Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[OH-].[Na+].[CH:16]1([CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][N:22]=2)[CH2:18][CH2:17]1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[NH4+].[OH-]>CCO.O.CO.[O-]S([O-])(=O)=O.[Cu+2].CC(O)=O>[CH:16]1([CH2:19][NH:20][C:21]2[N:22]=[CH:23][C:24]([C:27]3[N:3]=[N:2][N:1]([C:4]4[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=4[CH3:13])[C:7]([OH:9])=[O:8])[CH:28]=3)=[CH:25][CH:26]=2)[CH2:17][CH2:18]1
Reactant: C#Cc1ccc(NCC2CC2)nc1
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(NCC3CC3)nc2)nn1
Reaction time: 14 h
Yield: 66.7 %

Procedure:
3-Azido-4-methyl benzoic acid (497 mg; 2.81 mmol) was suspended in 6.5 mL of EtOH. To this mixture was added 4N NaOH until the mixture became homogeneous, followed then by 2-(cyclopropylmethyl)amino-5-ethynyl pyridine (460 mg; 2.61 mmol) and 529 mg (2.67 mmol) of sodium ascorbate in 0.7 mL of water. The mixture was stirred rapidly as 2.67 mL of a 0.1 M CuSO4 solution was added. A yellow precipitate formed and the mixture was stirred rapidly for 14 h. The mixture was poured into water and acidified carefullly with HOAc. The resulting precipitate was filtered and washed with water. A fine yellow powder was isolated. This material was crushed in 1 mL of MeOH and 5 mL of NH4OH was added. The resulting green mixture was stirred for 10 min, then HOAc was carefully added until a white precipitate formed (pH 8-9). The precipitate was filtered and washed with 1% HOAc in water, then with water and hexanes to provide 607 mg (1.74 mmol; 65%) of 3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzoic acid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1.[Cl-].[NH4+]>C1COCC1>[CH:26]1([C:11]([C:10]2[S:9][C:8]([NH:17][C:18]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[O:19])=[N:7][C:6]=2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:16])[CH2:28][CH2:27]1
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CC2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
Compound 98 (127 mg, 0.355 mmol) was suspended in THF (2.5 mL), and a 0.5 mol/L solution of cyclopropylmagnesium bromide in THF (4.00 mL, 2.00 mmol) was added thereto under ice-cooling, followed by stirring at room temperature for 2.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with a mixed solvent (4:1) of chloroform and 2-propanol. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried, over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 417 (94.1 mg, 78%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9]2)(=[O:3])[CH3:2].[Si:18](OS(C(F)(F)F)(=O)=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:18]([O:3][C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9]2)=[CH2:2])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc2cccc(C(C)=O)c2n1
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2ccc(C(=O)OC)nc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of methyl 8-acetylquinoline-2-carboxylate (1.98 g, 8.64 mmol) in DCM (25 mL) at 0° C. was added TEA (1.56 mL, 11.23 mmol) followed by TBSOTf (1.66 mL, 9.50 mmol). The reaction mixture was stirred at 0° C. for 50 min. The mixture was then partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted with DCM (2×). The combined organic layers were then dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give methyl 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)quinoline-2-carboxylate as a brown oil: 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.12 (dd, J=7.3, 1.3 Hz, 1H), 7.80 (dd, J=8.1, 1.3 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 6.12 (s, 1H), 4.99 (s, 1H), 4.05 (s, 3H), 1.01 (s, 9H), 0.28 (s, 6H). m/z (ESI, +ve ion) 344.0 (M+H)+. This oil was taken up in THF (10 mL), treated with water (2.5 mL, 138 mmol) and NBS (1.61 g, 9.07 mmol), and stirred at RT for 20 min. The reaction mixture was then partitioned between water and Et2O, and the organic layer was separated and sequentially washed with saturated NaHCO3, water, and brine, then dried over MgSO4, filtered, and concentrated in vacuo to give methyl 8-(2-bromoacetyl)quinoline-2-carboxylate as a greenish-brown solid. This material was used without purification in the subsequent step assuming the theoretical yield: 1H NMR (400 MHz, CDCl3) δ ppm 8.40 (d, J=8.6 Hz, 1H), 8.30 (d, J=7.0 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 5.32 (br. s., 2H), 4.08 (s, 3H). m/z (ESI, +ve ion) 308.0/310.