Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1([C:7]([O:9]CC)=[O:8])[CH2:6][CH2:5]1.C[S-].[Na+].CS(OCC1(C(OCC)=O)CC1)(=O)=O>CN(C)C=O.O>[CH3:1][S:2][CH2:3][C:4]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1(CSC)CC1
Agent: CCOC(=O)C1(COS(C)(=O)=O)CC1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCC1(C(=O)O)CC1
Temperature: 23 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
Preparation of ethyl 1-(methylthiomethyl)cyclopropanecarboxylate—Sodium methanethiolate (700 mg, 9.9 mmol, 2.0 equiv) was added to a stirred solution of ethyl 1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate (1.1 g, 4.9 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) at 23° C. The resulting brown suspension was stirred at 23° C. for 18 h. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4×100 mL). The combined organic layers were dried (MgSO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a brown oil (860 mg, 99%): 1H NMR (300 MHz, CDCl3) δ 4.14 (q, J=7 Hz, 2H), 2.83 (s, 2H), 2.16 (s, 3H), 1.31 (dd, J=7, 4 Hz, 2H), 1.25 (t, J=7 Hz, 3H), 0.89 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].[BrH:31]>C1(C)C=CC=CC=1>[Br:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Reactant: Br
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCBr)cn2)CC1

Procedure:
To a solution of 419 mg of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in 20 ml of toluene was added 0.60 ml of a 47% hydrobromic acid and the mixture was heated under reflux for one hour. The reaction solution was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was chromatographed over a silica gel column to afford 400 mg of the title compound.
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4]1.O1CCN([C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=2)CC1.C(N(CC)CC)C>ClCCl>[O:15]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:2]([C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)=[N:14]1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@H]1CC[C@@H](c2noc3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
To a solution of cis/trans-ethyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (1.20 g, 5.13 mmol) and 1-morpholinocyclohexene (1.72 g, 10.3 mmol) in dichloromethane (50 ml) was added triethylamine (0.72 ml, 5.1 mmol) at 0-5° C. The cooling bath was removed 30 minutes after completed addition. After stirring for 4 h the solvent was evaporated. The residue was redissolved in 6 M aqueous hydrochloric acid solution (50 ml), and the mixture was and heated at reflux for 1 h. After cooling to room temperature the reaction mixture was partitioned between crushed ice (100 g) and ethyl acetate (50 ml). The layers were separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave cis-4-(4,5,6,7-tetrahydro-benzo[d]isoxazol-3-yl)-cyclohexanecarboxylic acid (0.40 g, 31%) as white solid (MS m/e: 248 ([M−H]−)) and trans-4-(4,5,6,7-tetrahydro-benzo[d]isoxazol-3-yl)-cyclohexanecarboxylic acid (0.09 g, 7%) as white solid (MS m/e: 248 ([M−H]−)).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:12]1[N:17]=[C:16]([Cl:18])[CH:15]=[C:14]([O:19][CH3:20])[N:13]=1.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22]>C1COCC1>[CH2:25]([O:24][C:21](=[O:23])[CH2:22][C:12]1[N:17]=[C:16]([Cl:18])[CH:15]=[C:14]([O:19][CH3:20])[N:13]=1)[CH3:26]
Reactant: CCOC(C)=O
Reactant: COc1cc(Cl)nc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nc(Cl)cc(OC)n1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
91.4 ml of 1M lithium bis(trimethylsilyl)amide (THF) are added dropwise to a solution of 7.4 g of 2,4-dichloro-6-methoxypyrimidine and 4.5 ml of ethyl acetate in 100 ml of anhydrous THF cooled to −75° C. in a dry ice/acetone bath. The reaction medium is stirred at −75° C. for one hour. The cooling bath is removed so as to allow the temperature to rise to 22° C. The reaction medium is stirred at 22° C. for one hour. 100 ml of water and 400 ml of ethyl acetate are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure so as to give 9.5 g of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid ethyl ester in the form of an orange oil, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:20]C(=O)C1C=CC=CC=1)=[N:9]2.C1CCN2C(=NCCC2)CC1>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH2:20])=[N:9]2
