Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][C:7]1=[O:13].[CH:20]([NH2:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH:20]([NH:33][CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7](=[O:13])[CH2:8]1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(CN2CCC(=O)CC2=O)c(OC)c1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CN2CCC(NC(c3ccccc3)c3ccccc3)CC2=O)c(OC)c1
Reaction time: 18 h
Yield: 76.6 %

Procedure:
A mixture of 1-(2,4-dimethoxy-benzyl)-piperidine-2,4-dione (2.63 g, 10.0 mmol), benzhydrylamine (1.72 mL, 10.0 mmol) and sodium sulfate (5 g) in acetic acid (2.29 mL, 40.0 mmol) and DCM (40 mL) was stirred at ambient temperature for 6 hours before the addition of sodium triacetoxyborohydride (3.18 g, 15.0 mmol). The resulting mixture was stirred for 18 hours then filtered through Celite®, the filtrate washed with brine then dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 2.5% methanol in DCM). The residue was re-dissolved in acetic acid (300 μL) and methanol (30 mL) and treated with sodium cyanoborohydride (1.46 g, 23.2 mmol) and the resulting mixture stirred at ambient temperature for 18 hours. The mixture was concentrated under vacuum, the residue dissolved in DCM and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford 3.3 g (77%) of racemic 4-(benzhydryl-amino)-1-(2,4-dimethoxy-benzyl)-piperidin-2-one as an oil. LCMS (Method H, ESI): RT=2.47 min, m+H=431.3; 1H NMR (400 MHz, CDCl3) δ: 7.31 (m, 13H), 6.41 (s, 2H), 4.64 (d, 1H), 4.40 (d, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.32 (m, 1H), 3.13-3.05 (m, 1H), 2.95 (m, 1H), 2.72 (dd, 1H), 2.30 (dd, 1H), 2.02-1.92 (m, 1H), 1.74-1.57 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:3].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: BrCc1ccccc1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.2 %

Procedure:
404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester (1 mmol) is dissolved in 15 ml of dimethylformamide and mixed with 188 mg (1.1 mmol) of benzyl bromide and 358 mg of cesium carbonate. It is stirred for 48 hours at room temperature, the reaction mixture s worked up as described in Example 26, and after chromatography, 194 mg of 5-benzyloxy-4-methoxymethyl-9-benzyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O-:25])(=[O:24])[CH:22]=[CH2:23].[K+].C1(C=CC(O)=CC=1)O>CN(C)C=O>[C:21]([O:25][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)[O-]
Agent: Oc1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1 mole triphenylchloromethane was stirred with 1.5 moles potassium acrylate in 998 g dimethyl formamide in the presence of 0.14 g hydroquinone under the conditions described in Example 1. The precipitated potassium chloride was filtered off and the triphenyl methyl acrylate solution was concentrated by rotary evaporation at 65° to 100° C. and reduced to produce liquid triphenylmethyl acrylate. This was dissolved at 70 percent in xylene and filtered.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([C:20]#[CH:21])[CH:17]=[CH:18][CH:19]=1.C(NCC)C.[Li+].[OH-].Cl>CN(C=O)C.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.