Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)[CH3:2].[Cl:11][S:12](O)(=[O:14])=[O:13]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[S:12]([Cl:11])(=[O:14])=[O:13])[CH3:2]
Reactant: CCOc1ccc(C)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOc1ccc(C)cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
A solution of 6.8 g (50 mmol) of 4-ethoxytoluene in 20 mL of dichloromethane was added to a solution of 10 mL (150 mmol) of chlorosulfonic acid in 10 mL of dichloromethane at 0° C. with cooling and stirring. The mixture was stirred 1 hour at 0° C. and was then warmed to ambient temperature and stirred another hour. The resulting tan solution was poured into 200 mL of ice water and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The residual 7.9 g (68 percent of theory) of light tan solid melting at 59-61° C. was the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=3[F:22])[C@@H:10]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:9]2)=[CH:4][CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][C@H:11]([C:14]4[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=4[F:22])[C@@H:10]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:9]3)=[CH:4][CH:3]=2)=[CH:37][CH:36]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(N[C@H]1CN(c2ccc(Cl)nn2)CC[C@@H]1c1cc(F)c(F)cc1F)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CN(c2ccc(-c3ccc(F)cc3)nn2)CC[C@@H]1c1cc(F)c(F)cc1F)OCc1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 58 mg (0.12 mmol) of the product of Step A and 27 mg (0.19 mmol) of 4-fluorophenylboronic acid in 4 mL of 1:1 ethanol/toluene was added 0.60 mL (1.2 mmol) 2N aqueous sodium carbonate solution followed by 200 mg (0.245 mmol) of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II). The resulting solution was stirred under nitrogen at 100° C. for 24 h, then allowed to cool to ambient temperature. The reaction mixture was then filtered through a pad of Celite and the filter cake washed with ethyl acetate and methanol. The combined filtrate and washings were concentrated and the crude material was purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 10 to 90% acetonitrile/water with 0.1% TFA) to afford the title compound as a yellow oil. LC/MS 537.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:33]([O-:35])=[O:34])[CH:13]([OH:32])[CH2:14][CH2:15][C:16]([C:30]#[N:31])([CH:27]([CH3:29])[CH3:28])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:36](OC(=O)C)(=[O:38])[CH3:37]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:36]([O:32][CH:13]([CH2:14][CH2:15][C:16]([C:30]#[N:31])([CH:27]([CH3:29])[CH3:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH:12]([N+:33]([O-:35])=[O:34])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:38])[CH3:37]
Reactant: COc1ccc(CC(C(O)CCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CC(C(CCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)OC(C)=O)[N+](=O)[O-])cc1OC

Procedure:
A mixture of 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol (8, 75 g, 0.154 mol), 4-dimethylaminopyridine ("DMAP," 1.5 g, Aldrich), and acetic anhydride (23 mL) in CH2Cl2 (700 mL) was heated at reflux for 40 minutes to yield 1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane (9), which was used in the next step without isolation.
Reaction SMILES: C(C1C=CC(C)=CC=1)(C)(C)C.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(O)(=O)C>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([CH:34]=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(C(C)(C)C)cc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C=O)cc1

