Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>N1CCCCC1.C(O)C>[O:16]=[C:10]1[C:9](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1[nH]cc2c1CCOC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (50 mg, 0.24 mmol), 4-oxo-2,4,6,7-tetrahydropyrano[3,4-c]pyrrole-1-carbaldehyde (39.2 mg, 0.24 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 48 hours. The precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give 15 mg (17%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].Cl[CH2:13][CH:14]1[CH2:16][O:15]1>CN(C=O)C>[O:15]1[CH2:16][CH:14]1[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: ClCC1CO1
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC2CO2)c1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (2.0 g, 16.38 mmol) in DMF (25 mL) was added NaH (60%, 982.6 mg, 24.57 mmol) at 0° C. in portions. The mixture was stirred at this temperature for 30 minutes before a solution of 2-(chloromethyl)oxirane (2.27 g, 24.57 mmol) in DMF (5 mL) was slowly added into the reaction mixture which was then allowed to reach room temperature slowly and stirred for 16 h. The solvent was removed by concentration and the residue dissolved in ethyl acetate and washed with water. T the separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was then purified by column chromatography. (2.2 g, yield 75%) MS (ESI+) e/z: 179.1 [M+1]+.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][N:12]1[C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=O)C1C=CC=CC=1>CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]([N:12]2[CH2:13][CH:14]([O:16][CH3:17])[CH2:15][NH:11]2)=[O:27])=[CH:21][CH:22]=1
Reactant: COC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Solvent: CO
Product: COC1CNN(C(=O)Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-methoxy-pyrazolidine-1-carboxylic acid benzyl ester, 46, (12.0 g, 32.2 mmol) is dissolved in methyl alcohol (300 mL). The flask is flushed with nitrogen and charged with 10% palladium on carbon (1.2 g). The reaction mixture is stirred vigorously at room temperature under 1 atmosphere of hydrogen gas for 3 hours. The flask is flushed with nitrogen and the reaction mixture filtered through a pad of Celite, rinsing with ethyl acetate (100 mL). The filtrate is concentrated in vacuo to afford 7.67 g of the desired product as a viscous, clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH3:11][O-:12].[Na+]>CN(C=O)C.CO>[CH3:11][O:12][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: C[O-]
Agent: Brc1ccc2sccc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2sccc2c1
Temperature: 145 °C
Yield: 64 %

Procedure:
To a solution of 1.8 g of 5-bromobenzo[b]thiophene in 2 mL of anhydrous DMF and 1 mL of MeOH was added 686 mg of NaOMe. The mixture was heated to 110° C. (bath temp), and 121 mg of CuBr was added. The brown suspension was heated at 110° C. for ˜2 h and at ˜145° C. for 30 min. The reaction was quenched with ca. 50 mL of H2O and the mixture was extracted with 100 mL of Et2O (2×), EtOAc (1×), and CH2Cl2 (1×). The organic layers were washed with 50 mL of brine, combined, dried over MgSO4, concentrated, and flash chromatographed with 3% Et2O-hexanes to afford 894.5 mg (64%) of the title compound along with 168.8 mg (9.4%) of 5-bromobenzo[b]-thiophene.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C@H:17]1[CH2:26][OH:27])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>CCCCCC>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C@H:17]1[CH2:26][O:27][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCOC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1

Procedure:
A 1.6M solution (4.2 ml) of butyllithium in hexane was added to a solution of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (2.00 g) at -30°-20° C. with stirring in a stream of nitrogen and the mixture was stirred at the same temperature for 30 minutes. Ethyl bromoacetate (2.4 ml) was added to the mixture at -30°~-20° C. and the solution was stirred at 10-15° C. for 3 hours. The solution was poured into 0.1N hydrochloric acid (50 ml) extracted with ethyl acetate (50 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with chloroform to give (2S,4R)-1-benzyloxycarbonyl-2-(ethoxycarbonylmethyl)oxymethyl-4-methanesulfonyloxypyrrolidine (1.87 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:18])=[C:10]([F:17])[CH:11]=2)[N:6]=1)[CH3:4].C(C1C(C)=C([O:32][C:33]([CH:35]2[CH2:37][CH2:36]2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.[CH2:40]([C:42]1[C:51]([CH3:52])=[C:50]([O:53][C:54]([CH:56]2[CH2:58][CH2:57]2)=[O:55])[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([F:60])[C:48]=2F)[N:43]=1)[CH3:41]>O1CCCC1.O>[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:33]([CH:35]2[CH2:37][CH2:36]2)=[O:32])[C:12]2[C:7](=[CH:8][C:9]([Cl:18])=[C:10]([F:17])[CH:11]=2)[N:6]=1)[CH3:4].[CH2:40]([C:42]1[C:51]([CH3:52])=[C:50]([O:53][C:54]([CH:56]2[CH2:58][CH2:57]2)=[O:55])[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([F:60])[C:48]=2[Cl:18])[N:43]=1)[CH3:41]
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Reactant: CCc1nc2cc(Cl)c(F)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2cc(Cl)c(F)cc2c(OC(=O)C2CC2)c1C
Product: CCc1nc2ccc(F)c(Cl)c2c(OC(=O)C2CC2)c1C
Reaction time: 1 h