[Cu]I>[F:13][C:14]1[CH:15]=[C:16]([C:20]#[C:21][C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C#Cc1cccc(F)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: O=C(O)c1ccc(C#Cc2cccc(F)c2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 4-Iodobenzoate (10.0 g, 36.2 mmol) in DMF (30 mL) was added 3-fluorophenylacetylene (5.22 g, 43.4 mmol), Pd(Ph3P)4 (1.04 g, 0.91 mmol), CuI (346 mg, 1.82 mmol) and diethylamine (6 mL). The reaction vessel was sealed and heated at 60° C. for 1 h in a microwave reactor. The reaction was cooled to room temperature, diluted with EtOAc:hexanes (2:1, 250 mL) and washed with water (2×200 mL) and brine (200 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was dissolved in THF (130 mL) added MeOH (28 mL) and a solution of LiOH (3.04 g, 72.4 mmol) in water (28 mL). The reaction was stirred at room temperature and for 4 h. The reaction was acidified with 1 N HCl (100 mL) and 4-((3-fluorophenyl)ethynyl)benzoic acid was isolated (6.89 g, 79%) as a light tan solid; 1H-nmr (400 MHz, d6-DMSO) δ 7.97 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 1H), 7.55-7.42 (m, 3H), 7.21 (td, J=8.0, 2.0 Hz, 1H); LC (290 nM) 5.27 min (>98%); MS (ESI) m/z=240.7.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([OH:25])=O)([O-:15])=[O:14].Cl.[CH3:27][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]1)=[O:30].C(N(CC)CC)C>C(OCC)(=O)C.CC(C)=O.C(Cl)Cl>[CH3:27][O:28][C:29]([C@H:31]1[CH2:36][CH2:35][C@H:34]([CH2:37][NH:38][C:23](=[O:25])[CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])[CH2:33][CH2:32]1)=[O:30]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)C1CCC(CN)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H](CNC(=O)Cc2ccccc2[N+](=O)[O-])CC1
Reaction time: 1 h

Procedure:
CDI (27.6 mmol, 4.47 g) was added portion wise to a stirring solution of o-nitrophenyl acetic acid (27.6 mmol, 5.00 g) in ethyl acetate (20 mL) at room temperature. The mixture was left stirring for 1 h and then was sequentially added of a solution of 4-Aminomethyl-cyclohexanecarboxylic acid methyl ester hydrogen chloride salt in ethyl acetate (20 mL), triethyl amine (72.5 mmol, 10 mL), DCM (5 mL) and acetone (5 mL). The final mixture was stirred at room temperature overnight. The reaction mixture was filtered through a paper filter, the filtered solution was washed with a (1N) NaOH (2×15 mL) and then with brine, the organic phase was dried over anhydrous Na2SO4, the solvent was removed under reduced pressure to obtain the titled compound. (8.2 g, 90%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1.[CH3:25][O-:26].[Na+].Cl>CN(C)C=O.CCOCC>[ClH:1].[CH:25]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1)=[O:26]
Reactant: C[O-]
Reactant: CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCC2(CC1)CN(c1ccccc1NC=O)c1ccccc12
Temperature: 90 °C

Procedure:
To a mixture of 15.0 g of 1-(2-aminophenyl)-1'-methylspiro[indoline-3,4'-piperidine] dihydrochloride, Example 16, in 75 ml of dimethylformamide at 90° C. under nitrogen is added 8.6 g of sodium methoxide. Following this addition the reaction temperature is increased to 110°-115° C. and maintained at this temperature for 40 minutes. The resulting dark brown mixture is permitted to cool to 90° C. and then poured onto 800 ml of ice-water. The mixture is filtered and the filter cake is washed with water and then dissolved in chloroform. The chloroform solution is successively washed with brine, dried and concentrated leaving a red colored glass. The glass is dissolved in ether, where it is converted to its hydrochloric acid salt which is collected by filtration and then washed with ether and finally dried. The salt is recrystallized from a methyl alcohol-ether mixture to provide the product, mp 287.5° C., dec of 1-(2-formamidophenyl)-1'-methylspiro[indoline-3,4'-piperidine] hydrochloride.
Reaction SMILES: [CH:1]1([C:4]2[C:5](=[O:18])[N:6]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:7]([CH3:10])[C:8]=2[CH3:9])[CH2:3][CH2:2]1.[Br:19]Br>O1CCOCC1.O.CCOC(C)=O>[Br:19][CH2:9][C:8]1[N:7]([CH3:10])[N:6]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:5](=[O:18])[C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: BrBr
Reactant: Cc1c(C2CC2)c(=O)n(-c2ccc(F)cc2)n1C
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(CBr)c(C2CC2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 4-cyclopropyl-2-(4-fluoro-phenyl)-1,5-dimethyl-1,2-dihydro-pyrazol-3-one (0.32 g) in a round bottom flask under argon in dioxane (5 mL) was added bromine (0.20 g). The reaction was stirred at ambient temperature for 2 days. The reaction was diluted with water and EtOAc and the phases were separated. The aqueous phase was extracted with more EtOAc and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was purified via ISCO combiflash chromatography (EtOAc/heptane) to afford the desired 5-bromomethyl-4-cyclopropyl-2-(4-fluoro-phenyl)-1-methyl-1,2-dihydro-pyrazol-3-one as a light brown solid. MS (ESI+): 327.1 ([M+H]+).
Reaction SMILES: CS[C:3]1[N:13]2[C:14]3[N:9]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)=[CH:11][CH2:12]2)[N:8]=[CH:7][C:6]=3[C:5](=[O:25])[N:4]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27].C(O)C>C(O)(=O)C>[CH3:27][CH:26]([NH:29][C:3]1[N:13]2[C:14]3[N:9]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[CH:11][CH2:12]2)[N:8]=[CH:7][C:6]=3[C:5](=[O:25])[N:4]=1)[CH3:28]
Reactant: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Reactant: CC(C)N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a suspension of 5.0 g of 5-(methylthio)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one in 35 ml of acetic acid is added 2.64 g of isopropylamine. The reaction mixture is heated on a steambath for 18 hours. The resulting solution is cooled to room temperature and 17 ml of ethanol added. The mixture is cooled to 10° C. and 35 ml of ethanol and 20 g of ice added. The mixture is stirred for an additional 30 minutes at -10° C. The product is collected by filtration, washed with ethanol (2×20 ml) and air-dried to give 3.2 g (62.3%) of the desired product.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])SC)#[N:5]>C(O)C>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])#[N:5]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CCN
Solvent: CCO
Product: CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Anhydrous ethylamine (9.0 g.) was added to a solution of N-cyano-N'[2-((4-methyl-5-imidazolyl)methylthio)ethyl]S-methylisothiourea (Example 3(c), 5.0 g.) in ethanol. The solution was heated under reflux for 8 hours and concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, filtered, and diluted with water. The white solid obtained was recrystallised from isopropyl alcohol-ether to yield N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 118°-120°. (Found: C, 49.6; H, 6.8; N, 31.2; S, 11.7. C11H18N6S requires: C, 49.6; H, 6.8; N, 31.6; S, 12.0). (b) (i) A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (6.9 g.) and ethyl isothiocyanate (3.84 g.) in ethanol was heated under reflux for 2 hours. Concentration followed by recrystallisation of the residue from aqueous ethanol gave N-ethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (9.0 g.), m.p. 140°-141°. (Found: C, 46.5; H, 7.1; N, 21.7; S, 25.1. C10H18N4S2 requires: C, 46.5; H, 7.0; N, 21.7; S, 24.8).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[O:10]([CH2:17][C:18](N)=[NH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:18]([CH2:17][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:19]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COc1ccccc1
Solvent: CCO