Procedure:
In 3 mL of acetic acid was dissolved 300 mg of p-t-butyltoluene to give a solution, and the solution was further combined with 150 mg of the catalyst A and 33 mg of N-hydroxyphthalimide, followed by stirring at 100° C. in an oxygen atmosphere for 6 hours. The reaction mixture was analyzed through gas chromatography to find that p-t-butylbenzoic acid and p-t-butylbenzaldehyde were obtained in yields of 66.5% and 3.8%, respectively, with a conversion from p-t-butyltoluene of 82.2%. The catalyst A was separated from the reaction mixture through filtration, washed with ethyl acetate two times, dried at room temperature (25° C.) under reduced pressure, and recovered as a catalyst A1. The cobalt ion concentration in the reaction mixture, from which the catalyst A1 had been separated through filtration, was measured through atomic absorption spectrometry and was found to be 24 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=[O:23])[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Si:26]([CH:29](O)[CH3:30])([CH3:28])[CH3:27].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([O:24][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[O:23])[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(O)[Si](C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(Benzyloxy)carbonyl]-3-[(tert-butoxycarbonyl)amino]-L-alanine (1000.0 mg, 2.96 mmol) [Rane, F. Dinanath et al.; Tetrahedron Lett.; EN; 34; 20; 1993; 3201-3204] is dissolved in dichloromethane (20 ml), and trimethylsilylethanol (4.2 ml, 3.5 g, 29.55 mmol, 10 eq.), DCC (1.22 g, 5.91 mmol, 2 eq.) and DMAP (361.1 mg, 2.96 mmol, 1 eq.) are successively added to the solution at −20° C. The reaction is warmed to RT and stirred at this temperature overnight and brought to complete conversion. For the workup, the mixture is concentrated, and the residue is taken up in diethyl ether and subsequently extracted twice with water and once with a sat. aq. sodium chloride solution. The etheric phase is dried over sodium sulfate, the desiccant is removed by filtration through silica gel, and most of the solvent is removed from the filtrate on a rotary evaporator. If a precipitate separates out during the concentration, this can be removed again where appropriate through silica gel. The residue obtained is then fine purified by chromatography (method 31) and 1.1 g (86.4% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C:3]1([CH3:18])[CH3:17].CO>C(=O)=O>[NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C:3]1([CH3:18])[CH3:17]
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1N
Agent: O=C=O
Solvent: CO
Product: CC1(C)CN(C(=O)OCc2ccccc2)C[C@H]1N
Yield: 42 %

Procedure:
(+/−)-Benzyl 4-amino-3,3-dimethylpyrrolidine-1-carboxylate (Intermediate 11, 0.48 g was resolved via chiral SFC chromatography under the following conditions: column OD-H (0.46×25 cm), 20% MeOH with 0.1% DEA in CO2, 3 mL/min, 40° C., 140 bars. The second fraction was concentrated to afford the title compound (S)-benzyl 4-amino-3,3-dimethylpyrrolidine-1-carboxylate (0.2 g, 42% yield).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl>[CH:21]([C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH2:22]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 2-iodoadenosine (1.585 g, 4.03 mmol) and bis(acetonitrile)palladium chloride (0.053 g, 0.20 mmol) in DMF (20 ml) was added vinyltributyltin (1.24 ml, 4.23 mmol), and the mixture stirred at 100° C. for 1 h. The reaction mixture was cooled and filtered. The solvent was evaporated and the residue was purified through silica gel with chloroform and 10% methanol/chloroform to give 1.099 g (92%) of 2-vinyladenosine: 1H NMR (Me2SO-d6) δ3.66 (m, 2H), 3.98 (m, 1H), 4.16 (m, 1H), 4.65 (m, 1H), 5.18 (d, 1H), 5.38-5.62 (m, 3H), 5.89 (d, 1H), 6.41 (dd, 1H), 6.59 (dd, 1H), 7.27 (br.s, 2H), 8.32 (s, 1H); UV (EtOH) λmax 293 nm, 271 nm, 265 nm.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:19]1([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=[N:20]1>>[N:19]1([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:27])[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-n1cccn1
Product: O=C(c1ccccc1-n1cccn1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-pyrazol-1-yl-benzoic acid. MS (ESI) mass calcd. for C24H22N6O, 410.48; m/z found, 411.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].C[O-].[Na+].Cl>CO.C(OCC)(=O)C.CO>[OH:6][CH2:5][CH2:4][CH2:3][O:7][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CBr
Reactant: OCCCO
Agent: C[O-]
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)COCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To sodium hydride (9.6 g, 0.40 mol) was dropwise added trimethylene glycol (144.5 ml, 2.0 mol) at 0° C. The mixture was stirred at room temperature for 3 hours. Thereto was dropwise added, at 0° C., methyl bromoacetate (44.4 ml, 0.40 mol). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was subjected to silica gel column chromatography (developing solvent: ethyl acetate / methanol=19/1) to remove sodium bromide. After concentration, the concentrate was dissolved in sodium methoxide (2.16 g, 0.04 mol) and methanol (200 ml ). The mixture was stirred at room temperature for 10 minutes, then neutralized with 6N hydrochloric acid, and concentrated. The concentrate was purified by silica gel column chromatography (developing solvent=ethyl acetate / methanol=19/1) to obtain methyl 3-hydroxypropyloxyacetate (36.25 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([CH2:14][O:15][Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[CH2:26]([O:33][C@@H:34]1[C@@H:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:39]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:38]([CH2:57][O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:37][CH:35]1O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C@H:35]2[C@H:34]([O:33][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:40]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:39]([O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C@@H:38]([CH2:57][O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[O:37]2)=[CH:3][C:4]=1[CH2:14][OH:15]
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COc1c(CO[Si](C(C)C)(C(C)C)C(C)C)cc(Br)c2ccccc12
Product: COc1c(CO)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2ccccc12
Yield: 84.9 %

