Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[O:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-chloro-benzyl)-piperidin-1-yl]-oxo-acetic acid and 6-amino-3H-benzoxazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 215° C. (isopropanol)
Reaction SMILES: C[C@@H](O)[C@H](O)/C(/C)=[CH:5]/[CH2:6][CH:7](/[CH:9]=[C:10]1/[CH2:11][C@@:12]([OH:20])(C)[C@H]2N(C/1)CCC2)C.C1C=C[C:27]([CH2:30][O:31]CCC#N)=[CH:26]C=1.C(#N)C=C.C(O)C1C=CC=CC=1.[AlH](CC(C)C)CC(C)C>>[CH2:12]([O:20][CH2:26][CH2:27][CH:30]=[O:31])[C:11]1[CH:5]=[CH:6][CH:7]=[CH:9][CH:10]=1
Reactant: N#CCCOCc1ccccc1
Reactant: C/C(=C\CC(C)/C=C1\CN2CCC[C@H]2[C@@](C)(O)C1)[C@@H](O)[C@@H](C)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: OCc1ccccc1
Solvent: C=CC#N
Product: O=CCCOCc1ccccc1

Procedure:
To generate indolizidine alcohol and aldehyde intermediates useful in the synthesis of pumiliotoxin B, it is necessary to assemble a chiral silylalkyne from esters of (S)-5-(benzyloxy)-1-trimethyl-silyl-1-pentyn-3-ol. This involves the reduction of 3-(benzyloxy)propanitrile, the latter reagent being prepared from acrylonitrile and benzyl alcohol as described by Gaiffe and Launay in Academy of Science, Serial C, Pages 1379-1380 (1968), with i-Bu2AlH to give 3-benzyloxy propanal which is condensed with ethynyllithium, prepared as described by Midland in the Journal of Organic Chemistry, Volume 40, Page 2250 (1975), to yield the racemic propargylic alcohol in about 50% yield following distillation. Reaction of the propargylic alcohol with R-(+)-2-methylbenzylamine gives the corresponding diastereomeric carbamates that upon chromatographic separation and carbamate cleavage with Cl3SiH as described by Pirkle in the Journal of Organic Chemistry, Volume 42, Page 2781 (1971) yields the (S)-alcohol and (R)-alcohol derivatives in yields of about 20%.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)=[CH:54][CH:53]=[N:52]1>CN(C=O)C>[CH3:50][N:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)=[CH:54][CH:53]=[N:52]1
Reactant: Cn1nccc1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccnn4C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 77% yield: LCMS (ESI) m/z 376 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:20][C:21](=[O:40])[NH:22][C@@H:23]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8][CH2:9][C:10](ON1C(=O)CCC1=O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:42][C@@H:43]([CH2:47][CH2:48][CH2:49][CH2:50][N:51]([CH2:66][C:67]1[N:68]([CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:69]=[CH:70][N:71]=1)[CH2:52][C:53]1[N:54]([CH2:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH:55]=[CH:56][N:57]=1)[C:44]([OH:46])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[C:61]([O:60][C:59](=[O:65])[CH2:58][N:54]1[CH:55]=[CH:56][N:57]=[C:53]1[CH2:52][N:51]([CH2:66][C:67]1[N:68]([CH2:72][C:73](=[O:74])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH:69]=[CH:70][N:71]=1)[CH2:50][CH2:49][CH2:48][CH2:47][C@H:43]([NH:42][C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[NH:20][C:21](=[O:40])[NH:22][C@H:23]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:31][CH2:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:44]([OH:46])=[O:45])([CH3:62])([CH3:64])[CH3:63]
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)N[C@@H](CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 85.6 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-5-(2,5-dioxopyrrolidin-1-yloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate (138 mg, 0.236 mmol), (S)-2-amino-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (127 mg, 0.237 mmol) and DIPEA (0.50 mL) in DMF (1.0 mL) was stirred at rt for overnight. The Solvent was removed under reduced pressure to give a residue, which was purified by biotage eluting with 1% to 50% MeOH in DCM to afford (2S,7S,11S)-2-(4-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-16,16-dimethyl-4,9,14-trioxo-15-oxa-3,8,10-triazaheptadecan-1-oic acid (203 mg, 86%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.40 (brs, 1H), 6.99 (s, 2H), 6.79 (s, 2H), 6.12 (brs, 1H), 5.62 (brs, 1H), 4.67-4.28 (m, 7H), 3.68 (d, J=14.0 Hz, 2H), 3.62 (d, J=14.0 Hz, 2H), 2.62-2.53 (m, 2H), 2.34-2.02 (m, 8H), 1.83-1.42 (m, 51H); MS (ESI), 503.5 (M/2+H)+.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28](O)=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.[OH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH:53]([NH:56]C(=O)OC(C)(C)C)[CH2:52][CH2:51]1>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:47][CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][CH:53]([NH2:56])[CH2:54][CH2:55]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: c1ccc2[nH]ccc2c1