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:11][C:12]1[C:13]([I:27])=[C:14]([C:18]([I:26])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[C:20]=1[I:21])[C:15](Cl)=[O:16])(=[O:10])[CH3:9].Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][NH:34][CH3:35])[CH3:30]>CN(C)C=O>[CH2:29]([O:31][C:32](=[O:36])[CH2:33][N:34]([C:15](=[O:16])[C:14]1[C:13]([I:27])=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[C:20]([I:21])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[C:18]=1[I:26])[CH3:35])[CH3:30]
Reactant: CCOC(=O)CNC
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
840 ml (6.1 Mol) triethylamine is added to a solution of 759 g (1.2 Mol) 3,5-diacetamido-2,4,6-triiodobenzoyl chloride and 276 g (1.8 Mol) sarcosine ethyl ester hydrochloride in 7600 ml N,N-dimethylformamide and stirred for 1 hr. at 60° C. The reaction mixture is cooled to room temperature, the crystallized triethyl ammonium chloride is filtered, washed with N,N-dimethylformamide and reduced under vacuum in a rotary evaporator. The residue is dissolved in 650 ml methanol and added dropwise to 3 l ethyl acetate. The precipitate is crystallized overnight, filtered to a dry state and finally washed with water, 1N hydrochloric acid, cold saturated sodium bicarbonate, water and dried under vacuum at 60° C. Yield: 685 g (80%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCCCCCCCCCCCC.[C:23](=O)=[O:24].CN(C)C.S(=O)(=O)=O.C(=O)(OCCCCCCCC)N.N(C)(C)C>C(OCC)C.C(#N)C>[CH2:1]([N:9]=[C:23]=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C=O
Reactant: CCCCCCCCN
Agent: CCCCCCCCCCCCC
Agent: CCCCCCCCOC(N)=O
Agent: CN(C)C
Solvent: CCOCC
Solvent: CC#N
Product: CCCCCCCCN=C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
A Fischer-Porter bottle was charged with 0.55 g (4.2 mmol) of octyl amine, 0.99 g of P1 tBu (3 mmol), 25 mL of acetonitrile and 130 mg (0.84 mmol) of tridecane as an internal standard. The bottle was pressurized to 80 psig with carbon dioxide and the solution was stirred for 30 min. at room temperature. A second Ficher-Porter bottle was charged with 0.65 g (4.7 mmol) of sulfur trioxide trimethylamine adduct (SO3 -NMe3) and 20 mL of acetonitrile then pressurized to 80 psig with CO2. The two solutions were cooled to 0° C. in an ice bath for 10 min after which time the octyl carbamate solution was added rapidly to the SO3 -NMe3 suspension. An aliquot was taken after five minutes and diluted with diethyl ether prior to G.C. analysis which indicated a yield of 11% octyl isocyanate. Further monitoring of the reaction progress over 48 hrs gave a maximum yield of 27% octyl isocyanate.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])[CH3:19]>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]1=[O:8])=[O:26])[CH3:19]
Reactant: CN(C)CCCCCC(=O)Cl
Reactant: O=C1CCCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)CCCCCC(=O)C1CCCCNC1=O
Temperature: 101 °C
Yield: 83.9 %

Procedure:
To a 1000 mL three-necked round-bottomed flask equipped with a reflux condenser, internal thermometer, argon inlet, and mechanical stirrer, are added ε-caprolactam (48.04 g, 0.42 mol), toluene (340 mL), and triethylamine (189.00 g, 1.87 mol). The mixture is heated to reflux (ca. 101° C.) for 15 min. While at that temperature, acid chloride 3 (100.00 g, 0.47 mol) is added as a solid over 30 min. The reaction is maintained at reflux for an additional 1.75 h before the heat is removed. At room temperature, the mixture is filtered and the salts washed with toluene. The dark filtrate is washed with saturated sodium bicarbonate solution (3×250 mL), water (100 mL), and dried over MgSO4. The mixture is filtered and concentrated by rotary evaporation at about 50° C. (water aspirator) and then by Kugelrohr distillation at 60° C. for 1 h to give 89.64 g (83%) of 4 as a dark red oil.