Procedure:
In 5 ml of tetrahydrofuran was suspended 90.3 mg of 60% sodium hydride. Separately, 400 mg of the mixture of 2-ethyl-3-methyl-4-hydroxy-6-fluoro-7-chloroquinoline with 2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline (starting material 1) prepared as described in Example 6 was suspended in 10 ml of tetrahydrofuran, and this suspension was added dropwise to the above suspension under ice cooling. The mixture was stirred for one hr. Cyclopropanecarbonyl chloride (starting material 2) (240 mg) was then added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (200 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 245.4 mg of 2-ethyl-3-methyl-4-cyclopropanecarbonyloxy-6-fluoro-7-chloroquinoline (compound 20) and 129.2 mg of 2-ethyl-3-methyl-4-cyclopropanecarbonyloxy-5-chloro-6-fluoroquinoline (compound 21). 1H-NMR data are shown in Table 3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N:10]1([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]([C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(CBr)cc1
Reactant: N#Cc1ccc(Nn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
4-hydroxybenzylbromide (15.6 g, 84.3 mmol, prepared following Wissner A. et al., J. Med. Chem. 1992, 35, 1650) was added to a mixture of 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (10.00 g, 54.30 mmol) and K2CO3 (8.20 g, 59.70 mmol) in dry THF (150 ml) at room temperature. The mixture was then stirred at room temperature for 2 h and after poured into water and extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (16.00 g as solid). Crystallization from ethyl acetate with ethanol yielded the expected product (6.50 g, 41%, mp: 180° C.)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])[CH:3]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Product: CSc1nc(Cl)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1

Procedure:
Method 24 was followed using 6-chloro-2-(methylthio)pyrimidin-4-amine (1.0 equiv.), BOC2O (2.0 equiv.), and DMAP (cat.) to afford 6-chloro-N,N-di-BOC-2-(methylthio)pyrimidin-4-amine in >95%. LCMS (m/z): 376.1 (MH+); LC Rt=4.9 min.
Reaction SMILES: Br.[C:2]([NH:5][CH2:6][C:7](=[NH:21])[S:8][CH2:9][C:10]([C:12]1[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=1)=O)(=[O:4])[CH3:3]>C(O)C>[C:2]([NH:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[N:21]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)NCC(=N)SCC(=O)c1csc(N=C(N)N)n1
Agent: Br
Solvent: CCO
Product: CC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Yield: 74.4 %

Procedure:
A suspension of 4-[(2-acetylamino-1-iminoethylthio)acetyl]-2-(diaminomethyleneamino)thiazole hydrobromide (11.4 g) in ethanol (100 ml) was refluxed for 2.5 hours. The resulting precipitate was collected by filtration and suspended in water (150 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from water afforded 4-(2-acetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (6.36 g).
Reaction SMILES: [CH2:1](I)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][S:8](=[S:11])([O-:10])=[O:9].[Na+].[Al].[I-]>O.CN(C=O)C>[CH3:7][S:8](=[S:11])([O:10][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:9]
Reactant: CS(=O)([O-])=S
Reactant: CC(C)(C)CI
Agent: [Al]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COS(C)(=O)=S
Temperature: 90 °C