Product: NC1CCN(CCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is tert-butyl 1-(2-hydroxyethyl)piperidin-4-ylcarbamate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.92 (s, 2 H), 8.37 (s, 1 H), 8.08 (d, J=1.6 Hz, 2 H), 7.41-7.30 (m, 4 H), 4.39 (t, J=4.6 Hz, 2 H), 3.21-3.11 (m, 2 H), 2.98-2.85 (m, 1 H), 2.75 (t, J=4.6 Hz, 2 H), 2.37-2.25 (m, 2 H), 2.06-1.96 (m, 2 H), 1.78-1.65 (m, 2 H); MS (ESI) m/z 465.1 (M−H)−; MS (ESI) m/z 467.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[CH3:19][S:20]([CH2:23][CH2:24][CH2:25]OS(C)(=O)=O)(=[O:22])=[O:21]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:25][CH2:24][CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)CCCOS(C)(=O)=O
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCCS(C)(=O)=O)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
Step B To a solution of 3-methoxy-4-nitrophenol (0.5 g, 3 mmol) prepared in Example 132 Step A in anhydrous DMF (25 mL) were added K2CO3 (0.8 g, 5.9 mmol) and methanesulfonic acid 3-methanesulfonyl-propyl ester (0.7 g, 3.2 mmol) sequentially. The reaction mixture was heated at 70° C. for 4 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 2-methoxy-4-(3-(methylsulfonyl)propoxy)-1-nitrobenzene as a off white solid (0.58 g, 68%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:35])(=[O:34])[C:15]=2[CH:36]=1)=[O:10].CO>O>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([N:25]([C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:34])(=[O:35])[C:15]=2[CH:36]=1)=[O:10]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Reactant: O=C(Cl)C1CC1
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCN3CCCC3)C(=O)C3CC3)cc(Cl)c1O2
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (0.44 mL, 4.8 mmol) was added to a solution of Example 72k (0.3 g, 0.64 mmol) and the reaction mixture was stirred at 55° C. for 2 h. It was treated with methanol (1 mL), water and extracted with chloroform. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.280 g, (81.63%); 1H NMR (DMSO-d6): δ 0.71 (bs, 2H, CH2), 0.88 (bs, 2H, CH2), 1.87 (bs, 2H, CH2), 2.01 (bs, 2H, CH2), 2.70 (s, 3H, CH3), 3.00 (bs, 2H, CH2), 3.18 (bs, 2H, CH2), 3.57 (bs, 2H, CH2), 3.70 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.04 (bs, 2H, CH2), 5.38 (s, 2H, CH2), 7.78 (s, 1H, Ar), 7.98 (s, 1H, Ar), 8.19 (s, 1H, Ar). 8.22 (s, 1H, Ar); MS: m/e (CI+) 533 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C(C1C=CC=CC=1)CCC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCc1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 832 mg (5.52 mmol) of 2-cyclopropyl-6-methylphenol were added normal butylbenzene (2.76 g) and 333 mg (5.65 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 308 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 61%) and 2.9 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: COc1cccc(CBr)c1
Product: COc1ccc(CN(Cc2cccc(OC)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and 3-methoxybenzyl bromide. MS (M−H, 440.50); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.58 (s, 3H), 3.68 (s, 3H), 4.24 (s, 2H), 4.25 (s, 2H), 6.50 (s, 1H), 6.64 (d, J=4 Hz, 1H), 6.73 (m, 1H), 6.77 (d, J=8 Hz, 2H), 7.00 (d, J=8 Hz, 2H), 7.12 (t, J=8 Hz, 1H), 7.94 (d, J=8 Hz, 2H), 8.09 (d, J=8 Hz, 2H), 13.49 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[S:6].S(=O)(=O)(O)O.[CH3:22]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH3:22])=[S:6]
Reactant: Cc1cc(C(O)=S)ccc1-c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=S)c1ccc(-c2ccccc2)c(C)c1

Procedure:
A mixture was 85 g of 3-methyl-4-phenylthiobenzoic acid, 20 ml of concentrated sulfuric acid, and 1.2 liters of methanol was refluxed for 4 hours while stirring. After reaction, the reaction mixture was concentrated in vacuo, and 1.5 liters of ethyl acetate was added to the residue, and the mixture was washed with saturated brine (400 ml×3), and dried with anhydrous sodium sulfate, concentrated in vacuo, and methyl 3-methyl-4-phenylthiobenzoate was obtained (80.33 g).