Procedure:
With similar method described in Step 3 of Example 92, ((4-bromo-1-methoxynaphthalen-2-yl)methoxy)-triisopropylsilane (compound 68b, 21.3 g, 50.3 mmol) and 2,3,4,6-tetra-O-benzyl-D-glucopyranose (compound 2, 22.6 g, 41.9 mmol) were converted to title compound (25.3 g, 85%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Methoxy-4-methylphenyl)-1,3-benzoxazole (1.0 g, 4.1 mmol), carbon tetrachloride (18 mL), benzoyl peroxide (66 mg, 0.3 mmol) and N-bromosuccinimide (970 mg, 5.4 mmol) was heated to reflux conditions under argon and placed under a UV light. After 1 h, no starting material was observed by TLC. After cooling mixture to rt, filtered, washing with dichoromethane. After concentrating filtrate in vacuo, the resulting colorless solid was purified by flash chromatography, using a gradient elution of 1:4 EtOAc:hexanes to EtOAc. This afforded the desired intermediate, 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole, as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:21][NH:22][C@@H:23]([CH3:35])[CH2:24][C:25]2[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CCO.[Pd]>[Si:37]([O:36][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][C@@H:23]([CH3:35])[CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:28]=[CH:29][CH:30]=1)([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:39])[CH3:38]
Reactant: C[C@@H](Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of (3-{(S)-2-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)ethylamino]propyl}phenyl)acetic acid (˜1.3 mmol) in EtOH (8 mL) was purged with dry nitrogen and then palladium on carbon (10%, ˜50% water, Degussa type, 300 mg) was added. This mixture was purged with hydrogen and then stirred under an atmosphere of hydrogen (balloon) for 1 h. The mixture was then filtered through Celite and the filter bed washed with MeOH (20 mL) and EtOAc (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography (0-20% MeOH in DCM) to give the title compound (300 mg, 40% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[N:6][C:5]=1[Cl:12].S(Cl)(C)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:19]=[N+:20]=[N-:21])=[N:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1ccc(CO)nc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(CN=[N+]=[N-])nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a cold (0° C.) solution of 2-chloro-6-hydroxymethyl-nicotinic acid methyl ester (4.98 g, 24.8 mmol) in dichloromethane (161 mL) was added mesyl chloride (2.5 mL, 29.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was taken up in dimethylformamide (62 mL) and sodium azide (4.03 g, 62 mmol) added. After stirring at room temperature for 16 hours, the reaction mixture was cooled to 0° C., quenched with water (ca. 50 mL), and extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was subjected to flash chromatography (Si-PPC, gradient 0% to 50%, ethyl acetate in hexane) to afford the title compound as a pale yellow oil (4.76 g, 85%). LCMS (method B): RT=3.22 min, [M+H]+=227.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[CH2:23]([O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([Cl:31])=[O:30])[CH2:24][CH3:25]>C(=O)=O.C(Cl)Cl>[ClH:31].[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[O:26][CH2:23][CH2:24][CH3:25])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: CCCOc1ccccc1C(=O)Cl
Agent: Cl
Agent: O=C=O
Agent: [Ba+2]
Solvent: O
Solvent: ClCCl
Product: CCCOc1ccccc1C(=O)NC1CN2CCC1CC2