Procedure:
The reaction mixture of neopentyl iodide (3.054 g, 0.0154 mol), sodium methanethiosulfonate (2.272 g, 0.0170 mol) and dry DMF (4 mL) was heated at 90° C. for 90 hr. The reaction flask was wrapped with aluminum foil to avoid direct sunlight to the reaction mixture, since the iodide was sensitive to sunlight. At the end of the heating, the reaction mixture was red-brown in color. At room temperature, water (15 mL) was added and the mixture was extracted with ether (3×30 mL). The combined ether extracts were washed twice with brine, dried, concentrated and the residue was subjected to column chromatography on silica gel with EtOAc-hexanes (1:2) to afford a colorless oil which slowly solidified (1.2395 g, 44%). The product was recrystallized from 95% EtOH. mp: 28.5-29.0° C.; IR (CH2Cl2 cast): 3021 (m), 2956 (m), 2868 (m), 1467 (m), 1433 (m), 1321 (st), 1310 (st), 1125 (st), 951 (m), 757 (m) and 724 cm−1 (m); 1H NMR (200 MHz, CDCl3): δ 3.32 (s, 3H, CH3SO2S), 3.13 (s, 2H, SCH2C), 1.05 (s, 9H, CMe3); 13C NMR (50 MHz, CDCl3): δ 50.23, 50.09, 32.14, 28.79, MS (El): 182 (M+), 57 (base peak, CMe3+).
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Cl:5])/[Cl:3].[F:10][C:11]([F:25])([F:24])[C:12]1[CH:13]=[C:14]([NH:22][NH2:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>C(O)C>[Cl:3][C:2]1[CH:1]=[N:23][N:22]([C:14]2[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=[C:12]([C:11]([F:10])([F:24])[F:25])[CH:13]=2)[C:6](=[O:7])[C:4]=1[Cl:5]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: NNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCO
Product: O=c1c(Cl)c(Cl)cnn1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 28.1 grams (0.166 mol.) of mucochloric acid dissolved in 120 milliliters of ethanol were added 37 grams (0.151 mol.) of 3,5-bis-(trifluoromethyl)phenylhydrazine. The mixture was stirred for about one hour, and then the ethanol was removed from the solution by evaporation under reduced pressure. Eighty milliliters of glacial acetic acid and 80 milliliters of acetic anhydride were added to the residue in one portion. The mixture was heated to reflux for four hours, and then cooled and the solvent was removed by evaporation under reduced pressure. Recrystallization of the residue from ethanol produced 51.7 grams of 4,5-dichloro-1-[3,5-bis(trifluoromethyl)-phenyl]-1,6-dihydro-6-oxopyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([F:22])[CH:13]=2)[CH2:9][C:10]#[N:11])=[N:6][CH:7]=1.[NH2:30][OH:31]>CCO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[C:14]([F:22])[CH:13]=2)([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:9]/[C:10](/[NH2:11])=[N:30]/[OH:31])=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)N[C@](CC#N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: NO
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)[S@](=O)N[C@](C/C(N)=N/O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 70 °C

Procedure:
(S)-N-((R)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl) phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.030 g, 0.067 mmol) was dissolved in EtOH (1 mL) in a 2 dram vial. NH2OH (1 mL, 50% solution in water) was added and the sealed screw capped vial was heated to 70° C. for 3 h. The cooled solution was diluted with DCM (10 mL) and transferred to a separation funnel. The organic layer was separated and the aqueous portion was washed further with DCM (5 mL). The combined organic portions were dried, decanted and concentrated yielding (R,Z)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-N′-hydroxy-3-((S)-2-methylpropan-2-ylsulfinamido)propanamidine as a tan oil (0.032 mg, quantitative yield). LCMS: 1.50 min [M+1] 481.1 (2 min gradient, MeOH/H2O 0.1% TFA). The crude oil was dissolved in dry DCM (1 mL), cooled to 0° C. and TEA (25pL) was added followed by acetic anhydride (11 μL). The reaction mixture was allowed to reach room temperature with stirring over 18 h. The solution was diluted with DCM (10 mL), transferred to a separation funnel, washed with sat. NaCl (10 mL), dried, decanted and concentrated yielding a white solid. LCMS: 1.87 min [M+1] 523.1 (2 min gradient, MeOH/H2O 0.1% TFA). The intermediate N-((R,Z)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(hydroxyimino)-3-((S)-2-methylpropan-2-ylsulfinamido)propyl)acetamide was redissolved in anhydrous THF (2 mL) and anhydrous Cs2CO3 was added (0.063 g). The solution was heated to 105° C. for 3 h whereupon the solvent evaporated leaving a pale brown solid which was dissolved in MeOH (1 mL) and purified by prep HPLC (YMC ODSA30×100 mm, 0-100% over 10 min, MeOH/H2O/0.1% TFA) yielding (S)-N-((R)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide as a colorless oil (0.015 g, 44% yield over 3 steps). LCMS: 1.96 min [M+1] 505.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.80 min (4 min gradient, MeOH/H2O 0.2% PPA) Purity 96%.
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[CH2:8][C@H:7]([CH3:9])[CH2:6][NH:5]1.[C:10](#[N:13])[CH:11]=[CH2:12]>>[OH:2][CH2:3][C@H:4]1[CH2:8][C@H:7]([CH3:9])[CH2:6][N:5]1[CH2:12][CH2:11][C:10]#[N:13]
Reactant: C=CC#N
Reactant: C[C@@H]1CN[C@@H](CO)C1
Agent: Cl
Product: C[C@H]1C[C@H](CO)N(CCC#N)C1

