Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:47])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH:21]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH2:20][CH:19]2[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:4].[OH-].[K+]>CO.O>[C:43]([O:42][C:40]([CH:19]1[CH2:20][CH:21]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[N:18]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:47])[NH:12][C:8]1[CH:7]=[C:6]([CH2:5][C:3]([OH:4])=[O:2])[CH:11]=[CH:10][CH:9]=1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(S(=O)(=O)c3ccc(Cl)cc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CC(S(=O)(=O)c2ccc(Cl)cc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Temperature: 20 °C
Yield: 38.8 %

Procedure:
A To a solution of 2.5 g of tert-butyl (2RS,4SR,5RS)-1-{2-[3-(3-methoxycarbonylmethylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(4-chlorophenyl)sulphonyl-2-pyrrolidinecarboxylate in 60 cm3 of methanol and 30 cm3 of distilled water is added, at a temperature in the region of 20° C., 0.2 g of potassium hydroxide. The reaction mixture is stirred for twenty hours at a temperature in the region of 20° C., and then concentrated under reduced pressure. The residue is taken up in 100 cm3 of distilled water, washed with three times 75 cm3 of diethyl ether, acidified to a pH in the region of 1 by aqueous normal hydrochloric acid and extracted with three times 75 cm3 of ethyl acetate. The extracts are combined, washed with three times 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on 80 g of silica contained in a column 3.2 cm in diameter [eluent: dichloromethane/methanol (95/5 by volume)]. The fractions containing the expected product are combined and concentrated under reduced pressure. 0.95 g of (2RS,4SR,5RS)-3-(3-{2-[2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-(4-chlorophenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)phenylacetic acid is thus obtained [Rf=0.5; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (250 MHz, (CH3)2SO with addition of a few drops of CD3COOD, at a temperature of 393 K, δ in ppm): 1.54 (s, 9H: C(CH3)3); from 2.40 to 2.60 and 2.85 (2 mts, 1H each: CH2 at 3); 3.50 (s, 2H: ArCH2COO); 3.70 and 3.97 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 4.09 (mt, 1H: H4); 4.68 (t, J=8 Hz, 1H: H2); 5.73 (d, J=3 Hz, 1H: H5); 6.86 (broad d, J=7.5 Hz, 1H: aromatic H (H4: ortho to the CH2)); from 7.00 to 7.40 (mt, 6H: aromatic H); 7.68 (broad d, J=8.5 Hz, 2H: H of the aromatic at 4 (H ortho to the Cl)); 7.82 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 7.96 (broad d, J=8.5 Hz, 2H: aromatic H at 4 (H meta to the Cl))].
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4]/[CH:5]=[CH:6]/[Cl:7].[OH-].[Na+].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>C1(C)C=CC=CC=1>[CH3:17][Si:18]([CH3:21])([CH3:20])[N:3]([CH3:2])[CH2:4]/[CH:5]=[CH:6]/[Cl:7]
Reactant: CNC/C=C/Cl
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C/C=C/Cl)[Si](C)(C)C
Temperature: 22.5 °C
Reaction time: 0.33 h

Procedure:
Into a reactor under an inert nitrogen atmosphere are introduced 80 g (0.56 mol) trans-1-methylamino-3-chloro-2-propene hydrochloride, 400 ml toluene, 160 ml 25% NaOH and the mixture is stirred for 20 minutes at 20-25° C. The organic phase is separated and the aqueous phase extracted with 100 ml toluene. To the combined organic phases are added 150 ml triethylamine (1.07 mol, 1.9 eq.) and 98 ml trimethylchlorosilane (0.77 mol, 1.4 eq.) are added dropwise at 20/25° C. over a period of 1 hour. Upon complete addition, the suspension thus obtained is stirred for 2 hours at 20°/25° C. The salts are filtered in an inert nitrogen atmosphere, washing them with 160 ml toluene; the organic solution is then concentrated to a small volume under vacuum and used as such in the subsequent step.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCC1CCNCC1)Cc1ccccc1
Reactant: Brc1ccncc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(CCC1CCN(c2ccncc2)CC1)Cc1ccccc1
