Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:8](=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([OH:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[P:26](=[O:44])(Cl)([S:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:26](=[O:44])([S:38][CH2:39][CH2:40][CH2:41][CH3:42])([O:18][C:7]1[C:8]2[C:17](=[CH:16][C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=1
Reactant: CCCCSP(=O)(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(O)c2cc3ccccc3cc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCSP(=O)(Oc1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Nitro-1-anthrol (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(4-trifluoromethylphenyl) S-butyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(4-trifluoromethylphenyl) O-(4-nitro-1-anthryl) S-butyl phosphorothioate.
Reaction SMILES: [C:1]1([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[C:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][Si](C=[N+]=[N-])(C)C>CCOCC.CO>[C:1]1([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[C:9]([O:11][CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C(=O)C(=O)[O-])c1ccccc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(=O)C(C)(C)c1ccccc1
Temperature: 0 °C
Yield: 87.7 %

Procedure:
To a 0° C. (ice water bath) solution of 3-phenyl-3-methyl-2-oxobutanoate (9.0 g, 47 mmol, from Reference Example 35) in ether (40 mL) and methanol (60 mL). Trimethylsilyl diazomethane (2.0 M solution in hexanes, 35 mL, 70 mmol, Aldrich) is added dropwise until the evolution of gas ceased and the yellow color of the reagent persisted in solution. The solvents are evaporated under reduced pressure and the residue is taken up in ether/hexanes (1:1) and washed with 2% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The combined extracts are then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a straw-colored liquid (8.5 g, 88%). MS (ES+): (M+H)=206.9
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[C:12]1([O:18]C2C=CC=CC=2)C=CC=[CH:14][CH:13]=1.CCCC(C)C>C(#N)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:5]=1[N:6]=[CH:14][CH:13]=[C:12]2[OH:18]
Reactant: Nc1ccccc1OC(F)F
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CC#N
Solvent: CCCC(C)C
Product: Oc1ccnc2c(OC(F)F)cccc12

Procedure:
2-difluoromethoxyaniline (7.63 g) and the product from step a) were stirred in acetonitrile (100 ml) overnight. The solvent was removed by evaporation and the solid triturated with 4:1 isohexane/diethyl ether (200 ml) before filtering to give a light green solid. The solid was added portionwise to refluxing diphenylether (120 ml) and continued heating for a further 10 minutes before cooling. The solution was poured into isohexane (600 ml) and the solid filtered off to give the title compound (12.0 g).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9]S[C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:6]2=[C:5]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[C:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]1[C:3]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][C:5]([C:16]([O:18][CH3:19])=[O:17])=[C:6]2[N:7]1[CH:8]=[CH:9][C:11]1[CH:15]=[CH:14][S:13][C:12]=12
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SC=C2
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12

Procedure:
4.4 g of methyl 8-oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepine-11-carboxylate were heated under reflux and under argon together with 90 ml of xylene until the reaction was completed. The solution was evaporated in vacuo and the residue was treated with 100 ml of n-hexane whereupon the product was removed by filtration. By recrystallization from ethyl acetate, there was obtained methyl 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate as yellow crystals of m.p. 153°-156°.
Reaction SMILES: [CH2:1](C([SnH3])=C(CCCC)CCCC)[CH2:2]CC.[C:16]([N:24]1[C:32]2[C:27](=[CH:28][C:29](Br)=[CH:30][CH:31]=2)[C:26]([C:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH:39]=2)=[CH:25]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[NH3:24].[C:16]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([CH:1]=[CH2:2])=[CH:30][CH:31]=2)[C:26]([C:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH:39]=2)=[CH:25]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ccc(Br)cc23)CC1
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(c1)c(C1=CCN(C)CC1)cn2C(=O)c1ccccc1
Product: N
Temperature: 100 °C
Yield: 5 %