Reaction SMILES: [OH:1][C:2]([CH3:17])([CH3:16])[CH:3]([NH:8][C:9](=[O:15])OC(C)(C)C)[C:4](=[O:7])[NH:5][CH3:6].FC(F)(F)C(O)=O.[CH:25]1([C:28]2[C:29]([O:37][C@@H:38]([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:30][C:31](C(O)=O)=[N:32][CH:33]=2)[CH2:27][CH2:26]1>ClCCl>[CH:25]1([C:28]2[C:29]([O:37][C@@H:38]([CH3:43])[C:39]([F:42])([F:40])[F:41])=[CH:30][C:31]([C:9]([NH:8][CH:3]([C:2]([OH:1])([CH3:16])[CH3:17])[C:4]([NH:5][CH3:6])=[O:7])=[O:15])=[N:32][CH:33]=2)[CH2:27][CH2:26]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: CNC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C(NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2CC2)cn1)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[2-hydroxy-2-methyl-1-(methylcarbamoyl)propyl]carbamate (example 236a, 760 mg, 1.94 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (3.00 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated down to dryness and the crude residue was dissolved in toluene. Volatiles were removed in vacuo to afford a white solid which was dried in HV overnight to yield the crude amine (680 mg) as a trifluroacetate salt which was used without any purification. The crude amine salt was used to synthesize the title compound in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) as starting materials and the title compound was isolated (76 mg, 59%); MS (ESI, m/z): 404.6 (M+H+).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Si:9]([N:16]1[C:19](=[O:20])[CH2:18][C@H:17]1[C:21]([OH:23])=[O:22])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1CCC1.CC(C1C=C(C(C)C)C(S([N:43]=[N+:44]=[N-:45])(=O)=O)=C(C(C)C)C=1)C>C1COCC1>[N:43]([C@H:18]1[C:19](=[O:20])[N:16]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:17]1[C:21]([OH:23])=[O:22])=[N+:44]=[N-:45]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Agent: C1CNC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@H](N=[N+]=[N-])[C@H]1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To LDA (1.8M, 4.99 mL) and THF (10 mL) at −78° C. was added dropwise (S)-1-t-butyldimethylsilyl-4-oxo-2-azetidinecarboxylic acid (4, 1.0 g) in THF (15 mL). The resulting solution was warmed to −30° C. or −10° C. for 30 min. If a slurry formed, additional THF was added to solublize the azetidine. After 30 min., the solution was cooled to −78° C. A pre-cooled solution (−10° C.) of trisyl azide (1.61 g) in THF (10 mL) was added slowly. The reaction mixture was stirred for one hour before quenching with TMSCl (0.82 mL). The cold bath was then removed and the solution allowed to stir for an additional hour. Saturated sodium bicarbonate (100 mL) was added and the aqueous layer was extracted with diethyl ether (2×100 mL). The organic extracts were discarded. The aqueous layer was then brought to pH=7 by slow addition of 1N HCl and extracted with Et2O (2×100 mL) and the organic layers were discarded. The aqueous layer was then brought to pH=3 by slow addition of 1N HCl and extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield 131 which was taken on to the next step without further purification.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:3]([N:10]([CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(CNCCCSc2ccncc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N(CCCSc1ccncc1)Cc1ccccc1
Yield: 50.2 %

Procedure:
To a solution of 400 mg (1.21 mmol) of 4-[3-(N-benzylamino)propylthio] pyridine dihydrochloride and 0.55 ml (4.00 mmol) of triethylamine in 5 ml of methylene chloride, 0.17 ml (1.45 mmol) of benzoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 0.22 g of the desired compound (yield: 50.4%, yellow oil).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:15][CH:16]=2)[CH2:11][NH:10][CH2:9]1.[CH2:28]=O.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:15][CH:16]=2)[CH2:11][N:10]([CH3:28])[CH2:9]1
Reactant: Fc1ccccc1C1CNCc2cc(OCCCN3CCCCC3)ncc21
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1Cc2cc(OCCCN3CCCCC3)ncc2C(c2ccccc2F)C1
Temperature: 55 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