Reaction time: 16 h
Yield: 56 %

Procedure:
N-Benzyl-N-methyl-2-(piperidin-4-yl)ethanamine (600 mg, 2.58 mmol, 1 eq) and 4-bromo-pyridine HBr (553 mg, 2.84 mmol, 1.1 eq) were dissolved in n-butanol (15 ml); DIPEA (2.34 ml, 12.9 mmol, 5 eq) was added, and refluxing was carried out for 16 h. After monitoring by thin-layer chromatography, the reaction mixture was concentrated and the residue was purified by column chromatography (Alox 5-7% MeOH in dichloromethane). Yield: 56% (450 mg, 1.45 mmol).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH2:17][CH2:18][C:19]([N:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][O:31][C:32]2[C:40]3[N:39]=[C:38]([O:41][CH3:42])[N:37]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[C:36]=3[CH:35]=[CH:34][CH:33]=2)[C:24]=1[Cl:50])[CH3:22])=[O:20].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:50][C:24]1[C:25]([CH2:30][O:31][C:32]2[C:40]3[N:39]=[C:38]([O:41][CH3:42])[N:37]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[C:36]=3[CH:35]=[CH:34][CH:33]=2)=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19](=[O:20])[CH2:18][NH:17][C:14](=[O:16])[CH2:13][CH2:12][C:9]1[CH:10]=[N:11][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Nc1ccc(CCC(=O)O)cn1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCc4ccc(NS(C)(=O)=O)nc4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
Compound 5 was prepared from 3-(6-(methylsulfonamido)pyridin-3-yl)propanoic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide described for compound 1. MS (APCI) 737(M+), 1H NMR (CDCl3) 2.41-2.51 (m, 2H), 2.65 (s, 3H), 2.81-2.92 (m, 2H), 3.05 (s, 3H), 3.22 (s, 3H), 3.33-3.52 (m, 1H), 3.37-3.90 (m, 1H), 5.40 (s, 2H), 5.61 (s, 2H), 6.50-6.61 (m, 1H), 6.71 (s, 1H), 7.17-7.3 (m, 4H), 7.34-7.42 (m, 1H), 7.42-7.52 (m, 1H), 7.55-7.63 (m, 2H), 7.70-7.80 (m, 1H), 7.82-7.95 (m, 1H), 8.04 (s, 1H), 8.61-8.68 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH:10]([CH3:17])[CH2:11][CH:12]=[C:13]([CH3:16])[CH2:14][CH3:15])=[CH:3][CH2:4]C(OCC)=O.[H-].C[O:20]CCO[Al+]OCCOC.[Na+].[H-].O.CCOCC>C1C=CC=CC=1>[CH3:1][C:2]([CH:10]([CH3:17])[CH2:11][CH:12]=[C:13]([CH3:16])[CH2:14][CH3:15])=[CH:3][CH2:4][OH:20]
Reactant: CCOC(=O)CC=C(C)C(C)CC=C(C)CC
Reactant: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC(C)=CCC(C)C(C)=CCO
Temperature: 40 °C
Reaction time: 2 h

Procedure:
157 g. of ethyl 3,4,7-trimethyl-2,6-nonadienecarboxylate are dissolved in 300 ml. of benzene and added dropwise while cooling with ice to a solution of 370 g. of 70% sodium bis-(methoxyethoxy)-aluminum hydride in benzene. The mixture is then stirred at 40° C. for 2 hours and subsequently worked up with water/ether as described earlier. The 3,4,7-trimethyl-2,6-nonadien-1-ol obtained boils at 79°-84° C./0.09 mmHg.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C(=O)C2C=CC=CC=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:20]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@:21]21[O:24][CH2:23][CH2:22]2.CO.C[O-].[Na+].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[C@@H:20]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@:21]32[O:24][CH2:23][CH2:22]3)=[C:2]([NH:39][CH:36]2[CH2:38][CH2:37]2)[N:10]=1
Reactant: O=C(Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@]34CCO4)c2n1)c1ccccc1
Reactant: NC1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(NC2CC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@]34CCO4)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
110 (800 mg, 1.85 mmol) in cyclopropylamine (10 mL) was stirred at room temperature for 24 h. To the solution were added MeOH (10 mL) and 5.4 M NaOMe (1.71 mL, 9.26 mmol) and the resulting mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0 to 20% MeOH in CH2Cl2) to give 6-cyclopropylamino-nucleoside 111 (500 mg, 76%) as a white solid. 1H NMR (400 MHz, CD3OD) δ: 8.02 (s, 1H), 6.21 (s, 1H), 4.53 (m, 2H), 4.43 (d, 1H, J=8.8 Hz), 3.96 (m, 1H), 3.82-3.77 (m, 2H), 2.91 (m, 1H), 2.56 (m, 1H), 2.27 (m, 1H), 0.83 (m, 2H), 0.60 (m, 2H). LCMS (ESI): 349 (M+H)+.