Reaction SMILES: Cl.Cl[S:3]([C:6]1[CH:7]=[C:8]([CH2:14][C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])(=O)=O>C(O)(=O)C.O>[SH:3][C:6]1[CH:7]=[C:8]([CH2:14][C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CC(C)=O)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CC(C)=O)cc1S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
While ice-cooling a suspension of 84 g of stannous chloride --2H2O in 320 ml of glacial acetic acid with stirring until a transparent solution was obtained, hyrochloric acid gas was introduced into the solution and then 14.3 g of 3-chlorosulfonyl-4-methoxyphenylacetone was added to the solution at 25°-30° C. After further stirring the mixture at room temperature for 30 minutes, the reaction mixture obtained was poured into 320 ml of concentrated hydrochloric acid and after diluting the mixture with 640 ml of water, the product was extracted with 400 ml of chloroform. The chloroform layer formed was washed with water and then chloroform was distilled off to provide 10 g of oily 3-mercapto-4-methoxyphenylacetone.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:11][O:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2ocnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2ocnc12
Yield: 90.6 %

Procedure:
To a suspension of 4-hydroxybenzoxazole (2.00 g, 14.8 mmol) (Musser et al., J. Med. Chem., 30, pp. 62-67 (1987)) in acetone (80.0 ml) was added dried K2CO3 (2.25 g, 16.3 mmol) followed by iodomethane (1.38 ml, 22.2 mmol). The reaction was heated under reflux under N2 for 4.5 h, then filtered and reduced in vacuo to afford the crude product. The resulting residue was purified by flash chromatography (25:75 ethyl acetate/hexane) to give 2.0 g (91%) of the title compound as a white crystalline solid: m.p. 72°-74° C.; IR (KBr) 3089, 1619, 1610, 1503, 1496, 1322, 1275, 1090, 1071, 780, 741; 1H NMR (CDCl3) δ 8.02 (1H, s), 7.32 (1H, t, J=8.0), 7.18 (1H, d, J=8.0), 6.81 (1H, d, J=8.0), 4.04 (3H, s). Anal. Calcd. for C8H7NO2 : C, 64.42; H, 4.73; N, 9.39. Found: C, 64.40; H, 4.84; N, 9.31; m/z (EI) 149 (M+ +1, 100%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.[CH3:26][O:27][C:28](=[O:34])[CH:29](O)[CH:30]([CH3:32])[CH3:31].CO>C(OCC)(=O)C>[CH3:26][O:27][C:28](=[O:34])[CH:29]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)C(O)C(C)C
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(C)C

Procedure:
Following the procedures of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol and 2-hydroxy-3-methyl-butyric acid methyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give racemic 3-Methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid methyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=3.70 min, [M+H]+=466
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:14]Br.S([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:14][C:10]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of 1-tert-butyl-4-nitrobenzene (8.95 g, 50 mmol) and silver sulfate (10 g, 32 mmol) in 50 mL of 90% sulfuric acid was added dropwise bromine (7.95 g, 50 mmol). Stirring was continued at room temperature overnight, and then the mixture was poured into dilute sodium hydrogen sulfite solution and was extracted with EtOAc three times. The combined organic layers were washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated to give 2-bromo-1-tert-butyl-4-nitrobenzene (12.7 g, 98%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=2.5 Hz, 1H), 8.11 (dd, J=8.8, 2.5 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 1.57 (s, 9H); HPLC ret. time 4.05 min, 10-100% CH3CN, 5 min gradient.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][O:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[N:11][C:12]=3[NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:17]([Cl:29])[CH:16]=3)[NH:7][N:6]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 46 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-acetylpiperazine to give the title compound in 46% yield; NMR Spectrum: 1.96 (s, 3H), 2.44 (t, 2H), 2.50 (hidden by DSMO, 2H), 2.83 (t, 2H), 3.37-3.41 (m, 4H), 4.43 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.46 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 523 (MH+).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[Cl:8][CH2:9][C:10](=O)/[CH:11]=[CH:12]/[Cl:13].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C1COCC1.O.[Ti](Cl)(Cl)(Cl)Cl>[C:3]([C:2](=[C:11]([CH2:12][Cl:13])/[CH:10]=[CH:9]\[Cl:8])[C:1]([OH:7])=[O:6])([OH:5])=[O:4]
Reactant: O=C(/C=C/Cl)CCl
Reactant: O=C(O)CC(=O)O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(C(=O)O)=C(/C=C\Cl)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.6 %

Procedure:
Titanium tetrachloride (2.5 ml., 25 mmol) in carbon tetrachloride (7.5 ml) was added to THF (60 ml) at 0° C. Malonic acid (1.0 g., 10 mmol) and trans 1,4-dichlorobut-3-en-2-one (1,4 g., 10 mmol) in THF (10 ml) was added. Pyridine (3.3 ml., 40 mmol) in THF (10 ml) was added dropwise over fifteen minutes at 0° C. The reaction mixture was stirred at room temperature for three hours, diluted with water (50 ml) and extracted with ether (50 ml., 2×25 ml). The extracts were washed with brine, N sodium bicarbonate solution, brine, dried (Na2SO4) and evaporated to give the title product (0.35 g., 12%). ≢ (CDCl3) 5.00 (2H, s, CH2), 6.91 (1H, d, J 5 Hz, CH=), 8.01 (1H, d, J 5 Hz, CH=), 9.68 (2H, s, --OH). νmax (CHCl3) 1720 cm-1.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:33])(=[O:32])[NH:26][CH2:27][CH2:28][CH2:29][C:30]#[N:31])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CC#N>[C:30]([CH2:29][CH2:28][CH2:27][N:26]([CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:23][CH2:22]2)(=[O:32])=[O:33])#[N:31]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NCCCC#N)C4(CC4)C3)ncnc21
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCCCN(CCCc1ccccc1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reaction time: 16 h

Procedure:
4-[4-(3-Cyano-propylsulfamoyl)-4,7-diaza-spiro[2.5]oct-7-yl]-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 18) was dissolved in CH3CN (0.4 mL), added Cs2CO3 and (3-bromo-propyl)-benzene. Stirred at for 16 h and then added additional (3-bromo-propyl)-benzene (2 equivalents) before being stirred at rt for 3 days. The crude reaction mixture was filtered through a syringe filter (0.45 μm) and purified by standard preparative HPLC purification. The residual oil was dissolved in THF (1 mL), added TFA (0.5 mL) and then stirred at rt for 2 h. The crude reaction mixture was concentrated in vacuo and redissolved in MeOH (0.5 mL). The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([CH:11]=[CH2:12])=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1>C(OC(=O)C)C.[Pd]>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([CH2:11][CH3:12])=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1
Reactant: C=Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(Nc3ccc4cn[nH]c4c3)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(Nc3ccc4cn[nH]c4c3)c12
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 2-chloro-N-(1H-indazol-6-yl)-5-vinyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.11 g) in ethylacetate (5 mL) was added palladium on carbon (Pd/C) (0.1 g). The flask was then charged with H2. After 3 h, the Pd/C was filtered off, and the filtrate was concentrated to give 2-chloro-N-(1H-indazol-6-yl)-5-ethyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (84 mg).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6]([CH:8]1[CH2:10][CH:9]1[C:11]#[N:12])=[O:7].[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[CH:6]([OH:7])[CH:8]1[CH2:10][CH:9]1[C:11]#[N:12]
Reactant: N#CC1CC1C(=O)c1ccc(F)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC1CC1C(O)c1ccc(F)cc1F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
342 mg (9.03 mmol) of sodium borohydride were added to 1.70 g (8.21 mmol) of the compound from Example 123A in 35 ml of ethanol and 15 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 1 h. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 9/1) to result in 1.50 g (87% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[Cl-].[Na+].C(O[C@@H:14]1[O:26][C@H:25]([CH3:27])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=O)C.[F:28][C:29]1[C:30]([NH2:36])=[N:31][C:32](=[O:35])[NH:33][CH:34]=1>C(#N)C>[C:17]([O:16][C@@H:15]1[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:25]([CH3:27])[O:26][C@H:14]1[N:33]1[CH:34]=[C:29]([F:28])[C:30]([NH2:36])=[N:31][C:32]1=[O:35])(=[O:19])[CH3:18]
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: CC(=O)O[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A solution of sodium iodide (3.6 g) and chlorotrimethylsilane (794 ml) in dry acetonitrile (15 ml) was stirred with molecular sieves 4A (200 mg) at 0° C. for 5 minutes (colorless sodium chloride deposited during stirring). 1,2,3-Tri-O-acetyl-5-deoxy-β-D-ribofuranose (2.0 g) was added and the mixture was stirred at 0° C. for 30 min. Then, a solution of the trimethylsilylated 5-fluorocytosine, freshly prepared from 5-fluorocytosine (1.12 g), in dry acetonitrile (5 ml) was added at 0° C. and stirring was continued for 3 h at room temperature. The mixture was filtered, the filtrate was concentrated in vacuo, and the residue was partitioned between dichloromethane and saturated aq. sodium bicarbonate solution. The aqueous layer was extracted with CH2Cl2 /MeOH (10:1). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography using CH2Cl2 /MeOH (15:1) as an eluent, followed by recrystallization from isopropanol to give 1.24 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine.