Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:34])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[O:32][CH3:33])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[F:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:23]2[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[O:34])[CH:24]=2)[CH:30]=1
Reactant: COc1ccc(F)cc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(F)cc1-c1cc(NC(=O)C2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
4-[6-(5-Fluoro-2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXI) (0.39 g, 0.84 mmol) was dissolved in methanol (15 ml) and 10% Pd/C (0.2 g) was added under an atmosphere of nitrogen. The mixture was stirred at room temperature under hydrogen balloon pressure for 18 hours. The catalyst was removed from the reaction mixture by filtration through a celite bed and the filtrate was evaporated to dryness. The resulting crude product was triturated with dry diethyl ether (5 ml) and the solid was filtered off to obtain piperidine-4-carboxylic acid [6-(5-fluoro-2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #11A) (0.076 g, 27%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:10](=[O:25])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>CO.[OH-].[Pd+2].[OH-]>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH2:15][C@@:9]1([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:10](=[O:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccc(F)cc1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccc(F)cc1)N2Cc1ccccc1
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
(1R*,5S*,6R*)-8-Benzyl-1-(4-fluorophenyl)-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3-ene-2-one (Description 12; 13.88 g, 31.05 mmol) was dissolved in methanol (25 ml) and ethyl acetate (25 ml) and 10% palladium hydroxide (1.80 g) added and the mixture hydrogenated at 30 psi for 30 minutes. The mixture was filtered and concentrated in vacuo to give the title compound as a yellow oil (11.65 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=O.[CH3:18][C:19]([S:22]([NH2:24])=[O:23])([CH3:21])[CH3:20].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=[N:24][S:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23]
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Reaction time: 1 h
Yield: 97 %

Procedure:
6-Bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-one (Intermediate 26, 2.007 g, 6.75 mmol), 2-methylpropane-2-sulfinamide (1.228 g, 10.13 mmol) and titanium ethoxide (2.78 mL, 13.51 mmol) were dissolved in methyl THF (16 mL) and heated to reflux for 19 h. The reaction was left to cool down to r.t. when EtOAc (80 mL) and NaHCO3 (sat., 5 mL) were added under stirring. The mixture was let standing for 1 h. The organic phase was collected by filtration, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in heptane. The desired fractions were evaporated to give the title compound as a mixture of diastereomers in a ratio 1:1 as determined by NMR (2.63 g, 97% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.34 (s, 9H), 1.50-1.57 (m, 0.5H), 1.60-1.68 (m, 1H), 1.73 (m, 0.5H) 1.87-2.09 (m, 2H), 2.99 (d, 0.5H), 3.26 (d, 0.5H), 3.33 (d, 0.5H), 3.45-3.61 (m, 2H), 3.64 (d, 0.5H), 3.77-3.93 (m, 2H), 6.88-6.93 (m, 1H), 7.48 (dd, 1H), 7.98 (dd, 1H); MS (ES+) m/z 401.9 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.O=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)C>C(O)(=O)C>[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]2[C:4]=1[NH:10][C:13]1[CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:16][CH2:17][C:18]2=1
Reactant: NNc1ccc(F)cc1Br
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCCc2c1[nH]c1c(Br)cc(F)cc21
Yield: 29.5 %

Procedure:
To a suspension of 7.24 g of (2-bromo-4-fluorophenyl)hydrazine hydrochloric acid salt in 100 mL of acetic acid, 5.5 g of ethyl 2-(2-oxocyclohexyl)-acetate was added. The resulting mixture was heated to reflux for 1 h. Then 10 mL of ethanol was added and the reaction mixture was heated at reflux overnight. The solvent was evaporated and the residue was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, water, and brine successively. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography over silica gel (5% EtOAc/hexane) to afford 3.12 g of desired compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[N:22]4)=[CH:17][CH:16]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.[CH:29]1([CH2:35][NH2:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:35][NH:36][C:2]2[C:7]([C:8]3[CH:9]=[C:10]([O:14][C:15]4[CH:24]=[C:23]5[C:18]([CH:19]=[CH:20][CH:21]=[N:22]5)=[CH:17][CH:16]=4)[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(Cl)n1
Reactant: NCC1CCCCC1
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(NCC2CCCCC2)n1

Procedure:
According to the procedure described in Example 188, 7-[6-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yloxy]-quinoline (Example 187) (110 mg, 0.27 mmol) and cyclohexanemethylamine (43 μL, 0.33 mmol, Aldrich), after purification by silica gel chromatography (gradient, 0 to 3% MeOH/CH2Cl2) and then preparative TLC (4% MeOH/ CH2Cl2), provided the title compound as a yellow solid. MP: 151–152° C. MS (ESI, pos. ion) m/z: 480 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])[CH:2]=[CH2:3].[CH2:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC>>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])/[CH:2]=[CH:3]\[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: C=CCCCCCCCCCCCCCC
Reactant: C=CCN1C(=O)c2ccccc2C1=O
Product: CCCCCCCCCCCCCC/C=C\CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Following the allylic amide cross metathesis general procedure, 2-allylisoindoline-1,3-dione (5.50 mg, 0.0290 mmol) was treated with 1-hexadecene (63.8 mg, 0.290 mmol), 5.0 mol % of in situ-generated complex 2 (75.0 μL, 0.02 M, 1.50 i&mol; final substrate concentration=0.19 M) and allowed to stir for 1 h. The unpurified product is 85% Z (as determined by 400 MHz 1H NMR analysis). The resulting brown oil was purified by silica gel chromatography (96:2:2 hexanes:EtOAc:CH2Cl2) to afford 19g (9.80 mg, 0.0260 mmol, 87.0% yield, 85% Z isomer) as a white, crystalline solid. M.P. 56-60° C.; IR (neat): 2954(w), 2916 (s), 2849 (m), 1771 (w), 1698 (s), 1614 (w), 1464 (m), 1429 (m), 1400 (m), 1356 (w), 1335 (w), 1294 (w), 1189 (w), 1173 (w), 1155 (w), 1089 (w), 1071 (w), 1052 (w), 1024 (w), 962 (m), 930 (m); 1H NMR (400 MHz, CDCl3): 7.84 (2H, dd, J=5.4, 3.0 Hz), 7.70 (2H, dd, J=5.4, 3.0 Hz), 5.78-5.7 1 (1H, m), 5.54-5.44 (1H, m), 4.23 (2H, dd, J=6.2, 0.8 Hz), [diagnostic E isomer signal: 4.22 (1H, d, J=8 Hz)], 1.99 (2H, dd, J=13.6, 6.8 Hz), 1.43-1.19 (24H, m), 0.88 (3H, t, J=6.8 Hz); 13C NMR (100 MHz, CDCl3): 168.2, 135.6, 134.0, 132.4, 123.4, 123.3, 123.1, 77.4, 39.8, 32.3, 32.1, 29.9, 29.8, 29.8, 29.7, 29.7, 29.6, 29.6,−29.5, 29.3, 29.0,22.8, 14.3; HRMS (ESI+) [M+H]+ calcd for C25H38NO2: 384.2903, found: 384.2905.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].N1C=CC=CC=1.Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24]([NH:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])=[O:25]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)Nc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 0.6 g (2.75 mmol) of methyl 3-amino-4,7-dimethylindole-2-carboxylate, 0.22 ml (3.3 mmol) of pyridine and 15 ml of anhydrous THF was prepared. 10 ml of a solution of 0.26 ml (3.3 mmol) of methyl chloroformate in anhydrous THF was added dropwise at 0° C. over a period of 15 minutes and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into 150 ml of ice water and extracted with 30 ml of ethyl acetate three times. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solids thus obtained were recrystallized from ethyl acetate to provide 600 mg of red crystals. Yield: 79% m.p.: 184°-185° C.; 1H-NMR (300 MHz, DMSO-d6 /TMS; δppm): 8.64 (brs, 1H), 6.98 (d, 1H), 6.80 (d, 1H), 6.63 (brs, 1H), 3.92 (s, 3H), 3.79 (brs, 3H), 2.59 (s, 3H), 2.42 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:22][C:21]1[C:16]([NH:15][C:10]([C:7]2([C:5]3[O:4][N:3]=[C:2]([CH3:1])[CH:6]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:17][CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:20]=1
Reactant: Cc1cc(C2(C(=O)O)CC2)on1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2(C(=O)Nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3N)CC2)on1
Temperature: 40 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
1-(3-Methylisoxazol-5-yl)cyclopropanecarboxylic acid (40 mg, 0.24 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (86 mg, 0.24 mmol), and diisopropylethylamine (200 μL, 1.2 mmol) were combined and dissolved in N,N-dimethylformamide (1.25 mL). O-Benzotriazole-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HBTU) (109 mg, 0.287 mmol) was added and the reaction mixture was stirred at 40° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide (56 mg, 53%). MS (ES+) (M+H) 439.2; LCMS retention time 1.94 min (Method L).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1)C(OCC)=O)C.[OH-].[K+]>O.CO>[CH:11]1([CH2:5][C:4]([OH:17])=[O:3])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: CCOC(=O)C(C(=O)OCC)C1C=CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1C=CCCC1

Procedure:
100 g of 2-(2-cyclohexenyl)malonic acid diethyl ester and 52 g of potassium hydroxide in 100 ml of water/methanol=1/4 was refluxed overnight. Then the alcohol was withdrawn on a forced circulation evaporator, the residue was diluted with about 200 ml of water and then combined under ice cooling with about 70 ml of concentrated hydrochloric acid to pH 1. The mixture was repeatedly extracted with ether, the combined organic phases were washed with saturated sodium chloride solution and evaporated to dryness. The residue was heated for 4 hours to 130° C. with liberation of CO2 and thereafter distilled under vacuum, thus obtaining 55.5 g, bp1 98°-107° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[Na+].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][S:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCc1cccnc1Cl
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cc1cccnc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A chloroform (10 ml) solution of (2-chloropyridin-3-yl)methanol (204 mg, 1.42 mmol) and thionyl chloride (0.31 ml, 4.26 mmol) was stirred at 50° C. for 8.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in butanol (15 ml), followed by the addition of sodium 4-chlorobenzenesulfinate (423 mg, 2.13 mmol) and potassium acetate (418 mg, 4.26 mmol). The mixture was stirred at 70 to 80° C. for 15 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure, whereby the title compound (252 mg, 59%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O.O>[F:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cc2c(OC)cnc(Cl)c2cc1F
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(OC)cnc(F)c2cc1F
Temperature: 145 °C
Yield: 25.5 %

Procedure:
To a solution of 1-chloro-7-fluoro-4,6-dimethoxyisoquinoline (2 g, 8.28 mmol) in DMSO (5 ml) was added cesium fluoride (2.51 g, 16.55 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (475 mg, 25.5%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.69-7.67 (d, J=8 Hz, 1H), 7.53-7.51 (d, J=8 Hz, 1H), 7.45-7.44 (m, 1H), 4.05 (s, 3H), 4.03 (s, 3H); 19F NMR: δ ppm −129.58 (1 F), −79.2 (1 F); MS: MS m/z 226.0 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH:10]([OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][O:14][S:17]([CH3:16])(=[O:19])=[O:18])[CH:10]([OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CN(Cc2ccccc2)CC1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCC1CN(Cc2ccccc2)CC1O
Yield: 53.5 %

Procedure:
The known compound, 1-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine [see J. Org. Chem., 30, 740 (1965)] (110 g) was allowed to react in chloroform with methanesulfonyl chloride (60.9 g) in the presence of triethylamine to yield 1-benzyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine (81 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[F:10].C([O-])([O-])=O.[K+].[K+].[CH2:17]([Zn]CC)[CH3:18]>C1COCC1>[CH2:17]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[F:10])[CH3:18]
Reactant: OCc1cnc(Cl)c(F)c1
Reactant: CC[Zn]CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ncc(CO)cc1F
Yield: 40.3 %