Product: Nc1nc(COc2ccccc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 3.0 g (0.025 mole) of 3-amino-2-pyrazinecarbonitrile and 3.8 g (0.025 mole) of 2-phenoxyacetamidine [prepared according to C. Djerassi and C. R. Scholz, J. Am. Chem. Soc. 1947, 69, 1688] in 100 ml of absolute ethanol. Refluxing time: 4 hours. Yld: 5.4 g (85%), m.p. 202°-204° C. (ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)C>[O:12]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[CH:23][CH:22]=3)=[CH:3][CH:4]=2)[NH:9]1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(COc2ccc3c(c2)NC(=O)CC3)cc1
Temperature: 60 °C
Yield: 55.4 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (2.015 g, 12.35 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added potassium carbonate (1.880 g, 13.60 mmol) with stirring, and tert-butyl 4-(bromomethyl)benzoate (2.960 g, 10.83 mmol) in N,N-dimethylformamide (10 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then heated to 60° C. for 72 hours. The mixture was cooled, the solvent volume reduced to half under reduced pressure, and the residue poured slowly into water (100 mL) with stirring. Diethyl ether (5 mL) was added, the mixture sonicated, filtered, and the white solid thus obtained was washed with saturated sodium carbonate (60 mL), water (200 mL), diethyl ether (15 mL), and dried to afford tert-butyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoate (2.122 g, 6.00 mmol, 55%). LCMS mz 376.0 (M+Na), anal HPLC>92% in purity, 1H NMR (400 MHz; CDCl3) 8.00 (d, J=8.6 Hz, 1H); 7.55 (s, 2H); 7.45 (d, J=8.6 Hz, 2H); 7.05 (d, J=8.2 Hz, 1H); 6.57 (dd, J=8.4 and 2.5 Hz, 1H); 6.35 (d, J=2.3 Hz, 1H); 2.90 (m, 2H); 2.61 (m, 2H); 1.60 (s, 9H).
Reaction SMILES: [Li+].[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([O-:14])=O)[S:11][C:4]=12.[NH:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(CC)CC>O=S(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([N:15]3[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]3)=[O:14])[S:11][C:4]=12
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 59.7 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid lithium salt (2.27 g, 10.33 mmole), SOCl2 (10 ml), tert-butyl pyrrolidin-3-ylmethylcarbamate 44a (2.07 g, 10.33 mmole) and Et3N (1.44 ml, 10.33 mmole) in a manner as previously described for example 9d to give a yellow solid (2.44 g, 60%). 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, s), 7.34 (1H, d, J=5.1 Hz), 4.73 (1H, s), 3.96 (1H, m), 3.85 (1H, m), 3.70 (1H, m), 3.55 (1H, m), 3.42 (1H, m), 3.22 (2H, m), 2.54 (1H, m), 2.12 (1H, m), 1.43, 1.41 (9H, s); ESIMS (M+): 396.05.
Reaction SMILES: [CH3:1][Se:2][C:3]1[C:4]([NH2:48])=[N:5][C:6](=[O:47])[N:7]([CH:46]=1)[C@@H:8]1[O:38][C@H:12]([CH2:13][O:14][C:15]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:24][CH3:25])([O:22][CH3:23])[CH2:18][CH:17]=2)[C@@:10]([Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])([OH:11])[CH2:9]1.[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(OCC)(=O)C>CCCCCC>[C:49]([NH:48][C:4]1[C:3]([Se:2][CH3:1])=[CH:46][N:7]([C@@H:8]2[O:38][C@H:12]([CH2:13][O:14][C:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])([O:24][CH3:25])[CH2:20][CH:21]=3)[C@@:10]([Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41])([OH:11])[CH2:9]2)[C:6](=[O:47])[N:5]=1)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: COC1(OC)C=CC(C(OC[C@H]2O[C@@H](n3cc([Se]C)c(N)nc3=O)C[C@@]2(O)[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccccc2)=CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC1(OC)C=CC(C(OC[C@H]2O[C@@H](n3cc([Se]C)c(NC(=O)c4ccccc4)nc3=O)C[C@@]2(O)[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccccc2)=CC1
Reaction time: 1 h

Procedure:
5-methylseleno-3′-t-butyldimethylsilyl-5′-O-(4,4-dimethoxytrityl)-2′-deoxycytidine (compound 2) 300 mg (MW 751.3, 0.4 mmol) was placed in a flask and dried on high vacuum for one hour before addition of anhydrous pyridine 10 ml. Benzoyl chloride 0.03 ml (0.6 mmol, 1.5 eq.) was added dropwise before the reaction solution was stirred for 1 hour. After the reaction was completed (monitored on TLC, 30% ethyl acetate in hexane, Rf=0.5), the crude product was extracted with saturated NaCl solution and ethyl acetate. The organic phase was removed and aqueous phase was extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous MgSO4, the salt was filtered, and the organic solvents were evaporated under reduced pressure. The residue was purified on a silica gel column (equilibrated with hexane) and eluted with an ethyl acetate/hexane gradient (EtOAc in hexane, 10-50%). Compound 3 was isolated and dried to afford a yellow-green solid 287 mg. (yield=84%). 1H-NMR (400 MHz, DMSO) δ: 0.09 and 0.04 [2×s, 6H, Si(CH3)2], 0.86 (s, 9H, t-butyl), 2.02 (s, 3H, SeCH3), 2.18-2.20 and 2.43-2.52 (2×m, 2H, H-2′), 3.29-3.33 and 3.43-3.46 (2×m, 2H, H-5′), 3.81 (s, 6H, 2×OMe), 4.05-4.08 (m, 1H, H-3′), 4.41-4.45 (m, 1H, H-4′), 6.30-6.34 (t, J=6.4 Hz, 1H, H-1′), 6.86-7.56 (m, 18H, arom-H), 7.88 (s, 1H, NH), 8.32 (s, 1H, H-6). 13C NMR (100 MHz, DMSO) δ: −4.89 and −4.69 [Si(CH3)2], 1.03 (SeCH3), 17.95 [SiC(CH3)], 25.73 [SiC(CH3)], 41.86 (C-2′), 55.26 (OMe), 63.05 (C-5′), 72.41 (C-3′), 86.30 (C-4′), 86.77 (C-5), 87.24 (C-1′), 113.27 (arom-C), 127.07 (arom-C), 128.13 (arom-C), 128.27 (arom-C), 129.38 (arom-C), 130.09 (arom-C), 132.67 (arom-C), 133.68 (C-6), 135.51 (NHCO), 144.41 (arom-C), 144.36 (C-2), 158.69 (C-4). HR-MS (ESI-TOF, negative ion mode): molecular formula, C44H51N3O7SeSi: [M−H]−: 840.2570 (calc. 840.2583)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12.O[N:15]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[OH-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[C:7]([C:8]([NH2:15])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc2[nH]ccc2c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cnc2[nH]ccc2c1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 10.8 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (840 mg) in N,N-dimethylformamide (8.4 mL) were added 1-hydroxybenzotriazole (808 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (929 mg). The mixture was stirred at 60° C. for 30 minutes. The solution was cooled to ambient temperature and added 28% ammonium hydroxide aqueous solution (1.2 mL). The mixture was stirred at ambient temperature for 1 hour. To the solution were added water and chloroform and the mixture was extracted with chloroform. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (90 mg) as a pale yellow powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[C:55]([CH2:57][C:58]([O:60][CH2:61][CH3:62])=[O:59])[N:56]=1>C(Cl)Cl>[CH2:61]([O:60][C:58](=[O:59])[CH2:57][C:55]1[N:56]=[C:52]([NH:51][C:35](=[O:37])[CH:34]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([C:47]([F:49])([F:48])[F:50])(=[O:45])=[O:46])=[CH:42][CH:43]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[S:53][CH:54]=1)[CH3:62]
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(S(=O)(=O)C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
A solution of triphenylphosphine (97 mg, 0.371 mmol) in methylene chloride (1.5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (66 mg, 0.371 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (100 mg, 0.285 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min, allowed to warm to 25° C., and then treated with ethyl 2-amino-4-thiazoleacetate (123 mg, 0.657 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl-amino]-thiazol-4-yl}-acetic acid ethyl ester (107 mg, 72%) as a yellow foam: mp 48-51 ° C.; EI-HRMS m/e calcd for C22H25F3N2O5S2 (M+) 518.1157, found 518.1157.