Procedure:
To a solution of 3.82 g (0.0192 mole) of 3-amino quinuclidine dihydrochloride in about 25 ml of carbon dioxide-free water was added 8 g (0.025 mole) of barium hydroxide octahydrate. The mixture was warmed for 5 minutes and then dried to a powder on a rotary evaporator. While protecting from contamination with carbon dioxide in the atmosphere, the powder was extracted in sequence with hot benzene and a 1:1 mixture of benzene-methylene chloride solution. The combined extracts were dried over magnesium sulfate and the mixture filtered. To the filtrate with agitation was added dropwise a solution of 3.4 g (0.0171 mole) of 2-propoxybenzoyl chloride in 50 ml of methylene chloride. The mixture was warmed on a steam bath to evaporate about 75% of the methylene chloride. Ligroin (60-110) was added and the mixture solidified. The solid was recrystallized from anhydrous ethyl alcohol to give 3.9 g (62.0%), m.p. 210°-211° C.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O-])=O>[Pd].C(O)C>[N:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][NH:6][C:5]3[C:4]([NH2:1])=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccccc1NCC1CCN(c2ccncc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of 2-nitro-N-[1-(4-pyridyl)piperidin-4-yl-methyl]aniline (235 mg, 0.75 mmol) and 10% palladium on carbon (200 mg) in ethanol (4 mL) was placed under an atmosphere of hydrogen gas. After 1 h, the mixture was filtered through diatomaceous earth. The filtrate was concentrated yielding 212 mg of the title compound, which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[NH:15][C:16](=[O:18])[CH3:17])[NH:11][N:10]=[C:9]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:5])C.Cl>C(O)C.[OH-].[Na+]>[C:16]([NH:15][C:14]1[CH:13]=[C:12]2[C:8]([C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[N:10][NH:11]2)=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])(=[O:18])[CH3:17]
Reactant: CCOC(=O)c1cc2c(-c3cccc(F)c3)n[nH]c2cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C(=O)O
Temperature: 25 °C

Procedure:
A total of 160 mg of-6-acetylamino-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid ethyl ester obtained in Production Example II-7-e was dissolved in 3 ml of ethanol and 1 ml of 5 N aqueous sodium hydroxide solution, and the solution was stirred at 50° C. for 2 hours. After cooling to room temperature, 1 N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated, to give 155 mg of the title compound as pale yellow crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29]([CH:31]4[CH2:32][CH2:33]4)=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:8][CH:9]=1)([CH3:15])[CH3:14]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Product: CC(C)c1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-isopropylphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 433.2 (M+H)+.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=[O:8].BrCCOC1C=CC(OC)=C(OC)C=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=[O:8]
Reactant: COc1ccc(OCCOC(=O)C2CCCCN2C(=O)OC(C)(C)C)cc1OC
Agent: COc1ccc(OCCBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(OCCOC(=O)C2CCCCN2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butyl 2-(2-(3,4-dimethoxyphenoxy)ethyl) piperidine-1,2-dicarboxylate (456 mg, 1.1 mmol), prepared by reacting 1-tert-butyl-piperidine-1,2-dicarboxylate and 4-(2-bromoethoxy)-1,2-dimethoxybenzene in acetone in the presence of potassium carbonate, was dissolved in 10 ml 20% TFA in DCM and was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and used for next step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][N:18]1[C:25]2[N:21]([N:22]=[CH:23][CH:24]=2)[CH:20]=[CH:19]1)=[O:6])[CH:2]=[CH2:3].[C:26]([O-:29])(=[S:28])[CH3:27].[K+].C(OCC)(=O)C.[Cl-].[Na+]>C(#N)C>[C:26]([S:28][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][N:18]2[C:25]3[N:21]([N:22]=[CH:23][CH:24]=3)[CH:20]=[CH:19]2)[CH2:9]1)(=[O:29])[CH3:27]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccn2nccc12
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cn1ccn2nccc12
Yield: 81 %

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-2-(imidazo [1,2-b]pyrazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (3.04 g) and potassium thioacetate (1.41 g) in acetonitrile (60 ml) was stirred under refluxing for 4 hours. To the reaction mixture were added ethyl acetate (100 ml) and aqueous sodium chloride (50 ml) with stirring and then the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (5:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl -2-(imidazo[1,2-b]pyrazol-1-yl)methylpyrrolidine (2.33 g).