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514-522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[C:5]([N:7]([CH3:14])[C@@H:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=O)=[O:6].Cl.[CH3:20][O:21][CH2:22][CH:23]1[CH2:26][NH:25][CH2:24]1.[B-]C#N.[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[C:5]([N:7]([C@@H:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][N:25]1[CH2:26][CH:23]([CH2:22][O:21][CH3:20])[CH2:24]1)[CH3:14])=[O:6]
Reactant: COCC1CNC1
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)c1ccc(F)c(F)c1
Agent: Cl
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Product: COCC1CN(C[C@H](C(C)C)N(C)C(=O)c2ccc(F)c(F)c2)C1
Yield: 20.7 %

Procedure:
(S)-3,4-Difluoro-N-methyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.3) (0.25 g, 0.98 mmol) in MeOH (1.5 mL) was added to 3-(methoxymethyl)azetidine hydrochloride (0.202 g, 1.47 mmol) and TEA (0.679 mL, 4.90 mmol) in MeOH (1.5 mL). Sodium cyanotrihydroborate (0.103 mL, 1.96 mmol) was added and the resultant mixture was stirred at rt over night. The solvent was removed and the residue diluted with DCM. The organic phase was washed with LiOH (aq., 3 mL, 1M), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak AD 5 μm 20×250 mm column and Heptan/EtOH/TEA 80/20/0.1, as mobile phase to give the title compound (69 mg, 21%). Enantiomeric excess: 99.9%. Mixture of rotamers: (400 MHz, CD3OD) δ 0.77-0.86, 0.93, 1.06, 1.70-1.90, 2.57-2.88, 2.94-3.09, 3.22-3.36, 3.40-3.57, 4.18-4.36, 7.23-7.52, 7.63-7.74. Total no of protons: 26. HRMS (M+H)+: calculated 341.2040. found 341.2051.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21](I)[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(I)c(N)nc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(C#C[Si](C)(C)C)c(N)nc1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5'-deoxy-2',3'-di-O-acetyl-5-iodocytidine (1.35 g, 3.087 mmol) in CH2Cl2 (15 ml) there was added N,N-diisopropylethylamine (0.537 ml, 3.087 mmol), Cul (58 mg, 0.309 mmol), Pd(PPh3)2Cl2 (60 mg, 0.085 mmol), and trimethylsilyl-acetylene (0.523 ml, 3.704 mmol) at room temperature under Ar. The reaction mixture was then heated to 60° C. After stirring for 2 hours, the mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the residue dissolved in EtOAc (200 ml), washed with 2% aq. EDTA.2Na, water and brine, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography on SiO2 (f2.2×25 cm, eluent: EtOAc) to give 2',3'-di-O-acetyl-5'-deoxy-5-[2-(trimethylsilyl)ethynyl]cytidine as a pale yellow solid. (1.20 g, 95% y.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])C.[N+:35]([C:38]1[CH:39]=[C:40]([C:47](Cl)=[O:48])[CH:41]=[C:42]([CH:46]=1)[C:43](Cl)=[O:44])([O-:37])=[O:36]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C:47](=[O:48])[C:40]1[CH:39]=[C:38]([N+:35]([O-:37])=[O:36])[CH:46]=[C:42]([C:43]([N:30]([CH2:31][CH2:32][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:33][CH2:34][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[O:44])[CH:41]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(NCCNCCNC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=C(NCCN(CCNC(=O)OCc1ccccc1)C(=O)c1cc(C(=O)N(CCNC(=O)OCc2ccccc2)CCNC(=O)OCc2ccccc2)cc([N+](=O)[O-])c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.86 g (40 mmol) of the bis[2-(benzyloxycarbonylamino)-ethyl]-amine described in Example 1a and 20.24 g (200 mmol) of triethylamine are dissolved in dimethylformamide and mixed with 4.96 g (20 mmol) of 5-nitro-isophthalic acid dichloride (J. Chem. Soc. 1957, 1172-1175) and stirred overnight at room temperature. The solution is concentrated by evaporation in a vacuum and the residue is chromatographed with ethyl acetate on silica gel.
Reaction SMILES: [Br:1]Br.C1(P([C:16]2[CH:21]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([CH2:28][CH2:29][CH2:30]Br)[CH:24]=1>>[Br:1][CH2:21][CH2:16][CH2:30][CH2:29][CH2:28][C:25]1[CH:24]=[C:23]([CH3:22])[O:27][N:26]=1
Reactant: BrBr
Reactant: Cc1cc(CCCBr)no1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(CCCCCBr)no1
Yield: 77 %

Procedure:
3-(5-Bromopentyl)-5-methylisoxazole [XXVII; R9 =CH3, Hal=Br] was prepared by reacting 3-(5-hydroxpentyl)-5-methylisoxazole with bromine and triphenylphosphine according to the procedure of part (f) above, and was obtained in 77% yield as an oil, b.p. 140°-150° C.(0.05 mm).