Reactant: CO[C@H]1CC[C@]2(c3ccccc3F)N=C(NC(=O)c3ccccc3)SC[C@@H]2C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CO[C@H]1CC[C@]2(c3ccccc3F)N=C(N)SC[C@@H]2C1
Temperature: 25 °C

Procedure:
(±)-N-[(4aR*,6S*,8aS*)-8a-(2-Fluorophenyl)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in Preparation Example 59-(8) (3.11 g) was dissolved in methanol (100 mL). Then, DBU (2.34 mL, specific gravity: 1.018 g/cm3) was added, and the mixture was stirred with heating under reflux for two hours and 15 minutes. Then, the reaction solution was stirred at 64° C. for 13 hours and 30 minutes. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (1.96 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].[F:16][C:17]1[CH:18]=[CH:19][C:20](I)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23].Cl>C1(C)C=CC=CC=1.O.CCOC(C)=O.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:15][C:20]1[CH:19]=[CH:18][C:17]([F:16])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under N2 in a round-bottomed flask fitted with a reflux condenser and magnetic stirrer were placed 6.37 g (19.55 mmol) of cesium carbonate and 3.2 g (19.55 mmol) of 3,4-dichlorophenol (both from Aldrich Chem. Co., Milwaukee, Wis.) in 60 mL of anhydrous toluene. After stirring the mixture for 5 min., 89 mg (0.24 mmol) of copper (II) trifluoromethansulfonate (copper triflate) and 0.26 g (9.78 mmol) of 5-fluoro-2-iodobenzoic acid (prepared according to the method in Collection of Czechoslovakian Chemical Communications, 1975, vol. 40, p728) were added and the mixture was heated to reflux overnight. Progress of the reaction was monitored using thin layer chromatography (tlc), eluting with CHCl3:CH3OH:AcOH (9:1:0.5). After allowing the reaction to cool to room temperature, the mixture was diluted with water and EtOAc; the aqueous layer was acidified with 6 N HCl and re-extracted with additional EtOAc. The organic layers were combined, washed with H2O and saturated NaCl and dried over MgSO4. Removal of the solvent in vacuo gave a dark brown colored oil, 2.6 g, as a mixture of title product and unreacted 5-fluoro-2-iodobenzoic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-:44][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1COCC1>[CH3:11][Si:10]([C:9]#[C:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:44])[CH:7]=1)([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccnc(N)c1
Temperature: 60 °C
Yield: 94.3 %

Procedure:
2-Chloro-4-trimethylsilanylethynyl-pyridine (9.3 g, 44 mmol), tris(dibenzylideneacetone)dipalladium(0) (8.1 g, 8.9 mmol) and 2-(dicyclohexylphosphino)biphenyl (8.1 g, 23 mmol) are added into the de-gased dry THF (60 mL). Then 1.0 M LiHMDS (155 mL, 155 mmol) is added. The reaction mixture is heated at 60° C. for 16 hrs before it is cooled down to room temperature and saturated NH4Cl aqueous solution (100 mL) is added along with water (100 mL). The mixture is extracted with EtOAc (2×200 mL) and the organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using 33% EtOAc in hexanes affords 7.9 g of the desired product.
Reaction SMILES: ClC1C=CC2OC(NC[C@@H]3[C@H](C)CCCN3C(OCC=C)=O)=NC=2C=1.[NH2:26][CH2:27][C@@H:28]1[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]1[C:35]([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[N:44]1[N:48]=[C:47]([CH3:49])[CH:46]=[N:45]1)=[O:36].Cl[C:51]1[O:52][C:53]2[CH:59]=[CH:58][C:57]([F:60])=[CH:56][C:54]=2[N:55]=1>>[F:60][C:57]1[CH:58]=[CH:59][C:53]2[O:52][C:51]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:35]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[N:44]3[N:48]=[C:47]([CH3:49])[CH:46]=[N:45]3)=[O:36])=[N:55][C:54]=2[CH:56]=1
Reactant: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc2oc(Cl)nc2c1
Agent: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(F)ccc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-fluorobenzo[d]oxazole. ESI-MS (m/z): 463 [M+1]+.
Reaction SMILES: [OH:1][C@@H:2]1[C@:10]2([CH3:11])[C@H:5]([CH2:6][C@@H:7]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)=[CH:37][CH:36]=3)[C@@H:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=3)[CH2:9]2)[CH2:4][CH2:3]1.[C:48](OC(=O)C)(=[O:50])[CH3:49].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:48]([O:1][C@@H:2]1[C@:10]2([CH3:11])[C@H:5]([CH2:6][C@@H:7]([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)=[CH:39][CH:40]=3)[C@@H:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:14][CH:13]=3)[CH2:9]2)[CH2:4][CH2:3]1)(=[O:50])[CH3:49]
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCSCCCC(F)(F)C(F)(F)F)cc3)[C@H](c3ccc(OC4CCCCO4)cc3)C[C@@H]1CC[C@@H]2O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H]2C[C@@H](c3ccc(OC4CCCCO4)cc3)[C@@H](c3ccc(OCCCCCSCCCC(F)(F)C(F)(F)F)cc3)C[C@@]21C
Yield: 86 %

Procedure:
The solution of 1.43 g (2.51 mmol) of the compound that is presented in Example 2c is reacted analogously to Example 1, and after working-up, a mixture that consists of the title compound is isolated, and (1S,3S,4R,6S,9S)-9-hydroxy-4-[4-(tetrahydropyran-2-yloxy)phenyl]-1-methyl-3-[4-(10,10,11,11,11-pentafluoro-6-thia-undecyloxy)phenyl]-bicyclo[4.3.0]nonane, which is dissolved in 25 ml of anhydrous pyridine, is mixed with 3 ml of acetic anhydride and a spatula tip full of 4-dimethylaminopyridine, and it is stirred for 2 hours at 23° C. It is poured into saturated sodium bicarbonate solution, extracted several times with dichloromethane, the combined organic extracts are washed with saturated sodium chloride solution-and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on about 400 ml of fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 1.57 g (2.16 mmol, 86%) of the title compound is isolated as a colorless foam.
Reaction SMILES: [NH+]1C=CC=CC=1.F[C:8]1[C:9](=[O:22])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([CH2:18][CH:19]=C)=[C:13]([OH:21])[CH:12]=2.C1C(=O)N(I)C(=O)C1>N1C=CC=CC=1>[CH:18]1[C:14]2=[CH:15][C:16]3[CH:17]=[CH:8][C:9](=[O:22])[O:10][C:11]=3[CH:12]=[C:13]2[O:21][CH:19]=1
Reactant: C=CCc1cc2cc(F)c(=O)oc2cc1O
Agent: O=C1CCC(=O)N1I
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: O=c1ccc2cc3ccoc3cc2o1

Procedure:
Similarly the fluorine atom was introduced during the formation of the pyrone moiety through a Pechmann reaction with ethyl 2-fluoro-acetoacetate as the fluorine carrier. Thus, 3-fluoro-4,8-dimethyl-6-allyl-7-hydroxycoumarin (3, R═F, R′=H) was prepared in 3 steps from 2-methylresorcinol (36% overall yield). Then, ring closure was achieved in two steps in a 66% overall yield following the same route employed with the 3-cyano derivatives giving a mixture 89:11 of (5, R═F, T═Br) and its pyrano isomer (6, R═F) in favor of the expected psoralen. Finally, this 89:11 mixture was reacted with refluxing anhydrous pyridine affording pure target compound (5, R═F, T═pyridinium, Br salt) in 73% yield. Alternatively, the 3-fluoro-6-allyl-7-hydroxycoumarin (3, R═F, R′=H) could be ring closed with NIS in 91% yield to give 3-fluoro-4,8-dimethyl-4′,5′-dihydro-5′-iodomethylpsoralen (5, R═F, T═I). The resulting 3-fluoro-4,8-dimethyl-4′,5′-dihydro-5′-iodomethylpsoralen was reacted with pyridine to form the pyridinium iodine salt (5, R═F, T═pyridinium iodide). Ring closure of 3-fluoro-6-allyl-7-hydroxycoumarin (3, R═F, R′=H) with mercury acetate in ethanol gave the 5′-acetomercurimethyl-4,8-dimethyl-4′,5′-dihydropsoralen (5, R═F, T═HgOAc) in 92% yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:34][C:33](=[O:35])[N:32]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]4[N:47]=[CH:46][N:45]=[C:44]([C:48]([OH:50])=O)[CH:43]=4)[CH2:38][CH2:37]3)[CH2:31][CH2:30][C:29]=2[CH:51]=1.Cl.Cl.