Procedure:
Tributylvinylstannane was added to a solution of 1-benzoyl-5-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (Example 6g) in DMF and the reaction mixture was heated to 100° C. overnight. The mixture was partitioned between ethyl acetate and water, sequentially washed with water and brine, and dried over sodium carbonate. Flash chromatography (silica gel, 5% 2M methanolic ammonia in dichloromethane) yielded 1-benzoyl-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-vinylindole.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.Br[CH2:19][CH2:20][CH3:21].CC(C)([O-])C.[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:17][CH2:19][CH2:20][CH3:21])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2
Reactant: COC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(=O)OC
Temperature: 100 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
A mixture of (S)-methyl 6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.110 g, 0.366 mmol), 1-bromopropane (0.166 mL, 1.832 mmol), and potassium tert-butoxide (0.103 g, 0.916 mmol) in DMF (3.0 mL) was heated in a sealed tube at 100° C. After 24 h, additional 1-bromopropane (0.166 mL, 1.832 mmol) and potassium tert-butoxide (0.103 g, 0.916 mmol) were added and the mixture was heated in a sealed tube at 100° C. for 24 h. The reaction mixture was cooled to rt and water was added. The mixture was extracted with dichloromethane and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-methyl 6-bromo-2-methyl-5-propoxy-3,4-dihydroquinoline-1 (2H)-carboxylate (0.120 g, 96%) as a colorless oil. MS (ESI, pos. ion) m/z 342, 344 [M+H]+.
Reaction SMILES: Cl.[N:2]1[C:9]([NH2:10])=[N:8][C:6]([NH2:7])=[N:5][C:3]=1[NH2:4].[C:11]([CH:14]([CH:16]([C:18]([O-:20])=[O:19])[OH:17])[OH:15])([O-:13])=[O:12].[Na+].[Na+]>>[N:2]1[C:9]([NH2:10])=[N:8][C:6]([NH2:7])=[N:5][C:3]=1[NH2:4].[C:18]([OH:20])(=[O:19])[CH:16]([CH:14]([C:11]([OH:13])=[O:12])[OH:15])[OH:17]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: Cl
Agent: Nc1nc(N)nc(N)n1
Agent: [Na+]
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
A salt of melamine and tartaric acid was prepared by mixing an aqueous solution containing two molecular parts of melamine hydrochloride with an aqueous solution containing one molecular part of disodium tartrate. The precipitate which was formed was washed with water and dried to constant weight in a vacuum oven at 80° C. The dried precipitate was found by analysis to comprise melamine tartrate.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=[O:4])[CH:2]=[CH2:3].[Br:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>C(OCC)(=O)C>[Br-:11].[C:16]([C:15]1[CH:14]=[C:13]([CH2:12][N+:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH:26]=[CH:25][CH:24]=1)(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CC(=O)OCCN(C)C
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Solvent: CCOC(C)=O
Product: C=CC(=O)OCC[N+](C)(C)Cc1cccc(C(=O)c2ccccc2)c1
Product: [Br-]
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Dimethylaminoethyl acrylate (11.4 mls) was added to a stirred solution of 3-bromomethylbenzophenone (20.6g) in ethyl acetate (100 mls) at 60° C. and the mixture stirred for 1 hour at 60° C. After cooling to room temperature the mixture was stirred for 1 hour prior to filtration. After washing the residue with ethyl acetate (3x) the solid was dried under vacuo at room temperature. The crude title compound was obtained as a cream solid (27.3g, MP 165°-168° C.) which was recrystallised from propan-2-ol/isopropyl ether. Filtration followed by washing with isopropyl ether then drying under vacuo at room temperature gave the title compound as pale cream crystals. (20.2g, yield =64.5%, MP 168°-169° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:35])=[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[C:13]=3[O:12]2)=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]=2[OH:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OC(Cc2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Oc1ccc2c(O)c(Cc3c[nH]c4ccccc34)oc2c1CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
A solution of tert-butyl 4-({2-[(1H-indol-3-yl)methyl]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 0.042 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was added with triethylamine and thereby made basic. Then, the mixture was azeotroped twice with toluene under reduced pressure, and the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain 2-[(1H-indol-3-yl)methyl]-7-(piperazin-1-ylmethyl)benzofuran-3,6-diol (0.011 g, 69%).
Reaction SMILES: [Br:1][C:2]1S[C:5]([N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[CH3:13])=[N:4][CH:3]=1.N[C:15]1[CH:20]=CC(Br)=CN=1>>[Br:1][C:2]1[CH:15]=[CH:20][C:5]([N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[CH3:13])=[N:4][CH:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1ccc(C)n1-c1ncc(Br)s1
Product: Cc1ccc(C)n1-c1ccc(Br)cn1

