). 1HNMR (CDCl3) δ 7.37 (d, 2H), 7.19 (d, 2H), 7.12 (d, 2H), 6.92 (m, 6H), 5.01 (s, 2H), 4.97 (s, 2H), 4.68 (m, 1H), 4.59 (m, 1H), 3.96 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 2.77 (m, 2H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[Cl:12][CH2:13][Si:14]([CH3:17])([CH3:16])Cl.Cl>O1CCCC1>[Cl:12][CH2:13][Si:14]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1)([CH3:17])[CH3:16]
Reactant: C[Si](C)(Cl)CCl
Reactant: CCOc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc([Si](C)(C)CCl)cc1
Temperature: -78 °C
Yield: 23.1 %

Procedure:
To a mixture of 5.1 g (0.21 mole) of powdered magnesium metal in 100 mL of dry tetrahydrofuran was added dropwise 40 g (0.20 mole) of ethyl 4-bromophenyl ether. Upon completion of addition this mixture was heated at reflux for one hour. In a second flask was placed 28.5 g (0.199 mole) of (chloromethyl)dimethylchlorosilane in 100 mL of tetrahydrofuran, and this flask was cooled to -78° C. The contents of the first flask were added dropwise to the second flask. The temperature of the reaction mixture was maintained at -78° C. for one hour after addition was complete, and it was then poured into 200 mL of 10% hydrochloric acid. The organic phase was washed once with 10% hydrochloric acid. The aqueous phase was extracted with diethyl ether, and these extracts were combined with the organic phase. After being dried, filtered, and having the solvent evaporated under reduced pressure, the residue was vacuum distilled, yielding 10.5 g of (chloromethyl)(4-ethoxyphenyl)dimethylsilane, b.p. 99-110 ° C./0.12 mm of Hg. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1(Cl)[CH2:5][C:4](=[O:6])[CH2:3]1.CC(O)=O.O.[CH:13]([OH:16])([CH3:15])[CH3:14].O>[Zn]>[C:4]1(=[O:6])[CH2:3][CH2:2][CH2:5][CH2:15][C:13](=[O:16])[CH2:14]1
Reactant: CC(C)O
Reactant: O=C1CC(Cl)(Cl)C1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCCC(=O)C1
Reaction time: 1 h

Procedure:
Dichlorocyclobutanone 3 (128 g, 0.48 mol) was dissolved in 520 mL of 1:1 isopropanol-water in a 2 L, 3-neck flask with an overhead stirrer. Zinc granules (126 g, 1.9 mol, −30+100 mesh) were added in one portion. After 60 min at room temperature, 130 mL of AcOH plus 260 mL of water were added dropwise via addition funnel (ca. 4 mL are added initially, followed by a 10 min hold to check for exotherms; 20 ml were then added, followed by another 10 min hold; once any exotherm has abated, the remaining acid solution was added dropwise; the entire addition takes 1.5-2 h). After 16 h, the mixture was transferred to a separatory funnel, decanting away from most of the zinc (several small isopropanol rinses were used). The isopropanol-AcOH-water mixture was then extracted with 5 portions of toluene (250 mL each), which are combined and concentrated to provide 51.7 g of product as a dark, orange-brown oil (85% crude mass balance, ca. 85% pure by 1H nmr). This material is suitable for subsequent reactions, or can be purified by distillation, which provided 29.4 g (0.23 mol, 49% yield) of product as a clear, colorless oil (b.p. 65-75° C. at 1.2 mm). It's spectral properties (1H nmr, GC/MS) were identical to samples prepared by the oxymercurafion route of Chandrasekaran (Synthetic Communications 1984, 14, 339-345).
Reaction SMILES: Cl.[C:2]1(=[O:20])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[NH:13])[C:5](=[O:15])[C:4]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:3]12.C(N(CC)CC)C.Cl[C:29](=[CH2:32])[C:30]#[N:31]>CCO>[NH2:31][C:30]1[CH:29]=[CH:32][N:14]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]2[C:5](=[O:15])[C:4]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:3]3[C:2]2=[O:20])[N:13]=1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)CCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccnc(CCCCCN2C(=O)c3ccccc3C2=O)n1