Reaction SMILES: [CH2:1]([O:19][C:20](=[O:61])[CH:21]([CH2:43][C:44]1[CH:49]=[C:48]([C:50]([CH2:53]C(C)(C)C)([CH3:52])[CH3:51])[C:47](O)=[C:46]([CH3:59])[C:45]=1[CH3:60])[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(C1C([OH:72])=C(C)C(C)=C(CN(C)C)C=1)(C)(C)C>>[CH2:1]([O:19][C:20](=[O:61])[CH:21]([CH:43]([OH:72])[C:44]1[CH:49]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:47]=[C:46]([CH3:59])[C:45]=1[CH3:60])[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1c(CN(C)C)cc(C(C)(C)C)c(O)c1C
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)C(Cc1cc(C(C)(C)CC(C)(C)C)c(O)c(C)c1C)C(=O)OCCCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(C(=O)OCCCCCCCCCCCCCCCCCC)C(O)c1cc(C(C)(C)C)cc(C)c1C

Procedure:
Di-n-octadecyl(5-tert.-octyl-2,3-dimethyl-4-hydroxybenzyl)malonate was made in a similar manner to that of Example 5 by substituting the intermediate of Example 2 for 6-tert.-butyl-2,3-dimethyl-4-(dimethylaminomethyl)phenol (Example 1).
Reaction SMILES: [SH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C[O-].[Na+].CO.[Si:25]([O:32][C@H:33]1[CH2:37][N:36]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:39])[C@H:35]([CH2:51]OS(C)(=O)=O)[CH2:34]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CO.C(OCC)(=O)C>[Si:25]([O:32][C@H:33]1[CH2:37][N:36]([C:38]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=2)=[O:39])[C@H:35]([CH2:51][S:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)=[O:8])[CH2:3]2)[CH2:34]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](S)C1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CS[C@H]2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
To a solution of (3S)-3-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.36 g) in methanol (5 ml) was added 28% sodium methoxide-methanol solution (0.97 ml) under ice-cooling and the mixture was stirred at the same temperature for 10 minutes. This solution was added to a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-methanesulfonyloxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2 g) in methanol (20 ml). The mixture was stirred at ambient temperature for 3 hours and then at 50°-60° C. for 5 hours. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (50 ml). The solution was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2 -[{(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio}methyl]pyrrolidine (1.95 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.[OH-].[Na+]>C(O)(=O)C>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:17]1
Reactant: c1csc(C2CNCCN2)c1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)N1CCNC(c2cccs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution of ethyl chloroformate (20.4 g, 0.19 mol) in acetic acid (150 ml) is added dropwise with stirring to a solution of 2-(2-thienyl)-piperazine (31.6 g, 0.19 mol; Preparation 1) in acetic acid (150 ml) at 65° C. under an atmosphere of dry nitrogen. After 1 h, the solution is allowed to cool to room temperature, and stirring is maintained for an additional 16 h. The reaction mixture is added to chilled 10N NaOH (750 ml) and ice is added to control the exothermic reaction. The mixture is extracted with methylene chloride (4×300 ml), the organic solution is dried(potassium carbonate), and the solvent removed under reduced pressure to give the carbamate (30.0 g) as a light brown oil. This material is dissolved in methanol (250 ml), and the solution added to a solution of maleic acid (18.6 g; 1 eq) in methanol (250 ml). The mixture is treated with charcoal and the solvent removed under reduced pressure to give an oil which crystallizes on trituration with ethyl acetate. The maleate salt melts at 165°-166° C.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C@@H:11]([O:13][CH2:14][C@H:15]([O:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][N:37]=3)[N:34]=[CH:35][C:28]=12)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)=[O:17])[CH3:12])(C(C)(C)C)(C)C>C1COCC1>[Cl:42][C:41]1[C:36]([N:33]2[C:29]3=[N:30][CH:31]=[N:32][C:27]([O:26][C@@H:15]([CH2:14][O:13][C@@H:11]([CH3:12])[CH2:10][OH:9])[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=4)=[O:17])=[C:28]3[CH:35]=[N:34]2)=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(F)cn1