Procedure:
Prepare using procedures essentially as described for 5-bromo-2-(2,5-dimethylpyrrol-1-yl)thiazole (Preparation 25) starting with 2-amino-5-bromopyridine. MS (ES): m/z 252 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9]C=2N=N1.N1CCC[CH2:12][CH2:11]1.[F:16][C:17]([F:50])([F:49])[C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:31]=1[CH:32]=O)[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1>C(O)C>[F:50][C:17]([F:49])([F:16])[C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=[CH:34][C:31]=1[CH:32]([N:1]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH2:11][CH3:12])[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Reactant: c1ccc2[nH]nnc2c1
Reactant: C1CCNCC1
Solvent: CCO
Product: CCC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N1CCCCC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 23.2 %

Procedure:
To a solution of benzotriazole (12.8 mg, 0.1075 mmoles) in ethanol (2.5 mL) was added piperidine (9.2 mg, 0.1075 mmoles) and the reaction was stirred for 10 minutes. 2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (50 mg, 0.0977 mmoles) was added to the reaction mixture and it was further stirred for 16 hours. The imine fragment was observed MH+=579.4. Parent ion for the intermediate was not found. Ethanol was evaporated and the crude product was taken to the next step. To the crude product in toluene (2 mL) was added ethyl magnesium bromide (97 □L, 0.2916 mmoles of a 3M solution in ether). The reaction mixture was heated at 50° C. for 2 hours. LC-MS indicated formation of product. The reaction mixture was diluted with ethyl acetate (2 mL). The organic layer was washed with saturated aqueous NH4Cl solution followed by 1N NaOH solution. The organic layer was concentrated and the residue was dissolved in DMSO and purified on prepHPLC (Shimadzu, 30×50 C18, Basic, 30-95%, 0.1% NaOH, 8 min gradient, 220 UV) to yield the title compound as clear oil 13.8 mg (23%). MS (ES+) Calc: 608.5, Found: 609.1 (M+1).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[C:20](Br)Br)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:23](Cl)(=[O:26])[O:24][CH3:25].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]#[C:20][C:23]([O:24][CH3:25])=[O:26])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C#CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.57N hexane solution, 3.11 ml) was added dropwise to a solution with 1-(tert-butoxycarbonyl)-4-(2,2-dibromovinyl)piperidine (WO9806720) (900 mg) dissolved in tetrahydrofuran (16 ml) at −78° C., and the mixture was stirred for 1 hour. Methyl chlorocarbonate (377 μl) was added to the reaction mixture to heat the mixture to room temperature in 1 hour. Diethyl ether (30 ml) and a saturated aqueous A solution (50 ml) of ammonium chloride were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (634 mg) as a colorless transparent oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][S:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:20])=[O:19].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1.Cl>C(OCC)(=O)C.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:17][S:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:19])=[O:20])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)CCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)NS(=O)(=O)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1.0 g), DMF (10 ml), 3-(aminosulfonyl)propylacetic acid (0.95 ml), CDI(0.85 g), and DBU (0.80 g) was stirred at room temperature for 3 days. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate, and the organic layer was separated. The organic layer was washed with a saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3-{[({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]sulfonyl}propylacetic acid (1.2 g).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br-].[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O>O1CCCC1.BrCCBr>[Br:25][C:21]1[CH:20]=[C:19]([C:17]([C:3]2[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)=[CH2:16])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: COc1ccc(Br)cc1C(F)(F)F
Agent: [Br-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OC)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of magnesium turnings (565 mg, 23.5 mmol, 1.2 eq) in 5 mL of dry tetrahydrofuran, 0.1 mL of 1,2-dibromoethane were added followed by 5 mL of a tetrahydrofuran solution of 5-bromo-2-methoxy-benzotrifluoride (5.0 g, 19.6 mmol, 1.0 eq in 30 mL tetrahydrofuran). The resulting mixture was gently heated to initiate the reaction. The remaining solution of bromide was added dropwise at such a rate that the reaction could reflux without external heating. After the addition the reaction mixture was heated at reflux for further 2 hours. The mixture was cooled to 0° C. and a solution of 3-bromoacetophenone (3.9 g, 19.6 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added dropwise. After 2 hours LC-MS showed complete conversion to the desired product. 50 mL of water were added followed by 25 mL of 1 M aqueous HCl. The organic fraction was washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in toluene (50 mL) and a few crystals of p-toluenesulfonic acid were added. The solution was heated to reflux for 2 hours in a flask equipped with a Dean-Stark apparatus. After this time, the mixture was cooled to room temperature, concentrated and the crude purified by flash chromatography eluting with cyclohexane/ethyl acetate (100:0 to 95:5). 5.1 g of clean product was obtained as colorless liquid (yield: 73%).
Reaction SMILES: [I:1][C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[CH:25]1([CH2:24][N:11]([C:10]2[C:9]([S:19][CH3:20])=[N:8][N:7]3[C:2]([I:1])=[CH:3][CH:4]=[CH:5][C:6]=23)[C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nn2c(I)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[7-iodo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (600 mg) in N,N-dimethylformamide (6 mL) was added sodium hydride (60% in oil; 80 mg) with ice bath, and the reaction mixture was stirred for 30 minutes at room temperature. (Bromomethyl)cyclopropane (0.22 mL) was added to the reaction mixture at the same temperature, and stirring was continued for 1 hour at 40° C. After completion of the reaction, the reaction mixture was gradually added to ice, extraction was performed with ethyl acetate, and the organic extract was washed with water and brine. The organic extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[I:16]Cl.O>C(O)(=O)C>[I:16][C:7]1[C:6]([F:9])=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: ClI
Reactant: Nc1cc(F)ccc1F
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc(F)c(I)cc1F
Yield: 66.6 %