A solution of 4-(2-fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-[2,6]naphthyridine (50.2 mg, 0.136 mmol) in MeOH (5 mL) was treated with paraformaldehyde (62 mg). The mixture was heated at 55° C. for 1 h, cooled to 0° C., and was treated with NaBH4 (66 mg, 1.74 mmol). After 2 h at 0° C., the mixture was diluted with satd. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated. The residue was chromatographed (SiO2; 1-10% 2 M NH3 in MeOH/DCM) to give the title compound (20.4 mg, 39%) as an oil. MS (ESI): mass calcd. for C23H30FN3O, 383.24; m/z found, 384.5 [M+H]+. 1H NMR (CDCl3): 7.69 (s, 1H), 7.23-7.17 (m, 1H), 6.47 (s, 1H), 4.57-4.54 (m, 1H), 4.26 (t, J=6.7, 2H), 3.62 (d, J=15.9, 1H), 3.58 (d, J=15.9, 1H), 2.97 (dd, J=12.0, 5.1, 1H), 2.65 (dd, J=11.5, 7.5, 1H), 2.47-2.36 (m, 9H), 1.98-1.91 (m, 2H), 1.61-1.55 (m, 4H), 1.47-1.39 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)C.[Pt]=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: c1cncc(-c2ncc[nH]2)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: c1c[nH]c(C2CCCNC2)n1
Yield: 108 %

Procedure:
3-(1H-imidazol-2-yl)pyridine (4.0 g, 0.0275 M) and platinum oxide (0.5 g) in ethyl alcohol (50 ml) and 1 NHCl (50 ml) was reduced at 45 psig of hydrogen for 4 hrs. The reaction mixture was filtered and the filtrate was stripped to dryness and crystallized from MeOH-EtOH to give 3-(1H-imidazol-2-yl)piperidine (4.5 g, 74% yield, mp 295° dec.).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]12[CH2:11][N:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6][CH2:5]2.C([Li])CCC>C1COCC1.CCCCCC>[C:3]([C:4]12[CH2:11][N:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6][CH2:5]2)#[CH:2]
Reactant: BrC(Br)=CC12CCCN(CC1)C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CC12CCCN(CC1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A solution of crude (±) 5-(2,2-dibromoethenyl)-1-azabicyclo[3.2.1]octane (10 g, 34 mM) (D5) in dry THF (200 ml) was cooled to -78° C. under nitrogen and treated with n-butyl lithium in hexane (49 ml of a 1.6 molar solution, 0.078 mol). The solution was stirred at this temperature for 1 h and then allowed to warm to room temperature over a period of 1 h. The reaction mixture was then cooled to -70° C. and quenched by the addition of acetic acid (10 ml). The solution was then concentrated in vacuo to a gum and the residue partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo to a gum which was distilled in vacuo to afford the title compound (D6, 2.5 g, 51%) as a colourless oil (B.pt 110°-120° at 0.5 mM) which crystallised on standing m.p. 41°-42° C.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][NH3+:23])=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:2]([O:6][C:7](=[O:8])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][NH:23][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(SCCC[NH3+])nc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1c(SCCCNC(=O)c2ccccc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(1-tert-butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-propyl-ammonium chloride (Precursor U-08b, 6 mg, 0.02 mmol) in dichloromethane (0.4 ml) are added subsequently DIPEA (10 mg, 15 μl, 0.085 mmol) and benzoyl chloride (3.9 mg, 3.241l, 0.03 mmol) and the resulting solution is allowed to stir for 1 h at rt. Tris-(2-aminoethyl)amine polystyrene (3.4 mmol/g, 33 mg, 0.11 mmol) is added and the mixture is allowed to stir for another 3 h at rt. The solvent is evaporated and the residue dried under high vacuum, yielding the title compound as a colourless oil: tR=2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:23][CH2:24][CH:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:26][CH2:27]1)#[N:20]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCCCC2)CC1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCC(N2CCCCC2)CC1
Yield: 27.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.0 g) and 5-amino-2-(4-piperidinopiperidin-1-yl)benzonitrile (1.4 g), the title compound (0.6 g) was obtained. melting point: 275° C.