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@H](CO)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(F)cn1
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
HCl (4M in Dioxane) (0.530 mL, 2.12 mmol) was added to (2S)-3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide (Intermediate AO3) (638 mg, 1.06 mmol) in THF (5 mL) at room temperature. The resulting solution was stirred for 20 minutes. The reaction mixture was evaporated and the residue partitioned between EtOAc (25 mL) and sat NaHCO3 (10 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by preparative chiral-HPLC on a Merck 50 mm 20 μm Chiralpak AS column, eluting isocratically with 30% EtOH in isohexane (modified with Et3N) as eluent to afford the product (397 mg, 77%). 1H NMR (400 MHz, CDCl3) δ1.16 (d, 3H), 2.73 (s, 1H), 3.51-3.68 (m, 2H), 3.69-3.78 (m, 1H), 4.12-4.28 (m, 2H), 6.06 (t, 1H), 7.42-7.50 (m, 2H), 7.99-8.03 (m, 1H), 8.13 (d, 1H), 8.21-8.26 (m, 1H), 8.47 (s, 1H), 8.60-8.65 (m, 2H), 9.09 (s, 1H); m/z (ESI+) (M+H)+=488.42; HPLC tR=1.75 min
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[S:54][S:53][C:52](=[S:55])[CH:51]=2)=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C:44]3[CH:45]=[CH:46][C:47]([C:50]4[S:54][S:53][C:52](=[S:55])[CH:51]=4)=[CH:48][CH:49]=3)=[O:16])[CH:12]=2)[CH:7]=1
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)C(=O)Oc3ccc(-c4cc(=S)ss4)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To the solution of 1 (naproxen, 595 mg, 2.58 mmol) in 20 mL of dimethylformamide, hydroxybenzotriazole (388 mg, 2.87 mmol) and DCC (593 mg, 2.87 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 5-p-hydroxyphenyl-1,2-dithiole-3-thione (2; 650 mg, 2.87 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product was loaded on a silica gel open column and eluted with dichloromethane, from which 4-(5-thioxo-5H-1,2-dithiol-3-yl)phenyl 2-(2-methoxynaphthalen-6-yl)propanoate (3) was obtained (406 mg, 36% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16].C([O-])(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[C:18]([N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(C)[N+](=O)[O-])c(OC)c1OC
Yield: 85.4 %

Procedure:
A mixture of 3.9 g of 2,3,4-trimethoxybenzaldehyde, 3.7 g of nitroethane, 2.5 g of Amberlite IR-45 acetate and 200 ml of toluene is refluxed for 20 hours while removing the resultant water. After the reaction is completed, the reaction mixture is filtered, and the filtrate is evaporated to remove solvent. The residue thus obtained is recrystallized from a mixture of isopropyl ether and hexane. 4.3 g of 1-(2,3,4-trimethoxyphenyl)-2-nitropropene are thereby obtained as yellow cubes. M.p. 57°-58° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:10][N:11]([CH2:13][CH2:14]O)[CH:12]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=N[N:32]([CH2:40]CO)[C:33]=2C2C=CN=CC=2)=CC=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:10][N:11]([CH2:13][CH2:14][N:32]([CH3:40])[CH3:33])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCCn1ncc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: OCCn1cc(-c2ccc(F)cc2)c(-c2ccncc2)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)CCn1cc(-c2ccc(F)cc2)c(-c2ccncc2)n1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