Procedure:
A mixture of 6-phthalimidohexanamidine hydrochloride (71.1 g.), triethylamine (170 ml.) and 2-chloroacrylonitrile (57.4 ml.) in EtOH (500 ml.) was heated under reflux for 2 hours. The solvent was evaporated and the residue was partitioned between EtOAc and 2 N aqueous HCl. The aqueous layer was basified with 10 N aqueous NaOH and the product was extracted with EtOAc, dried (MgSO4) and evaporated to dryness. The residual gum was dissolved in EtOAc and treated with excess of a solution of maleic acid in EtOAc. The precipitated solid was dissolved in water, basified with 10 N aqueous sodium hydroxide, extracted with EtOAc, the extract dried (MgSO4) and evaporated. The residual solid was triturated with acetonitrile to give 4-amino-2-(5-phthalimidopentyl)pyrimidine as a brown solid (37.9 g.), m.p. 101°-104°.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:14][SiH:15]([Cl:17])[Cl:16]>[Pt].C1(C)C=CC=CC=1>[Cl:14][Si:15]([Cl:17])([Cl:16])[CH2:3][CH2:2][CH2:1][C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCc1ccc(-c2cccs2)s1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)CCCc1ccc(-c2cccs2)s1

Procedure:
The hydrosilylation reaction of Example 1 was repeated using 18.7 g of 5-allyl-2,2′-bithiophene in place of 2-allylthiophene, 10 g of anhydrous toluene, 20 g of trichlorosilane, and 150 mg of Platinum Catalyst. 5-(3-Trichlorosilylpropyl)-2,2′-bithiophene was obtained as a colorless liquid: 1H NMR (CDCl3) δ 7.20 (dd, 1H, J=5.1, 1.2 Hz); 7.14 (dd, 1H, J=3.6, 0.9 Hz); 7.02 (m, 2H); 6.74 (d, 1H, J=3.6 Hz); 2.93 (t, 2H, J=7.2 Hz); 1.99 (m, 2H); 1.49 (m, 2H).
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:58])[CH2:16][N:17]([CH2:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:45])=[O:37])[CH2:18][C:19](=[O:34])[NH:20][CH2:21][CH2:22][O:23][C@@H:24]2[O:32][C@@H:31]([CH3:33])[C@@H:29]([OH:30])[C@@H:27]([OH:28])[C@@H:25]2[OH:26])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].Cl.[NH2:60][CH2:61][C@@H:62]([C:81]([OH:83])=[O:82])[NH:63][C:64]([O:66][CH2:67][CH:68]1[C:80]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[C:74]2[C:69]1=[CH:70][CH:71]=[CH:72][CH:73]=2)=[O:65].CCN(C(C)C)C(C)C>CN(C=O)C>[O:58]=[C:15]([NH:14][CH2:13][CH2:12][O:11][C@@H:1]1[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3])[CH2:16][N:17]([CH2:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([NH:60][CH2:61][C@@H:62]([C:81]([OH:83])=[O:82])[NH:63][C:64]([O:66][CH2:67][CH:68]1[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][C:74]=2[C:75]2[C:80]1=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:65])=[O:45])=[O:37])[CH2:18][C:19]([NH:20][CH2:21][CH2:22][O:23][C@@H:24]1[O:32][C@@H:31]([CH3:33])[C@@H:29]([OH:30])[C@@H:27]([OH:28])[C@@H:25]1[OH:26])=[O:34]
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCCCCC(=O)Oc2c(F)c(F)c(F)c(F)c2F)CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCCCCC(=O)NC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of pentafluorophenyl 6-[({bis[2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-2-oxoethyl]amino}acetyl)amino]hexanoate (270 mg, 0.318 mmol) in DMF at 0° C. was added 3-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine hydrochloride (303 mg, 0.306 mmol) and, 5 min later, DIPEA (111 μL, 0.636 mmol). After stirring at 0° C. for 2 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (22 g), eluting first with 100 mL of EtOAc and then 0-20% of Solvent B in Solvent A (Solvent A: v/v EtOAc/MeOH/AcCN/H2O: 6/1/1/1; Solvent B v/v EtOAc/MeOH/AcCN/H2O: 2/1/1/1) to afford the title compound. LC-MS Method A: m/e=991.66 [M+1]; Rt=1.84 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][SH:4].[NH2:5][C:6]1[CH:11]=[N:10][C:9](Br)=[CH:8][N:7]=1>CN(C)C=O.O.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>[NH2:5][C:6]1[N:7]=[CH:8][C:9]([S:4][CH2:3][CH2:2][OH:1])=[N:10][CH:11]=1