Procedure:
2,5-Difluoroaniline (38 g) was dissolved in acetic acid (120 ml), and then pyridine (25 g) was added thereto, followed by stirring. A mixed solution of iodine monochloride (50 g) with acetic acid (30 ml) was added dropwise thereto. After stirring at room temperature for 1 hour, the mixed solution was further stirred at 70° to 80° C. for 2 hours. Then, the reaction solution was poured into water, and the precipitated crystals were filtered, followed by washing with water. The resulting crystals were dissolved in chloroform, and then washed with water twice, further with 10% potassium hydroxide aqueous solution twice, and furthermore with water twice, followed by distilled off chloroform therefrom. The residue was distilled under reduced pressure (b.p. 130° to 140° C./20 mmHg), and then recrystallized from methanol, to give 4-iodo-2,5-difluoroaniline (50 g).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:11]1O)(=O)C1C=CC=CC=1>CO.O>[C@H:12]1([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[O:13][C@@H:14]([CH2:15][OH:16])[C@@H:10]([OH:9])[CH2:11]1
Reactant: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Product: O=c1ccn([C@@H]2C[C@H](O)[C@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
A solution of 1-(3,5-di-O-benzoyl-β-L-xylofuranosyl)-uracil (6a) (1.4 g: 3.21 mmol) in ammoniacal methanol (previously saturated at 10° C. and hermetically closed) (90 ml) is stirred for two days at room temperature. The solution is evaporated several times with methanol under reduced pressure. The crude material obtained is dissolved in water and the resulting solution is washed several times with chloroform. The aqueous phase is evaporated and the residue is directly crystallized from methanol to give 0.6 g (yield 82%) of pure 7a: m.p.: 165-167° C.; 1H NMR (DMSO-d6), δ ppm=11.23 (s, 1H, 3-NH), 7.92 (d, 1H H-6; J=8.1 Hz), 6.04 (dd, 1H, H-1′; J=2.0 and 8.3 Hz), 5.26 (d, H, H-5; J=8.1 Hz), 5.26 (d, 1H, OH-3′; J=3.2 Hz), 4.69 (t, 1H, OH-5′; J=5.3 Hz), 4.20 (m, 1H, H-3′), 3.81 (m, 1H, H-4′), 3.80-3.60 (m, 2H, H-5′ and 5″), 2.6-2.5 (m, 1H, H-2′, partially obscured by DMSO-d5), 1.85 (dd, 1H, H-2″; J=2.0 and 14.7 Hz); mass spectra (matrix: glycerol-thioglycerol: 50:50, v/v): FAB>0 321 [M+glycerol+H]+, 229 [M+H]+, 117 [s]+ and 113 [BH2]+; FAB<0 227 [M−H]−.