4-(4-Fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol (or 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol) prepared as set forth in Example 11 (1.36 g) was dissolved in 30 mL pyridine and cooled to 0° C., whereupon methanesulfonyl chloride (0.6 mL) was added. After stirring at 0° C. for 12 hours, about 20 g of ice was added, and the mixture was extracted with toluene (300 ml). After evaporation, the residue was used directly without further purification. 0.7 g of the above obtained compound was dissolved in methanol (25 mL), and dimethylamine/THF solution (4M, 2 mL) was added. The reaction mixture was refluxed for 12 hours, then evaporated to dryness. The residue was purified by chromatography (methanol/dichloromethane 1:10). A mixture (0.59 g) of 4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine and 4-(4-fluorophenyl)-N,N-dimethyl-5-(4-pyridinyl)-1H-pyrazole-1ethanamine were obtained. 1H NMR: consistent with the assigned structure. Mass spectrum, m/z: 311 (M+1). Anal. calc'd C18H19N4F.0.55H2O: C, 67.50; H, 6.33; N, 17.49. Found: C, 67.21; H, 6.46; N, 17.14.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[OH-].[K+]>[Pd].CO>[O:14]1[CH2:13][CH2:12][N:11]([C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[CH:2][N:3]=2)[CH2:16][CH2:15]1
Reactant: Brc1cn2ccnc2c(N2CCOCC2)n1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1cn2ccnc2c(N2CCOCC2)n1
Reaction time: 12 h
Yield: 94.1 %

Procedure:
200 mg of palladium on charcoal (10% palladium) are added to a solution containing 0.5 g (1.77 mmol) of 6-bromo-8-morpholinoimidazo[1,2-a]pyrazine for 120 ml of anhydrous methanol and 2 g of potassium hydroxide. The mixture is hydrogenated at atmospheric pressure for 12 hours. The solution is filtered, concentrated and taken up with water; after extraction with dichloromethane and evaporation of the solvent, 0.34 g (92%) of 8-morpholinoimidazo[1,2-a]pyrazine (m.p. 127° C.) is obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.C(OP([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:43]/[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.2 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), ethyl diethylphosphonoacetate (0.25 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) under ice-cooling. The mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give ethyl (2E)-3-(3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoate as colorless crystals (0.48 g, yield 83%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 142-143° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH2:25][OH:26])[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][C:17]([N:22]([CH3:24])[CH3:23])=[CH:16][CH:15]=3)C1C=CC=CC=1.[C:27](O)(=O)C>CO.[Pd]>[CH3:23][N:22]([CH3:24])[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:25][O:26][CH3:27])[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:21][C:20]2=1
Reactant: CC(=O)O
Reactant: CN(C)c1ccc2c(c1)c1cc(OCc3ccccc3)ccc1n2CO
Agent: [Pd]
Solvent: CO
Product: COCn1c2ccc(O)cc2c2cc(N(C)C)ccc21
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of [3-(benzyloxy)-6-(dimethylamino)-9H-carbazol-9-yl]methanol 7 (120 mg), Pd/C (100 mg) and acetic acid (cat. amount) in MeOH (15 mL) was hydrogenated at room temperature for 4 hrs. It was filtered through a short Celite pad. The filtrate was concentrated in vacuo to give the desired product (94 mg, 100%). NMR (acetone-d6, 400 MHz) δ: 7.38-7.50 (m, 4H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 6.97 (dd, J=8.4, 2.4 Hz, 1H), 5.62 (s, 2H), 3.20 (s, 3H), 2.94 (s, 6H). MS: m/z=271 (M+H+)+.