Procedure:
To a solution of (6-chloro-5-fluoro-3-pyridinyl)methanol (300 mg, 1.857 mmol) (see Preparation 5(b) above), K2CO3 (770 mg, 5.57 mmol), and [1,1′-Bis(diphenylphosphino) ferrocene]dichloro-palladium(II) (136 mg, 0.186 mmol) in THF (6 ml), was added diethylzinc (3.71 ml, 3.71 mmol). The mixture was stirred under reflux for 6 h in a pressure tube. The resulting mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography using Flashmaster II, a 10 g spherical silica gel cartridge BP-SUP 20-40μ, and DCM/MeOH 98:2 mixture as eluent to give 116 mg of desired compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([CH2:16][C:17](=O)[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:16]=[C:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:8]2)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(CC(=O)c2cccnc2)c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2cc(-c3cccnc3)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a solution of tert-butyl [5-chloro-4-methoxy-2-(2-oxo-2-pyridin-3-ylethyl)phenyl]carbamate (1.28 g) in dichloromethane (17 mL) was added trifluoroacetic acid (3.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (812 mg). 1H-NMR (CDCl3) δ ppm: 3.95 (3H, s), 6.77-6.85 (1H, m), 7.14 (1H, s), 7.38 (1H, dd, J=4.8, 8.0 Hz), 7.45 (1H, s), 7.86-7.96 (1H, m), 8.36 (1H, br s), 8.53-8.60 (1H, m), 8.90-8.97 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.Cl.[OH-:21].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:10])=[O:21])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: COc1cc(C#N)ccc1-c1nc2ncncc2[nH]1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1cc(C(N)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
One gram of 8-(2'-methoxy-4'-cyano-phenyl)-purine was dissolved in 75 ml of 2N sodium hydroxide solution and refluxed for 15 minutes. Then, the mixture was acidified with hydrochloric acid, and the mixture precipitated was separated into its components by use of silica gel [eluant: methylene chloride/ethanol (7:3 to 1:1)].
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:36][CH2:35][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29])[CH3:34]
Reactant: C[C@@H](N)CO
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](C)CO)[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (2.25 g, 5.03 mmol) synthesized in Example (106c) was dissolved in methanol (50 mL), and D-alaninol (0.70 mL, 8.97 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (3.05 g, 11.02 mmol) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with ethyl acetate (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=80%-100%) to afford the desired compound (1.95 g, yield 75%) as a white solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=[O:7].[CH2:11]([N:18]1[C:23](=[O:24])[CH:22]2[CH2:25][CH2:26][CH:19]1[CH2:20][CH2:21]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[CH:22]2[CH2:25][CH2:26][CH:19]1[C:20](=[O:7])[CH2:21]2)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C2CCC(CC2)N1Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CC2CCC1N(Cc1ccccc1)C2=O
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of dimethyl sulphoxide (2.34 g) in dichloromethane (5 ml) was added to a cooled (-60° C.) solution of oxalyl chloride (1.78 g) in dichloromethane (5 ml) and after 2 minutes the mixture was treated with a solution of 2-benzyl-2-azabicyclo[2.2.2]octan-3-one (2.31 g--commercially available) in dichloromethane (10 ml), stirred at -60° C. for 30 minutes, treated with triethylamine (5.05 g), allowed to warm up to room temperature, quenched with water and extracted into dichloromethane. The dichloromethane extracts were dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica using hexane plus 50% ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give the desired compound (2.10 g, 92%) as a colourless oil which was used directly in Preparation 3 without characterisation or further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28]C(OCC4C=CC=CC=4)=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)OCc4ccccc4)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
1-{4′-[4-(Benzyloxycarbonylamino-methyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.462 g, 0.90 mmol) was treated with trifluoroacetic acid (10 mL) and the reaction was stirred at 85° C. for 1 hour. The mixture was concentrated to give the title compound.