[CH3:54][C:55]1([CH3:64])[CH2:60][NH:59][CH2:58][C:57]2[CH:61]=[N:62][NH:63][C:56]1=2.C(N(CC)CC)C>CN(C=O)C>[CH3:54][C:55]1([CH3:64])[CH2:60][N:59]([C:48]([C:44]2[N:45]=[CH:46][N:47]=[C:42]([N:39]3[CH2:40][CH2:41][CH:36]([N:32]4[CH2:31][CH2:30][C:29]5[CH:51]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=5[NH:34][C:33]4=[O:35])[CH2:37][CH2:38]3)[CH:43]=2)=[O:50])[CH2:58][C:57]2[CH:61]=[N:62][NH:63][C:56]1=2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: CC1(C)CNCc2cn[nH]c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5cn[nH]c5C(C)(C)C4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
105 mg (0.28 mmol) TBTU were added to 100 mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 80.0 mg (0.36 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 1.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC, the product fractions were combined and then lyophilised.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10]C=[N:8][C:7]=1C(OC)=O.[ClH:15]>>[ClH:15].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:7][NH2:8])=[O:10]
Reactant: COC(=O)c1ncoc1-c1cccs1
Agent: Cl
Product: NCC(=O)c1cccs1
Yield: 93 %

Procedure:
53.9 g of 5-(2-thienyl)-4-methoxycarbonyloxazole and 200 ml of 6N hydrochloric acid are treated in the same manner as described in Preparation 1-(2). 42.5 g of N-[(2-thienylcarbonyl)methyl]amine hydrochloride are thereby obtained. Yield: 93%
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9](F)[CH:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1>CO>[NH2:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[CH:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1
Reactant: Nc1nc(F)cc(OC(F)(F)F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC(F)(F)F)nc(N)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At -5° to 0° C. and over a period of 15 minutes, 2.7 g (0.015 mol) of 30% strength sodium methylate was added, while stirring, to 2.95 g (0.015 mol) of 2-amino-4-fluoro-6-trifluoromethoxypyrimidine in 50 ml of methanol. The reaction mixture was stirred for 1 hour at 0° C., heated to 25° C., evaporated down under reduced pressure, stirred with water and extracted twice with methylene chloride. Drying and evaporation under reduced pressure gave 3.1 g (98% of theory) of the title compound; nD25 =1.4770.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=2[O:27]1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:31]2[CH:30]=[CH:29][C:28]3[O:27][CH2:26][O:34][C:33]=3[CH:32]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc3c(c2)OCO3)C1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 44.7 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (200 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium carbonate, and 150 mg of (3,4-methylenedioxy)benzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 100 mg of 2,2-dimethyl-4-(3,4-methylenedioxyphenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.60 (s, 6H), 3.07 (s, 3H), 5.99 (s, 2H), 6.74 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.94 (d, J=8.7 Hz, 2H). IR (cm−1): 1697, 1503, 1404, 1245, 1148, 959, 770.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]([C:16]2[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO[CH2:26][CH2:27]OC>[Br-].C[P+](C)(C)C.C(O)C>[CH:26]([C:17]1[CH:18]=[CH:19][CH:22]=[CH:23][C:16]=1[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[CH2:27]
Reactant: COCCOC