Reactant: OCCS
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cnc(SCCO)cn1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
According to the method described in WO2004/052869, 2-hydroxy-1-ethanethiol (0.93 mL) and tetrakis(triphenylphosphine)palladium (3.39 g) were added to a solution of 2-amino-5-bromopyrazine (1.00 g, 5.75 mmol) in N,N-dimethylformamide (15.1 mL), and the mixture was heated and stirred at 120° C. in a sealed tube for about 3 hours. After cooling, the reaction mixture was diluted with water and extracted with a mixed solution (dichloromethane:ethanol=5:1) (100 mL×6). The organic layer was dried over anhydrous sodium sulfate and then filtrated, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate, and then ethyl acetate:methanol=10:1) and was recrystallized (using chloroform) to give the title compound as yellow needle crystals (470 mg, yield: 44%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[CH2:33][C@H:32]2[C@@H:22]([CH2:23][C:24]3[C:34]4[C:27](=[CH:28][CH:29]=[CH:30][C:31]2=4)[NH:26][CH:25]=3)[N:21]([CH3:35])[CH2:20]1)(=O)=O.C>ClCCl.CN(C)C=O>[CH3:35][N:21]1[C@H:22]2[C@@H:32]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:34]=3[C:24]([CH2:23]2)=[CH:25][NH:26]4)[CH2:33][C@@H:19]([CH2:18][N:13]2[CH:12]=[CH:11][N:10]=[C:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:20]1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C[C@H](Cn2ccnc2-c2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
1.0 g of 50% sodium hydride in an oil was added in small portions to a mixture of 10.5 g of 2-phenylimidazole and 60 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 3.5 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with acetone). The product thus obtained was treated with charcoal in dichloromethane, and recrystallized from dichloromethaneisopropyl acetate to obtain 1.0 g of the titled compound as colorless prisms having a melting point of 193°-195° C.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[N:16]=[C:15]2[CH:17]=[CH:18][N:19](C(OC(C)(C)C)=O)[C:14]2=[CH:13][CH:12]=1)C)=O)(C)(C)C.[ClH:27].O1CCOCC1>CO.C(Cl)Cl>[ClH:27].[CH3:6][NH:8][CH2:10][C:11]1[N:16]=[C:15]2[CH:17]=[CH:18][NH:19][C:14]2=[CH:13][CH:12]=1
Reactant: CN(Cc1ccc2c(ccn2C(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CNCc1ccc2[nH]ccc2n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 96.1 %

Procedure:
To a stirred solution of tert-butyl 5-((tert-butoxycarbonyl(methyl)amino)-methyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (140.0 mg, 0.387 mmol) in MeOH (2 mL) and DCM (2 mL) was added HCl in dioxane (2.3 mL, 9.05 mmol, 4M) and the reaction mixture was stirred at 50° C. under N2 for 7 h. The solvent was removed in vacuo and the crude product was pumped dry on high-vacuum line to afford 87.1 mg (96.1%) of the desired product as HCl salt: 1H NMR (400 MHz, DMSO-d6) δ 12.51 (br s, 1H), 9.74 (br s, 2H), 8.38 (d, J=7.9 Hz, 1H), 8.10 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 4.52 (s, 2H), 2.63 (s, 3H); MS (ESI) m/z: 162.3 [M+1]+.