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: C[P+](C)(C)C
Agent: [Br-]
Agent: [H-]
Solvent: CCO
Product: C=Cc1ccccc1N(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
4.6 g of sodium hydride and 700 mL of 1, 2-dimethoxyethane were placed in a three-neck flask, and while stirring at room temperature, 130.8 g of tetramethylphosphonium bromide was added. After adding one drop of anhydrous ethanol, the mixture was stirred for 4 hours at 70° C. Then 100 g of 4-(N, N-diphenylamino) benzaldehyde was added; the mixture was hold at 70° C. for 5 hours. The solution was filtered, and an ether extract of the precipitate and the filtrate were washed with water. Next, the ether solution was dried over calcium chloride, the ether was removed, and the crude product was obtained. This was recrystallized from ethanol, and a needle-form, lemon- yellow vinyltriphenylamine was obtained. The yield was 83.4 g (84.0%). Synthesis of 4-[2 (triethoxysilyl) ethyl] triphenylamine 15 40 mL of toluene, 9.9 g (60 mmol) of triethoxysilane, and 0.018 mmol of a tris (tetramethyldivinyldisiloxane) platinum (0) complex in a toluene solution were placed in a three-neck flask, and while stirring under room temperature, 20 mL of a toluene solution of 8.2 g of 4-vinyltriphenylamine was added. Upon completion of the addition, the mixture was stirred for 3 hours at 70° C., then the. solvent was removed under reduced pressure. As a result, a lemon-yellow oily substance of 4-[2-(triethoxysilyl) ethyl] triphenylamine was obtained. The amount obtained was 12.1 g (91.7%).
Reaction SMILES: [Li].[N:2]1([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11]3[CH2:29][CH2:30][CH2:31][C:10]=3[N:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>O1CCCC1>[N:2]1([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4([CH2:26][OH:27])[CH2:22][CH2:23][CH2:24][CH2:25]4)=[CH:19][CH:20]=3)[C:11]3[CH2:29][CH2:30][CH2:31][C:10]=3[N:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: O=C(O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCCC1
Agent: [Li]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCCC1
Reaction time: 10 h
Yield: 38.2 %

Procedure:
Lithium aluminumhydride (2M solution in tetrahydrofuran, 1.0 mL) was added drop-wise to a solution of 1-[4-(2-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclopentanecarboxylic acid (0.3 g, 0.73 mmol) prepared using a procedure as described in example 22; in anhydrous tetrahydrofuran (10 mL) at 0° C. to 5° C. After addition, the reaction mixture was warmed to a temperature in the range of 15° C. to 40° C. and stirring continued for an additional 10 hours. The reaction was quenched by addition of aqueous sodium hydroxide. The precipitated solid was filtered and washed with ethyl acetate. The combined filtrates were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel) to afford the title compound as a white solid (0.11 g, 39% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][NH:9]C(OC(C)(C)C)=O>O>[NH2:9][N:8]1[CH2:7][CH2:6][O:5][CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]1=[O:2]
Reactant: COC(=O)C(OCCNNC(=O)OC(C)(C)C)c1ccccc1
Solvent: O
Product: NN1CCOC(c2ccccc2)C1=O
Yield: 79.3 %

Procedure:
tert-Butyl 2-(2-(2-methoxy-2-oxo-1-phenylethoxy)ethyl)hydrazinecarboxylate (390 mg, 1.2 mmol) in water (85 mL) was heated to 95° C. for 12 h. The reaction mixture was extracted with dichloromethane, the organic layers were combined, dried over Na2SO4 and the solvent was evaporated to give the title compound as light yellow oil (183 mg, 79%).